Prognostic Significance of Patient-Reported Outcomes in Cancer.
Performance status (PS), an established prognostic surrogate of cancer survival, is a physician-synthesized metric of patient symptoms and mobility that is prone to bias and subjectivity. The National Cancer Institute (NCI) Patient-Reported Outcomes Measurement Information System-Cancer (PROMIS-Ca) Bank, a patient-centric patient-reported outcome (PRO) evaluation of physical function (PF), fatigue, depression, anxiety, and pain, shares subject matter with PS and, therefore, may also be prognostic while eliminating physician interpretation. Patients at Huntsman Cancer Institute were assessed using the NCI PROMIS-Ca Bank. Using tablets at routine office visits, PF, fatigue, depression, anxiety, and pain scores were collected from patients with advanced melanoma, non-small-cell lung cancer, colorectal cancer, and breast cancer. A PRO score collected at a single time point within 6 months of metastatic diagnosis for each patient was merged with curated clinical outcome data. The association of PROs, overall survival (OS), and hospitalization-free survival (HFS) were assessed in multivariable analysis that included sex and cancer type. Two hundred eighty-two complete sets of patient data were available for analysis. All 5 PRO domains were strongly prognostic of OS and HFS. While the PRO domains were interrelated with moderate to strong correlations (0.40-0.79), multivariable regression suggested that PF was most strongly associated with the clinical outcomes of OS (P < .001) and HFS (P < .001). NCI PROMIS-Ca PROs may be prognostic of both cancer survival and likelihood of hospitalization. Future prospective studies are needed for all major prognostic factors to fully understand the independent prognostic value of PROs.


Predicting Drug-Target Interactions Over Heterogeneous Information Network.
Identifying Drug-Target Interactions (DTIs) is a critical step in studying pathogenesis and drug development. Due to the fact that conventional experimental methods usually suffer from high costs and low efficiency, various computational methods have been proposed to detect potential DTIs by extracting features from the biological information of drugs and their target proteins. Though effective, most of them fall short of considering the topological structure of the DTI network, which provides a global view to discover novel DTIs. In this paper, a network-based computational method, namely LG-DTI, is proposed to accurately predict DTIs over a heterogeneous information network. For drugs and target proteins, LG-DTI first learns not only their local representations from drug molecular structures and protein sequences, but also their global representations by using a semi-supervised heterogeneous network embedding method. These two kinds of representations consist of the final representations of drugs and target proteins, which are then incorporated into a Random Forest classifier to complete the task of DTI prediction. The performance of LG-DTI has been evaluated on two independent datasets and also compared with several state-of-the-art methods. Experimental results show the superior performance of LG-DTI. Moreover, our case study indicates that LG-DTI can be a valuable tool for identifying novel DTIs.


Preliminary clinical results of two techniques for addressing graft tunnel mismatch in endoscopic anterior cruciate ligament reconstruction.
This study reports the initial clinical results of 540 degrees of graft rotation or free tibial bone block to address graft tunnel mismatch in endoscopic anterior cruciate ligament (ACL) reconstruction. The operative reports of patients who underwent endoscopic ACL reconstruction between 1999 and 2001 were reviewed. Nine of 11 patients treated with a free tibial bone block and 14 of 17 patients treated with 540 degrees of graft rotation were evaluated. Mean follow-up was 20 months (range: 13-40 months) for the bone block group and 34 months (range: 18-48 months) for the 540 degrees group. There were statistically significant improvements in physical examination test results postoperatively, and only one patient in the 540 degrees group had a grade one positive pivot shift test. KT-1000 arthrometer testing demonstrated a statistically significant decrease in manual maximum and side-to-side differences at final follow-up. Mean Lysholm and Noyes sports function scores were excellent or good for all patients. One patient required reoperation for flexion contracture, one patient required an arthroscopic irrigation and debridement for a minor infection, and one patient required arthroscopic subtotal medial meniscectomy for failed meniscal repair. No difference was noted between these results and previous results of patients undergoing conventional endoscopic ACL reconstruction. These results demonstrate graft rotation and free bone block techniques are effective in addressing graft tunnel mismatch in endoscopic ACL reconstruction.


Temporal regulation of terpene synthase gene expression in Eucalyptus globulus leaves upon ozone and wounding stresses: relationships with stomatal ozone uptake and emission responses.
Ozone and wounding are key abiotic factors but, their interactive effects on temporal changes in terpene synthase gene expression and emission responses are poorly understood. Here, we applied combined acute ozone and wounding stresses to the constitutive isoprenoid-emitter Eucalyptus globulus and studied how isoprene, 1,8-cineole, and isoledene synthase genes were regulated, and how the gene expression was associated with temporal changes in photosynthetic characteristics, product emission rates, and stomatal ozone uptake through recovery phase. Photosynthetic characteristics and emission rate of isoprene, 1,8-cineole, and isoledene were synergistically altered, while three TPS gene expressions were antagonistically altered by combined stress applications. A time-delay analysis indicated that the best correspondences between gene expression and product emission rates were observed for 0 h time-shift for wounding and 0-2 h time-shifts for separate ozone, and combined ozone and wounding treatments. The best correspondence between ozone uptake and gene expression was observed for 0-4 h time-shifts for separate ozone and combined ozone and wounding treatments. Overall, this study demonstrated that expression profiles of isoprene, the monoterpene 1,8-cineole, and the sesquiterpene isoledene synthase genes differentially influenced their corresponding product emissions for separate and combined ozone and wounding treatments through recovery.


Combining traditional and microsurgical reconstruction after a complex hand trauma with multiple tissue defects. A case report.
Complex injuries involving bones, tendons and soft tissues of the hand still represent a difficult challenge for reconstructive surgeons. Hereby, we present a case of a man suffering from a complex crush injury of the right hand that led to a wide three-dimensional defect with loss of two metacarpal bones, extensor tendons and skin. For composite hand defects, the most common surgical approach provides for a one-stage composite reconstruction or for an early restoration of bone and skin, with delayed tendon grafts. For the peculiarity of the defect, a one-stage reconstruction was not feasible. Hence, we opted for a two-stage reconstruction but the usual surgical steps have been inverted. First we secured tendon and skin restoration through a composite teno-cutaneous radial free flap. A month later, we reconstructed the two metacarpals with a modified Masquelet technique using fibular cortical graft. This strategy allowed the patient to start an early rehabilitation program and obtain a satisfactory recovery of his dominant hand. KEY WORDS: Composite flap, Hand trauma, Hand reconstruction, Microsurgery.


Family meals among parents: Associations with nutritional, social and emotional wellbeing.
A growing body of research suggests that children and adolescents who share frequent meals with their families report better nutrition indicators, family relationships and mental health. Yet, little research has examined whether parents who share meals with their families report the same indicators of wellbeing. The current paper addresses this question using population-based survey data and a sample of parents in the United States (n = 889, mean age 31 years) that responded to the fourth wave of the Project EAT study in 2015-16. Multiple regression models were used to examine associations between frequency of family meals and indicators of nutritional, social and emotional wellbeing, controlling for demographic and household characteristics. Analyses also examined if associations were moderated by sex, as mothers tend to be more responsible for household and childcare tasks. Results suggested that parent report of frequent family meals was associated with higher levels of family functioning, greater self-esteem, and lower levels of depressive symptoms and stress (p-value for all <0.001). Frequency of family meals was also related to greater fruit and vegetable consumption (both p < 0.05), but was unrelated to other indicators of parent body size and nutritional wellbeing. Associations between frequency of family meals and parent wellbeing were similar for both mothers and fathers. Findings from the current study suggest that frequent family meals may contribute to the social and emotional wellbeing of parents. Future strategies to promote family meals should consider the potential impacts on the health and wellbeing of the whole family.


Altered smooth muscle function in worm-free gut regions of Trichinella-infected rats.
We have extended a recent study demonstrating increased contractility of jejunal smooth muscle of rats infected with the nematode parasite Trichinella spiralis, the primary habitat of which is the jejunum. In this study, muscle from the worm-free ileum of infected rats showed decreased contractility compared with control, illustrating regional differences in muscle responses to the infection. However, in jejunal muscle from worm-free segments that had been excluded from the rest of the gut before the infection, we observed increased tension generation, suggesting a systemic mechanism. To evaluate whether the changes in jejunal muscle were due to the host's inflammatory reaction, the effect of beta-methasone was examined. In a dose of 3.0 mg/kg sc daily, the steroid abolished the increase in myeloperoxidase activity associated with the infection and attenuated the increased tension generation in jejunal muscle from Trichinella-infected rats. These results support the hypothesis that alterations in intestinal smooth muscle function in this model do not require the presence of the parasite in the lumen and are mediated by the host's inflammatory reaction.


Assessment of environmental pollutants at trace levels using ionic liquids-based liquid-phase microextraction.
Sample preparation is the crucial and most challenging part of analytical chemistry for the speciation of environmental pollutants' traces. Along with the development of the sample preparation methods, the ionic liquid-based microextraction technique plays an important role. Due to the unequivocally unique "green" characteristic of ionic liquids (ILs), they owe their tunable properties, such as highly selective and high reaction efficiency, reusability, and good thermal stability, to present advancements in the sample preparation process. The ionic liquid-based microextraction techniques miniaturize the sample preparation process. Liquid phase microextraction intermediate solvents, desorption solvent extractants, and mediators have been used. They are quoting the benefits and limitations of each method. A few essential sample preparation methods covered the microextraction technique. In this context, miniaturized microextraction methods have been developed. They are generally used for their unlimited positive features, including easy, simple, and environmentally friendly; they also extract inorganic and organic species with low-cost instrumentation. This review advances the sample preparation process using ILs-based liquid phase microextraction as an intermediate solvent, extractant desorption, and mediator solvents.


