The migraine postdrome: An electronic diary study.
To report migraine postdrome symptoms in patients who report nonheadache symptoms as part of their attacks. A prospective daily electronic diary study was conducted over 3 months in 120 patients with migraine. Nonheadache symptoms before, during, and after headache were collected on a daily basis. Visual analogue scales were used to capture the overall level of functioning and the severity of the headache. The postdrome was defined as the time from resolution of troublesome headache to return to normal. Of 120 evaluable patients, 97 (81%) reported at least one nonheadache symptom in the postdrome. Postdrome symptoms, in order of frequency, included feeling tired/weary and having difficulty concentrating and stiff neck. Many patients also reported a mild residual head discomfort. In most attacks (93%), there was return to normal within 24 hours after spontaneous pain resolved. There was no relationship between medication taken for the headache and the duration of the postdrome. The severity of the migraine was not associated with the duration of the postdrome. Overall state of health scores remained low during the postdrome. Nonheadache symptoms in the postdrome were common and may contribute to the distress and disability in the patients studied. Postdrome symptoms merit larger observational studies and careful recording in clinical trials of acute and preventive migraine treatments.


Tough magnesium phosphate-based 3D-printed implants induce bone regeneration in an equine defect model.
One of the important challenges in bone tissue engineering is the development of biodegradable bone substitutes with appropriate mechanical and biological properties for the treatment of larger defects and those with complex shapes. Recently, magnesium phosphate (MgP) doped with biologically active ions like strontium (Sr2+) have shown to significantly enhance bone formation when compared with the standard calcium phosphate-based ceramics. However, such materials can hardly be shaped into large and complex geometries and more importantly lack the adequate mechanical properties for the treatment of load-bearing bone defects. In this study, we have fabricated bone implants through extrusion assisted three-dimensional (3D) printing of MgP ceramics modified with Sr2+ ions (MgPSr) and a medical-grade polycaprolactone (PCL) polymer phase. MgPSr with 30 wt% PCL (MgPSr-PCL30) allowed the printability of relevant size structures (>780 mm3) at room temperature with an interconnected macroporosity of approximately 40%. The printing resulted in implants with a compressive strength of 4.3 MPa, which were able to support up to 50 cycles of loading without plastic deformation. Notably, MgPSr-PCL30 scaffolds were able to promote in vitro bone formation in medium without the supplementation with osteo-inducing components. In addition, long-term in vivo performance of the 3D printed scaffolds was investigated in an equine tuber coxae model over 6 months. The micro-CT and histological analysis showed that implantation of MgPSr-PCL30 induced bone regeneration, while no bone formation was observed in the empty defects. Overall, the novel polymer-modified MgP ceramic material and extrusion-based 3D printing process presented here greatly improved the shape ability and load-bearing properties of MgP-based ceramics with simultaneous induction of new bone formation.


A Novel Virus Causes Scale Drop Disease in Lates calcarifer.
From 1992 onwards, outbreaks of a previously unknown illness have been reported in Asian seabass (Lates calcarifer) kept in maricultures in Southeast Asia. The most striking symptom of this emerging disease is the loss of scales. It was referred to as scale drop syndrome, but the etiology remained enigmatic. By using a next-generation virus discovery technique, VIDISCA-454, sequences of an unknown virus were detected in serum of diseased fish. The near complete genome sequence of the virus was determined, which shows a unique genome organization, and low levels of identity to known members of the Iridoviridae. Based on homology of a series of putatively encoded proteins, the virus is a novel member of the Megalocytivirus genus of the Iridoviridae family. The virus was isolated and propagated in cell culture, where it caused a cytopathogenic effect in infected Asian seabass kidney and brain cells. Electron microscopy revealed icosahedral virions of about 140 nm, characteristic for the Iridoviridae. In vitro cultured virus induced scale drop syndrome in Asian seabass in vivo and the virus could be reisolated from these infected fish. These findings show that the virus is the causative agent for the scale drop syndrome, as each of Koch's postulates is fulfilled. We have named the virus Scale Drop Disease Virus. Vaccines prepared from BEI- and formalin inactivated virus, as well as from E. coli produced major capsid protein provide efficacious protection against scale drop disease.


Promoting cancer control training in resource limited environments: Lagos, Nigeria.
In resource limited nations, cancer control is often a lower priority issue creating challenges for the prevention, early diagnosis, and treatment of cancer. Training and education are vital components of efforts to tackle this problem. A 3-day cancer control workshop was conducted at the Lagos State University Teaching Hospital (LASUTH), Nigeria, in 2013. The curriculum included didactic lectures, panel discussions, and interactive sessions on local cancer statistics, preventive strategies, cancer registries, screening and diagnostic options, and treatment approaches with limited resources (chemotherapy, radiotherapy, surgery, and palliative care) and several site-specific (breast, lung, cervical, prostate, and colon) topics. Pre-workshop and post-workshop questionnaires were completed by participants. Eighty-six percent of the 50 workshop participants completed at least one questionnaire. Participants were mainly nurses and physicians (89% of responders), and 40% reported >25 years of practice experience. The more common local needs identified were professional education (65%) and increasing public cancer awareness (63%). The greatest interest for future programs was on research collaborations (70%). An immediate impact of the workshop was the commencement of monthly tumor board conferences and a review of the current cancer registry data. Capacity building is critical for the execution of effective cancer control strategies. Conducting collaborative workshops represents a cost-effective means of launching programs and energizing the medical community to pursue ongoing education and research addressing the anticipated cancer epidemic on the African continent.


A functional link between MT neurons and depth perception based on motion parallax.
As an observer translates, objects lying at different distances from the observer have differential image motion on the retina (motion parallax). It is well established psychophysically that humans perceive depth rather precisely from motion parallax and that extraretinal signals may be used to correctly perceive the sign of depth (near vs far) when binocular and pictorial depth cues are absent or weak. However, the neural basis for this capacity remains poorly understood. We have shown previously that neurons in the macaque middle temporal (MT) area combine retinal image motion with smooth eye movement command signals to signal depth sign from motion parallax. However, those studies were performed in animals that were required simply to track a visual target, thus precluding direct comparisons between neural activity and behavior. Here, we examine the activity of MT neurons in rhesus monkeys that were trained to discriminate depth sign based on motion parallax, in the absence of binocular disparity and pictorial depth cues. We find that the most sensitive MT neurons approach behavioral sensitivity, whereas the average neuron is twofold to threefold less sensitive than the animal. We also find that MT responses are predictive of perceptual decisions (independent of the visual stimulus), consistent with a role for MT in providing sensory signals for this behavior. Our findings suggest that, in addition to its established roles in processing stereoscopic depth, area MT is well suited to contribute to perception of depth based on motion parallax.


Institutional prescreening for detection and eradication of methicillin-resistant Staphylococcus aureus in patients undergoing elective orthopaedic surgery.
Surgical site infection has been identified as one of the most important preventable sources of morbidity and mortality associated with medical treatment. The purpose of the present study was to evaluate the feasibility and efficacy of an institutional prescreening program for the preoperative detection and eradication of both methicillin-resistant and methicillin-sensitive Staphylococcus aureus in patients undergoing elective orthopaedic surgery. Data were collected prospectively during a single-center study. A universal prescreening program, employing rapid polymerase chain reaction analysis of nasal swabs followed by an eradication protocol of intranasal mupirocin and chlorhexidine showers for identified carriers, was implemented. Surgical site infection rates were calculated and compared with a historical control period immediately preceding the start of the screening program. During the study period, 7019 of 7338 patients underwent preoperative screening before elective surgery, for a successful screening rate of 95.7%. One thousand five hundred and eighty-eight (22.6%) of the patients were identified as Staphylococcus aureus carriers, and 309 (4.4%) were identified as methicillin-resistant Staphylococcus aureus carriers. A significantly higher rate of surgical site infection was observed among methicillin-resistant Staphylococcus aureus carriers (0.97%; three of 309) compared with noncarriers (0.14%; seven of 5122) (p = 0.0162). Although a higher rate of surgical site infection was also observed among methicillin-sensitive Staphylococcus aureus carriers (0.19%; three of 1588) compared with noncarriers, this difference did not achieve significance (p = 0.709). Overall, thirteen cases of surgical site infection were identified during the study period, for an institutional infection rate of 0.19%. This rate was significantly lower than that observed during the control period (0.45%; twenty-four cases of surgical site infection among 5293 patients) (p = 0.0093). Implementation of an institution-wide prescreening program for the identification and eradication of methicillin-resistant and methicillin-sensitive Staphylococcus aureus carrier status among patients undergoing elective orthopaedic surgery is feasible and can lead to significant reductions in postoperative rates of surgical site infection. Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.


Asp-ase Activity of the Opossum Granzyme B Supports the Role of Granzyme B as Part of Anti-Viral Immunity Already during Early Mammalian Evolution.
Granzyme B is one of the key effector molecules in our defense against viruses and intracellular bacteria. This serine protease together with the pore forming protein perforin, induces caspase or Bid-dependent apoptosis in target cells. Here we present the first characterization of a granzyme B homolog, the grathepsodenase, in a non-placental mammal, the American opossum (Monodelphis domestica). The recombinant enzyme was produced in a human cell line and used to study its primary and extended cleavage specificity using a panel of chromogenic substrates and recombinant protein substrates. The opossum granzyme B was found to have a specificity similar to human granzyme B, although slightly less restrictive in its extended specificity. The identification of a granzyme B homolog with asp-ase (cleaving after aspartic acid) specificity in a non-placental mammal provides strong indications that caspase or Bid-dependent apoptosis by a serine protease with a conserved primary specificity has been part of anti-viral immunity since early mammalian evolution. This finding also indicates that an asp-ase together with a chymase were the first two serine protease genes to appear in the mammalian chymase locus.


