Urinary NMP22 and karyometry in the diagnosis and follow-up of patients with superficial bladder cancer.
To study the value of two outpatient urine tests with regard to the diagnosis and recurrence of bladder tumors. Fifty patients with a history of superficial bladder cancer were evaluated with urinary NMP22 levels (cutoff level 10 U/ml), bladder wash karyometry (low versus intermediate and high risk) and cystoscopy. All patients were followed for 1 year. Diagnostic negative and positive predictive values (NPV and PPV) of the tests were, respectively: NMP22 91.2 and 56.3%, and karyometry 80 and 33.3%. Prognostic NPV and PPV with regard to a subsequent recurrence were, respectively: NMP22 77.8 and 27.3%, and karyometry 82.6 and 50%. The diagnostic value of NMP22 is good. Since the 3 false-negative results were in low-stage and low-grade lesions, this test could be used as a prescreening for cystoscopy. The NPV of these tests with regard to tumor recurrence is around 80%, but only karyometry has a significant PPV. Change in the follow-up policy on the basis of these tests remains difficult. In patients with neobladders NMP22 appears to be of little use, because of the high urinary NMP22 levels in the absence of malignancy.


The N-glycome of human plasma.
N-linked glycans isolated from human plasma proteins have been profiled and sequenced by mass spectrometry using an ion trap instrument (ITMSn). The released glycans were prepared as reduced, methylated analogues and directly infused into a chip-based nanoelectrospray ionization system and analyzed by ITMSn. The resulting mass profiles (MS1) of IgG-depleted and nondepleted plasma samples were contrasted and these results were again compared with recent literature reports. Before depletion, approximately 50 independent glycan ions were detected; this more than doubled to 106 after depletion. The mass range profiled was 1-5 kDa which included many doubly and triply charged ions that were resolved by higher MS resolution. Selected ions in the depleted sample were disassembled to define their detailed structure providing a high-performance sequencing result. The simplicity of this nonchromatographic, direct infusion and gas-phase structural characterization compares most favorably with the latest reports using alternative instrumentation and adjunct techniques.


Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors.
Insulin-regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non-peptide IRAP inhibitors derived from a spiro-oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)-promoted three-component reaction, or by a two-step one-pot procedure. For decoration of the oxindole ring system, rapid MW-assisted Suzuki-Miyaura cross-couplings (1 min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S-configuration of the spiro-oxindole dihydroquinazolinones accounts for the inhibition of IRAP.


Analysis of the virulence of an atypical enteropathogenic Escherichia coli strain in vitro and in vivo and the influence of type three secretion system.
Atypical enteropathogenic Escherichia coli (aEPEC) inject various effectors into intestinal cells through a type three secretion system (T3SS), causing attaching and effacing (A/E) lesions. We investigated the role of T3SS in the ability of the aEPEC 1711-4 strain to interact with enterocytes in vitro (Caco-2 cells) and in vivo (rabbit ileal loops) and to translocate the rat intestinal mucosa in vivo. A T3SS isogenic mutant strain was constructed, which showed marked reduction in the ability to associate and invade but not to persist inside Caco-2 cells. After rabbit infection, only aEPEC 1711-4 was detected inside enterocytes at 8 and 24 hours pointing to a T3SS-dependent invasive potential in vivo. In contrast to aEPEC 1711-4, the T3SS-deficient strain no longer produced A/E lesions or induced macrophage infiltration. We also demonstrated that the ability of aEPEC 1711-4 to translocate through mesenteric lymph nodes to spleen and liver in a rat model depends on a functional T3SS, since a decreased number of T3SS mutant bacteria were recovered from extraintestinal sites. These findings indicate that the full virulence potential of aEPEC 1711-4 depends on a functional T3SS, which contributes to efficient adhesion/invasion in vitro and in vivo and to bacterial translocation to extraintestinal sites.


Nickel mine soil is a potential source for soybean plant growth promoting and heavy metal tolerant rhizobia.
Mine soil is not only barren but also contaminated by some heavy metals. It is unclear whether some rhizobia survived under extreme conditions in the nickel mine soil. Therefore, this study tries to isolate some effective soybean plant growth promoting and heavy metal resistant rhizobia from nickel mine soil, and to analyze their diversity. Soybean plants were used to trap rhizobia from the nickel mine soil. A total of 21 isolates were preliminarily identified as rhizobia, which were clustered into eight groups at 87% similarity level using BOXA1R-PCR fingerprinting technique. Four out of the eight representative isolates formed nodules on soybean roots with effectively symbiotic nitrogen-fixing and plant growth promoting abilities in the soybean pot experiment. Phylogenetic analysis of 16S rRNA, four housekeeping genes (atpD-recA-glnII-rpoB) and nifH genes assigned the symbiotic isolates YN5, YN8 and YN10 into Ensifer xinjiangense and YN11 into Rhizobium radiobacter, respectively. They also showed different tolerance levels to the heavy metals including cadmium, chromium, copper, nickel, and zinc. It was concluded that there were some plant growth promoting and heavy metal resistant rhizobia with the potential to facilitate phytoremediation and alleviate the effects of heavy metals on soybean cultivation in nickel mine soil, indicating a novel evidence for further exploring more functional microbes from the nickel mine soil.


COVID-19 and kidney transplantation: an Italian Survey and Consensus.
Italy was the first Western country to face the COVID-19 pandemic. Here we report the results of a national survey on kidney transplantation activity in February and March 2020, and the results of a three-round Delphi consensus promoted by four scientific societies: the Italian Society of Organ Transplantation, the Italian Society of Nephrology, the Italian Society of Anesthesia and Intensive Care, and the Italian Group on Antimicrobial Stewardship. All 41 Italian transplant centers were invited to express their opinion in the Delphi rounds along with a group of seven experts. The survey revealed that, starting from March 2020, there was a decline in kidney transplantation activity in Italy, especially for living-related transplants. Overall, 60 recipients tested positive for SARS-CoV2 infection, 57 required hospitalization, 17 were admitted to the ICU, and 11 died. The online consensus had high response rates at each round (95.8%, 95.8%, and 89.5%, respectively). Eventually, 27 of 31 proposed statements were approved (87.1%), 12 at the first or second round (38.7%), and 3 at the third (9.7%). Based on the Italian experience, we discuss the reasons for the changes in kidney transplantation activity during the COVID-19 pandemic in Western countries. We also provide working recommendations for the organization and management of kidney transplantation under these conditions.


Polarization-sensitive full-field optical coherence tomography.
We present a polarization-sensitive full-field optical coherence tomography system that can produce high-resolution images of the linear retardance and reflectivity properties of biological media. En face images can be delivered at a frame rate of 3.5 Hz by combination of interferometric images acquired by two CCD cameras in an interference microscope illuminated with a tungsten halogen lamp. Isotropic spatial resolution of approximately 1.0 microm is achieved. The technique is demonstrated on ex vivo muscle tissues.


The RET oncogene in papillary thyroid carcinoma.
Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for greater than 80% of cases. Surgical resection, with or without postoperative radioiodine therapy, remains the standard of care for patients with PTC, and the prognosis is generally excellent with appropriate treatment. Despite this, significant numbers of patients will not respond to maximal surgical and medical therapy and ultimately will die from the disease. This mortality reflects an incomplete understanding of the oncogenic mechanisms that initiate, drive, and promote PTC. Nonetheless, significant insights into the pathologic subcellular events underlying PTC have been discovered over the last 2 decades, and this remains an area of significant research interest. Chromosomal rearrangements resulting in the expression of fusion proteins that involve the rearranged during transfection (RET) proto-oncogene were the first oncogenic events to be identified in PTC. Members of this fusion protein family (the RET/PTC family) appear to play an oncogenic role in approximately 20% of PTCs. Herein, the authors review the current understanding of the clinicopathologic role of RET/PTC fusion proteins in PTC development and progression and the molecular mechanisms by which RET/PTCs exert their oncogenic effects on the thyroid epithelium.


Upscaling of fungal-bacterial interactions: from the lab to the field.
Fungal-bacterial interactions (FBI) are an integral component of microbial community networks in terrestrial ecosystems. During the last decade, the attention for FBI has increased tremendously. For a wide variety of FBI, information has become available on the mechanisms and functional responses. Yet, most studies have focused on pairwise interactions under controlled conditions. The question to what extent such studies are relevant to assess the importance of FBI for functioning of natural microbial communities in real ecosystems remains largely unanswered. Here, the information obtained by studying a type of FBI, namely antagonistic interactions between bacteria and plant pathogenic fungi, is discussed for different levels of community complexity. Based on this, general recommendations are given to integrate pairwise and ecosystem FBI studies. This approach could lead to the development of novel strategies to steer terrestrial ecosystem functioning.


