Avoiding the ingestion of cytotoxic concentrations of ethanol may reduce the risk of cancer associated with alcohol consumption.
Alcohol consumption is a known risk factor for cancer. Almost 6% of all cancers worldwide are attributable to alcohol use. Approximately half of them occur in tissues highly exposed to ethanol, such as the oral cavity, pharynx, upper larynx and esophagus. However, since ethanol is not mutagenic and the mutagenic metabolite of ethanol (acetaldehyde) is mainly produced in the liver, it is unclear why alcohol consumption preferentially exerts a local carcinogenic effect. Recent findings indicate that the risk of cancer in a tissue is strongly correlated with the number of stem cell divisions accumulated by the tissue; the accumulation of stem cell divisions leads to the accumulation of cancer-promoting errors such as mutations occurring during DNA replication. Since cell death activates the division of stem cells, we recently proposed that the possible cytotoxicity of ethanol on the cells lining the tissues in direct contact with alcoholic beverages could explain the local carcinogenic effect of alcohol. Here we report that short-term exposures (2-3 s) to ethanol concentrations between 10% and 15% start to cause a marked cytotoxic effect on human epithelial keratinocytes in a concentration-dependent manner. We propose that choosing alcoholic beverages containing non-cytotoxic concentrations of ethanol, or diluting ethanol to non-cytotoxic concentrations, may be a simple and effective way to reduce the risk of cancers of the oral cavity, pharynx, larynx and esophagus in alcohol users. This preventive strategy may also reduce the known synergistic effect of alcohol drinking and tobacco smoking on the risk of these cancers.


Economic Evaluation of an Internet-Based Stress Management Intervention Alongside a Randomized Controlled Trial.
Work-related stress is widespread among employees and associated with high costs for German society. Internet-based stress management interventions (iSMIs) are effective in reducing such stress. However, evidence for their cost-effectiveness is scant. The aim of this study was to assess the cost-effectiveness of a guided iSMI for employees. A sample of 264 employees with elevated symptoms of perceived stress (Perceived Stress Scale≥22) was assigned to either the iSMI or a waitlist control condition (WLC) with unrestricted access to treatment as usual. Participants were recruited in Germany in 2013 and followed through 2014, and data were analyzed in 2017. The iSMI consisted of 7 sessions plus 1 booster session. It was based on problem-solving therapy and emotion regulation techniques. Costs were measured from the societal perspective, including all direct and indirect medical costs. We performed a cost-effectiveness analysis and a cost-utility analysis relating costs to a symptom-free person and quality-adjusted life years (QALYs) gained, respectively. Sampling uncertainty was handled using nonparametric bootstrapping (N=5000). When the society is not willing to pay anything to get an additional symptom-free person (eg, willingness-to-pay [WTP]=€0), there was a 70% probability that the intervention is more cost-effective than WLC. This probability rose to 85% and 93% when the society is willing to pay €1000 and €2000, respectively, for achieving an additional symptom-free person. The cost-utility analysis yielded a 76% probability that the intervention is more cost-effective than WLC at a conservative WTP threshold of €20,000 (US $25,800) per QALY gained. Offering an iSMI to stressed employees has an acceptable likelihood of being cost-effective compared with WLC. German Clinical Trials Register DRKS00004749; https://www.drks.de/DRKS00004749. RR2-10.1186/1471-2458-13-655.


Influenza immunization in the elderly: knowledge and attitudes do not explain physician behavior.
The records of 847 elderly clinic patients were reviewed and the 95 primary care physicians who managed their care were surveyed to determine factors related to their ordering of influenza immunization. Overall, 41 percent of the eligible patients were offered vaccine (range 0-90 percent). Physician offering of vaccine was unrelated to patient age, sex, or race but was higher in patients seen on multiple visits (47 vs 39 percent) and in those vaccinated during the prior year (61 vs 35 percent). Physician offering of vaccine was not associated with perceived incidence of severe side effects or estimates of vaccine efficacy.


Accumulative charge separation for solar fuels production: coupling light-induced single electron transfer to multielectron catalysis.
The conversion and storage of solar energy into a fuel holds promise to provide a significant part of the future renewable energy demand of our societies. Solar energy technologies today generate heat or electricity, while the large majority of our energy is used in the form of fuels. Direct conversion of solar energy to a fuel would satisfy our needs for storable energy on a large scale. Solar fuels can be generated by absorbing light and converting its energy to chemical energy by electron transfer leading to separation of electrons and holes. The electrons are used in the catalytic reduction of a cheap substrate with low energy content into a high-energy fuel. The holes are filled by oxidation of water, which is the only electron source available for large scale solar fuel production. Absorption of a single photon typically leads to separation of a single electron-hole pair. In contrast, fuel production and water oxidation are multielectron, multiproton reactions. Therefore, a system for direct solar fuel production must be able to accumulate the electrons and holes provided by the sequential absorption of several photons in order to complete the catalytic reactions. In this Account, the process is termed accumulative charge separation. This is considerably more complicated than charge separation on a single electron level and needs particular attention. Semiconductor materials and molecular dyes have for a long time been optimized for use in photovoltaic devices. Efforts are made to develop new systems for light harvesting and charge separation that are better optimized for solar fuel production than those used in the early devices presented so far. Significant progress has recently been made in the discovery and design of better homogeneous and heterogeneous catalysts for solar fuels and water oxidation. While the heterogeneous ones perform better today, molecular catalysts based on transition metal complexes offer much greater tunability of electronic and structural properties, they are typically more amenable to mechanistic analysis, and they are small and therefore require less material. Therefore, they have arguably greater potential as future efficient catalysts but must be efficiently coupled to accumulative charge separation. This Account discusses accumulative charge separation with focus on molecular and molecule-semiconductor hybrid systems. The coupling between charge separation and catalysis involves many challenges that are often overlooked, and they are not always apparent when studying water oxidation and fuel formation as separate half-reactions with sacrificial agents. Transition metal catalysts, as well as other multielectron donors and acceptors, cycle through many different states that may quench the excited sensitizer by nonproductive pathways. Examples where this has been shown, often with ultrafast rates, are reviewed. Strategies to avoid these competing energy-loss reactions and still obtain efficient coupling of charge separation to catalysis are discussed. This includes recent examples of dye-sensitized semiconductor devices with molecular catalysts and dyes that realize complete water splitting, albeit with limited efficiency.


Extended subtemporal transtentorial approach to the anterior incisural space and upper clival region: experience with posterior circulation aneurysms.
Although most posterior circulation aneurysms are currently treated by endovascular means, some are not amenable to this treatment modality. The narrow working window afforded by the anterolateral and lateral surgical approaches often translates into suboptimal visualization and limited maneuverability. We present a modified technique of tentorial incision and reflection that optimizes the exposure achieved with the traditional subtemporal approach and report our clinical experience in a series of posterior circulation aneurysms. Retrospective review of patients operated via an extended subtemporal transtentorial approach for posterior circulation aneurysms. The modified tentorial incision implies dissection of the trochlear nerve along its dural canal up to its entrance into the cavernous sinus and incision of a tentorial flap that extends up to Meckel cave, which is then reflected far anterolaterally. Clinical and radiological data were reviewed. This series comprises 18 patients (21 procedures). Ten patients presented (56%) with a subarachnoid hemorrhage. Aneurysms most frequently arose from the basilar tip (61%) and were of small size (50%) and saccular morphology (72%). Two patients underwent surgery following unsuccessful endovascular treatment. Aneurysm treatment was successful on the first attempt in 90% (19/21) and after a second attempt in 10% (2/21). Documented postoperative palsies of the oculomotor (n = 3) and trochlear (n = 1) nerves were all transient. No procedure-related mortality occurred. This modified technique of tentorial incision and reflection optimizes visibility, anatomic orientation, and maneuverability by increasing the rostrocaudal and anterolateral exposure obtained via the extended subtemporal transtentorial route without permanent postoperative trochlear nerve deficit.


Unraveling Interactions between Ionic Liquids and Phospholipid Vesicles Using Nanoplasmonic Sensing.
Owing to their unique properties and unlimited structural combinations, the ubiquitous use of ionic liquids (ILs) is steadily increasing. The objective of the present work is to shed light onto the effects of amidinium- and phosphonium-based ILs on phospholipid vesicles using a nanoplasmonic sensing measurement technique. A new and relatively simple method was developed for the immobilization of large unilamellar vesicles on two different hydrophilic surfaces composed of titanium dioxide and silicon nitride nanolayers. Among the pretreatment conditions studied, vesicle attachment on both substrate materials was achieved with HEPES buffer in the presence of sodium hydroxide and calcium chloride. To get an understanding of how ILs interact with intact vesicles or with supported lipid bilayers, the ILs 1,5-diazabicyclo(4.3.0)non-5-enium acetate ([DBNH][OAc]), tributyl(tetradecyl)phosphonium acetate ([P14444][OAc]), and tributylmethylphosphonium acetate ([P4441][OAc]) were introduced into the biomimetic system, and the characteristics of their interactions with the immobilized vesicles were determined. Depending on the IL, in situ real-time IL binding and/or phospholipid removal processes were observed. Although [DBNH][OAc] did not have any significant effect on the phospholipid vesicles, the strongest and the most significant effect was observed with [P14444][OAc]. The latter caused clear changes in the phospholipid bilayer: the ILs interacted with the bilayers, resulting in deformation of the vesicles most probably due to the formation of vesicle-IL aggregates. Only a mild effect was observed when [P4441][OAc], at a very high concentration, was exposed to the intact vesicles. In general, these results led to new insights into the effects of ILs on phospholipid vesicles, which are of great importance to the overall understanding of the harmfulness of ILs on biomembranes and biomimicking systems. In addition, the present work highlights the pivotal role of this highly surface-sensitive indirect biosensing technique in scrutinizing and dissecting the integrity and architecture of phospholipid vesicles in the nanoscale range.


