Biometry and formula accuracy with intraocular lenses used for cataract surgery in extreme hyperopia.
To audit intraocular lens (IOL) power predictions for cataract surgery in extreme hyperopia and to compare the accuracy across different biometry formulae and IOL types. A retrospective analysis of 76 eyes from 56 patients undergoing cataract surgery with IOLs ranging in power from 30 to 35 diopters (D). Axial lengths, corneal powers and anterior chamber depths were measured with ultrasound or optical methods, and the IOLMaster (Carl Zeiss Meditech, Inc, Dublin, California, USA) software was used to predict the refractive outcome for each IOL used. Differences between the predicted and actual postoperative refraction were then analyzed for each formula. In practice, 55% of patients were within +/-1.0 D of the refraction predicted by their surgeon. In theory, the Haigis formula would have given the smallest mean refractive error (+0.51 +/- 0.12 D), followed by the Hoffer Q (-0.70 +/- 0.14 D), Holladay 1 (-1.11 +/- 0.13 D), and SRK/T formulae (-1.45 +/- 0.14 D). The Haigis formula overpredicted the lens power required, which would have generated a myopic result. The other formulae underpredicted the lens power required and would have generated a hyperopic result. There was a significant difference between lens designs: the Haigis was more accurate for open-loop, whereas the Hoffer Q was more accurate for plate-haptic lenses. The anterior chamber depth measurement could also be used to predict changes in intraocular pressure after surgery. This represents the largest published series to date of biometry predictions for cataract surgery in extreme hyperopia and confirms the Haigis formula to be the most accurate. A consistent difference between open-loop and plate-haptic lenses suggests that haptic design may influence the effective lens position in very small eyes. We further propose a simple formula to optimize the Haigis and Hoffer Q formulae in patients with extreme hyperopia.


Scientific teaching: defining a taxonomy of observable practices.
Over the past several decades, numerous reports have been published advocating for changes to undergraduate science education. These national calls inspired the formation of the National Academies Summer Institutes on Undergraduate Education in Biology (SI), a group of regional workshops to help faculty members learn and implement interactive teaching methods. The SI curriculum promotes a pedagogical framework called Scientific Teaching (ST), which aims to bring the vitality of modern research into the classroom by engaging students in the scientific discovery process and using student data to inform the ongoing development of teaching methods. With the spread of ST, the need emerges to systematically define its components in order to establish a common description for education researchers and practitioners. We describe the development of a taxonomy detailing ST's core elements and provide data from classroom observations and faculty surveys in support of its applicability within undergraduate science courses. The final taxonomy consists of 15 pedagogical goals and 37 supporting practices, specifying observable behaviors, artifacts, and features associated with ST. This taxonomy will support future educational efforts by providing a framework for researchers studying the processes and outcomes of ST-based course transformations as well as a concise guide for faculty members developing classes.


Semi-empirical or non-empirical double-hybrid density functionals: which are more robust?
The development of non-empirical double-hybrid density functionals (DHDFs) is a very active research area with the number of approaches in this field having increased rapidly. At the same time, there is a lack of published work that provides a fair assessment and comparison between non-empirical and semi-empirical DHDFs on an equal footing. Herein, we close this gap and present a thorough analysis of both classes of DHDFs on the large GMTKN55 benchmark database for general main-group thermochemistry, kinetics, and noncovalent interactions [Goerigk et al., Phys. Chem. Chem. Phys., 2017, 19, 32184-32215]. In total, 115 variations of dispersion-corrected and -uncorrected DHDFs are tested, which will be condensed to an in-depth assessment of 31 methods: 19 non-empirical and 12 semi-empirical DHDFs. As such, our study represents the largest DHDF study ever conducted and can serve as an important benchmark informing method developers and users alike. Our results show that semi-empirical DHDFs are the most robust density functional approximations and more reliable and accurate than non-empirical ones. In fact, some non-empirical approaches are even outperformed by hybrid approaches or even dispersion-corrected and -uncorrected MP2 and SCS-MP2. SOS0-PBE0-2-D3(BJ) is the only exception and the only non-empirical DHDF that we can safely recommend for general applicability. However, it is still outperformed by six semi-empirical DHDFs, of which we would like to particularly recommend the following five: ωB97X-2-D3(BJ), DSD-BLYP-D3(BJ), DSD-PBEP86-D3(BJ), B2NC-PLYP-D3(BJ), and B2GPPLYP-D3(BJ). Our findings seriously question current trends in the field and they highlight that novel strategies have to be found in order to outperform the currently best density functional theory methods on the market. We hope that our study can function as an important cornerstone inspiring such a change of direction in the field.


Learning medical alarms whilst performing other tasks.
Two studies are reported which first observe, and then attempt to replicate, the cognitive demands of intensive care unit (ICU) activity whilst concurrently learning audible alarms. The first study, an observational study in an ICU ward, showed that the alarms are very frequent and co-occur with some activities more than others. The three most frequently observed activities observed in the ICU were drugs (calculation, preparation and administration), patient observation and talking. The cognitive demands of these activities were simulated in a second, laboratory-based experiment in which alarms were learned. The results showed that performance in the alarm task generally improved as participants were exposed to more repetitions of those alarms, but that performance decrements were observed in the secondary tasks, particularly when there were two or three of them. Some confusions between the alarms persisted to the end of the study despite prolonged exposure to the alarms, confusions which were likely caused by both acoustic and verbal labelling similarities. The cognitive demands of working in an ICU were observed and simulated whilst alarms were learned. Alarms should generally avoid sharing similar rhythmic (and other) characteristics. The simulation task described here could be used for testing alarm learning without requiring a clinical environment.


Intravenous iron supplementation in distance runners with low or suboptimal ferritin.
Iron deficiency is prevalent in distance runners and may impair endurance performance. The current practice of oral supplementation is slow and often not well tolerated. The aim of this study was to assess the efficacy of intravenous (IV) iron supplementation (ferric carboxymaltose) compared with oral supplementation (ferrous sulfate) on iron status, hemoglobin mass (Hbmass), and physiological indices of running performance in distance runners. Twenty-seven highly trained distance runners with low (LOW) (ferritin <35 μg·L(-1) and transferrin saturation <20%, or ferritin <15 μg·L(-1)) or suboptimal (SUB) iron status (ferritin <65 μg·L(-1)) were supplemented with either IV iron (Ferinject®) or oral (ORAL) supplements (Ferrogradumet) for 6 wk. Iron status and Hbmass were assessed before supplementation and at 1, 2, 4, 6, and 8 wk in the four groups (IV LOW, IV SUB, ORAL LOW, and ORAL SUB). In addition, athletes completed a treadmill running test for running economy, lactate threshold, and V˙O2max before and after supplementation. Both forms of supplementation substantially increased ferritin levels in all four groups. IV supplementation resulted in higher ferritin in both IV groups compared with both ORAL groups from week 1 onward. Hemoglobin concentration did not change substantially in any group. Hbmass increased in IV LOW (mean = +4.9%, 90% confidence interval [CI] = 1.1%-8.9%) and was accompanied by an increase in V˙O2max (mean = +3.3%, 90% CI = 0.4%-6.3%) and run time to exhaustion (mean = +9.3%, 90% CI = 0.9%-18.3%. IV supplementation can effectively increase iron stores in iron-deficient runners within 6 wk and, if Hbmass is compromised, may enhance endurance capacity by facilitating erythropoiesis. Hbmass appears a more sensitive tool for measuring changes in whole body hemoglobin than hemoglobin concentration and may be useful in the diagnosis and follow-up for iron deficiency.


Inotropic actions of protein kinase C activation by phorbol dibutyrate in guinea-pig isolated ventricular myocytes.
The mechanisms which underlie the inotropic actions of phorbol dibutyrate (PDBu), a synthetic compound which can directly activate protein kinase C (PKC), were investigated in guinea-pig isolated ventricular myocytes. Exposure of cells to PDBu (10(-7) M) reduced myocyte contraction amplitude to 46 +/- 3% of control (n = 8; P < 0.05) with an associated shortening in action potential duration (action potential duration at 90% repolarisation (APD90) was reduced to 83 +/- 1% of control; P < 0.05). The negative inotropic actions of PDBu and the shortening in action potential duration were abolished in the presence of a selective PKC inhibitor, Ro31-8220. Calcium transients (constructed from calcium-activated tail currents following interruption of action potentials by voltage clamp to -70 mV) were reduced following exposure to 10(-7) M PDBu by 38 +/- 2% (n = 9, P < 0.05). L-type calcium currents were not significantly altered following exposure to 10(-7) M PDBu (98 +/- 2% of control; P > 0.05). In contrast, delayed rectifier potassium currents (I(K)) were enhanced to 154 +/- 8% of control (n = 7; P < 0.05) by 10(-7) M PDBu. This enhancement of I(K) may contribute to the observed shortening in action potential duration observed following exposure to PDBu under the conditions of our experiments. When the action potential configuration was maintained throughout the experiment by applying a voltage-clamp waveform, 10(-7) M PDBu still reduced contraction amplitude to 57 +/- 3% of control (P < 0.05). Exposure to 10(-7) M PDBu also suppressed spontaneous activity (both spontaneous potential fluctuations induced by the beta-adrenergic agonist isoprenaline (40 nM), and transient inward currents induced by the cardiac glycoside ouabain (1 microM) under voltage clamp). It therefore appears that the reduction in myocyte contraction amplitude induced by exposure to PDBu may result in part through mechanisms independent of action potential shortening, which may include direct actions of protein kinase C on the function of the sarcoplasmic reticulum (SR) calcium store and/or on contractile proteins (though action potential shortening would be expected to cause a further decrease as a consequence of reduced calcium loading of the SR). The reduction of spontaneous activity caused by PDBu may also result from changes in the function of the SR store mediated by protein kinase C.