Listeria monocytogenes and Listeria spp. contamination patterns in retail delicatessen establishments in three U.S. states.
Postprocessing contamination in processing plants has historically been a significant source of Listeria monocytogenes in ready-to-eat delicatessen meats, and therefore a major cause of human listeriosis cases and outbreaks. Recent risk assessments suggest that a majority of human listeriosis cases linked to consumption of contaminated deli meats may be due to L. monocytogenes contamination that occurs at the retail level. To better understand the ecology and transmission of Listeria spp. in retail delicatessens, food and nonfood contact surfaces were tested for L. monocytogenes and other Listeria spp. in a longitudinal study conducted in 30 retail delis in three U.S. states. In phase I of the study, seven sponge samples were collected monthly for 3 months in 15 delis (5 delis per state) prior to start of daily operation; in phase II, 28 food contact and nonfood contact sites were sampled in each of 30 delis during daily operation for 6 months. Among the 314 samples collected during phase I, 6.8% were positive for L. monocytogenes. Among 4,503 samples collected during phase II, 9.5% were positive for L. monocytogenes; 9 of 30 delis showed low L. monocytogenes prevalence (<1%) for all surfaces. A total of 245 Listeria spp. isolates, including 184 Listeria innocua, 48 Listeria seeligeri, and 13 Listeria welshimeri were characterized. Pulsed-field gel electrophoresis (PFGE) was used to characterize 446 L. monocytogenes isolates. PFGE showed that for 12 of 30 delis, one or more PFGE types were isolated on at least three separate occasions, providing evidence for persistence of a given L. monocytogenes subtype in the delis. For some delis, PFGE patterns for isolates from nonfood contact surfaces were distinct from patterns for occasional food contact surface isolates, suggesting limited cross-contamination between these sites in some delis. This study provides longitudinal data on L. monocytogenes contamination patterns in retail delis, which should facilitate further development of control strategies in retail delis.


Generation of Entanglement from Mechanical Rotation.
Many phenomena and fundamental predictions, ranging from Hawking radiation to the early evolution of the Universe rely on the interplay between quantum mechanics and gravity or more generally, quantum mechanics in curved spacetimes. However, our understanding is hindered by the lack of experiments that actually allow us to probe quantum mechanics in curved spacetime in a repeatable and accessible way. Here we propose an experimental scheme for a photon that is prepared in a path superposition state across two rotating Sagnac interferometers that have different diameters and thus represent a superposition of two different spacetimes. We predict the generation of genuine entanglement even at low rotation frequencies and show how these effects could be observed even due to the Earth's rotation. These predictions provide an accessible platform in which to study the role of the underlying spacetime in the generation of entanglement.


Two isoforms of Geobacter sulfurreducens PilA have distinct roles in pilus biogenesis, cytochrome localization, extracellular electron transfer, and biofilm formation.
Type IV pili of Geobacter sulfurreducens are composed of PilA monomers and are essential for long-range extracellular electron transfer to insoluble Fe(III) oxides and graphite anodes. A previous analysis of pilA expression indicated that transcription was initiated at two positions, with two predicted ribosome-binding sites and translation start codons, potentially producing two PilA preprotein isoforms. The present study supports the existence of two functional translation start codons for pilA and identifies two isoforms (short and long) of the PilA preprotein. The short PilA isoform is found predominantly in an intracellular fraction. It seems to stabilize the long isoform and to influence the secretion of several outer-surface c-type cytochromes. The long PilA isoform is required for secretion of PilA to the outer cell surface, a process that requires coexpression of pilA with nine downstream genes. The long isoform was determined to be essential for biofilm formation on certain surfaces, for optimum current production in microbial fuel cells, and for growth on insoluble Fe(III) oxides.


Antibodies to Toxoplasma gondii major surface protein (SAG-1, P30) inhibit infection of host cells and are produced in murine intestine after peroral infection.
Monoclonal and polyclonal, monospecific antibodies to the major surface antigen of Toxoplasma gondii (SAG-1, P30) inhibit infection of human fibroblasts and murine enterocytes. Fab prepared from polyclonal, monospecific antibody to P30 also have this inhibitory effect on invasion, which indicates that this antibody directly blocks parasite infection of host cells rather agglutinating the parasite. Antibodies to another surface protein (P22) did not alter in vitro infection. If the inhibitory effect of antibody to P30 was due to steric hindrance or complexing of surface epitopes contiguous to P30, antibodies to other surface epitopes would also be inhibitory and they are not. Urea treatment of antibody (which permits discrimination of high and low avidity antibody) did not alter the effect of anti-P30 antibody. This observation indicates that the effect of the antibody to P30 was not an artifact of differences in the avidity of the antibody to P22 and P30. Heat inactivated antisera from mice infected with either RH or PTg strain T. gondii (P30+) inhibit infection of fibroblasts when challenged with autologous wild-type parasites by 87 and 40%, respectively. In contrast, these antisera have little inhibitory effect (13 and 19%, respectively) against infection of human fibroblasts by a P30-deficient mutant (PTgB). Antisera raised to the P30-deficient mutant had no significant effect on infection of cells by wild-type strains that have surface P30. The neoglycoprotein, BSA-glucosamide, competitively blocks infection of human fibroblasts by P30+ tachyzoites with surface P30 in higher level than those without surface P30. This observation indicates that there is likely to be a glycosylated host cell receptor to which T. gondii's major surface Ag SAG-1 (P30) binds. Mice infected perorally develop intestinal IgA antibody to the major 30-kDa epitope of T. gondii. Thus, the major surface epitope of T. gondii, SAG-1 (P30), has an important, functional role in infection of host cells by T. gondii and elicits an intestinal antibody response after peroral infection.


A single synonymous nucleotide change impacts the male-killing phenotype of prophage WO gene wmk.
Wolbachia are the most widespread bacterial endosymbionts in animals. Within arthropods, these maternally transmitted bacteria can selfishly hijack host reproductive processes to increase the relative fitness of their transmitting females. One such form of reproductive parasitism called male killing, or the selective killing of infected males, is recapitulated to degrees by transgenic expression of the prophage WO-mediated killing (wmk) gene. Here, we characterize the genotype-phenotype landscape of wmk-induced male killing in D. melanogaster using transgenic expression. While phylogenetically distant wmk homologs induce no sex-ratio bias, closely-related homologs exhibit complex phenotypes spanning no death, male death, or death of all hosts. We demonstrate that alternative start codons, synonymous codons, and notably a single synonymous nucleotide in wmk can ablate killing. These findings reveal previously unrecognized features of transgenic wmk-induced killing and establish new hypotheses for the impacts of post-transcriptional processes in male killing variation. We conclude that synonymous sequence changes are not necessarily silent in nested endosymbiotic interactions with life-or-death consequences.


Delayed recovery of left ventricular function after antithyroid treatment. Further evidence for reversible abnormalities of contractility in hyperthyroidism.
Sequential measurements of systolic time intervals, left ventricular dimensions, and the derived indices of contractility were undertaken at rest and during isometric exercise in 15 hyperthyroid patients before, during, and after antithyroid treatment. At rest hyperthyroidism was characterised by a shortened pre-ejection period and increased velocity of circumferential shortening of the left ventricle. During isometric exercise, however, the pre-ejection period increased significantly beyond that predicted for normal subjects, and the velocity of circumferential fibre shortening fell by 30%. In contrast, both the pre-ejection period and the velocity of circumferential fibre shortening were unchanged during exercise after a stable euthyroid state had been achieved for at least three months. Comparison between exercise responses and thyroid status during antithyroid treatment showed that a biochemical euthyroid state may be achieved many weeks before normalisation of contractile response to exercise. These findings support the hypothesis of reversible depression of left ventricular function in hyperthyroidism. Responses at rest principally reflect the peripheral actions of thyroid hormone excess.


Upregulation of PODXL and ITGB1 in pancreatic cancer tissues preoperatively obtained by EUS-FNAB correlates with unfavorable prognosis of postoperative pancreatic cancer patients.
The upregulation of PODXL and ITGB1 in surgically resected pancreatic cancer tissues is correlated with an unfavorable postoperative prognosis. The aim of this study was to investigate whether PODXL and ITGB1 are useful preoperative markers for the prognosis of postoperative pancreatic cancer patients in comparison with the TNM staging system. Immunohistochemistry was performed using anti-PODXL and anti-ITGB1 antibodies on 24 pancreatic cancer tissue samples preoperatively obtained by endoscopic ultrasound-guided fine-needle aspiration biopsy. Cox proportional hazards regression analysis was performed to investigate if the UICC TNM stage and upregulation of PODXL and ITGB1 were correlated with postoperative overall survival rates. Univariate analysis revealed that PODXL, TNM stage, lymphatic invasion and the combination of PODXL with ITGB1 are correlated with postoperative survival. Multivariate analysis demonstrated TNM stage and the combination of PODXL with ITGB1 to be correlated with postoperative survival, and the combination of PODXL with ITGB1 most accurately predicted the postoperative outcomes of pancreatic cancer patients before resection. Therefore, upregulation of PODXL and ITGB1 may indicate preoperative neoadjuvant therapy for pancreatic cancer patients by accurately predicting the postoperative prognosis.


Temporal and spatial expression of murine acid beta-glucosidase mRNA.
The hydrolysis of glucosylceramide (GC) to ceramide and glucose requires the action of the lysosomal enzyme, acid beta-glucosidase (GCase), encoded by gba in the mouse. Gaucher disease, an autosomal recessive disorder, results from the inherited deficiency of this enzyme. Although enzyme activity is present in all mammalian tissues, the patterns of mRNA expression have not been explored. In situ hybridization analyses of mouse embryonic, newborn, and adult tissues were conducted to evaluate the spectrum of gba mRNA expression. Signals were present in all tissues and cell types. Distinct patterns of differential expression were identified in specific tissues and cell types, and at defined developmental stages. Differential expression was first observed around E14 in the intestinal tract, kidneys, skeletal system, and skin. At E18, moderate intensity signals were in adipocytes of brown fat and pancreatic cells. Differential expression remained in skin, bone, and the GI tract postnatally. In the postnatal and adult animals increasing expression was observed throughout the CNS, esophageal epithelium, intestinal villi, pancreas, and thymus and lymph node capsular cells. These tissue-, cell-, and developmental stage-specific variations of the gba mRNA level indicate major developmentally regulated changes in the expression pattern of gba in the late gestational period and postnatally.