Hyperspectral imaging with a liquid crystal polarization interferometer.
A novel hyperspectral imaging system has been developed that takes advantage of the tunable path delay between orthogonal polarization states of a liquid crystal variable retarder. The liquid crystal is placed in the optical path of an imaging system and the path delay between the polarization states is varied, causing an interferogram to be generated simultaneously at each pixel. A data set consisting of a series of images is recorded while varying the path delay; Fourier transforming the data set with respect to the path delay yields the hyperspectral data-cube. The concept is demonstrated with a prototype imager consisting of a liquid crystal variable retarder integrated into a commercial 640x480 pixel CMOS camera. The prototype can acquire a full hyperspectral data-cube in 0.4 s, and is sensitive to light over a 400 nm to 1100 nm range with a dispersion-dependent spectral resolution of 450 cm(-1) to 660 cm(-1). Similar to Fourier transform spectroscopy, the imager is spatially and spectrally multiplexed and therefore achieves high optical throughput. Additionally, the common-path nature of the polarization interferometer yields a vibration-insensitive device. Our concept allows for the spectral resolution, imaging speed, and spatial resolution to be traded off in software to optimally address a given application. The simplicity, compactness, potential low cost, and software adaptability of the device may enable a disruptive class of hyperspectral imaging systems with a broad range of applications.


Choosing cooperation over competition; hospital strategies in response to selective contracting.
With the introduction of market competition in health care, the Dutch government enabled health insurers to contract hospital care selectively. The assumption is that "selective contracting" will stimulate efficiency, effectiveness, and innovation and will diminish overcapacity. In 2010, the first Dutch health insurers started experimenting with "selective contracting" by setting a minimum treatment volume per year for complex treatments. In an explorative, multiple case study among 15 hospitals in five regions, we found that instead of competing, hospitals started to cooperate and strengthen their networks. The government intended to remove redundant hospital capacity and improve quality by stimulating specialization and concentration. Our study showed that specialization was indeed stimulated, which may have increased quality of care. However, facilitated by the absence of a countervailing power (government or insurer), hospitals in our cases negotiated to the effect of preserving hospital capacity. Within the current political debate between supporters of competition and advocates of a national health service, the importance and role of the (medical) networks should be taken into account. Otherwise, the outcomes of health care governance will be different than intended by either party.


Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin-23-driven chronic intestinal inflammation.
In interleukin-23 (IL-23)-dependent colitis, there is excessive accumulation of short-lived neutrophils and inflammatory monocytes in the intestine. It is unknown whether this reflects changes in mature cell populations or whether the IL-23-driven colitogenic T cell program regulates upstream hematopoietic stem and progenitor cells (HSPC). Here we have shown dysregulation of hematopoiesis in colitis mediated by inflammatory cytokines. First, there was an interferon-gamma-dependent accumulation of proliferating hematopoietic stem cells in the bone marrow and spleen. Second, there was a strong skew toward granulocyte-monocyte progenitor (GMP) production at the expense of erythroid and lymphoid progenitors. Extramedullary hematopoiesis was also evident, and granulocyte macrophage-colony stimulating factor (GM-CSF) blockade reduced the accumulation of splenic and colonic GMPs, resulting in amelioration of colitis. Importantly, transfer of GMPs exacerbated colitis. These data identify HSPCs as a major target of the IL-23-driven inflammatory axis suggesting therapeutic strategies for the treatment of inflammatory bowel disease.


An In vivo study: Adjuvant activity of poly-n-vinyl-2-pyrrolidone-co-acrylic acid on immune responses against Melanoma synthetic peptide.
Peptides have been studied as an important class of components in medicine to control many major diseases with vaccination. Polymers as adjuvants are capable of enhancing the vaccine potential against various diseases by improving the delivery of antigens, and they reduce the booster doses of vaccines. In brief, polymers are promising candidates for peptide-based vaccine delivery platforms. The purpose of the present study was to create a possible alternative approach in the treatment of malignant melanoma and/or to prevent metastasis of melanoma. The study was designed as both an experimental and an in vivo study. We prepared a complex and covalent conjugate of MAGE-3 121-134 (L-L-K-Y-R-A-R-E-P-V-T-K-A-E) T-cell epitope as a vaccine candidate for melanoma. These conjugates were able to generate an immune response in mice after a single immunization, without the help of any external adjuvant. The peptide-polymer complexes activated the immune system in the best way and formed the highest antigen specific immune response. These results indicate the adjuvant activity of Poly(N-vinyl-2- pyrrolidone-co-acrylic acid) [P(VP-co-AA)] and the potential use of P(VP-coAA)-peptide based vaccine prototypes for future melanoma cancer vaccine formulations.


Challenges and strategies for implementing genomic services in diverse settings: experiences from the Implementing GeNomics In pracTicE (IGNITE) network.
To realize potential public health benefits from genetic and genomic innovations, understanding how best to implement the innovations into clinical care is important. The objective of this study was to synthesize data on challenges identified by six diverse projects that are part of a National Human Genome Research Institute (NHGRI)-funded network focused on implementing genomics into practice and strategies to overcome these challenges. We used a multiple-case study approach with each project considered as a case and qualitative methods to elicit and describe themes related to implementation challenges and strategies. We describe challenges and strategies in an implementation framework and typology to enable consistent definitions and cross-case comparisons. Strategies were linked to challenges based on expert review and shared themes. Three challenges were identified by all six projects, and strategies to address these challenges varied across the projects. One common challenge was to increase the relative priority of integrating genomics within the health system electronic health record (EHR). Four projects used data warehousing techniques to accomplish the integration. The second common challenge was to strengthen clinicians' knowledge and beliefs about genomic medicine. To overcome this challenge, all projects developed educational materials and conducted meetings and outreach focused on genomic education for clinicians. The third challenge was engaging patients in the genomic medicine projects. Strategies to overcome this challenge included use of mass media to spread the word, actively involving patients in implementation (e.g., a patient advisory board), and preparing patients to be active participants in their healthcare decisions. This is the first collaborative evaluation focusing on the description of genomic medicine innovations implemented in multiple real-world clinical settings. Findings suggest that strategies to facilitate integration of genomic data within existing EHRs and educate stakeholders about the value of genomic services are considered important for effective implementation. Future work could build on these findings to evaluate which strategies are optimal under what conditions. This information will be useful for guiding translation of discoveries to clinical care, which, in turn, can provide data to inform continual improvement of genomic innovations and their applications.


Community health workers: a front line for primary care?
Among the potential changes invoked in discussions on health system transformation, a need to revitalize primary care remains paramount. One way of doing this, most agree, is to move more in the direction of team-based care. Professionals such as physician assistants and nurse practitioners may be able to ease some of the physician's clinical care load, but some populations also need help accessing services and basic health education in a familiar setting. Enter the community health worker (CHW), known by many titles and playing a variety of roles, who comes from the community he or she is serving and therefore can interact with and effectively motivate clients. This paper examines what CHWs do, how they are trained, and the outlook for their incorporation into mainstream health care, as well as the challenges for developing the profession further.


HMGB1 is a cofactor in mammalian base excision repair.
Deoxyribose phosphate (dRP) removal by DNA polymerase beta (Pol beta) is a pivotal step in base excision repair (BER). To identify BER cofactors, especially those with dRP lyase activity, we used a Pol beta null cell extract and BER intermediate as bait for sodium borohydride crosslinking. Mass spectrometry identified the high-mobility group box 1 protein (HMGB1) as specifically interacting with the BER intermediate. Purified HMGB1 was found to have weak dRP lyase activity and to stimulate AP endonuclease and FEN1 activities on BER substrates. Coimmunoprecipitation experiments revealed interactions of HMGB1 with known BER enzymes, and GFP-tagged HMGB1 was found to accumulate at sites of oxidative DNA damage in living cells. HMGB1(-/-) mouse cells were slightly more resistant to MMS than wild-type cells, probably due to the production of fewer strand-break BER intermediates. The results suggest HMGB1 is a BER cofactor capable of modulating BER capacity in cells.


Listeria phage A511, a model for the contractile tail machineries of SPO1-related bacteriophages.
Recognition of the bacterial host and attachment to its surface are two critical steps in phage infection. Here we report the identification of Gp108 as the host receptor-binding protein of the broad host-range, virulent Listeria phage A511. The ligands for Gp108 were found to be N-acetylglucosamine and rhamnose substituents of the wall teichoic acids of the bacterial cell wall. Transmission electron microscopy and immunogold-labelling allowed us to create a model of the A511 baseplate in which Gp108 forms emanating short tail fibres. Data obtained for related phages, such as Staphylococcus phages ISP and Twort, demonstrate the evolutionary conservation of baseplate components and receptor-binding proteins within the Spounavirinae subfamily, and contractile tail machineries in general. Our data reveal key elements in the infection process of large phages infecting Gram-positive bacteria and generate insights into the complex adsorption process of phage A511 to its bacterial host.


Healthy habits: efficacy of simple advice on weight control based on a habit-formation model.
To evaluate the efficacy of a simple weight loss intervention, based on principles of habit formation. An exploratory trial in which overweight and obese adults were randomized either to a habit-based intervention condition (with two subgroups given weekly vs monthly weighing; n=33, n=36) or to a waiting-list control condition (n=35) over 8 weeks. Intervention participants were followed up for 8 months. A total of 104 adults (35 men, 69 women) with an average BMI of 30.9 kg m(-2). Intervention participants were given a leaflet containing advice on habit formation and simple recommendations for eating and activity behaviours promoting negative energy balance, together with a self-monitoring checklist. Weight change over 8 weeks in the intervention condition compared with the control condition and weight loss maintenance over 32 weeks in the intervention condition. At 8 weeks, people in the intervention condition had lost significantly more weight (mean=2.0 kg) than those in the control condition (0.4 kg), with no difference between weekly and monthly weighing subgroups. At 32 weeks, those who remained in the study had lost an average of 3.8 kg, with 54% losing 5% or more of their body weight. An intention-to-treat analysis (based on last-observation-carried-forward) reduced this to 2.6 kg, with 26% achieving a 5% weight loss. This easily disseminable, low-cost, simple intervention produced clinically significant weight loss. In limited resource settings it has potential as a tool for obesity management.