Robotic coloanal anastomosis with or without intersphincteric resection for low rectal cancer: starting with the perianal approach followed by robotic procedure.
Coloanal anastomosis (CAA)/intersphincteric resection (ISR) is a promising method of sphincter-preserving surgery for very low rectal cancer. Recently, a robotic system has been attempted in CAA/ISR. By means of a robotic system, an excellent stereoscopic view may be obtained with high illumination, and adequate traction and countertraction can be easily performed in a narrow pelvis using the Endowrist function. During robotic CAA/ISR, although the robotic system is necessary to perform pelvic dissection that comes before the perianal approach, the huge robotic arms located in the low abdominal region could interfere with comfortable perianal dissection for the surgeon. Therefore, the robotic system has to be withdrawn and then set up again above the patient's abdomen, which is time-consuming. Moreover, this process also makes it difficult to maintain the aseptic circumstance of the robotic system. To address this problem, it is necessary to change the sequence of the procedure. Patients with low rectal adenocarcinoma located within 6 cm above the anal verge were recruited and underwent robotic CAA/ISR. We performed the perianal approach first before docking the robotic system. In the transanal approach, manual dissection started at the level of the dentate line (for cases of CAA) or intersphincteric groove (for cases of ISR). The mucosa was stripped from the starting point to just above the levators. Robotic dissection was followed while maintaining pneumoperitoneum via packed gauzes in the anus. The surgical principles included high ligation of inferior mesenteric vessels and total mesorectal excision. Splenic flexure mobilization was selectively performed when the end of the remaining sigmoid colon could not reach the anal canal after the routine mobilization of the left colon side. After completion of total mesorectal excision, further dissection continued to the pelvic floor (Fig. 1). The puborectalis muscle sling was laterally exposed, and the anococcygeal ligament was noted on the posterior side of the anal canal. Intersphincteric dissection through the puborectalis ended at the intra-anal canal. Finally, the dissection plane could meet the perianal dissection plane. At this point, we could identify the gauze, which was packed via the perianal approach before beginning robotic dissection. The muscular rectal wall was divided by a cautery at the level of the puborectalis muscle by robotic arms. While performing the CAA/ISR, secure and meticulous dissection through the pelvic floor is important for oncological safety, which could be easily performed with the aid of robotic ergonomic Endowrist function and a magnified three-dimensional view even in a narrow pelvic cavity. Specimen extraction was done through the anus or additional minilaparotomy skin incision. In some cases, a planned ileostomy site was used as the minilaparotomy incision. For patients with bulky and heavy mesorectum, it is difficult and even dangerous to extract the specimen via the anus, which could induce traction injuries to the marginal vessels. Hand-sewn coloanal anastomosis was performed after removing the robotic cart from the operation field. The entire operative procedure is shown in the video. Early surgical outcomes, morbidity, and short-term follow-up data were extracted from a prospectively collected database. Robotic CAA/ISR for low rectal cancer was performed on 47 patients between August 2007 and December 2010. Forty-one patients underwent robotic CAA, and six patients underwent robotic ISR. There were 28 male and 19 female patients. The median age was 58 (range 32-86) years. The median body mass index was 23.3 (range 14.6-28.0) kg/m(2). Five patients (10.6%) had a history of abdominal surgery. According to American Society of Anesthesiology disease classification, 35 patients (74.5%) were class I, and 12 (25.5%) patients class II. The median distance between adenocarcinoma and the anal verge was 4 (range 1-6) cm. Preoperative chemoradiotherapy was provided to 19 patients (40.4%). There was no conversion to laparoscopic or open procedure. Operation time for robotic CAA/ISR was 360.9 ± 128.5 (mean ± standard deviation) min. For specimen retrieval, transanal extraction was performed in 23 cases (49%) and minilaparotomy was created for 24 cases (51%), including three cases of planned ileostomy site. Protective ileostomy was performed for 37 patients (78.7%). Blood loss was 158.0 ± 236.5 ml. The disease stage of the patients was as follows: stage 0, n = 1; stage I, n = 20; stage II, n = 5; stage III, n = 12; and pathologic complete response, n = 9. Tumor size was 2.7 ± 1.5 cm. The distal resection margin was 1.0 ± 1.2 cm. The circumferential resection margins were positive in 3 patients (6.4%). The number of retrieved lymph nodes was 9.8 ± 5.8. The first postoperative bowel movement was observed on day 2 (range, days 1-5). The median diet consumption began on day 3 (range, days 2-21). The median hospital stay was 9 (range 5-30) days. There were 10 complications in the early postoperative period (21.3%): 3 anastomotic leakages (6.4%), 1 wound infection (2.1%), 5 pelvic abscesses (10.6%), and 1 postoperative ileus (2.1%). During the short-term follow-up periods (median 21.3 months, range 3.5-40.7 months), one local recurrence, three distal metastases, and one combined recurrence were observed. Two-year disease-free survival rate was 83.7%. Robotic CAA/ISR can be performed with good technical efficiency and acceptable morbidity. Further randomized, controlled studies assessing long-term survival, pelvic autonomic nerve function, and bowel function are needed before robotic CAA/ISR becomes widely accepted. Changing the sequence of the procedure, and thus performing the perianal approach before robotic dissection, may be a feasible method to avoid interference of the robotic system in the surgeon's moves using nonrobotic instruments while performing robotic CAA/ISR.


Expression of the filaggrin gene in umbilical cord blood predicts eczema risk in infancy: A birth cohort study.
Filaggrin gene (FLG) expression, particularly in the skin, has been linked to the development of the skin barrier and is associated with eczema risk. However, knowledge as to whether FLG expression in umbilical cord blood (UCB) is associated with eczema development and prediction is lacking. This study sought to assess whether FLG expression in UCB associates with and predicts the development of eczema in infancy. Infants enrolled in a birth cohort study (n=94) were assessed for eczema at ages 3, 6, and 12 months. Five probes measuring FLG transcripts expression in UCB were available from genomewide gene expression profiling. FLG genetic variants R501X, 2282del4, and S3247X were genotyped. Associations were assessed using Poisson regression with robust variance estimation. Area under the curve (AUC), describing the discriminatory/predictive performance of fitted models, was estimated from logistic regression. Increased level of FLG expression measured by probe A_24_P51322 was associated with reduced risk of eczema during the first year of life (RR=0.60, 95% CI: 0.38-0.95). In contrast, increased level of FLG antisense transcripts measured by probe A_21_P0014075 was associated with increased risk of eczema (RR=2.02, 95% CI: 1.10-3.72). In prediction models including FLG expression, FLG genetic variants, and sex, discrimination between children who will and will not develop eczema at 3 months of age was high (AUC: 0.91, 95% CI: 0.84-0.98). This study demonstrated, for the first time, that FLG expression in UCB is associated with eczema development in infancy. Moreover, our analysis provided prediction models that were capable of discriminating, to a great extent, between those who will and will not develop eczema in infancy. Therefore, early identification of infants at increased risk of developing eczema is possible and such high-risk newborns may benefit from early stratification and intervention.


Pharmacological activities of Justicia adhatoda.
The current study focused on the pharmacological activities of Justicia adhatoda; including antibacterial, antifungal, phytotoxic, cytotoxic, haemagglutination, insecticidal, in vitro antiglycation, DPPH antioxidant and anti-termite. The crude methanolic extract (Crd. Met. Ext) showed 46.4 % antibacterial activity against M. morganii while the n-hexane fraction showed good (71.4%) and moderate (55.1%) activity against M. morganii and A. baumannii respectively. The EtOAc and aqueous fractions, in most of the cases, showed low to no activity against the selected bacterial pathogens, against A. niger, T. harzianum, A. parasiticus and V. dahliae. The Crd. Met. Ext and fractions showed low activity, against P. notatum and P. digitatum, Crd. Met. Ext. and all fractions were inactive. The percent growth regulation, in case of phytotoxic activity, by Crd. Met. Ext was 25 and 16.6, n-hexane fraction 16.6, 16.6 and 0, CHCl3 25, 8.33 and 0 % and EtOAc fractions 8.33, 8.33 and 0% at 1000 and 100 and 10µg/ml respectively. The aqueous fraction was inactive at all the test concentrations. The results of brine shrimp cytotoxic activity for Crd. Met. Ext was 13.33% and n-hexane fraction 20% at 1000, µg/ml respectively. All of the other fractions showed low to no activity at different test concentrations. All of the test samples were inactive against RBC's of the blood groups at all concentration indicating that the selected plant lack phytolectins and haemagglutination activity. The Crd. Met. Ext and various fraction showed low activity against the test insects i.e. C. pulicaria, C. chinensis and T. castaneum. The absorbance value of plant extract for anti-glycation activity at various concentration were: 0.08, 0.067, 0.053 and 0.04 in comparison with Aminoguanidine 0.04, 0.035, 0.03 and 0.02 respectively at 10, 50, 90 and 130μl. The DPPH radical scavenging activities were proportional to the concentration of the fractions, as the concentration of these increased, the percent scavenging activity also increased. The CHCl3 and EtOAc fractions killed all the termites in 24 hours while Crd. Met. Ext, n-hexane and aqueous fractions took 2-3 days.


Human mature milk zearalenone and deoxynivalenol levels in Turkey.
Zearalenone (ZEA) and deoxynivalenol (DON) are toxic fungal secondary metabolites, found mainly in contaminated food, that are associated with serious health problems. It is important to identify undesirable toxins and metabolites that may be present in human milk. The aim of this study was to evaluate human milk ZEA and DON levels, total daily intake of ZEA and DON; and their possible relationship with maternal dietary habits. We enrolled 90 lactating mothers who had 7- to 90-day-old babies. A dietary questionnaire was completed by each of the mothers. Human milk samples were obtained from 90 mothers, and human milk ZEA and DON levels were evaluated with the solid-phase direct enzyme immunoassay. The total daily intake (TDI) was calculated for the 63 exclusively breastfed infants. ZEA was detected in all human milk samples; median was 173.8 ng/L (35.7-682 ng/L). The calculated median TDI for ZEA was 33.0 ng/kg body weight (bw) (10.4-120.5 ng/kg) among exclusively breast-fed infants, none of them had a TDI that was above the previously defined threshold levels. Human milk ZEA levels were associated with the maternal consumption of meat, fish, dry fig, dried apricot, flaked red spice and spice. The median DON levels was 3924 ng/L (400-14997 ng/L). The median TDI of DON was 750 ng/kg (240-2774 ng/kg) among exclusively breastfed infants and 36% out of them, the TDI for DON was above the previously defined threshold level. Human milk DON levels were associated with the maternal meat consumption. Our findings are indicative of dietary exposure to mycotoxins during the pregnancy and lactation periods in nursing mothers. Further, the excessive TDI values for DON observed in 36% of the exclusively breastfed infants point to the need for further regulations and recommendations on the dietary habits of pregnant/nursing mothers in order to avoid exposure to potential mycotoxins.