Hyperbaric oxygen therapy in treating post-ischemic pain caused by polycythemia vera complications: a case report.
One of the complications of polycythemia vera (PV) can be acute thrombotic occlusion. The severity and prolonged duration of this condition can lead to nerve damage. In this case a 34-year-old male had thrombotic occlusions of the popliteal artery, resulting in chronic limb ischemia, which was treated with thrombectomy and amputation of one digit. The administered therapy consisted of hydroxyurea, analgesics, antidepressants and acetylsalicylic acid. When the patient was admitted he suffered from ischemic pain, he had developed an ulcer on his big toe and he was emotionally unstable, with suicidal thoughts. The patient was treated with 14 hyperbaric oxygen (HBO2) treatments in total. There was evident paint relief after four treatments and healing of the ulcerous tissue after three weeks. During the patient's medical examination eight months after the treatment, his condition was still satisfactory, with no presence of pain, ulcer or signs of depression, and with no changes in hemodynamics. This case provides additional evidence to the data for HBO2 use in ischemic pain management.


A randomized trial of surgery in the treatment of single metastases to the brain.
To assess the efficacy of surgical resection of brain metastases from extracranial primary cancer, we randomly assigned patients with a single brain metastasis to either surgical removal of the brain tumor followed by radiotherapy (surgical group) or needle biopsy and radiotherapy (radiation group). Forty-eight patients (25 in the surgical group and 23 in the radiation group) formed the study group; 6 other patients (11 percent) were excluded from the study because on biopsy their lesions proved to be either second primary tumors or inflammatory or infectious processes. Recurrence at the site of the original metastasis was less frequent in the surgical group than in the radiation group (5 of 25 [20 percent] vs. 12 of 23 [52 percent]; P less than 0.02). The overall length of survival was significantly longer in the surgical group (median, 40 weeks vs. 15 weeks in the radiation group; P less than 0.01), and the patients treated with surgery remained functionally independent longer (median, 38 weeks vs. 8 weeks in the radiation group; P less than 0.005). We conclude that patients with cancer and a single metastasis to the brain who receive treatment with surgical resection plus radiotherapy live longer, have fewer recurrences of cancer in the brain, and have a better quality of life than similar patients treated with radiotherapy alone.


Agonism of Peroxisome Proliferator Receptor-Gamma may have Therapeutic Potential for Neuroinflammation and Parkinson's Disease.
Evidence suggests inflammation, mitochondria dysfunction, and oxidative stress play major roles in Parkinson's disease (PD), where the primary pathology is the significant loss of dopaminergic neurons in the substantia nigra (SN). Current methods used to treat PD focus mainly on replacing dopamine in the nigrostriatal system. However, with time these methods fail and worsen the symptoms of the disease. This implies there is more to the treatment of PD than just restoring dopamine or the dopaminergic neurons, and that a broader spectrum of factors must be changed in order to restore environmental homeostasis. Pharmacological agents that can protect against progressive neuronal degeneration, increase the level of dopamine in the nigrostriatal system, or restore the dopaminergic system offer various avenues for the treatment of PD. Drugs that reduce inflammation, restore mitochondrial function, or scavenge free radicals have also been shown to offer neuroprotection in various animal models of PD. The activation of peroxisome proliferator receptor- gamma (PPAR-gamma ) has been associated with altering insulin sensitivity, increasing dopamine, inhibiting inflammation, altering mitochondrial bioenergetics, and reducing oxidative stress - a variety of factors that are altered in PD. Therefore, PPAR-gamma activation may offer a new clinically relevant treatment approach to neuroinflammation and PD related neurodegeneration. This review will summarize the current understanding of the role of PPAR-gamma agonists in neuroinflammation and discuss their potential for the treatment of PD.


Susceptibility of anaerobic bacteria to beta-lactam antibiotics in the United States.
beta-Lactam antibiotics are critical agents in the treatment of anaerobic infections. Susceptibility to these agents, however, varies widely, depending on the specific drug and organism; has not been constant over time; and differs in various geographic locations within the United States for many species. For the organisms in the Bacteroides fragilis group, the beta-lactam antibiotics with the most consistent activity are imipenem and combinations of a beta-lactam drug plus a beta-lactamase inhibitor, such as ticarcillin/clavulanate and ampicillin/sulbactam. Antibiotics with less activity include cefoxitin, piperacillin, cefotetan, and ceftizoxime. In other species of anaerobic gram-negative bacilli, beta-lactamase production is seen with increasing frequency. In vitro susceptibility of these strains is now similar to that of the B. fragilis group, with imipenem, ticarcillin/clavulanate, ampicillin/sulbactam, and cefoxitin being the most active drugs. The anaerobic gram-positive cocci and bacilli remain, for the most part, highly susceptible to penicillins and imipenem.


Recurrent deep venous thrombosis in an HIV-positive and injecting drug user woman.
We report a case of recurrent deep venous thrombosis in a 44-year-old woman, intravenous drug user and HIV-infected, who injected cocaine in the groins and veins of the dorsum of the feet. She suffered several episodes of deep venous thrombosis and soft-tissue infections in the lower limbs. Images of Doppler ultrasound scan revealed thrombosis in the right popliteal vein with partial recanalization and calcified thrombi in the territory of the right femoral vein. After use of heparin and oral anticoagulation, her clinical evolution was uneventful, and she was asymptomatic at the occasion of the hospital discharge. This report calls for better awareness about injections in the groins and superficial femoral veins, which are part of the deep venous system. Thrombosis related to HIV infection is highlighted.


The Triangular Axes of Universal Health Coverage Achievement: The Success Factors Behind Korean Community-Based Health Insurance Expansion.
Though it has passed over 30 years, Korea's community-based health insurance (CBHI) expansion can provide useful policy implications to developing countries with similar conditions, that is, lack of fiscal resources, health infrastructure, and medical resources to expand coverage to the informal sector. We summarized three groups of success factors through in-depth interviews and narrative analysis: system design, system operation, and public perception of the system. Korean CBHI could expand to the informal sector with the same system design as the formal sector such as mandatory enrolment, compulsory designation of medical service providers along with the low-benefit, low-contribution, and a low-payment system. However, expansion to the informal sector was somewhat different, as the CBHI exercised and operated the scheme with flexibility, semi-autonomy and leadership to fit for local context in terms of operation. Moreover, cultural factors that encouraged public awareness and increased participation significantly contributed in appealing to the informal sector. Overall, the systemic, operational, and cultural factors interacted with each other and created a synergy effect that local members in the informal sector found attractive.


Case report: Urolithiasis, nephrolithiasis and a urinary bladder malformation in a seven-month-old alpaca cria.
Urolithiasis is a common condition in male small ruminants where predisposing factors have been identified. Occasionally, urolithiasis is diagnosed in South American camelids (SACs). However, nephrolithiasis is rarely diagnosed in ruminants. To our knowledge, this is the first report focusing on a combined appearance of nephrolithiasis and urolithiasis in an alpaca cria. A 7-month-old alpaca cria suffering from impaired urinary flow was presented for examination. On admission, the alpaca had a wet prepuce and showed a standing posture with a wide-based stance. Ultrasonographic examination of the abdomen showed a distended bladder. Clinical chemistry revealed azotemia and hypophosphatemia. After the first examination, repeated urination was observed. Conservative therapy using antibiotics, anti-inflammatory and spasmolytic drugs was started with the suspected diagnosis of urinary calculus. During the first 24 h, plasma concentrations of creatinine and urea decreased, but increased again during the following days. During the second day after admission, urination was not observed for 16 h while the concentration of urea and creatinine further increased. Therefore, the animal was euthanized due to financial concerns of the owner. Necropsy revealed that calculi were located in the left kidney as well as in the urethra. In addition, the animal exhibited uroperitoneum. The urinary bladder was intact, moderately distended with urine and showed a malformation, which was covered with a translucent mucosal membrane. Histologic examination revealed that this malformation was a bladder diverticulum. The extent to which the unilateral nephroliths affected the general condition and renal function of the animal is unclear, since the uroliths also cause azotemia, and abdominal pain. Further studies are needed for a better understanding of obstructive urinary disease in SACs.


[Partial deletion 10qter. A new case].
A newborn with 10qter deletion is described and compared with the others previously reported cases. We confirm that the clinical features are not characteristic enough to delineate a syndrome in this chromosomal abnormality.


Binding of ovarian cancer cells to peritoneal mesothelium in vitro is partly mediated by CD44H.
Epithelial cancer of the ovary spreads by implantation of tumor cells onto the mesothelial lining of the peritoneal cavity. We have developed an in vitro binding assay using confluent monolayers of normal peritoneal mesothelial cells in order to assess the role of known adhesion proteins in this process. Cells from normal ovarian surface epithelium and the ovarian cancer cell lines CAOV-3 and SKOV-3 exhibited significant adhesion to mesothelium in vitro (range 33-56% specific binding). Although these cells expressed several adhesion molecules, including CD44 and integrins such as alpha 4 beta 1, alpha 5 beta 1, and alpha v beta 3, only anti-CD44 antibody was capable of inhibiting mesothelial binding (range 42-44% inhibition). Adhesion molecule expression was also determined for fresh ovarian specimens, with CD44 being expressed in 2 of 2 cases of normal ovarian epithelium, 15 of 16 (94%) cases of tissue-derived tumor (from primary sites or peritoneal implants), and only 2 of 8 (25%) cases of free-floating tumor cells from ascites. Three of three CD44-positive cases derived from peritoneal implants exhibited significant mesothelial binding which was partly blocked by anti-CD44 antibody, whereas 2 of 2 CD44-negative cases derived from ascites showed minimal binding. CD44-mediated binding of ovarian cancer cells was determined to be due to recognition of mesothelium-associated hyaluronate, suggesting that the CD44H isoform was involved in this process. Immunoprecipitation of the CD44 species expressed by ovarian cancer cells revealed 2 major bands at 85-90 and 180 kDa, consistent with the known molecular masses of CD44H. These results suggest that CD44H may be an important mediator of ovarian cancer cell implantation and that decreased CD44H expression may be associated with release of cells into the peritoneal space during ascites formation. It is possible that strategies to interfere with CD44H function may result in decreased intraabdominal spread of this highly lethal neoplasm.


