eDNA and specific primers for early detection of invasive species--A case study on the bivalve Rangia cuneata, currently spreading in Europe.
Intense human activities facilitate the successful spread and establishment of non-indigenous aquatic organisms in marine and freshwater ecosystems. In some cases such intrusions result in noticeable and adverse changes in the recipient environments. In the Baltic Sea, the discovery and rapid initial spread of the North American wedge clam Rangia cuneata represents a new wave of invasion which may trigger unpredictable changes of the local benthic communities. In this study we present a species-specific DNA-based marker developed in silico and experimentally tested on environmental samples. Marker specificity and sensitivity were assessed in vitro from water samples containing different mixtures of the target species and other five bivalves currently present in the region: the native Cerastoderma glaucum, Macoma balthica and Mytilus trossulus, the invasive Dreissena polymorpha and the cryptogenic Mya arenaria. Cross-species amplification was not found in any case. The method allows to detecting at least 0.4 ng of R. cuneata DNA per μl, and 0.1 g of tissue per liter of water. Finally, the marker performance was assessed in water samples from the Baltic Sea and Vistula Lagoon. The coincidence between independent visual observations of R. cuneata and positive PCR amplification of the marker from the water samples confirmed the efficiency of this highly reproducible, fast, and technically easy method. R. cuneata traces can be detected from environmental DNA even when the population is sparse and small, enabling rapid management responses and allowing to track the invasion dynamics.


Outcome of sleeve gastrectomy as a primary bariatric procedure.
Sleeve gastrectomy is being performed increasingly in Europe. Data on long-term outcome would be helpful in defining the role of sleeve gastrectomy. The aim of this study was to evaluate the outcome of sleeve gastrectomy as a primary bariatric procedure. Medical charts of all patients who underwent a primary sleeve gastrectomy at the authors' institution between August 2006 and December 2012 were reviewed retrospectively using a prospective online data registry. For evolution of weight loss and co-morbidity, only patients with follow-up of at least 1 year were included. A subgroup analysis was done to compare patients with an intended stand-alone procedure and those with an intended two-stage procedure. A total of 1041 primary sleeve gastrectomies were performed in the study period. Median duration of surgery was 47 min, and median hospital stay was 2 days. Intra-abdominal bleeding occurred in 27 patients (2·6 per cent) and staple-line leakage in 24 (2.3 per cent). Some 866 patients had at least 1 year of follow-up. Mean excess weight loss was 68.4 per cent after 1 year (P < 0.001) and 67.4 per cent after 2 years. Smaller groups of patients achieved a mean excess weight loss of 69.3 per cent (163 patients), 70.5 per cent (62) and 58.3 per cent (19) after 3, 4 and 5 years respectively. No difference in postoperative complications was found between the subgroups. Seventy-one (8.2 per cent) of 866 patients had a revision of the sleeve gastrectomy; reflux or dysphagia was the indication in 34 (48 per cent) of these patients. Sleeve gastrectomy is a safe and effective bariatric procedure. Maximum weight loss was achieved after 4 years. Long-term results regarding weight loss and co-morbidities were satisfactory.


Chlorine dioxide-loaded poly(acrylic acid) gels for prolonged antimicrobial effect.
Chlorine dioxide, the so-called "ideal biocide", can be successfully applied as an antiseptic agent based on its rapid and safe antimicrobial property. One of the significant limitations of its topical or oral use is that the chlorine dioxide residence time in aqueous solution is very short due to the volatility of the gas. Therefore, the primary purpose of the present study was to increase the duration of chlorine dioxide effect by creating a system capable of loading the gas for a prolonged time and gradually releasing it at the site of action. Poly(acrylic acid) gels of various chlorine dioxide and polymer concentrations were formulated to achieve this goal. A two-factor, three-level face-centred central composite design was applied for the formulation. The microstructure of the gels was tracked by positron annihilation lifetime spectroscopy based on the ortho-positronium (o-Ps) lifetime distributions with the residual chlorine concentrations, determined by iodometric titration and their antibacterial effects. The results indicate that the polymer possesses two functions. On the one hand, as a diffusion barrier inhibits the fugacity of the gaseous chlorine dioxide but on the other side, the polymer chains form an arranged supramolecular structure with the hydrated forms of chlorine dioxide thus resulting in its sustained fugacity. The latter showed optimum as a function of the polymer concentration in the investigated range (0.1-0.3% w/w). The o-Ps lifetime distributions confirmed the microstructural changes of the formulations and were in good agreement with the analytical and microbiological evaluation. The application of chlorine dioxide-loaded bioadhesive gels could be a promising alternative for the effective and safe treatment of topical infections.


Simulation of epileptiform activity in the hippocampus using transputers.
Transputer technology is exploited to provide fast and interactive simulations of the electrical behaviour in large networks of neurones derived from experimental data of individual neurones and their connections. A synchronous numerical integration routine and an efficient communication scheme have been developed to run on toroidally configured transputer arrays of any sizes. A population of neurones up to 6400 from the hippocampus has been simulated on 19 Inmos T800 transputers. The activity of individual cells has been modelled using a similar approach to that of Traub; but the non-linear dynamics of the Na(+)-K+ channels is emphasised to explain intrinsic bursting. This model includes a description of the cellular channel currents INa, IK(DR), IK(C), ICa and IAHP. Preliminary studies indicate that this anatomically based model can be used to study the dynamic properties of neurones in the hippocampus, including monitoring the behaviour of subpopulation of cells that contribute to epileptiform activity.


Iontophoretic transport of a homologous series of ionized and nonionized model compounds: influence of hydrophobicity and mechanistic interpretation.
An in vitro study was carried out to elucidate the mechanisms controlling iontophoretic transport. The investigation focused on three areas, including the nature of the permeant (state of ionization and hydrophobicity), skin structures (hair follicle distribution and stratum corneum), and various parameters influencing iontophoresis (current, permeant concentration, and competitive ion effects). The data indicate that iontophoretic-facilitated transport is essentially pore mediated and that the transport of ionized and nonionized molecules may be enhanced through the pore-type pathway. The data presented show that iontophoresis has a detrimental effect on the lipoidal transport pathway and that the transport of more hydrophobic nonionized molecules is decreased compared with passive diffusion. The iontophoretic enhancement values decreased linearly with increasing alkyl chain length of n-alkanols. The iontophoretic permeability coefficients of ionized n-alkanoic acids was shown to decrease with increasing permeant hydrophobicity.


Oligomerization and phase separation in globular protein solutions.
We have chemically crosslinked a globular protein, gamma IIIb-crystallin, to produce a system of well-defined oligomers: monomers, dimers, trimers and a mixture of higher n-mers. Gel electrophoresis, size exclusion chromatography, quasielastic light scattering spectroscopy, and electrospray ionization mass spectrometry were used to characterize the oligomers formed. The liquid-liquid phase separation boundaries of the various oligomers were measured. We find that at a given concentration the phase separation temperature strongly increases with the molecular weight of the oligomers. This phase behavior is very similar to previous findings for gamma II-crystallin, for which oxidation-induced oligomerization is accompanied by an increase in the phase separation temperature. These findings imply that for phase separation, the detailed changes of the surface properties of the proteins are less important than the purely steric effects of oligomerization.


Intradermal sterile water injections for the relief of low back pain in labour -- a systematic review of the literature.
To search literature published on the administration of intradermal sterile water injections to women in labour who experience severe low back pain, and to critically evaluate the evidence for therapeutic merit. A systematic review of six randomised controlled trials from countries including Canada, Denmark, Iran, Sweden and Thailand was conducted. Statistically significant findings (p<0.0001) of relief of low back pain in labour lasting from 10 min to 2 h post-administration. Intradermal injections of sterile water possess powerful analgesic benefits for women experiencing low back pain in labour and their use in this therapeutic setting is justifiable.


Cardiac contractility: how calcium activates the myofilaments.
In both cardiac and skeletal muscle, the force-generating molecular motors (crossbridges) are turned on by increasing the intracellular free calcium level that regulates the troponin-tropomyosin system. However, calcium activation is a two-way process in the sense that activated crossbridges also affect the troponin-tropomyosin system. Here we review the mechanism of calcium action on myofilament proteins, particularly tropomyosin, that affects both the extent and the rate of force development and hence the contractility of the myocardium. At low myoplasmic Ca2+ concentrations tropomyosin is located at the edge of the thin filament, thereby interfering with the formation of strong actin-myosin linkages (blocked state). An increase in Ca2+ activity causes an azimuthal shift of tropomyosin around the filament (by about 30 degrees), thereby increasing the probability of low-force crossbridge interaction, a process which by cooperative effects induces further tropomyosin movement (by an additional 10 degrees) which results in the open state of the filament characterized by forceful crossbridge interaction. (This mechanism may be analogous to that in ligand-gated ion channels, where ligand binding increases the open probability of the pore.) The extent of activation then depends on the free Ca2+ concentration and on the calcium sensitivity of the thin filament that may be affected by protein phosphorylation, crossbridge attachment, the troponin isoform composition of the filament, and novel calcium-sensitizing drugs that act on the contractile or regulatory proteins and thus increase the force of the heart.


Nicotine and brain-stimulation reward: interactions with morphine, amphetamine and pimozide.
Using a rate-independent discrete trial method of determining thresholds for rewarding electrical intracranial stimulation in rats, we evaluated the pharmacological interaction of nicotine plus morphine, d-amphetamine, or the D2 receptor antagonist, pimozide. Both morphine and amphetamine shifted the dose-response curve for nicotine down and to the left, indicating increased efficacy and potency, respectively. Pimozide at doses that have no effect on performance and only minimal effect on brain-stimulation reward blocked the effect of nicotine. These data suggest that the same dopaminergic substrate that supports the positive reinforcing effects of other drugs of abuse also supports nicotine reward.