Investigation of nanoscale structural alterations of cell nucleus as an early sign of cancer.
The cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients (i.e., prognosis) if no frank cancer is found. The recent development in optical microscopy techniques now permit the nanoscale structural imaging and quantitative structural analysis of tissue and cells, which offers a new opportunity to investigate the structural properties of cell and tissue below 200 - 250 nm as an early sign of carcinogenesis, prior to the presence of microscale morphological abnormalities. Identification of nanoscale structural signatures is significant for earlier and more accurate cancer detection and prognosis. Our group has recently developed two simple spectral-domain optical microscopy techniques for assessing 3D nanoscale structural alterations - spectral-encoding of spatial frequency microscopy and spatial-domain low-coherence quantitative phase microscopy. These two techniques use the scattered light from biological cells and tissue and share a common experimental approach of assessing the Fourier space by various wavelengths to quantify the 3D structural information of the scattering object at the nanoscale sensitivity with a simple reflectance-mode light microscopy setup without the need for high-NA optics. This review paper discusses the physical principles and validation of these two techniques to interrogate nanoscale structural properties, as well as the use of these methods to probe nanoscale nuclear architectural alterations during carcinogenesis in cancer cell lines and well-annotated human tissue during carcinogenesis. The analysis of nanoscale structural characteristics has shown promise in detecting cancer before the microscopically visible changes become evident and proof-of-concept studies have shown its feasibility as an earlier or more sensitive marker for cancer detection or diagnosis. Further biophysical investigation of specific 3D nanoscale structural characteristics in carcinogenesis, especially with well-annotated human cells and tissue, is much needed in cancer research.


Race/ethnicity in biomedical research and clinical practice.
There is ongoing debate as to whether persons of different racial/ethnic groups are biologically significantly different, and, if such differences exist, whether they are relevant in relation to disease susceptibility and to treatment outcomes. There is also debate about the benefits of using race/ethnicity as a factor in clinical decision making, and as a variable in biomedical or public health research, because of the emotional sensitivities attached to race/ethnic categorisation. Such categorisation may also divert attention from underlying issues such as socioeconomic status and lack of access to modern health care. In this short article we will discuss these controversies, and will emphasize the importance of responsible and sensitive use of race/ethnicity as a variable in biomedical research and in clinical practice.


Analysis of Spounaviruses as a Case Study for the Overdue Reclassification of Tailed Phages.
Tailed bacteriophages are the most abundant and diverse viruses in the world, with genome sizes ranging from 10 kbp to over 500 kbp. Yet, due to historical reasons, all this diversity is confined to a single virus order-Caudovirales, composed of just four families: Myoviridae, Siphoviridae, Podoviridae, and the newly created Ackermannviridae family. In recent years, this morphology-based classification scheme has started to crumble under the constant flood of phage sequences, revealing that tailed phages are even more genetically diverse than once thought. This prompted us, the Bacterial and Archaeal Viruses Subcommittee of the International Committee on Taxonomy of Viruses (ICTV), to consider overall reorganization of phage taxonomy. In this study, we used a wide range of complementary methods-including comparative genomics, core genome analysis, and marker gene phylogenetics-to show that the group of Bacillus phage SPO1-related viruses previously classified into the Spounavirinae subfamily, is clearly distinct from other members of the family Myoviridae and its diversity deserves the rank of an autonomous family. Thus, we removed this group from the Myoviridae family and created the family Herelleviridae-a new taxon of the same rank. In the process of the taxon evaluation, we explored the feasibility of different demarcation criteria and critically evaluated the usefulness of our methods for phage classification. The convergence of results, drawing a consistent and comprehensive picture of a new family with associated subfamilies, regardless of method, demonstrates that the tools applied here are particularly useful in phage taxonomy. We are convinced that creation of this novel family is a crucial milestone toward much-needed reclassification in the Caudovirales order.


Protocol for a meta-research study of protocols for diet or nutrition-related trials published in indexed journals: general aspects of study design, rationale and reporting limitations.
The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) reporting guideline establishes a minimum set of items to be reported in any randomised controlled trial (RCT) protocol. The Template for Intervention Description and Replication (TIDieR) reporting guideline was developed to improve the reporting of interventions in RCT protocols and results papers. Reporting completeness in protocols of diet or nutrition-related RCTs has not been systematically investigated. We aim to identify published protocols of diet or nutrition-related RCTs, assess their reporting completeness and identify the main reporting limitations remaining in this field. We will conduct a meta-research study of RCT protocols published in journals indexed in at least one of six selected databases between 2012 and 2022. We have run a search in PubMed, Embase, CINAHL, Web of Science, PsycINFO and Global Health using a search strategy designed to identify protocols of diet or nutrition-related RCTs. Two reviewers will independently screen the titles and abstracts of records yielded by the search in Rayyan. The full texts will then be read to confirm protocol eligibility. We will collect general study features (publication information, types of participants, interventions, comparators, outcomes and study design) of all eligible published protocols in this contemporary sample. We will assess reporting completeness in a randomly selected sample of them and identify their main reporting limitations. We will compare this subsample with the items in the SPIRIT and TIDieR statements. For all data collection, we will use data extraction forms in REDCap. This protocol is registered on the Open Science Framework (DOI: 10.17605/OSF.IO/YWEVS). This study will undertake a secondary analysis of published data and does not require ethical approval. The results will be disseminated through journals and conferences targeting stakeholders involved in nutrition research.


Sequence analysis and enzyme kinetics of the L2 serine beta-lactamase from Stenotrophomonas maltophilia.
The L2 serine active-site beta-lactamase from Stenotrophomonas maltophilia has been classified as a clavulanic acid-sensitive cephalosporinase. The gene encoding this enzyme from S. maltophilia 1275 IID has been cloned on a 3.3-kb fragment into pK18 under the control of a Ptac promoter to generate recombinant plasmid pUB5840; when expressed in Escherichia coli, this gene confers resistance to cephalosporins and penicillins. Sequence analysis has revealed an open reading frame (ORF) of 909 bp with a GC content of 71.6%, comparable to that of the L1 metallo-beta-lactamase gene (68.4%) from the same bacterium. The ORF encodes an unmodified protein of 303 amino acids with a predicted molecular mass of 31.5 kDa, accommodating a putative leader peptide of 27 amino acids. Comparison of the amino acid sequence with those of other beta-lactamases showed it to be most closely related (54% identity) to the BLA-A beta-lactamase from Yersinia enterocolitica. Sequence identity is most obvious near the STXK active-site motif and the SDN loop motif common to all serine active-site penicillinases. Sequences outside the conserved regions display low homology with comparable regions of other class A penicillinases. Kinetics of the enzyme from the cloned gene demonstrated an increase in activity with cefotaxime but markedly less activity with imipenem than previously reported. Hence, the S. maltophilia L2 beta-lactamase is an inducible Ambler class A beta-lactamase which would account for the sensitivity to clavulanic acid.


Effects of dexamethasone and high terrestrial altitude on cognitive performance and affect.
This study examined the effects of dexamethasone and exposure to high terrestrial altitude on cognitive performance, affect, and personality. Cognitive performance was evaluated by five cognitive tasks, affect was evaluated by the Clyde Mood Scale and the Multiple Affect Adjective Check List, and personality was examined using the Minnesota Multiphasic Personality Inventory. Sixteen healthy young men received either dexamethasone (4 mg every 6 h) (n = 7) or placebo (n = 9) for 34 h prior to and 52 h after ascent to 4,300 m. Subjects treated with dexamethasone correctly performed more computer interaction and addition problems than did placebo-treated subjects. They also were less sleepy, dizzy, depressed, and anxious than placebo-treated subjects at altitude. No adverse effects on cognitive performance, affect, or personality were noted after dexamethasone was discontinued on the third day at altitude. Results indicate that dexamethasone at the present dose positively influences cognitive performance and mood states at altitude, but has no residual effect on personality.


Deficits in coordinated neuronal activity and network topology are striatal hallmarks in Huntington's disease.
Network alterations underlying neurodegenerative diseases often precede symptoms and functional deficits. Thus, their early identification is central for improved prognosis. In Huntington's disease (HD), the cortico-striatal networks, involved in motor function processing, are the most compromised neural substrate. However, whether the network alterations are intrinsic of the striatum or the cortex is not fully understood. In order to identify early HD neural deficits, we characterized neuronal ensemble calcium activity and network topology of HD striatal and cortical cultures. We used large-scale calcium imaging combined with activity-based network inference analysis. We extracted collective activity events and inferred the topology of the neuronal network in cortical and striatal primary cultures from wild-type and R6/1 mouse model of HD. Striatal, but not cortical, HD networks displayed lower activity and a lessened ability to integrate information. GABAA receptor blockade in healthy and HD striatal cultures generated similar coordinated ensemble activity and network topology, highlighting that the excitatory component of striatal system is spared in HD. Conversely, NMDA receptor activation increased individual neuronal activity while coordinated activity became highly variable and undefined. Interestingly, by boosting NMDA activity, we rectified striatal HD network alterations. Overall, our integrative approach highlights striatal defective network integration capacity as a major contributor of basal ganglia dysfunction in HD and suggests that increased excitatory drive may serve as a potential intervention. In addition, our work provides a valuable tool to evaluate in vitro network recovery after treatment intervention in basal ganglia disorders.