Current and future sustainability of island coral reef fisheries.
Overexploitation is one of the principal threats to coral reef diversity, structure, function, and resilience [1, 2]. Although it is generally held that coral reef fisheries are unsustainable [3-5], little is known of the overall scale of exploitation or which reefs are overfished [6]. Here, on the basis of ecological footprints and a review of exploitation status [7, 8], we report widespread unsustainability of island coral reef fisheries. Over half (55%) of the 49 island countries considered are exploiting their coral reef fisheries in an unsustainable way. We estimate that total landings of coral reef fisheries are currently 64% higher than can be sustained. Consequently, the area of coral reef appropriated by fisheries exceeds the available effective area by approximately 75,000 km(2), or 3.7 times the area of Australia's Great Barrier Reef, and an extra 196,000 km(2) of coral reef may be required by 2050 to support the anticipated growth in human populations. The large overall imbalance between current and sustainable catches implies that management methods to reduce social and economic dependence on reef fisheries are essential to prevent the collapse of coral reef ecosystems while sustaining the well-being of burgeoning coastal populations.


Stimulant Medication Treatment in Children with Congenital Heart Disease and Attention-Deficit/Hyperactivity Disorder: Cardiovascular Outcomes.
Children with congenital heart disease (CHD) are at increased risk for attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to determine whether children with CHD and ADHD clinically treated with stimulant medication were at increased risk for changes in cardiovascular parameters or death compared with CHD-matched controls. In this retrospective cohort study, patients with CHD + ADHD treated with stimulant medication (exposed group [EG]) were matched by CHD diagnosis and visit age to patients not on stimulants (nonexposed group [NEG]). Cardiovascular parameters (heart rate [HR] and systolic and diastolic blood pressure [SBP and DBP]) and electrocardiograms (ECGs) from medical records over 12 months were compared using mixed effects models. Cardiovascular parameters for 151 children with CHD (mean age 8 ± 4 years) were evaluated (N = 46 EG and N = 105 NEG). Stimulant medication use was not associated with sudden cardiac death. HR and SBP did not significantly change over time in the EG and remained similar between groups. EG children had higher DBP compared with NEG children over time ( p = 0.001). Group × time interactions for HR, SBP, and DBP were not different between the EG and NEG. QTc was not significantly different between the EG and NEG (447 ms vs 439 ms, p = 0.23). EG children demonstrated improvement in ADHD symptoms. Stimulant medication use in children with CHD was not associated with clinically significant changes in cardiovascular parameters compared with controls. Stimulants should be considered for ADHD treatment in children with CHD when prescribed with appropriate monitoring and coordination with the cardiologist.


[Influenza and other acute respiratory infections. Republic of Cuba, 1989].
Information is provided on the epidemiological situation of influenza and other acute respiratory tract diseases in Cuba during 1989. General mortality rate was 25.4 per 105 inhabitants. Global morbidity rate was 373.9 per 1,000 inhabitants. The highest morbidity rate reported corresponded to children 5-14 years old and under 1 year of age. Serologically, the viral agent proportionally most identified was influenza virus type A (H3N2).


A synthetic glycoconjugate representing the genus-specific epitope of chlamydial lipopolysaccharide exhibits the same specificity as its natural counterpart.
The tetrasaccharide 3-deoxy-alpha-D-manno-2-octulosonic acid (alpha-KDO) (2----8)-alpha-KDO(2----4)-alpha-KDO(2----6)-beta GlcNAc, a partial structure of chlamydial lipopolysaccharide (LPS) representing a genus-specific epitope, was synthesized and covalently linked to bovine serum albumin, resulting in an artificial glycoconjugate antigen. Mice were immunized with the glycoconjugate to prepare chlamydia-specific monoclonal antibodies. They were selected with chlamydia-specific LPS antigens and the structurally and antigenically related Re-type LPS of a Salmonella minnesota rough mutant. Characterization of the selected antibodies was by (i) hemagglutination of sheep erythrocytes coated with recombinant chlamydia-specific LPS, (ii) inhibition by synthetic polyacrylamide derivatives containing the genus-specific epitope or partial structures thereof, (iii) enzyme immunoassay with recombinant LPS and synthetic bovine serum albumin glycoconjugates as solid-phase antigens, (iv) immunofluorescence of L929 monolayers infected with Chlamydia psittaci or C. trachomatis, and (v) Western immunoblots with glycoconjugates and LPS as the antigen. Two groups of monoclonal antibodies were obtained; the monoclonal antibodies in one group cross-reacted with chlamydial and Re-type LPS, but those of the other group were chlamydia specific. Among the latter, KDO trisaccharide-specific antibodies that had the same epitope specificity as antibodies obtained after immunization with chlamydial elementary bodies were identified; however, they exhibited a more than 100-fold higher affinity. In addition, antibodies that bound preferentially to the 2.8-linked KDO disaccharide were detected, although with lower affinity. The data show that the artificial glycoconjugate antigen is similar to its natural counterpart.


[Free radical processes and erythron in pregnant rats and their fetuses in chronic nitrite intoxication].
The purpose of the investigation was to study changes in the intensity of induced chemiluminescence of serum and erythrocytes, as well as the erythrocytic system in pregnant rats and fetuses in chronic nitrite intoxication. In nitrite-intoxicated pregnant rats, the level of erythropenia was less than that in intact pregnant rats, fetuses being observed to have stimulated erythropoiesis. In intact pregnant animals, the intensity of induced chemiluminescence on day 20 was higher than the baseline and throughout the follow-up in nitrite-intoxicated adult animals and fetuses.


Cerebrospinal fluid physiology and the management of increased intracranial pressure.
Increased intracranial pressure can result in irreversible injury to the central nervous system. Among the many functions of the cerebrospinal fluid, it provides protection against acute changes in venous and arterial blood pressure or impact pressure. Nevertheless, trauma, tumors, infections, neurosurgical procedures, and other factors can cause increased intracranial pressure. Both surgical and nonsurgical therapeutic modalities can be used in the management of increased intracranial pressure attributable to traumatic and nontraumatic causes. In patients with cerebral injury and increased intracranial pressure, monitoring of the intracranial pressure can provide an objective measure of the response to therapy and the pressure dynamics. Intraventricular, intraparenchymal, subarachnoid, and epidural sites can be used for monitoring, and the advantages and disadvantages of the various devices available are discussed. With the proper understanding of the physiologic features of the cerebrospinal fluid, the physician can apply the management principles reviewed herein to minimize damage from intracranial hypertension.


Design thinking during a health emergency: building a national data collection and reporting system.
Design thinking allows challenging problems to be redefined in order to identify alternative user-center strategies and solutions. To address the many challenges associated with collecting and reporting data during the 2014 Ebola outbreak in Guinea, Liberia and Sierra Leone, we used a design thinking approach to build the Global Ebola Laboratory Data collection and reporting system. We used the five-stage Design Thinking model proposed by Hasso-Plattner Institute of Design at Stanford in Guinea, Liberia and Sierra Leone. This approach offers a flexible model which focuses on empathizing, defining, ideating, prototyping, and testing. A strong focus of the methodology includes end-users' feedback from the beginning to the end of the process. This is an iterative methodology that continues to adapt according to the needs of the system. The stages do not need to be sequential and can be run in parallel, out of order, and repeated as necessary. Design thinking was used to develop a data collection and reporting system, which contains all laboratory data from the three countries during one of the most complicated multi-country outbreaks to date. The data collection and reporting system was used to orient the response interventions at the district, national, and international levels within the three countries including generating situation reports, monitoring the epidemiological and operational situations, providing forecasts of the epidemic, and supporting Ebola-related research and the Ebola National Survivors programs within each country. Our study demonstrates the numerous benefits that arise when using a design thinking methodology during an outbreak to solve acute challenges within the national health information system and the authors recommend it's use during future complex outbreaks.


Effects of Promotility Agents on Gastric Emptying and Symptoms: A Systematic Review and Meta-analysis.
Studies have reported a lack of association between improvements in gastric emptying (GE) and upper gastrointestinal (UGI) symptoms with promotility drugs. However, GE test methods were suboptimal in some studies. We assessed improvements in GE and UGI symptoms in patients given promotility agents in studies with optimal or moderate test methods (scintigraphy or breath test, solid meal, >2 hours duration) compared to studies with suboptimal GE test methods. With an expert librarian, we completed an extensive search of publications in the Ovid MEDLINE (1946 to present), EMBASE (1988 to January 2018), and EBM Reviews Cochrane Central Register of Controlled Trials, without restrictions on language or year. Two independent reviewers evaluated the following inclusion criteria: randomized, blinded, parallel, or crossover trials of 5HT4 agonists, D2 receptor antagonist, or ghrelin agonists; trials that measured change in GE (T1/2) or composite UGI symptoms; trials of patients with functional dyspepsia and gastroparesis; and trials of GE test methods. Standardized mean differences (units expressed as SD) were used to standardize symptom assessments that were not uniform across studies. Random effects model was used to analyze data and meta-regression was used to evaluate the association between change in GE and UGI symptoms. Of 899 studies considered, 22 studies assessed change in GE; 23 evaluated UGI symptoms; and 14 evaluated GE and UGI symptoms. Promotility agents significantly accelerated GE (T1/2) in all studies (mean reduction in T1/2, 16.3 minutes; 95% confidence interval, -22.1 to -10.6 minutes) and in studies that used optimal GE test methods (mean reduction in T1/2, 23.6 minutes; 95% confidence interval, -32.3 to -14.9 minutes). Promotility agents also significantly reduced UGI symptoms (mean reduction, 0.25 SD; 95% confidence interval, -0.37 to -0.13 SD). Meta-regression found no significant association between change in GE and UGI symptoms. However, when only studies with optimal GE test methods were evaluated, there was a significant positive association between improvement in GE and UGI symptoms (P = .02). In a meta-analysis of published trials, we found promotility agents to significantly accelerate GE (when optimal test methods were used) and to produce significant improvements in UGI symptoms.


