Pediatric occupant car safety: clinical implications based on recent literature.
Seat belts and child safety seats can provide effective protection against serious and fatal injuries, but motor vehicle crashes (MVCs) remain a leading cause of death and injury among infants and children. Recent fatalities associated with air bags have intensified awareness of pediatric occupant car safety issues. A review of pediatric literature from 1989 to 1997 summarizes studies on the correct use, incorrect use, and non-use of child safety restraint devices; injuries patterns to children as occupants in MVCs; transporting children with special needs; lethal air bag injuries; and injury prevention educational programs.


The effect of the Varian amorphous silicon electronic portal imaging device on exit skin dose.
Measurements have been made of the increase in exit surface dose resulting from backscattered radiation generated by the Varian amorphous silicon electronic portal imaging device (EPID). An increase of < or = 14% was demonstrated at both 6 MV and 10 MV, in a manner which suggests that backscatter from the EPID acts to re-establish electronic equilibrium at the exit surface, normally absent in the build-down region. The magnitude of this effect was influenced by field size, measurement depth and exit surface to EPID distance. Assuming typical constraints of portal imaging frequency and geometry, the results suggest that EPID generated backscatter is unlikely to alter the frequency or severity of exit skin reactions. However, the results do suggest that a limit on the minimum separation between the EPID and the exit surface should be set, and that similar investigations should be made for other EPID models.


Structural and functional studies of ferredoxin and oxygenase components of 3-nitrotoluene dioxygenase from Diaphorobacter sp. strain DS2.
3-nitrotoluene dioxygenase (3NTDO) from Diaphorobacter sp. strain DS2 catalyses the conversion of 3-nitrotoluene (3NT) into a mixture of 3- and 4-methylcatechols with release of nitrite. We report here, X-ray crystal structures of oxygenase and ferredoxin components of 3NTDO at 2.9 Å and 2.4 Å, respectively. The residues responsible for nitrite release in 3NTDO were further probed by four single and two double mutations in the catalytic site of α-subunit of the dioxygenase. Modification of Val 350 to Phe, Ile 204 to Ala, and Asn258 to Val by site directed mutagenesis resulted in inactive enzymes revealing the importance of these residues in catalysis. Docking studies of meta nitrotoluene to the active site of 3NTDO suggested possible orientations of binding that favor the formation of 3-methylcatechol (3MC) over 4-methylcatechol energetically. The electron transfer pathway from ferredoxin subunit to the active site of the oxygenase subunit is also proposed.


The ethical basis for promoting nutritional health in public schools in the United States.
Schools may have an ethical obligation to act in response to the precipitous increase in the incidence of obesity among children. Using a bioethics framework, we present a rationale for school programs to improve the nutritional quality of students' diets. Because children are required to spend half their waking hours in school and because they consume a substantial portion of their daily food there, school is a logical focus for efforts to encourage healthy dietary behaviors to prevent obesity and its consequent individual and collective costs. We suggest that beyond strategic considerations, the concept of the common good justifies actions that may appear to conflict with freedom of choice of children, parents, and school staff, or with the interests of food and beverage companies.


Gelria glutamica gen. nov., sp. nov., a thermophilic, obligately syntrophic, glutamate-degrading anaerobe.
A novel anaerobic, gram-positive, thermophilic, spore-forming, obligately syntrophic, glutamate-degrading bacterium, strain TGO(T), was isolated from a propionate-oxidizing methanogenic enrichment culture. The axenic culture was obtained by growing the bacterium on pyruvate. Cells were rod-shaped and non-motile. The optimal temperature for growth was 50-55 degrees C and growth occurred between 37 and 60 degrees C. The pH range for growth was 5.5-8 with optimum growth at pH 7. In pure culture, strain TGO(T) could grow on pyruvate, lactate, glycerol and several sugars. In co-culture with the hydrogenotrophic methanogen Methanobacterium thermautotrophicum strain Z-245, strain TGO(T) could grow on glutamate, proline and Casamino acids. Glutamate was converted to H2, CO2, propionate and traces of succinate. Strain TGO(T) was not able to utilize sulphate, sulphite, thiosulphate, nitrate or fumarate as electron acceptors. The G+C content was 33.8 mol%. Sequence analysis of the 16S rDNA revealed that strain TGO(T) belongs to the thermophilic, endospore-forming anaerobes, though no close relations were found. Its closest relations were Moorella glycerini (92%) and Moorella thermoacetica (90%). Strain TGOT had an unusually long 16S rDNA of more than 1700 bp. The additional base pairs were found as long loops in the V1, V7 and V9 regions of the 16S rDNA. However, the loops were not found in the 16S rRNA. The name Gelria glutamica gen. nov., sp. nov. is proposed for strain TGO(T).


Topical Ophthalmic Formulation of Trichostatin A and SurR9-C84A for Quick Recovery Post-alkali Burn of Corneal Haze.
Alkali burn injury is a true ocular emergency of the conjunctiva and cornea that requires immediate precision. Lack of an immediate therapy can lead to a substantial damage in the ocular surface and anterior segment further causing visual impairment and disfigurement. We explored the regenerative capability of dominant negative survivin protein (SurR9-C84A) and histone deacetylase inhibitor trichostatin-A (TSA) in vivo, in a rat alkali burn model. A topical insult in rat eyes with NaOH led to degradation of the conjunctival and corneal epithelium. The integrity of the conjunctival and corneal tissue was increased by TSA and SurR9-C84A by improving the clathrin and claudin expressions. Wound healing was initiated by an increase in TGF-beta-1 and, increased endogenous survivin which inhibited apoptosis post-TSA and SurR9-C84A treatments. Protein expressions of fibronectin and alpha-integrin 5 were found to increase promoting corneal integrity. The cytokine analysis confirmed increased expressions of IL-1beta, IL-6, IL-12, IL-13, IFN-gamma, TNF-alpha, GMCSF, Rantes, and MMP-2 in injured cornea, which were found to be significantly downregulated by the combined treatment of SurR9-C84A and TSA. The ocular and systemic pharmacokinetic (PK) parameters were measured post-topical ocular administration of TSA and SurR9-C84A. The SurR9-C84A and TSA sustained relatively longer in the cornea, conjunctiva, and aqueous humor than in the tear fluid and plasma. Our results confirmed that a combination of TSA with SurR9-C8A worked in synergy and showed a promising healing and anti-inflammatory effect in a very short time against alkali burn. Therefore, a combination of TSA and SurR9-C84A can fulfill the need for an immediate response to wound healing in alkali burnt cornea. We also synthesized ultra-small chitosan nanoparticles (USC-NPs) targeted with alpha-SMA antibodies that can be used for delivery of TSA and SurR9-C84A specifically to the ocular burn site.


Phylogenetic and functional diversity of metagenomic libraries of phenol degrading sludge from petroleum refinery wastewater treatment system.
In petrochemical refinery wastewater treatment plants (WWTP), different concentrations of pollutant compounds are received daily in the influent stream, including significant amounts of phenolic compounds, creating propitious conditions for the development of particular microorganisms that can rapidly adapt to such environment. In the present work, the microbial sludge from a refinery WWTP was enriched for phenol, cloned into fosmid vectors and pyrosequenced. The fosmid libraries yielded 13,200 clones and a comprehensive bioinformatic analysis of the sequence data set revealed a complex and diverse bacterial community in the phenol degrading sludge. The phylogenetic analyses using MEGAN in combination with RDP classifier showed a massive predominance of Proteobacteria, represented mostly by the genera Diaphorobacter, Pseudomonas, Thauera and Comamonas. The functional classification of phenol degrading sludge sequence data set generated by MG-RAST showed the wide metabolic diversity of the microbial sludge, with a high percentage of genes involved in the aerobic and anaerobic degradation of phenol and derivatives. In addition, genes related to the metabolism of many other organic and xenobiotic compounds, such as toluene, biphenyl, naphthalene and benzoate, were found. Results gathered herein demonstrated that the phenol degrading sludge has complex phylogenetic and functional diversities, showing the potential of such community to degrade several pollutant compounds. This microbiota is likely to represent a rich resource of versatile and unknown enzymes which may be exploited for biotechnological processes such as bioremediation.


Inducible NO synthase inhibition attenuates shear stress-induced pulmonary vasodilation in the ovine fetus.
Recent studies have suggested that type II (inducible) nitric oxide (NO) synthase (NOS II) is present in the fetal lung, but its physiological roles are uncertain. Whether NOS II activity contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) during shear stress-induced pulmonary vasodilation is unknown. We studied the hemodynamic effects of two selective NOS II antagonists [aminoguanidine (AG) and S-ethylisothiourea (EIT)], a nonselective NOS antagonist [nitro-L-arginine (L-NNA)], and a nonselective vasoconstrictor (U-46619) on PVR during partial compression of the ductus arteriosus (DA) in 20 chronically prepared fetal lambs (mean age 132 +/- 2 days, term 147 days). At surgery, catheters were placed in the left pulmonary artery (LPA) for selective drug infusion, an ultrasonic flow transducer was placed on the LPA to measure blood flow, and an inflatable vascular occluder was placed loosely around the DA for compression. On alternate days, a brief intrapulmonary infusion of normal saline (control), AG, EIT, L-NNA, or U-46619 was infused in random order into the LPA. The DA was compressed to increase mean pulmonary arterial pressure (MPAP) 12-15 mmHg above baseline values and held constant for 30 min. In control studies, DA compression reduced PVR by 42% from baseline values (P < 0.01). L-NNA treatment completely blocked the fall in PVR during DA compression. AG and EIT attenuated the decrease in PVR by 30 and 19%, respectively (P < 0.05). Nonspecific elevation in PVR by U-46619 did not affect the fall in PVR during DA compression. Immunostaining for NOS II identified this isoform in airway epithelium and vascular smooth muscle in the late-gestation ovine fetal lung. We conclude that selective NOS II antagonists attenuate but do not block shear stress-induced vasodilation in the fetal lung. We speculate that stimulation of NOS II activity, perhaps from smooth muscle cells, contributes in part to the NO-mediated fall in PVR during shear stress-induced pulmonary vasodilation.


