Channel-lining residues in the M3 membrane-spanning segment of the cystic fibrosis transmembrane conductance regulator.
The cystic fibrosis transmembrane conductance regulator (CFTR) forms a chloride-selective channel. Residues from the 12 putative membrane-spanning segments form at least part of the channel lining. We need to identify the channel-lining residues in order to understand the structural basis for the channel's functional properties. Using the substituted-cysteine-accessibility method we mutated to cysteine, one at a time, 24 consecutive residues (Asp192-Ile215) in the M3 membrane-spanning segment. Cysteines substituted for His199, Phe200, Trp202, Ile203, Pro205, Gln207, Leu211, and Leu214 reacted with charged, sulfhydryl-specific reagents that are derivatives of methanethiosulfonate (MTS). We infer that these residues are on the water-accessible surface of the protein and probably form a portion of the channel lining. When plotted on an alpha-helical wheel the exposed residues from Gln207 to Leu214 lie within an arc of 60 degrees; the exposed residues in the cytoplasmic half (His199-Ile203) lie within an arc of 160 degrees. We infer that the secondary structures of the extracellular and cytoplasmic halves of M3 are alpha-helical and that Pro205, in the middle of the M3 segment, may bend the M3 segment, moving the cytoplasmic end of the segment in toward the central axis of the channel. The bend in the M3 segment may help to narrow the channel lumen near the cytoplasmic end. In addition, unlike full-length CFTR, the current induced by the deletion construct, Delta259, is inhibited by the MTS reagents, implying that the channel structure of Delta259 is different than the channel structure of wild-type CFTR.


Self-Assembling Peptide-Based Hydrogel: Regulation of Mechanical Stiffness and Thermal Stability and 3D Cell Culture of Fibroblasts.
A histidine-containing peptide-based amphiphile (P1) forms a transparent hydrogel within a pH range of 5.5 to 8.5 in phosphate buffer solution. Interestingly, thermal stability and mechanical stiffness are modulated by incorporating different types of dicarboxylic acids into the hydrogels. Inclusion of succinic acid with the molar ratio 2:1 (peptide:dicarboxylic acid) yields improved properties compared to the other tested dicarboxylic acids such as oxalic, glutaric and octanedioic acids. Transmission electron microscopic (TEM) images show the assembly of nanospheres is responsible for the hydrogel obtained from the assembly of native peptide. However, a morphological transformation takes place from nanosphere to nanofibers, when the peptide gels with succinic acid. XRD and FT-IR studies reveal interactions between peptide amphiphiles and the acids are responsible for the formation of a two-component hydrogel. Gel stiffness is enhanced considerably upon the addition of succinic acid to P1 with a 1:2 molar ratio. The two-component gel consisting of peptide and succinic acid has been successfully used for three-dimensional cell culture using mouse fibroblast cell line (NIH-3T3). This indicates future promise for the application of such peptide-based gels as tunable biomaterials in cell culture and regenerative medicine.


Rapid Detection of Strong Correlation with Machine Learning for Transition-Metal Complex High-Throughput Screening.
Despite its widespread use in chemical discovery, approximate density functional theory (DFT) is poorly suited to many targets, such as those containing open-shell, 3d transition metals that can be expected to have strong multireference (MR) character. For discovery workflows to be predictive, we need automated, low-cost methods that can distinguish the regions of chemical space where DFT should be applied from those where it should not. We curate more than 4800 open-shell transition-metal complexes up to hundreds of atoms in size from prior high-throughput DFT studies and evaluate affordable, finite-temperature DFT fractional occupation number (FON)-based MR diagnostics. We show that intuitive measures of strong correlation (i.e., the HOMO-LUMO gap) are not predictive of MR character as judged by FON-based diagnostics. Analysis of independently trained machine learning (ML) models to predict HOMO-LUMO gaps and FON-based diagnostics reveals differences in the metal and ligand sensitivity of the two quantities. We use our trained ML models to rapidly evaluate MR character over a space of ∼187000 theoretical complexes, identifying large-scale trends in spin-state-dependent MR character and finding small HOMO-LUMO gap complexes while ensuring low MR character.


Influence of stent design and use of protection devices on outcome of carotid artery stenting: a pooled analysis of individual patient data.
Carotid artery stenting is an alternative to endarterectomy for the treatment of symptomatic carotid stenosis but was associated with a higher risk of procedural stroke or death in randomized controlled trials (RCTs). Technical aspects of treatment may partly explain these results. The purpose of this analysis was to investigate the influence of technical aspects such as stent design or the use of protection devices, as well as clinical variables, on procedural risk. We pooled data of 1557 individual patients receiving stent treatment in three large RCTs comparing stenting versus endarterectomy for symptomatic carotid stenosis. The primary outcome event was any procedural stroke or death occurring within 30 days after stenting. Procedural stroke or death occurred significantly more often with the use of open-cell stents (61/595 patients, 10.3%) than with closed-cell stents (58/962 patients, 6.0%; RR 1.76; 95% CI 1.23 to 2.52; P=0.002). Procedural stroke or death occurred in 76/950 patients (8.0%) treated with protection devices (predominantly distal filters) and in 43/607 (7.1%) treated without protection devices (RR 1.10; 95% CI 0.71 to 1.70; P=0.67). Clinical variables predicting the primary outcome event were age, severity of the qualifying event, history of prior stroke, and level of disability at baseline. The effect of stent design remained similar after adjustment for these variables. In symptomatic carotid stenosis, the use of stents with a closed-cell design is independently associated with a lower risk of procedural stroke or death compared with open-cell stents. Filter-type protection devices do not appear to reduce procedural risk.


Sequential Ag+/biothiol and synchronous Ag+/Hg2+ biosensing with zwitterionic Cu2+-based metal-organic frameworks.
Zwitterionic metal-organic frameworks (MOFs) of {[Cu(Cbdcp)(Dps)(H2O)3]·6H2O}n (MOF 1) and [Cu4(Dcbb)4(Dps)2(H2O)2]n (MOF 2) (H3CbdcpBr = N-(4-carboxybenzyl)-(3,5-dicarboxyl)pyridinium bromide; H2DcbbBr = 1-(3,5-dicarboxybenzyl)-4,4'-bipyridinium bromide; Dps = 4,4'-dipyridyl sulfide) quench the fluorescence of cytosine-rich DNA tagged with 5-carboxytetramethylrhodamine (TAMRA, emission at 582 nm, denoted as C-rich P-DNA-1) and yield the corresponding P-DNA-1@MOF hybrids. Exposure of these hybrids to Ag+ results in the release of the P-DNA-1 strands from the MOF surfaces as double-stranded, hairpin-like C-AgI-C (ds-DNA-1@Ag+) with the restoration of TAMRA fluorescence. The ds-DNA-1@Ag+ formed on the surface of 1 can subsequently sense biothiols cysteine (Cys), glutathione (GSH), and homocysteine (Hcy) due to the stronger affinity of mercapto groups for Ag+ that serves to unfold the ds-DNA-1@Ag+ duplex, reforming P-DNA-1, which is re-adsorbed by MOF 1 accompanied by quenching of TAMRA emission. Meanwhile, MOF 2 is also capable of co-loading a thymine-rich probe DNA tagged with 5-carboxyfluorescein (FAM, emission at 518 nm, denoted as T-rich P-DNA-2) to achieve synchronous sensing of Ag+ and Hg2+, resulting from the simultaneous yet specific ds-DNA-1@Ag+ and T-HgII-T duplex (ds-DNA-2@Hg2+) formation, as well as the distinctive emission wavelengths of TAMRA and FAM. Detection limits are as low as 5.3 nM (Ag+), 14.2 nM (Cys), 13.5 nM (GSH), and 9.1 nM (Hcy) for MOF 1, and 7.5 nM (Ag+) and 2.6 nM (Hg2+) for MOF 2, respectively. The sequential sensing of Ag+ and biothiols by MOF 1, and the synchronous sensing of Ag+ and Hg2+ by MOF 2 are rapid and specific, even in the presence of other mono- and divalent metal cations or other biothiols at much higher concentrations. Molecular simulation studies provide insights regarding the molecular interactions that underpin these sensing processes.


Infusing bioethics into biology and microbiology courses and curricula: a vertical approach.
With the rise of biomedicine and biotechnology, there has been a corresponding growth in the need for better understanding of consequent ethical questions. Increasingly, biologists are being asked not only to offer technical clarifications but also to venture ethical opinions, for which most feel poorly equipped. This expectation puts pressure on biology instructors at the university level to provide biology majors the skills and experience to discuss with some confidence and competence bioethical issues which may arise in either the workplace or through public discourse in everyday contexts. Many fine curricular resources about bioethics are available for varied pedagogical purposes, but few target undergraduate biology or microbiology student audiences. When it occurs in the context of a course, bioethics instruction often is taught by non-biologists outside standard biology curricula. We propose that biologists should strive to "infuse" bioethical thinking into their courses and major curricula but not in such a way as merely to point at ethical problems, treating them at a surface level. We suggest what we call "vertical infusion": taking one bioethical issue per course and integrating this issue within the context of a relevant biological topic, challenging students to push their thinking beyond their initial intuitions toward underlying scientific and ethical principles. While the vertical approach lacks widespread coverage of ethical issues throughout a single course, it has the advantage of taking the bioethical dimension seriously and in intimate relation to contemporary discoveries in biology and to the biological principles, processes, or procedures that occasioned the ethical quandaries in the first place.