Tumor necrosis factor-alpha gene polymorphism in severe and mild-moderate rheumatoid arthritis.
To examine whether severe rheumatoid arthritis (RA) carries a -238 or +489 tumor necrosis factor-alpha (TNF-alpha) genotype different from mild-moderate RA. We investigated 163 patients (66 with severe disease) and 67 healthy blood donor controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Patients with severe RA (all active disease despite disease modifying antirheumatic drug combination therapy) disclosed the -238 GG genotype in 100% of cases versus 92.8% of the mild-moderates and 92.5% of controls (OR 11.7, Cl 0.6-216, p = 0.03). The +489 AA genotype was seen less often in patients than in controls (OR 4.2. CI 0.97-18.4, p = 0.045), and the contribution to this trend appeared predominant in the anti-TNF treated subgroup. The -238 AG genotype was absent in severe RA; in contrast, patients with mild-moderate RA disclosed the same frequency as controls. Thus -238 GG homozygosity is associated with severe RA. The +489 AA genotype might instead protect against worse outcome in RA.


A novel SMARCA2-CREM fusion: expanding the molecular spectrum of intracranial mesenchymal tumors beyond the FET genes.
A novel histomolecular tumor of the central nervous system, the "intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive" has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient's death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology "IMT, FET-CREB fusion-positive", and that further series of cases are needed to better characterize them.


Neuromuscular blockade-assisted oral intubation versus nasotracheal intubation in the prehospital care of injured patients.
To compare nasotracheal intubation (NTI) to neuromuscular blockade-assisted oral intubation (NMB-assisted oral intubation) in the prehospital care of injured patients. Prospective, randomized study conducted over 21 months. A university hospital-sponsored helicopter service. Consecutive adult (more than 12 years old) injured patients at the accident scene with an initial Glasgow Coma Scale of 8 or less in whom the airway was not managed immediately by unrelaxed oral intubation or cricothyrotomy. Subjects were randomized by 24-hour time blocks into NTI or NMB-assisted oral intubation treatment groups. Forty-four were entered into the NTI group (39 randomized, two crossed over to NMB-assisted oral intubation), and 33 were entered into the NMB-assisted oral intubation group (38 randomized, seven crossed over to NTI). NMB-assisted oral intubation (succinylcholine 1.5 mg/kg IV) or NTI was carried out according to standard protocols. The success rate for NTI was 79.5% (35 of 44) and was similar to that of NMB-assisted oral intubation, 75.8% (25 of 33; chi 2 = .16; P = .69). There were no significant differences between the NTI and the NMB-assisted oral intubation groups with regard to sex, age, outcome, and Glasgow Coma Scale. For those patients in whom the initial technique was successful, NTI was significantly quicker than NMB-assisted oral intubation (mean time of NTI, 2.9 minutes; mean time of NMB-assisted oral intubation, 5.9 minutes; Mann-Whitney U, 168.0; P < .01). In the prehospital management of severely injured patients, there is no significant difference between NMB-assisted oral intubation and NTI in the rate at which endotracheal intubation is achieved. However, practitioners may prefer NTI because it requires significantly less time to perform than NMB-assisted oral intubation.


The expanded histologic spectrum of myxoid liposarcoma with an emphasis on newly described patterns: implications for diagnosis on small biopsy specimens.
The variety of histologic patterns in myxoid liposarcoma is underappreciated. The diversity of these patterns can lead to diagnostic difficulty. We examined the morphologic spectrum of myxoid liposarcoma by cataloguing and describing different patterns identified in biopsy and resection specimens of 46 primary, recurrent, and metastatic myxoid liposarcomas. The patterns identified in the 46 cases included traditional myxoid (43 [93%]), traditional round cell (17 [37%]), pseudoacinar (24 [52%]), lipoblast-rich (13 [28%]), island (11 [24%]), lipomatous (10 [22%]), stromal hyalinization (7 [15%]), cord-like (5 [11%]), nested (3 [7%]), chondroid metaplasia (2 [4%]), and hemangiopericytoma (HPC)-like (1 [2%]). Island and nested patterns had not previously been described. The diagnosis of myxoid liposarcoma was confirmed by fluorescence in situ hybridization studies for DDIT3 (also known as CHOP) rearrangement. The morphologic spectrum of myxoid liposarcoma spans well beyond its typical appearance of spindle cells in a myxoid stroma with a prominent vascular pattern. Awareness of the variety of histologic patterns is critical to avoid misdiagnosis, especially in small biopsy specimens.


A Randomized Controlled Trial Comparing Analgesic Efficacies of an Ultrasound-Guided Approach with and without a Combined Pressure Measurement Technique for Thoracic Paravertebral Blocks After Open Thoracotomy.
Ultrasound-guided thoracic paravertebral block (TPVB) is an established means for providing postoperative analgesia in thoracic surgery. However, there are conflicting results regarding the efficacy of post-thoracotomy pain management of ultrasound-guided TPVB when compared with that using traditional landmark approach. We therefore conducted a comparative study to evaluate the analgesic efficacy of TPVB when pressure measurement during needle advancement is combined with an ultrasound-guided approach. The patients scheduled for lobectomy through thoracotomy were randomly allocated to receive either the ultrasound-guided approach only group (U group) or the ultrasound-guided approach combined with pressure measurement group (UP group) (n = 36 per group). Before thoracic muscle closure, 0.375% ropivacaine (20 mL) was administered as a bolus, followed by a continuous infusion of 0.2% ropivacaine (0.1 mL/kg/hr) in both groups. Postoperative pain was assessed using the visual analogue scale (VAS) pain score while resting and coughing. Local anesthetics and pethidine usage and sensory block area were also evaluated. The UP group showed significantly lower VAS scores, local anesthetics and pethidine usage, and a wider sensory block area than the U group. A combined technique with ultrasound guidance and pressure measurement provided a superior analgesic effect over that of an ultrasound-guided approach alone for the management of post-thoracotomy pain.


Respiratory viruses induce the expression of type I and III IFNs in MSCs through RLR/IRF3 signaling pathways.
Mesenchymal stem cells (MSCs) comprise a primitive cell population and reside in various tissues and organs. These cells exhibit immunomodulatory activity and are effective in treating respiratory viral infections. The activation of type I and III interferons, which protect cells against viral infections, can be induced after pattern recognition receptors (PRRs) recognize viral nucleic acid species. Although certain viruses can upregulate IFN-β expression in MSCs, the underlying mechanisms and responsiveness to different IFNs are unclear. We found that foreskin-derived fibroblast-like stromal cells (FDSCs), a kind of functional MSC, were permissive to IAV PR8, HCoV-229E, and EV-D68. Infection by IAV PR8 and HCoV-229E increased the expression of IFN-β and IFN-λ species in FDSCs in an IRF-3-dependent manner. RIG-I was critical for detecting IAV PR8 in FDSCs, and IAV PR8 infection induced a significant increase in the expression of interferon signaling genes (ISGs). Interestingly, only IFN-β, but not IFN-λ species, could induce the expression of ISGs, a finding supported by our observation that only IFN-β induced STAT1 and STAT2 phosphorylation in FDSCs. We also proved that treatment with IFN-β suppressed the propagation of IAV PR8 and promoted the survival of virus-infected FDSCs. Respiratory viruses could infect FDSCs and induce the expression of IFN-β and IFN-λ1, but only IFN-β could protect FDSCs against viral infection.


Seizures and epilepsy in infancy and childhood.
The evaluation, diagnosis, and treatment of childhood epilepsy or isolated seizures deserve special consideration. Whenever possible, a working diagnosis of an epilepsy syndrome should be implemented early in the course of evaluation to help plan the necessary investigations and acute and chronic treatment. The plan will evolve over a number of years as the patient's syndrome is better defined. The overall neurologic status of the child and response to therapy are important prognostic factors. Treatment proceeds after balancing antiepileptic drug efficacy versus adverse drug effects. The length of treatment, discussion of prognosis, and likelihood for genetic transmission are all related to the proper diagnosis of epilepsy syndromes.


Prevalence of an Intestinal ST40 Enterococcus faecalis over Other E. faecalis Strains in the Gut Environment of Mice Fed Different High Fat Diets.
E. faecalis is a commensal bacterium with specific strains involved in opportunistic and nosocomial infections. Therefore, it is important to know how the strains of this species are selected in the gut. In this study, fifteen E. faecalis strains, isolated over twelve weeks from the faeces of mice fed standard chow or one of three high fat diets enriched with extra virgin olive oil, refined olive oil or butter were subjected to a genetic "Multilocus Sequence Typing" study that revealed the presence of mainly two genotypes, ST9 and ST40, the latter one prevailing at the end of the research. A V3-V5 sequence comparison of the predominant ST40 strain (12B3-5) in a metagenomic study showed that this sequence was the only E. faecalis present in the mouse cohort after twelve weeks. The strain was subjected to a comparative proteomic study with a ST9 strain by 2D electrophoresis and mass spectrometry. After comparing the results with a E. faecalis database, unshared entries were compared and 12B3-5 showed higher antimicrobial production as well as greater protection from environmental factors such as xenobiotics, oxidative stress and metabolite accumulation, which could be the reason for its ability to outcompete other possible rivals in an intestinal niche.


Partial penile amputation due to Klingsor syndrome: A case report with a successful macroscopic reconstruction.
Traumatic penile amputation is a highly uncommon surgical emergency that requires immediate intervention. Most reported cases involve genital self-mutilation induced by underlying psychiatric disorder, especially schizophrenia. The self-mutilation of external genitals in psychiatric patients, also known as Klingsor syndrome, is a rare form of urotrauma. We present a case of partial penile amputation in a 46-year-old male with Klingsor syndrome admitted to the hospital 3 days after the incident. Urological examination revealed a subtotal cut of the penis, including the distal part of the mons pubis, dorsal and lateral parts of the penile skin, corpus cavernosum, and corpus spongiosum, as well as a partial bulbous urethra rupture. The penis remained suspended by only a thin ventral part of the penile skin. After macroscopic surgical replantation, the patient recovered well and could urinate without any symptoms of urethral stricture. The entire penis remained viable with minimal scarring at the surgical site, and penile erection could be achieved and maintained. The case demonstrates a rare instance of the successful proximal penile shaft amputation via macrosurgical techniques by an experienced urologic surgeon.