Association of the Centers for Medicare & Medicaid Services' National Partnership to Improve Dementia Care With the Use of Antipsychotics and Other Psychotropics in Long-term Care in the United States From 2009 to 2014.
The Centers for Medicare & Medicaid Services' National Partnership to Improve Dementia Care in Nursing Homes (hereafter referred to as the partnership) was established to improve the quality of care for patients with dementia, measured by the rate of antipsychotic prescribing. To determine the association of the partnership with trends in prescribing of antipsychotic and other psychotropic medication among older adults in long-term care. This interrupted time-series analysis of a 20% Medicare sample from January 1, 2009, to December 31, 2014, was conducted among 637 426 fee-for-service Medicare beneficiaries in long-term care with Part D coverage. Data analysis was conducted from May 1, 2017, to January 9, 2018. Quarterly prevalence of use of antipsychotic and nonantipsychotic psychotropic medications (antidepressants, mood stabilizers [eg, valproic acid and carbamazepine], benzodiazepines, and other anxiolytics or sedative-hypnotics). Among the 637 426 individuals in the study (446 538 women and 190 888 men; mean [SD] age at entering nursing home, 79.3 [12.1] years), psychotropic use was declining before initiation of the partnership with the exception of mood stabilizers. In the first quarter of 2009, a total of 31 056 of 145 841 patients (21.3%) were prescribed antipsychotics, which declined at a quarterly rate of -0.53% (95% CI, -0.63% to -0.44%; P < .001) until the start of the partnership. At that point, the quarterly rate of decline decreased to -0.29% (95% CI, -0.39% to -0.20%; P < .001), a postpartnership slowing of 0.24% per quarter (95% CI, 0.09%-0.39%; P = .003). The use of mood stabilizers was growing before initiation of the partnership and then accelerated after initiation of the partnership (rate, 0.22%; 95% CI, 0.18%-0.25%; P < .001; rate change, 0.14%; 95% CI, 0.10%-0.18%; P < .001), reaching 71 492 of 355 716 patients (20.1%) by the final quarter of 2014. Antidepressants were the most commonly prescribed medication overall: in the beginning of 2009, a total of 75 841 of 145 841 patients (52.0%) were prescribed antidepressants. As with antipsychotics, antidepressant use declined both before and after initiation of the partnership, but the decrease slowed (rate change, 0.34%; 95% CI, 0.18%-0.50%; P < .001). Findings were similar when limited to patients with dementia. Prescribing of psychotropic medications to patients in long-term care has declined, although the partnership did not accelerate this decrease. However, the use of mood stabilizers, possibly as a substitute for antipsychotics, increased and accelerated after initiation of the partnership in both long-term care residents overall and in those with dementia. Measuring use of antipsychotics alone may be an inadequate proxy for quality of care and may have contributed to a shift in prescribing to alternative medications with a poorer risk-benefit balance.


Profile of the orthodontist practicing in the State of São Paulo--part 2.
The choice of brackets, bands and wires is a very important aspect of orthodontic treatment. Stainless steel prevailed for a long time, but new alloys and resources have emerged to diversify the orthodontic wire mechanics. This study aimed to investigate the profile and materials used by orthodontists practicing in the State of São Paulo, Brazil. A questionnaire was sent to 2,414 specialists in Orthodontics and Dentofacial Orthopedics registered with the Regional Board of Dentistry of São Paulo State (CRO-SP). To assess the association between qualitative variables, the Chi-square association test was employed at 5% significance level. Five hundred and ninety-three (24.65%) questionnaires were completed and sent back. Efficiency was the key reason given by the professionals for choosing a particular material. The majority showed a preference for metal brackets (98%), followed by ceramics (32%) and polycarbonate (7.8%). The most widely used brackets had 0.022 x 0.028-in slots (73.2%). Regarding orthodontic wires, 88.2% employed round steel wires and conventional round NiTi wires, while 52.6% used round heat-activated NiTi and 46.5% rectangular TMA wires. Elastics (92.9%) were the most widely used method to tie the orthodontic archwire to the bracket. In this survey, the orthodontists claimed that efficiency was the major motivator for choosing orthodontic materials. Conventional brackets tied with conventional elastic ligatures are still the most used by the professionals. Among steel and conventional Nitinol wires, round wires ranked first. The use of resources recently available to Brazilian orthodontists, such as self-ligating brackets and mini-implants, was not significant.


Reliability of eliciting physical signs in examination of the chest.
Agreement between 24 physicians on the presence or absence of respiratory signs was investigated. The physicians were divided into six sets of 4; each set examined 4 patients with well-defined chest signs. There was generally poor agreement about particular signs. Overall, the 4 physicians in a set were in complete agreement only 55% of the time. Some signs such as wheezing seemed to be more reliably elicited than others such as whispering pectoriloquy. Comparison of diagnoses based on the clinical findings with the correct diagnoses supported by investigations showed that 28% of physicians' diagnoses were incorrect. The more often the examiners differed from the majority on the presence or absence of a sign, the more likely they were to make an incorrect diagnosis. A ranked order of the reliability with which chest signs are elicited would improve the teaching of chest medicine.


Trypanosoma cruzi-cardiomyocytes: new contributions regarding a better understanding of this interaction.
The present paper summarizes new approaches regarding the progress done to the understanding of the interaction of Trypanosoma cruzi-cardiomyocytes. Mannose receptors localized at the surface of heart muscle cell are involved in binding and uptake of the parasite. One of the most striking events in the parasite-heart muscle cells interaction is the disruption of the actin cytoskeleton. We have investigated the regulation of the actin mRNA during the cytopathology induced in myocardial cells by the parasite. T. cruzi invasion increases calcium resting levels in cardiomyocytes. We have previously shown that Ca2+ ATPase of the sarcoplasmic reticulum (SERCA) is involved in the invasion of T. cruzi in cardiomyocytes. Treating the cells with thapsigargin, a drug that binds to all SERCA ATPases and causes depletion of intracellular calcium stores, we found a 75% inhibition in the T. cruzi-cardiomyocytes invasion.


Safety and efficacy of APSA PHYTAFEED® (6-phytase) as a feed additive for laying hens and other laying birds.
Following a request from the European Commission, the EFSA Panel on Additives and products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of APSA PHYTAFEED ® 20,000 GR/L (6-phytase) as a zootechnical feed additive for laying hens and other poultry species for laying. The additive is a preparation of 6-phytase produced by a genetically modified strain of Komagataella phaffii and has been previously assessed by the FEEDAP Panel in the context of three applications for its use in different species/categories. The Panel concluded in those opinions that the production strain is safe, and that the use of the additive as a feed additive would raise no safety concerns for the consumers and the environment. The additive was also considered not to be irritant to skin or eyes or a dermal sensitiser but it should be considered as a respiratory sensitiser. The Panel considered that the new use in laying hens and other poultry species for laying would not modify the previously drawn conclusions with respect to the consumers, users and the environment. A tolerance trial in laying hens and a subchronic oral toxicity study were made available to support the safety of the additive for the target species/categories subject of this new application; from the results obtained, the Panel concluded that the additive is safe for laying hens at the recommended level of use (300 U/kg feed) with a wide margin of safety and therefore the conclusion was extrapolated to other laying birds. The FEEDAP Panel concluded that the additive has the potential to be efficacious in laying hens at the level of 300 U/kg feed and this conclusion was extrapolated to other laying birds.


Electromagnetic concentrators with reduced material parameters based on coordinate transformation.
Omni-directional electromagnetic field concentrators have been recently reported by Marco Rahm et al. [Photon. Nanostruct.: Fundam. Appl. 6, 87 (2008)] based on form-invariant coordinate transformations related to its Jacobi transformation matrix. Using transverse-electric wave illumination, we reduced the complex material parameters of the concentrator for future practical implementation. Concentrators with different set of permittivity and permeability tensors are proposed. The electromagnetic concentrating performance and the scattering properties at the inner and outer boundary of these concentrators are theoretically and numerically analyzed. Finally we obtain a set of material tensors for a concentrator that simultaneously has perfect matched interior and exterior interfaces.


Temperament as Risk and Protective Factors in Obesogenic Eating: Relations Among Parent Temperament, Child Temperament, and Child Food Preference and Eating.
Children's food preferences and eating behaviors have implications for their health and weight status, serving as risk or protective factors for obesity. Although parent and child factors influence children's eating, few studies have examined parent and child temperament simultaneously in relation to child food preference and eating behaviors. The authors addressed this research gap. Participants were 115 ethnically diverse children between 4 and 6 years old and their parents. Measures included parental temperament traits, parental anxiety, child temperament traits, and child food preference and eating behaviors observed using a laboratory procedure. Results show that children preferred candies over grapes, and that aspects of both child and adult temperament were related to child eating behaviors. Child surgency was linked to eating more candies, while child effortful control was linked to eating more grapes. Parent effortful control was related to children's preference toward grapes. No relations were found between child eating behaviors and child or parent negative affectivity and parental anxiety. Overall, findings suggest that highly impulsive and poorly self-regulated children may be at risk for obesogenic eating habits.


Gender-Related Differences in Patients Presenting with Suspected Acute Coronary Syndromes: Clinical Presentation, Biomarkers and Diagnosis.
Gender differences in patients presenting with suspected acute coronary syndromes (ACS) have not yet been fully characterized. The aim of this study was to assess gender-related disparities in clinical profiles, biomarkers and diagnoses of patients with suspected ACS. This single-centre, prospective cohort study included 377 consecutive patients presenting with suspected ACS to the emergency department. Suspected ACS was defined as a request for conventional troponin T (c-cTnT) measurements on clinical grounds. Women were older than men (p = 0.004), and had a lower prevalence of known coronary artery and peripheral vascular disease (p < 0.05). c-cTnT was positive in 8% of female and in 14% of male patients (p = 0.16), TIMI risk score and cardiac biomarkers including c-cTnT, hs-cTnT, myoglobin, creatine kinase, N-terminal pro-brain natriuretic peptide, myeloid-related protein 8/14 and pregnancy-associated plasma protein A were lower in women (p < 0.05). Women were less frequently diagnosed with ACS (30 vs. 51%), and were not referred for urgent coronary angiography as often as men (p < 0.001). In multivariate analysis, female gender was associated with a lower referral for coronary angiography (HR 0.41, 95% CI 0.23-0.78, p = 0.006). In patients with suspected ACS, women presented with different biomarker profiles, and were less often diagnosed with ACS and referred to coronary angiography.


Directional selection and variation in finite populations.
Predictions are made of the equilibrium genetic variances and responses in a metric trait under the joint effects of directional selection, mutation and linkage in a finite population. The "infinitesimal model" is analyzed as the limiting case of many mutants of very small effect, otherwise Monte Carlo simulation is used. If the effects of mutant genes on the trait are symmetrically distributed and they are unlinked, the variance of mutant effects is not an important parameter. If the distribution is skewed, unless effects or the population size is small, the proportion of mutants that have increasing effect is the critical parameter. With linkage the distribution of genotypic values in the population becomes skewed downward and the equilibrium genetic variance and response are smaller as disequilibrium becomes important. Linkage effects are greater when the mutational variance is contributed by many genes of small effect than few of large effect, and are greater when the majority of mutants increase rather than decrease the trait because genes that are of large effect or are deleterious do not segregate for long. The most likely conditions for "Muller's ratchet" are investigated.


Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder.
Although recent neuroimaging and therapeutic transcranial magnetic cortex stimulation (TMS) studies suggest imbalance between left and right dorsolateral prefrontal cortex (DLPFC) in major depressive disorder (MDD) the fundamental neuropsychological characterization of left DLPFC hypoactivity and right DLPFC hyperactivity in MDD remains poorly understood. We used event-related functional magnetic resonance imaging (fMRI) to investigate neural activity in left and right DLPFC related to unattended (unexpected) and attended (expected) judgment of emotions. Participating in the study were 20 medication-free patients with MDD and 30 healthy subjects. The MDD patients showed hypoactivity in the left DLPFC during both unattended and attended emotional judgment and hyperactivity in the right DLPFC during attended emotional judgment. In contrast to healthy subjects, left DLPFC activity during emotional judgment was not parametrically modulated by negative emotional valence and was inversely modulated by positive emotional valence in MDD patients. Hyperactivity in the right DLPFC correlated with depression severity. Results demonstrate that left DLPFC hypoactivity is associated with negative emotional judgment rather than with emotional perception or attention while right DLPFC hyperactivity is linked to attentional modulation. Left-right DLPFC imbalance is characterized in neuropsychological regard, which bridges the gap from resting metabolism and therapeutic repetitive transcranial magnetic stimulation effects to functional neuroanatomy of altered emotional-cognitive interaction in MDD.


Comparative evaluation of antibacterial activity of caffeic acid phenethyl ester and PLGA nanoparticle formulation by different methods.
The aim of the present study was to evaluate the antimicrobial activity of nanoparticle and free formulations of the CAPE compound using different methods and comparing the results in the literature for the first time. In parallel with this purpose, encapsulation of CAPE with the PLGA nanoparticle system (CAPE-PLGA-NPs) and characterization of nanoparticles were carried out. Afterwards, antimicrobial activity of free CAPE and CAPE-PLGA-NPs was determined using agar well diffusion, disk diffusion, broth microdilution and reduction percentage methods. P. aeroginosa, E. coli, S. aureus and methicillin-resistant S. aureus (MRSA) were chosen as model bacteria since they have different cell wall structures. CAPE-PLGA-NPs within the range of 214.0 ± 8.80 nm particle size and with an encapsulation efficiency of 91.59 ± 4.97% were prepared using the oil-in-water (o-w) single-emulsion solvent evaporation method. The microbiological results indicated that free CAPE did not have any antimicrobial activity in any of the applied methods whereas CAPE-PLGA-NPs had significant antimicrobial activity in both broth dilution and reduction percentage methods. CAPE-PLGA-NPs showed moderate antimicrobial activity against S. aureus and MRSA strains particularly in hourly measurements at 30.63 and 61.25 μg ml(-1) concentrations (both p < 0.05), whereas they failed to show antimicrobial activity against Gram-negative bacteria (P. aeroginosa and E. coli, p > 0.05). In the reduction percentage method, in which the highest results of antimicrobial activity were obtained, it was observed that the antimicrobial effect on S. aureus was more long-standing (3 days) and higher in reduction percentage (over 90%). The appearance of antibacterial activity of CAPE-PLGA-NPs may be related to higher penetration into cells due to low solubility of free CAPE in the aqueous medium. Additionally, the biocompatible and biodegradable PLGA nanoparticles could be an alternative to solvents such as ethanol, methanol or DMSO. Consequently, obtained results show that the method of selection is extremely important and will influence the results. Thus, broth microdilution and reduction percentage methods can be recommended as reliable and useful screening methods for determination of antimicrobial activity of PLGA nanoparticle formulations used particularly in drug delivery systems compared to both agar well and disk diffusion methods.


Regional gas exchange and cellular metabolic activity in ventilator-induced lung injury.
Alveolar overdistension and repetitive derecruitment-recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident. The authors assessed cellular metabolic activity with [(18)F]fluorodeoxyglucose and regional gas exchange with [(13)N]nitrogen. In 12 sheep, the left ("test") lung was overdistended with end-inspiratory pressure of 50 cm H(2)O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of -10 cm H(2)O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H(2)O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right ("control") lung was protected from VILI. Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [(18)F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [(18)F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone. The authors could detect regional neutrophil activation in VILI even when end-expiratory derecruitment was prevented and impairment of gas exchange was not evident. Concomitant end-expiratory derecruitment converted this activation into profound inflammation with decreased aeration and regional shunting.


Vapor hydrogen and oxygen isotopes reflect water of combustion in the urban atmosphere.
Anthropogenic modification of the water cycle involves a diversity of processes, many of which have been studied intensively using models and observations. Effective tools for measuring the contribution and fate of combustion-derived water vapor in the atmosphere are lacking, however, and this flux has received relatively little attention. We provide theoretical estimates and a first set of measurements demonstrating that water of combustion is characterized by a distinctive combination of H and O isotope ratios. We show that during periods of relatively low humidity and/or atmospheric stagnation, this isotopic signature can be used to quantify the concentration of water of combustion in the atmospheric boundary layer over Salt Lake City. Combustion-derived vapor concentrations vary between periods of atmospheric stratification and mixing, both on multiday and diurnal timescales, and respond over periods of hours to variations in surface emissions. Our estimates suggest that up to 13% of the boundary layer vapor during the period of study was derived from combustion sources, and both the temporal pattern and magnitude of this contribution were closely reproduced by an independent atmospheric model forced with a fossil fuel emissions data product. Our findings suggest potential for water vapor isotope ratio measurements to be used in conjunction with other tracers to refine the apportionment of urban emissions, and imply that water vapor emissions associated with combustion may be a significant component of the water budget of the urban boundary layer, with potential implications for urban climate, ecohydrology, and photochemistry.


The role of perceived speed in vection: does perceived speed modulate the jitter and oscillation advantages?
Illusory self-motion ('vection') in depth is strongly enhanced when horizontal/vertical simulated viewpoint oscillation is added to optic flow inducing displays; a similar effect is found for simulated viewpoint jitter. The underlying cause of these oscillation and jitter advantages for vection is still unknown. Here we investigate the possibility that perceived speed of motion in depth (MID) plays a role. First, in a 2AFC procedure, we obtained MID speed PSEs for briefly presented (vertically oscillating and smooth) radial flow displays. Then we examined the strength, duration and onset latency of vection induced by oscillating and smooth radial flow displays matched either for simulated or perceived MID speed. The oscillation advantage was eliminated when displays were matched for perceived MID speed. However, when we tested the jitter advantage in the same manner, jittering displays were found to produce greater vection in depth than speed-matched controls. In summary, jitter and oscillation advantages were the same across experiments, but slower MID speed was required to match jittering than oscillating stimuli. Thus, to the extent that vection is driven by perceived speed of MID, this effect is greater for oscillating than for jittering stimuli, which suggests that the two effects may arise from separate mechanisms.


A rare case of congenital hyperinsulinism (CHI) due to dual genetic aetiology involving HNF4A and ABCC8.
Background Congenital hyperinsulinism (CHI) occurs due to an unregulated insulin secretion from the pancreatic β-cells resulting in hypoglycaemia. Causative mutations in multiple genes have been reported. Phenotypic variability exists both within and between different genetic subgroups. Case presentation A male infant born at 35+6 weeks' gestation with a birth weight of 4.3 kg [+3.6 standard deviation score (SDS)] had recurrent hypoglycaemic episodes from birth. Biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and the dose was progressively increased to maintain euglycaemia. His father was slim and had been diagnosed with type 2 diabetes in his 30s. Sequence analysis identified a heterozygous hepatocyte nuclear factor 4 alpha (HNF4A) mutation (p.Arg245Pro, c.734G>C) and compound heterozygous ABCC8 mutations (p.Gly92Ser, c.274G>A and p.Ala1185Val, c.3554C>T) in the patient. The p.Ala1185Val ABCC8 mutation was inherited from his unaffected mother and the p.Arg245Pro HNF4A and p.Gly92Ser ABCC8 mutations from his father. All three mutations were predicted to be pathogenic. Identification of the HNF4A mutation in the father established a diagnosis of maturity-onset diabetes of the young (MODY), which enabled medication change resulting in improved glycaemic control. Conclusions We report a rare patient with CHI due to dual genetic aetiology. Although he is currently responsive to the maximum dose of diazoxide, the long-term prognosis remains unclear.


Stigma and functioning in patients with bipolar disorder.
The aim of this study was to investigate the impact of self-rated stigma and functioning in patients with bipolar disorder in Latin-America. Two-hundred and forty-one participants with bipolar disorder were recruited from three Latin American countries (Argentina, Brazil, and Colombia). Functional impairment was assessed with the Functioning Assessment Short Test (FAST) and experiences with and impact of perceived stigma was evaluated using the Inventory of Stigmatizing Experiences (ISE). Higher scores of self-perceived stigma were correlated with lower scores of functioning. After multiple regression analysis, being on disability benefit, current mood symptoms and functioning were associated with self-perceived stigma. This is the first study to demonstrate an association between stigma and poor functioning in bipolar disorder. Possible implications of such findings for practitioners are discussed. The main limitation of this study is that the Inventory of Stigmatizing Experiences has not yet been validated in a population of bipolar patients in our countries. The sample size and heterogeneous clinical subjects from different countries and cultures limit the generalization of the present findings.