Software tools of the Computis European project to process mass spectrometry images.
Among the needs usually expressed by teams using mass spectrometry imaging, one that often arises is that for user-friendly software able to manage huge data volumes quickly and to provide efficient assistance for the interpretation of data. To answer this need, the Computis European project developed several complementary software tools to process mass spectrometry imaging data. Data Cube Explorer provides a simple spatial and spectral exploration for matrix-assisted laser desorption/ionisation-time of flight (MALDI-ToF) and time of flight-secondary-ion mass spectrometry (ToF-SIMS) data. SpectViewer offers visualisation functions, assistance to the interpretation of data, classification functionalities, peak list extraction to interrogate biological database and image overlay, and it can process data issued from MALDI-ToF, ToF-SIMS and desorption electrospray ionisation (DESI) equipment. EasyReg2D is able to register two images, in American Standard Code for Information Interchange (ASCII) format, issued from different technologies. The collaboration between the teams was hampered by the multiplicity of equipment and data formats, so the project also developed a common data format (imzML) to facilitate the exchange of experimental data and their interpretation by the different software tools. The BioMap platform for visualisation and exploration of MALDI-ToF and DESI images was adapted to parse imzML files, enabling its access to all project partners and, more globally, to a larger community of users. Considering the huge advantages brought by the imzML standard format, a specific editor (vBrowser) for imzML files and converters from proprietary formats to imzML were developed to enable the use of the imzML format by a broad scientific community. This initiative paves the way toward the development of a large panel of software tools able to process mass spectrometry imaging datasets in the future.


Evaluation of Perioperative Medication Errors and Adverse Drug Events.
The purpose of this study is to assess the rates of perioperative medication errors (MEs) and adverse drug events (ADEs) as percentages of medication administrations, to evaluate their root causes, and to formulate targeted solutions to prevent them. In this prospective observational study, anesthesia-trained study staff (anesthesiologists/nurse anesthetists) observed randomly selected operations at a 1,046-bed tertiary care academic medical center to identify MEs and ADEs over 8 months. Retrospective chart abstraction was performed to flag events that were missed by observation. All events subsequently underwent review by two independent reviewers. Primary outcomes were the incidence of MEs and ADEs. A total of 277 operations were observed with 3,671 medication administrations of which 193 (5.3%; 95% CI, 4.5 to 6.0) involved a ME and/or ADE. Of these, 153 (79.3%) were preventable and 40 (20.7%) were nonpreventable. The events included 153 (79.3%) errors and 91 (47.2%) ADEs. Although 32 (20.9%) of the errors had little potential for harm, 51 (33.3%) led to an observed ADE and an additional 70 (45.8%) had the potential for patient harm. Of the 153 errors, 99 (64.7%) were serious, 51 (33.3%) were significant, and 3 (2.0%) were life-threatening. One in 20 perioperative medication administrations included an ME and/or ADE. More than one third of the MEs led to observed ADEs, and the remaining two thirds had the potential for harm. These rates are markedly higher than those reported by retrospective surveys. Specific solutions exist that have the potential to decrease the incidence of perioperative MEs.


The first transmembrane domain of lipid phosphatase SAC1 promotes Golgi localization.
The lipid phosphatase Sac1 cycles between endoplasmic reticulum and cisternal Golgi compartments. In proliferating mammalian cells, a canonical dilysine motif at the C-terminus of Sac1 is required for coatomer complex-I (COP-I)-binding and continuous retrieval to the ER. Starvation triggers accumulation of Sac1 at the Golgi. The mechanism responsible for Golgi retention of Sac1 is unknown. Here we show that the first of the two transmembrane regions in human SAC1 (TM1) functions in Golgi localization. A minimal construct containing only TM1 and the adjacent flanking sequences is concentrated at the Golgi. Transplanting TM1 into transferrin receptor 2 (TfR2) induces Golgi accumulation of this normally plasma membrane and endosomal protein, indicating that TM1 is sufficient for Golgi localization. In addition, we determined that the N-terminal cytoplasmic domain of SAC1 also promotes Golgi localization, even when TM1 is mutated or absent. We conclude that the distribution of SAC1 within the Golgi is controlled via both passive membrane thickness-dependent partitioning of TM1 and a retention mechanism that requires the N-terminal cytoplasmic region.


Inhibition of Tryptophan Hydroxylases and Monoamine Oxidase-A by the Proton Pump Inhibitor, Omeprazole-In Vitro and In Vivo Investigations.
Serotonin (5-HT) is a hormone and neurotransmitter that modulates neural activity as well as a wide range of other physiological processes including cardiovascular function, bowel motility, and platelet aggregation. 5-HT synthesis is catalyzed by tryptophan hydroxylase (TPH) which exists as two distinct isoforms; TPH1 and TPH2, which are responsible for peripheral and central 5-HT, respectively. Due to the implication of 5-HT in a number of pathologies, including depression, anxiety, autism, sexual dysfunction, irritable bowel syndrome, inflammatory bowel disease, and carcinoid syndrome, there has been a growing interest in finding modulators of these enzymes in recent years. We thus performed high-throughput screening (HTS) using a fluorescence-based thermal shift assay (DSF) to search the Prestwick Chemical Library containing 1,280 compounds, mostly FDA-approved drugs, for TPH1 binders. We here report the identification of omeprazole, a proton pump inhibitor, as an inhibitor of TPH1 and TPH2 with low micromolar potency and high selectivity over the other aromatic amino acid hydroxylases. The S-enantiomer of omeprazole, esomeprazole, has recently also been described as an inhibitor of monoamine oxidase-A (MAO-A), the main enzyme responsible for 5-HT degradation, albeit with lower potency compared to the effect on TPH1 and TPH2. In order to investigate the net effect of simultaneous inhibition of TPH and MAO-A in vivo, we administered high-dose (100 mg/kg) omeprazole to CD-1 mice for 4 days, after which the animals were subjected to the tail suspension test. Finally, central (whole brain) and peripheral (serum) 5-HT content was measured using liquid chromatography-mass spectrometry (LC-MS). Omeprazole treatment significantly increased 5-HT concentrations, both in brain and in serum, and reduced the time spent immobile in the tail suspension test relative to vehicle control. Thus, the MAO-A inhibition afforded by high-dose omeprazole appears to overcome the opposing effect on 5-HT produced by inhibition of TPH1 and TPH2. Further modification of proton pump inhibitor scaffolds may yield more selective modulators of 5-HT metabolism.


Far eastern curlew and whimbrel prefer flying low - wind support and good visibility appear only secondary factors in determining migratory flight altitude.
In-flight conditions are hypothesized to influence the timing and success of long-distance migration. Wind assistance and thermal uplift are thought to reduce the energetic costs of flight, humidity, air pressure and temperature may affect the migrants' water balance, and clouds may impede navigation. Recent advances in animal-borne long-distance tracking enable evaluating the importance of these factors in determining animals' flight altitude. Here we determine the effects of wind, humidity, temperature, cloud cover, and altitude (as proxy for climbing costs and air pressure) on flight altitude selection of two long-distance migratory shorebirds, far eastern curlew (Numenius madagascariensis) and whimbrel (Numenius phaeopus). To reveal the predominant drivers of flight altitude selection during migration we compared the atmospheric conditions at the altitude the birds were found flying with conditions elsewhere in the air column using conditional logistic mixed effect models. Our results demonstrate that despite occasional high-altitude migrations (up to 5550 m above ground level), our study species typically forego flying at high altitudes, limiting climbing costs and potentially alleviating water loss and facilitating navigation. While mainly preferring migrating at low altitude, notably in combination with low air temperature, the birds also preferred flying with wind support to likely reduce flight costs. They avoided clouds, perhaps to help navigation or to reduce the risks from adverse weather. We conclude that the primary determinant of avian migrant's flight altitude selection is a preference for low altitude, with wind support as an important secondary factor. Our approach and findings can assist in predicting climate change effects on migration and in mitigating bird strikes with air traffic, wind farms, power lines, and other human-made structures.


Mutations of the adenomatous polyposis coli gene in familial polyposis coli patients and sporadic colorectal tumors.
We have isolated several genes in the chromosome 5q21 region tightly linked to hereditary familial polyposis coli (FAP) and Gardner's syndrome (GS). Two of these genes (MCC and APC) were found to be somatically altered by point mutation, deletion or insertion in tumors of sporadic colorectal cancer patients. One of them (adenomatous polyposis coli; APC) was also found to mutate in the germ-line of both APC and GS patients. The identification of these genes has significant implications for understanding the pathogenesis of colorectal neoplasia and for the diagnosis and counseling of individuals with inherited predispositions to colorectal cancer. Furthermore, in one colon carcinoma, we identified an interesting mechanism causing dysfunction of the APC gene. This gene was disrupted by a somatic insertion of a long interspersed repetitive element (LINE-1 sequence: L1) into the last exon. As an insertional sequence contains a 3' portion of the L1 consensus sequence including the poly(A) tract and an 8 bp target-site duplication was observed, this insertion is suspected to be caused by a retrotranscriptional insertion of one of the L1 sequences. This is the first case of the disruption of a tumor suppressor gene by the insertion of a movable genetic element.


SNHG1/miR-21 axis mediates the cardioprotective role of aloin in sepsis through modulating cardiac cell viability and inflammatory responses.
Aloin has cardioprotective effects, however, its cardioprotective role in sepsis remains unclear. This study aimed to analyze whether aloin could prevent sepsis-related myocardial damage and explore the underlying mechanisms by examining the expression of long-noncoding RNA (lncRNA) SNHG1 and microRNA-21 (miR-21). The interaction of SNHG1 with miR-21 was identified by dual-luciferase reporter assay. The levels of SNHG1 and miR-21 were measured by real-time quantitative PCR. The cardioprotective function of aloin was assessed in a sepsis animal model, which was induced by cecal ligation and puncture, and in a myocardial injury cell model in H9C2 cells stimulated by lipopolysaccharide. Myocardial injury biomarker levels and hemodynamic indicators in mice model were measured to evaluate cardiac function. The viability of H9C2 cells was assessed by cell counting kit-8 assay. Inflammatory cytokine levels were examined by an ELISA method. Decreased SNHG1 and increased miR-21 were found in sepsis patients with cardiac dysfunction, and they were negatively correlated. Aloin significantly attenuated myocardial damage and inflammatory responses of mice model, and increased the viability and suppressed inflammation in H9C2 cell model. In addition, SNHG1 expression was upregulated and miR-21 expression was downregulated by aloin in both mice and cell models. Moreover, in mice and cell models, SNHG1/miR-21 axis affected sepsis-related myocardial damage, and mediated the cardioprotective effects of aloin. Our findings indicated that aloin exerts protective effects in sepsis-related myocardial damage through regulating cardiac cell viability and inflammatory responses via regulating the SNHG1/miR-21 axis.