Self-organizing continuous attractor network models of hippocampal spatial view cells.
Single neuron recording studies have demonstrated the existence of hippocampal spatial view neurons which encode information about the spatial location at which a primate is looking in the environment. These neurons are able to maintain their firing even in the absence of visual input. The standard neuronal network approach to model networks with memory that represent continuous spaces is that of continuous attractor networks. It has recently been shown how idiothetic (self-motion) inputs could update the activity packet of neuronal firing for a one-dimensional case (head direction cells), and for a two-dimensional case (place cells which represent the place where a rat is located). In this paper, we describe three models of primate hippocampal spatial view cells, which not only maintain their spatial firing in the absence of visual input, but can also be updated in the dark by idiothetic input. The three models presented in this paper represent different ways in which a continuous attractor network could integrate a number of different kinds of velocity signal (e.g., head rotation and eye movement) simultaneously. The first two models use velocity information from head angular velocity and from eye velocity cells, and make use of a continuous attractor network to integrate this information. A fundamental feature of the first two models is their use of a 'memory trace' learning rule which incorporates a form of temporal average of recent cell activity. Rules of this type are able to build associations between different patterns of neural activities that tend to occur in temporal proximity, and are incorporated in the model to enable the recent change in the continuous attractor to be associated with the contemporaneous idiothetic input. The third model uses positional information from head direction cells and eye position cells to update the representation of where the agent is looking in the dark. In this case the integration of idiothetic velocity signals is performed in the earlier layer of head direction cells.


RANKL inhibition blocks osteolytic lesions and reduces skeletal tumor burden in models of non-small-cell lung cancer bone metastases.
Bone metastasis is a serious complication in patients with lung cancer, occurring in up to 40% of patients. Tumor cell-mediated osteolysis occurs ultimately through induction of RANK ligand (RANKL) within the bone stroma although this hypothesis has not been tested extensively in the setting of non-small-cell lung cancer (NSCLC). By using two novel NSCLC bone metastasis mouse models, we examined the effects of RANKL inhibition on osteolysis and tumor progression. We treated mice bearing skeletal NSCLC tumors with osteoprotegerin-Fc (OPG-Fc) to assess whether osteoclast inhibition through RANKL inhibition would affect bone metastases at early or late stages of bone colonization. Progression of skeletal tumor was determined by radiography, longitudinal bioluminescent imaging, and histological analyses. OPG-Fc reduced development and progression of radiographically evident osteolytic lesions and also significantly reduced skeletal tumor progression in both NSCLC bone metastasis models. In the H1299 human NSCLC bone metastasis model, OPG-Fc plus docetaxel in combination resulted in significantly greater inhibition of skeletal tumor growth compared with either single agent alone. The observed ability of RANKL inhibition to reduce NSCLC osteolytic bone destruction or skeletal tumor burden was associated with decreases in tumor-associated osteoclasts. These results demonstrate that RANKL is required for the development of tumor-induced osteolytic bone destruction caused by NSCLC cells in vivo. RANKL inhibition also reduced skeletal tumor burden, presumably through the indirect mechanism of blocking tumor-induced osteoclastogenesis and resultant production of growth factors and calcium from the bone microenvironment. RANKL inhibition also provided an additive benefit to docetaxel treatment by augmenting the reduction of tumor burden.


Correlation of blue-on-yellow visual fields with scanning confocal laser optic disc measurements.
Visual field defects and changes in the optic nerve head are signs of glaucoma. It has been shown that blue-on-yellow (B-Y) perimetry can reveal visual field defects earlier and shows them larger than does white-on-white (W-W) perimetry. The Heidelberg retina tomograph (HRT) can produce three-dimensional images of the optic disc. The aim of this study was to find out how B-Y perimetry results correlate with optic disc parameters in comparison with W-W perimetry results. One randomly chosen eye was evaluated in each of 40 normal subjects and 37 patients with ocular hypertension and different stages of glaucoma. B-Y and W-W visual fields (program 30-2) were obtained with a Humphrey perimeter. B-Y perimetry results were adjusted for the patient's age and lens transmission index measured with a lens fluorometer. The B-Y visual field adjusted mean deviation (MD) was calculated as the difference between the measured and expected mean sensitivity values, predicted by the regression model fitted in normal subjects. The HRT with software version 1.11 was used to acquire and evaluate topographic measurements of the optic disc. The cup shape measure showed strongest correlation with the MD of both the B-Y and W-W visual fields. The multiple correlation coefficients from quadratic regression were 0.65 for both visual fields. Except for peripapillary retinal nerve fiber layer measurements, the statistically significant correlations of the B-Y visual field indexes with other HRT parameters were equal to or better than those of W-W perimetry. B-Y perimetry MDs are well correlated with optic nerve head parameters measured with the HRT. In early stages of glaucoma, most HRT variables were better correlated with the B-Y MD than with the W-W MD.


Sex biases in bird and mammal natural history collections.
Natural history specimens are widely used across ecology, evolutionary biology and conservation. Although biological sex may influence all of these areas, it is often overlooked in large-scale studies using museum specimens. If collections are biased towards one sex, studies may not be representative of the species. Here, we investigate sex ratios in over two million bird and mammal specimen records from five large international museums. We found a slight bias towards males in birds (40% females) and mammals (48% females), but this varied among orders. The proportion of female specimens has not significantly changed in 130 years, but has decreased in species with showy male traits like colourful plumage and horns. Body size had little effect. Male bias was strongest in name-bearing types; only 27% of bird and 39% of mammal types were female. These results imply that previous studies may be impacted by undetected male bias, and vigilance is required when using specimen data, collecting new specimens and designating types.


The curative management of synchronous rectal and prostate cancer.
Neoadjuvant "long-course" chemoradiation is considered a standard of care in locally advanced rectal cancer. In addition to prostatectomy, external beam radiotherapy and brachytherapy with or without androgen suppression (AS) are well established in prostate cancer management. A retrospective review of ten cases was completed to explore the feasibility and safety of applying these standards in patients with dual pathology. To our knowledge, this is the largest case series of synchronous rectal and prostate cancers treated with curative intent. Eligible patients had synchronous histologically proven locally advanced rectal cancer (defined as cT3-4Nx; cTxN1-2) and non-metastatic prostate cancer (pelvic nodal disease permissible). Curative treatment was delivered to both sites simultaneously. Follow-up was as per institutional guidelines. Acute and late toxicities were reviewed, and a literature search performed. Pelvic external beam radiotherapy (RT) 45-50.4 Gy was delivered concurrent with 5-fluorouracil (5FU). Prostate total dose ranged from 70.0 to 79.2 Gy. No acute toxicities occurred, excluding AS-induced erectile dysfunction. Nine patients proceeded to surgery, and one was managed expectantly. Three relapsed with metastatic colorectal cancer, two with metastatic prostate cancer. Five patients have no evidence of recurrence, and four remain alive with metastatic disease. With a median follow-up of 2.2 years (range 1.2-6.3 years), two significant late toxicities occurred; G3 proctitis in a patient receiving palliative bevacizumab and a G3 anastomotic stricture precluding stoma reversal. Patients proceeding to synchronous radical treatment of both primary sites should receive 45-50.4 Gy pelvic RT with infusional 5FU. Prostate dose escalation should be given with due consideration to the potential impact of prostate cancer on patient survival, as increasing dose may result in significant late morbidity. Review of published series explores the possibility of prostate brachytherapy as an alternative method of boost delivery. Frequent use of bevacizumab in metastatic rectal cancer may compound late rectal morbidity in this cohort. To our knowledge, this is the largest case series of synchronous rectal and prostate cancers treated with curative intent. This article contributes to the understanding of how best to approach definitive treatment in these patients.


Phototransformation of 5-nitro-2-furaldehyde in aqueous solution. A laser flash photolysis and product analysis study.
Laser flash photolysis of 5-nitro-2-furaldehyde (NFA) in solution shows a short-lived transient absorption with λmax = 475 ± 5 nm, which is relatively insensitive to solvent polarity and is assigned to the lowest triplet state of NFA (3NFA*). In water, the 3NFA* absorption decays to a long-lived absorption, the study of which, at different times after the end of the laser pulse, reveals it to be due to a furyloxyl radical (λmax ≈ 375 nm) and to the radical anion NFA˙- (λmax ≈ 400 nm). These radicals were produced independently to confirm the assignment. The lifetime of 3NFA* depends both on the solvent and the ground-state concentration of NFA. An (n, π*) nature is attributed to 3NFA* on the basis of the propensity of 3NFA* to abstract a hydrogen-atom from the solvent. Kinetic evidence for triplet excimer formation was obtained from the self-quenching of 3NFA* in solvents where the triplet decay is slower. The effect of acidity on the triplet lifetime is discussed with respect to an electron-transfer self-quenching mechanism, assisted by the triplet excimer which is proposed to dissociate into radical ions. Chromatographic and spectroscopic analysis of the photolysed aqueous solution of NFA enabled the identification of 5-hydroxymethylene-2(5H)-furanone, nitrite ion and an unknown substance as the major photoproducts. Conclusive evidence is presented that the observed 5-hydroxymethylene-2(5H)-furanone is formed from the furyloxyl radical. It is shown that the unknown substance can also be obtained from both the photoreduction of NFA in propan-2-ol and chemical reduction of NFA by Fe(s) in water (along with 5-amino-2-furaldehyde). Based on 1H- and 13C-NMR (with 2-D HMQC) and vibrational absorption spectroscopy, a tentative structure is proposed for the substance of tR 3.69 minutes obtained as a photoreduction product of NFA in water. Inorganic anions are shown to be one-electron oxidised by 3NFA* (as indicated by the observation of both the radical anion of NFA and the inorganic radical) with second-order rate constants being dependent on E of the inorganic radical. The implications of the results from complete quenching of 3NFA* by inorganic anions, and subsequent product analysis, for the phototransformation mechanism of NFA in water are discussed.