A novel sensor for bite force determinations.
The clinical usefulness, accuracy and precision of a novel bite force sensor based on force sensing resistors were tested in six subjects wearing maxillary removable partial dentures retained by conical crowns. The surfaces of the sensor were manufactured in a silicone material that had mechanical properties similar to those of tough foodstuffs. In two separate series of standardized bite force tests, submaximum force levels were recorded with the sensor and with a strain gaged bite fork. Subjects were assisted in the loading tests with visual feedback instrumentation. Reliability estimates for the bite force sensor were calculated in order to show their reproducibility. Strain gages attached to the prostheses were used to determine the pattern of force distribution during loading tests. The bite force results obtained with the new bite force sensor and with the bite fork were analyzed with ANOVA and Scheffés tests. The strain patterns registered with strain gages were analyzed with F-test. The bite force sensor and the bite fork transducer showed no statistically significant differences in respect of intra-individual bite force levels (range 50-300N). The bite forces registered with the new sensor were dependent on the loading position (p<0.05), sex (p<0.05) and test subject (p<0.05). The reliability of the new sensor for submaximum bite forces was calculated to be 93%. Strain gage results showed that the new sensor generated strain patterns of less variance (p<0.05) than the bite fork and therefore allowed for higher precision during biting tests. The presented instrument has such clinical merits, as to favor its use in experimental clinical studies on the biomechanics of prosthetic appliances.


Bilevel noninvasive positive pressure ventilation for acute respiratory failure: survey of Ontario practice.
To determine physicians' stated practices regarding the use of bilevel noninvasive ventilation (NIV) for acute respiratory failure and the predictors of practice variation. Cross-sectional postal survey. Province of Ontario, Canada. Attending physicians and residents in four specialties at 15 teaching hospitals. We used literature searches and focus groups to design questions related to NIV utilization with respect to frequency, location of and indications for use, awareness of supporting literature, and perceived efficacy. We assessed the survey's clinical sensibility and reliability. We used regression analyses to evaluate practice variation among hospitals and specialties and to determine predictors of more frequent NIV use, initiation of and continued use in nonmonitored settings, and use for specific indications. Three hundred eighty-five (48%) of 808 physicians responded; 242 used NIV. The two most common indications for NIV use were chronic obstructive pulmonary disease and congestive heart failure. NIV guidelines, protocols, or policies were available in 12 of 15 hospitals. We found variation in NIV utilization among specialties but not hospitals. Specialty (critical care and respirology versus internal and emergency medicine), fewer years of postgraduate experience, and a greater number of noninvasive ventilators were predictors of more frequent NIV use (all p < or = .001). Only 6% of respondents reported initiation of use and continued use most frequently in nonmonitored settings, which increased with the number of noninvasive ventilators (p = .02). Physician characteristics such as awareness of the literature were predictive of NIV use for exacerbations of chronic obstructive pulmonary disease, whereas perceived NIV efficacy was predictive of use for many indications, including congestive heart failure. Self-reported practice variation for bilevel NIV exists among specialties but not hospitals and differs with respect to frequency, location of use, and use for specific indications. Some factors associated with variation in NIV use may be suitable targets for utilization improvement interventions.


Differences in the quality of care for women with an abnormal mammogram or breast complaint.
To examine factors associated with variation in the quality of care for women with 2 common breast problems: an abnormal mammogram or a clinical breast complaint. Cross-sectional patient survey and medical record review. Ten general internal medicine practices in the Greater Boston area. Women who had an abnormal radiographic result from a screening mammogram or underwent mammography for a clinical breast complaint (N = 579). Three measures of the quality of care were used: (1) whether or not a woman received an evaluation in compliance with a clinical guideline; (2) the number of days until the appropriate resolution of this episode of breast care if any; and (3) a woman's overall satisfaction with her care. Sixty-nine percent of women received care consistent with the guideline. After adjustment, women over 50 years (odds ratio [OR], 1.58; 95% [CI], 1.06 to 2.36) and those with an abnormal mammogram (compared with a clinical breast complaint: OR, 1.75; 95% CI, 1.16 to 2.64) were more likely to receive recommended care and had a shorter time to resolution of their breast problem. Women with a managed care plan were also more likely to receive care in compliance with the guideline (OR, 1.72; 95% CI, 1.12 to 2.64) and have a more timely resolution. There were no differences in satisfaction by age or type of breast problem, but women with a managed care plan were less likely to rate their care as excellent (43% vs 53%, P <.05). We found that a substantial proportion of women with a breast problem managed by generalists did not receive care consistent with a clinical guideline, particularly younger women with a clinical breast complaint and a normal or benign-appearing mammogram.


Glycoengineering HIV-1 Env creates 'supercharged' and 'hybrid' glycans to increase neutralizing antibody potency, breadth and saturation.
The extensive glycosylation of HIV-1 envelope (Env) glycoprotein leaves few glycan-free holes large enough to admit broadly neutralizing antibodies (bnAb). Consequently, most bnAbs must inevitably make some glycan contacts and avoid clashes with others. To investigate how Env glycan maturation regulates HIV sensitivity to bnAbs, we modified HIV-1 pseudovirus (PV) using various glycoengineering (GE) tools. Promoting the maturation of α-2,6 sialic acid (SA) glycan termini increased PV sensitivity to two bnAbs that target the V2 apex and one to the interface between Env surface gp120 and transmembrane gp41 subunits, typically by up to 30-fold. These effects were reversible by incubating PV with neuraminidase. The same bnAbs were unusually potent against PBMC-produced HIV-1, suggesting similar α-2,6 hypersialylated glycan termini may occur naturally. Overexpressing β-galactosyltransferase during PV production replaced complex glycans with hybrid glycans, effectively 'thinning' trimer glycan coverage. This increased PV sensitivity to some bnAbs but ablated sensitivity to one bnAb that depends on complex glycans. Other bnAbs preferred small glycans or galactose termini. For some bnAbs, the effects of GE were strain-specific, suggesting that GE had context-dependent effects on glycan clashes. GE was also able to increase the percent maximum neutralization (i.e. saturation) by some bnAbs. Indeed, some bnAb-resistant strains became highly sensitive with GE-thus uncovering previously unknown bnAb breadth. As might be expected, the activities of bnAbs that recognize glycan-deficient or invariant oligomannose epitopes were largely unaffected by GE. Non-neutralizing antibodies were also unaffected by GE, suggesting that trimers remain compact. Unlike mature bnAbs, germline-reverted bnAbs avoided or were indifferent to glycans, suggesting that glycan contacts are acquired as bnAbs mature. Together, our results suggest that glycovariation can greatly impact neutralization and that knowledge of the optimal Env glycoforms recognized by bnAbs may assist rational vaccine design.


A thrombopoietin receptor antagonist is capable of depleting myelofibrosis hematopoietic stem and progenitor cells.
Recently, interactions between thrombopoietin (TPO) and its receptor, the myeloproliferative leukemia (MPL) virus oncogene, have been shown to play a role in the development and progression of myeloproliferative neoplasms including myelofibrosis (MF). These observations have led to the development of strategies to disrupt the association of TPO with its receptor as a means of targeting MF hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). In this report, we show that although both splenic and peripheral blood MF CD34(+) cells expressed lower levels of MPL than normal CD34(+) cells, TPO promoted the proliferation of MF CD34(+) cells and HPCs in a dose-dependent fashion. Furthermore, the treatment of MF but not normal CD34(+) cells with a synthesized MPL antagonist, LCP4, decreased the number of CD34(+)Lin(-) cells and all classes of assayable HPCs (colony-forming unit-megakaryocyte [CFU-MK], CFU-granulocyte/macrophage, burst-forming unit-erythroid/CFU-erythroid, and CFU-granulocyte/erythroid/macrophage/MK) irrespective of their mutational status. In addition, LCP4 treatment resulted in the depletion of the number of MF HPCs that were JAK2V617F(+) Moreover, the degree of human cell chimerism and the proportion of malignant donor cells were significantly reduced in immunodeficient mice transplanted with MF CD34(+) cell grafts treated with LCP4. These effects of LCP4 on MF HSCs/HPCs were associated with inhibition of JAK-STAT activity, leading to the induction of apoptosis. These findings demonstrate that such specific anti-cytokine receptor antagonists represent a new class of drugs that are capable of targeting MF HSCs.


Fasting therapy for treating and preventing disease - current state of evidence.
Periods of deliberate fasting with restriction of solid food intake are practiced worldwide, mostly based on traditional, cultural or religious reasons. There is large empirical and observational evidence that medically supervised modified fasting (fasting cure, 200-500 kcal nutritional intake per day) with periods of 7-21 days is efficacious in the treatment of rheumatic diseases, chronic pain syndromes, hypertension, and metabolic syndrome. The beneficial effects of fasting followed by vegetarian diet in rheumatoid arthritis are confirmed by randomized controlled trials. Further beneficial effects of fasting are supported by observational data and abundant evidence from experimental research which found caloric restriction and intermittent fasting being associated with deceleration or prevention of most chronic degenerative and chronic inflammatory diseases. Intermittent fasting may also be useful as an accompanying treatment during chemotherapy of cancer. A further beneficial effect of fasting relates to improvements in sustainable lifestyle modification and adoption of a healthy diet, possibly mediated by fasting-induced mood enhancement. Various identified mechanisms of fasting point to its potential health-promoting effects, e.g., fasting-induced neuroendocrine activation and hormetic stress response, increased production of neurotrophic factors, reduced mitochondrial oxidative stress, general decrease of signals associated with aging, and promotion of autophagy. Fasting therapy might contribute to the prevention and treatment of chronic diseases and should be further evaluated in controlled clinical trials and observational studies.