Update on medication-induced peripheral neuropathy.
Despite improvements in the identification of causes of peripheral neuropathy, idiopathic polyneuropathy remains common. Medication and toxic neuropathy account for a small but important percentage of potentially preventable or reversible causes of neuropathy. New drugs that can induce neuropathy have been approved over the past several years, including the anticancer agents bortezomib, ixabepilone, and oxaliplatin. We review the neurotoxic effects of tumor necrosis factor-alpha blockers infliximab and etanercept, the inflammatory arthritis agent leflunomide, and the antibiotic linezolid. The controversy of statin-induced neuropathy continues to unfold; the large Fremantle Diabetes Study has suggested that statins may have neuroprotective effects. Dichloroacetate is a promising agent for lactic acidosis-associated disorders, but toxic neuropathy is a treatment-limiting factor. We also describe a progressive inflammatory neuropathy in swine slaughterhouse workers that appears to be a toxin-induced immune response.


Interaction of radio frequency electromagnetic fields and passive metallic implants--a brief review.
During the last decade, use of radio frequency (RF) applications like mobile phones and other wireless devices, has increased remarkably. This has triggered numerous studies related to possible health risks due to the exposure of RF electromagnetic (EM) fields. One safety aspect is the coupling of EM fields with active and passive implants in the human body. While interactions with active implants have been quite extensively researched, only a few studies have focused on passive implants. The present article reviews interaction mechanisms and studies of passive metallic, that is, conductive, implants in common external RF EM fields. It is found that implants have been mostly studied numerically, and experimental studies are rare. Furthermore, the studies cover mostly far-field conditions and only a few have studied implants in near fields. A summary of results indicates that a conductive object in tissues may cause notable local enhancement of the EM field and thus enhanced power absorption. The degree of enhancement depends, for example, on the orientation, the dimensions, the shape, and the location of the implant. However, in most of the cases, the field enhancement has not been strong enough to cause remarkable excess heating (more than 1 degrees C) of tissues.


Distinct requirements for achievement of allotolerance versus reversal of autoimmunity via nonmyeloablative mixed chimerism induction in NOD mice.
Mixed hematopoietic chimerism is associated with islet allograft tolerance and may reverse autoimmunity. We developed low intensity regimens for the induction of mixed chimerism and examined the effects on autoimmunity in prediabetic nonobese diabetic (NOD) mice. NOD mice received various combinations of total body irradiation, anti-CD154, anti-CD8alpha, anti-CD4, and anti-Thy1.2 monoclonal antibodies, with or without transplantation of C57BL/6 bone marrow cells and were followed up for development of diabetes, chimerism, and donor skin graft survival. Autoimmunity was assessed by histologic examination of salivary glands and pancreata. Although conditioning alone prevented or delayed the onset of diabetes, stable mixed chimerism was required for the reversal of isletitis. Mixed chimerism and skin graft tolerance were achieved in NOD mice receiving anti-CD154 with bone marrow transplantation as the means of tolerizing peripheral CD4 T cells to alloantigens. However, isletitis was not reversed in allotolerant mixed chimeras prepared with this regimen. Partial depletion of peripheral autoreactive NOD CD4 T cells is needed to achieve full reversal of isletitis by mixed chimerism induction from a protective donor strain, but it is not required for induction of specific tolerance to donor alloantigens. Thus, the requirements for tolerizing alloreactive and autoreactive NOD CD4 cells are distinct.


Arsenic ingestion and internal cancers: a review.
Inorganic arsenic is known to cause skin cancer by ingestion and lung cancer by inhalation. However, whether arsenic ingestion causes internal cancers is still a matter of debate. This paper has reviewed the epidemiologic literature that bears on this question. Published studies of populations who have ingested arsenic in medicines, wine substitutes, or water supplies, as well as workers exposed to arsenic by inhalation, were considered in terms of whether the observed associations might be explained by the presence of biases, the consistency of the evidence, and the biologic plausibility of the associations. Many studies were found to be uninformative because of low statistical power or potential biases. The most informative studies, which were from Taiwan and Japan, involved exposure to arsenic in drinking water. These studies strongly suggest that ingested inorganic arsenic does cause cancers of the bladder, kidney, lung, and liver, and possibly other sites. However, confirmatory studies are needed.


Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets.
Chronic inflammation in the stomach induces metaplasia, the pre-cancerous lesion that precedes inflammation-driven neoplastic transformation. While Hedgehog signaling contributes to the initiation of some cancers, its role in gastric transformation remains poorly defined. We found that Helicobacter-infected C57BL/6 mice develop extensive mucous cell metaplasia at 6 month but not at 2 months post-infection. Gastric metaplasia coincided with the appearance of CD45(+)MHCII(+)CD11b(+)CD11c(+) myeloid cells that were normally not present in the chronic gastritis at 2 months. The myeloid regulatory gene Schlafen-4 was identified in a microarray analysis comparing infected WT versus Gli1 null mice and was expressed in the CD11b(+)CD11c(+) myeloid population. Moreover this same population expressed IL-1β and TNFα pro-inflammatory cytokines. By 6 months, the mucous neck cell metaplasia (SPEM) expressed IL-6, phosphorylated STAT3 and the proliferative marker Ki67. Expression was not observed in Gli1 mutant mice consistent with the requirement of Gli1 to induce this pre-neoplastic phenotype. Ectopic Shh ligand expression alone was not sufficient to induce SPEM, but with Helicobacter infection synergistically increased the histologic severity observed with the inflammation. Therefore Hedgehog signaling is required, but is not sufficient to generate pre-neoplastic changes during chronic gastritis. Gli1-dependent myeloid cell differentiation plays a pivotal role in the appearance of myeloid cell subtypes ostensibly required for SPEM development. Moreover, it suggests that therapies capable of targeting this phenotypic switch might prevent progression to metaplasia, the pre-neoplastic change that develops prior to dysplasia and gastric cancer, which also occurs in other epithelial-derived neoplasias initiated by chronic inflammation.


Totality of evidence of the effectiveness of repurposed therapies for COVID-19: Can we use real-world studies alongside randomized controlled trials?
Rapid and robust strategies to evaluate the efficacy and effectiveness of novel and existing pharmacotherapeutic interventions (repurposed treatments) in future pandemics are required. Observational "real-world studies" (RWS) can report more quickly than randomized controlled trials (RCTs) and would have value were they to yield reliable results. Both RCTs and RWS were deployed during the coronavirus disease 2019 (COVID-19) pandemic. Comparing results between them offers a unique opportunity to determine the potential value and contribution of each. A learning review of these parallel evidence channels in COVID-19, based on quantitative modeling, can help improve speed and reliability in the evaluation of repurposed therapeutics in a future pandemic. Analysis of all-cause mortality data from 249 observational RWS and RCTs across eight treatment regimens for COVID-19 showed that RWS yield more heterogeneous results, and generally overestimate the effect size subsequently seen in RCTs. This is explained in part by a few study factors: the presence of RWS that are imbalanced for age, gender, and disease severity, and those reporting mortality at 2 weeks or less. Smaller studies of either type contributed negligibly. Analysis of evidence generated sequentially during the pandemic indicated that larger RCTs drive our ability to make conclusive decisions regarding clinical benefit of each treatment, with limited inference drawn from RWS. These results suggest that when evaluating therapies in future pandemics, (1) large RCTs, especially platform studies, be deployed early; (2) any RWS should be large and should have adequate matching of known confounders and long follow-up; (3) reporting standards and data standards for primary endpoints, explanatory factors, and key subgroups should be improved; in addition, (4) appropriate incentives should be in place to enable access to patient-level data; and (5) an overall aggregate view of all available results should be available at any given time.


Multiple Interactions of Glucose with the Extra-Membranous Loops of GLUT1 Aid Transport.
Molecular dynamics simulations amounting to ≈8 μs demonstrate that the glucose transporter GLUT1 undergoes structural fluctuations mediated by the fluidity of the lipid bilayer and the proximity to glucose. The fluctuations of GLUT1 increase as the glucose concentration is raised. These fluctuations are more pronounced when the lipid bilayer is in the fluid compared to the gel phase. Glucose interactions are confined to the extra-membranous residues when the lipid is in the gel phase but diffuses into the transmembrane regions in the fluid phase. Proximity of glucose to GLUT1 causes asynchronous expansions of key bottlenecks at the internal and external openings of the central pore. This is accomplished only by small conformational changes at the single residue level that lower the resistance to glucose movements, thereby permitting unsteered glucose and water movements along the entire length of the pore. When glucose is near salt bridges located at the external and internal openings of the central pore, the distance separating the polar amino acid residues guarding these apertures tends to increase in both fluid and gel phases. It is evident that the multiplicity of glucose interactions, obtained with high concentrations, amplifies the structural fluctuations in GLUT1. The findings that most of the salt bridges and the bottlenecks appear to be operated by glucose proximity suggest that the main triggers to activation of transport are located within the solvent accessible linker regions in the extramembranous zones.


Fractional Fourier transforms, symmetrical lens systems, and their cardinal planes.
We study the relation between optical lens systems that perform a fractional Fourier transform (FRFT) with the geometrical cardinal planes. We demonstrate that lens systems symmetrical with respect to the central plane provide an exact FRFT link between the input and output planes. Moreover, we show that the fractional order of the transform has real values between 0 and 2 when light propagation is produced between principal planes and antiprincipal planes, respectively. Finally, we use this new point of view to design an optical lens system that provides FRFTs with variable fractional order in the range (0,2) without moving the input and output planes.


Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts.
Inflammation is a significant player in the progression of heart failure and has detrimental effects on cardiac function. Prostaglandin (PG)E2, a major proinflammatory prostanoid in the cardiovascular system, is a potent stimulus in inducing intracellular cAMP but minimally affects cardiac contractile function. Here, we show that the PGE2 stimulation attenuates the adrenergic-induced cardiac contractile response in animal hearts. Stimulation with PGE2 leads to stimulatory G protein (Gs)-dependent production of cAMP. However, the induced cAMP is spatially restricted because of its degradation by phosphodiesterase (PDE)4 and cannot access the intracellular sarcoplasmic reticulum (SR) for increasing calcium signaling and myocyte contraction. Moreover, pretreatment with PGE2 significantly inhibits PKA activities at the SR induced by a β-adrenergic agonist, isoproterenol, and subsequently blocks isoproterenol-induced PKA phosphorylation of phospholamban and contractile responses in myocytes. Further analysis reveals that the PGE2-induced cAMP/PKA is sufficient to phosphorylate and activate PDE4D isoforms, which, in turn, spatially inhibits the diffusion of adrenergic-induced cAMP from the plasma membrane to the SR. Inhibition of PDE4 rescues the adrenergic-induced increase in cAMP/PKA activities at the SR, PKA phosphorylation of phospholamban, and contractile responses in PGE2-pretreated myocytes. Thus, this offers an example that one Gs-coupled receptor is able to inhibit the intracellular signaling transduction initiated by another Gs-coupled receptor via controlling the diffusion of cAMP, presenting a paradigm for G protein-coupled receptor (GPCR) signal transduction. It also provides a mechanism for the integration of signaling initiated by different neurohormonal stimuli, as well as long-term effects of chronically circulating proinflammatory factors in myocardium.