Undifferentiated carcinoma of the colon containing exocrine, neuroendocrine and squamous cells.
The light microscopic, electron microscopic and histochemical features of a highly malignant colonic tumor resected from a 39 year old man are presented. The tumor was composed predominantly of undifferentiated cells with focally admixed neuroendocrine, exocrine and squamous cells, occasionally arranged in an organoid manner. Histochemically the tumor contained argyrophilic cells as well as cells that reacted positively with the antibodies to alpha-1-antitrypsin, alpha-1-antichymotrypsin, carcinoembryonic antigen and lysozyme. The term "stem cell carcinoma of the intestine" is proposed for this highly malignant tumor composed of undifferentiated cells exhibiting only focally their multidirectional developmental capacity.


Roles of intestinal microbiota in response to cancer immunotherapy.
Cancer immunotherapy has been significantly effective on multiple cancers; however, there are still a distinct number of non-responding patients and various immune-related adverse events in responding patients. It is known that heterogeneity of intestinal microbiota may lead to different outcomes of therapy. Previous studies have reported that intestinal microbiota is probably attributed to influence the efficacy of cancer immunotherapy. Some intestinal bacteria could synergize with immune checkpoint blockade agents and optimize the immune response against multiple cancers. Therefore, understanding the roles of intestinal microbiota could help to improve the clinical efficacy of cancer immunotherapy. In this review, we first introduced the close relationships between intestinal microbiota and intestinal immune system. Then, we described the emerging evidences that intestinal microbiota responses to cancer immunotherapy. Finally, we briefly reviewed the technical development on intestinal microbiota research.


[Acid-excreting activity of the kidneys in dogs administered ammonium chloride into the carotid artery].
Injection of 0.5 mM of ammonium chloride into the dog carotid artery caused no changes in the blood acid-base balance, but distinctly increased the urinary excretion of both titratable acids and active hydrogen ions. The rate of glomerular filtration was slightly increased. The amount of sodium reabsorbed in the tubules was also risen. The role of humoral factors stimulating the renal acid-excreting activity, is discussed.


Synchrotron FTIR micro-spectroscopy for structural analysis of Lewy bodies in the brain of Parkinson's disease patients.
Lewy bodies (LBs), which mainly consist of α-synuclein (α-syn), are neuropathological hallmarks of patients with Parkinson's disease (PD). The fine structure of LBs is unknown, and LBs cannot be made artificially. Nevertheless, many studies have described fibrillisation using recombinant α-syn purified from E. coli. An extremely fundamental problem is whether the structure of LBs is the same as that of recombinant amyloid fibrils. Thus, we used synchrotron Fourier transform infrared micro-spectroscopy (FTIRM) to analyse the fine structure of LBs in the brain of PD patients. Our results showed a shift in the infrared spectrum that indicates abundance of a β-sheet-rich structure in LBs. Also, 2D infrared mapping of LBs revealed that the content of the β-sheet structure is higher in the halo than in the core, and the core contains a large amount of proteins and lipids.


Pregnancy following ovarian drilling in a woman with polycystic ovary syndrome and nine previous first trimester miscarriages.
We report a woman with a history of polycystic ovary syndrome (PCOS) and nine first-trimester miscarriages following ovulation induction and in vitro fertilization. The majority of these attempts were associated with ovarian hyperstimulation syndrome. No causes of recurrent miscarriages other than PCOS were found. Following laparoscopic ovarian drilling (LOD) she delivered a live neonate at 30 weeks of gestation. This case describes the difficulties associated with the management of patients with PCOS and recurrent abortions. We believe that LOD has helped prevent miscarriage in this patient. The early application of this technique in such patients needs to be formally assessed by a prospective study.


Jumping the Queue:Willingness to Pay for Faster Access to COVID-19 Vaccines in Seven European Countries.
Given the initial shortage of vaccines to protect against coronavirus disease 2019 (COVID-19), many countries set up priority lists, implying that large parts of the population had to wait. We therefore elicited the willingness to pay (WTP) for access to two hypothetical COVID-19 vaccines. Respondents were asked how much they would be willing to pay to get an immediate COVID-19 vaccination rather than waiting for one through the public system. We report data collected in January/February 2021 from the European COVID Survey (ECOS) comprising representative samples of the population in Denmark, France, Germany, Italy, Portugal, the Netherlands, and the UK (N = 7068). In total, 73% (68.5%) of respondents were willing to pay for immediate access to a 100% (60%) effective vaccine, ranging from 66.4% (59.4%) in the Netherlands to 83.3% (81.1%) in Portugal. We found a mean WTP of 54.36 euros (median 37 euros) for immediate access to the 100% effective COVID-19 vaccine and 43.83 euros (median 31 euros) for the 60% effective vaccine. The vaccines' effectiveness, respondents' age, country of residence, income, health state and well-being were significant determinants of WTP. Willingness to be vaccinated (WTV) was also strongly associated with WTP, with lower WTV being associated with lower WTP. A higher perceived risk of infection, higher health risk, more trust in the safety of vaccines, and higher expected waiting time for the free vaccination were all associated with a higher WTP. We find that most respondents would have been willing to pay for faster access to COVID vaccines (jumping the queue), suggesting welfare gains from quicker access to these vaccines. This is an important result in light of potential future outbreaks and vaccines.


Pulmonary hemodynamics and maintenance of palliation following polytetrafluoroethylene shunts for cyanotic congenital heart disease.
Subclavian-to-pulmonary artery anastomoses with interposition polytetrafluoroethylene (PTFE) conduits provide excellent early palliation for many forms of cyanotic heart disease. It is important to assess whether patients with this condition maintain adequate arterial oxygenation without developing pulmonary artery distortion or hypertension. From October, 1980, to December, 1982, 29 PTFE shunts were performed. There were no hospital deaths or shunt failures. Catheterization was performed in 14 patients from 2 months to 2.5 years (mean 13.4 months) following operation. All shunts were patent. Arterial Po2 at the late study ranged from 33 to 96 torr (mean 57.1 +/- 17.3 torr) and was not significantly different from values obtained before hospital discharge at the time of the shunt procedure (mean 47.6 +/- 5.9 torr). Only one patient demonstrated moderate pulmonary hypertension (44/25 mm Hg), believed to be secondary to ventricular dysfunction. No patient demonstrated pulmonary artery distortion or kinking, and none required a second shunt because of inadequacy of the original procedure. The results in these patients, as well as the continued excellent clinical course of the patients not as yet recatheterized, have prompted us to use this shunt as our procedure of choice in neonates.


Localization of orexin-A-immunoreactive fibers in the mesencephalic trigeminal nucleus of the rat.
Orexin A is a neuropeptide located exclusively in neurons in the hypothalamic nuclei involved in the central regulation of many brain functions, related to motor activity and state-dependent processes. Orexins modulate behavioral state via actions across multiple terminal fields. In order to determine whether the mesencephalic trigeminal neurons may receive a direct hypothalamic orexinergic input, the distribution of orexin A immunoreactivity was examined in the rat mesencephalic trigeminal nucleus (MTN), using orexin A immunohistochemistry. Orexin-A-immunostained nerve fibers and terminals were found in a close apposition to the perikarya of primary afferent neurons in the MTN with a marked rostrocaudal gradient in their density. In the caudal pontine MTN, only scattered orexin-A-immunoreactive fibers were found, while more rostrally in the pons, and in the midbrain-pontine junction part of the nucleus, orexin-A-immunopositive varicosities were relatively more abundant, located in close proximity to or often surrounding the neuronal profiles. At the level of the inferior or superior colliculi, a large number of orexin-A-containing neuronal processes and terminal arborizations were observed traveling toward and contacting mesencephalic trigeminal neurons, some of which were multipolar. The results of this study show that MTN neurons receive orexin A hypothalamic innervation with a somatotopic arrangement of the projections in the nucleus. The central orexinergic system may exert direct influence upon jaw movements at the level of the MTN and thus to participate in the control of feeding behavior.


Whipple's disease: multiple hospital admissions of a man with diarrhoea, fever and arthralgia.
Whipple's disease is a rare chronic multi-systemic infectious disorder caused by the Gram-positive bacillus, Tropheryma whippelii. Infection may involve any organ in the body, and most commonly affects white men in the fourth to sixth decades of life. The most common presenting symptoms are gastrointestinal and include abdominal pain, diarrhoea, anorexia and associated weight loss. However, the variability in presentation is considerable and some patients may present with intermittent low-grade fever, neurological abnormalities (nystagmus, ophthalmoplegia, cranial nerve defects), migratory arthralgia, lymphadenopathy, or involvement of the cardiovascular system. In typical Whipple's disease, the most severe changes are seen in the proximal small intestine and biopsy reveals mucosal and lymph node infiltration with large, foamy histocytes, containing granules that stain positive with periodic acid-Schiff (PAS) reagent and represent intact or partially degraded bacteria. Extended antibiotic treatment (up to 1-year) is indicated. Life-long surveillance for recurrence is essential, once primary treatment has been completed. We report the case of a 58-year-old man who developed a rare infection with the actinobacterium, T. whippelii. The patient had suffered intermittent episodes of varying clinical symptoms associated with multiple hospital admissions and clinical diagnoses, spanning a period of 22 years. Historically, arthralgia was the primary manifestation in this patient and also was the chief complaint for which he was first hospitalized 22 years ago. At his most recent admission to our hospital department, his presenting symptoms were persistent fatigue, weight loss, arthralgia and diarrhoea. Thus, it is essential that clinicians retain a high index of suspicion for T. whippelii infection in patients who have a long-term history of arthritis, fever and diarrhoea.


Influence of yellow gypsum on nutrient uptake and yield of groundnut in different acid soils of Southern India.
Yellow gypsum (YG), a synthetic product from Linz-Donawitz slag containing high iron (Fe) (5.41%), zinc (Zn) (0.37%) and silicon (Si) (3.41%) can be used as a source of these nutrients along with calcium (Ca) and sulphur (S) for groundnut production. Three field experiments were conducted to know the effect of different rates (500 and 625 kg YG ha-1) and time of application (basal alone and basal + split) of YG on growth, yield and economic returns of groundnut, and micronutrient and Si availability and their uptake in comparison with basal application of 500 kg natural gypsum (NG) ha-1. Basal alone and basal + split application of YG significantly increased the growth, yield and economic returns of groundnut. Further, it increased the soil pH, availability of micronutrients, Si and their uptake by haulm and kernel of groundnut over NG. Irrespective of the location, YG application recorded higher plant available nutrient (PAN) coefficient of micronutrients, while NG application recorded higher PAN recovery coefficient of Si. Basal + split application of YG resulted in better growth and yield of groundnut than basal application of YG. In conclusion, YG can be a potential alternative for NG as a source of Fe, Zn and Si along with Ca and S for groundnut production.