Calibration and Noise Identification of a Rolling Shutter Camera and a Low-Cost Inertial Measurement Unit.
A low-cost inertial measurement unit (IMU) and a rolling shutter camera form a conventional device configuration for localization of a mobile platform due to their complementary properties and low costs. This paper proposes a new calibration method that jointly estimates calibration and noise parameters of the low-cost IMU and the rolling shutter camera for effective sensor fusion in which accurate sensor calibration is very critical. Based on the graybox system identification, the proposed method estimates unknown noise density so that we can minimize calibration error and its covariance by using the unscented Kalman filter. Then, we refine the estimated calibration parameters with the estimated noise density in batch manner. Experimental results on synthetic and real data demonstrate the accuracy and stability of the proposed method and show that the proposed method provides consistent results even with unknown noise density of the IMU. Furthermore, a real experiment using a commercial smartphone validates the performance of the proposed calibration method in off-the-shelf devices.


Synthesis and anti-HIV activity of new metabolically stable alkenyldiarylmethane non-nucleoside reverse transcriptase inhibitors incorporating N-methoxy imidoyl halide and 1,2,4-oxadiazole systems.
The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are capable of inhibiting HIV-1 reverse transcriptase (RT) through an allosteric mechanism. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties that are hydrolyzed by nonspecific esterases present in blood plasma, resulting in the formation of the inactive carboxylic acid metabolites. Therefore, to discover metabolically stable ADAMs, the design and synthesis of a new class of ADAMs with N-methoxy imidoyl halide and 1,2,4-oxadiazole systems were attempted. The resulting new ADAM 6 displayed enhanced metabolic stability in rat plasma (t1/2 = 61 h) along with the ability to inhibit HIV-1 reverse transcriptase and the cytopathic effect of HIV-1RF and HIV-1IIIB at submicromolar concentrations.


Nutritional status, hospitalization and mortality among patients with sickle cell anemia in Tanzania.
Reduced growth is common in children with sickle cell anemia, but few data exist on associations with long-term clinical course. Our objective was to determine the prevalence of malnutrition at enrollment into a hospital-based cohort and whether poor nutritional status predicted morbidity and mortality within an urban cohort of Tanzanian sickle cell anemia patients. Anthropometry was conducted at enrollment into the sickle cell anemia cohort (n=1,618; ages 0.5-48 years) and in controls who attended screening (siblings, walk-ins and referrals) but who were found not to have sickle cell anemia (n=717; ages 0.5-64 years). Prospective surveillance recorded hospitalization at Muhimbili National Hospital and mortality between March 2004 and September 2009. Sickle cell anemia was associated with stunting (OR=1.92, P<0.001, 36.2%) and wasting (OR=1.66, P=0.002, 18.4%). The greatest growth deficits were observed in adolescents and in boys. Independent of age and sex, lower hemoglobin concentration was associated with increased odds of malnutrition in sickle cell patients. Of the 1,041 sickle cell anemia patients with a body mass index z-score at enrollment, 92% were followed up until September 2009 (n=908) or death (n=50). Body mass index and weight-for-age z-score predicted hospitalization (hazard ratio [HZR]=0.90, P=0.04 and HZR=0.88, P=0.02) but height-for-age z-score did not (HZR=0.93, NS). The mortality rate of 2.5 per 100 person-years was not associated with any of the anthropometric measures. In this non-birth-cohort of sickle cell anemia with significant associated undernutrition, wasting predicted an increased risk of hospital admission. Targeted nutritional interventions should prioritize treatment and prevention of wasting.


A 1.375-approximation algorithm for sorting by transpositions.
Sorting permutations by transpositions is an important problem in genome rearrangements. A transposition is a rearrangement operation in which a segment is cut out of the permutation and pasted in a different location. The complexity of this problem is still open and it has been a 10-year-old open problem to improve the best known 1.5-approximation algorithm. In this paper, we provide a 1.375-approximation algorithm for sorting by transpositions. The algorithm is based on a new upper bound on the diameter of 3-permutations. In addition, we present some new results regarding the transposition diameter: we improve the lower bound for the transposition diameter of the symmetric group and determine the exact transposition diameter of simple permutations.


Specialist training and medical research in developing countries of tropical Africa: a case for the establishment of postgraduate medical schools.
Developing countries like developed ones need highly skilled medical personnel, referred to as 'specialists'. In the case of developing countries, the training of these specialists abroad is expensive to the sponsoring governments, imposes a lot of hardship on the doctors and, above all, the course-content of such training takes little or no cognizance of the environment in which these doctors would later practise. The developing countries also cannot afford the loss of years in valuable services which the training abroad entails. Attempts are now being made to train specialists wholly or partly at home, in some developing countries. The approach is still not much divorced from what obtains in Britain and North America, that is, one of being trained on the job, with the onus for self-education being placed on the prospective students. Such students in most developing countries of tropical Africa have little or no facilities for further education outside their places of work. It is proposed that purpose-designed postgraduate medical schools may provide a temporary solution to specialist training in developing countries of tropical Africa. Such schools would in addition provide highly skilled medical service as well as obviate the need and the expense for the setting up of government sponsored medical research and training institutes.


The Risk of Dementia in Relation to Cognitive and Brain Reserve.
Individual differences in the risk to develop dementia remain poorly understood. These differences may partly be explained through reserve, which is the ability to buffer cognitive decline due to neuropathology and age. To determine how much early and late-life cognitive reserve (CR) and brain reserve (BR) contribute to the risk of dementia. 4,112 dementia-free participants (mean age = 66.3 years) from the Rotterdam Study were followed up for on average 6.0 years. Early-life CR and BR were defined as attained education and intracranial volume, respectively. Late-life CR was derived through variance decomposition based on cognition. Late-life BR was set as the total non-lesioned brain volume divided by intracranial volume. Higher early-life CR (hazard ratio = 0.48, 95% CI = [0.21; 1.06]) but not early-life BR associated with a lower risk of incident dementia. Higher late-life CR (hazard ratio = 0.57, 95% CI = [0.48; 0.68]) and late-life BR (hazard ratio = 0.54, 95% CI = [0.43; 0.68]) also showed lower levels of dementia. Combining all proxies into one model attenuated the association between early-life CR and dementia (hazard ratio = 0.56, 95% CI = [0.25; 1.25]) whereas the other associations were unaffected. These findings were stable upon stratification for sex, age, and APOEɛ4. Finally, high levels of late-life CR and BR provided additive protection against dementia. The findings illustrate the importance of late-life over early-life reserve in understanding the risk of dementia, and show the need to study CR and BR conjointly.


A biomechanical comparison of suture constructs used for coracoclavicular fixation.
There is no consensus regarding surgical treatment for severely dislocated acromioclavicular joints. Although many treatments are suture-based, the suture materials and resulting suture-bone constructs have been subjected to limited systematic evaluation. This study identifies the strongest and least deforming suture construct among those commonly used for such repairs. Each suture-based repair was tested on a simulated clavicle and coracoid process with the skeletal components distracted until the suture failed to obtain tensile strength. Additional groups of sutures were subjected to cyclic loading to determine resistance to deformation. Panacryl braid had significantly greater tensile strength than all other constructs: Polydioxanone (PDS) braid, Mersilene tape, and Ethibond #5. Deformation after cyclic loading of Panacryl braid, PDS braid, and two strands of Mersilene tape was significantly less than that of the other constructs. A bioabsorbable suture loop, such as Panacryl, can act as a temporary internal splint, maintaining acromioclavicular joint reduction long enough for ligamentous healing during rehabilitation, and can avoid complications associated with permanent fixation materials. Panacryl braid deserves serious consideration for coracoclavicular fixation because of its strength, resistance to deformation, and bioabsorbable properties.


Hemoptysis: diagnosis and management.
Hemoptysis is the spitting of blood that originated in the lungs or bronchial tubes. The patient's history should help determine the amount of blood and differentiate between hemoptysis, pseudohemoptysis, and hematemesis. A focused physical examination can lead to the diagnosis in most cases. In children, lower respiratory tract infection and foreign body aspiration are common causes. In adults, bronchitis, bronchogenic carcinoma, and pneumonia are the major causes. Chest radiographs often aid in diagnosis and assist in using two complementary diagnostic procedures, fiberoptic bronchoscopy and high-resolution computed tomography, which are useful in difficult cases and when malignancy is suspected. The goals of management are threefold: bleeding cessation, aspiration prevention, and treatment of the underlying cause. Mild hemoptysis often is caused by an infection that can be managed on an outpatient basis with dose monitoring. If hemoptysis persists, consulting with a pulmonologist should be considered. Patients with risk factors for malignancy or recurrent hemoptysis also require further evaluation with fiberoptic bronchoscopy or high-resolution computed tomography. In up to 34 percent of patients, no cause of hemoptysis can be found.


Primary Care Management of Skin Abscesses Guided by Ultrasound.
Primary care providers often manage skin abscesses in the outpatient setting. Estimating the size and depth of an abscess, and distinguishing abscess from cellulitis by clinical examination can be challenging due to surrounding firm tissue induration. Definitive treatment of abscess requires incision and drainage, and the approach chosen may be altered by abscess size, depth, and surrounding neurovascular structures. For 31 consecutive patients seen in the primary care outpatient clinic, we prospectively compared the estimated size of skin abscesses by clinical examination with that determined by ultrasound. Prior to incision and drainage, a limited point-of-care ultrasound examination was performed and the abscess dimensions were measured, the depth was determined, and adjacent vascular structures were noted. Based on ultrasound findings, physicians reported whether the decision to perform the procedure or the techniques used to perform the procedure were altered by the scan. The clinical examination was inaccurate for size estimation by >0.5 cm in 16 of 31 patients (52%). Ultrasound examination changed the physician decision of whether or not incision and drainage should be performed in 7 patients (23%) and altered the technique/approach in an additional 10 patients (32%); thus, management was changed in 55% of cases. Physician confidence in performing the procedure was improved in 16 cases (52%). Outpatient procedural management of skin abscesses by primary care physicians was altered in more than half the cases by performing point-of-care ultrasound prior to incision and drainage.