From sound to shape: auditory perception of drawing movements.
This study investigates the human ability to perceive biological movements through friction sounds produced by drawings and, furthermore, the ability to recover drawn shapes from the friction sounds generated. In a first experiment, friction sounds, real-time synthesized and modulated by the velocity profile of the drawing gesture, revealed that subjects associated a biological movement to those sounds whose timbre variations were generated by velocity profiles following the 1/3 power law. This finding demonstrates that sounds can adequately inform about human movements if their acoustic characteristics are in accordance with the kinematic rule governing actual movements. Further investigations of our ability to recognize drawn shapes were carried out in 2 association tasks in which both recorded and synthesized sounds had to be associated to both distinct and similar visual shapes. Results revealed that, for both synthesized and recorded sounds, subjects made correct associations for distinct shapes, although some confusion was observed for similar shapes. The comparisons made between recorded and synthesized sounds lead to conclude that the timbre variations induced by the velocity profile enabled the shape recognition. The results are discussed in the context of the ecological and ideomotor frameworks.


Evaluation of Reconstruction Algorithms to Validate the NEMA Phantom Results in Clinical Scenario - A Comparative Study Using Time-of-Flight versus Non-Time-of-Flight Positron Emission Tomography Imaging.
The objective is to standardize the reconstruction parameters for the time-of-flight (TOF) versus non-TOF positron-emission tomography/computed tomography (PET/CT) imaging data and validation of the same in a clinical setting. The four spheres (10.0/13.0/17.0/22.0 mm) of the PET phantom (NEMA IQ Nu 2-2001) were filled with four times higher activity of [18F]-NaF than the background (5.3kBq/mL). Imaging (image matrix - 128 × 128 × 47, 2 min, 3D model) was done using two different (TOF/non-TOF) PET scanners. Phantom data were reconstructed in TOF and non-TOF modes for lutetium-yttrium oxyorthosilicate and non-TOF mode for bismuth germanate-based PET scanners. The reconstructed data (by varying iteration and subsets) that provided the best image contrast and signal-to-noise ratio (SNR) were evaluated. The whole-body [18F]-fludeoxyglucose (FDG) PET/CT scans (7-8 frames; 2.0 min/frame) in 16 lymphoma patients were acquired at 60 min after injecting the radioactivity (370.0-444.0 MBq of [18F]-FDG. The clinical PET/CT data were reconstructed using phantom-derived reconstruction parameters and evaluated for image contrast and SNR of the detected lesions. TOF reconstruction at second iteration provided significantly (P ≤ 0.02) higher SNR (20.7) and contrast (contrast recovery coefficient/background variability = 3.21) for the smallest hot lesions (10.0 mm) in the phantom than the non-TOF system. Similarly, in patient data analysis for the selected FDG avid lesions, the SNR values were significantly (P = 0.02) higher (13.3 ± 6.49) in TOF than (11 ± 6.48) in non-TOF system. Further, the small (≤10.0 mm) lesions were seen more distinctly in TOF system. It is thus observed that TOF reconstruction converged faster than the non-TOF, and the applicability of the same may impact the image quality and interpretation in the clinical PET data. The validation of the phantom-based experimental reconstruction parameters to clinical PET imaging data is highly warranted.


A systematic review of PFE pre-prostatectomy.
Male Stress Urinary Incontinence is a complication post robotic radical prostatectomy. This is a major problem that needs to be solved, since it has great impact on quality of life affecting the patient's physical activity and social well-being. A systematic review relating to literature on impact of preoperative PFE on continence outcomes for patients undergoing prostatectomy was conducted. The search strategy aimed to identify all references related to pelvic floor exercises and post-prostatectomy. Search terms used were as follows: (Pelvic floor exercises) AND (incontinence) AND (prostatectomy). The following databases were screened from 2000 to September 2017: CINAHL, MEDLINE (NHS Evidence), Cochrane, AMed, EMBASE, PsychINFO, SCOPUS, Web of Science. In addition, searches using Medical Subject Headings (MeSH) and keywords were conducted using Cochrane databases. Two UK-based experts in prostate cancer and robotic surgery were consulted to identify any additional studies. In the 6 months following surgery, the continence rates, as defined by the use of one pad or less per day, were 94% (44 of 47) and 96% (48 of 50) in the PFE and biofeedback groups and control groups (PFE alone), respectively (P = 0.596) (Bales et al. in Urology 56: 627-630, 2000). This demonstrates preoperative PFE may improve early continence after RP. Geraerts et al. (Eur Urol 64:766-772, 2013) demonstrated the "incontinence impact" was in favour of a group with PFE at 3 and 6 months after surgery. This demonstrates again the advantage of preoperative PFE. Cornel et al. [World J Urol 23:353-355, 2005] determined the benefit of starting pelvic floor muscle exercise (PFE) 30 days before RP and of continuing PFE postoperatively for early recovery of continence as part of a randomised, prospective study (Moher quality A). This demonstrated preoperative PFE may improve early continence and QoL outcomes after RP. Post-prostatectomy incontinence is a bothersome complication of radical prostatectomy [Chughtai et al. in Rev Urol 15:61-66, 2013]. Weak pelvic floor muscles compromised normal pelvic floor function and led to urinary incontinence and erectile dysfunction. Strengthening the pelvic floor muscles was shown to significantly improve post-prostatectomy urinary continence, post-micturition dribble and erectile function. It would be prudent for all men to exercise their pelvic floor muscles to maintain normal pelvic floor function and start prior to surgery.


Regulation of skeletal muscle glycogen phosphorylase and PDH during maximal intermittent exercise.
The time course for the activation of glycogen phosphorylase (Phos) and pyruvate dehydrogenase (PDH) and their allosteric regulators was determined in human skeletal muscle during repeated bouts of maximal exercise. Six subjects completed three 30-s bouts of maximal isokinetic cycling separated by 4-min recovery periods. Muscle biopsies were taken at rest and at 6, 15, and 30 s of exercise during bouts 1 and 3. Phos was rapidly activated within the first 6 s of bout 1 from 12% at rest to 47% at 6 s. The activation of PDH increased from 14% at rest to 48% at 6 s and 95% at 15 s of bout 1. Phos reverted back to basal values at the end of the first bout, whereas PDH remained fully activated. In contrast, in the third bout, PDH was 42% at rest and was activated more rapidly and was nearly completely activated by 6 s, whereas Phos remained at basal levels (range 14-20%). Lactate accumulation was marked in the first bout and increased progressively from 2.7 to 76.1 mmol/kg dry wt with no further increase in bout 3. Glycogen utilization was also marked in the first bout and was negligible in bout 3. The rapid activation of Phos and slower activation of PDH in bout 1 was probably due to Ca(2+) release from the sarcoplasmic reticulum. Lactate accumulation appeared to be due to an imbalance of the relative activities of Phos and PDH. The increase in H(+) concentration may have served to reduce pyruvate production by inhibiting Phos transformation and may have simultaneously activated PDH in the third bout such that there was a better matching between pyruvate production and oxidation and minimal lactate accumulation. As each bout progressed and with successive bouts, there was a decreasing ability to stimulate substrate phosphorylation through phosphocreatine hydrolysis and glycolysis and a shift toward greater reliance on oxidative phosphorylation.


Testing the H2O2-H2O hypothesis for life on Mars with the TEGA instrument on the Phoenix lander.
In the time since the Viking life-detection experiments were conducted on Mars, many missions have enhanced our knowledge about the environmental conditions on the Red Planet. However, the martian surface chemistry and the Viking lander results remain puzzling. Nonbiological explanations that favor a strong inorganic oxidant are currently favored (e.g., Mancinelli, 1989; Plumb et al., 1989; Quinn and Zent, 1999; Klein, 1999; Yen et al., 2000), but problems remain regarding the lifetime, source, and abundance of that oxidant to account for the Viking observations (Zent and McKay, 1994). Alternatively, a hypothesis that favors the biological origin of a strong oxidizer has recently been advanced (Houtkooper and Schulze-Makuch, 2007). Here, we report on laboratory experiments that simulate the experiments to be conducted by the Thermal and Evolved Gas Analyzer (TEGA) instrument of the Phoenix lander, which is to descend on Mars in May 2008. Our experiments provide a baseline for an unbiased test for chemical versus biological responses, which can be applied at the time the Phoenix lander transmits its first results from the martian surface.


Experiences of maternity care among women at increased risk of preterm birth receiving midwifery continuity of care compared to women receiving standard care: Results from the POPPIE pilot trial.
Midwifery continuity of care models for women at low and mixed risk of complications have been shown to improve women's experiences of care. However, there is limited research on care experiences among women at increased risk of preterm birth. We aimed to explore the experiences of care among women with risk factors for preterm birth participating in a pilot trial (POPPIE) of a midwifery continuity of care model which included a specialist obstetric clinic. A total of 334 pregnant women identified at increased risk of preterm birth were randomly allocated to either midwifery continuity of care (POPPIE group) or standard maternity care. Women in both groups were followed up at six-to-eight weeks postpartum and were invited to complete a postnatal survey either online or by post. An equal status exploratory sequential mixed method design was chosen to collect and analyse the quantitative postnatal survey data and qualitative interviews data. The postnatal survey included measures of social support, trust, perceptions of safety, quality of care, control during childbirth, bonding and quality of life. Categorical data were analysed with chi-squared tests and continuous data were analysed with t-tests and/or Mann-Whitney U test to measure differences in measures scores among groups. The qualitative interview data were subjected to a thematic framework analysis. Data triangulation brought quantitative and qualitative data together at the interpretation stage. A total of 166 women completed the survey and 30 women were interviewed (90 and 16 in POPPIE group; 76 and 14 in standard group). We found survey respondents in the POPPIE group, compared to respondents in the standard group, were significantly more likely to report greater trust in midwives (Mann-Whitney U, p<0.0001), greater perceptions of safety during the antenatal care (t-test, p = 0.0138), have a particular midwife to contact when they needed during their pregnancy (t-test, p<0.0001) and the postnatal period (chi-squared, p<0.0001). They reported increased involvement in decisions regarding antenatal, intrapartum and postnatal care (t-test, p = 0.002; p = 0.008; p = 0.006 respectively); and greater postnatal support and advice about: feeding the baby (chi-squared, p<0.0001), handling, settling and looking after the baby (chi-squared, p<0.0001), baby's health and progress (chi-squared, p = 0.039), their own health and recovery (chi-squared, p = 0.006) and who to contact about any emotional changes (chi-squared, p = 0.005). There were no significant differences between groups in the reporting of perceptions of safety during birth and the postnatal period, concerns raised during labour and birth taken seriously, being left alone during childbirth at a time of worries, control during labour, bonding, social support, and physical and mental health related quality of life after birth. Results from qualitative interviews provided insight and depth into many of these findings, with women in the POPPIE group reporting more positive experiences of bonding towards their babies and more positive physical health postnatally. Compared with standard maternity care, women at increased risk of PTB who received midwifery continuity of care were more likely to report increased perceptions of trust, safety and quality of care. ISRCTN (Number: 37733900); UK CRN (ID: 31951).