Purification and Characterization of γ-Glutamylmethylamide Synthetase from Methylophaga sp. AA-30.
γ-Glutamylmethylamide synthetase [L-glutamate: methylamine ligase (ADP-forming), EC 22.214.171.124] was purified about 70-fold from a cell-free extract of Methylophaga sp. AA-30 by ammonium sulfate fractionation, Octyl-Sepharose column chromatography, and Sephacryl S-300 gel filtration. Only a single protein band was detected after SDS-polyacrylamide gel electrophoresis of the purified preparation; the band was at a position corresponding to a molecular weight of 56,000. The molecular weight of the enzyme was calculated to be 440,000 by Superose 6HR gel filtration, so we suggest that the enzyme is an octomer of identical subunits. The enzyme had maximum activity at pH 7.5 and 40°C. It could use ethylamine and propylamine instead of methylamine as the substrate, but it could not use D-glutamate or L-glutamine instead of L-glutamate.


New evidence in one-lung ventilation.
Mechanical ventilation in thoracic surgery has undergone significant changes in recent years due to the implementation of the protective ventilation. This review will analyze recent ventilatory strategies in one-lung ventilation. A MEDLINE research was performed using Mesh term "One-Lung Ventilation" including randomized clinical trials, metanalysis, reviews and systematic reviews published in the last 6 years. Search was performed on 21st March 2017. A total of 75 articles were initially found. After title and abstract review 14 articles were included. Protective ventilation is not simply synonymous of low tidal volume ventilation, but it also includes routine use of PEEP and alveolar recruitment maneuver. New techniques are still in discussion namely PEEP adjustment, ratio inspiration:expiration, ideal type of anesthesia during one-lung ventilation and hypercapnic ventilation.


Surgical outcome of desmoid tumors: adjuvant radiotherapy delayed the recurrence, but did not affect long-term outcomes.
We retrospectively reviewed the outcomes of desmoid tumor (DT) patients treated by surgical excision. Among 155 consecutive patients, 119 patients satisfied our inclusion criteria. The mean follow-up duration was 82 months. Age, gender, location, size, depth, resection margin, adjuvant radiotherapy, and excision history were analyzed for the outcomes. The recurrence-free survival (RFS) rates were 75% at 5 years and 72% at 10 years. Twenty-seven (93.1%) out of 29 recurrences were detected within 5 years. In multivariate analysis, positive resection margin and excision history were independently associated with the RFS. In the comparison between the propensity score matched groups, adjuvant radiotherapy was not significantly associated with the RFS. The mean time interval from surgery to recurrence was 30.0 ± 28.7 months (median, 20 months; range, 4-123 months). This interval was significantly longer for patients who received adjuvant radiotherapy than for those who received surgical resection only, both in all recurrences and in recurrences in matched cases. Surgical excision appears to be a reliable treatment option for DTs. However, positive outcomes require a clear resection margin. Adjuvant radiotherapy may delay the recurrence of the tumor, although it seems to have no effect on the ultimate relapse rate.


Usefulness of lumbar AP spine DXA for measuring the percentage of perilumbar regional fat and predicting visceral fat in obese postmenopausal women.
We investigated whether measurement of the perilumbar regional fat amount by lumbar spine DXA is as good a predictor of visceral fat in obese postmenopausal women. Twenty-two obese (BMI 30-383 kg/m(2)) and 18 nonobese (BMI 20.1-24.7 kg/m(2)) postmenopausal women with similar age were recruited. Lumbar AP spine DXA for measuring the percentage of perilumbar regional fat and CT scanning for estimation of the abdominal visceral fat areas were performed. In obese subjects, visceral fat areas as measured by CT were significantly correlated with BMI, waist circumference, WHR, and DXA-measured perilumbar regional fat percentage. In nonobese subjects, visceral fat areas measured with CT were correlated with BMI, waist circumference, WHR, and DXA-measured perilumbar regional fat percentage. The results of multiple regression analysis were that the perilumbar regional fat percent by DXA was the best predictor of visceral fat amount in obese postmenopausal women (R(2) = 0.750) and BMI predicted visceral fat amount in nonobese postmenopausal women (R(2) = 0.343). This study suggests that lumbar regional fat percentage, as measured by DXA, is a better predictor of abdominal visceral fat amount than waist circumference, WHR, or BMI in obese postmenopausal women.


The Role of CaV2.1 Channel Facilitation in Synaptic Facilitation.
Activation of CaV2.1 voltage-gated calcium channels is facilitated by preceding calcium entry. Such self-modulatory facilitation is thought to contribute to synaptic facilitation. Using knockin mice with mutated CaV2.1 channels that do not facilitate (Ca IM-AA mice), we surprisingly found that, under conditions of physiological calcium and near-physiological temperatures, synaptic facilitation at hippocampal CA3 to CA1 synapses was not attenuated in Ca IM-AA mice and facilitation was paradoxically more prominent at two cerebellar synapses. Enhanced facilitation at these synapses is consistent with a decrease in initial calcium entry, suggested by an action-potential-evoked CaV2.1 current reduction in Purkinje cells from Ca IM-AA mice. In wild-type mice, CaV2.1 facilitation during high-frequency action potential trains was very small. Thus, for the synapses studied, facilitation of calcium entry through CaV2.1 channels makes surprisingly little contribution to synaptic facilitation under physiological conditions. Instead, CaV2.1 facilitation offsets CaV2.1 inactivation to produce remarkably stable calcium influx during high-frequency activation.


Risk factors for acute respiratory failure in bariatric surgery: data from the Nationwide Inpatient Sample, 2006-2008.
Acute respiratory failure (ARF) can be a life-threatening postoperative complication after bariatric surgery and is defined as the presence of acute respiratory distress or pulmonary insufficiency. We sought to identify predictors of ARF in patients who underwent bariatric surgery. Using the Nationwide Inpatient Sample database, from 2006 to 2008, the clinical data from morbidly obese patients who underwent bariatric surgery were examined. Multivariate regression analysis was performed to identify the independent factors predictive of ARF. The factors examined included patient characteristics, co-morbidities, payer type, teaching status of hospital, surgical techniques (laparoscopic versus open), and type of bariatric operation (gastric bypass versus nongastric bypass). A total of 304,515 patients underwent bariatric surgery during the 3-year period. The overall ARF rate was 1.35%. The greatest rate of ARF (4.10%) was observed after open gastric bypass surgery. The ARF rate was lower after laparoscopic than after the open surgical technique (.94% versus 3.87%, respectively; P < .01) and after nongastric bypass versus gastric bypass (.82% versus 1.54%, respectively; P < .01). Using multivariate regression analysis, congestive heart failure (adjusted odds ratio [AOR] 5.1), open surgery (AOR 3.3), chronic renal failure (AOR 2.9), gastric bypass (AOR 2.5), peripheral vascular disease (AOR 2.4), male gender (AOR 1.9), age >50 years (AOR 1.8), Medicare payer (AOR 1.8), alcohol abuse (AOR 1.8), chronic lung disease (AOR 1.6), diabetes mellitus (AOR 1.2), and smoking (AOR 1.1) were factors associated with greater rates of ARF. Compared with patients without ARF, patients with ARF had significantly greater in-hospital mortality (5.69% versus .04%, P < .01). We identified multiple risk factors that have an effect on the development of acute respiratory failure after bariatric surgery. Surgeons should consider these factors in surgical decision-making and inform patients of their risk of this potentially life-threatening complication.


[Interventional left atrial appendage occlusion. A reasonable alternative to oral anticoagulation - even in the era of the new substances?].
As a potential alternative to long-term oral anticoagulation with vitamin K antagonists in patients with atrial fibrillation, the interventional left atrial appendage occlusion has shown to be non-inferior regarding neurological events. With the new oral direct factor II and factor Xa inhibitors playing an emerging role in stroke prophylaxis, an individual treatment strategy has to be found weighing bleeding and stroke risk against the peri-interventional complication rate based on established risk scores.


Interleukin-6 mediates delirium-like phenotypes in a murine model of urinary tract infection.
Urinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI. C57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 108 Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR. Compared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r2 = 0.2653, p < 0.0001). These data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.


Transcription factor IIIA induced bending of the Xenopus somatic 5S gene promoter.
Transcription factor IIIA (TFIIIA), the canonical zinc-finger protein, is a protein of relative molecular mass 39,000 (39K) that is required for transcription of 5S-ribosomal subunit genes in Xenopus. It binds in a sequence-specific manner to the internal control region of the 5S gene (see Fig. 1) and facilitates transcription of the gene by RNA polymerase III. It also binds to the 5S gene product to form a 7S ribonucleoprotein particle. In oocytes the 7S particle acts as a storage form of the RNA to be utilized later in development. TFIIIA binds to DNA through its 30 K N-terminal domain, which contains nine zinc-fingers. TFIIIA was the first protein described to have this type of DNA binding motif, but numerous other proteins have now been shown to have zinc-finger domains. A structure for a single zinc-finger from the yeast protein ADR1, was recently proposed based on two-dimensional NMR data (ref. 8), and a similar structure was proposed based on comparison with crystal structures of other metalloproteins. Although models for the interaction of TFIIIA with the 5S-ribosomal gene DNA have been proposed, based on nuclease digestion and methylation interference data, little precise structural information is available for TFIIIA and the physical basis for the interaction of zinc-fingers with DNA is not understood. Using both circular permutation and circularization assays we provide convincing biochemical evidence that TFIIIA bends the DNA at the internal promoter of the 5S gene.