Optimizing reproducibility of operant testing through reinforcer standardization: identification of key nutritional constituents determining reward strength in touchscreens.
Reliable and reproducible assessment of animal learning and behavior is a central aim of basic and translational neuroscience research. Recent developments in automated operant chamber technology have led to the possibility of universal standard protocols, in addition to increased translational potential, reliability and accuracy. However, the impact of regional and national differences in the supplies of available reinforcers in this system on behavioural performance and inter-laboratory variability is an unknown and at present uncontrolled variable. Therefore, we aimed to identify which constituent(s) of the reward determines reinforcer strength to enable improved standardization of this parameter across laboratories. Male C57BL/6 mice were examined in the touchscreen-based fixed ratio (FR) and progressive ratio (PR) schedules, reinforced with different kinds of milk-based reinforcers to directly compare the incentive values of plain milk (PM, high-calorie: high-fat/low-sugar), strawberry-flavored milk (SM, high-calorie: low-fat/high-sugar), and semi-skimmed low-fat milk (LM, low-calorie: low-fat/low-sugar) on the basis of differences in caloric content, sugar/fat content, and flavor. Use of a higher caloric content reward was effective in increasing operant training acquisition rate. Total trial number completed in FR and breakpoint in PR were higher using the two isocaloric milk products (PM and SM) than the lower caloric LM, with comparable outcomes between PM and SM conditions, suggesting that total caloric content determines reward strength. Analysis of within-session changes in response rate revealed that overall outputs in FR and PR primarily depend on the response rate at the initial phase of a session, which itself was dependent on reinforcer caloric content. Interestingly, the rate of satiation, indicated by decay in response rate within a FR session, was highest when reinforced with SM, suggesting a rapid satiating effect of sugar. The key contribution of reward caloric content to operant performance was confirmed in a multi-laboratory study using the touchscreen 5-choice serial reaction time task (5-CSRTT) reinforced by two isocaloric milk-based liquid rewards with different countries of origin, which yielded consistent performance parameters across sites. Our results indicate that milk-based liquid reinforcer standardization can be facilitated by matching caloric content across laboratories despite regional or national differences in other non-caloric aspects of the reinforcers.


Self-enhancement processing in the default network: a single-pulse TMS study.
Much research has been done on positive self-evaluation and its relationship to mental health. However, little is known about its neural underpinnings. Imaging studies have suggested that the brain's default network is involved with self-related processing and that one portion of the default network, medial prefrontal cortex (MPFC), is particularly involved with self-evaluation. Here, we used transcranial magnetic stimulation (TMS) to causally demonstrate that this network, and particularly MPFC, is involved with self-evaluative processing. In a first experiment, 27 healthy volunteers judged whether adjectives, evenly divided between desirable and undesirable traits, described themselves or their best friends, and a robust self-enhancement bias effect was found. In a second experiment, single-pulse TMS was applied targeting three locations (MPFC and left and right parietal cortex) in a different group of healthy volunteers while they performed the adjective task. In each trial, TMS was applied at one of five different times relative to onset of the adjective ranging from 0 to 480 ms. TMS affected self-enhancement bias in a site- and latency-specific manner: at MPFC, the self-enhancement bias actually reversed at 160 ms, with subjects favoring their best friend over themselves. TMS may thus be of use in investigating areas of mental illness in which self-evaluation is abnormal, potentially as a diagnostic tool. In addition, the present study, combined with our previous reports (Lou et al., Proc Natl Acad Sci USA 101(17):6827-6832, 2004, Exp Brain Res 207:27-38, 2010), causally demonstrates two kinds of self-related processing within the default network, one centered in parietal cortex and concerned with retrieval of self-related associations, and the other MPFC-centered and involved in self-evaluative processing.


Is Medication Information for Children with Autism Spectrum Disorder Monitored and Coordinated Across Professionals? Findings from a Teacher Survey.
Prescription medications are commonly used for children with autism spectrum disorder (ASD), however, there is little research regarding how the effect of medication is monitored across settings once prescribed. The present study addressed this issue for children with ASD in school by administering a questionnaire to teachers of students with ASD who were and were not being given medication. Specifically, the questionnaire assessed the teachers' knowledge about whether the child was being given medication, and whether behavior changes or side effects were being communicated in any way to the child's family and prescribing physician. The results showed that for children who were being given medication, fewer than half of the teachers reported knowing the child was being given medication. For those children who were not being given medication, only 53% of the teachers reported correct information for their students. Of the teachers who knew their students were being given medication, all reported that they were not conferring with the child's prescribing physician regarding behavioral observations or side effects. Whether teachers are blind to the medication types and dosage the students are being given or not, some type of communication to physicians about the children's behavior at school is important. Given the importance of monitoring medication for children with ASD, implications for system change, for professionals and for funding agencies are discussed.


Effect of Yoga-nidra on Adolescents Well-being: A Mixed Method Study.
Adolescent well-being is a priority area for health-care interventions in the 21st century. Yoga-nidra is an ancient Indian method of enabling individuals to attain a positive state of deep physical, mental, and emotional relaxation. The practice produces a state of simultaneous relaxation and detachment resulting in inner awareness and release of stress on all planes of one's being. This mixed method study was carried out in adolescent students aged 13-15 years with an aim to assess effects of Yoga-nidra on various dimensions of well-being. Thirty-six students received Yoga-nidra sessions 30 min daily for 3 days in a week for 1 month. Primary outcome measures were happiness, perceived stress, overall quality of life, and psychological general well-being. These and other experiential dimensions of well-being comprising of enthusiasm, alertness, quietude, clarity of thought, control over anger, self-confidence, and self-awareness were evaluated before and after intervention. Qualitative observations were recorded from participants, their teachers, and parents. Results of quantitative and qualitative methods were analyzed and compared. Yoga-nidra intervention resulted in significant improvement in all primary outcome measures. Participants reported significant improvement in the feelings of happiness, enthusiasm, quietude, being more inspired and alert, active, having clarity of thought, control over anger, and self-confidence at the end of the study period. Mixed method design of the study provided cross-validation and convergence of results obtained from quantitative and qualitative assessment tools. Yoga-nidra is beneficial in improving multiple dimensions of adolescent well-being.


Urban-rural differences in oral and maxillofacial trauma.
The aim of this research was to assess oral and maxillofacial trauma in urban and rural populations of the same region. The data collected included age, gender, year and month of trauma occurrence, origin (rural and urban), cause of injury, and the type of oral and maxillofacial trauma. Records from 1121 patients with 790 instances of oral and maxillofacial trauma were evaluated. Statistical analysis was performed with the Statistical Package for Social Sciences (SPSS) version 17.0 software and involved descriptive statistics and Pearson's chi-squared test. Male patients were more prone to maxillofacial trauma (n = 537; 68%), and the patients were mostly from urban areas (n = 534; 67.6%). The male-to-female ratio was found to be 2.12:1 (urban zone, 1.72:1; rural zone, 3.49:1). The average age was 25.7 years (SD = 14.1). A traffic accident was the most common cause of oral and maxillofacial trauma (27%). The jaw (18%) was the most commonly fractured bone in the facial skeleton, followed by the zygoma (12.9%). Avulsion (8.5%) was the most common dental trauma. A significant statistical relationship was found between place of origin and gender (p < 0.001). Accidents involving animals were more frequent in rural areas (P < 0.001). Zygomatic fractures (p < 0.001), contusion (p = 0.003), and abrasion (p = 0.051) were the most common injuries among individuals from rural areas. Nasal fracture (p = 0.011) was the most frequent type of trauma in individuals from urban areas. According to these data, it seems reasonable to assume that specific preventive public policy for urban and rural areas must respect the differences of each region.


Prenatal maternal depression symptoms and nutrition, and child cognitive function.
Little is currently known about how maternal depression symptoms and unhealthy nutrition during pregnancy may developmentally interrelate to negatively affect child cognitive function. To test whether prenatal maternal depression symptoms predict poor prenatal nutrition, and whether this in turn prospectively associates with reduced postnatal child cognitive function. In 6979 mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK, maternal depression symptoms were assessed five times between 18 weeks gestation and 33 months old. Maternal reports of the nutritional environment were assessed at 32 weeks gestation and 47 months old, and child cognitive function was assessed at age 8 years. During gestation, higher depressive symptoms were related to lower levels of healthy nutrition and higher levels of unhealthy nutrition, each of which in turn was prospectively associated with reduced cognitive function. These results were robust to postnatal depression symptoms and nutrition, as well as a range of potential prenatal and postnatal confounds (i.e. poverty, teenage mother, low maternal education, parity, birth complications, substance use, criminal lifestyle, partner cruelty towards mother). Prenatal interventions aimed at the well-being of children of parents with depression should consider targeting the nutritional environment.


The Influence of Selective and Divided Attention on Audiovisual Integration in Children.
This article aims to investigate whether there is a difference in audiovisual integration in school-aged children (aged 6 to 13 years; mean age = 9.9 years) between the selective attention condition and divided attention condition. We designed a visual and/or auditory detection task that included three blocks (divided attention, visual-selective attention, and auditory-selective attention). The results showed that the response to bimodal audiovisual stimuli was faster than to unimodal auditory or visual stimuli under both divided attention and auditory-selective attention conditions. However, in the visual-selective attention condition, no significant difference was found between the unimodal visual and bimodal audiovisual stimuli in response speed. Moreover, audiovisual behavioral facilitation effects were compared between divided attention and selective attention (auditory or visual attention). In doing so, we found that audiovisual behavioral facilitation was significantly difference between divided attention and selective attention. The results indicated that audiovisual integration was stronger in the divided attention condition than that in the selective attention condition in children. Our findings objectively support the notion that attention can modulate audiovisual integration in school-aged children. Our study might offer a new perspective for identifying children with conditions that are associated with sustained attention deficit, such as attention-deficit hyperactivity disorder.