Intramedullary limb lengthening with the Intramedullary Skeletal Kinetic Distractor in the lower limb.
We report the results of intramedullary leg lengthening conducted between 2002 and 2009 using the Intramedullary Skeletal Kinetic Distractor in 69 unilateral lengthenings involving 58 femora and 11 tibiae. We identified difficulties that occurred during the treatment and assessed whether they were specifically due to the implant or independent of it. Paley's classification for evaluating problems, obstacles and complications with external fixators was adopted, and implant-specific difficulties were continuously noted. There were seven failures requiring premature removal of the device, in four due to nail breakage and three for other reasons, and five unsuccessful outcomes after completion of the lengthening. In all, 116 difficulties were noted in 45 patients, with only 24 having problem-free courses. In addition to the difficulties arising from the use of external fixators, there were almost the same number again of implant-specific difficulties. Nevertheless, successful femoral lengthening was achieved in 52 of the 58 patients (90%). However, successful tibial lengthening was only achieved in five of 11 patients (45%).


Observation and modeling of conformational molecular structures driving the self-assembly of tri-adamantyl benzene on Ag(111).
The self-organization of tri-adamantyl (TAB) benzene molecules has been investigated using low temperature scanning tunneling microscopy (LT-STM). The molecular structures have also been studied using molecular modeling. In particular, these calculations have been performed on large areas (1000 nm(2)) from the atomic structure of the molecular building block, combining molecular dynamics (MD) and Monte-Carlo (MC) approaches. These investigations show that the structure of the molecule and its flexibility allow for the formation of different networks as a function of surface coverage. The calculations demonstrate that the stability of the largest structures is obtained through the increase of the interfacial energy induced by the rotation of the adamantyl groups, a behavior whose consequences explain the subtle contrasts observed in the experimental STM images.


SU-E-T-23: TomoTherapy Patient QA Using Exit Detector Measurement of Pre-Treatment In-Air Delivery.
Currently, the recommended TomoTherapy patient specific QA involves setting up a DQA procedure and delivering it to a phantom with an ion chamber and film measurement. The process is time-consuming and the DQA result is susceptible to errors in phantom setup. Our study explores the feasibility of using TomoTherapy's intrinsic exit detectors to perform patient specific QA by measuring the fluence received by the detectors during pre-treatment in-air delivery for our STAT-RAD workflow. A TomoTherapy patient plan is converted into a calibration procedure in which the couch remains out of the gantry. The signal measured by the exit detector is exported through manufactory provided software. In-house developed software is used to reconstruct exit detector signal from the dicom-exported delivery plan. The software relies on individual leaf profiles as well as tongue-and-groove profiles of each adjacent leaf-pair extracted from an in-house developed calibration procedure. The difference between the reconstructed and measured detector signal can be analyzed by a simple algorithm which has been developed to estimate the dose difference of any given point inside a patient or phantom. Several patient plans have been tested with this in-air delivery QA method. In some of the tested plans, errors have been introduced to assure the estimated point dose error agrees with the ion chamber measurement in a phantom. The in-house exit detector reconstruction software has been validated to be able to reconstruct the exit detector signal with errors <1%. The software estimated point dose agrees within 3% to the ion chamber measurement. Our study shows that it is feasible and efficient to perform patient specific QA using the exit detector signal recorded during the in-air pretreatment delivery. This approach is easy to perform and it is faster than conventional QA approach.


Detection of infectious myonecrosis virus in penaeid shrimps using immunoassays: usefulness of monoclonal antibodies directed to the viral major capsid protein.
Despite the economic impact of the infectious myonecrosis virus (IMNV) on shrimp farms in several countries, no method for immunological detection is currently available. With the aim of developing immunodiagnostic methods for IMNV detection in infected shrimps, a recombinant fragment of the IMNV major capsid protein gene encoding amino acids 105-297 (rIMNV₁₀₅₋₂₉₇ was heterologously expressed in Escherichia coli and used to immunize Balb/c mice, generating monoclonal antibodies (MAbs). Six hybridomas were obtained, and four of these recognized the presence of IMNV in tissue homogenates from naturally infected shrimps by immunodot blot assay. Among these MAbs, three were able to detect a ~100-kDa protein, which corresponds to the predicted mass of the IMNV major capsid protein, as well as viral inclusion bodies in muscle fibroses by western blot and immunohistochemistry. Two MAbs showed high specificity and sensitivity, showing no cross-reaction with healthy shrimp tissues in any assays, indicating their usefulness for IMNV detection.


Attention network dysfunction underlies memory impairment in posterior cortical atrophy.
Accumulating evidence suggests that memory is impaired in posterior cortical atrophy (PCA), alongside the early and defining visual disorder. The posterior parietal cortex is a key region of pathology in PCA and memory impairment may be the result of dysfunction of parietally dependent network function rather than the medial temporal lobe dependent dysfunction that defines the storage deficits in typical Alzheimer's disease. We assessed episodic memory performance and network function in16 PCA patients and 19 healthy controls who underwent structural and resting-state functional MRI and neuropsychological testing. Memory was assessed using the Free and Cued Selective Reminding Test (FCSRT), a sensitive test of episodic memory storage and retrieval. We examined correlations between memory performance and functional connectivity in the dorsal attention (DAN) and default mode network (DMN). Immediate recall on the FCSRT was relatively preserved in PCA patients. Total recall performance was impaired in patients relative to healthy controls and performance benefitted from retrieval cues. In patients only, disrupted connectivity in the DAN, but not the DMN, was associated with total recall. Memory impairment may arise from disruption to the dorsal attention network, subserved by the dorsal posterior parietal cortex, a key region of pathology in PCA, rather than classic medial temporal lobe memory circuitry.We propose that functional dysconnectivity in attentional circuits underpins memory impairment in PCA.


Automatic rupture of unused intraport catheter. Case report.
Totally Implantable Central Venous Access Devices (Intraports) are commonly used in cancer patients to administer chemotherapy or parenteral nutrition. These devices are placed by Seldinger technique. We report an unusual case of intraport catheter rupture before the use of the device. The ruptured part of the catheter migrated into the left pulmonary vein via right ventricle. The ruptured part was removed by means of interventional radiology before causing any problems to the patient. All the reported ruptures of port catheters refer to port devices that had been used to administer chemotherapy, fluids, or parenteral nutrition. The unique feature of this case is that the catheter had not been used at all. It is of great interest also the removal of the broken part from the pulmonary vein.


The immunologic modulation of morbidity in schistosomiasis. Studies in athymic mice and in vitro granuloma formation.
These studies were designated to test the hypothesis that granulomatous hypersensitivity associated with schistosomiasis, its modulation, and subsequent morbidity are contingent on thymic-dependent lymphocyte function. Studies in athymic mice were integrated with in vitro studies on granuloma formation. Athymic animals tolerate low levels of infection well but are increasingly susceptible to morbidity as the challenge burden increases or becomes associated with simultaneous additional stress such as bacterial infection. In addition, the athymic animals produce smaller granulomas and fail to demonstrate accelerated granuloma formation, the spontaneous modulation of granulomas, or significant resistance to reinfection. These deficiencies could be reversed by thymic reconstitution. In vitro studies indicate that the response to egg antigens was due to the interaction of two subpopulations of T lymphocytes. Studies of "in vitro granuloma formation" augmented the in vivo findings, suggesting that the "in vitro granuloma" represents an excellent analog for delayed hypersensitivities; granuloma production was contingent on a macrophage function and a specific subpopulation of T lymphocytes defined as Ly1+. Granuloma modulation was due to two mechanisms, one contingent on direct suppression by ly2,3+ cells and the other by feedback inhibition requiring Ly,2,3+ cells. These studies suggest the feasibility of combined in vivo and in vitro technology to study the mechanisms of granuloma formation and subsequent morbidity.


Automatic and manual image fusion of In-pentetreotide SPECT and diagnostic CT in neuroendocrine tumor imaging - An evaluation.
In the clinical diagnosis of neuroendocrine tumors (NET), the results of examinations, such as high-resolution computed tomography (CT) and single photon computerized tomography (SPECT), have conventionally been interpreted separately. The aim of the present study was to evaluate Hermes Multimodality™ 5.0 H Image Fusion software-based automatic and manual image fusion of SPECT and CT for the localization of NET lesions. Out of 34 NET patients who were examined by means of somatostatin receptor scintigraphy (SRS) with 111In- pentetreotide along with SPECT, 22 patients had a CT examination of the abdomen, which was used in the fusion analysis. SPECT and CT data were fused using software with a registration algorithm based on normalized mutual information. The criteria for acceptable fusion were established at a maximum cranial or caudal dislocation of 25 mm between the images and at a reasonable consensus (in order of less than 1 cm) between outline of the reference organs. The automatic fusion was acceptable in 13 of the 22 examinations, whereas 9 fusions were not. However all the 22 examinations were acceptable at the manual fusion. The result of automatic fusion was better when the slice thickness of 5 mm was applied at CT examination, when the number of slices was below 100 in CT data and when both examinations included uptakes of pathological lesions. Retrospective manual image fusion of SPECT and CT is a relatively inexpensive but reliable method to be used in NET imaging. Automatic image fusion with specified software of SPECT and CT acts better when the number of CT slices is reduced to the SPECT volume and when corresponding pathological lesions appear at both SPECT and CT examinations.