A case of brucella spondylodiscitis with extended, multiple-level involvement.
Brucellosis is a zoonosis that affects several organs and has a protean presentation. The authors report the case of a 61-year-old male patient with brucellar spondylodiscitis involving several vertebrae and a paravertebral abscess localized in the erector spinae muscle. Diagnosis was made by positive blood culture and MRI. No relapse was seen with a combined treatment (doxycycline/rifampin) for 3 months, followed by doxycycline alone for 6 months. Almost all radiologic findings disappeared at the end of a 1-year follow-up without any further treatment.


Synthetic microvessels.
The microvasculature is an immense organ that defines the environmental conditions within tissues in both health and disease, and is vital for the proper functions of all tissues. Here, we describe existing tools to study vascular cell function and our work using one platform of in vitro microvessels, which we employed to study vessel structure and remodeling, endothelial barrier function, angiogenesis, interactions between endothelial cells and perivascular cells, interactions between blood cells and the endothelium, and microvascular thrombosis. We also briefly discuss the potential future applications of these platforms in biology and medicine.


Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration.
Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.


Effects of a surfactant-based gel on acute and chronic paediatric wounds: a panel discussion and case series.
On 20 November 2018, following the International Society for Paediatric Wound Care conference, a closed panel meeting took place in which the use of a surfactant-based gel (PluroGel (PMM), Medline Industries, Illinois, US) in paediatric wound care was discussed. The authors shared their experiences, thoughts, experimental data and clinical results. The panel identified the need for a product that can gently cleanse paediatric wounds and remove devitalised tissue without causing discomfort or skin reactions, as well as potentially promote healing. In adults, PMM has been shown to assist healing by hydrating the wound, controlling exudate and debriding non-viable tissue. Islands of neo-epithelium have also been reported to appear rapidly in different parts of the wound bed. No adverse effects on these proliferating cells have been observed. In vitro data suggest that PMM can remove biofilm, as well as potentially promote healing through cell salvage. The panel, therefore, set out to discuss their experiences of using PMM in the paediatric patients and to establish a consensus on the indications for its use and application in this population. This article will describe the main outcomes of that discussion and present case studies from paediatric patients with a variety of wound types, who were treated with PMM by members of the panel.


Survival following a concomitant aortic valve procedure during left ventricular assist device surgery: an ISHLT Mechanically Assisted Circulatory Support (IMACS) Registry analysis.
The aim of this study was to compare early- and late-term survival and causes of death between patients with and without a concomitant aortic valve (AoV) procedure during continuous-flow left ventricular assist device (LVAD) surgery. All adult primary continuous-flow LVAD patients on the International Society of Heart and Lung Transplantation (ISHLT) Mechanically Assisted Circulatory Support (IMACS) Registry (n = 15 267) were included in this analysis and stratified into patients submitted to a concomitant AoV procedure (AoV replacement or AoV repair) and patients without an AoV procedure. The primary outcome was early (≤90 days) survival post-LVAD surgery. Secondary outcomes were late survival (survival during the entire follow-up period) and conditional survival (in patients who survived the first 90 days post-LVAD surgery), and determinants. Patients who underwent concomitant AoV replacement (n = 457) had significantly reduced late survival compared with patients with AoV repair (n = 328) or without an AoV procedure (n = 14 482) (56% vs. 61% and 62%, respectively; P = 0.001). After adjustment for other significant predictors, concomitant AoV replacement remained an independent predictor for early [hazard ratio (HR) 1.226, 95% confidence interval (CI) 1.037-1.449] and late (HR 1.477, 95% CI 1.154-1.890) mortality. However, patients undergoing AoV replacement or repair, in whom the presence of moderate-to-severe AoV regurgitation was diagnosed prior to LVAD implantation, had survival similar to patients not undergoing AoV interventions. Concomitant AoV surgery in patients undergoing LVAD implantation is an independent predictor of mortality. Additional research is needed to determine the best AoV surgical strategy at the time of LVAD surgery.


Reconstruction of an Alar Defect With a Fusiform Nasolabial Turnover Flap With a Proximal, Superiorly Tapered Apex.
The nasolabial turnover flap was first described by Spear et al in 1987 for the coverage of full thickness defects of the lateral ala. It offered a single-stage repair that recreated the internal nasal lining, the external nasal valve, and the rounded contour of the ala without requiring a cartilage graft. A frequently encountered problem with the execution of Spear's original design is elevation of the ipsilateral commissure of the adjacent lip due to its broad proximal pedicle. Here, the authors describe a fusiform-type design with a proximal, superiorly tapered apex that relies on anteriorly coursing perforators from the underlying angular artery. The authors also review the inherent advantages and disadvantages of the flap itself and the unique situation where there is a skin cancer adjacent to the donor site.


Differential proinflammatory responses induced by diesel exhaust particles with contrasting PAH and metal content.
Exposure to diesel engine exhaust particles (DEPs), representing a complex and variable mixture of components, has been linked with cellular production and release of several types of mediators related to pulmonary inflammation. A key challenge is to identify the specific components, which may be responsible for these effects. The aim of this study was to compare the proinflammatory potential of two DEP-samples with contrasting contents of polycyclic aromatic hydrocarbons (PAHs) and metals. The DEP-samples were compared with respect to their ability to induce cytotoxicity, expression and release of proinflammatory mediators (IL-6, IL-8), activation of mitogen-activated protein kinases (MAPKs) and expression of CYP1A1 and heme oxygenase-1 (HO-1) in human bronchial epithelial (BEAS-2B) cells. In addition, dithiothreitol and ascorbic acid assays were performed in order to examine the oxidative potential of the PM samples. The DEP-sample with the highest PAH and lowest metal content was more potent with respect to cytotoxicity and expression and release of proinflammatory mediators, CYP1A1 and HO-1 expression and MAPK activation, than the DEP-sample with lower PAH and higher metal content. The DEP-sample with the highest PAH and lowest metal content also possessed a greater oxidative potential. The present results indicate that the content of organic components may be determinant for the proinflammatory effects of DEP. The findings underscore the importance of considering the chemical composition of particulate matter-emissions, when evaluating the potential health impact and implementation of air pollution regulations.


Social service providers navigating the rapid transition to telehealth with Latinx immigrants during the COVID-19 pandemic.
The COVID-19 pandemic radically altered social service provision with significant public health implications as social services often target society's most vulnerable with preventative health services addressing social determinants of health. Social service providers serve as crucial linkages to services for low-income Latinx immigrants who face substantial barriers to health and social care. However, little is known regarding how social service providers working with Latinx immigrants navigated service delivery and the rapid transition to telehealth during the COVID-19 pandemic. This mixed-methods (QUAL-quant; capitalization denotes primacy) study used survey data collected from April 2020 to October 2020 with Latinx immigrant serving as social service providers in the Maryland-Washington, DC, region. Social ecological theory guided the analysis of narrative data and the integration of quantitative data with qualitative themes. Participants (N = 41) were majority women (85.4%), identified as Latinx (48.6%) and elucidated themes related to their transition to telehealth, including adjusting from in-person to telehealth, barriers to telehealth implementation, impact on quality of services, working to prevent clients' disconnection to social services, and work-related stress and satisfaction. Through the firsthand experiences of frontline social service providers, results reveal conditions of scarcity endemic in social services for Latinx immigrants that preexisted the pandemic and became further constrained during a time of heightened health and social need. Further, critical insights regarding the use of remote modalities with vulnerable populations (language minorities and immigrants) can be instructive in the development of improved and accessible telehealth and remote programming and services for Latinx immigrants. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


[Adverse drug reactions of psychotropic agents: adverse drug reactions and safety monitoring of psychotropic agents].
Pharmacological treatments of psychiatric illness have been developed and many psychotropic drugs are now on the market. The body of safety information regarding psychotropic agents is so large that it is difficult for clinicians to consider all the details of possible adverse drug reactions(ADRs) in daily clinical practice. Although it is impossible to predict and prevent all occurrences of ADRs, many of them may be preventable. In this context, there is a strong need for compact manuals of diagnosis and treatment for ADRs arising from psychotropic agents that are likely to be used in daily practice. Under the auspices of the Japanese Society of Psychiatry and Neurology, a task force was convened to answer this need. This review focuses on the general considerations of ADRs with psychotropic agents, based on discussions of the task force. We also discuss the guidelines for drug safety monitoring, targeted towards specific psychiatric disorders or patients taking specific classes of drugs. Finally, we introduce the Adverse Drug Reactions Relief System in Japan.


Inflammaging and cancer: a challenge for the Mediterranean diet.
Aging is considered the major risk factor for cancer, one of the most important mortality causes in the western world. Inflammaging, a state of chronic, low-level systemic inflammation, is a pervasive feature of human aging. Chronic inflammation increases cancer risk and affects all cancer stages, triggering the initial genetic mutation or epigenetic mechanism, promoting cancer initiation, progression and metastatic diffusion. Thus, inflammaging is a strong candidate to connect age and cancer. A corollary of this hypothesis is that interventions aiming to decrease inflammaging should protect against cancer, as well as most/all age-related diseases. Epidemiological data are concordant in suggesting that the Mediterranean Diet (MD) decreases the risk of a variety of cancers but the underpinning mechanism(s) is (are) still unclear. Here we review data indicating that the MD (as a whole diet or single bioactive nutrients typical of the MD) modulates multiple interconnected processes involved in carcinogenesis and inflammatory response such as free radical production, NF-κB activation and expression of inflammatory mediators, and the eicosanoids pathway. Particular attention is devoted to the capability of MD to affect the balance between pro- and anti-inflammaging as well as to emerging topics such as maintenance of gut microbiota (GM) homeostasis and epigenetic modulation of oncogenesis through specific microRNAs.