The Asp285 variant of DNA polymerase beta extends mispaired primer termini via increased nucleotide binding.
Endogenous DNA damage occurs at a rate of at least 20,000 lesions per cell per day. Base excision repair (BER) is a key pathway for maintaining genome stability. Several pol beta variants were identified as conferring resistance to 3'-azido-3'-deoxythymidine (AZT) in Escherichia coli (Kosa et al. (1999) J. Biol. Chem. 274, 3851-3858). Detailed biochemical studies on one of these AZT-resistant variants, His285 to Asp, have shown that the H285D variant of pol beta possesses pre-steady-state kinetics that are similar to the wild-type polymerase. In gap filling assays with 5-bp gapped DNA, H285D showed a slight mutator phenotype. In depth single turnover kinetic analysis revealed that H285D is much more efficient than wild-type pol beta at extending mispaired primer termini. This mispair extension property of H285D is attributed to a greatly increased binding to the next correct nucleotide in the presence of a mispair. This change in K d(dNTP),app is not accompanied by a change in k pol; values for k pol are the same for both H285D and wild-type. Close examination of available structural data, as well as molecular modeling, has shown that residue 285 is able to make several stabilizing contacts in the fingers domain of the polymerase, and the introduction of a negatively charged side chain could have important effects on the enzyme. It is postulated that the loss of the contact between His285, Lys289, and Ile323 is responsible for the ability of H285D to extend mispairs through disruption of contacts near the C-terminal end of pol beta and propagation into the nucleotide binding pocket.


Not just surveys and indicators: narratives capture what really matters for health system strengthening.
Health system strengthening remains elusive and challenging. Health systems in many countries in sub-Saharan Africa are frequently characterised as weak, with inadequate management and accountability mechanisms, and poor human and financial resources. Putting patients and staff at the heart of health systems is an essential step towards strengthening them. As one of the three pillars of quality in health care, understanding patient experiences is key to moving towards people-centred care. Yet patient experiences are not a singular concept. Patient narratives can convey individual experiences of illness and health care, which complement and augment epidemiological and public health evidence. These narratives, gathered with rigorous, interview-based research and shared with digital tools (audio and video), can generate persuasive evidence. This evidence has important potential for influencing policy and practice, and for supporting people-centred care, but has not been tested systematically in low-income countries. In the Kenyan context of newborn health, work under way is generating evidence to show the transformative potential of patient narratives.


Real-time estimation of horizontal gaze angle by saccade integration using in-ear electrooculography.
The manuscript proposes and evaluates a real-time algorithm for estimating eye gaze angle based solely on single-channel electrooculography (EOG), which can be obtained directly from the ear canal using conductive ear moulds. In contrast to conventional high-pass filtering, we used an algorithm that calculates absolute eye gaze angle via statistical analysis of detected saccades. The estimated eye positions of the new algorithm were still noisy. However, the performance in terms of Pearson product-moment correlation coefficients was significantly better than the conventional approach in some instances. The results suggest that in-ear EOG signals captured with conductive ear moulds could serve as a basis for light-weight and portable horizontal eye gaze angle estimation suitable for a broad range of applications. For instance, for hearing aids to steer the directivity of microphones in the direction of the user's eye gaze.


Mood state and gambling: using mobile telephones to track emotions.
Mobile telephones were used to collect data on the relationship between gambling and mood state from gamblers in the field. Seventeen gamblers called an interactive voice response system running on a computer before, during and after a gambling episode. Measures taken in this way included self-reports of anxiety/arousal, the amount of money gambled, whether the result was a win or loss, the amount won or lost, and the type of gambling engaged in. Other measures were taken during an initial briefing session using conventional questionnaires that included self-reports of anxiety/arousal taken in a non-gambling situation, dissociation during gambling, and a measure of degree of impairment of control. The results showed that subjective anxiety/arousal levels were significantly higher during and after gambling than during the urge to gamble or at baselines. Losing was associated with increased subjective anxiety/arousal after play, and winning was associated with a decrease in subjective anxiety/arousal. This suggests that gambling may be a cause of increased subjective anxiety/arousal, rather than functioning to relieve it. A cluster of variables associated with impaired control and subjective anxiety/arousal levels was also identified. The method of collecting data using mobile telephones appears to be a valuable development.


TrkB receptor signaling in the nucleus tractus solitarius mediates the food intake-suppressive effects of hindbrain BDNF and leptin.
Brain-derived neurotrophic factor (BDNF) and TrkB receptor signaling contribute to the central nervous system (CNS) control of energy balance. The role of hindbrain BDNF/TrkB receptor signaling in energy balance regulation is examined here. Hindbrain ventricular BDNF suppressed body weight through reductions in overall food intake and meal size and by increasing core temperature. To localize the neurons mediating the energy balance effects of hindbrain ventricle-delivered BDNF, ventricle subthreshold doses were delivered directly to medial nucleus tractus solitarius (mNTS). mNTS BDNF administration reduced food intake significantly, and this effect was blocked by preadministration of a highly selective TrkB receptor antagonist {[N2-2-2-Oxoazepan-3-yl amino]carbonyl phenyl benzo (b)thiophene-2-carboxamide (ANA-12)}, suggesting that TrkB receptor activation mediates hindbrain BDNF's effect on food intake. Because both BDNF and leptin interact with melanocortin signaling to reduce food intake, we also examined whether the intake inhibitory effects of hindbrain leptin involve hindbrain-specific BDNF/TrkB activation. BDNF protein content within the dorsal vagal complex of the hindbrain was increased significantly by hindbrain leptin delivery. To assess if BDNF/TrkB receptor signaling acts downstream of leptin signaling in the control of energy balance, leptin and ANA-12 were coadministered into the mNTS. Administration of the TrkB receptor antagonist attenuated the intake-suppressive effects of leptin, suggesting that mNTS TrkB receptor activation contributes to the mediation of the anorexigenic effects of hindbrain leptin. Collectively, these results indicate that TrkB-mediated signaling in the mNTS negatively regulates food intake and, in part, the intake inhibitory effects of leptin administered into the NTS.


Ice age climate, evolutionary constraints and diversity patterns of European dung beetles.
Current climate and Pleistocene climatic changes are both known to be associated with geographical patterns of diversity. We assess their associations with the European Scarabaeinae dung beetles, a group with high dispersal ability and well-known adaptations to warm environments. By assessing spatial stationarity in climate variability since the last glacial maximum (LGM), we find that current scarab richness is related to the location of their limits of thermal tolerance during the LGM. These limits mark a strong change in their current species richness-environment relationships. Furthermore, northern scarab assemblages are nested and composed of a phylogenetically clustered subset of large-range sized generalist species, whereas southern ones are diverse and variable in composition. Our results show that species responses to current climate are limited by the evolution of assemblages that occupied relatively climatically stable areas during the Pleistocene, and by post-glacial dispersal in those that were strongly affected by glaciations.


From the Centers for Disease Control. State tobacco prevention, control activities: results of 1989-1990 Association of State, Territorial Health Officials Survey-Final Report.
In October 1989, the Association of State and Territorial Health Officials (ASTHO) conducted a survey of state health department personnel regarding programs, policies, and public health systems that stress the prevention and control of the use of tobacco. This survey provided detailed data associated with state tobacco-use control programs and their essential components (e.g., budgets, planning, coalitions, surveillance systems, smoking cessation programs, educational activities, legislative actions, and health department policies). States vary widely in the strength and coverage of their programs for preventing and controlling tobacco use. The ASTHO survey data may be used to help plan and evaluate state health department programs as part of an effort to prevent chronic diseases related to tobacco use. Outcomes of state activities may be evaluated through surveys such as CDC's Behavioral Risk Factor Surveillance System (BRFSS) and the Current Population Survey (CPS) of the Bureau of the Census. Future surveys of state activities for controlling the use of tobacco may be included in the evaluation of the upcoming (1993) American Stop Smoking Intervention Study (ASSIST), which is cosponsored by the National Cancer Institute and the American Cancer Society.


Live texturing of augmented reality characters from colored drawings.
Coloring books capture the imagination of children and provide them with one of their earliest opportunities for creative expression. However, given the proliferation and popularity of digital devices, real-world activities like coloring can seem unexciting, and children become less engaged in them. Augmented reality holds unique potential to impact this situation by providing a bridge between real-world activities and digital enhancements. In this paper, we present an augmented reality coloring book App in which children color characters in a printed coloring book and inspect their work using a mobile device. The drawing is detected and tracked, and the video stream is augmented with an animated 3-D version of the character that is textured according to the child's coloring. This is possible thanks to several novel technical contributions. We present a texturing process that applies the captured texture from a 2-D colored drawing to both the visible and occluded regions of a 3-D character in real time. We develop a deformable surface tracking method designed for colored drawings that uses a new outlier rejection algorithm for real-time tracking and surface deformation recovery. We present a content creation pipeline to efficiently create the 2-D and 3-D content. And, finally, we validate our work with two user studies that examine the quality of our texturing algorithm and the overall App experience.


Prevalence of Substance Use in Patients With Cancer Receiving Radiation Therapy.
Individuals with cancer and risky alcohol and illicit substance use (AISU) are more likely to suffer diminished quality of life and subpar treatment outcomes. The prevalence of AISU in patients with cancer is poorly understood. This article reports on the results of a needs assessment to quantify AISU in individuals with cancer seeking care in the radiation oncology department of a large, academic medical center. Medical records were reviewed for all patients seen in the radiation oncology department in a one-week (five-day) period in the fall of 2014 (N = 397). Demographic and prevalence data were analyzed. The prevalence rates of AISU in this sample were slightly lower than estimates for the general population and inconsistency was noted in the documentation of relevant information. Despite the limitations, data analyses suggested that a significant percentage of patients receiving radiation therapy for cancer diagnoses exhibited substance use patterns that placed them at increased risk for negative short- and long-term outcomes. The findings support the need for systematic substance use screening, assessment, and risk-based interventions as an essential component of comprehensive cancer care.