Flexible recalibration of binary clinical prediction models.
Calibration in binary prediction models, that is, the agreement between model predictions and observed outcomes, is an important aspect of assessing the models' utility for characterizing risk in future data. A popular technique for assessing model calibration first proposed by D. R. Cox in 1958 involves fitting a logistic model incorporating an intercept and a slope coefficient for the logit of the estimated probability of the outcome; good calibration is evident if these parameters do not appreciably differ from 0 and 1, respectively. However, in practice, the form of miscalibration may sometimes be more complicated. In this article, we expand the Cox calibration model to allow for more general parameterizations and derive a relative measure of miscalibration between two competing models from this more flexible model. We present an example implementation using data from the US Agency for Healthcare Research and Quality.


Nonlinear dynamics of seizure prediction in a rodent model of epilepsy.
Epilepsy is a dynamical disorder with intermittent crises (seizures) that until recently were considered unpredictable. In this study, we investigated the predictability of epileptic seizures in chronically epileptic rats as a first step towards a subsequent timely intervention for seizure control. We look at the epileptic brain as a nonlinear complex system that undergoes spatio-temporal state transitions and the Lyapunov exponents as indices of its stability. We estimated the spatial synchronization or desynchronization of the maximum short-term Lyapunov exponents (STLmax, approximate measures of chaos) among multiple brain sites over days of electroencephalographic (EEG) recordings from 5 rats that had developed chronic epilepsy according to the lithium pilocarpine rodent model of epilepsy. We utilized this synchronization of EEG dynamics for the construction of a robust seizure prediction algorithm. The parameters of the algorithm were optimized using receiver operator curves (ROCs) on training EEG datasets from each rat for the algorithm to provide maximum sensitivity and specificity in the prediction of their seizures. The performance of the algorithm was then tested on long-term testing EEG datasets per rat. The thus optimized prediction algorithm on the testing datasets over all rats yielded a seizure prediction mean sensitivity of 85.9%, specificity of 0.180 false predictions per hour, and prediction time of 67.6 minutes prior to a seizure onset. This study provides evidence that prediction of seizures is feasible through analysis of the EEG within the framework of nonlinear dynamics, and thus paves the way for just-in-time pharmacological or physiological inter-ventions to abort seizures tens of minutes before their occurrence.


The process-knowledge model of health literacy: evidence from a componential analysis of two commonly used measures.
We investigated the effects of domain-general processing capacity (fluid ability such as working memory), domain-general knowledge (crystallized ability such as vocabulary), and domain-specific health knowledge for two of the most commonly used measures of health literacy (S-TOFHLA and REALM). One hundred forty six community-dwelling older adults participated; 103 had been diagnosed with hypertension. The results showed that older adults who had higher levels of processing capacity or knowledge (domain-general or health) performed better on both of the health literacy measures. Processing capacity interacted with knowledge: Processing capacity had a lower level of association with health literacy for participants with more knowledge than for those with lower levels of knowledge, suggesting that knowledge may offset the effects of processing capacity limitations on health literacy. Furthermore, performance on the two health literacy measures appeared to reflect a different weighting for the three types of abilities. S-TOFHLA performance reflected processing capacity as well as general knowledge, whereas performance on the REALM depended more on general and health knowledge than on processing capacity. The findings support a process-knowledge model of health literacy among older adults, and have implications for selecting health literacy measures in various health care contexts.


Antibacterial prophylaxis in patients with neutropenia.
Patients with cancer and chemotherapy-induced neutropenia are at risk for severe bacterial infections. This risk is not uniform among all cancer patients but is dependent primarily on the depth and duration of neutropenia and the type of underlying disease. Accordingly, the decision whether to use antibacterial prophylaxis to prevent serious infections in these patients requires a balance between expected benefit and the risks for infection, adverse drug-related events, and emergence of antibiotic resistance. Although antibacterial prophylaxis has the potential to benefit all patients with chemotherapy-induced neutropenia, the benefit regarding reduction in documented infections has been firmly established only in patients with neutropenia expected to exceed 7 days. A recent meta-analysis showed enhanced survival in patients receiving antibacterial prophylaxis during neutropenia; most patients enrolled in the analyzed trials had a hematologic malignancy. Among patients with neutropenia at lower risk for infectious complications (a category that includes most patients with solid tumor malignancies), the main benefit of antibacterial prophylaxis relates to a reduction in fever rather than documented infections. The authors advise quinolone prophylaxis (levofloxacin is preferred), in patients with an expected duration of neutropenia (absolute neutrophil count < 1000/microL) of more than 7 days. Trimethoprim-sulfamethoxazole should be used in patients at risk for Pneumocystis jiroveci (formerly P carinii), such as childhood acute lymphoblastic leukemia. In patients with neutropenia expected to last 7 days or less and not receiving immunosuppressive regimens (e.g., systemic corticosteroids), the authors recommend no initial prophylaxis. However, if such patients develop fever during neutropenia, they should be considered for outpatient empiric therapy with an oral quinolone-containing regimen if they meet criteria for low risk for complications.


Airway Clearance Using Suction Devices in Prehospital Combat Casualty Care: A Systematic Review.
Airway management is at the forefront for combat medics dealing with battlefield trauma. For military service members, compromised airways are the second leading cause of potentially survivable death on the battlefield, accounting for one in ten preventable combat deaths. Effective suction is a critical component of airway clearance. However, currently available devices are too heavy and bulky to be carried by combat medics and are insufficiently powered. The industry has not responded to the need, with companies continuing to produce models using 1970s technology. A literature review was completed with the assistance of a librarian. The databases searched included: Biomedical Research Database (BRD), Computer Retrieval of Information of Scientific Projects (CRISP), Federal Research in Progress (FEDRIP), Defense Technical Information Center (DTIC), Pub Med/Medline, and OVID. Additionally, a Google Scholar search was performed to identify nonstandard sources. After screening, a total of 40 articles were used. There were no randomized controlled trials or other high-quality evidence that addressed the issues; there was limited peer-reviewed literature on the use, effectiveness, adverse effects, and safety of suction for use in combat casualty care. A review of the available literature revealed no standards, either proposed, validated, or accepted, for the safety or avoidance of adverse effects for portable suction device use in combat casualty care. Similarly, there are no accepted standards to guide the safe use and anticipated adverse effects of suction for use in prehospital combat or emergency care. Nevertheless, there are meaningful data that can be extracted from the few studies available combined with non-clinical studies, narrative reviews and case reports, and expert opinions.


Food prices and body fatness among youths.
We examine the effect of food prices on clinical measures of obesity, including body mass index (BMI) and percentage body fat (PBF) measures derived from bioelectrical impedance analysis (BIA) and dual energy X-ray absorptiometry (DXA), among youths ages 12 through 18 in the National Health and Nutrition Examination Survey. This is the first study to consider clinically measured levels of body composition rather than BMI to investigate the effects of food prices on obesity outcomes among youths classified by gender and race/ethnicity. Our findings suggest that increases in the real price per calorie of food for home consumption and the real price of fast-food restaurant food lead to improvements in obesity outcomes among youths. We also find that a rise in the real price of fruits and vegetables leads to increased obesity. Finally, our results indicate that measures of PBF derived from BIA and DXA are no less sensitive and in some cases more sensitive to the prices just mentioned than BMI, and serve an important role in demonstrating that rising food prices (except fruit and vegetable prices) are indeed associated with reductions in obesity rather than with reductions in body size proportions alone.


Assembly and core transformation properties of two tetrahedral clusters: [Fe(III)13P8W60O227(OH)15(H2O)2]30- and [Fe(III)13P8W60O224(OH)12(PO4)4]33-.
Two nanosized 2.6 nm Fe(III) substituted polyoxotungstates [Fe(III)13P8W60O227(OH)15(H2O)2](30-) (1) and [Fe(III)13P8W60O224(OH)12(PO4)4](33-) (2) are presented herein. Both clusters are synthesized from the reactions of trilacunary polyoxotungstate precursor [α-P2W15O56](12-) and FeCl3 under strict pH control at atmospheric pressure. The compounds are fully characterised in the solid state (FTIR and single-crystal XRD, elemental and thermogravimetric analyses), solution (cyclic voltammetry and UV-Vis spectroscopy) and in the gas phase (ESI-MS). An {Fe(III)13} core is present in both clusters which can be described as Archimedean solids (truncated tetrahedron, 1; elongated cuboctahedron, 2). 1 shows iron delivery properties coupled to a K(+)-triggered transformation of the {Fe13} core to a {K⊂Fe12} core in solution. Cyclic voltammetry shows the presence of independent W- and Fe-centred redox processes that support the stability of the clusters in solution. ESI-MS analyses confirm further the stability of 1 and 2 in the gas phase.


A neural mechanism for deprivation state-specific expression of relevant memories in Drosophila.
Motivational states modulate how animals value sensory stimuli and engage in goal-directed behaviors. The motivational states of thirst and hunger are represented in the brain by shared and unique neuromodulatory systems. However, it is unclear how such systems interact to coordinate the expression of appropriate state-specific behavior. We show that the activity of two brain neurons expressing leucokinin neuropeptide is elevated in thirsty and hungry flies, and that leucokinin release is necessary for state-dependent expression of water- and sugar-seeking memories. Leucokinin inhibits two types of mushroom-body-innervating dopaminergic neurons (DANs) to promote thirst-specific water memory expression, whereas it activates other mushroom-body-innervating DANs to facilitate hunger-dependent sugar memory expression. Selection of hunger- or thirst-appropriate memory emerges from competition between leucokinin and other neuromodulatory hunger signals at the level of the DANs. Therefore, coordinated modulation of the dopaminergic system allows flies to prioritize the expression of the relevant state-dependent motivated behavior.