Differential effect on survival of pelvic lymph node dissection at radical cystectomy for muscle invasive bladder cancer.
To compare long-term cancer outcomes after radical cystectomy (RC) alone or RC with pelvic lymph node dissection (PLND) according to different age and comorbidities categories. Using the SEER-Medicare dataset, 3314 patients diagnosed with urothelial carcinoma of the urinary bladder and treated with RC alone or RC with PLND were identified. After propensity score matching to reduce potential selection bias, all cause mortality (ACM)-free and cancer specific mortality (CSM)-free survival rates were estimated. Multivariable regression models (MVA) addressed the effect of PLND on ACM and CSM. Subgroups analyses according to age and comorbidities were performed. After matching, 688 and 688 patients treated with RC alone or RC with PLND remained. The 5-year ACM-free survival rate was 36 after RC alone and 45% after RC with PLND (p < 0001). In MVA, PLND exerted a protective effect on ACM (HR 0.77, p < 0.001). The 5-year CSM-free survival rate was 54 after RC alone and 65% after RC with PLND (p < 0.001). In MVA, PLND exerted a protective effect on CSM (HR 0.71, p < 0.001). Similar results were observed in younger (age ≤75) and healthier (CCI = 0) patients, where PLND exerted a protective effect on ACM (HR 0.64, p = 0.001) and CSM (HR 0.65, p = 0.01). Conversely, in older (age >75) and sicker (CCI ≥1) patients, PLND was not associated with ACM (HR 0.98, p = 0.8) or CSM (HR 1.01, p = 0.9). RC with PLND is associated with improved all cause and cancer specific survival in younger and healthier RC candidates but not in older and sicker patients.


The distribution, ontogeny and origin in the rat of Ia-positive cells with dendritic morphology and of Ia antigen in epithelia, with special reference to the intestine.
Ia antigens were localized in cryostat sections of rat intestine and other tissues by an indirect immunoperoxidase technique using monoclonal antibodies that recognize the rat antigens homologous to the gene products of the I-A and I-E subregions of the mouse major histocompatibility complex (MHC). Two categories of Ia+ cells were characterized, namely epithelial cells and bone marrow-derived cells with dendritic morphology. In the small intestine Ia antigen was present in the distal 2/3 of the absorptive epithelium but absent from the bases of the villi, the crypts and the epithelium covering the Peyer's patches. The distribution in nude rats was similar, indicating that T lymphocytes are not obligatory for its expression. In ontogeny Ia antigen was absent in the epithelium of neonatal gut, appearing at about 4 weeks of age and reaching adult levels at about 6 weeks. Different rat strains showed large differences in the amount of Ia antigen expressed by villus epithelium and the traits for the level of expression were shown to map outside the MHC. The levels of expression of Ia antigen in the proximal tubules of the kidney followed that of the gut epithelium in the different strains and in both tissues was mostly intracellular. Studies with chimeras showed that the Ia antigen in epithelial cells was not acquired from bone marrow-derived cells. The second category of cell studied had a characteristic dendritic morphology and was present in large numbers in the lamina propria of the villi and in the crypts. In the Peyer's patches these cells were present both in the subepithelial dome region and within the epithelium itself. These Ia+ dendritic cells were present in nude rat jejunum and appeared in normal fetal gut by 18 days gestation and were also shown to migrate into antigen-free grafts of fetal gut. This suggests that they do not require stimulation from antigens, bacterial products or T lymphocytes in order to localize in the gut or to express Ia antigen. Studies with other cell surface markers suggest that the Ia+ cells with dendritic morphology represent a range of cell types, some with similarities to macrophages and others to nonphagocytic dendritic cells.


ManLMN is a glucose transporter and central metabolic regulator in Streptococcus pneumoniae.
Streptococcus pneumoniae is a common colonizer of the human nasopharynx and a leading cause of bacterial pneumonia and otitis media, among other invasive diseases. During both colonization and invasive disease S. pneumoniae ferments host-derived carbohydrates as its primary means of generating energy. This pathogen is adept at transporting and metabolizing a wide variety of carbohydrates. We found the highly conserved PTS ManLMN contributes to growth on glucose and is also essential for growth on a variety of nonpreferred carbohydrates, suggesting it is a multisubstrate transporter. Exploration of this phenotype revealed ManLMN is required for inducing expression of downstream metabolic genes in response to carbohydrate stimuli. We further demonstrate that ManLMN's role as a constitutively expressed transporter is likely unique and integral to pneumococcus's strategy of carbon catabolite repression (CCR). Using a selection for suppressors, we explored how ManLMN is integrated into the CCR regulatory framework in S. pneumoniae. We identified two hypothetical small proteins and the virulence regulator SmrC as potential mediators of CCR in connection with ManLMN. Characterization of these two hypothetical proteins revealed they influence transcriptional regulation of carbohydrate transporters. We propose a model unifying these observations in which ManLMN is a versatile surveyor of available carbohydrates in S. pneumoniae.


The effect of geography and citizen behavior on motor vehicle deaths in the United States.
Death due to motor vehicle collisions (MVCs) remains a leading cause of death in the US and alcohol plays a prominent role in a large proportion of these fatalities nationwide. Rates for these incidents vary widely among states and over time. Here, we explore the extent to which driving volume, alcohol consumption, legislation, political ideology, and geographical factors influence MVC deaths across states and time. We specify structural equation models for extracting associations between the factors and outcomes for MVC deaths and compute correlation functions of states' relative geographic and political positions to elucidate the relative contribution of these factors. We find evidence that state-level variation in MVC deaths is associated with time-varying driving volume, alcohol consumption, and legislation. These relationships are modulated by state spatial proximity, whereby neighboring states are found to share similar MVC death rates over the thirty-year observation period. These results support the hypothesis that neighboring states exhibit similar risk and protective characteristics, despite differences in political ideology.


Stilbene epoxidation and detoxification in a Photorhabdus luminescens-nematode symbiosis.
Members of the gammaproteobacterial Photorhabdus genus share mutualistic relationships with Heterorhabditis nematodes, and the pairs infect a wide swath of insect larvae. Photorhabdus species produce a family of stilbenes, with two major components being 3,5-dihydroxy-4-isopropyl-trans-stilbene (compound 1) and its stilbene epoxide (compound 2). This family of molecules harbors antimicrobial and immunosuppressive activities, and its pathway is responsible for producing a nematode "food signal" involved in nematode development. However, stilbene epoxidation biosynthesis and its biological roles remain unknown. Here, we identified an orphan protein (Plu2236) from Photorhabdus luminescens that catalyzes stilbene epoxidation. Structural, mutational, and biochemical analyses confirmed the enzyme adopts a fold common to FAD-dependent monooxygenases, contains a tightly bound FAD prosthetic group, and is required for the stereoselective epoxidation of compounds 1 and 2. The epoxidase gene was dispensable in a nematode-infective juvenile recovery assay, indicating the oxidized compound is not required for the food signal. The epoxide exhibited reduced cytotoxicity toward its producer, suggesting this may be a natural route for intracellular detoxification. In an insect infection model, we also observed two stilbene-derived metabolites that were dependent on the epoxidase. NMR, computational, and chemical degradation studies established their structures as new stilbene-l-proline conjugates, prolbenes A (compound 3) and B (compound 4). The prolbenes lacked immunosuppressive and antimicrobial activities compared with their stilbene substrates, suggesting a metabolite attenuation mechanism in the animal model. Collectively, our studies provide a structural view for stereoselective stilbene epoxidation and functionalization in an invertebrate animal infection model and provide new insights into stilbene cellular detoxification.


Apolipoprotein C-I mediates Wnt/Ctnnb1 signaling during neural border formation and is required for neural crest development.
In vertebrates, the neural crest and placodes originate in the neural border, which is located between the neural plate and epidermal ectoderm. The neural crest and placodes give rise to a vast array of cell types. Formation of neural crest is a multi-step process, in which Wnt signals are used reiteratively, but it is currently not clear if a Wnt signal is required for neural border formation. Here, we have identified apolipoprotein C-I (apoc1) in a screen for genes regulated by Wnt/Ctnnb1 signaling in late blastula stage Xenopus tropicalis embryos. We show that Xenopus laevis apoc1 encodes a small, secreted protein, and is induced by Wnt/Ctnnb1 signaling. Depletion of Apoc1 protein results in a neural border formation defect and loss of border fates, including neural crest cells. However, unlike another Wnt/Ctnnb1 target, gbx2.2, apoc1 is not required for patterning of the neural border. We further show that gbx2.2 and apoc1 are independently regulated by Wnt signaling. Our results thus suggest that Wnt regulates border formation and patterning by distinct genetic mechanisms.