Outbreak of vancomycin-, ampicillin-, and aminoglycoside-resistant Enterococcus faecium bacteremia in an adult oncology unit.
An outbreak of bacteremia caused by Enterococcus faecium with high-level resistance to vancomycin (MIC of > or = 256 micrograms/ml), ampicillin (MIC of > or = 64 micrograms/ml), and gentamicin or streptomycin (MIC of > or = 2,000 micrograms/ml) occurred in an adult oncology unit from June 1991 to May 1992. Active surveillance for the presence of this organism in stool or perianal cultures was begun in September 1991. Between June 1991 and May 1992, seven patients with bacteremia and 22 noninfected carriers of the organism in stool were identified. The vanA gene, tested for by PCR and gene probe, was present in all isolates evaluated. All bacteremic patients also had resistant E. faecium present in a stool or perianal culture; the stool isolates tested were closely related to the respective blood isolates as determined by pulsed-field gel electrophoresis. Antibiotic regimens using high-dose ampicillin and an aminoglycoside were ineffective with four patients. Five patients (71%) had multiple positive blood cultures; four of these patients died. Following a multiple logistic regression analysis, it was found that bacteremic patients received a significantly greater number of total antibiotic days compared with noninfected stool carriers (P = 0.019). The emergence of E. faecium with high-level resistance to vancomycin, ampicillin, and aminoglycosides underscores the importance of performing susceptibility testing on all clinically significant isolates. In the neutropenic adult oncology patient, bacteremia with this organism is of probable gastrointestinal origin, is often persistent, and is refractory to treatment with ampicillin in combination with an aminoglycoside. Prolonged use of antibiotics may predispose patients with gastrointestinal colonization to develop bacteremia.


Gametocyte infectivity by direct mosquito feeds in an area of seasonal malaria transmission: implications for Bancoumana, Mali as a transmission-blocking vaccine site.
Infectivity of gametocytemic volunteers living in Bancoumana, a village 60 km from Bamako, Mali, was determined by direct feeds of laboratory-reared Anopheles gambiae s. l. Gametocytemic adolescents (10-18 years old) were as infectious to mosquitoes as younger volunteers and appear to be a more suitable population for testing transmission-blocking efficacy as compared with adults (> 18 years old). To begin to validate the membrane-feeding assay, sera collected from these same volunteers were subjected to a standard membrane-feeding assay. The data suggest that areas with intense but seasonal transmission might be feasible sites for testing transmission-blocking vaccines because of the high gametocytemic rates, high mosquito infectivity rates, and lack of pre-existing humoral-mediated transmission-blocking activity. The differences observed between field-based direct mosquito feeds and laboratory-based membrane feeding assays suggests that caution be used in interpreting Phase I study results in which laboratory-based membrane-feeding assays are used as a surrogate for vaccine efficacy.


Outcome after percutaneous coronary intervention for different indications: long-term results from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).
The aim of this study was to evaluate clinical outcome for different indications for PCI in an unselected, nationwide PCI population at short- and long-term follow-up. We evaluated clinical outcome up to six years after PCI in all patients undergoing a PCI procedure for different indications in Sweden between 2006 and 2010. A total of 70,479 patients were treated for stable coronary artery disease (CAD) (21.0%), unstable angina (11.0%), non-ST-elevation myocardial infarction (NSTEMI) (36.6%) and ST-elevation myocardial infarction (STEMI) (31.4%). Mortality was higher in STEMI patients at one year after PCI (9.6%) compared to NSTEMI (4.7%), unstable angina (2.2%) and stable CAD (2.0%). At one year after PCI until the end of follow-up, the adjusted mortality risk (one to six years after PCI) and the risk of myocardial infarction were comparable between NSTEMI and STEMI patients and lower in patients with unstable angina and stable CAD. The adjusted risk of stent thrombosis and heart failure was highest in STEMI patients. The risk of short-term mortality, heart failure and stent thrombosis is highest for STEMI patients after PCI. Therapies to reduce stent thrombosis and heart failure appear to be most important in decreasing mortality in patients with STEMI or NSTEMI undergoing PCI.


Optoacoustic multispectral imaging of radiolucent foreign bodies in tissue.
Optoacoustic imaging is an emerging medical technology that uniquely combines the absorption contrast of optical imaging and the penetration depth of ultrasound. While it is not currently employed as a clinical imaging modality, the results of current research strongly support the use of optoacoustic-based methods in medical imaging. One such application is the diagnosis of the presence of soft tissue foreign bodies. Because many radiolucent foreign bodies have sufficient contrast for imaging in the optical domain, laser-induced optoacoustic imaging could be advantageous for the detection of such objects. Common foreign bodies have been scanned over a range of visible and near infrared wavelengths by using an optoacoustic method to obtain the spectroscopic properties of the materials commonly associated with these foreign bodies. The derived optical absorption spectra compared quite closely to the absorption spectra generated when using a conventional spectrophotometer. By using the probe-beam deflection technique, a novel, pressure-wave detection method, we successfully generated optoacoustic spectroscopic plots of a wooden foreign body embedded in a tissue phantom, which closely resembled the spectrum of the same object obtained in isolation. A practical application of such spectra is to assemble a library of spectroscopic data for radiolucent materials, from which specific characteristic wavelengths can be selected for use in optimizing imaging instrumentation and provide a basis for the identification of the material properties of particular foreign bodies.


The influence of preoperative back pain on the outcome of lumbar decompression surgery.
Prospective study with 12-month follow-up. To examine how the relative severity of low back pain (LBP) to leg/buttock pain (LP) influences the outcome of decompression surgery for spinal stenosis. Decompression surgery is a common treatment for lumbar spinal canal stenosis, with generally good outcome. However, concomitant LBP at presentation can make it difficult to decide whether decompression alone will result in a good overall outcome. The Spine Society of Europe Spine Tango system was used to acquire the data from 221 patients. Inclusion criteria were lumbar degenerative spinal stenosis, first-time surgery, maximum 3 affected levels, and decompression as the only procedure. Before and 12 months after surgery, patients completed the multidimensional Core Outcome Measures Index (COMI; includes 0-10 LP and LBP scales); at 12 months, global outcome was rated on a Likert-scale and dichotomized into "good" and "poor" groups. There was a low but significant positive correlation between baseline LP-minus-LBP scores and both improvement in the multidimensional COMI score after 12 months (r = 0.21, P = 0.003) and the score on the 12-month global outcome scale (r = 0.19, P = 0.007). In the good outcome group, mean baseline LP was 2.3 (+/-3.7) points higher than LBP; in the poor group, the corresponding value was 0.8 (+/-3.4) (P = 0.01 between groups). In multivariate regression analyses (controlling for age, gender, comorbidity), baseline LBP intensity was the most significant predictor of the 12-month COMI score, and preoperative LP-minus-LBP score of the global outcome (each P < 0.05). Overall, greater back pain relative to LP at baseline was associated with a significantly worse outcome after decompression. This finding seems intuitive, but has rarely been quantified in the many predictor studies conducted to date. Consideration of relative LBP and LP scores may assist in clinical decision-making and in establishing realistic patient expectations.


Allometric scaling of lung volume and its consequences for marine turtle diving performance.
Marine turtle lungs have multiple functions including respiration, oxygen storage and buoyancy regulation, so lung size is an important indicator of dive performance. We determined maximum lung volumes (V(L)) for 30 individuals from three species (Caretta caretta n=13; Eretmochelys imbricata n=12; Natator depressus n=5) across a range of body masses (M(b)): 0.9 to 46 kg. V(L) was 114 ml kg(-1) and increased with M(b) with a scaling factor of 0.92. Based on these values for V(L) we demonstrated that diving capacities (assessed via aerobic dive limits) of marine turtles were potentially over-estimated when the V(L)-body mass effect was not considered (by 10 to 20% for 5 to 25 kg turtles and by >20% for turtles > or =25 kg). While aerobic dive limits scale with an exponent of 0.6, an analysis of average dive durations in free-ranging chelonian marine turtles revealed that dive duration increases with a mass exponent of 0.51, although there was considerable scatter around the regression line. While this highlights the need to determine more parameters that affect the duration-body mass relationship, our results provide a reference point for calculating oxygen storage capacities and air volumes available for buoyancy control.


Priorities for developing respiratory syncytial virus vaccines in different target populations.
The development of an effective vaccine against respiratory syncytial virus (RSV) has been hampered by major difficulties that occurred in the 1960s when a formalin-inactivated vaccine led to increased severity of RSV disease after acquisition of the virus in the RSV season after vaccination. Recent renewed efforts to develop a vaccine have resulted in about 38 candidate vaccines and monoclonal antibodies now in clinical development. The target populations for effective vaccination are varied and include neonates, young children, pregnant women, and older adults. The reasons for susceptibility to infection in each of these groups may be different and, therefore, could require different vaccine types for induction of protective immune responses, adding a further challenge for vaccine development. Here, we review the current knowledge of RSV vaccine development for these target populations and propose a view and rationale for prioritizing RSV vaccine development.