Positron emission tomography (PET) measurements of striatal D(2) receptors in untreated Parkinson's disease patients with follow-up after 6 and 12 months' treatment with SINEMET((R)) or SINEMET((R)) CR.
Untreated Parkinson's disease (FD) patients typically demonstrate an upregulation in striatal D(2) receptor binding. Reduced D(2) binding is found in levodopa-treated patients with a fluctuating response to this drug. Using PET and (11)C-raclopride, we determined striatal:background uptake ratios to provide a measure of D(2) receptor binding in 10 untreated, newly diagnosed PD patients who were treated subsequently with levodopa for 1 yr. At baseline, we found increased striatal D(2) receptor uptake ratios in patients (3.89) in comparison to normal controls (3.22; p < 0.02). Furthermore, the ratio between caudate and putamen D(2) uptake was significantly reduced in patients (0.86 vs. 0.98 in normals, p < 0.01). Patients were subsequently randomized to treatment with either SINEMET((R)) (300 mg of levodopa/d) or SINEMET((R)) CR (400 mg of levodopa/d). Patients in both groups received similar symptomatic benefit following treatment, and none developed motor fluctuations. All patients were rescanned after 6 months of treatment. There were no significant differences in striatal (or caudate and putamen considered singly) raclopride binding between the first and 6 month post-treatment scans. Similarly, there were no significant differences between pre- and 6 month post-treatment scans on the basis of levodopa preparations. Patients were subsequently treated with the other Sinemet preparation for another 6 month period before rescanning. Again, no differences in raclopride binding were found compared to pre-treatment or between type of levodopa preparation. We conclude that there is no evidence for downregulation of D(2) receptor binding after 1 yr of low-dose levodopa therapy in patients who receive symptomatic benefit without motor fluctuations, regardless of type of preparation. Follow-up of such individuals may permit determination of when and in what context D(2) receptor downregulation occurs.


Cytotoxic T lymphocyte discrimination between type A Epstein-Barr virus transformants is mapped to an immunodominant epitope in EBNA 3.
An immunodominant Epstein-Barr virus (EBV)-specific cytotoxic T lymphocyte (CTL) epitope, represented by peptide 68, has been mapped to the EBV nuclear antigen, EBNA 3. The epitope is recognized by class I-restricted CTLs through HLA-B8 and is functionally active on type A but not type B lymphoblastoid cell lines (LCLs). Herein we show that peptide 68 is not expressed as a functional CTL epitope by type A LCLs infected with an EBV B95-8 isolate. CTLs from cultures stimulated with autologous type A IARC-BL74 or QIMR-WIL LCLs lysed autologous cells stimulated with phytohaemagglutinin (PHA blasts) and coated with exogenous peptide 68. No peptide 68-specific CTLs were generated in cultures stimulated with autologous type A B95-8 or type B AG876 LCLs. However, the B95-8 LCL coated with peptide 68 was effective in the induction of a peptide-specific CTL response. A peptide 68-specific CTL clone failed to lyse the B95-8 LCL, type B AG876 LCL and PHA blasts, although such targets were lysed when coated with peptide 68.


Complement factor and T-cell interactions during alloimmune inflammation in transplantation.
Complement factor and T-cell signaling during an effective alloimmune response plays a key role in transplant-associated injury, which leads to the progression of chronic rejection (CR). During an alloimmune response, activated complement factors (C3a and C5a) bind to their corresponding receptors (C3aR and C5aR) on a number of lymphocytes, including T-regulatory cells (Tregs), and these cell-molecular interactions have been vital to modulate an effective immune response to/from Th1-effector cell and Treg activities, which result in massive inflammation, microvascular impairments, and fibrotic remodeling. Involvement of the complement-mediated cell signaling during transplantation signifies a crucial role of complement components as a key therapeutic switch to regulate ongoing inflammatory state, and further to avoid the progression of CR of the transplanted organ. This review highlights the role of complement-T cell interactions, and how these interactions shunt the effector immune response during alloimmune inflammation in transplantation, which could be a novel therapeutic tool to protect a transplanted organ and avoid progression of CR.


Influence of non-invasive blood pressure measurement intervals on the occurrence of intra-operative hypotension.
The American Society of Anesthesiologists Standards for Basic Monitoring recommends blood pressure (BP) measurement every 5 min. Research has shown distractions or technical factors can cause prolonged measurement intervals exceeding 5 min. We investigated the relationship between prolonged non-invasive BP (NIBP) measurement interval and the incidence of hypotension, detected post-interval. Our secondary outcome was to determine independent predictors of these prolonged NIBP measurement intervals. Retrospective data were analyzed from 139,509 general anesthesia cases from our institution's Anesthesia Information Management System (AIMS). Absolute hypotension (AH) was defined a priori as a systolic BP < 80 mmHg and relative hypotension (RH) was defined as a 40% decrease in systolic BP from the preoperative baseline. Odds ratios (OR) with 95% confidence intervals and Pearson's Chi square Test reported the association of prolonged NIBP measurement intervals on hypotension detected post-NIBP measurement interval. Logistic regression models were developed to determine independent predictors of NIBP measurement intervals. The analysis revealed that NIBP measurement intervals greater than 6 and 10 min are associated with an approximately four times higher incidence of a patient transitioning into hypotension (AH/RH > 6 min OR 4.0 / 3.6; AH/RH > 10 min OR 4.3 / 3.9; p < 0.001). A key finding was that the "> 10-minute AH model" indicated that age 41-80, increased co-morbidity profile, obesity and turning (repositioning) of the operative room table were significant predictors of prolonged NIBP measurement intervals (p < 0.001). While we do not suggest NIBP measurement intervals cause hypotension, intervals greater than 6 and 10 min are associated with a fourfold increase in the propensity of an undetected transition into both RH or AH. These data support current monitoring guidelines.


Perinucleolar relocalization and nucleolin as crucial events in the transcriptional activation of key genes in mantle cell lymphoma.
In mantle cell lymphoma (MCL), one allele of the cyclin D1 (Ccnd1) gene is translocated from its normal localization on chromosome 11 to chromosome 14. This is considered as the crucial event in the transformation process of a normal naive B-cell; however, the actual molecular mechanism leading to Ccnd1 activation remains to be deciphered. Using a combination of three-dimensional and immuno-fluorescence in situ hybridization experiments, the radial position of the 2 Ccnd1 alleles was investigated in MCL-derived cell lines and malignant cells from affected patients. The translocated Ccnd1 allele was observed significantly more distant from the nuclear membrane than its nontranslocated counterpart, with a very high proportion of IgH-Ccnd1 chromosomal segments localized next to a nucleolus. These perinucleolar areas were found to contain active RNA polymerase II (PolII) clusters. Nucleoli are rich in nucleolin, a potent transcription factor that we found to bind sites within the Ccnd1 gene specifically in MCL cells and to activate Ccnd1 transcription. We propose that the Ccnd1 transcriptional activation in MCL cells relates to the repositioning of the rearranged IgH-Ccnd1-carrying chromosomal segment in a nuclear territory with abundant nucleolin and active PolII molecules. Similar transforming events could occur in Burkitt and other B-cell lymphomas.


Sources of error in reported childlessness in a continuous British household survey.
A recent investigation of the British General Household Survey (GHS) found substantial over-reporting of childlessness in recent years, particularly at older ages. We examine the phenomenon in further detail and find that the principal cause was change in survey procedures. To some extent the bias can be corrected for by using information on own children in the household. Revised fertility histories give period estimates of total fertility that are in close agreement with national vital registration statistics, unlike those based on original fertility histories of recent years. Misreporting in fertility histories dates primarily from administrative changes in the GHS in the years 1998-2000, and particularly from 2003, when the option of laptop self-completion (CASI) was introduced for reporting demographic histories.


Lyophilized oral sustained release polymeric nanoparticles of nateglinide.
The objective of this study is to formulate lyophilized oral sustained release polymeric nanoparticles of nateglinide in order to decrease dosing frequency, minimize side effects, and increase bioavailability. Nateglinide-loaded poly Ɛ-caprolactone nanoparticles were prepared by emulsion solvent evaporation with ultrasonication technique and subjected to various studies for characterization including scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, photon correlation spectroscopy and evaluated for in vitro drug release and pharmacodynamic studies. The influence of increase in polymer concentration, ultrasonication time, and solvent evaporation rate on nanoparticle properties was investigated. The formulations were optimized based on the above characterization, and the formulation using 5% polymer, 3-min sonication time, and rota-evaporated was found to have the best drug entrapment efficiency of 64.09±4.27% and size of 310.40±11.42 nm. Based on SEM, nanoparticles were found to be spherical with a smooth surface. In vitro drug release data showed that nanoparticles sustained the nateglinide release for over 12 h compared to conventional tablets (Glinate 60 mg), and drug release was found to follow Fickian mechanism. In vivo studies showed that nanoparticles prolonged the antidiabetic activity of nateglinide in rats significantly (p≤0.05) compared to the conventional tablets (Glinate 60 mg) over a period of 12 h. Accelerated stability data indicated that there was minimal to no change in drug entrapment efficiency.


Modulating the band gap of germanane nanoribbons for quantum well devices.
The effective modulation of the band gaps in nanostructures is of both fundamental and technological interest because a tunable band gap gives great flexibility in the design and optimization of nanodevices. Using density functional theory calculations, we have shown that germanane nanoribbons of various widths or under various strains can provide rich band gaps. Width- and strain-induced changes in the band gaps of germanane nanoribbons result from a reduction in quantum confinement with width and the weakening of sp(3) hybridization with strain, respectively. Both changes represent a monotonous relationship. To utilize such a monotonous change in band gap, we designed a quantum well based on germanane nanoribbons in which photoexcited electrons and holes occupy the same spatial region, resulting in a desirable light-emitting device.