Enhanced Imaging and Language Assessments for Primary Progressive Aphasia.
It is widely agreed that primary progressive aphasia (PPA) is a clinical syndrome with at least 3 distinct variants that differ in phenotype, areas of atrophy, and most common underlying neurodegenerative disease. The distinction between logopenic variant PPA (lvPPA) and other variants is important for prognosis and medical management. However, differentiating logopenic from nonfluent agrammatic variant can be difficult. We aimed to identify a novel behavioral assessment that (1) distinguishes logopenic from the other variants with a high degree of accuracy and (2) correlates with left superior temporal-inferior parietal atrophy (previously shown to be associated with this variant). The location of atrophy was measured using a novel, clinically useful imaging analysis. In this observational cohort study of 227 individuals with PPA, participants were administered sentence reading and repetition subtests from a standard battery. A subset of 41 participants were administered enhanced reading and repetition subtests with 5 longer sentences, of which 13 had brain imaging. Ratios of word-level and sentence-level accuracy in reading:repetition were calculated. We used one-way analysis of variance (ANOVA) to determine whether either or both ratios of reading:repetition independently discriminated between variants and t test to determine whether the ratios distinguished between nonfluent and logopenic variants. We identified receiver operating characteristics and Pearson correlations between the reading:repetition ratios and ratio of left:right superior temporal-inferior parietal volume. The sentence reading:repetition ratio using the new stimuli significantly differed across the 3 variants (p < 0.00001) and differed between nonfluent and logopenic variants (t(27) = 4.1; p = 0.0003). The area under the curve for distinguishing logopenic from other variants was 0.85 (0.71-0.99), and the diagnostic accuracy was 87.5%. The sentence reading:repetition ratio correlated with left:right superior temporal-inferior parietal volume (r = 0.69; p = 0.0087), but not with left:right volume of regions of interest associated with other variants. Results provide an efficient and reliable clinical assessment, and a novel imaging analysis, to distinguish the clinical syndrome of logopenic variant from other variants of PPA. Results also support the proposal that lvPPA reflects a defect in phonological short-term memory caused by atrophy in the superior temporal-inferior parietal cortex. This study provides Class III evidence that the sentence reading:repetition ratio distinguished logopenic PPA from other PPA variants.


Valgus torque in youth baseball pitchers: A biomechanical study.
The purpose of this study was to determine the biomechanical and anthropometric factors contributing to elbow valgus torque during pitching. Video data of 14 youth pitchers throwing fastballs were used to calculate shoulder and elbow kinematics and kinetics. Peak elbow valgus torque averaged 18 Nm and occurred just before maximal shoulder external rotation. The magnitude of valgus torque was most closely correlated with the thrower's weight. When subject weight and height were controlled for, maximum shoulder abduction torque and maximum shoulder internal rotation torque were most strongly associated with elbow valgus torque, accounting for 85% of its variance (P <.001). When only kinematic variables were considered, maximum shoulder external rotation accounted for 33% of the variance in valgus torque. Given that the biomechanical variables correlated with peak valgus torque are not easily modifiable, limiting the number of innings pitched is likely the best way to reduce elbow injury in youth pitchers.


Blind-deconvolution optical-resolution photoacoustic microscopy in vivo.
Optical-resolution photoacoustic microscopy (OR-PAM) is becoming a vital tool for studying the microcirculation system in vivo. By increasing the numerical aperture of optical focusing, the lateral resolution of OR-PAM can be improved; however, the depth of focus and thus the imaging range will be sacrificed correspondingly. In this work, we report our development of blind-deconvolution optical-resolution photoacoustic microscopy (BD-PAM) that can provide a lateral resolution ~2-fold finer than that of conventional OR-PAM (3.04 vs. 5.78μm), without physically increasing the system's numerical aperture. The improvement achieved with BD-PAM is demonstrated by imaging graphene nanoparticles and the microvasculature of mice ears in vivo. Our results suggest that BD-PAM may become a valuable tool for many biomedical applications that require both fine spatial resolution and extended depth of focus.


Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel 18F-labelled PET tracer targeting P2X7.
The P2X7 receptor has been shown to play a fundamental role in the initiation and sustenance of the inflammatory cascade. The development of a novel fluorine-18 PET tracer superior and with a longer half-life to those currently available is a promising step towards harnessing the therapeutic and diagnostic potential offered by this target. Inspired by the known antagonist A-804598, the present study outlines the design via molecular docking, synthesis and biological evaluation of the novel P2X7 tracer [18F]EFB. The tracer was radiolabelled via a three-step procedure, in vitro binding assessed in P2X7-transfected HEK293 and in B16 cells by calcium influx assays and an initial preclinical evaluation was performed in a lipopolysaccharide (LPS)-injected rat model of neuroinflammation. The novel tracer [18F]EFB was synthesised in 210 min in 3-5% decay-corrected radiochemical yield (DC RCY), >99% radiochemical purity (RCP) and >300 GBq/μmol and fully characterised. Functional assays showed that the compound binds with nM K i to human, rat and mouse P2X7 receptors. In vivo, [18F]EFB displayed a desirable distribution profile, and while it showed low blood-brain barrier penetration, brain uptake was quantifiable and displayed significantly higher mean longitudinal uptake in inflamed versus control rat CNS regions. [18F]EFB demonstrates strong in vitro affinity to human and rodent P2X7 and limited yet quantifiable BBB penetration. Considering the initial promising in vivo data in an LPS rat model with elevated P2X7 expression, this work constitutes an important step in the development of a radiotracer useful for the diagnosis and monitoring of clinical disorders with associated neuroinflammatory processes.


An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase.
Gold(I) complexes are an important tool in the arsenal of established approaches for treating rheumatoid arthritis (RA), while some recent studies have suggested that gold nanoparticles (Au NPs) may also be therapeutically efficacious. These observations prompted the current biological studies involving gold(I) anti-RA agents and Au NPs, which are aimed towards improving our knowledge of how they work. The cytotoxicity of auranofin, aurothiomalate, aurothiosulfate and Au NPs towards RAW264.7 macrophages was evaluated using the MTT assay, with the former compound proving to be the most toxic. The extent of cellular uptake of the various gold agents was determined using graphite furnace atomic absorption spectrometry, while their distribution within macrophages was examined using microprobe synchrotron radiation X-ray fluorescence spectroscopy. The latter technique showed accumulation of gold in discrete regions of the cell, and co-localisation with sulfur in the case of cells treated with aurothiomalate or auranofin. Electrospray ionization mass spectrometry was used to characterize thioredoxin reductase (TrxR) in which the penultimate selenocysteine residue was replaced by cysteine. Mass spectra of solutions of TrxR and aurothiomalate, aurothiosulfate or auranofin showed complexes containing bare gold atoms bound to the protein, or protein adducts containing gold atoms retaining some of their initial ligands. These results support TrxR being an important target of gold(I) drugs used to treat RA, while the finding that Au NPs are incorporated into macrophages, but elicit little toxicity, indicates further exploration of their potential for treatment of RA is warranted.


Host, pathogen, and environmental characteristics predict white-nose syndrome mortality in captive little brown myotis (Myotis lucifugus).
An estimated 5.7 million or more bats died in North America between 2006 and 2012 due to infection with the fungus Pseudogymnoascus destructans (Pd) that causes white-nose syndrome (WNS) during hibernation. The behavioral and physiological changes associated with hibernation leave bats vulnerable to WNS, but the persistence of bats within the contaminated regions of North America suggests that survival might vary predictably among individuals or in relation to environmental conditions. To investigate variables influencing WNS mortality, we conducted a captive study of 147 little brown myotis (Myotis lucifugus) inoculated with 0, 500, 5000, 50,000, or 500,000 Pd conidia and hibernated for five months at either 4 or 10°C. We found that female bats were significantly more likely to survive hibernation, as were bats hibernated at 4°C, and bats with greater body condition at the start of hibernation. Although all bats inoculated with Pd exhibited shorter torpor bouts compared to controls, a characteristic of WNS, only bats inoculated with 500 conidia had significantly lower survival odds compared to controls. These data show that host and environmental characteristics are significant predictors of WNS mortality, and that exposure to up to 500 conidia is sufficient to cause a fatal infection. These results also illustrate a need to quantify dynamics of Pd exposure in free-ranging bats, as dynamics of WNS produced in captive studies inoculating bats with several hundred thousand conidia may differ from those in the wild.


Mitochondrial function in vascular endothelial cell in diabetes.
Micro- and macrovascular complications are commonly seen in diabetic patients and endothelial dysfunction contributes to the development and progression of the complications. Abnormal functions in endothelial cells lead to the increase in vascular tension and atherosclerosis, followed by systemic hypertension as well as increased incidence of ischemia and stroke in diabetic patients. Mitochondria are organelles serving as a source of energy production and as regulators of cell survival (e.g., apoptosis and cell development) and ion homeostasis (e.g., H(+), Ca(2+)). Endothelial mitochondria are mainly responsible for generation of reactive oxygen species (ROS) and maintaining the Ca(2+) concentration in the cytosol. There is increasing evidence that mitochondrial morphological and functional changes are implicated in vascular endothelial dysfunction. Enhanced mitochondrial fission and/or attenuated fusion lead to mitochondrial fragmentation and disrupt the endothelial physiological function. Abnormal mitochondrial biogenesis and disturbance of mitochondrial autophagy increase the accumulation of damaged mitochondria, such as irreversibly depolarized or leaky mitochondria, and facilitate cell death. Augmented mitochondrial ROS production and Ca(2+) overload in mitochondria not only cause the maladaptive effect on the endothelial function, but also are potentially detrimental to cell survival. In this article, we review the physiological and pathophysiological role of mitochondria in endothelial function with special focus on diabetes.


Multiphoton near-infrared quantum cutting luminescence phenomena of Tm3+ ion in (Y1-xTm(x))3Al5O12 powder phosphor.
In the present study, the multiphoton near-infrared downconversion quantum cutting luminescence phenomena of Tm3+ ion in (Y(1-x)Tm(x))(3)Al(5)O(12) powder phosphor, which is currently a hot research topic throughout the world, is reported. The x-ray diffraction spectra, the visible to near-infrared excitation and emission spectra, and fluorescence lifetimes are measured. It is found that Tm:YAG powder phosphor has intense two-photon quantum cutting luminescence, and, for the first time, it is found that Tm:YAG powder phosphor has strong four-photon near-infrared quantum cutting luminescence of 1788 nm (3)F4 → (3)H6 fluorescence of Tm(3+) ion. It is also found that the theoretical up-limit of four-photon near-infrared quantum cutting efficiency is about 282.12%, which results from both the {(1)D2 → (3)F2, (3)H6 → (3)H4} and {(3)H4 → (3)F4, (3)H6 → (3)F4} cross-energy transfers.