Fluticasone furoate-vilanterol 100-25 mcg compared with fluticasone furoate 100 mcg in asthma: a randomized trial.
The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β2-agonist vilanterol (VI) is under development for the treatment of asthma and chronic obstructive pulmonary disease. To compare the efficacy and safety of FF-VI and FF in patients (≥ 12 years old) with persistent asthma. In a randomized, double-blind, parallel-group study, patients (n = 609) (intent-to-treat population) received FF-VI 100-25 mcg, FF 100 mcg, or placebo once daily (evening) by using a dry powder inhaler for 12 weeks. Coprimary end points were change from baseline in trough FEV1 and serial (0-24 hours) weighted mean FEV1 (wmFEV(1)). Rescue-free 24-hour periods and safety also were assessed. Placebo increased trough FEV1 (196 mL) and wmFEV(1) (212 mL) versus baseline. Compared with placebo, FF-VI and FF significantly improved trough FEV1 (172 mL [P < .001] and 136 mL [P = .002]), respectively, and serial wmFEV(1) (302 mL [P < .001] and 186 mL [P = .003]), respectively. Treatment differences between FF-VI and FF approached significance for serial wmFEV(1) (116 mL; P = .060) but not for trough FEV1 (36 mL; P = .405). The percentage of rescue-free 24-hour periods with FF-VI was 10.6% greater than FF and 19.3% greater than placebo. Statistically significant (P = .032) urinary cortisol suppression was observed with FF-VI (ratio, 0.82) relative to placebo, but not with FF. Adverse event and safety profiles were similar across treatment groups. Significant improvement in lung function was observed with FF-VI and FF versus placebo in patients with persistent asthma. Improvement of FEV1 when VI was added to FF was not significant. The high placebo response in evening trough FEV1 may have influenced the assessment of efficacy.


Yolk androgens do not appear to mediate sexual conflict over parental investment in the collared flycatcher Ficedula albicollis.
Males and females are in conflict over parental care, as it would be favourable for one parent to shift labour to the other. Yolk hormones may offer a mechanism through which female birds could influence offspring traits in ways that increase the relative investment by the male. We studied the role of yolk androgens in mediating sexual conflict over parental care in the collared flycatcher (Ficedula albicollis). In a cross-fostering experiment, the male's proportion of total feeding visits increased with increasing androgen levels in the foster eggs. This could suggest that sexual conflict over parental care may be influenced by the female's differential allocation of yolk androgens or a maternal effect associated with yolk androgens. However, when we experimentally elevated yolk androgen levels, male feeding rates did not differ between control and androgen-manipulated nests. This suggests that other egg components correlated with yolk androgen levels, rather than yolk androgen levels per se, may influence male parental effort. In conclusion, yolk androgens per se do not appear to mediate sexual conflict over parental investment in the collared flycatcher.


Cortical thickness measured from MRI in the YAC128 mouse model of Huntington's disease.
A recent study found differences in localised regions of the cortex between the YAC128 mouse model of Huntington's Disease (HD) and wild-type mice. There are, however, few tools to automatically examine shape differences in the cortices of mice. This paper describes an algorithm for automatically measuring cortical thickness across the entire cortex from MRI of fixed mouse brain specimens. An analysis of the variance of the method showed that, on average, a 50 microm (0.05 mm) localised difference in cortical thickness can be measured using MR scans. Applying these methods to 8-month-old YAC128 mouse model mice representing an early stage of HD, we found an increase in cortical thickness in the sensorimotor cortex, and also revealed regions wherein decreasing striatal volume correlated with increasing cortical thickness, indicating a potential compensatory response.


Prevalence and phylogeny of coronaviruses in wild birds from the Bering Strait area (Beringia).
Coronaviruses (CoVs) can cause mild to severe disease in humans and animals, their host range and environmental spread seem to have been largely underestimated, and they are currently being investigated for their potential medical relevance. Infectious bronchitis virus (IBV) belongs to gamma-coronaviruses and causes a costly respiratory viral disease in chickens. The role of wild birds in the epidemiology of IBV is poorly understood. In the present study, we examined 1,002 cloacal and faecal samples collected from 26 wild bird species in the Beringia area for the presence of CoVs, and then we performed statistical and phylogenetic analyses. We detected diverse CoVs by RT-PCR in wild birds in the Beringia area. Sequence analysis showed that the detected viruses are gamma-coronaviruses related to IBV. These findings suggest that wild birds are able to carry gamma-coronaviruses asymptomatically. We concluded that CoVs are widespread among wild birds in Beringia, and their geographic spread and frequency is higher than previously realised. Thus, Avian CoV can be efficiently disseminated over large distances and could be a genetic reservoir for future emerging pathogenic CoVs. Considering the great animal health and economic impact of IBV as well as the recent emergence of novel coronaviruses such as SARS-coronavirus, it is important to investigate the role of wildlife reservoirs in CoV infection biology and epidemiology.


The state of melanoma: challenges and opportunities.
The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas - diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November. Each of the four groups has outlined their thoughts as per the current status, challenges, and opportunities in the four respective areas. The current state and immediate and long-term needs of the melanoma field, from basic research to clinical management, are presented in the following report.


Pregnancy in a woman with treated bladder extrophy, split pelvis and hypoplasia of ischial bones. Case report.
We present a case of a pregnancy in a 24 year old woman who was born with ectopia vesicae, split pelvis and hypoplasia of ischial bones. From childhood to adulthood she had undergone reconstructive surgeries of the abdomen and perineum, as well as urine diversion surgery. During pregnancy she experienced recurrent urinary tract infections which were treated with antibiotics. In spite of tocolysis, she delivered by cesarean section a premature baby boy at 35th week of gestation due to premature uterine contractions. The postoperative period was uneventful and they were discharged from the hospital in a good general condition.


Sur8/Shoc2 promotes cell motility and metastasis through activation of Ras-PI3K signaling.
Sur8 (also known as Shoc2) is a Ras-Raf scaffold protein that modulates signaling through extracellular signal-regulated kinase (ERK) pathway. Although Sur8 has been shown to be a scaffold protein of the Ras-ERK pathway, its interaction with other signaling pathways and its involvement in tumor malignancy has not been reported. We identified that Sur8 interacts with the p110α subunit of phosphatidylinositol 3-kinase (PI3K), as well as with Ras and Raf, and these interactions are increased in an epidermal growth factor (EGF)- and oncogenic Ras-dependent manner. Sur8 regulates cell migration and invasion via activation of Rac and matrix metalloproteinases (MMPs). Interestingly, using inhibitors of MEK and PI3K we found Sur8 mediates these cellular behaviors predominantly through PI3K pathway. We further found that human metastatic melanoma tissues had higher Sur8 content followed by activations of Akt, ERK, and Rac. Lentivirus-mediated Sur8-knockdown attenuated metastatic potential of highly invasive B16-F10 melanoma cells indicating the role of Sur8 in melanoma metastasis. This is the first report to identify the role of scaffold protein Sur8 in regulating cell motility, invasion, and metastasis through activation of both ERK and PI3K pathways.


Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol A in polycystic ovary syndrome: a case-control study.
Polycystic Ovary Syndrome (PCOS) is an endocrine-metabolic disorder that affects approximately 6-10% of women of child-bearing age. Although preliminary studies suggest that certain pollutants may act as endocrine disruptors in animals, little is known about their potential association with PCOS. The objective of this case-control pilot study is to determine whether women with PCOS have higher concentrations of specific environmental contaminants compared to women who have not developed PCOS. Fifty-two PCOS case-patients (diagnosed using the National Institutes of Health 1990 definition) and 50 controls were recruited in 2007-2008, from an urban academic medical center in Los Angeles, CA. Brominated diphenyl ethers, polychlorinated biphenyls (PCBs), organochlorine pesticides, and perfluorinated compounds (PFCs) were measured in serum, and phthalates metabolites and bisphenol A (BPA) in urine. PCOS case-patients had significantly higher geometric mean (GM) serum concentrations of two PFCs: perfluorooctanoate (PFOA) (GMcases = 4.1 μg/L, GMcontrols = 2.3 μg/L; p = 0.001) and perfluorooctane sulfonate (PFOS) (GMcases = 8.2 μg/L, GMcontrols = 4.9 μg/L; p = 0.01), and lower urinary concentrations of monobenzyl phthalate (mBzP) (GMcases = 7.5 μg/g creatinine, GMcontrols = 11.7 μg/g creatinine; p = 0.02). Logistic regression, controlling for body mass index, age and race, identified an increased likelihood of PCOS in subjects with higher serum concentrations of PFOA and PFOS (adjusted-ORs = 5.8-6.9, p < 0.05), and with lower urine concentrations of mBzP and mono-n-butyl phthalate (mBP) (aORs = 0.14-0.25, p < 0.05). Our data suggest that PCOS case-patients may differ from controls in their environmental contaminant profile. PCOS subjects had higher serum concentrations of two PFCs, PFOA and PFOS, and lower urine concentrations of mBP and mBzP. Future studies are needed to confirm these preliminary findings and determine if these chemicals or their precursors may have a role in the pathogenesis of PCOS.


Social Support Networks Among Young Men and Transgender Women of Color Receiving HIV Pre-Exposure Prophylaxis.
The aim of the study was to characterize perceived social support for young men and transgender women who have sex with men (YM/TWSM) taking HIV pre-exposure prophylaxis (PrEP). Mixed-methods study of HIV-negative YM/TWSM of color prescribed oral PrEP. Participants completed egocentric network inventories characterizing their social support networks and identifying PrEP adherence support figures. A subset (n = 31) completed semistructured interviews exploring adherence support and qualities of PrEP support figures. We calculated proportions of role types (e.g., family), individuals disclosed to regarding PrEP use, and PrEP-supportive individuals within each participant network. Interviews were analyzed using an inductive approach. Participants (n = 50) were predominately African American men who have sex with men. Median age was 22 years (interquartile range: 20-23). Biologic family were the most common support figures, reported by 75% of participants (mean family proportion .37 [standard deviation (SD): .31]), followed by 67% reporting friends (mean friend proportion .38 [SD: .36]). Most network members were aware (mean disclosed proportion .74 [SD: .31]) and supportive (mean supportive proportion .87 [SD: .28]) of the participants' PrEP use. Nearly all (98%) participants identified ≥1 figure who provided adherence support; more often friends (48%) than family (36%). Participants characterized support as instrumental (e.g., transportation); emotional (e.g., affection); and social interaction (e.g., taking medication together). Key characteristics of PrEP support figures included closeness, dependability, and homophily (alikeness) with respect to sexual orientation. Although most YM/TWSM identified family in their support networks, friends were most often cited as PrEP adherence support figures. Interventions to increase PrEP adherence should consider integrated social network and family-based approaches.


Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency.
Plectin, an intermediate filament linking protein, is normally associated with the sarcolemma, nuclear membrane, and intermyofibrillar network in muscle, and with hemisdesmosomes in skin. A 20-year-old female with epidermolysis bullosa simplex since birth had progressive ocular, facial, limb, and trunkal weakness and fatigability since age 9, fivefold CK elevation, a 25% decrement with myopathic motor unit potentials and increased electrical irritability on electromyography, and no anti-acetylcholine receptor (AChR) antibodies. Plectin expression was absent in muscle and severe plectin deficiency was noted in skin. Morphologic studies revealed necrotic and regenerating fibers and a wide spectrum of ultrastructural abnormalities: large accumulations of heterochromatic and lobulated nuclei, rare apoptotic nuclei, numerous cytoplasmic and few intranuclear nemaline rods, disarrayed myofibrils, thick-filament loss, vacuolar change, and pathologic alterations in membranous organelles. Many endplates (EPs) had an abnormal configuration with chains of small regions over the fiber surface and a few displayed focal degeneration of the junctional folds. The EP AChR content was normal. In vitro electrophysiologic studies showed normal quantal release by nerve impulse, small miniature EP potentials, and fetal as well as adult AChR channels at the EP. Our findings support the notion that plectin is essential for the structural integrity of muscle and skin, and for normal neuromuscular transmission.


Liver Transplantation in Groningen, The Netherlands: A Single Center Status Report.
The liver transplantation program of the University Medical Center Groningen in the Netherlands was started in 1979, making it one of the first programs worldwide. During the past 36 years, a total of 1478 liver transplantations have been performed, 459 of which were in children. One of the first patients transplanted in 1979 is still alive and is one of the longest surviving patients after liver transplantation worldwide. During the last decade, an increasing number of donation after circulatory death (DCD) donor livers have been accepted for transplantation. Over 30% of the livers transplanted in Groningen come from DCD donors. These livers have an increased risk of developing biliary complications, such as non-anastomotic biliary strictures (NAS). One of the main research topics in Groningen has been the pathogenesis and prevention of NAS. In an attempt to reduce the incidence of NAS after liver transplantation, machine perfusion technology has been developed as an alternative to the traditional method of static cold storage. Researchers of the Groningen liver transplant team were the first in the world to report a method of ex situ normothermic machine perfusion of human donor livers. The efficacy and safety of various types of machine perfusion are currently studied in both animal models and clinical trials. A second line of research in Groningen focuses on alterations in the blood coagulation system in patients with liver disease and undergoing liver transplantation. Groningen researchers were the first to describe a 'rebalanced state' of the coagulation system in patients with liver disease, making them prone to both bleeding and thrombo-embolic complications. Clinicians and researchers at the Groningen liver transplant program will continue to collaborate with a shared focus and the aim to provide innovation and the highest level of care to patients with endstage liver disease.


Direct-acting antiviral therapies for hepatitis C genotype 1 infection: a multiple treatment comparison meta-analysis.
New direct-acting antiviral agents for hepatitis C genotype 1 infection, boceprevir and telaprevir, offer enhanced sustained virologic response (SVR) among both treatment-naïve and treatment-experienced patients. To determine the relative efficacy of the new direct-acting antiviral agents by applying a multiple treatment comparison meta-analysis. We included published Phase II and III randomized controlled trials evaluating head-to-head comparisons between boceprevir, telaprevir, peg-interferon alpha-2a with ribavirin and peg-interferon alpha-2b with ribavirin in hepatitis C genotype 1 patients. We applied Bayesian multiple treatment comparison meta-analysis. We included data from four boceprevir, three telaprevir and six peg-interferon alpha-2a plus ribavirin vs. peg-interferon alpha-2b plus ribavirin randomized controlled trials. Both boceprevir and telaprevir offer statistically superior outcomes for SVR, relapse and discontinuation due to adverse events than either peg-interferons among both treatment-naïve and treatment-experienced patients. Among treatment-naïve patients, clinical outcomes were similar for boceprevir and telaprevir, for SVR [odds ratio (OR) 0.90, 95% credible interval (95% CrI) 0.41-1.91] and for relapse (OR 1.09, 95% CrI 0.19-4.84). Similarly, among treatment-experienced patients, clinical outcomes were similar for boceprevir and telaprevir and for SVR (OR 1.45, 95% CrI 0.70-3.08) and for relapse (OR 0.35, 95% CrI 0.13-1.02). For treatment-naïve patients receiving standard-duration therapy, telaprevir yielded lower rates of anemia and neutropenia, but higher rates of rash and pruritus. For treatment-experience patients, all adverse event rates were higher with telaprevir. Boceprevir and telaprevir exhibit similar effects among hepatitis C genotype 1 treatment-naïve and treatment-experienced patients.


Transitioning between preparatory and precisely sequenced neuronal activity in production of a skilled behavior.
Precise neural sequences are associated with the production of well-learned skilled behaviors. Yet, how neural sequences arise in the brain remains unclear. In songbirds, premotor projection neurons in the cortical song nucleus HVC are necessary for producing learned song and exhibit precise sequential activity during singing. Using cell-type specific calcium imaging we identify populations of HVC premotor neurons associated with the beginning and ending of singing-related neural sequences. We characterize neurons that bookend singing-related sequences and neuronal populations that transition from sparse preparatory activity prior to song to precise neural sequences during singing. Recordings from downstream premotor neurons or the respiratory system suggest that pre-song activity may be involved in motor preparation to sing. These findings reveal population mechanisms associated with moving from non-vocal to vocal behavioral states and suggest that precise neural sequences begin and end as part of orchestrated activity across functionally diverse populations of cortical premotor neurons.


Growth potential of Listeria monocytogenes in six different RTE fruit products: impact of food matrix, storage temperature and shelf life.
We tested the growth potential of Listeria monocytogenes on six RTE fruit products at low (4°C at the factory followed by 8°C retail/home storage) and abusive (4°C followed by 12°C) storage temperatures. Sliced coconut and fresh cut cantaloupe, as well as a fruit mix containing diced pineapple, cantaloupe, apples and grapes supported the growth of L. monocytogenes with a growth potential δ>0.5 log CFU/g over six days. Mangoes, a mix of diced kiwi, cantaloupe and pineapple as well as a mix of diced pineapple, mango, grapefruit, kiwi and pomegranate did not support a growth potential that exceeded 0.5 log CFU/g over six days. The growth potential of L. monocytogenes correlated significantly with the pH; no product with a pH below 4 showed a significant growth potential of L. monocytogenes. Time after inoculation was also a significant predictor of the growth potential, while the fruit type and storage temperature were not.


Oscillating magnetic field disrupts magnetic orientation in Zebra finches, Taeniopygia guttata.
Zebra finches can be trained to use the geomagnetic field as a directional cue for short distance orientation. The physical mechanisms underlying the primary processes of magnetoreception are, however, largely unknown. Two hypotheses of how birds perceive magnetic information are mainly discussed, one dealing with modulation of radical pair processes in retinal structures, the other assuming that iron deposits in the upper beak of the birds are involved. Oscillating magnetic fields in the MHz range disturb radical pair mechanisms but do not affect magnetic particles. Thus, application of such oscillating fields in behavioral experiments can be used as a diagnostic tool to decide between the two alternatives. In a setup that eliminates all directional cues except the geomagnetic field zebra finches were trained to search for food in the magnetic north/south axis. The birds were then tested for orientation performance in two magnetic conditions. In condition 1 the horizontal component of the geomagnetic field was shifted by 90 degrees using a helmholtz coil. In condition 2 a high frequently oscillating field (1.156 MHz) was applied in addition to the shifted field. Another group of birds was trained to solve the orientation task, but with visual landmarks as directional cue. The birds were then tested for their orientation performance in the same magnetic conditions as applied for the first experiment. The zebra finches could be trained successfully to orient in the geomagnetic field for food search in the north/south axis. They were also well oriented in test condition 1, with the magnetic field shifted horizontally by 90 degrees. In contrast, when the oscillating field was added, the directional choices during food search were randomly distributed. Birds that were trained to visually guided orientation showed no difference of orientation performance in the two magnetic conditions. The results indicate that zebra finches use a receptor that bases on radical pair processes for sensing the direction of the earth magnetic field in this short distance orientation behavior.


Effect of intracarotid prostaglandin E1 on regional cerebral blood flow in man.
The effect of prostaglandin E1 on regional cerebral blood flow (rCBF) was studied with the intra-arterial 133Xe method in ten awake patients under local anesthesia. Measurements were taken from 16 areas of a hemisphere in seven patients, from 35 areas of a hemisphere in two patients and from 256 areas of a hemisphere in one patient. The prostaglandin was dissolved from the crystalline state without the aid of alcohol. It was given intracarotidly as a constant infusion at a rate of 5 ng per kilogram per minute for five minutes before the measurement and continued during the measurement. In every patient a mild increase in blood flow during the prostaglandin infusion was seen. The flow increase took place in all parts of the hemisphere. It averaged 11.2% (p less than 0.01). During the infusion, the skin supplied by the internal carotid artery and the conjunctiva on the infused side became red and sometimes swollen. A slight pressure was noted by most patients, but none had pain. No side effects of the infusion were noted.