Novel metabolic risk factors for incident heart failure and their relationship with obesity: the MESA (Multi-Ethnic Study of Atherosclerosis) study.
The objectives of this study were to determine the associations of the metabolic syndrome, inflammatory markers, and insulin resistance with incident congestive heart failure (CHF), beyond established risk factors, and to examine whether these risk factors may provide the link between obesity and CHF. Recently, increasing interest has emerged on the potential role of novel risk factors such as systemic inflammation, insulin resistance, and albuminuria in the pathophysiology of CHF and their relationship with obesity. The MESA (Multi-Ethnic Study of Atherosclerosis) study is a community-based multicenter cohort study of 6,814 participants (age 45 to 84 years, 3,601 women) of 4 ethnicities: Caucasians, African Americans, Hispanics, and Chinese Americans. Participants were recruited between 2000 and 2002 from 6 U.S. communities. Median follow-up time was 4 years. Participants with history of symptomatic cardiovascular disease were excluded. Cox proportional hazards models were used to analyze the associations of the metabolic syndrome, inflammatory markers, insulin resistance, and albuminuria with incident CHF, independent of established risk factors (age, gender, hypertension, diabetes mellitus, left ventricular hypertrophy, obesity, serum total cholesterol, and smoking), an interim myocardial infarction, and baseline magnetic resonance imaging parameters of left ventricular structure and function. A total of 79 participants developed CHF during follow-up, and 26 participants (32.9%) had a myocardial infarction prior to CHF and 65% of the cases had CHF with preserved function (left ventricular ejection fraction >or=40%). In multivariable analyses, serum interleukin-6 (hazard ratio [HR] for 1 standard deviation 1.50, 95% confidence interval [CI] 1.10 to 2.03) or C-reactive protein (HR for 1 standard deviation 1.38; 95% CI 1.01 to 1.86) and macroalbuminuria (HR 4.31, 95% CI 1.58 to 11.76) were predictors of CHF, independent of obesity and the other established risk factors. Although obesity was significantly associated with incident CHF, this association was no longer significant after adding inflammatory markers (interleukin-6 or C-reactive protein) to the model. Inflammatory markers and albuminuria are independent predictors of CHF. The association of obesity and CHF may be related to pathophysiologic pathways associated with inflammation.


Chronic Model of Inflammatory Bowel Disease in IL-10-/- Transgenic Mice: Evaluation with Ultrasound Molecular Imaging.
Objective: Acute mouse models of inflammatory bowel disease (IBD) fail to mirror the chronic nature of IBD in patients. We sought to develop a chronic mouse IBD model for assessing long-term anti-inflammatory effects with ultrasound molecular imaging (USMI) by using dual P- and E-selectin targeted microbubbles (MBSelectin). Materials and Methods: Interleukin 10 deficient (IL-10-/- on a C57BL/6 genetic background; n=55) and FVB (n=16) mice were used. In IL-10-/-mice, various experimental regimens including piroxicam, 2,4,6-trinitrobenzenesulfonic acid (TNBS) or dextran sulfate sodium (DSS), respectively were used for promoting colitis; colitis was induced with DSS in FVB mice. Using clinical and small animal ultrasound scanners, evolution of inflammation in proximal, middle and distal colon, was monitored with USMI by using MBSelectin at multiple time points. Imaged colon segments were analyzed ex vivo for inflammatory changes on H&E staining and for P-selectin expression on immunofluorescence staining. Results: Sustained colitis was not detected with USMI in IL-10-/- or FVB mice with various experimental regimens. USMI signals either gradually decreased after the colitis enhancing/inducing drug/agents were discontinued, or the mortality rate of mice was high. Inflammation was observed on H&E staining in IL-10-/- mice with piroxicam promotion, while stable overexpression of P-selectin was not found on immunofluorescence staining in the same mice. Conclusion: Sustained colitis in IL-10-/- mice induced with piroxicam, TNBS or DSS, and in FVB mice induced with DSS, was not detected with USMI using MBSelectin, and this was verified by immunofluorescence staining for inflammation marker P-selectin. Thus, these models may not be appropriate for long-term monitoring of chronic colitis and subsequent treatment response with dual-selectin targeted USMI.


Self-assembled Fe3O4 nanoparticle clusters as high-performance anodes for lithium ion batteries via geometric confinement.
Although different kinds of metal oxide nanoparticles continue to be proposed as anode materials for lithium ion batteries (LIBs), their cycle life and power density are still not suitable for commercial applications. Metal oxide nanoparticles have a large storage capacity, but they suffer from the excessive generation of solid-electrolyte interphase (SEI) on the surface, low electrical conductivity, and mechanical degradation and pulverization resulted from severe volume expansion during cycling. Herein we present the preparation of mesoporous iron oxide nanoparticle clusters (MIONCs) by a bottom-up self-assembly approach and demonstrate that they exhibit excellent cyclic stability and rate capability derived from their three-dimensional mesoporous nanostructure. By controlling the geometric configuration, we can achieve stable interfaces between the electrolyte and active materials, resulting in SEI formation confined on the outer surface of the MIONCs.


[Effects of benzofurocaine, etaden and xanthinol nicotinate on reparative bone regeneration in animal experiments].
In the process of treatment of experimental close fractures of radius in rats by intramuscular administration of benzofurocaine (60 mg/kg), the regeneration processes of the bone tissue were activated to a greater degree than in case of administration of etadene (20 mg/kg) or xanthinol nicotinate (30 mg/kg). Under the influence of benzofurocaine, beginning on the 10-20-th day of the experiment, there have been noted the reorganization of young callus into the mature laminal bone. The preparations of comparison have demonstrated less expressed analogous action.


The reliability of peer assessments of quality of care.
To critically examine the literature regarding the interreviewer reliability of the standard practice of peer assessment of quality of care. Computerized searches of the English-language literature from 1966 through 1990 using MEDLINE, HEALTHLINE, and SCISEARCH databases were performed to identify studies reporting data on interreviewer agreement of implicit evaluations of patient care episodes. Seventeen studies were identified. Five studies were excluded from this review because of deficiencies in the methods or lack of data on chance-corrected indexes of agreement. DATA EXTRACTION SYNTHESIS: The degree of agreement beyond chance was compared with accepted standards in the 12 remaining studies. Most of these studies found agreement corrected for chance to be in the range regarded as poor, indicating that physician agreement regarding quality of care is only slightly better than the level expected by chance. Given the magnitude of the resources devoted to quality assurance and the centrality of peer assessment to these efforts, there is a need for a global reexamination of the peer review process. A number of proposals appear to have potential for improving the peer review process including more objective assessment procedures, multiple reviewers, higher standards for reviewers, elimination of systematic reviewer bias, use of outcome judgements, and adoption of practice guidelines.


User-Centered Design of the C3-Cloud Platform for Elderly with Multiple Diseases - Functional Requirements and Application Testing.
The number of patients with multimorbidity has been steadily increasing in the modern aging societies. The European C3-Cloud project provides a multidisciplinary and patient-centered "Collaborative Care and Cure-system" for the management of elderly with multimorbidity, enabling continuous coordination of care activities between multidisciplinary care teams (MDTs), patients and informal caregivers (ICG). In this study various components of the infrastructure were tested to fulfill the functional requirements and the entire system was subjected to an early application testing involving different groups of end-users. MDTs from participating European regions were involved in requirement elicitation and test formulation, resulting in 57 questions, distributed via an internet platform to 48 test participants (22 MDTs, 26 patients) from three pilot sites. The results indicate a high level of satisfaction with all components. Early testing also provided feedback for technical improvement of the entire system, and the paper points out useful evaluation methods.


New record of Akashiwo sanguinea (Dinophyta) in the tropical estuarine waters of Northeastern Brazil (Western Atlantic).
This study reports the occurrence and the effect of the environmental factors on the spatial and temporal distribution of the dinoflagellate Akashiwo sanguinea (Hirasaka) Hansen & Moestrup in estuarine waters of northeastern Brazil. Samples were collected at seven stations from March 2007 to February 2008 during high tide and low tide, using Van Dorn bottles. The samples were immediately fixed with Lugol and analyzed with the Utermöhl method. Water samples were also collected for the identification of the hydrological characteristics of the area. Akashiwo sanguinea occurred throughout the annual cycle and at all sampling sites with densities ranging between 5 and 410 x 103 cells.L-1. The highest densities were recorded at low tide, especially during the months of the rainy season (July: 210 x 103 cells.L-1; August: 410 x 103 cells.L-1). Density values were within the normal range and blooms were not detected. Despite being common in the area, the species showed preference for sites with high concentrations of orthophosphate and total dissolved phosphorus and with salinity in the mesohaline regime.


CO2 Biofixation of Actinobacillus succinogenes Through Novel Amine-Functionalized Polystyrene Microsphere Materials.
CO2-derived succinate production was enhanced by Actinobacillus succinogenes through polystyrene (PSt) microsphere materials for CO2 adsorption in bioreactor, and the adhesion forces between A. succinogenes bacteria and PSt materials were characterized. Synthesized uniformly sized and highly cross-linked PSt microspheres had high specific surface areas. After modification with amine functional groups, the novel amine-functionalized PSt microspheres exhibited a high adsorption capacity of 25.3 mg CO2/g materials. After addition with the functionalized microspheres into the culture broth, CO2 supply to the cells increased. Succinate production by A. succinogenes can be enhanced from 29.6 to 48.1 g L-1. Moreover, the characterization of interaction forces between A. succinogenes cells and the microspheres indicated that the maximal adhesive force was about 250 pN. The amine-functionalized PSt microspheres can adsorb a large amount of CO2 and be employed for A. succinogenes anaerobic cultivation in bioreactor for high-efficiency production of CO2-derived succinate.