Splinting for the non-operative management of developmental dysplasia of the hip (DDH) in children under six months of age.
Developmental dysplasia of the hip (DDH) describes the abnormal development of a hip in childhood, ranging from complete dislocation of the hip joint to subtle immaturity of a hip that is enlocated and stable within the socket. DDH occurs in around 10 per 1000 live births, though only one per 1000 are completely dislocated. There is variation in treatment pathways for DDH, which differs between hospitals and even between clinicians within the same hospital. The variation is related to the severity of dysplasia that is believed to require treatment, and the techniques used to treat dysplasia. To determine the effectiveness of splinting and the optimal treatment strategy for the non-operative management of DDH in babies under six months of age. We searched CENTRAL, MEDLINE, Embase, seven other electronic databases, and two trials registers up to November 2021. We also checked reference lists, contacted study authors, and handsearched relevant meetings abstracts. Randomised controlled trials (RCTs), including quasi-RCTs, as well as non-RCTs and cohort studies conducted after 1980 were included. Participants were babies with all severities of DDH who were under six months of age. Interventions included dynamic splints, static splints or double nappies (diapers), compared to no splinting or delayed splinting. Two review authors independently selected studies, extracted data and performed risk of bias and GRADE assessments. The primary outcomes were: measurement of acetabular index at years one, two and five, as determined by radiographs (angle): the need for operative intervention to achieve reduction and to address dysplasia; and complications. We also investigated other outcomes highlighted by parents as important, including the bond between parent and child and the ability of mothers to breastfeed. We included six RCTs or quasi-RCTs (576 babies). These were supported by 16 non-RCTs (8237 babies). Five studies had non-commercial funding, three studies stated 'no funding' and 14 studies did not state funding source. The RCTs were generally at unclear risk of bias, although we judged three RCTs to be at high risk of bias for incomplete outcome data. The non-RCTs were of moderate and critical risk of bias. We did not undertake meta-analysis due to methodological and clinical differences between studies; instead, we have summarised the results narratively. Dynamic splinting versus delayed or no splinting Four RCTs and nine non-RCTs compared immediate dynamic splinting and delayed dynamic splinting or no splinting. Of the RCTs, two considered stable hips and one considered unstable (dislocatable) hips and one jointly considered unstable and stable hips. No studies considered only dislocated hips. Two RCTs (265 babies, very low-certainty evidence) reported acetabular index at one year amongst stable or dislocatable hips. Both studies found there may be no evidence of a difference in splinting stable hips at first diagnosis compared to a strategy of active surveillance: one reported a mean difference (MD) of 0.10 (95% confidence interval (CI) -0.74 to 0.94), and the other an MD of 0.20 (95% CI -1.65 to 2.05). Two RCTs of stable hips (181 babies, very low-certainty evidence) reported there may be no evidence of a difference between groups for acetabular index at two years: one study reported an MD of -1.90 (95% CI -4.76 to 0.96), and another study reported an MD of -0.10 (95% CI -1.93 to 1.73), but did not take into account hips from the same child. No study reported data at five years. Four RCTs (434 babies, very low-certainty evidence) reported the need for surgical intervention. Three studies reported that no surgical interventions occurred. In the remaining study, two babies in the dynamic splinting group developed instability and were subsequently treated surgically. This study did not explicitly state if this treatment was to achieve concentric reduction or address residual dysplasia. Three RCTs (390 babies, very low-certainty evidence) reported no complications (avascular necrosis and femoral nerve palsy). Dynamic splinting versus static splinting One RCT and five non-RCTs compared dynamic versus static splinting. The RCT (118 hips) reported no occurrences of avascular necrosis (very low-certainty evidence) and did not report radiological outcomes or need for operative intervention. One quasi-RCT compared double nappies versus delayed or no splinting but reported no outcomes of interest. Other comparisons No RCTs compared static splinting versus delayed or no splinting or staged weaning versus immediate removal. There is a paucity of RCT evidence for splinting for the non-operative management of DDH: we included only six RCTs with 576 babies. Moreover, there was considerable heterogeneity between the studies, precluding meta-analysis. We judged the RCT evidence for all primary outcomes as being of very low certainty, meaning we are very uncertain about the true effects. Results from individual studies provide limited evidence of intervention effects on different severities of DDH. Amongst stable dysplastic hips, there was no evidence to suggest that treatment at any stage expedited the development of the acetabulum. For dislocatable hips, a delay in treatment onset to six weeks does not appear to result in any evidence of a difference in the development of the acetabulum at one year or increased risk of surgery. However, delayed splinting may reduce the number of babies requiring treatment with a harness. No RCTs compared static splinting with delayed or no splinting, staged weaning versus immediate removal or double nappies versus delayed or no splinting. There were few operative interventions or complications amongst the RCTs and the non-randomised studies. There's no apparent signal to indicate a higher frequency of either outcome in either intervention group. Given the frequency of this disease, and the fact that many countries undertake mandatory DDH screening, there is a clear need to develop an evidence-based pathway for treatment. Particular uncertainties requiring future research are the effectiveness of splinting amongst stable dysplastic hips, the optimal timing for the onset of splinting, the optimal type of splint to use and the need for 'weaning of splints'. Only once a robust pathway for treatment is established, can we properly assess the cost-effectiveness of screening interventions for DDH.


Anthrax and wildlife.
Although livestock anthrax is declining in many parts of the world, with an increasing number of countries probably truly free of the disease, anthrax remains enzootic in many national parks and even in some game ranching areas. These infected areas can present a persistent risk to surrounding livestock, which may otherwise be free of the disease, as well as a public health risk. The authors use as examples the national parks in southern Africa, the Wood Buffalo National Park in northern Alberta, Canada, and the deer ranching counties in south-west Texas, United States of America, to present the range of problems, epidemiology, and control procedures. While many advances have been achieved in the understanding of this disease, research is required into the genotypic grouping of anthrax isolates, improved field diagnostic techniques, and oral vaccines, as well as to provide a better understanding of spore survival in soil and the ecology of the disease under natural conditions.


An emerging role for long non-coding RNA dysregulation in neurological disorders.
A novel class of transcripts, long non coding RNAs (lncRNAs), has recently emerged as key players in several biological processes, including dosage compensation, genomic imprinting, chromatin regulation, embryonic development and segmentation, stem cell pluripotency, cell fate determination and potentially many other biological processes, which still are to be elucidated. LncRNAs are pervasively transcribed in the genome and several lines of evidence correlate dysregulation of different lncRNAs to human diseases including neurological disorders. Although their mechanisms of action are yet to be fully elucidated, evidence suggests lncRNA contributions to the pathogenesis of a number of diseases. In this review, the current state of knowledge linking lncRNAs to different neurological disorders is discussed and potential future directions are considered.


ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus.
Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. However, debate continues to surround the diagnosis and treatment of GDM despite several recent large-scale studies addressing these issues. The purposes of this document are the following: 1) provide a brief overview of the understanding of GDM, 2) review management guidelines that have been validated by appropriately conducted clinical research, and 3) identify gaps in current knowledge toward which future research can be directed.


Understanding and misunderstanding group mean centering: a commentary on Kelley et al.'s dangerous practice.
Kelley et al. argue that group-mean-centering covariates in multilevel models is dangerous, since-they claim-it generates results that are biased and misleading. We argue instead that what is dangerous is Kelley et al.'s unjustified assault on a simple statistical procedure that is enormously helpful, if not vital, in analyses of multilevel data. Kelley et al.'s arguments appear to be based on a faulty algebraic operation, and on a simplistic argument that parameter estimates from models with mean-centered covariates must be wrong merely because they are different than those from models with uncentered covariates. They also fail to explain why researchers should dispense with mean-centering when it is central to the estimation of fixed effects models-a common alternative approach to the analysis of clustered data, albeit one increasingly incorporated within a random effects framework. Group-mean-centering is, in short, no more dangerous than any other statistical procedure, and should remain a normal part of multilevel data analyses where it can be judiciously employed to good effect.


Neutron activation of NDDP, a liposomal platinum antitumor agent.
Cis-bis-neodecanoato-trans-R,R-1,2-diamminocyclohexane platinum (II) [NDDP] is a liposome-entrapped platinum compound currently, in phase II clinical trials, that has been shown to undergo intraliposomal activation. The objective of this study was to determine the feasibility of activating NDDP and using the induced radioactivity to monitor NDDP distribution and penetration. Neutron activation analysis (NAA) was done on NDDP using the nuclear reactor at Texas A & M University, College Station, Texas. After a 3-hour irradiation, the NDDP samples were analyzed using an HPGE (high purity germanium) detector to determine the activation of the radioisotopic platinum. This was followed by HPLC-UV analysis to determine the stability of NDDP after exposure to the reactor's core. Platinum radioisotopes were produced along with potassium-40 and sodium-24. Irradiation did not result in any significant degradation of NDDP. (1) Irradiating fully synthesized NDDP is feasible for diagnostic use if a purification step is taken after the irradiation, and (2) radiation exposure is lessened by irradiating NDDP after synthesis rather than starting with high-specific-activity isotopes.


The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation.
The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.


Synergistic effects of surfactant-assisted biodegradation of wheat straw and production of polysaccharides by Inonotus obliquus under submerged fermentation.
Current work proposes an innovative wheat straw biomass utilization strategy that connects efficient lignocellulose biodegradation with exo-polysaccharide (EPS) production in I. obliquus under submerged fermentation. The addition of Tween 80 increased the activities of ligninolytic enzymes MnP, LiP and Lac by 1200%, 125% and 39.9%, respectively. When wheat straw lignin recalcitrance was substantially reduced with the aid of Tween 80, I. obliquus was capable of utilizing the substrates and in turn accumulated EPS. The degradation of cellulose, hemicellulose and lignin reached 46.1%, 46.4% and 44.1% on Day 9 of growth, respectively. Meanwhile, the maximum mycelial biomass and EPS production increased by 23.3% and 142.9%, respectively. The EPS had higher contents of sugar, protein, uronic acid, and mannose ratio, and higher antioxidant activity against 2, 2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) and hydroxyl radicals.