Exploring the taxonomic composition of two fungal communities on the Swedish west coast through metabarcoding.
Fungi are heterotrophic, unicellular or filamentous organisms that exhibit a wide range of different lifestyles as, e.g., symbionts, parasites, and saprotrophs. Mycologists have traditionally considered fungi to be a nearly exclusively terrestrial group of organisms, but it is now known that fungi have a significant presence in aquatic environments as well. We know little about most fungi in limnic and marine systems, including aspects of their taxonomy, ecology, and geographic distribution. The present study seeks to improve our knowledge of fungi in the marine environment. The fungal communities of two coastal marine environments of the Kattegat sea, Sweden, were explored with metabarcoding techniques using the nuclear ribosomal internal transcribed spacer 2 (ITS2) metabarcode. Our data add new information to the current picture of fungal community composition in benthic and coastal habitats in Northern Europe. The dataset describes the number of operational taxonomic units (OTUs) and their taxonomic affiliations in two littoral gradients sampled on the Swedish west coast, Gothenburg municipality. Our data include basic diversity indices as well as chemical and edaphic sediment/soil parameters of the sampling sites. From the sites, 3470 and 4315 fungal OTUs, respectively, were recovered. The number of reads were 673,711 and 779,899, respectively, after quality filtering. Within the benthic sites, more than 80% of the sequences could not be classified taxonomically. The phylum composition of the classifiable sequences was dominated in both localities by Dikarya, which made up around 33% of the OTUs. Within Dikarya, Ascomycota was the dominant phylum. Guild assignment failed for more than half of the classifiable OTUs, with undefined saprotrophs being the most common resolved guild. This guild classification was slightly more common in the ocean sediment samples than in the terrestrial ones. Our metadata indicated that ocean sites contain organisms at a lower trophic level and that there are predominantly endophytic, parasitic, and pathogenic fungi in the marine environments. This hints at the presence of interesting and currently poorly understood fungus-driven ecological processes. It is also clear from our results that a very large number of marine fungi are in urgent need of taxonomic study and formal description.


A psychosocial study of male-to-female transgendered and male hustler sex workers in São Paulo, Brazil.
This study examined sociodemographic variables, personality characteristics, and alcohol and drug misuse among male sex workers in the city of Santo André, São Paulo, Brazil. A total of 45 male-to-female transgender sex workers and 41 male hustlers were evaluated in face-to-face interviews at their place of work from 2008 to 2010. A "snowball" sampling procedure was used to access this hard-to-reach population. Male-to-female transgender sex workers reported fewer conventional job opportunities, fewer school problems, and higher harm avoidance and depression levels than male hustlers. Also, transgender sex workers reported earning more money through sex work and more frequently living in hostels with peers than their counterparts. As biological male sex workers are a heterogeneous population, attempts to classify them into distinctive groups should be further carried out as a way to better understand and identify their behavior, design effective health interventions, and consequently minimize the likelihood of unintended adverse outcomes. Our study showed that gender performance can be an important variable to be considered by researchers and policy makers when working with sex workers and developing HIV/AIDS prevention and public health programs, given that transgender and male sex workers not only display distinctive behavior and physical appearance but also reveal differences on specific psychological measures, such as personality traits and depression levels. We recommend that counselors working with this population strike a balance between facilitating self-disclosure and establishing more evidence-based directive interventions.


Physical activity, sedentary time, and pericardial fat in healthy older adults.
Pericardial fat is emerging as a unique risk factor for coronary disease. We examined the relationship between objectively measured physical activity during free-living and pericardial fat. Participants were 446 healthy men and women (mean age = 66 ± 6 years), without history or objective signs of cardiovascular disease (CVD), drawn from the Whitehall II epidemiological cohort. Physical activity was objectively measured using accelerometers (Actigraph GT3X) worn around the hip during waking hours for 7 consecutive days (average daily wear time = 889 ± 68 min/day), and was classified as sedentary (<200 counts/min (cpm)), light (200-1,998 cpm), or moderate-vigorous physical activity (MVPA; ≥1,999 cpm). Pericardial fat volume was measured in each participant using electron beam computed tomography. Average daily cpm in men was 338.0 ± 145.0 and in women 303.8 ± 130.2. There was an inverse association between average cpm and pericardial fat (B = -0.070, 95% confidence interval (CI), -0.101, -0.040, P < 0.001), and this remained significant after adjusting for age, sex, registered wear time, BMI, lipids, glycemic control, blood pressure, smoking, statins, and social status. Both sedentary time (B = 0.081, 95% CI, 0.022, 0.14) and MVPA (B = -0.362, 95% CI, -0.527, -0.197) were also associated with pericardial fat, although associations for sedentary time did not remain significant after adjustment for MVPA. The inverse association between physical activity and pericardial fat was stronger among overweight and obese adults than in normal weight. Objectively assessed daily activity levels are related to pericardial fat in healthy participants, independently of BMI. This might be an important mechanism in explaining the association between physical activity and CVD prevention.


Gene expression patterns and gene copy number changes in dermatofibrosarcoma protuberans.
Dermatofibrosarcoma protuberans (DFSP) is an aggressive spindle cell neoplasm. It is associated with the chromosomal translocation, t(17:22), which fuses the COL1A1 and PDGFbeta genes. We determined the characteristic gene expression profile of DFSP and characterized DNA copy number changes in DFSP by array-based comparative genomic hybridization (array CGH). Fresh frozen and formalin-fixed, paraffin-embedded samples of DFSP were analyzed by array CGH (four cases) and DNA microarray analysis of global gene expression (nine cases). The nine DFSPs were readily distinguished from 27 other diverse soft tissue tumors based on their gene expression patterns. Genes characteristically expressed in the DFSPs included PDGF beta and its receptor, PDGFRB, APOD, MEOX1, PLA2R, and PRKCA. Array CGH of DNA extracted either from frozen tumor samples or from paraffin blocks yielded equivalent results. Large areas of chromosomes 17q and 22q, bounded by COL1A1 and PDGF beta, respectively, were amplified in DFSP. Expression of genes in the amplified regions was significantly elevated. Our data shows that: 1) DFSP has a distinctive gene expression profile; 2) array CGH can be applied successfully to frozen or formalin-fixed, paraffin-embedded tumor samples; 3) a characteristic amplification of sequences from chromosomes 17q and 22q, demarcated by the COL1A1 and PDGF beta genes, respectively, was associated with elevated expression of the amplified genes.


Estimating the prevalence of comorbid conditions and their effect on health care costs in patients with diabetes mellitus in Switzerland.
Estimating the prevalence of comorbidities and their associated costs in patients with diabetes is fundamental to optimizing health care management. This study assesses the prevalence and health care costs of comorbid conditions among patients with diabetes compared with patients without diabetes. Distinguishing potentially diabetes- and nondiabetes-related comorbidities in patients with diabetes, we also determined the most frequent chronic conditions and estimated their effect on costs across different health care settings in Switzerland. Using health care claims data from 2011, we calculated the prevalence and average health care costs of comorbidities among patients with and without diabetes in inpatient and outpatient settings. Patients with diabetes and comorbid conditions were identified using pharmacy-based cost groups. Generalized linear models with negative binomial distribution were used to analyze the effect of comorbidities on health care costs. A total of 932,612 persons, including 50,751 patients with diabetes, were enrolled. The most frequent potentially diabetes- and nondiabetes-related comorbidities in patients older than 64 years were cardiovascular diseases (91%), rheumatologic conditions (55%), and hyperlipidemia (53%). The mean total health care costs for diabetes patients varied substantially by comorbidity status (US$3,203-$14,223). Patients with diabetes and more than two comorbidities incurred US$10,584 higher total costs than patients without comorbidity. Costs were significantly higher in patients with diabetes and comorbid cardiovascular disease (US$4,788), hyperlipidemia (US$2,163), hyperacidity disorders (US$8,753), and pain (US$8,324) compared with in those without the given disease. Comorbidities in patients with diabetes are highly prevalent and have substantial consequences for medical expenditures. Interestingly, hyperacidity disorders and pain were the most costly conditions. Our findings highlight the importance of developing strategies that meet the needs of patients with diabetes and comorbidities. Integrated diabetes care such as used in the Chronic Care Model may represent a useful strategy.


Cardiovascular risk factors and Parkinson's disease in 500,000 Chinese adults.
The objectives of this study were to compare the risks of Parkinson's disease among those with versus those without prior stroke or heart disease at baseline in a prospective study of 0.5 million adults in China, and to examine associations of cardiovascular disease risk factors (cigarette smoking, hypertension, diabetes, obesity) with risk of Parkinson's disease. During an average of 11.5 years of follow-up of 503,497 middle-aged participants in the China Kadoorie Biobank study, 603 incident cases were hospitalized with a diagnosis of Parkinson's disease. Cox proportional hazards models were used to assess associations of history of heart disease or stroke with Parkinson's disease in all participants, and of cardiovascular disease risk factors with Parkinson's disease in a subset without prior cardiovascular disease. In this population the incidence rate of Parkinson's disease (mean [SD] age of cases, 61 [10] years) was 13.3 (95% confidence interval: 12.3-14.4) per 100,000 person-years. Incidence increased with age, and was higher in men than in women, and in urban than in rural residents. Prior stroke was associated with about twofold higher risk of Parkinson's disease (hazard ratio 1.94; 1.39-2.69). After adjustment for confounders in those without prior cardiovascular disease, a 5 kg/m2 higher body mass index was associated with 17% (1.17; 1.03-1.34: P = 0.019) higher risk of Parkinson's disease, but neither hypertension, diabetes, nor current cigarette smoking was significantly associated with Parkinson's disease. Prior stroke and adiposity were each associated with higher risks of Parkinson's disease, but none of the other cardiovascular disease risk factors were significantly associated with Parkinson's disease in this population.


Membrane fouling by cell-protein mixtures: in situ characterisation using multi-photon microscopy.
Fouling of the membrane by cell and protein mixtures can result in severe flux declines, leading to the eventual need to clean or replace the membrane. In this study multi-photon microscopy, a fluorescence-based technique is used to 3-D image in situ the fouling of microfiltration membranes by suspensions containing combinations of washed yeast, bovine serum albumin (BSA) and ovalbumin. Appropriate fluorescent labelling allows the three foulant species to be clearly identified. Images correlate well with filtration data and clearly show the cake of yeast cells capturing protein aggregates. The proteins exhibited very different filtration behaviour. When filtering washed yeast together with ovalbumin and/or a 50:50 mixture by mass of BSA and ovalbumin, the ovalbumin fouling dominates the system. Capture of aggregates by the cake did not reduce fouling of the membrane by the protein and increased the resistance of the cake. For mixtures of BSA and washed yeast, the presence of a cake of yeast cells did reduce fouling of the membrane by the protein, however, the extra resistance due to the cake resulted in a flux lower than that when filtering BSA alone.