Analysis of Tumor-Infiltrating T-Cell Transcriptomes Reveal a Unique Genetic Signature across Different Types of Cancer.
CD8+ and CD4+ T-cells play a key role in cellular immune responses against cancer by cytotoxic responses and effector lineages differentiation, respectively. These subsets have been found in different types of cancer; however, it is unclear whether tumor-infiltrating T-cell subsets exhibit similar transcriptome profiling across different types of cancer in comparison with healthy tissue-resident T-cells. Thus, we analyzed the single cell transcriptome of five tumor-infiltrating CD4-T, CD8-T and Treg cells obtained from different types of cancer to identify specific pathways for each subset in malignant environments. An in silico analysis was performed from single-cell RNA-sequencing data available in public repositories (Gene Expression Omnibus) including breast cancer, melanoma, colorectal cancer, lung cancer and head and neck cancer. After dimensionality reduction, clustering and selection of the different subpopulations from malignant and nonmalignant datasets, common genes across different types of cancer were identified and compared to nonmalignant genes for each T-cell subset to identify specific pathways. Exclusive pathways in CD4+ cells, CD8+ cells and Tregs, and common pathways for the tumor-infiltrating T-cell subsets were identified. Finally, the identified pathways were compared with RNAseq and proteomic data obtained from T-cell subsets cultured under malignant environments and we observed that cytokine signaling, especially Th2-type cytokine, was the top overrepresented pathway in Tregs from malignant samples.


Antitumor activity and immunotherapeutic properties of Flt3-ligand in a murine breast cancer model.
Flt3-Ligand (Flt3-L) is a stimulatory cytokine for a variety of hematopoietic lineages, including dendritic cells and B cells. The antitumor properties of Flt3-L were evaluated in C3H/HeN mice challenged with the syngeneic C3L5 murine breast cancer cell line. Eighty % of animals receiving 500 microg/kg/day of Chinese hamster ovary-derived human Flt3-L for 10 days were protected from tumor growth, whether the tumor challenge was administered on the first or fourth days of Flt3-L administration. The protection provided by soluble Flt3-L was transient. All tumor-free animals rechallenged 4 weeks after the primary challenge developed tumor. Transduction of C3L5 with retroviral vectors expressing human or murine Flt3-L did not influence in vitro growth or MHC expression but decreased in vivo tumor development to 0 and 10% of mice, respectively. This compares with tumor growth of 52% with interleukin-2 transduced C3L5 and over 85% with untransduced and control vector-transduced C3L5. Unlike animals treated with soluble Flt3-L, administration of Flt3-L as a tumor vaccine protected mice from a subsequent challenge with untransduced C3L5 in 60-78% of mice, compared to 0% of controls. Our initial work used the most common Flt3-L isoform, which is membrane bound but can undergo proteolytic cleavage to generate a soluble form. To evaluate the role of the various Flt3-L isoforms in preventing tumor formation, retroviral vectors encoding only the membrane-bound form or only the soluble isoform were evaluated in the C3L5 model. Tumor formation was similar with either isoform, preventing tumor formation in 80-90% of mice after the primary challenge and 88-89% after the secondary challenge. Splenocytes obtained 4 weeks after the secondary challenge conferred adoptive immunity to naive mice in 60% of animals. This initial report of antitumor activity by Flt3-L is consistent with its known stimulatory effect on antigen-presenting cells and suggests it may enhance the development of tumor vaccines.


Tinnitus and Coxsackie B infections: a case series.
Tinnitus is a frequent and often debilitating condition. There is consensus in the scientific community that there exist various forms of tinnitus, which differ in their pathogenesis. Here we report a series of five cases where the onset of tinnitus was associated with viral infections. In all five patients elevated antibodies against Coxsackie B have been detected. This observation suggests that Coxsackie B Virus infections might be involved in the development of some cases of tinnitus and indicate that further systematic investigations are warranted.


Elevated Ghrelin Promotes Hippocampal Ghrelin Receptor Defects in Humanized Amyloid-β Knockin Mice During Aging.
Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer's disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin (hAβ KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAβ KI mice as well as primary neuron cultures. We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings.


It's OK to Fail: Individual and Dyadic Regulatory Antecedents of Mastery Motivation in Preschool.
Mastery motivation is closely related to children's regulatory processes and is socialized by parents. However, we know little about how individual child and dyadic parent-child regulatory processes work together to foster the early development of mastery motivation in preschool. The present study examined dyadic persistence in parent-child interactions, children's effortful control, and children's successful versus failed attempts in a challenging object mastery task at age 3.5 years and their prediction of teacher ratings of object-oriented and social mastery motivation in preschool at a 4-month follow-up (N = 100). Path analytic models revealed that greater dyadic persistence during parent-child interactions predicted children's higher levels of social mastery. A greater rate of both successful and failed attempts at a challenging task predicted children's higher levels of object mastery. However, failed attempts were positively related to concurrent individual and dyadic regulatory measures, whereas successful attempts were not. Findings suggest that parent-child coregulation makes a significant contribution to mastery motivation development and that there may be distinct antecedents for object-oriented versus social forms of mastery motivation. Findings also suggest that a child's early ability to persist in the face of failure may be an important predictor of mastery motivation in preschool.


Mitochondrial Dysfunction-Associated Mechanisms in the Development of Chronic Liver Diseases.
The liver is a major metabolic organ that performs many essential biological functions such as detoxification and the synthesis of proteins and biochemicals necessary for digestion and growth. Any disruption in normal liver function can lead to the development of more severe liver disorders. Overall, about 3 million Americans have some type of liver disease and 5.5 million people have progressive liver disease or cirrhosis, in which scar tissue replaces the healthy liver tissue. An estimated 20% to 30% of adults have excess fat in their livers, a condition called steatosis. The most common etiologies for steatosis development are (1) high caloric intake that causes non-alcoholic fatty liver disease (NAFLD) and (2) excessive alcohol consumption, which results in alcohol-associated liver disease (ALD). NAFLD is now termed "metabolic-dysfunction-associated steatotic liver disease" (MASLD), which reflects its association with the metabolic syndrome and conditions including diabetes, high blood pressure, high cholesterol and obesity. ALD represents a spectrum of liver injury that ranges from hepatic steatosis to more advanced liver pathologies, including alcoholic hepatitis (AH), alcohol-associated cirrhosis (AC) and acute AH, presenting as acute-on-chronic liver failure. The predominant liver cells, hepatocytes, comprise more than 70% of the total liver mass in human adults and are the basic metabolic cells. Mitochondria are intracellular organelles that are the principal sources of energy in hepatocytes and play a major role in oxidative metabolism and sustaining liver cell energy needs. In addition to regulating cellular energy homeostasis, mitochondria perform other key physiologic and metabolic activities, including ion homeostasis, reactive oxygen species (ROS) generation, redox signaling and participation in cell injury/death. Here, we discuss the main mechanism of mitochondrial dysfunction in chronic liver disease and some treatment strategies available for targeting mitochondria.


[GABAC receptors: structure and functions].
Data on the structure, localization, physiology and pharmacology of GABA(C) receptors are reviewed. Thece receptors belong to cys-loop receptors and consist of rho1-3 subunits representing pentamers with five subunits that form a chloride channel. They are found in both central nervous system and peripheral organs. The pentamer can be homomeric, consisting of five similar protomers (e.g., p1), or heteromeric (pseudo-homomeric), consisting of rho1 and rho2 subunits. Chloride channel function also depends on the GABA(C) receptor subunit composition. The activation of GABAc receptors is accompanied by a change in the permeability of plasmatic membranes for C1 ions, which is followed by depolarization (presynaptic inhibition) or hyperpolarization (postsynaptic inhibition). There are a great number of the allosteric modulators, agonists and antagonists of GABA(C) receptors.


Gis analysis of patch use and group cohesiveness of bearded sakis (chiropotes sagulatus) in the upper essequibo conservation concession, Guyana.
This study examines how northern bearded sakis (Chiropotes sagulatus) in Guyana adjust group cohesiveness according to the distribution and quality of food patches. I introduce a GIS based method for quantifying food patch quality and how it relates to bearded saki group spread and group size. While the concept of food patch is central to most models of primate socioecology, defining what constitutes a patch has been notoriously problematic in primate studies. In addition, researchers have struggled to quantify group spread and group cohesiveness. Advances in spatial analysis software in the last decade now allow primate researchers to better quantify these variables. Group spread in bearded sakis was not significantly greater in lower quality patches and sakis were not more spread out during feeding than during other activities. However, the study group was significantly less spread out during social behavior. Bearded saki group size was significantly correlated with both monthly fruit abundance and patch quality. In fact, mean daily patch quality explained ∼40% of the variation in foraging party size. These results suggest that bearded sakis may rely on a highly fluid social structure to mitigate the effects of intragroup feeding competition while living in large groups. Sakis do not adjust group spread on a patch-by-patch basis but rather fission into smaller foraging parties when resources become scarce seasonally and patch quality is low. This study shows that GIS is a powerful tool for modeling the relationship between group cohesiveness and resource quality and distribution.


Substance Abuse and HIV/AIDS in the Caribbean.
The Caribbean and Central America represent a formidable challenge for researchers and policy makers in the HIV field, due to their pronounced heterogeneity in terms of social, economic, and cultural contexts and the different courses the HIV epidemic has followed in the region. Such contrasting contexts and epidemics can be exemplified by 2 countries that share the island of Hispaniola, the French Creole-speaking Haiti, and the Spanish-speaking Dominican Republic. Haiti has experienced the worst epidemics outside of sub-Saharan Africa. Following a protracted economic and social crisis, recently aggravated by a devastating earthquake, the local HIV epidemic could experience resurgence. The region, strategically located on the way between coca-producing countries and the profitable North American markets, has been a transshipment area for years. Notwithstanding, the impact of such routes on local drug scenes has been very heterogeneous and dynamic, depending on a combination of local mores, drug enforcement activities, and the broad social and political context. Injecting drug use remains rare in the region, but local drug scenes are dynamic under the influence of increasing mobility of people and goods to and from North and South America, growing tourism and commerce, and prostitution. The multiple impacts of the recent economic and social crisis, as well as the influence of drug-trafficking routes across the Caribbean and other Latin American countries require a sustained effort to track changes in the HIV risk environment to inform sound drug policies and initiatives to minimize drug-related harms in the region.