Trans-resveratrol boronic acid exhibits enhanced anti-proliferative activity on estrogen-dependent MCF-7 breast cancer cells.
Resveratrol (RSV), a natural compound present in the skin and seeds of red grapes, is considered a phytoestrogen and has structural similarity to the synthetic estrogen diethylstilbestrol. RSV inhibits tumor cell growth in estrogen receptor-positive (ER+) and negative (ER-) breast cancer cell lines resulting in cell specific regulation of the G1/S and G2/M stages of the cell cycle. However apoptotic cell death was only observed in ER+ MCF-7 cells. In this study, we designed and synthesized boronic acid derivative of RSV and evaluated their biological effects on ER+ MCF-7 breast cancer cells. The trans-4 analog inhibited the growth of MCF-7 cells and is not a substrate for p-glycoprotein. The trans-4 analog induces G1 cell cycle arrest, which coincides with marked inhibition of G1 cell cycle proteins and a greater pro-apoptotic effect. Finally, the trans-4 analog had no effect on the estrogen-stimulated growth of MCF-7 cells. Our results demonstrate that the trans-4 analog inhibits MCF-7 breast cancer cells by a different mechanism of action than that of RSV (S-phase arrest), and provides a new class of novel boronic acids of RSV that inhibit breast cancer cell growth.


[Folic acid fortification of bread recommendable].
Folic acid supplementation was recommended in the Netherlands after it had been demonstrated that periconceptional use of folic acid protected against foetal neural tube defects; this recommendation led to a slight decrease in prevalence only. According to the Dutch Health Council, fortification of bread should now be considered. Policy-making is complicated by uncertainties regarding potential side effects, such as adverse effects in children, for which scientific evidence is lacking however.


Breast imaging: how we manage diagnostic technology at a multidisciplinary breast center.
This paper discusses the most important aspects and problems related to the management of breast cancer imaging, at a center specialized in breast pathology. We review the established and emerging diagnostic techniques, their indications, and peculiarities: digital mammography, CAD systems, and the recent digital breast tomosynthesis, ultrasound and complementary elastography, molecular imaging techniques, magnetic resonance imaging, advanced sequences (diffusion), and positron emission mammography (PEM). The adequate integration and rational management of these techniques is essential, but this is not always easy, in order to achieve a successful diagnosis.


Jobs and job quality between the eve of the Great Recession and the eve of COVID-19.
In 2019, the employment rate among 25- to 64-year-olds in the UK reached 80 per cent - the highest on record, and considerably higher than the 76 per cent rate recorded shortly before the Great Recession. In this paper, we investigate the growth in employment between the eve of the Great Recession and the eve of COVID-19 across several dimensions. We analyse which sectors, demographic groups and regions accounted for the rise. We also investigate how job 'quality' - in both financial and non-financial terms - has changed. We find that almost all demographic groups and regions saw a rise in employment, especially those with low pre-existing employment rates and those near the bottom of the income distribution. Hourly pay growth was very weak over the period, with the median actually slightly falling. Other indicators of job quality show a more mixed picture: employees seem to have greater appreciation of their work and firm, but perceive less security and flexibility in their job.


[Inguinal hernioplasty with calibrated prosthesis (personal modification of the Trabucco technique].
From January 1994 to December 1997, the authors operated on 636 patients with primary inguinal hernia, using an original modification of Trabucco's tension-free and sutureless technique. The hernial defect is sized according to Gilbert's classification modified by Rutkow and Robbins and repaired with one or more plugs (up to four in the authors' experience) in relation to its extent. The posterior wall is reconstructed over the plugs encompassing the transversalis fascia and a wing of the plug superiorly and the iliopubic tract inferiorly. The double-layer polypropylene mesh is fashioned intraoperatively and the key-hole tailored to the variable distance between the spermatic cord and the pubic tubercle. All patients ambulated immediately after the operation, had a light meal two hours later and were discharged within one day of surgery. During a 3 months to 4 year follow-up only one recurrence has been recorded (0.16%). The proposed technique allows to perform a repair to measure ("calibrated") with minimal pain, immediate rehabilitation and early return to unrestricted activity.


Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes.
DNA double-strand breaks originating from diverse causes in eukaryotic cells are accompanied by the formation of phosphorylated H2AX (gammaH2AX) foci. Here we show that gammaH2AX formation is also a cellular response to topoisomerase I cleavage complexes known to induce DNA double-strand breaks during replication. In HCT116 human carcinoma cells exposed to the topoisomerase I inhibitor camptothecin, the resulting gammaH2AX formation can be prevented with the phosphatidylinositol 3-OH kinase-related kinase inhibitor wortmannin; however, in contrast to ionizing radiation, only camptothecin-induced gammaH2AX formation can be prevented with the DNA replication inhibitor aphidicolin and enhanced with the checkpoint abrogator 7-hydroxystaurosporine. This gammaH2AX formation is suppressed in ATR (ataxia telangiectasia and Rad3-related) deficient cells and markedly decreased in DNA-dependent protein kinase-deficient cells but is not abrogated in ataxia telangiectasia cells, indicating that ATR and DNA-dependent protein kinase are the kinases primarily involved in gammaH2AX formation at the sites of replication-mediated DNA double-strand breaks. Mre11- and Nbs1-deficient cells are still able to form gammaH2AX. However, H2AX-/- mouse embryonic fibroblasts exposed to camptothecin fail to form Mre11, Rad50, and Nbs1 foci and are hypersensitive to camptothecin. These results demonstrate a conserved gammaH2AX response for double-strand breaks induced by replication fork collision. gammaH2AX foci are required for recruiting repair and checkpoint protein complexes to the replication break sites.


The Diagnostic Value of Biomarkers in Acute Mesenteric Ischaemia Is Insufficiently Substantiated: A Systematic Review.
There is an urgent need for accurate biomarkers to support timely diagnosis of acute mesenteric ischaemia (AMI) and thereby improve clinical outcomes. With this systematic review, the aim was to substantiate the potential diagnostic value of biomarkers for arterial occlusive AMI. The Pubmed, Embase, and the Cochrane Library electronic databases were searched. A systematic review of the literature has been conducted to define the potential diagnostic value of biomarkers for arterial occlusive AMI. All studies including ≥ 10 patients describing biomarkers for macrovascular occlusive AMI between 1950 and 17 February 2023 were identified within the Pubmed, Embase, and the Cochrane Library electronic databases. There were no restrictions to any particular study design, but letters and editorials were excluded. The QUADAS-2 tool was used for the critical appraisal of quality. The study protocol was registered on Prospero (CRD42021254970). Fifty of 4334 studies were eligible for inclusion in this review. Ninety per cent of studies were of low quality. A total of 60 biomarkers were identified, with 24 in two or more studies and 15 in five or more studies. There was variation in reported units, normal range, and cut off values. Meta-analysis was not possible due to study heterogeneity. Biomarkers currently recommended by the European Journal of Vascular and Endovascular Surgery, European Society for Trauma and Emergency Surgery 2016, and World Society of Emergency Surgery 2017 guidelines also had heterogeneous low quality data for use in the diagnosis of AMI. This systematic review demonstrates high heterogeneity and low quality of the available evidence on biomarkers for arterial occlusive AMI. No clinical conclusions can be drawn on a biomarker or combination of biomarkers for patients suspected of arterial occlusive AMI. Restraint is advised when rejecting or determining AMI solely based on biomarkers.


Qutrit-Inspired Fully Self-Supervised Shallow Quantum Learning Network for Brain Tumor Segmentation.
Classical self-supervised networks suffer from convergence problems and reduced segmentation accuracy due to forceful termination. Qubits or bilevel quantum bits often describe quantum neural network models. In this article, a novel self-supervised shallow learning network model exploiting the sophisticated three-level qutrit-inspired quantum information system, referred to as quantum fully self-supervised neural network (QFS-Net), is presented for automated segmentation of brain magnetic resonance (MR) images. The QFS-Net model comprises a trinity of a layered structure of qutrits interconnected through parametric Hadamard gates using an eight-connected second-order neighborhood-based topology. The nonlinear transformation of the qutrit states allows the underlying quantum neural network model to encode the quantum states, thereby enabling a faster self-organized counterpropagation of these states between the layers without supervision. The suggested QFS-Net model is tailored and extensively validated on the Cancer Imaging Archive (TCIA) dataset collected from the Nature repository. The experimental results are also compared with state-of-the-art supervised (U-Net and URes-Net architectures) and the self-supervised QIS-Net model and its classical counterpart. Results shed promising segmented outcomes in detecting tumors in terms of dice similarity and accuracy with minimum human intervention and computational resources. The proposed QFS-Net is also investigated on natural gray-scale images from the Berkeley segmentation dataset and yields promising outcomes in segmentation, thereby demonstrating the robustness of the QFS-Net model.


The Shu complex, which contains Rad51 paralogues, promotes DNA repair through inhibition of the Srs2 anti-recombinase.
The Shu complex, which contains RAD51 paralogues, is involved in the decision between homologous recombination and error-prone repair. We discovered a link to ribosomal DNA (rDNA) recombination when we found an interaction between one member of the Shu complex, SHU1, and UAF30, a component of the upstream activating factor complex (UAF), which regulates rDNA transcription. In the absence of Uaf30, rDNA copy number increases, and this increase depends on several functional subunits of the Shu complex. Furthermore, in the absence of Uaf30, we find that Shu1 and Srs2, an anti-recombinase DNA helicase with which the Shu complex physically interacts, act in the same pathway regulating rDNA recombination. In addition, Shu1 modulates Srs2 recruitment to both induced and spontaneous foci correlating with a decrease in Rad51 foci, demonstrating that the Shu complex is an important regulator of Srs2 activity. Last, we show that Shu1 regulation of Srs2 to double-strand breaks is not restricted to the rDNA, indicating a more general function for the Shu complex in the regulation of Srs2. We propose that the Shu complex shifts the balance of repair toward Rad51 filament stabilization by inhibiting the disassembly reaction of Srs2.