An Observational Study on Acupuncture for Earthquake-Related Post-Traumatic Stress Disorder: The Experience of the Lombard Association of Medical Acupuncturists/Acupuncture in the World, in Amatrice, Central Italy.
Background and Objective: Earthquakes are associated with severe psychiatric disorders, such as anxiety, depression, and post-traumatic stress disorder (PTSD). Current first-line therapies for PTSD have well-known side-effects. Acupuncture is a complementary approach to help patients cope with mental problems after natural disasters and public health events. This article describes an acupuncture intervention conducted by the Lombard Association of Medical Acupuncturists/Acupuncture in the World in the earthquake-stricken area of Amatrice in Central Italy and measures the effect of acupuncture on earthquake-related pain and psychologic symptoms in the victims. Methods: The intervention lasted 5 weeks, from September to October 2016. Adult patients with psychologic symptoms and musculoskeletal pain were included. Treatments were performed by experienced medical acupuncturists. A verbal/numerical scale was developed to quantify the effect of intervention. A Wilcoxon rank-sum test was used for comparison of the scores before and after the acupuncture treatment. Results: Of the patients, 68.3% reported having both pain and psychologic symptoms. The most frequently used meridian points were Kidney (13.17%), followed by Large Intestine (12.46%), Spleen (12.04%) and Gall Bladder (10.34%). After 3 treatments performed in daily sessions, 54.05% and 60.6% of patients reported marked improvements in psychologic and pain symptoms, respectively. Statistical analysis showed a significant difference between the scores reported before the first treatment and after the third treatment, both for pain (P = 0.000) and psychologic symptoms (P = 0.000). No serious adverse events were reported. Conclusions: These results suggest that acupuncture could be a useful tool for reducing pain and psychologic symptoms related to earthquakes, but further research is required in this specific area.


Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design.
3-Hydroxy-3-methylglutaryl coenzyme A (CoA) synthase (HMGCS) catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA into 3-hydroxy-3-methylglutaryl CoA. It is ubiquitous across the phylogenetic tree and is broadly classified into three classes. The prokaryotic isoform is essential in Gram-positive bacteria for isoprenoid synthesis via the mevalonate pathway. The eukaryotic cytosolic isoform also participates in the mevalonate pathway but its end product is cholesterol. Mammals also contain a mitochondrial isoform; its deficiency results in an inherited disorder of ketone body formation. Here, we report high-resolution crystal structures of the human cytosolic (hHMGCS1) and mitochondrial (hHMGCS2) isoforms in binary product complexes. Our data represent the first structures solved for human HMGCS and the mitochondrial isoform, allowing for the first time structural comparison among the three isoforms. This serves as a starting point for the development of isoform-specific inhibitors that have potential cholesterol-reducing and antibiotic applications. In addition, missense mutations that cause mitochondrial HMGCS deficiency have been mapped onto the hHMGCS2 structure to rationalize the structural basis for the disease pathology.


The Peabody Developmental Fine Motor Scale: an interrater reliability study.
This study examined the interrater reliability of two raters on the Fine Motor scale of the Peabody Developmental Motor Scales (Folio & Fewell, 1983). The sample comprised 32 children who were 4 or 5 years of age. Half of the children were considered to have normal development and half had an identified developmental delay. The Pearson product-moment correlation coefficients between the two sets of ratings were r = .97 for the delayed group and r = .77 for the normal group. Intraclass correlations were .97 and .76 for the delayed and normal groups, respectively. These figures appear to reflect the increased variance of the performance of the children with developmental delays. The percentage agreement between the two raters was greater for the group of normal subjects. The results suggest that the Fine Motor scale of the Peabody scales includes enough items to minimize the total score difference between two raters. Individual test items with poor agreement between the two raters were identified.


Reaching the hard to reach: longitudinal investigation of adolescents' attendance at an after-school sexual and reproductive health programme in Western Cape, South Africa.
Adolescents need access to effective sexual and reproductive health (SRH) interventions, but face barriers accessing them through traditional health systems. School-based approaches might provide accessible, complementary strategies. We investigated whether a 21-session after-school SRH education programme and school health service attracted adolescents most at risk for adverse SRH outcomes and explored motivators for and barriers to attendance. Grade 8 adolescents (average age 13 years) from 20 schools in the intervention arm of an HIV prevention cluster randomised controlled trial in the Western Cape Province of South Africa, were invited to participate in an after-school SRH program and to attend school health services. Using a longitudinal design, we surveyed participants at baseline, measured their attendance at weekly after-school sessions for 6 months and surveyed them post-intervention. We examined factors associated with attendance using bivariate and multiple logistic and Poisson regression analyses, and through thematic analysis of qualitative data. The intervention was fully implemented in 18 schools with 1576 trial participants. The mean attendance of the 21-session SRH programme was 8.8 sessions (S.D. 7.5) among girls and 6.9 (S.D. 7.2) among boys. School health services were visited by 17.3 % (14.9 % of boys and 18.7 % of girls). Adolescents who had their sexual debut before baseline had a lower rate of session attendance compared with those who had not (6.3 vs 8.5, p < .001). Those who had been victims of sexual violence or intimate partner violence (IPV), and who had perpetrated IPV also had lower rates of attendance. Participants were motivated by a wish to receive new knowledge, life coaching and positive attitudes towards the intervention. The unavailability of safe transport and domestic responsibilities were the most common barriers to attendance. Only two participants cited negative attitudes about the intervention as the reason they did not attend. Reducing structural barriers to attendance, after-school interventions are likely to reach adolescents with proven-effective SRH interventions. However, special attention is required to reach vulnerable adolescents, through offering different delivery modalities, improving the school climate, and providing support for adolescents with mental health problems and neurodevelopmental academic problems. Current Controlled Trials ISRCTN56270821 ; Registered 13 February 2013.


The copper-transporting capacity of ATP7A mutants associated with Menkes disease is ameliorated by COMMD1 as a result of improved protein expression.
Menkes disease (MD) is an X-linked recessive disorder characterized by copper deficiency resulting in a diminished function of copper-dependent enzymes. Most MD patients die in early childhood, although mild forms of MD have also been described. A diversity of mutations in the gene encoding of the Golgi-resident copper-transporting P(1B)-type ATPase ATP7A underlies MD. To elucidate the molecular consequences of the ATP7A mutations, various mutations in ATP7A associated with distinct phenotypes of MD (L873R, C1000R, N1304S, and A1362D) were analyzed in detail. All mutants studied displayed changes in protein expression and intracellular localization parallel to a dramatic decline in their copper-transporting capacity compared to ATP7A the wild-type. We restored these observed defects in ATP7A mutant proteins by culturing the cells at 30°C, which improves the quality of protein folding, similar to that which as has recently has been demonstrated for misfolded ATP7B, a copper transporter homologous to ATP7A. Further, the effect of the canine copper toxicosis protein COMMD1 on ATP7A function was examined as COMMD1 has been shown to regulate the proteolysis of ATP7B proteins. Interestingly, in addition to adjusted growth temperature, binding of COMMD1 partially restored the expression, subcellular localization, and copper-exporting activities of the ATP7A mutants. However, no effect of pharmacological chaperones was observed. Together, the presented data might provide a new direction for developing therapies to improve the residual exporting activity of unstable ATP7A mutant proteins, and suggests a potential role for COMMD1 in this process.


Tungsten effects on microbial community structure and activity in a soil.
Tungsten, once deposited onto a soil as a result of private, industrial, and military activities, may persist as tungstate anion or, via polymerization, as a variety of poly-tungstate species, each with varying solubility and soil sorption characteristics. In this study, the impact of weathered tungsten on a soil microbial community was measured. Fatty acid analyses indicated that weathered tungsten at < or =2500 mg kg(-1) was associated with a significant increase in microbial biomass and that concentrations up to 6500 mg kg(-1) did not result in a significant decrease in measured biomass, relative to the control. Analysis of cellular fatty acids also identified significant microbial community shifts between 0 and 325, 1300 and 2600, and 3900 and 6500 mg W kg(-1) soil. In general, the positive effect of tungsten on microbial biomass coincided with an increase in Gram-negative bacterial fatty acids, whereas fatty acids indicative of actinomycetes and Gram-positive bacteria were more abundant at the highest soil tungsten concentrations. The weathered tungsten also inhibited N2 fixing activity of a free living diazotroph at > or =1300 mg W kg(-1) soil. These results indicate that tungsten in soil can alter both the structure and the function of an indigenous soil microbial community.


Acetylene bubble-powered autonomous capsules: towards in situ fuel.
A fuel-free autonomous self-propelled motor is illustrated. The motor is powered by the chemistry of calcium carbide and utilising water as a co-reactant, through a polymer encapsulation strategy. Expulsion of acetylene bubbles powers the capsule motor. This is an important step, going beyond the toxic hydrogen peroxide fuel used normally, to find alternative propellants for self-propelled machines.


Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418.
ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2-259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized "best dose" was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40-60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.