The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study.
Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) ('proposed' algorithm) in a screening algorithm for SSc-PAH. We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively. The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies.


Estimating the Effect of Targeted Screening Strategies: An Application to Colonoscopy and Colorectal Cancer.
Screening behavior depends on previous screening history and family members' behaviors, which can act as both confounders and intermediate variables on a causal pathway from screening to disease risk. Conventional analyses that adjust for these variables can lead to incorrect inferences about the causal effect of screening if high-risk individuals are more likely to be screened. Analyzing the data in a manner that treats screening as randomized conditional on covariates allows causal parameters to be estimated; inverse probability weighting based on propensity of exposure scores is one such method considered here. I simulated family data under plausible models for the underlying disease process and for screening behavior to assess the performance of alternative methods of analysis and whether a targeted screening approach based on individuals' risk factors would lead to a greater reduction in cancer incidence in the population than a uniform screening policy. Simulation results indicate that there can be a substantial underestimation of the effect of screening on subsequent cancer risk when using conventional analysis approaches, which is avoided by using inverse probability weighting. A large case-control study of colonoscopy and colorectal cancer from Germany shows a strong protective effect of screening, but inverse probability weighting makes this effect even stronger. Targeted screening approaches based on either fixed risk factors or family history yield somewhat greater reductions in cancer incidence with fewer screens needed to prevent one cancer than population-wide approaches, but the differences may not be large enough to justify the additional effort required. See video abstract at, http://links.lww.com/EDE/B207.


Clinico-investigative profile of infantile and late-infantile neuronal ceroid lipofuscinoses.
Neuronal ceroid lipofuscinosis is a group of progressive neurodegenerative disorders characterized by accumulation of ceroid lipopigment in lysosomes in neurons and other cell types. This study is a retrospective review of charts of patients with a diagnosis of infantile and late-infantile neuronal ceroid lipofuscinosis seen between January 2009 and December 2011. Of the 16 patients, 5 had infantile type and 11 had late-infantile neuronal ceroid lipofuscinosis. Diagnosis was confirmed by appropriate enzyme assay. Clinical presentation was quite varied. Common presenting features included refractory seizures, developmental delay/regression, and abnormal movements. Visual failure was not common in the present case series, and novel neuroimaging finding in the form of isolated dentate nucleus hyperintensities were noted. During follow-up, all patients had a progressive downhill course and one patient died. Prenatal diagnosis could be offered to one family. This study suggests that infantile and late-infantile neuronal ceroid lipofuscinosis is not uncommon in this region of the country and the phenotype may be different.


Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years.
To (1) identify greatest 6-minute walk distance (6MWD) from among several repetitions (best 6MWD) in a wide age range of healthy volunteers to develop reference values for the multiple repetition 6MWD, and (2) investigate the influence of demographics, anthropometrics, and habitual exercise activity on best 6MWD. Four 6MWD were performed on the same day in a 20-meter corridor by 41 male and 38 female healthy volunteers ranging in age from 20 to 80 years. The greatest 6MWD by each subject from among four 6MWDs was the primary outcome measure. Eighty-six percent had their best 6MWD after the first walk; an average increase of 43 meters was observed from first to best 6MWD (P < 0.003). Best 6MWD averaged 698 +/- 96 meters and was inversely related to age (P < 0.001), directly to height (P < 0.001), and was greater in men than women (P < 0.0002). A regression model accounted for 41% of between-subject variability in best 6MWD (P < 0.00000001). In a subset of older subjects, predicted 6MWD significantly underestimated measured best 6MWD when reference values were used from another study where test familiarization was not provided, but this difference disappeared when value were used from the present and a third study where test familiarization was provided. The present study is the first to provide predicted 6MWD values performed with multiple repetitions and for subjects in the 20-40-year-old age range. Selection of appropriate predicted 6MWD values for interpretation of performance should be guided by subject age and degree of test familiarization provided.


Sleep disorders and gout in Australian adults.
The aims of our study were two-fold. Firstly, to determine if there is an association between gout and OSA in a representative Australian adult population. Secondly, to explore associations between gout and patient reported sleep outcomes. A cross-sectional national online survey of a representative sample of Australian adults > 18 years assessed self-reported doctor-diagnosed OSA, insomnia and patient reported sleep outcomes. Possible undiagnosed OSA was estimated using self-reported frequent loud snoring and witnessed apnoeas. Participants self-reported physician-diagnosed gout and other health conditions. Multivariable logistic regression analyses were performed for both objectives. Odds ratios with 95% confidence intervals were reported. There were 1948 participants of whom 126 (6.5%) had gout and 124 (6.4%) had diagnosed sleep apnoea. After adjusting for age, body mass index (BMI), sex, alcohol intake and the presence of arthritis, those with obstructive sleep apnoea diagnosed on polysomnography were twice as likely to report having gout compared to those without. (OR = 2.6, 95% CI 1.5-4.6). Additionally, participants with symptoms suggestive of sleep apnoea were also twice as likely to have gout compared to those without (OR = 2.8, 95%CI 1.6-5.1). There was also a higher likelihood of restless legs syndrome, insomnia and worry about sleep in patients with gout. Diagnosed and suspected OSA are associated with higher likelihood of gout. Participants with gout are also more likely to report suffering from restless legs syndrome, insomnia and worry about their sleep. Given the morbidity associated with sleep problems, we should be vigilant regarding sleep health in our patients with gout.


[Filariae of rodents useful for the experimental study of human onchocerciasis].
In order to obtain skin and ocular lesions comparable to those which are found in human onchocerciasis, it is not necessary to use members of the genus Onchocerca which are found in large animals and difficult to use. Other Filariae with biological features comparable to Onchocerca volvulus can be used in which microfilariae are localized in capillaries and can escape from the walls and produce lesions similar to those in onchocerciasis. The life cycles of several filariae of rodents have been worked out and they are proposed as experimental models as the tick vectors and the rodent hosts are easily maintained in the laboratory.


Highly Cross-Linked Epoxy Nanofiltration Membranes for the Separation of Organic Chemicals and Fish Oil Ethyl Esters.
Membrane separations are highly desired for the chemical industry because they are inexpensive, avoid the use of heat, can be applied to the purification of a wide range of chemicals, and can be scaled to industrial levels. Separating chemicals with molecular weights between 100 and 300 g mol(-1) remains a significant challenge in the field of organic solvent nanofiltration (OSN) due to their similar sizes and rotational flexibility. In this work, we report the fabrication of poly(epoxy) membranes that show excellent selectivity of over 100:1 for chemicals in this range. The membranes are easily tuned to obtain different flux and selectivity by using interchangeable amine and epoxide monomers. These membranes were used to separate the important nutritional omega-3 fatty acid ethyl esters eicosapentaenoic ethyl ester (EPA-EE) and docosahexaenoic acid ethyl ester (DHA-EE) from each other, despite a small difference in molecular weight (26 g mol(-1)). This is the first example of a separation of EPA-EE and DHA-EE using a membrane process.


Development of a PC-based diabetes simulator in collaboration with teenagers with type 1 diabetes.
The main aim of this study was to develop and test in a pilot study a PC-based interactive diabetes simulator prototype as a part of future Internet-based support systems for young teenagers and their families. A second aim was to gain experience in user-centered design (UCD) methods applied to such subjects. Using UCD methods, a computer scientist participated in iterative user group sessions involving teenagers with Type 1 diabetes 13-17 years old and parents. Input was transformed into a requirements specification by the computer scientist and advisors. This was followed by gradual prototype development based on a previously developed mathematical core. Individual test sessions were followed by a pilot study with five subjects testing a prototype. The process was evaluated by registration of flow and content of input and opinions from expert advisors. It was initially difficult to motivate teenagers to participate. User group discussion topics ranged from concrete to more academic matters. The issue of a simulator created active discussions among parents and teenagers. A large amount of input was generated from discussions among the teenagers. Individual test runs generated useful input. A pilot study suggested that the gradually elaborated software was functional. A PC-based diabetes simulator may create substantial interest among teenagers and parents, and the prototype seems worthy of further development and studies. UCD methods may generate significant input for computer support system design work and contribute to a functional design. Teenager involvement in design work may require time, patience, and flexibility.


Cost-effectiveness of strategies to improve the utilization and provision of maternal and newborn health care in low-income and lower-middle-income countries: a systematic review.
Each year almost 3 million newborns die within the first 28 days of life, 2.6 million babies are stillborn, and 287,000 women die from complications of pregnancy and childbirth worldwide. Effective and cost-effective interventions and behaviours for mothers and newborns exist, but their coverage remains inadequate in low- and middle-income countries, where the vast majority of deaths occur. Cost-effective strategies are needed to increase the coverage of life-saving maternal and newborn interventions and behaviours in resource-constrained settings. A systematic review was undertaken on the cost-effectiveness of strategies to improve the demand and supply of maternal and newborn health care in low-income and lower-middle-income countries. Peer-reviewed and grey literature published since 1990 was searched using bibliographic databases, websites of selected organizations, and reference lists of relevant studies and reviews. Publications were eligible for inclusion if they report on a behavioural or health systems strategy that sought to improve the utilization or provision of care during pregnancy, childbirth or the neonatal period; report on its cost-effectiveness; and were set in one or more low-income or lower-middle-income countries. The quality of the publications was assessed using the Consolidated Health Economic Evaluation Reporting Standards statement. Incremental cost per life-year saved and per disability-adjusted life-year averted were compared to gross domestic product per capita. Forty-eight publications were identified, which reported on 43 separate studies. Sixteen were judged to be of high quality. Common themes were identified and the strategies were presented in relation to the continuum of care and the level of the health system. There was reasonably strong evidence for the cost-effectiveness of the use of women's groups, home-based newborn care using community health workers and traditional birth attendants, adding services to routine antenatal care, a facility-based quality improvement initiative to enhance compliance with care standards, and the promotion of breastfeeding in maternity hospitals. Other strategies reported cost-effectiveness measures that had limited comparability. Demand and supply-side strategies to improve maternal and newborn health care can be cost-effective, though the evidence is limited by the paucity of high quality studies and the use of disparate cost-effectiveness measures. PROSPERO_ CRD42012003255.