Correlation of cell membrane dynamics and cell motility.
Essential events of cell development and homeostasis are revealed by the associated changes of cell morphology and therefore have been widely used as a key indicator of physiological states and molecular pathways affecting various cellular functions via cytoskeleton. Cell motility is a complex phenomenon primarily driven by the actin network, which plays an important role in shaping the morphology of the cells. Most of the morphology based features are approximated from cell periphery but its dynamics have received none to scant attention. We aim to bridge the gap between membrane dynamics and cell states from the perspective of whole cell movement by identifying cell edge patterns and its correlation with cell dynamics. We present a systematic study to extract, classify, and compare cell dynamics in terms of cell motility and edge activity. Cell motility features extracted by fitting a persistent random walk were used to identify the initial set of cell subpopulations. We propose algorithms to extract edge features along the entire cell periphery such as protrusion and retraction velocity. These constitute a unique set of multivariate time-lapse edge features that are then used to profile subclasses of cell dynamics by unsupervised clustering. By comparing membrane dynamic patterns exhibited by each subclass of cells, correlated trends of edge and cell movements were identified. Our findings are consistent with published literature and we also identified that motility patterns are influenced by edge features from initial time points compared to later sampling intervals.


Embolic stroke, sinus rhythm and left atrial mechanical function.
A 64-year-old man manifested a stroke two years after restoration of sinus rhythm through a radiofrequency catheter ablation. Transesophageal echocardiography demonstrated the presence of a thrombus in the left atrial appendage. Left atrial volumes and different parameters of atrial emptying showed that, despite the persistence of the sinus rhythm, atrial mechanical function was severely impaired. After atrial ablation procedures echocardiography can be useful to stratify patients according to their risk of developing embolic events and hence be of help in deciding whether or not discontinuation of anticoagulant therapy is the appropriate choice.


The distribution of fake Australian vaccine digital certificates on an alt-tech platform.
This paper provides the first exploration of the online distribution of fake Australian COVID-19 vaccine certificates. Drawing on a collection of 2589 posts between five distributors and their community members on the alt-tech platform Gab, this study gathers key insights into the mechanics of illicit vaccine certificate distribution. The qualitative findings in this research demonstrate the various motivations and binding ideologies that underpinned this illicit distribution (e.g. anti-vaccine and anti-surveillance motivations); the unique cybercultural aspects of this online illicit network (e.g. 'crowdsourcing' the creation of fake vaccine passes); and how the online community was used to share information on the risks of engaging in this illicit service, setting the appropriate contexts of using fake vaccine passes, and the evasion of guardians in offline settings. Implications for future research in cybercrime, illicit networks, and organised crime in digital spaces are discussed.


Inflammaging, hormesis and the rationale for anti-aging strategies.
We propose in this review that hormesis, a concept profoundly and systematically addressed by Mark Mattson, has to be considered a sort of comprehensive "contact point" capable of unifying several conceptualizations of the aging process, including those focused on the stress response, oxidative stress and chronic inflammation/inflammaging. A major strength of hormesis and inflammaging is that they have a strong evolutionary basis. Moreover, both hormesis and inflammaging frame the aging process within a lifelong perspective of adaptation to different types of stresses. Such adaptation perspective also suggests that the aging process is malleable, and predicts that effective anti-aging strategies should mimic what evolution did in the course of million years and that we have to learn how to exploit the great potential inherent in the hormetic/inflammatory responses. To this regard, new topics such as the production of mitokines to cope with mitochondrial dysfunction are emerging as possible anti-aging target. This approach opens theoretically the door to the possibility of modulating the individual aging rate and trajectory by adopting the most effective scientifically-based lifestyle regarding fundamentally nutrition and physical activity. In this scenario Mark Mattson's lesson and personal example will permanently enlighten the aging field and the quest for a healthy aging and longevity.


Early puberty paradox: an investigation of anxiety levels of mothers and children, children's quality of life, and psychiatric diagnoses.
Early puberty signs lead to an increase in anxiety levels of parents and children. The aim of this study was to investigate the quality of life and anxiety levels of girls and their mothers who were admitted to a pediatric endocrinology clinic with concerns about early puberty. Girls and their mothers who were admitted to endocrinology outpatient clinic with concerns about early puberty were compared to healthy control group. Screen for Child Anxiety Related Emotional Disorders (SCARED) parent form, Quality of Life for Children Scale (PedsQL) parent form, and Beck Anxiety Inventory (BAI) were administered to the mothers. Children were evaluated with the Schedule for Affective Disorders and Schizophrenia for School-Age Children (Kiddie-SADS Lifetime Version) (K-SADS-PL). The study sample consisted of 92 girls and 62 of them were administered to clinic with concerns about early puberty. There were 30 girls in early puberty group (group 1), 32 girls were in the normal development group (group 2), and 30 were in the healthy control group (group 3). The anxiety level of group 1 and group 2 was significantly higher, and their quality of life was significantly lower when compared to group 3 (p < 0.001). Mother's anxiety level was found significantly higher in group 2 (p < 0.001). It has shown that anxiety level and quality of life of children were associated with anxiety level of mothers and the current Tanner stage (r = 0.302, p < 0.005). Conclusion: Mothers and children who have concerns about early puberty are negatively affected when early puberty is a possibility. For this reason, educating parents will prevent negative impacts of this situation on children. At the same time, it will decrease health burden. What is Known? • Early adolescence is one of the most common reasons for admission to pediatric endocrinology outpatient clinics. It is known that increasing early adolescence anxiety in the society causes cost and time losses in the field of health. However, studies investigating the reasons for this result are limited in the literature. What's New? • The level of anxiety increased significantly in girls with suspected precocious puberty and their mothers, and their quality of life was affected. • For this reason, we would like to emphasize the importance of multidisciplinary approaches before psychiatric disorders occur in children with suspected precocious puberty and their parents.


Accuracy of left atrial and pulmonary artery wedge pressure in pure mitral regurgitation in predicting left ventricular end-diastolic pressure.
In most clinical conditions pulmonary artery (PA) wedge pressure accurately reflects left ventricular (LV) end-diastolic pressure. In the presence of mitral regurgitation (MR), large V waves can distort PA wedge pressure and result in incorrect estimation of LV end-diastolic pressure. In 52 patients with MR simultaneous measurement of PA wedge pressure or left atrial pressure and LV end-diastolic pressure was recorded. Twenty-one (40%) patients had large V waves (V wave greater than A wave by greater than 10 mm Hg, group 1), and 31 (60%) patients had small V waves (group 2). Group 1 had significantly higher V waves than group 2 (46 +/- 3 vs 21 +/- 2 mm Hg, p less than 0.001). The LV end-diastolic pressure was similar in both groups (21 +/- 2 vs 19 +/- 2 mm Hg, difference not significant). The mean PA wedge or left atrial pressure in group 1 (26 +/- 2 mm Hg) overestimated LV end-diastolic pressure (21 +/- 2 mm Hg) by 30% (p less than 0.01), but the trough of the X descent (20 +/- 2 mm Hg) was similar to the LV end-diastolic pressure. In group 2 patients with small V waves the mean PA wedge pressure was not significantly different from the LV end-diastolic pressure (16 +/- 2 vs 19 +/- 2 mm Hg, p = 0.06), but the trough of the X descent (13 +/- 2 mm Hg) underestimated LV end-diastolic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


Clubbed [1,2,3] triazoles by fluorine benzimidazole: a novel approach to H37Rv inhibitors as a potential treatment for tuberculosis.
A Novel Clubbed [1,2,3] triazoles with fluorine benzimidazole series of H37Rv strain inhibitors, potentially useful for the treatment of tuberculosis is disclosed on the basis of promising results of preliminary antimicrobial study. Evaluation of the SAR of substitution within these series has followed the identification of a range of compounds. Some of the derivatives are under further evaluation showing better considerable activity compared to rifampin.


[Safety of the Living Kidney Donor - The German National Register - Development and Structure of a National Register in the Health Service Research].
The German living donor register Safety of the Living Kidney Donor - The German National Register (SOLKID-GNR) collects data of the medical and psychosocial outcome of living kidney donors. For the first time in Germany, a prospective data collection allows a scientifically based long-term analysis of how a living kidney donation influences the psychological and physical health of living kidney donors. This will contribute directly to improve the information and care of living kidney donors.


Emerging maps of allosteric regulation in cellular networks.
Allosteric regulation is classically defined as action at a distance, where a perturbation outside of a protein active site affects function. While this definition has motivated many studies of allosteric mechanisms at the level of protein structure, translating these insights to the allosteric regulation of entire cellular processes - and their crosstalk - has received less attention, despite the broad importance of allostery for cellular regulation foreseen by Jacob and Monod. Here, we revisit an evolutionary model for the widespread emergence of allosteric regulation in colocalized proteins, describe supporting evidence, and discuss emerging advances in mapping allostery in cellular networks that link precise and often allosteric perturbations at the molecular level to functional changes at the pathway and systems levels.


Inflammatory molecules: a target for treatment of systemic autoimmune diseases.
Inflammation is a process to protect the host against infection and danger signals. However, many pathologic conditions, including autoimmune diseases, are sustained by perpetual activation of the inflammatory process. In the past few years our knowledge about the molecular basis of inflammation have been uncovered and now much is known about the primary role of pro-inflammatory cytokines such as IL-1 and TNF. In the early '90s, anti-cytokine therapies started and confirmed the primary role of TNF in autoimmune diseases, such as rheumatoid arthritis, Crohn's Disease and psoriasis. Increasing understanding of the role of inflammatory mediators in inflammation and diseases is opening new avenues for the treatment of inflammatory-based diseases through selective targeting of cytokines and lipid mediators.