Enterovirus antibody levels during the first two years of life in prediabetic autoantibody-positive children.
We evaluated the role of enterovirus infections in the pathogenesis of Type I (insulin-dependent) diabetes mellitus by monitoring enterovirus antibody levels in prediabetic children who turned positive for diabetes-associated autoantibodies in a prospective birth cohort study. Serial serum samples taken during prospective observation starting at birth were analysed for IgG and IgA class antibodies against enterovirus antigens including purified coxsackievirus B4, echovirus 11, poliovirus 1 and a synthetic enterovirus peptide antigen using enzyme immunoassay. Maternal samples taken at the end of the third month of pregnancy were also studied. Analyses were done from 21 childen who developed autoantibodies and from 104 autoantibody-negative control children who were matched for the time of birth, gender and HLA susceptibility alleles. For comparison, adenovirus antibodies were also analysed from all samples collected. IgG class enterovirus antibody levels were high in maternal samples and in cord blood in both case and control children. After birth the IgG levels decreased reaching a nadir at the age of 6 months. No IgA class antibodies were detected at birth but started to emerge postnatally. Antibody levels did not differ between the autoantibody positive and the control children during the first 6 months of life. From 6 months to 24 months of age, the autoantibody positive children had higher IgG and IgA levels against coxsackievirus B4, echovirus 11 and the synthetic enterovirus peptide antigens than control children but poliovirus 1 and adenovirus antibodies were closely similar in the two groups. The difference between children with autoantibodies and control children was predominantly seen among boys and among those with the HLA-DQB1*0302/x genotype. Our data show that children who seroconverted for diabetes-associated auto-antibodies develop stronger humoral immune responses to coxsackievirus B4, echovirus 11 and a synthetic enterovirus peptide antigen than children who remained negative for autoantibodies. Poliovirus antibodies induced by uniform vaccinations did not differ between the prediabetic and control children suggesting that the regulation of antibody responses to enteroviruses is not disturbed. Accordingly, the results imply a stronger enterovirus exposure in prediabetic children supporting the role of enteroviruses in the pathogenesis of Type I diabetes.


Equity and adequacy of international donor assistance for global malaria control: an analysis of populations at risk and external funding commitments.
Financing for malaria control has increased as part of international commitments to achieve the Millennium Development Goals (MDGs). We aimed to identify the unmet financial needs that would be biologically and economically equitable and would increase the chances of reaching worldwide malaria-control ambitions. Populations at risk of stable Plasmodium falciparum or Plasmodium vivax transmission were calculated for 2007 and 2009 for 93 malaria-endemic countries to measure biological need. National per-person gross domestic product (GDP) was used to define economic need. An analysis of external donor assistance for malaria control was done for the period 2002-09 to compute overall and annualised per-person at-risk-funding commitments. Annualised malaria donor assistance was compared with independent predictions of funding needed to reach international targets of 80% coverage of best practices in case-management and effective disease prevention. Countries were ranked in relation to biological, economic, and unmet needs to examine equity and adequacy of support by 2010. International financing for malaria control has increased by 166% (from $0·73 billion to $1·94 billion) since 2007 and is broadly consistent with biological needs. African countries have become major recipients of external assistance; however, countries where P vivax continues to pose threats to control ambitions are not as well funded. 21 countries have reached adequate assistance to provide a comprehensive suite of interventions by 2009, including 12 countries in Africa. However, this assistance was inadequate for 50 countries representing 61% of the worldwide population at risk of malaria-including ten countries in Africa and five in Asia that coincidentally are some of the poorest countries. Approval of donor funding for malaria control does not correlate with GDP. Funding for malaria control worldwide is 60% lower than the US$4·9 billion needed for comprehensive control in 2010; this includes funding shortfalls for a wide range of countries with different numbers of people at risk and different levels of domestic income. More efficient targeting of financial resources against biological need and national income should create a more equitable investment portfolio that with increased commitments will guarantee sustained financing of control in countries most at risk and least able to support themselves. Wellcome Trust.


Immunoblot diagnostic test for neurognathostomiasis.
Neurognathostomiasis is a rare but severe form of human gnathostomiasis. Diagnosis of neurognathostomiasis is made presumably by using clinical manifestations. Serologic tests for neurognathostomiasis are not widely available and limited. We studied 12 patients with diagnoses of neurognathostomiasis at Srinagarind Hospital, Khon Kaen University, Thailand. There were three types of neurognathostomiasis (five patients with intracerebral hemorrhage, one patient with subarachnoid hemorrhage, and six patients with myelitis). All patients were tested for antibodies against Gnathostoma spinigerum by an immunoblotting technique. The sensitivity and specificity of the 21-kD and 24-kD diagnostic bands were 83.3% and 100%, and 91.7% and 100%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for the 21-kD and 24-kD diagnostic bands were all 100%. Both diagnostic bands are a helpful diagnostic tool for neuro gnathostomiasis and show good diagnostic properties.


Psychosocial Maturation, Race, and Desistance from Crime.
Research on maturation and its relation to antisocial behavior has progressed appreciably in recent years. Psychosocial maturation is a relatively recent concept of development that scholarship has linked to risky behavior. Psychosocial maturation appears to be a promising explanation of the process of exiting criminal behavior, known as desistance from crime. However, to date, research has not examined whether psychosocial maturation is related to desistance in similar ways across race/ethnicity. Using the Pathways to Desistance Study which followed a mixed-race/ethnicity group of serious adolescent offenders for 7 years, this research tested growth in psychosocial maturation across race/ethnic groups. The sample (14.46% female, average age 15.97 at baseline) was composed of white (n = 250), black (n = 463), and Hispanic (n = 414) individuals. The results showed variation in trajectories of psychosocial maturation with blacks having higher initial levels but slower growth in maturation over time compared to whites. Psychosocial maturation was negatively related to crime across all racial/ethnic groups. Across all racial/ethnic groups, differences in the magnitude of the association between psychosocial maturation and desistance were small. Rather than needing distinct theories for specific groups, psychosocial maturation appears to be a general theoretical perspective for understanding desistance from crime across races/ethnicities. Policy formulation based on psychosocial maturation would, therefore, be applicable across racial/ethnic groups.


Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships.
Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone.


Use of Empty Fruit Bunches from the oil palm for bioethanol production: a thorough comparison between dilute acid and dilute alkali pretreatment.
In the present work, two pretreatment techniques using either dilute acid (H2SO4) or dilute alkali (NaOH) have been compared for producing bioethanol from Empty Fruit Bunches (EFBs) from oil palm tree, a relevant feedstock for tropical countries. Treatments' performances under different conditions have been assessed and statistically optimized with respect to the response upon standardized enzymatic saccharification. The dilute acid treatment performed at optimal conditions (161.5°C, 9.44 min and 1.51% acid loading) gave 85.5% glucose yield, comparable to those of other commonly investigated feedstocks. Besides, the possibility of using fibers instead of finely ground biomass may be of economic interest. Oppositely, treatment with dilute alkali has shown lower performances under the conditions explored, most likely given the relatively significant lignin content, suggesting that the use of stronger alkali regime (with the associated drawbacks) is unavoidable to improve the performance of this treatment.


[Supervisors being assessed].
Since 2015, a permanent quality cycle is mandatory for medical residency specialist training. One aspect of this cycle is the System for Evaluation of Teaching Qualities (SETQ), which allows trainees to give feedback about their supervisor. We analysed how these quality evaluations are discussed within groups of supervisors. Questionnaire study amongst residency training program directors. From September 2013 till February 2014, an online questionnaire was distributed amongst 255 program directors of medical residency specialist training in 54 teaching hospitals. The questionnaire assessed (a) if feedback was discussed, (b) the purpose of the feedback discussions, (c) their format, (d) the perceived outcomes and (e) any need for supervisor support in relation to any future feedback discussions. The response rate for the questionnaire was 61%. The majority of supervisor groups (86%) followed up on their individual SETQ feedback. Formats included individually between the program director and supervisor (34%), in a peer group of supervisors (69%), and in group format involving both trainees and supervisors (68%). Respondents listed the mutual learning process and devising improvement plans as aims of discussing feedback in a group format. There is considerable variation between groups of supervisors in terms of how the feedback is discussed. Over fifty percent of the group discussions resulted in concrete agreements for improvement plans. The feedback by trainees on the teaching performance of their supervisors is not wasted. The vast majority of supervisors follow up on their teaching performance feedback in peer group meetings.


A content analysis of 32 years of Shark Week documentaries.
Despite evidence of their importance to marine ecosystems, at least 32% of all chondrichthyan species are estimated or assessed as threatened with extinction. In addition to the logistical difficulties of effectively conserving wide-ranging marine species, shark conservation is believed to have been hindered in the past by public perceptions of sharks as dangerous to humans. Shark Week is a high-profile, international programming event that has potentially enormous influence on public perceptions of sharks, shark research, shark researchers, and shark conservation. However, Shark Week has received regular criticism for poor factual accuracy, fearmongering, bias, and inaccurate representations of science and scientists. This research analyzes the content and titles of Shark Week episodes across its entire 32 years of programming to determine if there are trends in species covered, research techniques featured, expert identity, conservation messaging, type of programming, and portrayal of sharks. We analyzed titles from 272 episodes (100%) of Shark Week programming and the content of all available (201; 73.9%) episodes. Our data demonstrate that the majority of episodes are not focused on shark bites, although such shows are common and many Shark Week programs frame sharks around fear, risk, and adrenaline. While criticisms of disproportionate attention to particular charismatic species (e.g. great whites, bull sharks, and tiger sharks) are accurate and supported by data, 79 shark species have been featured briefly at least once. Shark Week's depictions of research and of experts are biased towards a small set of (typically visual and expensive) research methodologies and (mostly white, mostly male) experts, including presentation of many white male non-scientists as scientific experts. While sharks are more often portrayed negatively than positively, limited conservation messaging does appear in 53% of episodes analyzed. Results suggest that as a whole, while Shark Week is likely contributing to the collective public perception of sharks as bad, even relatively small alterations to programming decisions could substantially improve the presentation of sharks and shark science and conservation issues.