Innovative technology-based interventions for autism spectrum disorders: a meta-analysis.
This article reports the results of a meta-analysis of technology-based intervention studies for children with autism spectrum disorders. We conducted a systematic review of research that used a pre-post design to assess innovative technology interventions, including computer programs, virtual reality, and robotics. The selected studies provided interventions via a desktop computer, interactive DVD, shared active surface, and virtual reality. None employed robotics. The results provide evidence for the overall effectiveness of technology-based training. The overall mean effect size for posttests of controlled studies of children with autism spectrum disorders who received technology-based interventions was significantly different from zero and approached the medium magnitude, d = 0.47 (confidence interval: 0.08-0.86). The influence of age and IQ was not significant. Differences in training procedures are discussed in the light of the negative correlation that was found between the intervention durations and the studies' effect sizes. The results of this meta-analysis provide support for the continuing development, evaluation, and clinical usage of technology-based intervention for individuals with autism spectrum disorders.


Biocatalytic Self-Assembly of Tripeptide Gels and Emulsions.
We report on the biocatalytic activation of a self-assembling (unprotected) tripeptide to stabilize oil-in-water emulsions on-demand. This is achieved by the conversion of a phosphorylated precursor into a hydrogelator using alkaline phosphatase (AP) as the trigger. The rate of conversion, controlled by the amount of enzyme used, is shown to play a key role in dictating the morphology of the nanofibrous networks produced. When these amphiphilic tripeptides are used in biphasic mixtures, nanofibers are shown to self-assemble not only at the aqueous/organic interface but also throughout the surrounding buffer, thereby stabilizing the oil-in-water droplet dispersions. The use of enzymatic activation of tripeptide emulsions gives rise to enhanced control of the emulsification process because emulsions can be stabilized on-demand by simply adding AP. In addition, control over the emulsion stabilization can be achieved by taking advantage of the kinetics of dephosphorylation and consequent formation of different stabilizing nanofibrous networks at the interface and/or in the aqueous environment. This approach can be attractive for various cosmetic, food, or biomedical applications because both tunability of the tripeptide emulsion stability and on-demand stabilization of emulsions can be achieved.


Interactive Education on Sleep Hygiene with a Social Robot at a Pediatric Oncology Outpatient Clinic: Feasibility, Experiences, and Preliminary Effectiveness.
Children with cancer often experience sleep problems, which are associated with many negative physical and psychological health outcomes, as well as with a lower quality of life. Therefore, interventions are strongly required to improve sleep in this population. We evaluated interactive education with respect to sleep hygiene with a social robot at a pediatric oncology outpatient clinic regarding the feasibility, experiences, and preliminary effectiveness. Researchers approached children (8 to 12 years old) who were receiving anticancer treatment and who were visiting the outpatient clinic with their parents during the two-week study period. The researchers completed observation forms regarding feasibility, and parents completed the Children's Sleep Hygiene Scale before and two weeks after the educational regimen. The experiences of children and parents were evaluated in semi-structured interviews. We analyzed open answers by labeling each answer with a topic reflecting the content and collapsed these topics into categories. We used descriptive statistics to describe the feasibility and experiences, and a dependent-samples t-test to evaluate the preliminary effectiveness. Twenty-eight families participated (58% response rate) and all interactions with the robot were completed. The children and parents reported that they learned something new (75% and 50%, respectively), that they wanted to learn from the robot more often (83% and 75%, respectively), and that they applied the sleeping tips from the robot afterwards at home (54%). Regarding the preliminary effectiveness, children showed a statistically significant improvement in their sleep hygiene (p = 0.047, d = 0.39). Providing an educational regimen on sleep hygiene in a novel, interactive way by using a social robot at the outpatient clinic seemed feasible, and the children and parents mostly exhibited positive reactions. We found preliminary evidence that the sleep hygiene of children with cancer improved.


Targeting Inflammation in Primary Cardiovascular Prevention.
In the last decade, the development of anti-inflammatory strategies emerged as new trend in cardiovascular (CV) pharmacotherapy. Anti-inflammatory properties have been previously identified in different classes of drugs used in primary CV prevention. However, the extent to which the modification of inflammatory profile contributes in determining CV outcome remains controversial. Focusing on potential beneficial effects in primary prevention, this narrative review provides a comprehensive and critical analysis of randomized clinical trials testing anti-inflammatory treatments in CV disease. As upstream regulator of the hepatic production of C-reactive protein, tumor necrosis factor-α, interleukin (IL)-6 and IL-1 pathways early emerged as potential targets for CV prevention. More recently, additional strategies targeting lipoprotein-associated phospholipase A2, pro-protein convertase subtilisin/kexin type 9, and intracellular pathways (such as p38 MAPK and different isoforms of NADPH oxidase) have been tested. Conflicting results emerged from clinical trials, emphasized the need to characterize the inflammatory profile of the patients, to minimize the heterogeneity of study populations and to clarify the true value of CRP as specific biomarker of atherosclerosis-related inflammation.


The pervasive effects of lighting environments on sensory drive in bluefin killifish: an investigation into male/male competition, female choice, and predation.
Sensory drive predicts that the conditions under which signaling takes place have large effects on signals, sensory systems, and behavior. The coupling of an ecological genetics approach with sensory drive has been fruitful. An ecological genetics approach compares populations that experience different environments and asks whether population differences are adaptive and are the result of genetic and/or environmental variation. The multi-faceted effects of signaling environments are well-exemplified by the bluefin killifish. In this system, males with blue anal fins are abundant in tannin-stained swamps that lack UV/blue light but are absent in clear springs where UV/blue light is abundant. Past work indicates that lighting environments shape genetic and environmental variation in color patterns, visual systems, and behavior. Less is known about the selective forces creating the across population correlations between UV/blue light and the abundance of blue males. Here, we present three new experiments that investigate the roles of lighting environments on male competition, female mate choice, and predation. We found strong effects of lighting environments on male competition where blue males were more likely to emerge as dominant in tea-stained water than in clear water. Our preliminary study on predation indicated that blue males may be less susceptible to predation in tea-stained water than in clear water. However, there was little evidence for female preferences favoring blue males. The resulting pattern is one where the effects of lighting environments on genetic variation and phenotypic plasticity match the direction of selection and favor the expression of blue males in swamps.


Molecular biology of meniscus pathology: Lessons learned from translational studies and mouse models.
Injury to any individual structure in the knee interrupts the overall function of the joint and initiates a cascade of biological and biomechanical changes whose endpoint is often osteoarthritis (OA). The knee meniscus is an integral component of knee biomechanics and may also contribute to the biological homeostasis of the joint. Meniscus injury altering knee function is associated with a high risk of OA progression, and may also be involved in the initiation of OA. As the relationship between meniscus injury and OA is very complex; despite the availability of transcript level data on human meniscus injury and meniscus mediated OA, mechanistic studies are lacking, and available human data are difficult to validate in the absence of patient-matched noninjured control tissues. As similarities exist between human and mouse knee joint structure and function, investigators have begun to use cutting-edge genetic and genomic tools to examine the usefulness of the mouse as a model to study the intricate relationship between meniscus injury and OA. In this review, we use evidence from human meniscus research to identify critical barriers hampering our understanding of meniscus injury induced OA and discuss strategies to overcome these barriers, including those that can be examined in a mouse model of injury-mediated OA.


Role of vascular potassium channels in the regulation of renal hemodynamics.
K(+) conductance is a major determinant of membrane potential (V(m)) in vascular smooth muscle (VSMC) and endothelial cells (EC). The vascular tone is controlled by V(m) through the action of voltage-operated Ca(2+) channels (VOCC) in VSMC. Increased K(+) conductance leads to hyperpolarization and vasodilation, while inactivation of K(+) channels causes depolarization and vasoconstriction. K(+) channels in EC indirectly participate in the control of vascular tone by several mechanisms, e.g., release of nitric oxide and endothelium-derived hyperpolarizing factor. In the kidney, a change in the activity of one or more classes of K(+) channels will lead to a change in hemodynamic resistance and therefore of renal blood flow and glomerular filtration pressure. Through these effects, the activity of renal vascular K(+) channels influences renal salt and water excretion, fluid homeostasis, and ultimately blood pressure. Four main classes of K(+) channels [calcium activated (K(Ca)), inward rectifier (K(ir)), voltage activated (K(V)), and ATP sensitive (K(ATP))] are found in the renal vasculature. Several in vitro experiments have suggested a role for individual classes of K(+) channels in the regulation of renal vascular function. Results from in vivo experiments are sparse. We discuss the role of the different classes of renal vascular K(+) channels and their possible role in the integrated function of the renal microvasculature. Since several pathological conditions, among them hypertension, are associated with alterations in K(+) channel function, the role of renal vascular K(+) channels in the control of salt and water excretion deserves attention.