The perfect storm of information: combining traditional and non-traditional data sources for public health situational awareness during hurricane response.
Hurricane Isaac made landfall in southeastern Louisiana in late August 2012, resulting in extensive storm surge and inland flooding. As the lead federal agency responsible for medical and public health response and recovery coordination, the Department of Health and Human Services (HHS) must have situational awareness to prepare for and address state and local requests for assistance following hurricanes. Both traditional and non-traditional data have been used to improve situational awareness in fields like disease surveillance and seismology. This study investigated whether non-traditional data (i.e., tweets and news reports) fill a void in traditional data reporting during hurricane response, as well as whether non-traditional data improve the timeliness for reporting identified HHS Essential Elements of Information (EEI). HHS EEIs provided the information collection guidance, and when the information indicated there was a potential public health threat, an event was identified and categorized within the larger scope of overall Hurricane Issac situational awareness. Tweets, news reports, press releases, and federal situation reports during Hurricane Isaac response were analyzed for information about EEIs. Data that pertained to the same EEI were linked together and given a unique event identification number to enable more detailed analysis of source content. Reports of sixteen unique events were examined for types of data sources reporting on the event and timeliness of the reports. Of these sixteen unique events identified, six were reported by only a single data source, four were reported by two data sources, four were reported by three data sources, and two were reported by four or more data sources. For five of the events where news tweets were one of multiple sources of information about an event, the tweet occurred prior to the news report, press release, local government\emergency management tweet, and federal situation report. In all circumstances where citizens were reporting along with other sources, the citizen tweet was the earliest notification of the event. Critical information is being shared by citizens, news organizations, and local government representatives. To have situational awareness for providing timely, life-saving public health and medical response following a hurricane, this study shows that non-traditional data sources should augment traditional data sources and can fill some of the gaps in traditional reporting. During a hurricane response where early event detection can save lives and reduce morbidity, tweets can provide a source of information for early warning. In times of limited budgets, investing technical and personnel resources to efficiently and effectively gather, curate, and analyze non-traditional data for improved situational awareness can yield a high return on investment.


Model of unidirectional block formation leading to reentrant ventricular tachycardia in the infarct border zone of postinfarction canine hearts.
When the infarct border zone is stimulated prematurely, a unidirectional block line (UBL) can form and lead to double-loop (figure-of-eight) reentrant ventricular tachycardia (VT) with a central isthmus. The isthmus is composed of an entrance, center, and exit. It was hypothesized that for certain stimulus site locations and coupling intervals, the UBL would coincide with the isthmus entrance boundary, where infarct border zone thickness changes from thin-to-thick in the travel direction of the premature stimulus wavefront. A quantitative model was developed to describe how thin-to-thick changes in the border zone result in critically convex wavefront curvature leading to conduction block, which is dependent upon coupling interval. The model was tested in 12 retrospectively analyzed postinfarction canine experiments. Electrical activation was mapped for premature stimulation and for the first reentrant VT cycle. The relationship of functional conduction block forming during premature stimulation to functional block during reentrant VT was quantified. For an appropriately placed stimulus, in accord with model predictions: (1) The UBL and reentrant VT isthmus lateral boundaries overlapped (error: 4.8±5.7mm). (2) The UBL leading edge coincided with the distal isthmus where the center-entrance boundary would be expected to occur. (3) The mean coupling interval was 164.6±11.0ms during premature stimulation and 190.7±20.4ms during the first reentrant VT cycle, in accord with model calculations, which resulted in critically convex wavefront curvature with functional conduction block, respectively, at the location of the isthmus entrance boundary and at the lateral isthmus edges. Reentrant VT onset following premature stimulation can be explained by the presence of critically convex wavefront curvature and unidirectional block at the isthmus entrance boundary when the premature stimulation interval is sufficiently short. The double-loop reentrant circuit pattern is a consequence of wavefront bifurcation around this UBL followed by coalescence, and then impulse propagation through the isthmus. The wavefront is blocked from propagating laterally away from the isthmus by sharp increases in border zone thickness, which results in critically convex wavefront curvature at VT cycle lengths.


Cigarette price level and variation in five Southeast Asian countries.
To monitor and analyse impacts of the interaction between tobacco excise tax policy and industry price strategy, on the price level and variation of cigarettes sold in five Southeast Asian countries (Indonesia, Cambodia, Lao PDR, the Philippines and Vietnam). Prices of cigarette sold by sticks and packs were collected through an in-person survey of retailers during 2011. Mean cigarette prices and price variation were calculated in each study country for single cigarettes, whole packs and brand groups. Price variation of whole packs was greater in countries with ad-valorem excise tax structures (Cambodia, Lao PDR and Vietnam) than in countries with multitiered specific excise taxes (Indonesia and the Philippines). The price variation for single sticks appeared to be driven by local currency denomination. Cigarettes sold individually cost more per stick than cigarettes sold in whole packs in every brand group except for Indonesia's domestic brands. Tobacco industry strategy and excise tax structure drove the price level and variation of cigarettes sold in packs, while currency denominations influence the selling price of single sticks. To maximise the effectiveness of tobacco tax policies, countries should adopt specific excise tax structures to decrease cigarette price variation, which would minimise opportunities for smokers to 'trade down' to a cheaper brand to avoid a tax-driven price increase.


Clinical usefulness of bone turnover marker concentrations in osteoporosis.
Current evidence continues to support the potential for bone turnover markers (BTM) to provide clinically useful information particularly for monitoring the efficacy of osteoporosis treatment. Many of the limitations identified earlier remain, principally in regard to the relationship between BTM and incident fractures. Important data are now available on reference interval values for CTX and PINP across a range of geographic regions and for individual clinical assays. An apparent lack of comparability between current clinical assays for CTX has become evident indicating the possible limitations of combining such data for meta-analyses. Harmonization of units for reporting serum/plasma CTX (ng/L) and PINP (μg/L) is recommended. The development of international collaborations continues with an important initiative to combine BTM results from clinical trials in osteoporosis in a meta-analysis and an assay harmonization program are likely to be beneficial. It is possible that knowledge derived from clinical studies can further enhance fracture risk estimation tools with inclusion of BTM together with other independent risk factors. Further data of the relationships between the clinical assays for CTX and PINP as well as physiological and pre-analytical factors contributing to variability in BTM concentrations are required.


Sentinel lymph nodes and lymphatic vessels: noninvasive dual-modality in vivo mapping by using indocyanine green in rats--volumetric spectroscopic photoacoustic imaging and planar fluorescence imaging.
To noninvasively map sentinel lymph nodes (SLNs) and lymphatic vessels in rats in vivo by using dual-modality nonionizing imaging-volumetric spectroscopic photoacoustic imaging, which measures optical absorption, and planar fluorescence imaging, which measures fluorescent emission-of indocyanine green (ICG). Institutional animal care and use committee approval was obtained. Healthy Sprague-Dawley rats weighing 250-420 g (age range, 60-120 days) were imaged by using volumetric photoacoustic imaging (n = 5) and planar fluorescence imaging (n = 3) before and after injection of 1 mmol/L ICG. Student paired t tests based on a logarithmic scale were performed to evaluate the change in photoacoustic signal enhancement of SLNs and lymphatic vessels before and after ICG injection. The spatial resolutions of both imaging systems were compared at various imaging depths (2-8 mm) by layering additional biologic tissues on top of the rats in vivo. Spectroscopic photoacoustic imaging was applied to identify ICG-dyed SLNs. In all five rats examined with photoacoustic imaging, SLNs were clearly visible, with a mean signal enhancement of 5.9 arbitrary units (AU) + or - 1.8 (standard error of the mean) (P < .002) at 0.2 hour after injection, while lymphatic vessels were seen in four of the five rats, with a signal enhancement of 4.3 AU + or - 0.6 (P = .001). In all three rats examined with fluorescence imaging, SLNs and lymphatic vessels were seen. The average full width at half maximum (FWHM) of the SLNs in the photoacoustic images at three imaging depths (2, 6, and 8 mm) was 2.0 mm + or - 0.2 (standard deviation), comparable to the size of a dissected lymph node as measured with a caliper. However, the FWHM of the SLNs in fluorescence images widened from 8 to 22 mm as the imaging depth increased, owing to strong light scattering. SLNs were identified spectroscopically in photoacoustic images. These two modalities, when used together with ICG, have the potential to help map SLNs in axillary staging and to help evaluate tumor metastasis in patients with breast cancer.


Walnuts decrease risk of cardiovascular disease: a summary of efficacy and biologic mechanisms.
Given the pressing need to reduce cardiovascular disease (CVD) morbidity and mortality, there has been a focus on optimizing dietary patterns to reduce the many contributing risk factors. Over the past 2 decades, many studies have been conducted that have evaluated the effects of walnut consumption on CVD risk factors. Walnuts have been shown to decrease low density lipoprotein cholesterol (by ∼9-16%) and blood pressure (diastolic blood pressure by ∼2-3 mm Hg), 2 major risk factors for CVD. In addition, walnuts improve endothelial function, decrease both oxidative stress and some markers of inflammation, and increase cholesterol efflux. The effect of walnuts on multiple CVD targets over relatively short periods of time supports recommendations for their inclusion in a heart-healthy diet.


The impact of housing first and peer support on people who are medically vulnerable and homeless.
The purpose of this study was to assess the impact of a local initiative, Project H3, which used housing first, harm reduction, and peer support models to provide housing for 47 homeless people who were medically vulnerable. Comparisons of interviews with participants who were housed at the day of their move-in, and 6-months and 12-months after their move-in, were conducted. Ninety-eight percent of the participants remained in housing after 12 months. Individuals who were housed reported significant increases in their access to and utilization of planned health care services and quality of life, and reductions in their involvement in the criminal justice system. Housing first, harm reduction, and peer support models demonstrate effectiveness in decreasing substance use and improving the quality of life of people who are homeless over time.


Examining evidence based resistance plus balance training in community-dwelling older adults with complex health care needs: Trial protocol for the Muscling Up Against Disability project.
Progressive resistance plus balance training (PRBT) has been demonstrated as effective in reducing later life physical disability, falls risk and poor health, even among those with complex health care needs. However, few studies have examined the influence of PRBT on health service utilisation, cognitive wellbeing and training modality acceptance or undertaken a cost benefit analysis. This project will investigate the broad scope benefits of PRBT participation among community-dwelling older Australians receiving Government supported aged care packages for their complex health care needs. Using a modified stepped-wedge design, 248 community-dwelling adults 65 years and older with some level of government support aged care have been randomised into the study. Those randomised to exercise undertake six months of twice weekly machine-based, moderate to high intensity, supervised PRBT, followed by a six month unsupervised, unsupported follow-up. Controls spend six months undertaking usual activities, before entering the PRBT and follow-up phases. Data are collected at baseline and after each of the six month phases. Measures include level of and change in health and care needs, body composition, muscle capacity, falls, sleep, quality of life, nutritional and mental health status. In addition, acceptance and engagement is determined through telephone and focus group interviews complementing a multi-model health cost benefit evaluation. It is hypothesised this study will demonstrate the feasibility and efficacy of PRBT in improving primary and secondary health outcomes for older adults with aged care needs, and will support the value of this modality of exercise as an integral evidence-based service model of care.