Treatment of Surgical Brain Injury by Immune Tolerance Induced by Peripheral Intravenous Injection of Biotargeting Nanoparticles Loaded With Brain Antigens.
Once excessive, neurological disorders associated with inflammatory conditions will inevitably cause secondary inflammatory damage to brain tissue. Immunosuppressive therapy can reduce the inflammatory state, but resulting infections can expose the patient to greater risk. Using specific immune tolerance organs or tissues from the body, brain antigen immune tolerance treatment can create a minimal immune response to the brain antigens that does not excessively affect the body's immunity. However, commonly used immune tolerance treatment approaches, such as those involving the nasal, gastrointestinal mucosa, thymus or liver portal vein injections, affect the clinical conversion of the therapy due to uncertain drug absorption, or inconvenient routes of administration. If hepatic portal intravenous injections of brain antigens could be replaced by normal peripheral venous infusion, the convenience of immune tolerance treatment could certainly be greatly increased. We attempted to encapsulate brain antigens with minimally immunogenic nanomaterials, to control the sizes of nanoparticles within the range of liver Kupffer cell phagocytosis and to coat the antigens with a coating material that had an affinity for liver cells. We injected these liver drug-loaded nanomaterials via peripheral intravenous injection. With the use of microparticles with liver characteristics, the brain antigens were transported into the liver out of the detection of immune armies in the blood. This approach has been demonstrated in rat models of surgical brain injury. It has been proven that the immune tolerance of brain antigens can be accomplished by peripheral intravenous infusion to achieve the effect of treating brain trauma after operations, which simplifies the clinical operation and could elicit substantial improvements in the future.


Insured yet vulnerable: out-of-pocket payments and India's poor.
Protecting households from high out-of-pocket (OOP) payments for health care is an important health system goal. High OOP payments can push households into poverty and make them vulnerable to catastrophic health expenditures. This study, based in India, aims to: (a) estimate OOP payments for health and related impoverishment across economic groups; (b) decompose OOP payments and relate the contribution of their components to impoverishment; and (c) examine how well recently introduced national insurance schemes meant for the poor are able to provide financial protection. The analysis of nationally representative data from India shows that 3.5% of the population fall below the poverty line and 5% households suffer catastrophic health expenditures. The poverty deepening impact of OOP payments was at a maximum in people below the poverty line in comparison with those above (Rs. 10.45 vs. Rs. 1.50, respectively). Medicines constitute the main share (72%) of total OOP payments. This share reaches 82% for outpatient care, compared with 42% for inpatient care. Removing OOP payments for inpatient care leads to a negligible fall in the poverty headcount ratio and poverty gap. However, if OOP payments for either medicines or outpatient care are removed then only 0.5% people fall into poverty due to spending on health. These findings suggest that insurance schemes which cover only hospital expenses, like those being rolled out nationally in India, will fail to adequately protect the poor against impoverishment due to spending on health. Further, issues related to identifying the poor and their targeting also constrain the scheme's impact. A broader coverage of benefits, to include medicines and outpatient care for the poor and near poor (i.e. those just above the poverty line), is necessary to achieve significant protection from impoverishment.


Randomised-controlled trial of a fibre supplement on the symptoms of irritable bowel syndrome.
The aim of this study was to assess the effect of coarse wheat bran on specific bowel function parameters and symptoms in patients with irritable bowel syndrome (IBS). A longitudinal, prospective, randomised, placebo-controlled trial was undertaken. The duration of treatment was eight to 12 weeks and this consisted of 10-20 g/day of coarse wheat bran or a low fibre placebo taken in addition to the normal diet. Twenty-eight outpatients fulfilling the Rome criteria for constipation-predominant IBS were recruited to the trial (14 in the treatment group; 14 in the placebo group). Twelve people completed the trial in the treatment group and ten in the placebo group. The main outcome measures included changes in symptoms recorded in a diary, changes in objective measurements of bowel function and subjective overall feelings of improvement. The bran group significantly increased their non-starch polysaccharide (NSP) intake over that of the placebo group (p < 0.05). Mean stool wet weight increased significantly more in the bran group than in the placebo group (p < 0.05), but other bowel function measurements and all recorded symptoms were not different. Many patients reported changes in bowel habit that were not reflected in the objective measurements. The addition of coarse wheat bran to the diet increased NSP ingestion and stool wet weight in this group of IBS patients, but no evidence was obtained that such treatment was of benefit to these patients, other than a placebo effect on symptoms.


Health-related quality of life in nephrology research and clinical practice.
Physical, psychosocial, and lifestyle disturbances, along with physical and emotional symptoms, have been shown to impact the health-related quality of life (HRQOL) of those dependent on renal replacement therapy. The value of HRQOL measurement as a tool to improve clinical care has been recognized by patients, clinical investigators, and health care providers. The potential importance of HRQOL assessment lies in the additional information it provides and the impact it has on the clinical decision-making process between a patient and a physician. There remain a multitude of challenges facing renal providers who wish to incorporate HRQOL measurement to improve patient care. These challenges include the clinician's understanding of the conceptual model of HRQOL, the quality of the scientific process that contributed to the current literature on HRQOL, a willingness of the clinician to incorporate HRQOL information into clinical practice, and the logistic difficulties of collecting and applying HRQOL data in a busy practice setting. Arguably, optimizing HRQOL may be the most substantial impact the health care team will have on the person with kidney failure. In order to implement HRQOL assessment at the point of care, providers may consider using computer adaptive testing and scoring algorithms using item response theory, which will allow adequate reliability for interpretation of change among individuals. Moreover, the effective assessment and interpretation of HRQOL will be aided by continued publication of norms, outcomes of randomized controlled trials, and continued experience of investigators and clinicians.


Direct visualization of organ of corti kinematics in a hemicochlea.
The basilar membrane in the mammalian cochlea vibrates when the cochlea receives a sound stimulus. This mechanical vibration is transduced into hair cell receptor potentials and thereafter encoded by action potentials in the auditory nerve. Knowledge of the mechanical transformation that converts basilar membrane vibration into hair cell stimulation has been limited, until recently, to hypothetical geometric models. Experimental observations are largely lacking to prove or disprove the validity of these models. We have developed a hemicochlea preparation to visualize the kinematics of the cochlear micromechanism. Direct mechanical drive of 1-2 Hz sinusoidal command was applied to the basilar membrane. Vibration patterns of the basilar membrane, inner and outer hair cells, supporting cells, and tectorial membrane have been recorded concurrently by means of a video optical flow technique. Basilar membrane vibration was driven in a direction transversal to its plane. However, the direction of the resulting vibration was found to be essentially radial at the level of the reticular lamina and cuticular plates of inner and outer hair cells. The tectorial membrane vibration was mainly transversal. The transmission ratio between cilia displacement of inner and outer hair cells and basilar membrane vibration is in the range of 0.7-1.1. These observations support, in part, the classical geometric models at low frequencies. However, there appears to be less tectorial membrane motion than predicted, and it is largely in the transversal direction.


Machine-learning phenotypic classification of bicuspid aortopathy.
Bicuspid aortic valves (BAV) are associated with incompletely characterized aortopathy. Our objectives were to identify distinct patterns of aortopathy using machine-learning methods and characterize their association with valve morphology and patient characteristics. We analyzed preoperative 3-dimensional computed tomography reconstructions for 656 patients with BAV undergoing ascending aorta surgery between January 2002 and January 2014. Unsupervised partitioning around medoids was used to cluster aortic dimensions. Group differences were identified using polytomous random forest analysis. Three distinct aneurysm phenotypes were identified: root (n = 83; 13%), with predominant dilatation at sinuses of Valsalva; ascending (n = 364; 55%), with supracoronary enlargement rarely extending past the brachiocephalic artery; and arch (n = 209; 32%), with aortic arch dilatation. The arch phenotype had the greatest association with right-noncoronary cusp fusion: 29%, versus 13% for ascending and 15% for root phenotypes (P < .0001). Severe valve regurgitation was most prevalent in root phenotype (57%), followed by ascending (34%) and arch phenotypes (25%; P < .0001). Aortic stenosis was most prevalent in arch phenotype (62%), followed by ascending (50%) and root phenotypes (28%; P < .0001). Patient age increased as the extent of aneurysm became more distal (root, 49 years; ascending, 53 years; arch, 57 years; P < .0001), and root phenotype was associated with greater male predominance compared with ascending and arch phenotypes (94%, 76%, and 70%, respectively; P < .0001). Phenotypes were visually recognizable with 94% accuracy. Three distinct phenotypes of bicuspid valve-associated aortopathy were identified using machine-learning methodology. Patient characteristics and valvular dysfunction vary by phenotype, suggesting that the location of aortic pathology may be related to the underlying pathophysiology of this disease.


Down-regulation of USP8 Inhibits Cholangiocarcinoma Cell Proliferation and Invasion.
Cholangiocarcinoma is the second most common primary hepatobiliary malignancy with high incidence and recurrence rate. Ubiquitin-specific protease 8 (USP8) is recently reported to be involved in tumor progression. Herein, we aimed to investigate the effects of USP8 on the growth and metastasis abilities of cholangiocarcinoma cells. The siRNA interference was used to knock down USP8 in cholangiocarcinoma cell lines QBC939 and RBE; Hucct-1 cells were transfected with pcDNA3.1-USP8 to up-regulate its expression. The effects of USP8 on cholangiocarcinoma were detected by cell function assays. We analyzed the expressions of USP8, Bcl2, Bax, cleaved caspase-3, cleaved caspase-9, Akt, p-Akt, Cyclin D1 and P70S6K by Western blot analysis. We demonstrated that knockdown of USP8 significantly inhibited the proliferation, migration and invasion of QBC939 and RBE cells in vitro, while USP8 overexpression showed significant promoting effects on Hucct-1 cells. Moreover, silencing of USP8 also promoted apoptosis in cholangiocarcinoma cells by regulating the Bcl-2/Bax axis and Caspase cascade; up-regulation of USP8 decreased apoptosis in Hucct-1 cells. Importantly, knockdown of USP8 inhibited activation of the Akt signaling pathway by decreasing the phosphorylation level of Akt and up-regulated p53 expression, while USP8 overexpression increased activation of the Akt signaling pathway in Hucct-1 cells. Further, IGF-1 could reverse the inhibitory effects of USP8 knockdown on the Akt signaling pathway and the proliferation of QBC939 and RBE cells. Taken together, our findings suggest that USP8 exerts an oncogenic role in the progression of cholangiocarcinoma and may be a potential therapeutic target for cholangiocarcinoma treatment.