Electrophysiological properties of ventromedial medulla neurons in response to noxious and non-noxious stimuli in the awake, freely moving rat: a single-unit study.
The spontaneous and evoked activities of ventromedial medulla (VMM) neurons have been recorded in the chronic, awake, freely moving rat. The vast majority of neurons located at the level of the nucleus raphé magnus exhibited an irregular and variable (2-16 Hz) spontaneous activity and were activated by either cutaneous or auditory stimuli. Within this convergent neuronal class the neurons were activated by either cutaneous noxious and non-noxious inputs. The threshold for cutaneous activation was likely very low since a majority of units responded to air puffs, but the application of controlled brushing and pin-prick revealed that the VMM convergent neurons responded more for the noxious mechanical stimulation. Similar findings were found with pinch application. For both innocuous and noxious stimuli, the cutaneous receptive field was extremely extensive (almost all of the body); however, the application of the controlled brushing showed that for this innocuous stimulation, the most sensitive regions were the tail, back, snout and vibrissae and, to a lesser extent, the flank and paws. Preliminary experiments indicated that both the spontaneous and evoked activities of VMM convergent neurons were inhibited during stressful manipulations such as scruff lifting or defense reactions. These data contrast with other studies on VMM single unit recordings in anesthetized rats since the majority of these studies did not emphasize the VMM convergent group; in addition, with one exception, we did not find neurons exclusively driven by noxious inputs. Without excluding a role of the VMM convergent group in pain descending control systems, we proposed that this neuronal class is perhaps also involved in pain transmission or in general processess such as alertness and stress. Experiments are proposed in order to precisely determine the involvement of the VMM convergent neurons in alertness versus sensory discriminative aspects of nociception in the awake, freely moving rat.


Association of Vitamin D Deficiency in Patients with Tinnitus with Normal Audiogram.
In the present study we aim to evaluate serum vitamin D levels in participants having tinnitus with normal audiometric findings. Total 98 participants in the age range 20-70 year were included in the study. Participants underwent detail case history, ear examination, pure tone audiometry and impedance audiometry. 68 participants with subjective tinnitus for more than 3 months and with normal audiometric thresholds and "A" type tympanogram were included in study group and 30 participants without tinnitus in the control group. The participants fullfillng the inclusion criteria underwent thorough tinnitus evaluation which included administration of tinnitus severity index tinnitus handicap inventory, psychophysical evaluation of tinnitus (pitch matching, loudness matching) and assessment of Vitamin D levels. It was seen that the mean Vitamin D levels were significantly lower in study group, and out of 68 participants only 11 had optimal Vitamin D levels, 57 (83%) had Vitamin D levels less that 30 mg/dl. In the control group 20 (66%) had vitamin D deficiency. The difference came out to be statistically significant. Our study suggests that there is a link between vitamin D and tinnitus, in view of these findings we recommend evaluating serum Vitamin D levels in patients of chronic idiopathic tinnitus, especially in adults with normal hearing. Our study suggests vitamin D deficiency may be one of the risk factor for tinnitus in people with normal hearing in the absence of other manifestations.


Competency requirements. A new approach to medical school admissions.
The faculty of the University of Pennsylvania School of Medicine, Philadelphia, have substituted definitions of knowledge and skills for course requirements as requirements for admission. The school expects that this action will allow students more flexibility in the development of their undergraduate academic programs, while guiding them specifically to the necessary preparation in the sciences. It is further hoped that this action will encourage the faculties of undergraduate schools to examine the way in which they prepare students for careers in medicine. This article describes the approach used for bringing about this change in policy and presents the new admissions requirements.


Use of protein A-coated colloidal gold particles for immunoelectronmicroscopic localization of ACTH on ultrathin sections.
ACTH was localized in dissociated porcine adenohypophysial cells using a novel indirect EM immunocytochemical technique. Incubation of ultrathin resin sections in anti-ACTH was followed by incubation with protein A-coated colloidal gold particles. Protein A binds specifically to the Fc part of the IgG molecule, and thus the ACTH-containing secretory granules became labelled with electron-dense gold particles. With this method, the dissociated porcine ACTH cells was identified as containing numerous round or ovoid 170--300 nm secretory granules.


Skeletal structure of asymmetric mandibular prognathism and retrognathism.
This study aimed to compare the skeletal structures between mandibular prognathism and retrognathism among patients with facial asymmetry. Patients who had mandibular asymmetry with retrognathism (Group A) in The Netherlands were compared with those with deviated mandibular prognathism (Group B) in Korea. All the data were obtained from 3D-reformatted cone-beam computed tomography images from each institute. The right and left condylar heads were located more posteriorly, inferiorly, and medially in Group B than in Group A. The deviated side of Group A and the contralateral side of Group B showed similar condylar width and height, ramus-proper height, and ramus height. Interestingly, there were no inter-group differences in the ramus-proper heights. Asymmetric mandibular body length was the most significantly correlated with chin asymmetry in retrognathic asymmetry patients whereas asymmetric elongation of condylar process was the most important factor for chin asymmetry in deviated mandibular prognathism. Considering the 3D positional difference of gonion and large individual variations of frontal ramal inclination, significant structural deformation in deviated mandibular prognathism need to be considered in asymmetric prognathism patients. Therefore, Individually planned surgical procedures that also correct the malpositioning of the mandibular ramus are recommended especially in patients with asymmetric prognathism.


[Haemorrhage in arteriovenous malformations of the brain following radiosurgery: the importance of the latency period].
Arteriovenous malformations are abnormal communications between arteries and veins. Treatment can consist in surgery, embolisation and/or radiosurgery. To assess the influence of radiosurgery on the risk of bleeding and related factors. Retrospective study of 79 patients who were treated with a 6 MV linear accelerator. Clinical, morphological and dosimetric parameters were collected and a statistical analysis was performed to investigate their relationship with bleeding during the latency period. The mean age was 33.7 years, and 56% of patients were females. The mean volume was 6.16 cm(3). Bleeding occurred before treatment in 52.6% of cases. Altogether 25% had been embolised and 7.6% had been treated earlier using radiosurgery. Six patients suffered a haemorrhage after treatment. Bleeding occurred in 21% of those who had undergone embolisation versus 3.6% in non-embolised individuals (p < 0.02). Bleeding occurred in 33.3% of those who had been treated radiosurgically on more than one occasion, and only 5.7% if they were treated just once (p = 0.02). Bleeding took place in 28.6% of lesions above 10 cm(3) and in 3.2% when they were smaller (p < 0.01). Bleeding occurred in 16.1% of patients if they received less than 17 Gy, and in 2.22% if they received 17 or more (p < 0.01). All haemorrhages took place in treatments with more than one isocentre (p < 0.01) and with a higher homogeneity index (p < 0.01). Radiosurgery does not modify the risk of bleeding. The factors associated to higher percentages of bleeding are also related to poorer closure outcomes and longer latency periods.


Health-economic modelling of cost savings due to the use of rezafungin based on a German cost-of-illness study of candidiasis.
Candida species are responsible for fungal diseases and the development of nosocomial bloodstream infections. Treatment is resource-intensive and economically challenging for healthcare systems. Cost analyses of drugs against candidiasis, such as rezafungin, are thus of great interest to healthcare payers. We conducted a cost-of-illness study of patients with Candida infections based on real-word data of the Department I of Internal Medicine, University Hospital Cologne (Germany) between 2016 and 2021. Health-economic parameters were analysed to describe the economic impact of Candida infections. Potential cost savings due to the administration of rezafungin were modelled for patients with invasive candidiasis or candidaemia based on a 5 day reduction of ICU length of stay (LOS) shown by the STRIVE study. We found 724 cases (652 patients) with Candida infections, of which 61% received ICU treatment (n = 442) and 29% were mechanically ventilated (n = 207). Twenty-six percent died during hospitalization (n = 185). Median LOS was 25 and 15 days, on normal wards and ICU, respectively. Median total treatment costs per case accounted for €22 820. Based on the ICU LOS reduction, the retrospective model showed a median cost-saving potential of €7175 per hospital case with invasive candidiasis or candidaemia. Accumulated cost savings for 37 patients of €283 335 were found. Treatment of candidiasis is cost intensive due to increased hospital LOS. The ICU LOS reduction rezafungin showed in STRIVE would lead to sustainable cost savings.


In vitro effect of statins on cytokine production and mitogen response of human peripheral blood mononuclear cells.
The in vitro effect of the hydrophilic statin - pravastatin - and three hydrophobic statins - atorvastatin, lovastatin and simvastatin - on the production of IL-1beta, IL-1ra, IL-2, IL-6 and IFN-gamma by human peripheral blood mononuclear cells (PBMC) and their response to mitogens was examined. Lovastatin and simvastatin increased the production of IL-1beta in a dose dependent manner and reduced secretion of IL-1ra at high concentration. These two statins exerted a dose dependent inhibitory effect on IL-2 production and reduced the secretion of IFNgamma at high dose. Atorvastatin did not affect IL-1beta, but suppressed IL-1ra, IL-2 and IFNgamma production. Atorvastatin, lovastatin and simvastatin caused a dose dependent inhibition of mitogen-induced proliferation of PBMC. IL-6 production was not affected by any one of the statins. While pravastatin caused a slight reduction in the proliferative response of PBMC to PHA, it did not affect either their response to Con A and PWM, or the secretion of cytokines tested.


Functional diversity of protein fibrillar aggregates from physiology to RNA granules to neurodegenerative diseases.
Many proteins exhibit propensities to form fibrillar aggregates called amyloids that are rich in β-sheet structures. Abnormal accumulation of amyloids in the brain and spinal cords is well known as a major pathological change in neurodegenerative diseases; therefore, amyloids have long been considered as disease culprits formed via protein misfolding and should be avoided in healthy cells. Recently, however, increasing numbers of proteins have been identified that require formation of fibrillar states for exertion of their physiological functions, and the critical roles of such functional amyloids include a molecular switch for environmental adaptation, a structural template for catalysis, and a regulator of intracellular signaling. Protein amyloids will, therefore, be more prevailed in our physiologies than we have expected so far. Here, we have reviewed recent studies on such regulatory roles of protein fibrillar aggregates in various physiologies and further discussed possible relations of functional to pathological amyloids.