Differential role of actin in lung endothelial and epithelial barrier properties in perfused rabbit lungs.
Lung fluid balance is critically dependent on capillary endothelial and alveolar epithelial barrier properties, and cytoskeletal components have been implicated in these barrier functions. In an earlier study, we perfused Clostridium botulinum C2 toxin, which effects selective loss of non-muscle F-actin, through isolated rabbit lungs: a severalfold increase in the capillary filtration coefficient (Kfc) was noted, together with attenuations and disruptions of endothelial cells upon electron microscopic examination. In this model we have investigated the influence of the C2 toxin on alveolar epithelial barrier properties. Epithelial permeability was assessed by continuous monitoring of the transepithelial passage of technetium-labelled diethylenetriamine penta-acetic acid (99mTc-DTPA), offered to the alveolar surface by aerosol technique. Intravascular administration of hydrogen peroxide, used as control agent, was shown to provoke a four- to fivefold increase in the clearance rate of 99mTc-DTPA under conditions of severe fluid leakage into the lung interstitial and alveolar space. Intravascular administration of C2 toxin caused a dose- and time-dependent increase in Kfc values (8-15 fold), but the Tc-DTPA clearance rate was entirely unaffected. Moreover, transbronchial application of C2 toxin again reproduced the manifold increase in Kfc data (about six fold), but the rate of transepithelial passage of the hydrophilic Tc-DTPA complex remained unchanged. We conclude that the barrier properties of the lung microvascular endothelial and epithelial layer are differentially regulated. It is suggested that the actin microfilament system plays a decisive role in the structural and functional integrity of the endothelial but not the epithelial barrier.


BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors.
Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene) in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding) and Comparative Genome Hybridization (CGH) analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome) CGH-array platform. Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO) band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic changes identified in this work are at very small scales and thus may provide a more feasible basis for the identification of the target gene(s). Identification of the genes underlying these chromosome changes can provide new insights to the mechanisms of mammary carcinogenesis.


MicroRNAs in Tumor Exosomes Drive Immune Escape in Melanoma.
MicroRNAs (miRNA), small noncoding RNAs that regulate gene expression, exist not only in cells but also in a variety of body fluids. These circulating miRNAs could enable intercellular communication. miRNAs are packaged in membrane-encapsulated vesicles, such as exosomes, or protected by RNA-binding proteins. Here, we report that miRNAs included in human melanoma exosomes regulate the tumor immune response. Using microscopy and flow cytometry, we demonstrate that CD8+ T cells internalize exosomes from different tumor types even if these cells do not internalize vesicles as readily as other immune cells. We explored the function of melanoma-derived exosomes in CD8+ T cells and showed that these exosomes downregulate T-cell responses through decreased T-cell receptor (TCR) signaling and diminished cytokine and granzyme B secretions. The result reduces the cells' cytotoxic activity. Using mimics, we found that miRNAs enriched in exosomes-such as Homo sapiens (hsa)-miR-3187-3p, hsa-miR-498, hsa-miR-122, hsa-miR149, and hsa-miR-181a/b-regulate TCR signaling and TNFα secretion. Our observations suggest that miRNAs in melanoma-derived exosomes aid tumor immune evasion and could be a therapeutic target.


Left ventricular mass reduction during salt depletion in arterial hypertension.
Long-term therapy with antihypertensive agents that reduce sympathetic nervous system activity has been demonstrated by echocardiographic measurements to reverse left ventricular hypertrophy. This investigation evaluated the effects of salt depletion obtained by both chlorthalidone (25 mg/day) and severe restriction of salt intake (about 1016 mg Na+/day) on left ventricular mass (LVM) in as short a time as 12 weeks. Before the study, the patients had been off medication and on a balanced diet without salt restriction for at least 2 weeks; they were then randomly allocated to either the diuretic or low-salt regimen for 6 weeks and finally to alternative treatment according to a crossover model. Blood pressure, body weight, myocardial mass, and noninvasive measurements of left ventricular function (LVF) were determined at baseline and at the end of both periods of treatment. Results were evaluated by two-way analysis of variance in randomized blocks. Systolic and diastolic blood pressure and LVM were significantly and similarly reduced by diuretic therapy or salt restriction. A significant correlation was demonstrated between noninvasive measurements of LVM, expressed as cross-sectional area, and systolic blood pressure. No impairment of LVF could be detected over the treatment period.


Biomolecular hydration: from water dynamics to hydrodynamics.
Thermally driven rotational and translational diffusion of proteins and other biomolecules is governed by frictional coupling to their solvent environment. Prediction of this coupling from biomolecular structures is a longstanding biophysical problem, which cannot be solved without knowledge of water dynamics in an interfacial region comparable to the dry protein in volume. Efficient algorithms have been developed for solving the hydrodynamic equations of motion for atomic-resolution biomolecular models, but experimental diffusion coefficients can be reproduced only by postulating hundreds of rigidly bound water molecules. This static picture of biomolecular hydration is fundamentally inconsistent with magnetic relaxation dispersion experiments and molecular dynamics simulations, which both reveal a highly dynamic interface where rotation and exchange of nearly all water molecules are several orders of magnitude faster than biomolecular diffusion. Here, we resolve this paradox by means of a dynamic hydration model that explicitly links protein hydrodynamics to hydration dynamics. With the aid of this model, bona fide structure-based predictions of global biomolecular dynamics become possible, as demonstrated here for a set of 16 proteins for which accurate experimental rotational diffusion coefficients are available.


A Role for MINIYO and QUATRE-QUART2 in the Assembly of RNA Polymerases II, IV, and V in Arabidopsis.
RNA polymerases IV and V (Pol IV and Pol V) are required for the generation of noncoding RNAs in RNA-directed DNA methylation (RdDM). Their subunit compositions resemble that of Pol II. The mechanism and accessory factors involved in their assembly remain largely unknown. In this study, we identified mutant alleles of MINIYO (IYO), QUATRE-QUART2 (QQT2), and NUCLEAR RNA POLYMERASE B11/D11/E11 (NRPB/D/E11) that cause defects in RdDM in Arabidopsis thaliana We found that Pol IV-dependent small interfering RNAs and Pol V-dependent transcripts were greatly reduced in the mutants. NRPE1, the largest subunit of Pol V, failed to associate with other Pol V subunits in the iyo and qqt2 mutants, suggesting the involvement of IYO and QQT2 in Pol V assembly. In addition, we found that IYO and QQT2 were mutually dependent for their association with the NRPE3 subassembly prior to the assembly of Pol V holoenzyme. Finally, we show that IYO and QQT2 are similarly required for the assembly of Pol II and Pol IV. Our findings reveal IYO and QQT2 as cofactors for the assembly of Pol II, Pol IV, and Pol V and provide mechanistic insights into how RNA polymerases are assembled in plants.


HBV replication is significantly reduced by IL-6.
Interleukin-6 (IL-6) is a pleiotropic cytokine with pivotal functions in the regulation of the biological responses of several target cells including hepatocytes. The level of serum IL-6 has been reported to be elevated in patients with chronic hepatitis B, cirrhosis and hepatocellular carcinoma and represents the best marker of HBV-related clinical progression as compared with several other cytokines. In this study, we found that IL-6 was able to effectively suppress hepatitis B virus (HBV) replication and prevent the accumulation of HBV covalently closed circular DNA (cccDNA) in a human hepatoma cell line. We also demonstrated that the suppression of HBV replication by IL-6 requires concurrently a moderate reduction of viral transcripts/core proteins and a marked decrease in viral genome-containing nucleocapsids. Studies on the stability of existing viral capsids suggest that the IL-6 effect on the reduction of genome-containing nucleocapsids is mediated through the prevention of the formation of genome-containing nucleocapsids, which is similar to the effect of interferons. However, IFN-alpha/beta and IFN-gamma did not participate in the IL-6-induced suppression of HBV replication. Taken together, our results will provide important information to better understand the role of IL-6 in the course of HBV infection.


Optimization of chemical and instrumental parameters in hydride generation laser-induced breakdown spectrometry for the determination of arsenic, antimony, lead and germanium in aqueous samples.
A laser induced breakdown spectrometry hyphenated with on-line continuous flow hydride generation sample introduction system, HG-LIBS, has been used for the determination of arsenic, antimony, lead and germanium in aqueous environments. Optimum chemical and instrumental parameters governing chemical hydride generation, laser plasma formation and detection were investigated for each element under argon and nitrogen atmosphere. Arsenic, antimony and germanium have presented strong enhancement in signal strength under argon atmosphere while lead has shown no sensitivity to ambient gas type. Detection limits of 1.1 mg L(-1), 1.0 mg L(-1), 1.3 mg L(-1) and 0.2 mg L(-1) were obtained for As, Sb, Pb and Ge, respectively. Up to 77 times enhancement in detection limit of Pb were obtained, compared to the result obtained from the direct analysis of liquids by LIBS. Applicability of the technique to real water samples was tested through spiking experiments and recoveries higher than 80% were obtained. Results demonstrate that, HG-LIBS approach is suitable for quantitative analysis of toxic elements and sufficiently fast for real time continuous monitoring in aqueous environments.