Intense interval training in healthy older adults increases skeletal muscle [3H]ouabain-binding site content and elevates Na+,K+-ATPase α2 isoform abundance in Type II fibers.
Young adults typically adapt to intense exercise training with an increased skeletal muscle Na+,K+-ATPase (NKA) content, concomitant with reduced extracellular potassium concentration [K+] during exercise and enhanced exercise performance. Whether these changes with longitudinal training occur in older adults is unknown and was investigated here. Fifteen older adults (69.4 ± 3.5 years, mean ± SD) were randomized to either 12 weeks of intense interval training (4 × 4 min at 90-95% peak heart rate), 3 days/week (IIT, n = 8); or no exercise controls (n = 7). Before and after training, participants completed an incremental cycle ergometer exercise test until a rating of perceived exertion of 17 (very hard) on a 20-point scale was attained, with measures of antecubital venous [K+]v Participants underwent a resting muscle biopsy prior to and at 48-72 h following the final training session. After IIT, the peak exercise work rate (25%), oxygen uptake (16%) and heart rate (6%) were increased (P < 0.05). After IIT, the peak exercise plasma [K+]v tended to rise (P = 0.07), while the rise in plasma [K+]v relative to work performed (nmol.L-1J-1) was unchanged. Muscle NKA content increased by 11% after IIT (P < 0.05). Single fiber measurements, increased in NKA α2 isoform in Type II fibers after IIT (30%, P < 0.05), with no changes to the other isoforms in single fibers or homogenate. Thus, intense exercise training in older adults induced an upregulation of muscle NKA, with a fiber-specific increase in NKA α2 abundance in Type II fibers, coincident with increased muscle NKA content and enhanced exercise performance.


Development of a generalized theoretical model for the response of a phase/doppler measurement system to arbitrarily oriented fibers illuminated by gaussian beams.
We present a generalized theoretical model for the response of the phase/Doppler (P/D) measurement system to light scattered by cylindrical fibers. This theoretical model is valid for arbitrary fiber diameters and refractive indices, for Gaussian incident beams, and it accounts for arbitrary fiber orientations, fiber positions, and effects that are due to the two-dimensional receivers. The generalized P/D computer model (GPDCM) is the extension of an earlier study by the authors, combining past P/D simulation methodology with recent developments in modeling light scattering by tilted cylindrical fibers. A fortran computer program that implements the GPDCM theoretical development was written and tested against known P/D results and physical expectations. To illustrate the capabilities of the GPDCM, we present computation results, comparing the effect of fiber tilt, fiber position, and receiver aperture on the performance of P/D systems configured in backscatter and sidescatter arrangements. Calculations show that the effects of fiber tilt and position are most pronounced in the backscatter P/D arrangement, resulting in broadening of the measured phase distribution. The calculated mean phase shifts, however, were found to be essentially independent of the above factors. Computational results also showed that the effect of fiber tilt and position on phase-distribution measurements can be reduced through proper choice of aperture shape and by imposition of threshold criteria on measurable signal characteristics such as the amplitude ratio and visibilities. The GPDCM provides a computational tool that will be valuable in the design, optimization, and evaluation of P/D fiber measurement systems.


Trends in Morbidity and Mortality of Extremely Preterm Multiple Gestation Newborns.
To examine the risk of mortality and major morbidities in extremely preterm multiple gestation infants compared with singletons over time. This is a retrospective study of 15,402 infants born ≤27 weeks' gestation, admitted to NICUs in the Australian and New Zealand Neonatal Network from 1995 to 2009. Mortality and major morbidities were compared between singletons and multiples across three 5-year epochs. Extreme preterm multiples were more likely to have lower birth weight; higher maternal age; and higher rates of assisted conception, antenatal steroid use, and cesarean delivery compared with singletons. The mortality rate was significantly higher in multiples compared with singletons even as there was a trend of decreasing gestational-age stratified mortality in multiples over the time period investigated. The rates of major morbidities or composite adverse outcomes were not different between multiples and singletons across all epochs. The adjusted odds ratio (AOR) for mortality in multiples was significantly higher in multiples compared with singletons (AOR 1.20, 95% confidence interval [CI] 1.08-1.34). There were no differences in the adjusted odds for poor outcomes in multiples compared with singletons in the most recent epoch: mortality (AOR 1.00, 95% CI 0.84-1.19), major morbidity (0.95, 95% CI 0.81-1.10), and composite adverse outcome (0.96, 95% CI 0.83-1.11). Over the 15-year period, the odds for mortality in extremely preterm NICU infants of multiple gestation was significantly higher compared with singletons. The adjusted odds of poor outcomes in multiples were not significantly different from that of singletons in the most recent epoch.


Ureaplasma urealyticum causing persistent urethritis in a patient with hypogammaglobulinaemia.
Ureaplasma urealyticum organisms (ureaplasmas) were isolated in large numbers (up to 10(8) colour changing units (ccu)/ml) over a period of four years from the urethra of a man with hypogammaglobulinaemia and non-gonococcal urethritis. Elimination of Mycoplasma hominis by antibiotic treatment early in the course of the urethritis did not diminish the severity of his condition, which indicated that this mycoplasma was not a cause. Courses of treatment with tetracyclines, spectinomycin, erythromycin, rosaramicin, and clindamycin on each occasion reduced the numbers of ureaplasma isolated from the urethra and the severity of disease. The organisms were not eliminated, however, sometimes due to the development of antibiotic resistance, and the urethritis recurred. Though netilmicin was not particularly effective in vitro, it was effective clinically, the disease resolving and the organisms disappearing for five months. Recurrence of urethritis, accompanied by epididymitis, was associated this time with the recovery of a different (tetracycline sensitive) ureaplasma strain; the urethritis and epididymitis were treated successfully with a combination of netilmicin and doxycycline. The administration of ureaplasma antiserum did not seem to be instrumental in eradicating the ureaplasmas. The various antibiotics had a greater influence on the mycoplasmas in the urethra than on those in the throat and joints, perhaps because the antibiotics were concentrated in the urogenital tract. The close association between the occurrence of urethritis and the ureaplasmas suggests strongly that they were responsible for it.


Consolidation radiotherapy to bulky or semibulky lesions in the management of stage III-IV diffuse large B cell lymphomas.
To assess the impact on survival of consolidation radiotherapy to bulky or semibulky lesions in patients with advanced diffuse large B cell lymphoma (DLCL) in complete remission after primary chemotherapy. Ninety-four patients with stage III-IV DLCL and bulky ( > or =10 cm) or semibulky lesions (6-9 cm) in complete remission after primary chemotherapy were reviewed. Forty patients received consolidation radiotherapy to bulky (n = 20) or semibulky lesions (n = 20), while 54 (18 with bulky disease) did not. Twenty-eight patients were irradiated to the involved field and 12 to the extended field with a dose of 30-46 Gy. In patients with bulky disease, consolidation radiotherapy prevented relapses involving exclusively the bulky area, prolonged time to relapse (TTR) (median 41+ vs. 18 months; p = 0.05) and improved 5-year overall survival (OS) (73 vs. 57%; p = 0.05). Consolidation radiotherapy reduced relapses within the semibulky area, prolonged TTR (median 26+ vs. 20 months; p = 0.01) and improved 5-year OS (59 vs. 41%; p = 0.09) also in patients with semibulky lesions. Multivariate analyses confirmed the independent association between consolidation radiotherapy and survival, and showed that a dose > or =36 Gy was related to a longer OS, while the extension of the radiotherapy field did not modify outcome. No treatment-related deaths were observed. Four patients developed a second malignancy, none of whom had undergone consolidation radiotherapy. Consolidation radiotherapy to bulky or semibulky lesions significantly improved the outcome in patients with advanced DLCL in complete remission after primary chemotherapy. Involved-field irradiation with 36-45 Gy made a prolonged disease control possible without either lethal toxicity or a higher incidence of second malignancies.


Metacognitive therapy self-help for anxiety-depression: Single-blind randomized feasibility trial in cardiovascular disease.
One in three cardiovascular disease (CVD) patients experience significant anxiety and depression. Current psychological interventions have limited efficacy in reducing such symptoms and are offered as a face-to-face intervention that may be a barrier to accessing treatment. We evaluated the feasibility and acceptability of delivering assisted home-based self-help metacognitive therapy (home-MCT) to cardiac rehabilitation (CR) patients experiencing anxiety and depression. One hundred eight CR patients with elevated anxiety and/or depression were recruited to a single-blind randomized feasibility trial across two United Kingdom National Health Service Trusts and were randomized to usual CR or usual CR plus home-MCT. The feasibility and acceptability of adding home-MCT to CR was based on credibility or expectancy ratings, recruitment rate, drop-outs, number of CR and home-MCT modules completed, and ability of outcome measures to discriminate between patients. The study was used to refine the sample size estimate for a full-scale trial. The quality of telephone support calls delivered by CR staff trained in MCT was assessed. Home-MCT was found to be feasible and acceptable for the current CR patients with anxiety and depression. Recruitment and retention of participants was high, and attendance at CR was similar for both groups. Completion of home-MCT was high, but the quality of telephone support calls delivered was lower than expected. Home-MCT was acceptable and feasible to deliver to CR patients experiencing anxiety and depression, and the feasibility of conducting a full-scale trial of the intervention was established. Home-MCT may provide additional treatment options for cardiac patients experiencing psychological distress. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer.
Endoscopic ultrasonography is frequently used to locally stage esophageal cancer, but few studies exist to validate its accuracy for lymph node metastases. Our objective was to compare endoscopic ultrasonography with video-assisted thoracoscopic and laparoscopic staging in evaluating lymph node metastases in esophageal cancer. Twenty-six patients with potentially resectable esophageal cancer were identified by conventional imaging. Endoscopic ultrasonography was performed followed by laparoscopic and thoracoscopic staging, and locoregional staging was compared. In eight patients endoscopic ultrasonography indicated N0 disease, but laparoscopy and thoracoscopy documented N1 disease in six. In five of 26 (19%) obstruction prevented endoscopic ultrasonography; three had N1 by laparoscopy and thoracoscopy. Thirteen patients had N1 disease according to endoscopic ultrasonography, and 12 of 13 (92%) had N1 disease by laparoscopy and thoracoscopy. The sensitivity and specificity of endoscopic ultrasonography for nodal evaluation were 65% and 66%, respectively. Sensitivity decreased to 44% for lymph node metastases less than 1 cm. No instances of T4 disease were found by surgical staging when endoscopic ultrasonography indicated T3 disease. Endoscopic ultrasonography revealed no distant metastases in any patient, but in four of 26 (15%) laparoscopy identified liver metastases. The accuracy of endoscopic ultrasonography in the diagnosis of lymph node metastases in esophageal cancer was 65% and only 44% for lymph node metastases less than 1 cm diameter. Laparoscopy and thoracoscopy improved the accuracy of staging lymph node metastases in esophageal cancer and had the advantage of evaluating the thoracic and abdominal cavities for metastases.