Mesenchymal stem cells from different sources and their derived exosomes: A pre-clinical perspective.
Since the introduction of cell therapy as a strategy for the treatment of many diseases, mesenchymal stem cells have emerged as ideal candidates, yet the underlying mechanisms of their beneficial effects are only partially understood. At the start of the 21st century, a paracrine effect was proposed as a mechanism of tissue repair by these cells. In addition, a role was suggested for a heterogeneous population of extracellular vesicles in cell-to-cell communication. Some of these vesicles including exosomes have been isolated from most fluids and cells, as well as from supernatants of in vitro cell cultures. Recent research in the field of regenerative medicine suggests that exosomes derived from mesenchymal stem cells could be a powerful new therapeutic tool. This review examines the therapeutic potential of these exosomes obtained from the sources most used in cell therapy: bone marrow, adipose tissue, and umbilical cord.


Bone marrow derived cells for brain repair: recent findings and current controversies.
Adult stem cells were once thought to produce only the cell lineages characteristic of the tissues in which they reside. Recent studies suggest that cells derived from one adult tissue can be reprogrammed to change into cellular phenotypes not normally found in that tissue. Bone marrow (BM) derived cells have been demonstrated to differentiate into multiple lineages, including glial cells and neurons, both in vivo and in vitro. This unexpected plasticity of BM cells occurs not only under experimental conditions, but also in humans following BM transplantation. As a result, BM transplantation has emerged as a novel approach to enhance neural regeneration and restore injured brain tissue. Several research teams have reported that transplanted BM cells can differentiate into neural derivatives; indeed, some of these cells were capable of integration into the host brain, where they promoted functional recovery after brain injury. Other researchers conducting similar studies were unable to find any evidence of neural differentiation, concluding that differentiation 'from marrow to brain' is not a common phenomenon. More recently, two papers in Nature also cast doubt on the plasticity of adult stem cells, suggesting that the acquisition of different identities by grafted BM cells may merely reflect their fusion with host cells. Reasons for the wide discrepancies among findings in current BM stem cell research are unclear, making it difficult to understand the mechanisms by which transplanted marrow stem cells provide therapeutic benefit. Here, we summarize recent findings on this subject, and address some of the major controversies that have marked the evolution of adult stem cell research.


Hypertonic Saline Injection Model of Experimental Glaucoma in Rats.
A reliable method of creating chronic elevation of intraocular pressure (IOP) in rodents is an important tool in reproducing and studying the mechanisms of optic nerve injury that occur in glaucoma. In addition, such a model could provide a valuable method for testing potential neuroprotective treatments. This paper outlines the basic methods for producing obstruction of aqueous humor outflow and IOP elevation by injecting hypertonic saline (a sclerosant) into the aqueous outflow pathway. This is one of several rodent glaucoma models in use today. In this method, a plastic ring is placed around the equator of the eye to restrict injected saline to the limbus. By inserting a small glass microneedle in an aqueous outflow vein in the episclera and injecting hypertonic saline toward the limbus, the saline is forced into Schlemm's canal and across the trabecular meshwork. The resultant inflammation and scarring of the anterior chamber angle occurs gradually, resulting in a rise in IOP after approximately 1 week. This article will describe the equipment necessary for producing this model and the steps of the technique itself.


Brain responses mediating idiom comprehension: gender and hemispheric differences.
Processing figurative language, such as idioms, is unique in that it requires one to make associations between words and non-literal meanings that are contextually appropriate. At the neural level, processing idiomatic phrases has been linked to recruitment of bilateral dorsolateral prefrontal cortices (DLPFC), the left temporal cortex, superior medial prefrontal gyrus (MPFC), and the left inferior frontal gyrus (LIFG). This functional MRI study examined the brain responses associated with processing idiomatic compared to literal sentences. In addition, gender differences in neural responses associated with language comprehension were also explored. In an fMRI scanner, thirty-six healthy adult volunteers viewed sentences that were either literal or idiomatic in nature, and answered subsequent comprehension questions. This sentence comprehension tasks activated mainly prefrontal language areas (LIFG, LSFG, and RMFG). Consistent with previous findings, idiomatic sentences showed increased response in LIFG. These results are discussed in the backdrop of the graded salience hypothesis. Furthermore, we found gender differences in brain activation and functional connectivity during this task. Women showed greater overall activation than men when comprehending literal and idiomatic sentences; whereas men had significantly greater functional connectivity between LIFG and LMTG than women across tasks. Overall, the findings of this study highlight the gender differences in neural responses associated with figurative language comprehension.


Association between Plaque Score of the Carotid Artery and the Severity of Sleep Apnea Syndrome in Patients with Chronic Kidney Disease.
Recently, sleep apnea syndrome (SAS) has been associated with hypertension, cardiovascular disease and death. Patients with chronic kidney disease (CKD) have higher rates of SAS, atherosclerotic complications and death than do patients without CKD. Although the relationship between SAS and atherosclerosis is well known, few papers have described this relationship in humans, especially in CKD patients. This was a cross-sectional study of 110 clinically stable, non-dialysis patients with CKD who attended a CKD educational program from April 2014 to September 2015. The diagnosis of SAS and its severity were assessed using a type 3 portable monitor. Other atherosclerosis-related data were obtained from the patients' medical records in order to determine the factors associated with the severity of SAS. 95 men and 15 women with a mean age of 71.4 ± 9.9 years were included in the study. The patients' mean body mass index was 24.0 ± 3.9, their mean blood pressure 134.3 ± 21.2/73.6 ± 13.4 mm Hg and their mean estimated glomerular filtration rate 19.8 ± 9.5 ml/min/1.7 m(2). Adjusted plaque score was a significant predictor of severe SAS (odds ratio = 1.13, p = 0.0182). Mixed plaque was significantly associated with severe SAS (correlation ratio = 0.48, p < 0.0001). Many patients with CKD also have SAS. Our findings demonstrate the relationship between plaque score and the severity of SAS.


Echocardiographic and Cardiac Magnetic Resonance Imaging-Derived Strains in Relation to Late Gadolinium Enhancement in Hypertrophic Cardiomyopathy.
We compared speckle tracking echocardiography (STE) and feature tracking cardiovascular magnetic resonance (FT-CMR) in patients with hypertrophic cardiomyopathy (HC) with a varying extent of fibrosis as defined by late gadolinium enhancement to look at the level of agreement between methods and their ability to relate those to myocardial fibrosis. At 2 reference centers, 79 patients with HC and 16 volunteers (the control group) underwent STE and CMR with late gadolinium enhancement and FT-CMR. Patients were classified into 3 categories: no detectable, limited, and extensive fibrosis. Global longitudinal strain (GLS) and global radial strain (GRS) were derived using FT-CMR and STE. STE-derived GRS was decreased in all HC categories compared with the control group (p <0.001), whereas FT-CMR GRS was reduced only in patients with HC with fibrosis (p <0.05). Reduced STE-derived GLS was associated with extensive fibrosis (p <0.05) and a value less than -15.2% identified those with extensive fibrosis (sensitivity 79%, specificity 92%, area under the curve 0.863, 95% confidence interval [CI] 0.76 to 0.97, p <0.001). Inter-modality agreement was moderate for STE versus CMR-GLS (overall population intra-class correlation coefficient = 0.615, 95% CI 0.42 to 0.75, p <0.001; patients with HC 0.63, 0.42 to 0.76, p <0.001) and GRS (overall population intra-class correlation coefficient = 0.601, 95% CI 0.397 to 0.735, p <0.001). A low level of agreement for GRS was seen between methods in patients with HC. In conclusion, strain indexes measured using echocardiography and CMR are reduced in patients with HC compared with the control group and correlate well with the burden of myocardial fibrosis. Reduced STE-GLS can identify patients with extensive fibrosis, but whether there is an added value for risk stratification for sudden cardiac death remains to be determined.


Popular culture and genetics; friend, foe or something more complex?
While many people enjoy popular culture, these transactional experiences may not translate into formal or academic learning about a subject. In education and science communication settings popular culture is often presented as a source of inaccurate information about science. Different publics are often positioned as, at best, undiscriminating consumers and at worst victims of distorted scientific information. We explore how people use their own knowledge and interests to engage with genetics. Here, data from family interviews are used to illustrate how participants draw on popular culture as a resource to engage with and articulate their beliefs about genetics. Using qualitative data from family interviews we describe two perspectives: first, popular culture represents a source of narratives and metaphors used for rhetorical purposes. Second participants used fictional narratives in more depth - as sense-making devices - allowing people to explore the moral and ethical implications of genetics. We argue that by utilising patients' interests - such as popular culture - we can potentially enrich communication in a genetic counselling context.


Geriatric trauma: the role of immediate arthroplasty.
Periarticular fractures in elderly patients are challenging to manage because the fractures are typically comminuted and the bone is osteopenic, which often result in the failure of internal fixation. Patients who sustain these fractures demand immediate mobilization or they often do not recover their preinjury level of function. In geriatric patients, immediate arthroplasty provides an alternative to internal fixation for many periarticular fractures of the shoulder, elbow, and hip.