A spatiotemporal dissolved oxygen prediction model based on graph attention networks suitable for missing data.
The accurate prediction of dissolved oxygen concentration is crucial for the effective prevention and control of water pollution. A spatiotemporal prediction model for dissolved oxygen content that is suitable for missing data is proposed in this study. The model utilizes a module based on neural controlled differential equations (NCDEs) to handle missing data and graph attention networks (GATs) to capture the spatiotemporal relationship of dissolved oxygen content. To enhance the performance of model, it is optimized from three aspects: an iterative optimization method based on the k-nearest neighbor graph is proposed to enhance the quality of graph; Shapley additive explanations model (SHAP) is used to select the main features into model, enabling it to handle multiple features; and a fusion graph attention mechanism is introduced to improve the robustness of model to noise. The model is evaluated using data from water quality monitoring sites in Hunan Province, China, from January 14, 2021, to June 16, 2022. The proposed model outperforms other models in long-term prediction (step = 18), with MAE of 0.194, NSE of 0.914, RAE of 0.219, and IA of 0.977. The results demonstrate that constructing appropriate spatial dependencies can enhance the accuracy of dissolved oxygen prediction models, and the NCDE module confers robustness to missing data in the model.


Study of uranyl sorption onto hematite by in situ attenuated total reflection-infrared spectroscopy.
In this paper, we present results of ATR-IR spectroscopy of uranyl complexes adsorbed on hematite. This method allowed the in situ recording of infrared spectra of uranyl sorbed on hematite in presence of aqueous solution and to detect one peak at 906 cm(-1) attributed to the antisymmetric O=U=O stretching. The intensity of the peak increases with pH, but its shape does not evolve, indicating that the same surface species is responsible for the sorption in the pH range 5-8. The reversibility experiments confirm that the hematite deposit reacts in the same way as dispersed suspensions. Measurement of the stretching frequency of nitrate ions coming from electrolyte showed a pure electrostatic adsorption and exclude the formation of a ternary complex with uranyl.


Spinal cord injury induced changes of nuclear receptors PPARα and LXRβ and modulation with oleic acid/albumin treatment.
In previous studies with animal models of spinal cord injury (SCI) pharmacological activation of peroxisome proliferator activated receptors (PPAR) and liver X receptors (LXR) were used to reduce tissue damage and promote behavioral recovery in animal models. We have studied the endogenous expression of the transcription factors PPARα and LXRβ in the chronic stage after SCI in rats. The immunohistochemical investigation revealed a long lasting increase in the level of PPARα in white matter in the vicinity of the lesion site. The source of this signal was identified in a subpopulation of astrocytes outside of the glial scar area. Intrathecal injections of oleic acid/albumin reduced the lesion-induced PPARα immunoreactivity. In addition, ependymal cells displayed a prominent PPARα signal in the non-injured spinal cord, and continued to express the receptor as they proliferated and migrated within the damaged tissue. The nuclear receptor LXRβ was detected at similar levels after SCI as in sham operated animals. We found high levels of immunoreactivity in the gray matter, while in the white matter it was present in subpopulations of astrocytes and oligodendrocytes. Macrophages that had accumulated within the center of the lesion contained LXRβ in their cell nuclei. Possible endogenous functions of PPARα and LXRβ after SCI are discussed, specifically the control of fatty acid and cholesterol metabolism and the regulation of inflammatory reactions.


The validity of Acuros BV and TG-43 for high-dose-rate brachytherapy superficial mold treatments.
The purpose of this work is to validate the Acuros BV dose calculation algorithm for high-dose-rate (HDR) brachytherapy superficial mold treatments in the absence of full scatter conditions and compare this with TG-43 dose calculations. We also investigate the impact of additional back scatter material (bolus) applied above surface molds to the dose distributions under the mold. The absorbed dose at various depths was compared for simulations performed using either TG-43 or Acuros BV dose calculations. Parameter variations included treatment area, thickness of the bolus, and surface shape (flat or spherical). Film measurements were carried out in a flat phantom. Acuros BV calculations and film measurements agreed within 1.5% but were up to 15% lower than TG-43 dose calculations when no bolus was applied above the treatment catheters. The difference in dose at the prescription depth (1 cm below the central catheter) increased with increasing treatment area: 3.3% difference for a 3 × 3.5 cm2 source loading area, 7.4% for 8 × 9 cm2, and 13.4% for 18 × 19 cm2. The dose overestimation of the TG-43 model decreased when bolus was added above the treatment catheters. The TG-43 dosimetry formalism cannot model surface mold treatments in the absence of full scatter conditions within 5% for loading areas larger than approximately 5 × 5 cm2. The TG-43 model results in an overestimation of the delivered dose, which increases with treatment area. This confirms the need for model-based dose calculation algorithms as discussed in TG-186.


A controlled study of dimethyl sulfoxide in interstitial cystitis.
To evaluate the effectiveness of dimethyl sulfoxide in the treatment of patients with biopsies suggestive of interstitial cystitis, 33 patients underwent a controlled crossover trial. Patients were allocated randomly to receive 50 per cent dimethyl sulfoxide or placebo (saline). The medication was administered intravesically every 2 weeks for 2 sessions of 4 treatments each. Response was assessed urodynamically and symptomatically. Thirty women and 3 men (mean age 48 years and mean duration of symptoms 5.5 years) were entered into the study. No significant side effects to dimethyl sulfoxide were noted. When assessed subjectively, 53 per cent of dimethyl sulfoxide treated patients were markedly improved compared to 18 per cent of the placebo treated patients. Of the dimethyl sulfoxide group 93 per cent had objective improvement versus 35 per cent of the placebo group. Thus, dimethyl sulfoxide proved to be superior to placebo in the objective and subjective improvement of patients with interstitial cystitis.


Comparative venom toxicity between Pteromalus puparum and Nasonia vitripennis (Hymenoptera: Pteromalidae) toward the hemocytes of their natural hosts, non-target insects and cultured insect cells.
Crude venoms from two parasitoid species, Pteromalus puparum and Nasonia vitripennis (Hymenoptera: Pteromalidae) were assayed for biological activities toward hemocytes from two species of their natural hosts and eight species of their non-natural hosts as well as two lines of cultured Lepidoptera cells, respectively. By inhibiting the spreading and viability of insect hemocytes, the venom from P. puparum displayed significantly higher activities toward plasmatocytes and granular cells from both larvae and pupae of two natural hosts, Pieris rapae and Papilio xuthus, and lower activity toward those from Spodoptera litura, Musca domestica and Sarcophaga peregrina. However, no effect was found towards any type of hemocytes from other five insects tested, namely, Ectropis oblique, Galleria mellonella, Sesamia inferens, Bombyx mori and Parnara guttata. In contrast, the venom from N. vitripennis showed a narrower range of targeted insects. It appeared to have highly adverse effects on the spreading and viability of plasmatocytes and granular cells only from the natural hosts, M. domestica and S. peregrina, little toxicity to cells from P. rapae and P. xuthus, and no effect on any of the other insects tested. Pteromalus puparum venom also apparently presented a high ability to block the spreading of Tn-5B1-4 cells derived from Trichoplusia ni, and high cytotoxicity to the cells and Ha cells derived from Helicoverpa armigera. Nasonia vitripennis venom, however, only had a marked lethal effect to Ha cells. In addition, the possibility that the host range of a defined parasitoid could be assessed using our method of treating hemocytes from candidate insects with venom in vitro, and the potential of our venoms tested in the development of bio-insecticides, insect-resistant transgenic plants, are discussed.


Utilization of olive mill wastewater for selective production of lipids and carotenoids by Rhodotorula glutinis.
Olive mill wastewater (OMW) is a zero-cost substrate for numerous value-added compounds. Although several studies on the production of lipids and carotenoids by Rhodotorula glutinis in OMW exist, none of them has specifically focused on the conditions for a target lipid or carotenoid. This study presents cultivation conditions that selectively stimulate the cell biomass, individual carotenoids and lipids. It was found that supplemental carbon and nitrogen sources as well as illumination affected cell biomass the most. High temperature, low initial pH, illumination, lack of urea and presence of glycerol stimulated the lipid synthesis. The highest total lipid content obtained in undiluted OMW supplemented with urea was 11.08 ± 0.17% (w/w) whilst it was 41.40 ± 0.21% (w/w) when supplemented with glycerol. Moreover, the main fatty acid produced by R. glutinis in all media was oleic acid, whose fraction reached 63.94 ± 0.58%. Total carotenoid yield was significantly increased with low initial pH, high temperature, illumination, certain amounts of urea, glycerol and cultivation time. Up to 192.09 ± 0.16 μg/g cell carotenoid yield was achieved. Torularhodin could be selectively produced at high pH, low temperature and with urea and glycerol supplementation. To selectively induce torulene synthesis, cultivation conditions should have low pH, high temperature and illumination. In addition, low pH, high temperature and urea supplementation served high production of β-carotene. Up to 85.40 ± 0.76, 80.67 ± 1.40 and 39.45 ± 0.69% of torulene, torularhodin and β-carotene, respectively, were obtained under selected conditions. KEY POINTS: • Cultivation conditions selectively induced target carotenoids and lipids • 41.40 ± 0.21% (w/w) lipid content and 192.09 ± 0.16 μg/g cell carotenoid yield were achieved • Markedly high selectivity values for torularhodin and torulene were achieved.


Smoking cessation and outcome in stable outpatients with coronary, cerebrovascular, or peripheral artery disease.
The influence of smoking cessation on outcome in patients with peripheral arterial disease (PAD) has not been thoroughly studied. FRENA is an ongoing registry of stable outpatients with symptomatic coronary artery disease (CAD), cerebrovascular disease (CVD), or PAD. We compared the mortality rate of those who quit vs. those who continued smoking. As of December 2010, 3523 patients were recruited, of whom 1182 (34%) were current smokers. Of these, 475 patients (40%) had CAD, 240 (20%) had CVD, and 467 (40%) had PAD. In all, 512 patients (43%) quit smoking. Over a mean follow-up of 14 months, 32 patients (2.7%) died and 95 (8.0%) had subsequent ischaemic events (myocardial infarction 32, ischaemic stroke 20, critical limb ischaemia/disabling claudication 53). In patients with CAD, the mortality rate was significantly lower in recent quitters (0.77 vs. 3.73 deaths per 100 patient-years; p = 0.013) than in persistent smokers. No quitter with CVD died (0.0 vs. 2.18 deaths; p = 0.092); but in patients with PAD there was a trend towards a higher mortality in quitters than in those who continued smoking (4.29 vs. 2.27 deaths; p = 0.357). On multivariate analysis, the relative risk for death in quitters was 0.20 (95% CI 0.05-0.75) in patients with CAD, 0.0 in those with CVD, and 1.83 (95% CI 0.65-5.15) in those with PAD. Smoking cessation was associated with a significant decrease in mortality in patients with CAD, a non-significant decrease in those with CVD, and a non-significant increase in those with PAD.