Dimethyl sulfoxide protects tightly coupled mitochondria from freezing damage.
Dimethyl sulfoxide prevented loss of respiratory control and decrease in efficiency of oxidative phosphorylation when plant mitochondria were stored in liquid nitrogen. Respiration was severely inhibited and was not stimulated by adenosine diphosphate when mitochondria were frozen in liquid nitrogen without dimethyl sulfoxide. Thus, isolated mitochondria provide a model system for the study of the effects of freezing on biological membranes and of the prevention, by dimethyl sulfoxide, of freezing damage.


alpha7 receptor-selective agonists and modes of alpha7 receptor activation.
The alpha7-selective agonists 3-(2, 4-dimethoxybenzylidene)-anabaseine (GTS-21), also known as DMXB, and 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21) produce a variety of behavioral and cytoprotective effects that may be related to the activation of either large transient currents at high concentrations or small sustained currents at lower agonist concentrations. We are using acutely dissociated hypothalamic neurons, which express a central nervous system (CNS) alpha7-type receptor, to test a model for the concentration-dependent desensitization of alpha7-mediated responses. Our results confirm that 4OH-GTS-21 is a potent activator of neuronal alpha7 nicotinic-acetylcholine receptor. The rapid application of agonist leads to a brief period of maximal receptor-activation followed by desensitization. Rise rates, decay rates, and the degree to which current was desensitized were all concentration-dependent. Following the initial peak response to a 300-microM 4OH-GTS-21 application, current is reduced to baseline values within about 100 ms. Application of 30 microM 4OH-GTS-21 produced both a transient peak current and a sustained current that decayed only slowly after the removal of agonist. In the case of a 300-microM 4OH-GTS-21 application, after agonist was removed, we saw a rebound response up to the level of the 30-microM sustained current. The data, therefore, suggest that a sufficient level of agonist occupation can be retained on the receptor to promote activation for up to several hundred milliseconds.


Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.
In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied. Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions. One region, on 16p13, was significant at the genome-wide p <.05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p </=.01). Conditional analysis assuming epistasis identified a significant increase in linkage at four regions. Families linked to 6q24 showed a significant increase in nonparametric logarithms of the odds (NPL) scores at 5q11 and 7q21. Epistasis also was observed between 20p12 and 13q21, and 16p13 and 9q21. The findings are presented in rank order of nominal significance. Several of these regions have been previously implicated in independent studies of either bipolar disorder or schizophrenia. The strongest finding is at 16p13 at D16S748 with an NPL of 3.3, there is evidence of epistasis between this locus and 9q21. Application of conditional analyses is potentially useful in larger sample collections to identify susceptibility genes of modest influence that may not be identified in a genome-wide scan aimed to identify single gene effects.


Addition of a second opioid may improve opioid response in cancer pain: preliminary data.
Recent experimental data suggest a possible use of an opioid combination to improve analgesia. In cancer patients, a rapid opioid escalation due to either worsening of the pain condition or the development of tolerance is a critical phase, as this condition is associated with a negative prognosis. The aim of this study was to assess the effects of adding a second opioid at low doses in patients with a poor analgesic benefit after dose escalation. Fourteen patients receiving strong opioids who had increased their dosage more than 100% in the last week unsuccessfully were randomly chosen to add a second opioid to the first using an initial equivalent dosage of 20% of the previous therapy. The dose of the second opioid was then changed according to the clinical situation to obtain an acceptable pain control with minimal adverse effects. Pain and symptoms associated with opioid therapy were assessed, and an opioid escalation index (OEI) was calculated at weekly intervals. OEI significantly decreased after adding the second opioid, and this trend was also maintained for the following weeks. Similarly, pain intensity was significantly improved and maintained at acceptable levels for the following weeks. The second opioid did not induce significant opioid-related adverse effects. The opioid combination was able to break opioid escalation in patients with pain syndromes with a poor response to the previous opioid. It allowed for a regaining of analgesia, regardless of the opioid combination used. These preliminary observations should be confirmed in further studies.


Melanoma Reporting Practices of United States Dermatologists.
Accuracy of US cancer statistics depends on physicians' knowledge of and adherence to reporting mandates. Significant knowledge and practice gaps have been documented in regards to melanoma reporting requirements. To determine whether the gaps in dermatologists' knowledge and practice of melanoma reporting persist. The authors performed a survey of US dermatologists attending a national conference. The proportion aware of the melanoma reporting mandate and the proportion who routinely report newly diagnosed cases were calculated. Ninety-one percent (158/174) of those sampled completed the survey. Forty-nine percent correctly identified melanoma as being a disease of mandated reporting. Only 34% reported newly diagnosed cases to their state registry. Dermatologists seeing low melanoma volumes were less likely to routinely report newly diagnosed cases to registries than those seeing high volumes (22.9% vs 45.4%, p = .004). Those in practice for ≤10 years were less likely to be aware of the mandate than those in practice longer (32.6% vs 57.0%, p = .006). Most dermatologists remain unaware of melanoma reporting requirements. Resultant underestimates of the true incidence of melanoma could have resource allocation implications. Interventions aimed at improving knowledge of the mandate should focus on younger clinicians and those with lower melanoma case volumes.


An 802.11 n wireless local area network transmission scheme for wireless telemedicine applications.
In this paper, an 802.11 n transmission scheme is proposed for wireless telemedicine applications. IEEE 802.11n standards, a power assignment strategy, space-time block coding (STBC), and an object composition Petri net (OCPN) model are adopted. With the proposed wireless system, G.729 audio bit streams, Joint Photographic Experts Group 2000 (JPEG 2000) clinical images, and Moving Picture Experts Group 4 (MPEG-4) video bit streams achieve a transmission bit error rate (BER) of 10-7, 10-4, and 103 simultaneously. The proposed system meets the requirements prescribed for wireless telemedicine applications. An essential feature of this proposed transmission scheme is that clinical information that requires a high quality of service (QoS) is transmitted at a high power transmission rate with significant error protection. For maximizing resource utilization and minimizing the total transmission power, STBC and adaptive modulation techniques are used in the proposed 802.11 n wireless telemedicine system. Further, low power, direct mapping (DM), low-error protection scheme, and high-level modulation are adopted for messages that can tolerate a high BER. With the proposed transmission scheme, the required reliability of communication can be achieved. Our simulation results have shown that the proposed 802.11 n transmission scheme can be used for developing effective wireless telemedicine systems.


Blossom smart expander technology for tissue expander-based breast reconstruction facilitates shorter duration to full expansion: A pilot study.
This study evaluated the Blossom system, an innovative self-filling, rate-controlled, pressure-responsive saline tissue expander (TE) system. We investigated the feasibility of utilizing this technology to facilitate implant-based and combined flap with implant-based breast reconstruction in comparison to conventional tissue expansion. In this prospective, single-center, single-surgeon pilot study, participants underwent either implant-based breast reconstruction or a combination of autologous flap and implantbased breast reconstruction. Outcome measures included time to full expansion, complications, total expansion volume, and pain scores. Fourteen patients (TEs; n=22), were included in this study. The mean time to full expansion was 13.4 days (standard error of the mean [SEM], 1.3 days) in the combination group and 11.7 days (SEM, 1.4 days) in the implant group (P=0.78). The overall major complication rate was 4.5% (n=1). No statistically significant differences were found in the complication rate between the combination group and the implant group. The maximum patient-reported pain scores during the expansion process were low, but were significantly higher in the combination group (mean, 2.00±0.09) than in the implant group (mean, 0.29±0.25; P=0.005). The reported average duration for conventional subcutaneous TE expansion is 79.4 days, but this pilot study using the Blossom system achieved an average expansion duration of less than 14 days in both groups. The Blossom system may accommodate single-stage breast reconstruction. The overall complication rate of this study was 4.5%, which is promising compared to the reported complication rates of two-stage breast reconstruction with TEs (20%-45%).


Iloprost downregulates expression of adhesion molecules and reduces renal injury induced by abdominal aortic ischemia-reperfusion.
The aim of this study was to examine the effect of iloprost in renal injury induced by abdominal aortic ischemia-reperfusion (IR) and how it can modulate the expression of adhesion molecules during this effect. Twenty-four Wistar-Albino rats were randomized into three groups (n=8) as follows: control (sham laparotomy), aortic IR (120 min ischemia and 120 min reperfusion), and aortic IR + iloprost (0.45 microg/kg/hr intravenous infusion during 120 min reperfusion). Blood and renal tissue samples were obtained for biochemical analysis. A histological evaluation with both hematoxylin-eosin staining and immunostaining was also done. Biochemical analyses showed that aortic IR significantly increased (p<0.05 vs. control) whereas iloprost significantly decreased (p<0.05 vs. aortic IR) plasma levels of malondialdehyde, P-selectin, intercellular adhesion molecule-1 (ICAM-I), and tissue levels of malondialdehyde and catalase. Histological evaluation with immunostaining showed that aortic IR significantly increased (p<0.05 vs. control) whereas iloprost significantly decreased (p<0.05 vs. aortic IR) the immunoreactivity of P-selectin, tumor necrosis factor-alpha, CD11b, CD18, and ICAM-1. Hematoxylin-eosin staining showed that iloprost also attenuated the morphological changes associated with aortic IR. The results of this study show that iloprost reduces renal injury induced by aortic IR in rats and downregulates expression of adhesion molecules at both the local and systemic levels after aortic IR during this protective effect.