Directed formation of micro- and nanoscale patterns of functional light-harvesting LH2 complexes.
The precision placement of the desired protein components on a suitable substrate is an essential prelude to any hybrid "biochip" device, but a second and equally important condition must also be met: the retention of full biological activity. Here we demonstrate the selective binding of an optically active membrane protein, the light-harvesting LH2 complex from Rhodobacter sphaeroides, to patterned self-assembled monolayers at the micron scale and the fabrication of nanometer-scale patterns of these molecules using near-field photolithographic methods. In contrast to plasma proteins, which are reversibly adsorbed on many surfaces, the LH2 complex is readily patterned simply by spatial control of surface polarity. Near-field photolithography has yielded rows of light-harvesting complexes only 98 nm wide. Retention of the native optical properties of patterned LH2 molecules was demonstrated using in situ fluorescence emission spectroscopy.


The Critical Importance of Asking Good Questions: The Role of Epidemiology Doctoral Training Programs.
Epidemiologic methods have advanced tremendously in the last several decades. As important as they are, even the most sophisticated approaches are unable to provide meaningful answers when the user lacks a clear study question. Yet, instructors have more and more resources on how to conduct studies and analyze data but few resources on how to ask clearly defined study questions that will guide those methods. Training programs have limited time for coursework, and if novel statistical estimation methods become the focus of instruction, programs that go this route may end up underemphasizing the process of asking good study questions, designing robust studies, considering potential biases in the collected data, and appropriately interpreting the results of the analysis. Given the demands for space in curricula, now is an appropriate time to reevaluate what we teach epidemiology doctoral students. We advocate that programs place a renewed focus on asking good study questions and following a comprehensive approach to study design and data analysis in which questions guide the choice of appropriate methods, helping us avoid methods for methods' sake and highlighting when application of a new method can provide the opportunity to answer questions that were intractable with traditional approaches.


The effects of extracorporeal shock wave therapy on pain patients.
The method of shock wave therapy (ESWT) was used for the treatment of several symptoms of chronic pain. There were especially: cervical syndromes, lumbago, plantar fasciitis, achillodynia, metatarsalgia and humeral epicondylitis. We confirmed the positive effect of shock wave therapy for pain relief on these syndromes. This method is also effective in other pain syndromes. The effect of this application is very individual and therefore it is necessary to indicate differing numbers of therapeutic applications. We recommend this method as a very useful tool for completion possibilities in the treatment of chronic pain.


Technical note: Extension of Van Herk's treatment margin model for anisotropic systematic positioning errors in cartesian coordinate systema.
A coefficient of a treatment margin model for anisotropic systematic positioning errors has been calculated in Cartesian coordinate system based on van Herk's analytical formulation. Three-dimensional (3D) patient population distribution was formulated in Cartesian coordinate system to model anisotropic systematic positioning errors. Analytical 3D integration with anisotropic standard deviations Sigma's and the following Newton's method yielded the coefficient of van Herk's systematic positioning error model in Cartesian coordinate system. The treatment margins for the anisotropic systematic errors in Cartesian coordinate system were 2.1 Sigma for 90% patient population coverage and 2.4 Sigma for 95% patient population coverage. It was found that the treatment margins for anisotropic systematic positioning errors in Cartesian coordinate system were smaller than those for the isotropic model in spherical coordinate system for a given patient population coverage probability.


Configurational entropies of lipids in pure and mixed bilayers from atomic-level and coarse-grained molecular dynamics simulations.
Single-chain and single-fragment configurational entropies of lipid tails in hydrated lipid bilayers are evaluated from molecular dynamics simulations using the quasi-harmonic approximation. The entropy distribution along individual acyl tails is obtained and compared to that of corresponding hydrocarbon chains in the liquid phase. We consider pure dipalmitoylphosphatidylcholine and mixed dioleoylphosphatidylcholine/dioleoylphosphatidylethanolamine bilayers. The systems are modeled at different levels of spatial resolution: In an atomic-level (AL) model all (heavy) atoms are explicitly simulated; in a coarse-grained (CG) model particles (beads) representing groups of covalently bound atoms are used, which map approximately four non-hydrogen atoms to one interaction site. Single-chain and single-fragment entropies and correlations between the motions of (single) acyl chains are compared. A good correspondence is found between the flexibility of the AL and CG models. The loss in configurational entropy due to the reduction in the number of degrees of freedom upon coarse-graining of the model is estimated. The CG model shows about 4 times faster convergence of the chain entropies than the more detailed AL model. Corrections to the quasi-harmonic entropy estimates were found to be small for the CG model. For the AL model, the correction due to mode anharmonicities is small, but the correction due to pairwise (supralinear) mode correlations is sizable.


Diels-Alder approach to biaryls: elucidation of competing tandem [2+2] cycloaddition/[1,3] sigmatropic shift pathway.
Reaction of 2-halo-6-nitrophenylacetylene with an electron deficient diene gives rise to a [4+2] cycloaddition/cycloreversion biaryl product and a bicyclo[4.2.0]octadiene resulting from a competing [2+2] cycloaddition pathway. The cyclobutene can be opened to give a mixture of cyclooctatriene and biaryl in varying amounts depending on heat and light exposure. The conversion of the cyclobutene into biaryl occurs through a [1,3] sigmatropic carbon shift followed by [4+2] cycloextrusion of ethylene gas.


Structural basis for terminal loop recognition and stimulation of pri-miRNA-18a processing by hnRNP A1.
Post-transcriptional mechanisms play a predominant role in the control of microRNA (miRNA) production. Recognition of the terminal loop of precursor miRNAs by RNA-binding proteins (RBPs) influences their processing; however, the mechanistic basis for how levels of individual or subsets of miRNAs are regulated is mostly unexplored. We previously showed that hnRNP A1, an RBP implicated in many aspects of RNA processing, acts as an auxiliary factor that promotes the Microprocessor-mediated processing of pri-mir-18a. Here, by using an integrative structural biology approach, we show that hnRNP A1 forms a 1:1 complex with pri-mir-18a where both RNA recognition motifs (RRMs) bind to cognate RNA sequence motifs in the terminal loop of pri-mir-18a. Terminal loop binding induces an allosteric destabilization of base-pairing in the pri-mir-18a stem that promotes its downstream processing. Our results highlight terminal loop RNA recognition by RBPs as a potential general principle of miRNA biogenesis and regulation.


Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase.
Ectodomain shedding and intramembrane proteolysis of the amyloid precursor protein (APP) by alpha-, beta- and gamma-secretase are involved in the pathogenesis of Alzheimer disease (AD). Increased proteolytic processing and secretion of another membrane protein, the interleukin-1 receptor II (IL-1R2), have also been linked to the pathogenesis of AD. IL-1R2 is a decoy receptor that may limit detrimental effects of IL-1 in the brain. At present, the proteolytic processing of IL-1R2 remains little understood. Here we show that IL-1R2 can be proteolytically processed in a manner similar to APP. IL-1R2 expressed in human embryonic kidney 293 cells first undergoes ectodomain shedding in an alpha-secretase-like manner, resulting in secretion of the IL-1R2 ectodomain and the generation of an IL-1R2 C-terminal fragment. This fragment undergoes further intramembrane proteolysis by gamma-secretase, leading to the generation of the soluble intracellular domain of IL-1R2. Intramembrane cleavage of IL-1R2 was abolished by a highly specific inhibitor of gamma-secretase and was absent in mouse embryonic fibroblasts deficient in gamma-secretase activity. Surprisingly, the beta-secretase BACE1 and its homolog BACE2 increased IL-1R2 secretion resulting in C-terminal fragments nearly identical to the ones generated by the alpha-secretase-like cleavage. This suggests that both proteases may act as alternative alpha-secretase-like proteases. Importantly, BACE1 and BACE2 did not cleave several other membrane proteins, demonstrating that both proteases do not contribute to general membrane protein turnover but only cleave specific proteins. This study reveals a similar proteolytic processing of IL-1R2 and APP and may provide an explanation for the increased IL-1R2 secretion observed in AD.


Complications in acute pancreatitis.
In a group of 260 non-selected cases of acute or subacute pancreatitis, severe complications occurred in 60 (23.1%). Long lasting shock and/or massive internal bleeding (5.4%), severe renal problems (anuria, tubular necrosis, nephrosis) (5.4%) and frank hepatic failure due to extensive liver necrosis or other severe destruction (5.0%), invariably lead to death. The clinical group of findings pointing to a fatal course usually manifested themselves during the first three days. Severe renal and hepatic lesions were in many cases secondary to shock in fulminant rapidly deteriorating cases. Prevention and efficient management of shock are thus essential prerequisites for saving the patient. Other important complications included severe intra-abdominal suppuration and abscesses, peritonitis and sepsis (3.9%), pseudocysts of the pancreas (5.4%) and biliary stasis (18.4%). Severe obstruction to bile flow with associated jaundice occurred in only 4.6% of cases; unselected operative biliary decompression does not therefore appear indicated. If an early laparotomy is performed, efficient debridement and drainage are of utmost importance. Fatal pancreatitis was associated with extensive necrosis of the pancreas in about 80% of cases; possibly subtotal pancreatic resection at an early laparotomy would have given better results in these most severe cases, as recently reported in the literature.