Bending and circularization of site-specific and stereoisomeric carcinogen-DNA adducts.
The potent tumorigen and mutagen (+)-7(R),8(S)-dihydroxy-9(S), 10(R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene ((+)-anti-BPDE) is a metabolite of benzo[a]pyrene that binds predominantly to the exocyclic amino group of guanine residues in DNA in vivo and in vitro. While the (-)-7S,8R,9R,10Senantiomer, (-)-anti-BPDE, also reacts with DNA to form similar covalent N2-deoxyguanosyl adducts, this diol epoxide is nontumorigenic and its mutagenic activities are different from those of (+)-anti-BPDE. In this work, T4 ligase-induced cyclization methods have been employed to demonstrate that the (+)-anti-[BP]-N2-dG lesions (G*) cause significantly greater amounts of bending and circularization of the one-base overhang undecamer duplex 5'-d(CACAT[G*]TACAC).d(TGTACATGTGG) than the stereoisomeric oligonucleotide duplex with G* = (-)-anti-[BP]-N2-dG. In the case of the (+)-anti-BPDE-modified oligonucleotides, the ratio of circular to linear DNA multimers reaches values of 8-9 for circle contour sizes of 99-121 base pairs, while for the (-)-anti-[BP]-N2-dG-modified DNA this ratio reaches a maximum value of only approximately 1 at 154-176 base pairs. Assuming a planar circle DNA model, the inferred bending angles for 90-92% of the observed circular ligation products range from 30 to 51 degrees per (+)-trans-anti-[BP]-N2-dG lesion and from 20 to 40 degrees per (-)-trans-anti-[BP]-N2-dG lesion. In the case of unmodified DNA, the probability of circular product formation is at least 1 order of magnitude less efficient than in the BPDE-modified sequences and about 90% of the circular products exhibit bending angles in the range of 14 -19 degrees . In the most abundant circular products observed experimentally, the bending angles are 40 degrees and 26 +/- 2 degrees per (+)-anti-[BP]- or (-)-anti-[BP]-modified 11-mer; these values correspond to a net contribution of 21-26 degrees and 5-19 degrees , respectively, to the observed overall bending per lesion. The coexistence of circular DNA molecules of different sizes and, therefore, different average bending angles per lesion, suggest that the lesions induce both torsional flexibility and flexible bends, which permit efficient cyclization, especially in the case of (+)-trans-[BP]-N2-dG adducts. The NMR characteristics of (+)-trans-[BP]-N2-dG lesion in the 11-mer duplex 5'-d(CACAT[G*]TACAC).d(GTGTACATGTG) indicate that all base pairs are intact, except at the underlined base pairs. This suggests a distortion in the normal conformation of the duplex on the 5'-side of the modified guanosine residue, which may be due to bending enhanced base pair opening and bending induced by the bulky carcinogen residue. The implications of base sequence-dependent flexibilities and conformational mobilities of anti-[BP]-N2-dG lesions on DNA replication and mutation are discussed.


Estimating preference-based health utilities index mark 3 utility scores for childhood conditions in England and Scotland.
A common feature of studies that have compiled lists or catalogues of preference-based health-related quality-of-life weights for inclusion within quality-adjusted life years (QALYs) is their focus upon adult populations.More generally, utility measurement in or on behalf of children has been constrained by a number of methodological concerns. To augment previous catalogues of preference-based health-related quality-of-life weights by estimating preference-based Health Utilities Index Mark 3 (HUI3) multiattribute utility scores associated with a wide range of childhood conditions. Data for 2236 children from the "Disability Survey 2000: Survey of Young People With a Disability and Sport" formed the basis of this investigation. Ordinary least squares (OLS), Tobit, and censored least absolute deviations(CLAD) regression methods were used to estimate adjusted marginal disutilities for each condition from 2 thresholds: 1) a threshold of 1.0 representing perfect health and 2) a normative childhood utility threshold. Prespecified statistical tests indicated a preference for the OLS regression model over the Tobit and CLAD models. The unadjusted mean, median, 25th percentile and 75th percentile HUI3 multiattribute utility scores and adjusted marginal disutilities are presented for 43 conditions. Notably, based on the OLS estimator, the adjusted marginal disutilities for hydrocephalus; learning and physical disabilities; other syndromes and associations; meningitis, encephalitis, and other infections of the central nervous system; and microcephaly were estimated at -0.889 (95% confidence interval [CI]: -0.727, -1.000), -0.858 (95% CI: -0.727, -0.989), -0.838 (95% CI: -0.668, -1.000), -0.826(95% CI: -0.677, -0.975), and -0.820 (95% CI: -0.670, -0.970), respectively, when a perfect health threshold was applied, and -0.814 (95% CI: -0.656, -0.979), -0.783 (95%CI: -0.656, -0.918), -0.763 (95% CI: -0.597, -0.937), -0.751 (95% CI: -0.606, -0.904), and -0.745 (95% CI: -0.598, -0.899), respectively, when a normative childhood utility threshold was applied. Our estimates and their associated distributions can be used for the purposes of QALY estimation by analysts conducting economic evaluations within the childhood context.


The association between density of alcohol establishments and violent crime within urban neighborhoods.
Numerous studies have found that areas with higher alcohol establishment density are more likely to have higher violent crime rates, but many of these studies did not assess the differential effects of type of establishments or the effects on multiple categories of crime. In this study, we assess whether alcohol establishment density is associated with 4 categories of violent crime and whether the strength of the associations varies by type of violent crime and by on-premise establishments (e.g., bars, restaurants) versus off-premise establishments (e.g., liquor and convenience stores). Data come from the city of Minneapolis, Minnesota in 2009 and were aggregated and analyzed at the neighborhood level. Across the 83 neighborhoods in Minneapolis, we examined 4 categories of violent crime: assault, rape, robbery, and total violent crime. We used a Bayesian hierarchical inference approach to model the data, accounting for spatial auto-correlation and controlling for relevant neighborhood demographics. Models were estimated for total alcohol establishment density as well as separately for on-premise establishments and off-premise establishments. Positive, statistically significant associations were observed for total alcohol establishment density and each of the violent crime outcomes. We estimate that a 3.9 to 4.3% increase across crime categories would result from a 20% increase in neighborhood establishment density. The associations between on-premise density and each of the individual violent crime outcomes were also all positive and significant and similar in strength as for total establishment density. The relationships between off-premise density and the crime outcomes were all positive but not significant for rape or total violent crime, and the strength of the associations was weaker than those for total and on-premise density. Results of this study, combined with earlier findings, provide more evidence that community leaders should be cautious about increasing the density of alcohol establishments within their neighborhoods.


Decoding effector-dependent and effector-independent movement intentions from human parieto-frontal brain activity.
Our present understanding of the neural mechanisms and sensorimotor transformations that govern the planning of arm and eye movements predominantly come from invasive parieto-frontal neural recordings in nonhuman primates. While functional MRI (fMRI) has motivated investigations on much of these same issues in humans, the highly distributed and multiplexed organization of parieto-frontal neurons necessarily constrain the types of intention-related signals that can be detected with traditional fMRI analysis techniques. Here we employed multivoxel pattern analysis (MVPA), a multivariate technique sensitive to spatially distributed fMRI patterns, to provide a more detailed understanding of how hand and eye movement plans are coded in human parieto-frontal cortex. Subjects performed an event-related delayed movement task requiring that a reach or saccade be planned and executed toward one of two spatial target positions. We show with MVPA that, even in the absence of signal amplitude differences, the fMRI spatial activity patterns preceding movement onset are predictive of upcoming reaches and saccades and their intended directions. Within certain parieto-frontal regions we show that these predictive activity patterns reflect a similar spatial target representation for the hand and eye. Within some of the same regions, we further demonstrate that these preparatory spatial signals can be discriminated from nonspatial, effector-specific signals. In contrast to the largely graded effector- and direction-related planning responses found with fMRI subtraction methods, these results reveal considerable consensus with the parieto-frontal network organization suggested from primate neurophysiology and specifically show how predictive spatial and nonspatial movement information coexists within single human parieto-frontal areas.


Identifying nuclear phenotypes using semi-supervised metric learning.
In systems-based approaches for studying processes such as cancer and development, identifying and characterizing individual cells within a tissue is the first step towards understanding the large-scale effects that emerge from the interactions between cells. To this end, nuclear morphology is an important phenotype to characterize the physiological and differentiated state of a cell. This study focuses on using nuclear morphology to identify cellular phenotypes in thick tissue sections imaged using 3D fluorescence microscopy. The limited label information, heterogeneous feature set describing a nucleus, and existence of subpopulations within cell-types makes this a difficult learning problem. To address these issues, a technique is presented to learn a distance metric from labeled data which is locally adaptive to account for heterogeneity in the data. Additionally, a label propagation technique is used to improve the quality of the learned metric by expanding the training set using unlabeled data. Results are presented on images of tumor stroma in breast cancer, where the framework is used to identify fibroblasts, macrophages and endothelial cells--three major stromal cells involved in carcinogenesis.


Global coverage measurement planning strategies for mobile robots equipped with a remote gas sensor.
The problem of gas detection is relevant to many real-world applications, such as leak detection in industrial settings and landfill monitoring. In this paper, we address the problem of gas detection in large areas with a mobile robotic platform equipped with a remote gas sensor. We propose an algorithm that leverages a novel method based on convex relaxation for quickly solving sensor placement problems, and for generating an efficient exploration plan for the robot. To demonstrate the applicability of our method to real-world environments, we performed a large number of experimental trials, both on randomly generated maps and on the map of a real environment. Our approach proves to be highly efficient in terms of computational requirements and to provide nearly-optimal solutions.


Anomalous lattice vibrations of monolayer MoS2 probed by ultraviolet Raman scattering.
We present a comprehensive Raman scattering study of monolayer MoS2 with increasing laser excitation energies ranging from the near-infrared to the deep-ultraviolet. The Raman scattering intensities from the second-order phonon modes are revealed to be enhanced anomalously by only the ultraviolet excitation wavelength 354 nm. We demonstrate theoretically that such resonant behavior arises from a strong optical absorption that forms near the Γ point and ½ΓK of the band structure and an inter-valley resonant electronic scattering by the M-point phonons. These results advance our understanding of the double resonance Raman scattering process in low-dimensional semiconducting nanomaterials and provide a foundation for the technological development of monolayer MoS2 in the ultraviolet frequency range.