Diagnosis and treatment of iron deficiency anemia in patients with inflammatory bowel disease and gastrointestinal bleeding: iron deficiency anemia working group consensus report.
Iron deficiency (ID) and iron deficiency anemia (IDA) are important signs of gastrointestinal (GI) hemorrhage. Therefore, the evaluation of the GI tract should be a part of the diagnostic protocol in patients with IDA. GI hemorrhage is not a disease but a symptom, which might have different underlying causes. ID and IDA have significant negative impacts on the life quality and work ability, and they may lead to frequent hospitalization, delay of discharge, and increased healthcare costs. Therefore, an optimal management of the disease causing GI hemorrhage should include iron replacement therapy, along with the treatment of the underlying condition. IDA in inflammatory bowel disease (IBD) has received particular attention owing to its high prevalence, probably due to a number of other factors such as chronic hemorrhage, reduced dietary iron intake, and impaired absorption of iron. Historically, in IBD and in patients with GI hemorrhage, the diagnosis and management of IDA have been suboptimal. Options for iron replacement include oral and intravenous (IV) iron supplementation. Oral iron supplementation frequently results in GI side effects, and theoretically, it may exacerbate IBD activity; therefore, IV iron supplementation is usually considered in patients not responding to or not complying with oral iron supplementation or patients having low hemoglobin concentration and requiring prompt iron repletion. The aim of this report was to review the diagnostic and therapeutic considerations of IDA in IBD and GI hemorrhage with a multidisciplinary group of experts and to formulate necessary practical recommendations.


Voltage-clamp analysis of sodium channels in wild-type and mutant Drosophila neurons.
In this study we describe a preparation in which we examined directly, using tight-seal whole-cell recording, sodium currents from embryonic Drosophila neurons maintained in culture. Sodium currents were expressed in approximately 65% of the neurons prepared from wild-type Drosophila embryos when examined at room temperature, 24 hr after plating. While current density was low, other features of the sodium current in wild-type neurons, including the voltage sensitivity, steady-state inactivation, macroscopic time course, and TTX sensitivity were similar to those found in other excitable cells. Physiological and biochemical evidence has led to the suggestion that mutations in the nap, seizure, and tip-E loci of Drosophila may affect voltage-dependent sodium channels. There was no significant difference in the percentage of neurons expressing sodium currents in cultures prepared from embryos with mutations at the nap, sei or tip-E loci compared with wild-type cultures. Sodium currents recorded from napts appeared similar in all of the properties examined to those in wild-type cells. However, neuronal sodium current density was 40-60% lower in cultures prepared from both tip-E and seits1 embryos. The voltage dependence and gating properties of these sodium channels, as well as the TTX sensitivity, appear similar to wild type. These results indicate that both the tip-E and sei loci are important in regulation of sodium current density in embryonic neurons.


Venous thromboembolism prophylaxis for the medical patient: where do we stand?
Acutely ill medical patients are at moderate to high risk of venous thromboembolism: ~10 to 30% of general medical patients may develop deep vein thrombosis or pulmonary embolism, and the latter is a leading contributor to deaths in hospital. Medical conditions associated with a high risk of venous thromboembolism include cardiac disease, cancer, respiratory disease, inflammatory bowel disease, and infectious diseases. Predisposing risk factors in medical patients include a history of venous thromboembolism, history of malignancy, complicating infections, increasing age, thrombophilia, prolonged immobility, and obesity. Heparins, including unfractionated and low molecular weight, as well as fondaparinux have been shown to be effective agents in prevention of VTE in this setting. However, it has not yet been possible to demonstrate a significant effect on mortality rates in this population. In medical patients, unfractionated heparin has a higher rate of bleeding complications than low molecular weight heparin. There is no evidence for the use of aspirin, warfarin, or mechanical methods. We recommend either low molecular weight heparin or fondaparinux as safe and effective agents in the thromboprophylaxis of medical patients.


Identification of the rhizobium strains in pea root nodules using genetic markers.
Pea plants were inoculated jointly with pairs of genetically marked strains of Rhizobium leguminosarum. Out of 297 modules examined 56 contained both inoculant strains. The ratios of the strains in the inoculum did not affect the frequencies of mixed nodules. Generally one of the strains consistently occupied the majority of the nodules and ithe mixed nodules comprised the majority of bacteria. Transfer of the P-group R factor, RP4, between certain strains of Rhizobium within mixed nodules was detected. In some cases the non-parental progeny comprised 10% of the rhizobia isolated from such nodules.


Adherence to face-down and non-supine positioning after macular hole surgery.
This study aimed to investigate patient adherence to face-down positioning (FDP) and non-supine positioning (NSP) following vitrectomy with gas tamponade for treating macular holes (MHs). Nursing records of 92 patients who underwent vitrectomy with gas tamponade for small-diameter (diameter < 400 μm) MHs during April 2016-June 2017 were examined. Forty-seven and 45 patients were instructed to maintain FDP and NSP (FDP and NSP groups), respectively. Patient adherence was evaluated seven times a day for 3 days, and the adherence rate was calculated. The mean adherence rate was significantly higher in the NSP group (99.3% ± 2.7%) than in the FDP group (93.7% ± 13.3%; P < 0.001, Mann-Whitney U test). Forty-one patients (91.1%) in the NSP group had an adherence rate of 100%, which was significantly higher than that in the 24 patients in the FDP group (51.1%; P < 0.001, chi-squared test). No statistically significant difference was observed between the patients in the two groups regarding sex, age, MH diameter, and pre- and postoperative visual acuities. MH closure was achieved in all patients. Almost half of the patients in the FDP group did not obtain 100% adherence rate, suggesting that patient adherence was largely compromised. Patient adherence was better in the NSP group as patient compliance to NSP was better, however, 8.9% of patients were found in face-up positioning at least once. Incompleteness of patient adherence was common, although to differing degrees.


Manganese-resistant mutants of Escherichia coli: physiological and genetic studies.
Manganese is growth inhibitory for Escherichia coli. The manganese concentration required for inhibition is dependent upon the magnesium concentration of the medium. Mutants have been isolated which are partially resistant to manganese inhibition in both liquid and solid media. From conjugation experiments, the genetic locus for manganese-resistance, mng, appears to be between 34 and 37 min on the E. coli genetic map. Experiments with radioactive (28)Mg lead to the tentative conclusion that the mng mutants are altered in the inhibition constant for manganese as a competitive inhibitor for the mangnesium accumulation system. Once high manganese enters the cells, it displaces internal magnesium and leads to a net cellular loss and hence growth inhibition. The mng mutants are somewhat less subject to manganese-induced magnesium loss under comparable conditions than are manganese-sensitive wild-type cells.


Neck and shoulder pain after laminoplasty. A noticeable complication.
The authors retrospectively analyzed the prevalence and features of neck and shoulder pain (axial symptoms) after anterior interbody fusion and laminoplasty in patients with cervical spondylotic myelopathy. To reveal the difference in prevalence of postoperative axial symptoms between anterior interbody fusion and laminoplasty and to clarify the pathogenesis of axial symptoms after laminoplasty. Outcome of the cervical surgery is evaluated on neurologic status alone; axial symptoms after laminoplasty rarely have been investigated. Such symptoms, however, are often severe enough to interfere with a person's daily activity. Ninety-eight patients had surgery for their disability secondary to cervical spondylotic myelopathy. Of those patients, 72 had laminoplasty, and 26 had anterior interbody fusion. The presence or absence of axial symptoms was investigated before and after surgery. The duration, severity, and laterality of symptoms were also recorded. The prevalence of postoperative axial symptoms was significantly higher after laminoplasty than after anterior fusion (60% vs. 19%; P < 0.05). In 18 patients (25%) from the laminoplasty group, the chief complaints after surgery were related to axial symptoms for more than 3 months, whereas in the anterior fusion group, no patient reported having such severe pain after surgery. The prevalence and severity of axial symptoms after laminoplasty proved to be higher and more serious than has been believed. Such symptoms should be considered in the evaluation of the outcome of cervical spinal surgery.


Metastatic non-small cell lung cancer: a benchmark for quality end-of-life cancer care?
To investigate the quality of end-of-life care for patients with metastatic non-small cell lung cancer (NSCLC). Retrospective cohort study of patients from first hospitalisation for metastatic disease until death, using hospital, emergency department and death registration data from Victoria, Australia, between 1 July 2003 and 30 June 2010. Emergency department and hospital use; aggressiveness of care including intensive care and chemotherapy in last 30 days; palliative and supportive care provision; and place of death. Metastatic NSCLC patients underwent limited aggressive treatment such as intensive care (5%) and chemotherapy (< 1%) at the end of life; however, high numbers died in acute hospitals (42%) and 61% had a length of stay of greater than 14 days in the last month of life. Although 62% were referred to palliative care services, this occurred late in the illness. In a logistic regression model adjusted for year of metastasis, age, sex, metastatic site and survival, the odds ratio (OR) of dying in an acute hospital bed compared with death at home or in a hospice unit decreased with receipt of palliative care (OR, 0.25; 95% CI, 0.21-0.30) and multimodality supportive care (OR, 0.65; 95% CI, 0.56-0.75). Because early palliative care for patients with metastatic NSCLC is recommended, we propose that this group be considered a benchmark of quality end-of-life care. Future work is required to determine appropriate quality-of-care targets in this and other cancer patient cohorts, with particular focus on the timeliness of palliative care engagement.