Azide-Functional Extracellular Matrix Coatings as a Bioactive Platform for Bioconjugation.
In recent years, the development and application of decellularized extracellular matrices (ECMs) for use as biomaterials have grown rapidly. These cell-derived matrices (CDMs) represent highly bioactive and biocompatible materials consisting of a complex assembly of biomolecules. Even though CDMs mimic the natural microenvironment of cells in vivo very closely, they still lack specifically addressable functional groups, which are often required to tailor a biomaterial functionality by bioconjugation. To overcome this limitation, metabolic glycoengineering has emerged as a powerful tool to equip CDMs with chemical groups such as azides. These small chemical handles are known for their ability to undergo bioorthogonal click reactions, which represent a desirable reaction type for bioconjugation. However, ECM insolubility makes its processing very challenging. In this contribution, we isolated both the unmodified ECM and azide-modified clickECM by osmotic lysis. In a first step, these matrices were concentrated to remove excessive water from the decellularization step. Next, the hydrogel-like ECM and clickECM films were mechanically fragmentized, resulting in easy to pipette suspensions with fragment sizes ranging from 7.62 to 31.29 μm (as indicated by the mean d90 and d10 values). The biomolecular composition was not impaired as proven by immunohistochemistry. The suspensions were used for the reproducible generation of surface coatings, which proved to be homogeneous in terms of ECM fragment sizes and coating thicknesses (the mean coating thickness was found to be 33.2 ± 7.3 μm). Furthermore, they were stable against fluid-mechanical abrasion in a laminar flow cell. When primary human fibroblasts were cultured on the coated substrates, an increased bioactivity was observed. By conjugating the azides within the clickECM coatings with alkyne-coupled biotin molecules, a bioconjugation platform was obtained, where the biotin-streptavidin interaction could be used. Its applicability was demonstrated by equipping the bioactive clickECM coatings with horseradish peroxidase as a model enzyme.


Effect of staurosporine on the mobility and invasiveness of lung adenocarcinoma A549 cells: an in vitro study.
Lung cancer is one of the most malignant tumors, representing a significant threat to human health. Lung cancer patients often exhibit tumor cell invasion and metastasis before diagnosis which often render current treatments ineffective. Here, we investigated the effect of staurosporine, a potent protein kinase C (PKC) inhibitor on the mobility and invasiveness of human lung adenocarcinoma A549 cells. All experiments were conducted using human lung adenocarcinoma A549 cells that were either untreated or treated with 1 nmol/L, 10 nmol/L, or 100 nmol/L staurosporine. Electron microscopy analyses were performed to study ultrastructural differences between untreated A549 cells and A549 cells treated with staurosporine. The effect of staurosporine on the mobility and invasiveness of A549 was tested using Transwell chambers. Western blot analyses were performed to study the effect of staurosporine on the levels of PKC-alpha, integrin beta1, E-cadherin, and LnR. Changes in MMP-9 and uPA levels were identified by fluorescence microscopy. We demonstrated that treatment of A549 cells with staurosporine caused alterations in the cell shape and morphology. Untreated cells were primarily short spindle- and triangle-shaped in contrast to staurosporine treated cells which were retracted and round-shaped. The latter showed signs of apoptosis, including vacuole fragmentation, chromatin degeneration, and a decrease in the number of microvilli at the surface of the cells. The A549 cell adhesion, mobility, and invasiveness significantly decreased with higher staurosporine concentrations. E-cadherin, integrin beta1, and LnR levels changed by a factor of 1.5, 0.74, and 0.73, respectively compared to untreated cells. In addition, the levels of MMP-9 and uPA decreased in cells treated with staurosporine. In summary, this study demonstrates that staurosporine inhibits cell adhesion, mobility, and invasion of A549 cells. The staurosporine-mediated inhibition of PKC-alpha, induction of E-Cad expression, and decreased integrin beta1, LnR, MMP-9, and uPA levels could all possibly contribute to this biological process. These results represent a significant step forward in the ongoing effort to understand the development of lung carcinoma and to design novel strategies to inhibit metastasis of the tumor by targeting the cell-adhesion, mobility and invasion of tumor cells.


Comparison of real-time three-dimensional echocardiography with cardiovascular magnetic resonance for left ventricular volumetric assessment in unselected patients.
To compare left ventricular (LV) volume indices and the ejection fraction (EF) obtained using real-time three-dimensional echocardiography (RT3DE) and cardiovascular magnetic resonance (CMR) in unselected patients representative of 'real-world' clinical practice, and to determine the effect of RT3DE image quality on these parameters. Sixty consecutive patients undergoing CMR underwent same day RT3DE. LV volume and EF measurements were made using both modalities and compared. All scans were independently analysed by a second observer to assess inter-observer variability, and 40% were re-analysed to assess intra-observer variability. RT3DE image quality was graded as good, adequate, and non-analysable. Thirteen (22%) patients had good RT3DE image quality, 29 (48%) had adequate image quality, and 18 (30%) had image quality precluding analysis. Body mass index and arrhythmia frequency were higher in patients with suboptimal image quality. RT3DE significantly underestimated end-diastolic volume (EDV) (-45 ± 35 mL, P < 0.001), end-systolic volume (ESV) (-11 ± 24 mL, P = 0.004), and EF (-7 ± 9%, P < 0.001) compared with CMR although the degree of underestimation was substantially less when image quality was good. Eleven patients (18%) classified as having a normal EF by CMR had a reduced EF according to RT3DE, all but one of which had suboptimal image quality. Observer variability for RT3DE was higher than for CMR for all parameters, however, the difference was not significant when RT3DE image quality was good. In contrast to previously published data from highly selected patient groups, 'real-world' RT3DE substantially underestimates LV volumes and EF. The degree of underestimation is related to image quality.


Force estimation from OCT volumes using 3D CNNs.
Estimating the interaction forces of instruments and tissue is of interest, particularly to provide haptic feedback during robot-assisted minimally invasive interventions. Different approaches based on external and integrated force sensors have been proposed. These are hampered by friction, sensor size, and sterilizability. We investigate a novel approach to estimate the force vector directly from optical coherence tomography image volumes. We introduce a novel Siamese 3D CNN architecture. The network takes an undeformed reference volume and a deformed sample volume as an input and outputs the three components of the force vector. We employ a deep residual architecture with bottlenecks for increased efficiency. We compare the Siamese approach to methods using difference volumes and two-dimensional projections. Data were generated using a robotic setup to obtain ground-truth force vectors for silicon tissue phantoms as well as porcine tissue. Our method achieves a mean average error of [Formula: see text] when estimating the force vector. Our novel Siamese 3D CNN architecture outperforms single-path methods that achieve a mean average error of [Formula: see text]. Moreover, the use of volume data leads to significantly higher performance compared to processing only surface information which achieves a mean average error of [Formula: see text]. Based on the tissue dataset, our methods shows good generalization in between different subjects. We propose a novel image-based force estimation method using optical coherence tomography. We illustrate that capturing the deformation of subsurface structures substantially improves force estimation. Our approach can provide accurate force estimates in surgical setups when using intraoperative optical coherence tomography.


Prognostic factors for outcome after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism.
The aim of this study was to determine prognostic factors for outcome after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism (PDH). One veterinary neurosurgeon performed transsphenoidal hypophysectomies in 181 dogs with PDH over a 12-year period. Survival analysis was performed with the Kaplan-Meier method. Prognostic factors were analyzed with the univariate Cox proportional hazard analysis followed by stepwise multivariate analysis. The log-rank test was used to assess disease-free fractions in three groups categorized according to early postoperative urinary corticoid/creatinine (C/C) ratios. Multivariate analysis revealed that old age, large pituitary size, and high preoperative concentrations of plasma adrenocorticotropic hormone were associated with an increased risk of PDH-related death. In addition, large pituitary size, thick sphenoid bone, high C/C ratio, and high concentration of plasma alpha-melanocyte-stimulating hormone (alpha-MSH) before surgery were associated with an increased risk of disease recurrence in the dogs that went into remission after hypophysectomy. Disease-free fractions were significantly higher in dogs with postoperative urinary C/C ratios in the lower normal range (< 5 x 10(-6)) than in dogs with postoperative C/C ratios in the upper normal range (5-10 x 10(-6)). The results of this study indicate that pituitary size, sphenoid bone thickness, plasma alpha-MSH concentration, and preoperative level of urinary cortisol excretion are predictors of long-term remission after transsphenoidal hypophysectomy for PDH in dogs. Urinary C/C ratios measured 6 to 10 weeks after surgery can be used as a guide for predicting the risk of tumor recurrence.


Protein regulation of intrarenal crystallization.
In this review we discuss the key role renal proteins appear to play during initiation and growth of renal stones. Specific macromolecules have been identified in urine that can regulate crystal nucleation, growth, aggregation, and adhesion to renal cells. Many are incorporated into the matrix of crystals while they grow, including urinary prothrombin fragment 1, thereby increasing crystal susceptibility to degradation by cellular proteases. None of these macromolecular inhibitors appears to be quantitatively decreased in the urine of stone formers, although functional deficiencies thought due to abnormal glycosylation have been implicated, especially in the case of Tamm Horsfall protein. Increasing information is available on the nature and expression of crystal binding molecules on the renal cell surface, and they appear to be maximally expressed in response to stressful stimuli. Studies that employ atomic force microscopy and knockout mice are now being used to further clarify macromolecule-crystal interactions. The exact series of events that transform supersaturation to crystal formation and renal stones are poorly defined. Multiple anchored and soluble renal proteins potentially modulate or even regulate these events. A combination of proteomics and molecular biology seems likely to unravel these critical mediators in the coming years.


Clinical and genetic characterization of a Chinese family with pontocerebellar hypoplasia type 7.
We report compound heterozygous variants in TOE1 in siblings of Chinese origin who presented with dyskinesia and intellectual disabilities. Our report provides further information regarding the etiology and pathogenesis of pontocerebellar hypoplasia type 7 syndrome (PCH7). Clinical manifestations were obtained, and genomic DNA was collected from family members. Whole-exome and Sanger sequencing were performed to identify associated genetic variants. Bioinformatics analysis was conducted to identify and characterize the pathogenicity of the heterozygous variants. Following long-term rehabilitation, both siblings showed minimal improvement, and their condition tended to progress. Whole-exome sequencing revealed two unreported heterozygous variants, NM_025077: c.C553T (p.R185W) and NM_025077: c.G562T (p.V188L), in the TOE1 gene mapped to 1p34.1. Sanger sequencing confirmed that the two variants in the proband and her brother were inherited from their parents. The NM_025077: c.C553T (p.R185W) variant was inherited from the father, and the NM_025077: c.G562T (p.V188L) variant was inherited from the mother. Although the two variants in the TOE1 gene have not been reported previously, they were associated with PCH7 based on integrated analysis. Thus, our report contributes to our knowledge regarding the etiology and phenotype of PCH 7.