Negative self-imagery blocks inferences.
Previous research has shown that, unlike non-anxious individuals, people with social phobia fail to generate non-threatening inferences when ambiguous social information is first encountered (i.e. 'on-line'; Hirsch and Mathews Journal of Abnormal Psychology, 109 (2000) 705-712). Patients with social phobia also report negative self-imagery in social situations, while individuals without high social anxiety do not. The negative self-imagery in social phobia may prevent the generation of non-threatening inferences. If so, then training non-anxious individuals to hold in mind a negative self-image should remove the 'on-line' non-threat inferential bias normally evident in this population. In the present study, low anxious volunteers were allocated to negative image training or a control task that did not manipulate self-imagery. Following negative image training, or the control task, volunteers read descriptions of job interviews and at certain points during the text performed lexical decisions. Some decisions were made after ambiguous text that could have been interpreted in both a threatening and a non-threatening manner. In a baseline condition, decisions were made following the text for which there was only one possible inference (either threat or non-threat). The results for the control group replicated earlier findings of a non-threat inferential bias for non-anxious individuals. In contrast, and as predicted, non-anxious volunteers who were trained to hold a negative image in mind lacked any non-threatening inferential bias, and also experienced higher levels of state anxiety.


Adsorption of small inorganic molecules on a defective MoS2 monolayer.
We present a theoretical study of molecular adsorption on defects on a MoS2 monolayer. Based on Density Functional Theory, our calculations confirm that small inorganic molecules, such as CO2, CO, H2O, NO, NO2, H2 and N2, remain bonded to the pristine monolayer through weak van der Waals interactions, suggesting that the molecules may easily diffuse over the clean monolayer. On the other hand, the introduction of defects can lead to three different situations, depending on the defect and the molecule considered: physisorption, chemical (strong) bonding to the metallic defects, namely the Mo substitutional atoms on the S vacancies, and dissociation, that can take place spontaneously at 0 K in some specific cases or by the effect of thermal agitation in molecules such as CO2 or NO2 on the S vacancy. Our energetic and electronic analyses provide an explanation to such bonding possibilities, showing that in the low interacting situations, the molecules tend to adopt a planar configuration parallel to the monolayer, while a molecular rotation is favored in order to facilitate the bond formation on the reactive sites. Finally, the ab initio based Scanning Tunneling Microscopy (STM) simulations show the fingerprint of each molecule adsorbed on the most reactive site. This work opens the way to the possibility of tuning the catalytic properties of MoS2 by controlling the creation of specific defects in the MoS2 monolayer.


Nuclear translocation of heme oxygenase-1 confers resistance to imatinib in chronic myeloid leukemia cells.
Identification of imatinib mesylate as a potent inhibitor of the Abl kinase and the subsequent findings that this compound displays growth inhibitory and pro-apoptotic effects in Bcr-Abl+ cells, has deeply conditioned CML treatment. Unfortunately the initial striking efficacy of this drug has been overshadowed by the development of clinical resistance. A wide variety of molecular mechanisms can underlie such resistance mechanisms. In the recent years, heme oxygenase-1 (HO-1) expression has been reported as an important protective endogenous mechanism against physical, chemical and biological stress and this cytoprotective role has already been demonstrated for several solid tumors and acute leukemias. The aim of the present study was to investigate the effect of HO-1 expression on cell proliferation and apoptosis in chronic myeloid leukemia cells, K562 and LAMA-84 cell lines following imatinib treatment. Cells were incubated for 24h with Imatinib (1 μM) alone or in combination with Hemin (10μM), an inducer of HO-1. In addition, cells were also treated with HO byproducts, bilirubin and carbon monoxide (CO), or with a protease inhibitor (Ed64) to inhibit HO-1 nuclear translocation. Pharmacological induction of HO-1 was able to overcome the effect of imatinib. The cytoprotective effect of HO-1 was further confirmed after silencing HO-1 by siRNA. Interestingly, neither bilirubin nor CO was able to protect cells from Imatinib-induced toxicity. By contrast, the protective effect of HO-1 was mitigated by the addition of E64d, preventing HO-1 nuclear translocation. Finally, imatinib was able to increase the formation of cellular reactive oxygen species (ROS) and this effect was reversed by HO-1 induction or the addition of N-acetylcisteine (NAC). In conclusion, the protective effect of HO-1 on imatinib-induced cytotoxicity does not involve its enzymatic byproducts, but rather the nuclear translocation of HO-1 following proteolytic cleavage.


Effect of INTELLiVENT-ASV versus Conventional Ventilation on Ventilation Intensity in Patients with COVID-19 ARDS-An Observational Study.
Driving pressure (ΔP) and mechanical power (MP) are associated with outcomes in critically ill patients, irrespective of the presence of Acute Respiratory Distress Syndrome (ARDS). INTELLiVENT-ASV, a fully automated ventilatory mode, controls the settings that affect ΔP and MP. This study compared the intensity of ventilation (ΔP and MP) with INTELLiVENT-ASV versus conventional ventilation in a cohort of COVID-19 ARDS patients in two intensive care units in the Netherlands. The coprimary endpoints were ΔP and MP before and after converting from conventional ventilation to INTELLiVENT-ASV. Compared to conventional ventilation, INTELLiVENT-ASV delivered ventilation with a lower ΔP and less MP. With conventional ventilation, ΔP was 13 cmH2O, and MP was 21.5 and 24.8 J/min, whereas with INTELLiVENT-ASV, ΔP was 11 and 10 cmH2O (mean difference -2 cm H2O (95 %CI -2.5 to -1.2 cm H2O), p < 0.001) and MP was 18.8 and 17.5 J/min (mean difference -7.3 J/Min (95% CI -8.8 to -5.8 J/min), p < 0.001). Conversion from conventional ventilation to INTELLiVENT-ASV resulted in a lower intensity of ventilation. These findings may favor the use of INTELLiVENT-ASV in COVID-19 ARDS patients, but future studies remain needed to see if the reduction in the intensity of ventilation translates into clinical benefits.


Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma.
Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma. We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed. The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo. In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).


Intermaxillary fixation is not usually necessary to reduce mandibular fractures.
We undertook a retrospective study of all isolated mandibular fractures which had required active management over a 1-year period at the Maxillofacial Unit at Newcastle General Hospital. Patients with single or multiple fractures of the mandible were included in the study, if there were other simultaneous fractures of the facial skeleton, those patients were excluded. All case notes and radiographs were reviewed by a single operator. A total of 202 cases of fractured mandible were identified of which 115 fulfilled the selection criteria of: isolated fracture, no previous facial fracture, treatment by open reduction and internal fixation using titanium osteosynthesis miniplates, and all case notes and radiographs available to study. Sixty-six patients had their fractures reduced manually to obtain anatomical reduction without the use of peroperative intermaxillary fixation (IMF). Forty-nine were treated conventionally using peroperative IMF. The two groups were broadly similar in severity and type of fracture, and the method of reduction seemed to be decided by the operator according to their preference. IMF was not used routinely postoperatively. Overall there were significantly fewer occlusal discrepancies in the early postoperative period in those patients treated by anatomical reduction (6/66 compared with 16/49, P = 0.002) but there was no difference in the final outcome of the occlusion between the two methods of reduction. Avoidance of the use of peroperative IMF is more economical in time and cost, is safer for the operator, and more comfortable for the patient. As this technique produces comparable results in the long term with fewer early complications, we conclude that IMF is not usually necessary to reduce fractures confined to the mandibular bone.


Hyperbaric oxygen in multiple sclerosis: a double blind trial.
Eighty four patients with multiple sclerosis were treated in monoplace chambers with either hyperbaric oxygen at 2 atmospheres absolute or placebo. Comprehensive double blind assessment was carried out before, immediately after, and one month after treatment. There was no clinically important or significant benefit in any of the four major criteria of outcome--namely, the patient's subjective opinion, the examiner's opinion, the score on the Kurtzke disability status scale, or the time taken to walk 50 m. Out of 40 other clinical variables assessed, two (the sensory scale and timed writing with the left hand) showed a significant improvement without any subjective clinical correlate or change in any of seven other tests of left hand function. No group of symptoms was perceived by the patients as having improved more after treatment with hyperbaric oxygen than placebo. It is concluded that there is no basis for recommending hyperbaric oxygen in the treatment of multiple sclerosis.


Molecular Characterization of E-Type Prostanoid Receptor 4 (EP4) from Ayu (Plecoglossus altivelis) and Its Functional Analysis in the Monocytes/Macrophages.
Prostaglandin E2 (PGE2) plays an important role in a broad spectrum of physiological and pathological processes by interacting with E-type prostanoid receptors (EPs). EP4 is one of four EP subtypes known to mediate the immune response in mammalian monocytes/macrophages. However, the precise function and characteristics of EP4 in fish remain unclear. In this study, we characterized a novel EP4-like (PaEP4L) gene from ayu, Plecoglossus altivelis. The cDNA sequence of PaEP4L is 2781 nucleotides (nts) in length, encoding a polypeptide of 459 amino acid residues with a calculated molecular weight of 51.17 kDa. Sequence comparison and phylogenetic tree analysis showed that PaEP4L shared 76% amino acid identity with that of the Atlantic salmon (Salmo salar). PaEP4L mRNA was detected by real-time quantitative PCR (QPCR) in all tested tissues and head kidney-derived monocytes/macrophages (MO/MФ). It varied greatly in liver, spleen and MO/MФ upon Vibrio anguillarum infection. Western blot analysis revealed a significant increase of PaEP4L in cell homogenates from ayu MO/MФ upon V. anguillarum infection. Moreover, anti-PaEP4L IgG reversed the down-regulation of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) mRNA expression as well as phagocytosis in ayu MO/MФ caused by PGE2. There were no significant differences in the respiratory burst response between PGE2 treated and untreated cells. We further found that cAMP mediated PGE2/PaEP4L signal in ayu MO/MФ. In conclusion, our results indicate that PaEP4L mediates PGE2 effects on ayu MO/MФ function, revealing that EP4 also plays a role in the modulation of cells of the fish's innate immune system.