Incorporation of mammalian metabolism into mutagenicity testing.
In the 1950's and 1960's it became obvious that many chemicals in daily use were mutagenic or carcinogenic, but there seemed to be little relation between the two activities. As scientists were debating the cause of this discrepancy, it was hypothesized that mammalian metabolism could form highly reactive intermediates from rather innocuous chemicals and that these intermediates could react with DNA and were mutagenic. This commentary presents the historical development of metabolic activation in mutagenicity tests, beginning with Udenfriend's hydroxylation system, which mimics aspects of mammalian metabolism in a purely chemical mixture, and extending through procedures that moved closer and closer to incorporating actual mammalian metabolism into the test systems. The stages include microsomal activation systems, host-mediated assays, incorporation of human P450 genes into the target cells or organisms, and detecting mutations in single cells in vivo. A recent development in this progression is the insertion of recoverable vectors containing mutational targets into the mammalian genome. Since the target genes of transgenic assays are in the genome, they are not only exposed to active metabolites, but they also undergo the same repair processes as endogenous genes of the mammalian genome.


Pediatric invasive Haemophilus influenzae infections in Israel in the era of Haemophilus influenzae type b vaccine: a nationwide prospective study.
The conjugated Haemophilus influenzae (Hi) type b vaccine caused a marked decrease in invasive Hi disease rates. Nonencapsulated Hi infection now constitutes most invasive Hi morbidity and mortality. This study examines invasive Hi infection incidence in Israel in the postvaccine era years, 2003-2012, and characterizes the epidemiology, clinical diagnosis and case fatality rates of invasive Hi disease in children <15 years of age. An ongoing, nationwide prospective surveillance program for invasive Hi infections in Israel. Epidemiologic and clinical data were collected. Diagnoses were classified as meningitis, pneumonia, bacteremia/sepsis and other clinical foci. Overall, 389 cases of invasive Hi infections were identified; 242 (62%) nontypable Hi (NTHi), 103 (26%) Hi type b (Hib) and 41 (11%) encapsulated non-b Hi (enbHi). Children <1 year of age accounted for 51% of the overall disease. Invasive Hi disease incidence in children <15 years of age was stable with a mean annual incidence (per 100,000) of 2.0 ± 0.4. The highest incidence of invasive Hi infections was among infants <1 year with rates of 6.2, 4.9, 1.6 and 12.7 for NTHi, Hib, enbHi and total Hi, respectively. The clinical diagnoses of NTHi and enbHi were similar, but differed from Hib with the former presenting mostly as isolated sepsis/bacteremia and the latter primarily as meningitis. Among children with invasive Hib infection, 40% were classified as vaccine failure. In the post-Hib vaccination era, invasive Hi morbidity and mortality are largely attributed to NTHi sepsis. Still, with the changing epidemiology of invasive Hi, continued surveillance of all Hi strains is justified.


Microscopic insights into methane activation and related processes on Pt/ceria model catalysts.
Ceria-based supported noble-metal catalysts release oxygen, which may help to reduce the formation of carbonaceous residues, for example during hydrocarbon reforming. To gain insight into the microscopic origins of these effects, a model study is performed under ultrahigh-vacuum conditions using single-crystal-based supported model catalysts. The model systems are based on ordered CeO(2)(111) films on Cu(111), on which Pt nanoparticles are grown by physical vapor deposition. The growth and structure of the surfaces are characterized by means of scanning tunneling microscopy, and the electronic structure and reactivity are probed by X-ray photoelectron spectroscopy. Specifically, it is shown that the fully oxidized CeO(2) thin films undergo slight reduction upon Pt deposition (CeO(1.99)). This effect is enhanced upon annealing (CeO(1.96)), thus indicating facile oxygen release and reverse spillover. The model system is structurally stable up to temperatures exceeding 700 K. The activation of methane is investigated using high-kinetic-energy CH(4) (0.83 eV), generated by a supersonic molecular beam. It is shown that dehydrogenation occurs under rapid formation of CH or C species without detectable amounts of CH(3) being formed, even at low temperatures (100 K). The released hydrogen spills over to the CeO(2) support, which leads to the formation of OH groups. At 200 K and above, the OH groups start to decompose leaving additional Ce(3+) centers behind (CeO(1.97-1.94)). At up to 700 K, carbon deposits are quantitatively removed by reaction with oxygen, which is supplied by reverse spillover from the CeO(2) film, thus leading to substantial reduction of the support (approximately CeO(1.90-1.85)).


Drug2ways: Reasoning over causal paths in biological networks for drug discovery.
Elucidating the causal mechanisms responsible for disease can reveal potential therapeutic targets for pharmacological intervention and, accordingly, guide drug repositioning and discovery. In essence, the topology of a network can reveal the impact a drug candidate may have on a given biological state, leading the way for enhanced disease characterization and the design of advanced therapies. Network-based approaches, in particular, are highly suited for these purposes as they hold the capacity to identify the molecular mechanisms underlying disease. Here, we present drug2ways, a novel methodology that leverages multimodal causal networks for predicting drug candidates. Drug2ways implements an efficient algorithm which reasons over causal paths in large-scale biological networks to propose drug candidates for a given disease. We validate our approach using clinical trial information and demonstrate how drug2ways can be used for multiple applications to identify: i) single-target drug candidates, ii) candidates with polypharmacological properties that can optimize multiple targets, and iii) candidates for combination therapy. Finally, we make drug2ways available to the scientific community as a Python package that enables conducting these applications on multiple standard network formats.


Immunization, Antibiotic Use, and Pneumococcal Colonization Over a 15-Year Period.
Rates of invasive pneumococcal disease have declined since widespread introduction of pneumococcal conjugate vaccines (PCVs) in the United States. We evaluated the impact of immunization status and recent antibiotic use on an individual child's risk of colonization. This study extends previously reported data from children <7 years of age seen for well child or acute care visits in Massachusetts communities. Nasopharyngeal swabs were collected during 6 surveillance seasons from 2000 to 2014. Parent surveys and medical record reviews confirmed immunization status and recent antibiotic use. We estimated the proportions of children colonized with PCV7-included, additional PCV13-included, and non-PCV13 serotypes. Risk factors for colonization with additional PCV13-included and non-PCV13 serotypes were assessed by using generalized linear mixed models adjusted for clustering by community. Among 6537 children, 19A emerged as the predominant serotype in 2004, with substantial reductions in 2014. Among non-PCV serotypes, 15B/C, 35B, 23B, 11A, and 23A were most common in 2014. We observed greater odds for both additional PCV13 and non-PCV13 colonization in younger children, those with more child care exposure, and those with a concomitant respiratory tract infection. Adjusted odds for additional PCV13 colonization was lower (odds ratio 0.48 [95% confidence interval 0.31-0.75]) among children up-to-date for PCV13 vaccines. Recent antibiotic use was associated with higher odds of additional PCV13 colonization but substantially lower odds of non-PCV13 colonization. Despite the success of pneumococcal vaccines in reducing colonization and disease due to targeted serotypes, ongoing community-based surveillance will be critical to evaluate the impact of interventions on pneumococcal colonization and disease.


The Subchalcogenides Ir2In8Q (Q = S, Se, Te): Dirac Semimetal Candidates with Re-entrant Structural Modulation.
Subchalcogenides are uncommon compounds where the metal atoms are in unusually low formal oxidation states. They bridge the gap between intermetallics and semiconductors and can have unexpected structures and properties because of the exotic nature of their chemical bonding as they contain both metal-metal and metal-main group (e.g., halide, chalcogenide) interactions. Finding new members of this class of materials presents synthetic challenges as attempts to make them often result in phase separation into binary compounds. We overcome this difficulty by utilizing indium as a metal flux to synthesize large (millimeter scale) single crystals of novel subchalcogenide materials. Herein, we report two new compounds Ir2In8Q (Q = Se, Te) and compare their structural and electrical properties to the previously reported Ir2In8S analogue. Ir2In8Se and Ir2In8Te crystallize in the P42/mnm space group and are isostructural to Ir2In8S, but also have commensurately modulated (with q vectors q = 1/6a* + 1/6b* and q = 1/10a* + 1/10b* for Ir2In8Se and Ir2In8Te, respectively) low-temperature phase transitions, where the chalcogenide anions in the channels experience a distortion in the form of In-Q bond alternation along the ab plane. Both compounds display re-entrant structural behavior, where the supercells appear on cooling but revert to the original subcell below 100 K, suggesting competing structural and electronic interactions dictate the overall structure. Notably, these materials are topological semimetal candidates with symmetry-protected Dirac crossings near the Fermi level and exhibit high electron mobilities (∼1500 cm2 V-1 s-1 at 1.8 K) and moderate carrier concentrations (∼1020 cm-3) from charge transport measurements. This work highlights metal flux as a synthetic route to high quality single crystals of novel intermetallic subchalcogenides with Dirac semimetal behavior.


Interactions with glutathione S-transferases of porphyrins used in photodynamic therapy and naturally occurring porphyrins.
Several naturally occurring porphyrins and porphyrins used in photodynamic therapy inhibit glutathione S-transferase isoenzymes either purified from rat liver or lung or in cytosol from normal and from cancerous (Morris 7288C hepatoma) liver. Although differences occur in the type and amount of transferases in normal and cancerous liver and in the liver of rats bearing an extrahepatic tumour, these enzymes are potential binding sites for porphyrins. Porphyrin structure is an important factor in determining the affinity of binding, as shown by the relative inhibitory effectiveness. Of the dicarboxylic porphyrins in the mixture used clinically, OO'-diacetylhaematoporphyrin and monohydroxyethylmonovinyldeuteroporphyrin are more effective inhibitors than haematoporphyrin and protoporphyrin IX. Of the naturally occurring porphyrins the order of effectiveness is protoporphyrin IX (dicarboxylic) greater than coproporphyrin (tetracarboxylic) greater than uroporphyrin (octacarboxylic) and type I greater than type III isomers of both uroporphyrin and coproporphyrin, and the synthetic tetra-meso-phenylporphinetetrasulphonate is a better inhibitor (apparent Ki = 250 nM) than coproporphyrin, which contains a comparable number of negative charges. In addition, iron-porphyrin chelates are more effective inhibitors of the transferases, with 25-fold decrease in Ki value, than the free porphyrins. These results indicate that one means whereby porphyrins accumulate in tissues is the occupation of intracellular binding sites, such as the transferases. Since porphyrins inhibit the activity of these important detoxifying enzymes, there will be metabolic consequences to the cell.