Environmental variation, stochastic extinction, and competitive coexistence.
Understanding how environmental fluctuations affect population persistence is essential for predicting the ecological impacts of expected future increases in climate variability. However, two bodies of theory make opposite predictions about the effect of environmental variation on persistence. Single-species theory, common in conservation biology and population viability analyses, suggests that environmental variation increases the risk of stochastic extinction. By contrast, coexistence theory has shown that environmental variation can buffer inferior competitors against competitive exclusion through a storage effect. We reconcile these two perspectives by showing that in the presence of demographic stochasticity, environmental variation can increase the chance of extinction while simultaneously stabilizing coexistence. Our stochastic simulations of a two-species storage effect model reveal a unimodal relationship between environmental variation and coexistence time, implying maximum coexistence at intermediate levels of environmental variation. The unimodal pattern reflects the fact that the stabilizing influence of the storage effect accumulates rapidly at low levels of environmental variation, whereas the risk of extinction due to the combined effects of environmental variation and demographic stochasticity increases most rapidly at higher levels of variation. Future increases in environmental variation could either increase or decrease an inferior competitor's expected persistence time, depending on the distance between the present level of environmental variation and the optimal level anticipated by this theory.


Using eHealth to Increase Autonomy Supportive Care: A Multicenter Intervention Study in Antenatal Care.
eHealth solutions are increasingly implemented in antenatal care to enhance women's involvement. The main aim of this study was to evaluate women's assessment of autonomy supportive care during the antenatal care visits among low-risk pregnant women. An intervention study was conducted including a control group attending standard antenatal care and an intervention group having access to an eHealth knowledge base, in addition to standard care. A total of 87 women were included in the control group and a total of 121 women in the intervention group. Data were collected using an online questionnaire 2 weeks after participants had given birth. Data were analyzed using χ tests and Wilcoxon rank sums. Use of an eHealth knowledge base was associated with statistically significant higher scores for women's overall assessment of antenatal care visits, the organization of antenatal care visits, confidence after antenatal care visits, and involvement during antenatal care visits. We also found a statistically significant higher overall self-perceived autonomy supportive care in the intervention group compared with the control group.


Transmission of Mycobacterium chimaera from Heater-Cooler Units during Cardiac Surgery despite an Ultraclean Air Ventilation System.
Heater-cooler units (HCUs) were recently identified as a source of Mycobacterium chimaera causing surgical site infections. We investigated transmission of this bacterium from HCUs to the surgical field by using a thermic anemometer and particle counter, videotape of an operating room equipped with an ultraclean laminar airflow ventilation system, and bacterial culture sedimentation plates in a nonventilated room. Smoke from the HCU reached the surgical field in 23 s by merging with ultraclean air. The HCU produced on average 5.2, 139, and 14.8 particles/min in the surgical field at positions Off, On/oriented toward, and On/oriented away, respectively. Culture plates were positive for M. chimaera <5 m from the HCU in the test room. These experiments confirm airborne transmission of M. chimaera aerosols from a contaminated HCU to an open surgical field despite ultraclean air ventilation. Efforts to mitigate infectious risks during surgery should consider contamination from water sources and airflow-generating devices.


Attitudes of hospital leaders toward publicly reported measures of health care quality.
Public reporting of quality is considered a key strategy for stimulating improvement efforts at US hospitals; however, little is known about the attitudes of hospital leaders toward existing quality measures. To describe US hospital leaders' attitudes toward hospital quality measures found on the Centers for Medicare & Medicaid Services' Hospital Compare website, assess use of these measures for quality improvement, and examine the association between leaders' attitudes and hospital quality performance. We mailed a 21-item questionnaire from January 1 through September 31, 2012, to senior hospital leaders from a stratified random sample of 630 US hospitals, including equal numbers with better-than-expected, as-expected, and worse-than-expected performance on mortality and readmission measures. We assessed levels of agreement with statements concerning quality measures, examined use of measures for improvement activities, and analyzed the association between leaders' attitudes and hospital performance. Of 630 hospitals surveyed, 380 (60.3%) responded. For each of the mortality, readmission, process, and patient experience measures, more than 70% of hospitals agreed with the statement that "public reporting stimulates quality improvement activity at my institution"; agreement for measures of cost and volume was 65.2% and 53.3%, respectively. A similar pattern was observed for the statement that "our hospital is able to influence performance on this measure"; agreement for processes of care and patient experience measures was 96.4% and 94.2%, respectively. A total of 89.7% of hospitals agreed that the hospital's reputation was influenced by patient experience measures; agreement was 77.4% for mortality, 69.9% for readmission, 76.3% for process measures, 66.1% for cost measures, and 54.0% for volume measures. A total of 87.1% of hospitals reported incorporating performance on publicly reported measures into their hospital's annual goals, whereas 90.2% reported regularly reviewing the results with the hospital's board of trustees and 94.3% with senior clinical and administrative leaders. When compared with chief executive officers and chief medical officers, respondents who identified themselves as chief quality officers or vice presidents of quality were less likely to agree that public reporting stimulates quality improvement and that measured differences are large enough to differentiate among hospitals. Hospital leaders indicated that the measures reported on the Hospital Compare website exert strong influence over local planning and improvement efforts. However, they expressed concerns about the clinical meaningfulness, unintended consequences, and methods of public reporting.


Osteocytes: a proposed multifunctional bone cell.
Most cell types are ascribed a single function. The osteoclast holds the unique distinction of performing only one function in the body - that of resorbing bone. The osteoblast has been ascribed the major function of bone matrix production. Other less well-defined cell types include progenitor cells and the nebulous cell type that can support osteoclast formation upon stimulation with various bone resorbing cytokines. Obviously, these cells could have other functions. The definition of an osteocyte is descriptive of its location - cells surrounded by mineralized matrix - not its function. For this year's Sun Valley Workshop on osteocytes, several proposed functions will be presented. First, a general consensus exists that osteocytes are most likely sensitive to mechanotransduction and translate mechanical strain into biochemical signals. Consensus does not exist on the nature of the mechanical strain, the form of the biochemical signals, the target cell(s), or the viability status of the osteocyte. Second, it is also proposed that this cell is incredibly adaptable and expresses plasticity in response to mechanical stimuli. In other words, this cell can readjust its responses to strain in the presence of other bone agents such as hormones and bone factors. Third, it will also be presented that osteocytes maintain systemic mineral homeostasis by regulating mineral release and deposition over the enormous surface area over which these cells interface with the surrounding matrix. Although osteocytes are terminally differentiated osteoblasts, they appear to have separate and distinct properties from their predecessors. Bone cell biologists loaded with an arsenal of bone anabolic and catabolic factors are examining the expression and effects of these factors on osteocytes. Engineers trained in mathematical modeling have generated new models of strain and connectivity to be tested. The unique morphology of osteocytes suggests that the cytoskeleton in these cells may function differently from osteoblasts and other cell types. Osteocytes may consist of different subpopulations; some that possess receptors for parathyroid hormone (PTH) and others that only express receptors for carboxyl terminal PTH suggesting different functions and responses. Osteocytes may respond rapidly to strain through glutamate receptor-like mechanisms, through calcium influxes, through gap junctions, and less rapidly through the production of small molecules and factors. Strain may take the form of substrate stretching and/or fluid flow. Osteocytes may communicate with other osteocytes and/or bone surface cells such as lining cells, stromal cells, osteoblasts, and/or osteoclasts and their precursors. The viability status of the osteocyte may determine the type of signals sent from these cells. If the cells are deprived of oxygen or nutrients, the apoptotic cells may send signals for initiation of resorption. If the cells and/or their dendritic process are ripped or torn by microdamage, they may send signals of both resorption and formation. If the majority of these theories are correct, then the osteocyte is the 'smart' cell that can direct or orchestrate the bone resorbing and bone forming cells even in its death and dying.


Heritable variation in a family-diagnostic trait.
Derived characters that have not changed during the diversification of a clade provide traits that are diagnostic at higher taxonomic levels. The tetradynamous stamen condition (four long and two short stamens) of the Brassicaceae is an example of a diagnostic trait that has not changed during the diversification of this large flowering plant family. We investigated one hypothesis that might explain the long-term stasis of this trait-that tetradynamous stamens have persisted because of an absence of genetic variation underlying the trait. Through a sib-analysis with Raphanus raphanistrum and an artificial selection experiment with Brassica rapa, we demonstrate that significant genetic variation is present for the tetradynamous condition in both species and that the trait is therefore not constrained from evolutionary change by a lack of heritable genetic variation.


Racialized and beneficiary inequities in medication to treat opioid use disorder receipt within the US Military Health System.
Medication for opioid use disorder (MOUD) can be critical to managing opioid use disorder (OUD). It is unknown the extent to which US Military Health System (MHS) patients diagnosed with OUD receive MOUD. Healthcare records of MHS-enrolled active duty and retired service members (N = 13,334) with a new (index) OUD diagnosis were included between 2018 and 2021, without 90-day pre-index MOUD receipt were included. Elastic net logistic and Cox regressions evaluated care- and system-level factors associated with 1-year MOUD receipt (primary outcome) and time-to-receipt. Only 9% of patients received MOUD 1-year post-index; only 4% received MOUD within 14 days. Black patients (OR for receipt 0.38, 95% CI 0.30-0.49), Latinx patients (OR for receipt 0.44, 95% CI 0.33-0.59), and patients whose race and ethnicity was Other (OR for receipt 0.52, 95%CI 0.35, 0.77) experienced lower MOUD access (all p < 0.001). Retirees were more likely to receive MOUD relative to active duty service members (OR for receipt 1.81, 95%CI 1.52, 2.16, p <0.001). Institutional racism in MOUD prescribing, combined with the overall low rates of MOUD receipt after OUD diagnosis, highlight the need for evidence-based, multifaceted, and multilevel approaches to OUD care in the Military Health System. Without clear Defense Health Agency policy, including the designation of responsible entities, transparent and ongoing evaluation and responsiveness using standardized methodology, and resourced programming and public health campaigns, MOUD rates will likely remain poor and inequitable.