Smart chemistry in polymeric nanomedicine.
This review provides an overview of smart chemistry developed and utilized in the last 5-10 years in polymer-based drug delivery nanomedicine. Smart chemistry not only facilitates the controlled drug loading in a highly specific manner, but also potentially controls the drug release kinetics at the targeted tissues. This review highlights the emergence of new chemistry or unique utilization of conventional chemistry in drug delivery, which is believed to play an important role in developing next generation nanomedicine.


Structural and Biophysical Characterization of Human EXTL3: Domain Organization, Glycosylation, and Solution Structure.
Heparan sulfate proteoglycans are proteins substituted with one or more heparan sulfate (HS) polysaccharides, found in abundance at cell surfaces. HS chains influence the activity of many biologically important molecules involved in cellular communication and signaling. The exostosin (EXT) proteins are glycosyltransferases in the Golgi apparatus that assemble HS chains on HSPGs. The EXTL3 enzyme mainly works as an initiator in HS biosynthesis. In this work, human lumenal N-glycosylated EXTL3 (EXTL3ΔN) was cloned, expressed in human embryonic kidney cells, and purified. Various biophysical and biochemical approaches were then employed to elucidate the N-glycosylation sites and the function of their attached N-glycans. Furthermore, the stability and conformation of the purified EXTL3ΔN protein in solution have been analyzed. Our data show that EXTL3ΔN has N-glycans at least at two positions, Asn290 and Asn592, which seem to be critical for proper protein folding and/or release. EXTL3ΔN is quite stable, as high temperature (∼59 °C) was required for denaturation. Deconvolution of the EXTL3ΔN far-UV CD spectrum revealed a substantial fraction of β sheets (25%) with a minor proportion of α-helices (14%) in the secondary structure. Solution small-angle X-ray scattering and dynamic light scattering revealed an extended structure suggestive of a dimeric arrangement and consisting of two distinct regions, narrow and broad, respectively. This is consistent with bioinformatics analyses suggesting a 3-domain structure with two glycosyltransferase domains and a coiled-coil domain.


Malnutrition and risk of falling among elderly without home-help service--a cross sectional study.
The aim of this study was to explore the frequency of malnutrition risk and associated risk of falling, social and mental factors among elderly without home-help service. The aim was also to explore factors associated with risk of falling. A cross-sectional design was used. Elderly persons own homes. Data were collected during preventive home visits to 565 elderly (age range 73-90 years) without home-help service. Those with complete SCREEN II forms were included in the study (n = 465). MEASUREMENTS included rating scales regarding malnutrition risk (SCREEN II) and risk of falling (Downton). In addition, single-items: general health, satisfaction with life, tiredness, low-spiritedness, worries/anxiety and sleeping were used. According to the SCREEN II, 35% of the sample had no malnutrition risk, 35% had moderate risk and 30% had high malnutrition risk. In an ordinal regression analysis, increased malnutrition risk was associated with being a woman living alone (OR 4.63), male living alone (OR 6.23), lower age (OR 0.86), poorer general health (OR 2.03-5.01), often/always feeling tired (OR 2.38), and an increased risk of falling (OR 1.21). In a linear regression analysis, risk of falling was associated with higher age (B 0.020), not shopping independently (B 0.162), and low meat consumption (B 0.138). There are complex associations between malnutrition risk and the gender-cohabitation interaction, age, general health, tiredness, and risk of falling. In clinical practice comprehensive assessments to identify those at risk of malnutrition including associated factors are needed. These have to be followed by individual nutritional interventions using a holistic perspective which may also contribute to reducing the risk of falling.


Effects of ventricular entry on patient outcome during glioblastoma resection.
Tumor proximity to the ventricle and ventricular entry (VE) during surgery have both been associated with worse prognoses; however, the interaction between these two factors is poorly understood. Given the benefit of maximal tumor resection, it is imperative for surgical planning and technique to know if VE has negative consequences for patient survival and tumor dissemination. The University of California, San Francisco tumor registry was searched for patients with newly diagnosed and recurrent supratentorial glioblastoma (GBM) who underwent resection by the senior author between 2013 and 2018. Tumor location with respect to the subventricular zone (SVZ), size, and extent of resection were assessed using pre- and postoperative imaging. VE was determined by postoperative imaging and/or the operative report. In this 200-patient cohort of newly diagnosed and recurrent GBM, 26.5% of patients had VE during resection. Patients with VE were more likely to have preexisting subependymal disease (41.5% vs 15.0%, p < 0.001). Comparing patients with VE to those without VE, there was no difference in the rates of postoperative hydrocephalus (1.9% vs 4.8%, p = 0.36), ventriculoperitoneal shunting (0% vs 3.4%, p = 0.17), pseudomeningoceles (7.5% vs 5.4%, p = 0.58), or subdural hematomas (11.3% vs 3.4%, p = 0.07). Importantly, rates of subsequent leptomeningeal disease (7.5% vs 10.2%, p = 0.57) and distant parenchymal recurrence (17.0% vs 23.1%, p = 0.35) were not different between the groups. Newly diagnosed patients with tumors contacting the SVZ (type I or II) had worse survival than patients with tumors that did not contact the SVZ (type III or IV) (1.27 vs 1.84 years, p = 0.014, HR 1.8, 95% CI 1.08-3.03), but VE was not associated with worse survival in these patients with high-risk SVZ type I and II tumors (1.15 vs 1.68 years, p = 0.151, HR 0.59, 95% CI 0.26-1.34). VE was well tolerated, with postoperative complications being rare events. There was no increase in leptomeningeal spread or distant parenchymal recurrence in patients with VE. Finally, although survival was worse for patients with preoperative subependymal disease, VE did not change survival for patients with tumors contacting the ventricle. Therefore, VE during GBM resection is not associated with adverse patient outcomes and should be used by surgeons to enhance extent of resection.■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: retrospective cohort; evidence: class II.


Annotation concept synthesis and enrichment analysis: a logic-based approach to the interpretation of high-throughput experiments.
Annotation Enrichment Analysis (AEA) is a widely used analytical approach to process data generated by high-throughput genomic and proteomic experiments such as gene expression microarrays. The analysis uncovers and summarizes discriminating background information (e.g. GO annotations) for sets of genes identified by experiments (e.g. a set of differentially expressed genes, a cluster). The discovered information is utilized by human experts to find biological interpretations of the experiments. However, AEA isolates and tests for overrepresentation only individual annotation terms or groups of similar terms and is limited in its ability to uncover complex phenomena involving relationship between multiple annotation terms from various knowledge bases. Also, AEA assumes that annotations describe the whole object of interest, which makes it difficult to apply it to sets of compound objects (e.g. sets of protein-protein interactions) and to sets of objects having an internal structure (e.g. protein complexes). We propose a novel logic-based Annotation Concept Synthesis and Enrichment Analysis (ACSEA) approach. ACSEA fuses inductive logic reasoning with statistical inference to uncover more complex phenomena captured by the experiments. We evaluate our approach on large-scale datasets from several microarray experiments and on a clustered genome-wide genetic interaction network using different biological knowledge bases. The discovered interpretations have lower P-values than the interpretations found by AEA, are highly integrative in nature, and include analysis of quantitative and structured information present in the knowledge bases. The results suggest that ACSEA can boost effectiveness of the processing of high-throughput experiments. email@example.com.


Cation disorder in Ga1212.
Substitution of calcium for strontium in LnSr2-xCaxCu2GaO7 (Ln = La, Pr, Nd, Gd, Ho, Er, Tm, and Yb) materials at ambient pressure and 975 degrees C results in complete substitution of calcium for strontium in the lanthanum and praseodymium systems and partial substitution in the other lanthanide systems. The calcium saturation level depends on the size of the Ln cation, and in all cases, a decrease in the lattice parameters with calcium concentration was observed until a common, lower bound, average A-cation size is reached. Site occupancies from X-ray and neutron diffraction experiments for LnSr2-xCaxCu2GaO7 (x = 0 and x = 2) confirm that the A-cations distribute between the two blocking-layer sites and the active-layer site based on size. A quantitative link between cation distribution and relative site-specific cation enthalpy for calcium, strontium, and lanthanum within the gallate structure is derived. The cation distribution in other similar materials can potentially be modeled.


Thyroid Disease and Surgery in CHEER: The Nation's Otolaryngology-Head and Neck Surgery Practice-Based Network.
(1) Describe thyroid-related diagnoses and procedures in Creating Healthcare Excellence through Education and Research (CHEER) across academic and community sites. (2) Compare management of malignant thyroid disease across these sites. (3) Provide practice-based data related to flexible laryngoscopy vocal fold assessment before and after thyroid surgery based on the American Academy of Otolaryngology-Head and Neck Surgery Foundation's clinical practice guidelines. Review of retrospective data collection (RDC) database of the CHEER network using ICD-9 and CPT codes related to thyroid conditions. Multisite practice-based network. There were 3807 thyroid patients (1392 malignant, 2415 benign) with 10,160 unique visits identified from 1 year of patient data in the RDC. Analysis was performed for identified cohort of patients using demographics, site characteristics, and diagnostic and procedural distribution. Mean number of patients with thyroid disease per site was 238 (range, 23-715). In community practices, 19% of patients with thyroid disease had cancer versus 45% in the academic setting (P < .001). While academic sites manage more cancer patients, community sites are also surgically treating thyroid cancer and performed more procedures per cancer patient (4.2 vs 3.5, P < .001). Vocal fold function was assessed by flexible laryngoscopy in 34.0% of preoperative patients and in 3.7% postoperatively. This is the first overview of malignant and benign thyroid disease through CHEER. It shows how the RDC can be used alone and with national guidelines to inform of clinical practice patterns in academic and community sites. This demonstrates the potential for future thyroid-related studies utilizing the otolaryngology-head and neck surgery practice-based research network.