[Response of HeLa cells to mitomycine C. III. The analysis of nucleoli of mother and daughter cells].
The comparative analysis of the number of nucleoli in cells of the established HeLa-M line was carried out before and after exposure to mitomycin C in a concentration of 10 μg/ml for 2 h. Using time-lapse microscopy, nucleoli in mother and their respective daughter cells were computed. It has been shown that the average number of nucleoli per cell is generally higher in daughter cells than in mother cells, and a standard deviation, on the contrary, decreases. An average number of nucleoli in daughter cells, whose mother cells had been treated with mitomycin C, was higher than in corresponding cells of control group. The separate analysis has been performed for the cells having from 1 to 4 nucleoli. Nonrandom complete coincidence of the number of nucleoli in mather and daughter cells has been typicaly shown for about 1/7 of the total cell population. Mitomycin C reduces this value of about 1.5 times.


Glucose as a cause of and treatment for cutaneous necrosis.
Sclerotherapy remains one of the procedures most frequently performed by Brazilian vascular surgeons. Knowledge of its complications is indispensable to enable us to avoid them. The severe side effects of this method of treatment for telangiectasias of the lower limbs are rare and are often associated with technical errors or the dose injected. Complications are predominantly local, but are sometimes difficult to resolve. We report a case of formation of cutaneous necrosis after chemical sclerotherapy using hypertonic glucose (75%), which healed when treated with a topical preparation containing vaseline and 60% glucose, with satisfactory esthetic results.


Modeling the benzodiazepine receptor binding site by the general three-dimensional structure-directed quantitative structure-activity relationship method REMOTEDISC.
A novel computer-aided receptor modeling method, REMOTEDISC [J. Med. Chem. 32:746-756 (1989)], has been used to analyze the inhibition of labeled diazepam binding by 29 benzodiazepine receptor ligands. The method uses the three-dimensional structure, conformational energy, and important atom-based physicochemical properties to model the hypothetical binding site cavity. The model not only consists of the geometry of the binding cavity but also gives the weight of the various physicochemical properties of the ligands at different parts of the binding cavity responsible for their binding to the receptor. The model fitted the binding data with a correlation coefficient of 0.980, a SD of 0.223, and an explained variance of 0.898. It suggested that a small hydrophilic group is favored at position 1 of the benzodiazepine ring, the C = O region of this ring is favored by dispersive atoms and positive charge, the 4'-substituent of the 5-phenyl group is subject to strong steric repulsion, the 7- position is favored to be a hydrophilic group, and the 8- and 9- positions and their substituents are favored to be dispersive as well as hydrophilic groups. It also suggested that the substitution of the 5-phenyl group by the more dispersive 2-thiophene may increase the binding affinity. The model was allowed to predict the binding affinity data of five compounds with extensive variation of the structure from the training set; the prediction for four compounds was excellent. Some of the problems of the method have been discussed with their possible remedies.


Effect of deep tube well use on childhood diarrhoea in Bangladesh.
To determine whether the installation of deep tube wells to reduce exposure to groundwater arsenic in rural Bangladesh had an effect on the incidence of childhood diarrhoeal disease. Episodes of diarrhoeal disease in children aged under 5 years that occurred on one specified day each month between 2005 and 2006 were reported to community health workers for six rural villages. A geographical information system containing details of household water use and sanitation in the villages was built using data obtained by a global positioning system survey. The information system also included health, spatial and demographic data. A field survey was carried out to determine whether households obtained drinking water from deep tube wells installed in 2005. The effect of deep tube well use on the incidence of childhood diarrhoea was assessed using a random effects negative binomial regression model. The risk of childhood diarrhoea was 46% lower in the 179 households that used a deep tube well than in the 364 that used a shallow tube well (P=0.032). Neither socioeconomic status, latrine density, population density nor study year had a significant influence on disease risk. The incidence of childhood diarrhoea declined dramatically between 2005 and 2006, irrespective of water source. The introduction of deep tube wells to reduce arsenic in drinking water in rural Bangladesh had the additional benefit of lowering the incidence of diarrhoea among young children.


Inflight transmission of COVID-19 based on experimental aerosol dispersion data.
An issue of concern to the travelling public is the possibility of in-flight transmission of coronavirus disease 2019 (COVID-19) during long- and short-haul flights. The aviation industry maintains that the probability of contracting the illness is small based on reported cases, modelling and data from aerosol dispersion experiments conducted on-board aircraft. Using experimentally derived aerosol dispersion data for a B777-200 aircraft and a modified version of the Wells-Riley equation we estimate inflight infection probability for a range of scenarios involving quanta generation rate and face mask efficiency. Quanta generation rates were selected based on COVID-19 events reported in the literature while mask efficiency was determined from the aerosol dispersion experiments. The MID-AFT cabin exhibits the highest infection probability. The calculated maximum individual infection probability (without masks) for a 2-hour flight in this section varies from 4.5% for the 'Mild Scenario' to 60.2% for the 'Severe Scenario' although the corresponding average infection probability varies from 0.1% to 2.5%. For a 12-hour flight, the corresponding maximum individual infection probability varies from 24.1% to 99.6% and the average infection probability varies from 0.8% to 10.8%. If all passengers wear face masks throughout the 12-hour flight, the average infection probability can be reduced by ~73%/32% for high/low efficiency masks. If face masks are worn by all passengers except during a one-hour meal service, the average infection probability is increased by 59%/8% compared to the situation where the mask is not removed. This analysis has demonstrated that while there is a significant reduction in aerosol concentration due to the nature of the cabin ventilation and filtration system, this does not necessarily mean that there is a low probability or risk of in-flight infection. However, mask wearing, particularly high-efficiency ones, significantly reduces this risk.


Prioritizing Patient Safety: Analysis of the Procurement Process of Infusion Pumps in Spain.
To understand whether patient safety and human factors are considered in healthcare technology procurement, we analyzed the case of infusion pumps as their use critically affects patient safety. We reviewed infusion pump procurements in the Spanish Public Sector Procurement Database. Sixty-three batches in 29 tenders for supplying 12.224 volumetric and syringe infusion pumps and consumables for an overall budget of EUR 30.4 M were identified and reviewed. Concepts related to "ease of use" were identified in the selection requirements of 35 (55.6%) batches, as part of the criteria for the selection of pumps in 23 (36.5%) batches, related to "intuitiveness" in the selection requirements of 35 (55.6%) batches, and in the criteria in 10 (15.9%) batches. No method to evaluate the ease of use, intuitiveness, or usability was mentioned. A review of the procurement teams responsible for the evaluation of the tenders showed no reported human factors or patient safety expertise. We conclude that infusion pump procurement considers usability as a relevant criterion for selection. However, no human factor experts nor specific methods for evaluation of the technology in this field are usually defined. Potential room for refining the selection of healthcare technology to improve patient safety is detected.


Effect of Dog-Assisted Therapy on Psychomotor Development of Children with Intellectual Disability.
Although dog-assisted therapy (DAT) has been used for years, there is still a scarcity of research findings confirming efficacy of the method. The current study was designed to assess effects of DAT on psychomotor development of children with mild intellectual disabilities. The study involved 60 children with mild intellectual disabilities, aged 10-13 years, divided into a group participating in a 10-month DAT program, and the control group. Four tests were applied, i.e., finger identification, postural imitation, kinaesthesia, and Bourdon-Wiersma Dot Cancellation Test. The examinations were carried out before the start and at the end of the DAT, and at a two-month follow-up. The results obtained by the DAT group in all the four tests, at all the three timepoints, were not the same (p < 0.001). No statistically significant differences were found in the measurement at the end of the therapy between the DAT group and the controls. On the other hand, the DAT group achieved significantly better scores (p = 0.001 and p = 0.001), compared to the control, in the follow-up measurements two months after the end of the therapy in postural imitation and finger identification tests. Some of the scores achieved by the children in the DAT group improved in the measurements performed over time. Two months after the therapy ended, the children in the DAT group presented greater gains in motor planning (postural imitation test) and in the sense of touch, attention, and concentration (finger identification test), compared to the control group. Although the measurement performed immediately after the therapy did not show significant differences between the DAT group and the controls, the examination carried out at the two-month follow-up identified long-term gains in the treatment group in the domain of motor planning (postural imitation test).


Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, in Porphyromonas gingivalis.
Removal of one acyl chain from bacterial lipid A by deacylase activity is a mechanism used by many pathogenic bacteria to evade the host's Toll-like receptor 4 (TLR4)-mediated innate immune response. In Porphyromonas gingivalis, a periodontal pathogen, lipid A deacylase activity converts a majority of the initially synthesized penta-acylated lipid A, a TLR4 agonist, to tetra-acylated structures, which effectively evade TLR4 sensing by being either inert or antagonistic at TLR4. In this paper, we report successful identification of the gene that encodes the P. gingivalis lipid A deacylase enzyme. This gene, PGN_1123 in P. gingivalis 33277, is highly conserved within P. gingivalis, and putative orthologs are phylogenetically restricted to the Bacteroidetes phylum. Lipid A of ΔPGN_1123 mutants is penta-acylated and devoid of tetra-acylated structures, and the mutant strain provokes a strong TLR4-mediated proinflammatory response, in contrast to the negligible response elicited by wild-type P. gingivalis Heterologous expression of PGN_1123 in Bacteroides thetaiotaomicron promoted lipid A deacylation, confirming that PGN_1123 encodes the lipid A deacylase enzyme.IMPORTANCE Periodontitis, commonly referred to as gum disease, is a chronic inflammatory condition that affects a large proportion of the population. Porphyromonas gingivalis is a bacterium closely associated with periodontitis, although how and if it is a cause for the disease are not known. It has a formidable capacity to dampen the host's innate immune response, enabling its persistence in diseased sites and triggering microbial dysbiosis in animal models of infection. P. gingivalis is particularly adept at evading the host's TLR4-mediated innate immune response by modifying the structure of lipid A, the TLR4 ligand. In this paper, we report identification of the gene encoding lipid A deacylase, a key enzyme that modifies lipid A to TLR4-evasive structures.