Short-term associations between size-fractionated particulate air pollution and COPD mortality in Shanghai, China.
Particulate air pollution is a continuing challenge in China, and its adverse effects on chronic obstructive pulmonary disease (COPD) have been widely reported. However, epidemiological evidence on the associations between size-fractionated particle number concentrations (PNCs) and COPD mortality is limited. In this study, we utilized a time-series approach to investigate the associations between PNCs of particles at 0.25-10 μm in diameter and COPD mortality in Shanghai, China. Quasi-Poisson regression generalized additive models were applied to evaluate these associations, with adjustment of time trend, day of week, holidays, temperature and relative humidity. Stratification analyses were performed by season and gender. There were a total of 3238 deaths due to COPD during the study period. We found that daily COPD deaths were significantly associated with PNCs of particles <0.5 μm, and the magnitude of associations increased with decreasing particle size. An interquartile range (IQR) increase in PNC0.25-0.28, PNC0.28-0.3, PNC0.3-0.35, PNC0.35-0.4, PNC0.4-0.45 and PNC0.45--0.5 was associated with increments of 7.51% (95%CI: 2.45%, 12.81%), 7.22% (95%CI: 2.16%, 12.53%), 6.95% (95%CI: 1.81%, 12.35%), 6.26% (95%CI: 1.25%, 11.52%), 5.24% (95%CI: 0.56%, 10.13%) and 4.15% (95%CI: 0.14%, 8.32%), respectively. The associations remained robustness after controlling for the mass concentrations of gaseous air pollutants. In stratification analyses, significant associations between PNCs and COPD mortality were observed in the cold seasons, and in males. Our results suggested that particles <0.5 μm in diameter might be most responsible for the adverse effects of particulate air pollution on COPD mortality, and COPD patients are more susceptible to PM air pollution in the cold seasons, especially for males.


Association Between Travel Distance, Hospital Volume, and Outcomes Following Resection of Cholangiocarcinoma.
The objective of the current study was to characterize the association between travel distance/hospital volume relative to outcomes following resection of cholangiocarcinoma. Patients were identified using the 2004-2015 National Cancer Database and stratified into quartiles according to travel distance/hospital volume. Multivariable regression models were utilized to examine the impact of travel distance and hospital volume on quality-of-care metrics and overall survival. Among 5125 patients, the majority of patients had T1/2 (N = 2006, 41.1%) and N0 disease (N = 2498, 50.9%). Median hospital quartile surgical volumes in cases/year were low volume (LV) 6, intermediate low volume (ILV) 7, intermediate high volume (IHV) 12, and high volume (HV) 24 cases/year. Median travel distance quartiles in miles were short travel (ST) 2.7, intermediate short travel (IST) 7.9, intermediate long travel (ILT) 18.9, and long travel (LT) 84.7. Longer travel distances were associated with better overall survival, as every 10 miles was associated with a 2% decrease in mortality (p = 0.02). Differences in quality-of-care metrics were largely mediated through travel distance. Travel distance and hospital volume were associated with certain quality-of-care metrics among patients with cholangiocarcinoma. After controlling for hospital volume and travel distance simultaneously, only travel distance was associated with decreased risk of mortality.


Inhibition kinetics of mushroom tyrosinase by copper-chelating ammonium tetrathiomolybdate.
With a strategy of chelating coppers at tyrosinase active site to detect an effective inhibitor, several copper-specific chelators were applied in this study. Ammonium tetrathiomolybdate (ATTM) among them, known as a drug for treating Wilson's disease, turned out to be a significant tyrosinase inhibitor. Treatment with ATTM on mushroom tyrosinase completely inactivated enzyme activity in a dose-dependent manner. Progress-of-substrate reaction kinetics using the two-step kinetic pathway and dilution of the ATTM revealed that ATTM is a tight-binding inhibitor and high dose of ATTM irreversibly inactivated tyrosinase. Progress-of-substrate reaction kinetics and activity restoration with a dilution of the ATTM indicated that the copper-chelating ATTM may bind slowly but reversibly to the active site without competition with substrate, and the enzyme-ATTM complex subsequently undergoes reversible conformational change, leading to complete inactivation of the tyrosinase activity. Thus, inhibition by ATTM on tyrosinase could be categorized as complexing type of inhibition with a slow and reversible binding. Detailed analysis of inhibition kinetics provided IC50 at the steady-state and inhibitor binding constant (K(I)) for ATTM as 1.0+/-0.2 microM and 10.65 microM, respectively. Our results may provide useful information regarding effective inhibitor of tyrosinase as whitening agents in the cosmetic industry.


After more than 300 defibrillation shocks, patient still alive 12 years later refractory torsade de pointes due to polypharmacy and persistent vomiting.
Acquired torsade de pointes ventricular tachycardia (TdP) is a rare but serious life-threatening arrhythmia caused by an array of cardiac and non-cardiac drugs. It is often refractory to pharmacological therapy and may result in death or require frequent defibrillations. In our case study a young female patient with no underlying heart disease developed very frequent sustained TdP requiring frequent defibrillations without which she would have certainly died. The ventricular arrhythmia in this patient was of multifactorial origin - cisapride, drug-drug interaction and persistent vomiting resulting in electrolyte disturbance and malnutrition. The patient survived after more than 300 defibrillation shocks over a period of 5 days and she is still alive 12 years later.


Exogenous selenium in the brain. A histochemical technique for light and electron microscopical localization of catalytic selenium bonds.
Transcardial perfusion or intraperitoneal injections with sodium selenite result in the creation of selenium bonds that can be visualized by physical development. The present paper describes how these catalytic bonds are made visible in the tissues by surrounding them with shells of metallic silver. Based on experiments with chelating agents, the possibility that selenium-metal bonds are the catalysts is discussed. In the brain, the selenium pattern is delicate and highly laminated, the grains of silver being orderly arranged corresponding with the neuropil morphology. The precipitate is most densely packed in cortical regions. The difference in staining intensity seen in different regions of the CNS reflects the density of selenium reactive terminals. The visualized selenium bonds are predominantly located within boutons, and examination in the electron microscope reveals accumulation in the presynaptic regions. In a few places precipitates can also be found in axons, but have not been observed in perikarya or dendrites. The only non-neuronal locations of selenium were sparsely scattered, astrocyte-like neuroglia, predominantly found in the cerebellum and the hypothalamus; infrequently a few blood vessels were also stained. Sections from kidney and liver are presented as examples of localizations outside the CNS of exogenous selenium.


Building a collaborative culture in cardiothoracic operating rooms: pre and postintervention study protocol for evaluation of the implementation of teamSTEPPS training and the impact on perceived psychological safety.
The importance of effective communication, a key component of teamwork, is well recognised in the healthcare setting. Establishing a culture that encourages and empowers team members to speak openly in the cardiothoracic (CT) operating room (OR) is necessary to improve patient safety in this high-risk environment. This study will take place at Barnes-Jewish Hospital, an academic hospital in affiliation with Washington University School of Medicine located in the USA. All team members participating in cardiac and thoracic OR cases during this 17-month study period will be identified by the primary surgical staff attending on the OR schedule.TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety) training course will be taught to all CT OR staff. Before TeamSTEPPS training, staff will respond to a 39-item questionnaire that includes constructs from the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture, Edmondson's 'Measure of psychological safety' questionnaire, and questionnaires on turnover intentions, job satisfaction and 'burnout'. The questionnaires will be readministered at 6 and 12 months.The primary outcomes to be assessed include the perceived psychological safety of CT OR team members, the overall effect of TeamSTEPPS on burnout and job satisfaction, and observed turnover rate among the OR nurses. As secondary outcomes, we will be assessing self-reported rates of medical error and near misses in the ORs with a questionnaire at the end of each case. Ethics approval is not indicated as this project does not meet the federal definitions of research requiring the oversight of the Institutional Review Board (IRB). Patient health information (PHI) will not be generated during the implementation of this project. Results of the trial will be made accessible to the public when published in a peer-reviewed journal following the completion of the study.


A Preliminary Study of Stress, Mental Health, and Pain Related to the COVID-19 Pandemic and Odds of Persistent Prescription Opioid Use.
The COVID-19 pandemic has been associated with increased opioid prescribing. It is not known if perceived COVID-19 related stress is associated with increased odds of long-term opioid use. To determine if greater COVID-19-related stress and worsening pain attributed to the pandemic was associated with LTOT over a 6-month observation period. Longitudinal cohort. Patients (n=477) from two midwestern health care systems, with any acute or chronic non-cancer pain, starting a new period of 30-90-day prescription opioid use, were invited to participate in the Prescription Opioids and Depression Pathways Cohort Study, a longitudinal survey study of pain, opioid use, and mental health outcomes. Baseline and 6-month follow-up assessments were used to measure the association between perceived COVID-19 stressors, the perception that pain was made worse by the pandemic and the odds of persistent opioid use, i.e., remaining a prescription opioid user at 6-month follow-up. Multivariate models controlled for demographics, opioid dose, and change in pain characteristics, mental health measures, and social support. Participants were, on average, 53.9 (±11.4) years of age, 67.1% White race, and 70.9% female. The most frequently endorsed COVID-19 stressor was "worry about health of self/others" (85.7% endorsed) and the least endorsed was "worsened pain due to pandemic" (26.2%). After adjusting for all covariates, "worsened pain due to pandemic" (OR=2.88; 95%CI: 1.33-6.22), change in pain interference (OR=1.20; 95%CI: 1.04-1.38), and change in vital exhaustion (OR=0.90; 95%CI: 0.82-0.99) remained significantly associated with persistent opioid use. Patients who attribute worsening pain to the COVID-19 pandemic are more likely to be persistent opioid users. Further research is warranted to identify mechanisms underlying this association. Clinicians may consider discussing pain in the context of the pandemic to identify patients at high risk for persistent opioid use.