Are women with recent live births aware of the benefits of folic acid?
Each year, approximately 4,000 pregnancies result in spina bifida or anencephaly, serious and often fatal conditions for the newborn. The B vitamin folic acid can reduce the incidence of these conditions by 50%-70%. To examine folic acid awareness among women who had recently delivered a live-born infant, CDC analyzed Pregnancy Risk Assessment Monitoring System (PRAMS) data for 1995-1998. The question used to measure awareness was, "Have you ever heard or read that taking the vitamin folic acid can help prevent some birth defects?" During the study period, overall folic acid awareness increased 15%, from 64% in 1996 to 73% in 1998, although changes varied by state. Despite this increase, differences in folic acid awareness were observed among different groups of women. Women who obtained a high school education or less; who were black, Hispanic, or from other racial/ethnic groups; who entered prenatal care after the first trimester; and whose pregnancies were unintended were less aware of folic acid. This study indicates that gaps persist among women in low socioeconomic groups. Overall, PRAMS data indicated an increase in folic acid awareness among women with recent deliveries. However, this awareness might be too late for the pregnancy that has occurred, indicating a continued need to educate all reproductive-aged women regarding the need to take folic acid before they become pregnant.


Cognitive and visual development: influence of differences in breast and formula fed infants.
Several recent studies document a beneficial effect of breast-feeding on later neurodevelopmental outcomes. The mechanisms involved are still in need of elucidation, but evidence is accruing that the fatty acid (FA) composition of human milk plays a role. The composition of body fats, from circulating erythrocyte lipids to brain phospholipids, is linked in infants to the early feeding mode and which FA predominates among circulating lipids influences visual and neurodevelopmental performance test scores. In these studies, greater differences were found between breast-fed and standard formula-fed infants, the latter showing low tissue long-chain polyunsaturated fatty acids (LCPUFA: arachidonic acid, AA, 20:4n-6; eicosapentaenoic acid, EPA, 20:5n-3; docosahexaenoic acid, DHA, 22:6n-3) accretion and lower visual and neurodevelopmental test scores. Human milk contains LCPUFA, while most available formulas, especially those intended for full-term infants, do not. With the progressive introduction of solid foods, the question arises whether a specific or "ideal" dietary lipid mixture can be found to meet growth requirements and ensure a lipid balance adequate for the early and effective preventive purposes. These complementary aspects are challenges for the paediatric nutrition researcher today.


[Differential sensitivity of bacteria to histones].
The antimicrobial action of polycation proteins from the nuclei--histons with a high content of lysine (f1) and arginine (f3)--on Pseudomonas bacteria was studied. The sensitivity of various species of the same genus, and various strains of the same species, to histons was differential. The differences do not depend on the ability of the cells to liberate into a surrounding medium substances inactivating histons, and on the rate of histon sorption on the cells. Interaction between the bacteria and histons interferes with the permeability of the membranes, so that components of a low molecular weight, including those with the maximum of absorption in UV at 260 nm, are liberated into the surrounding medium. The total RNA of the cells is depolymerized and the activity of RNase increases. No correlation was established between these phenomena and the sensitivity of the bacteria to histons. The duration of the lag period was also studied, as well as the growth rate in the exponential phase and the total yield of the cells; a positive correlation was detected between the duration of the lag period and the sensitivity of the bacteria to histons.


Disulfide reshuffling triggers the release of a thiol-free anti-HIV agent to make up fast-acting, potent macromolecular prodrugs.
The release of azidothymidine from macromolecular prodrugs was designed to respond to the intracellular disulfide reshuffling. This drug has no thiol groups, and a response to this trigger was engineered using a self-immolative linker. The resulting formulations were fast-acting, efficacious, and highly potent with regards to suppressing the infectivity of the virus.


Three-dimensional Printing of Biomimetic Titanium Mimicking Trabecular Bone Induces Human Mesenchymal Stem Cell Proliferation: An In-vitro Analysis.
In vitro analysis. The aim of this study was to assess the effect of three-dimensional (3D) printing of porous titanium on human mesenchymal stem cell (hMSC) adhesion, proliferation, and osteogenic differentiation. A proprietary implant using three-dimensional porous titanium (3D-pTi) that mimics trabecu-lar bone structure, roughness, porosity, and modulus of elasticity was created (Ti-LIFE technology™, Spineart SA Switzerland). Such implants may possess osteoinductive properties augmenting fusion in addition to their structural advantages. However, the ability of 3D-pTi to affect in vitro cellular proliferation and osteogenic differentiation remains undefined. Disks of 3D-pTi with a porosity of 70% to 75% and pore size of 0.9 mm were produced using additive manufacturing technology. 2D Ti6Al4V (2D-Ti) and 2D polyetheretherketone (2D-PEEK) disks were prepared using standard manufacturing process. Tissue culture plastic (TCP) served as the control surface. All discs were characterized using 2D-micros-copy, scanning electron microscopy (SEM), and x-ray micro-computed tomography. Forty thousand hMSCs were seeded on the disks and TCP and cultured for 42 days. hMSC morphology was assessed using environmental SEM and confocal imaging following phalloidin staining. hMSC proliferation was evaluated using DNA fluorescent assay. hMSC differentiation was assessed using RT-qPCR for genes involved in hMSC osteogenic differentiation and biochemical assays were performed for alkaline phosphatase activity (ALP) and calcium content. 3D-pTi lead to a higher cell number as compared to 2D-Ti and 2D-PEEK at D21, D28 and D42. ALP activity of hMSCs seeded into 3D-pTi scaffolds was as high as or higher than that of hMSCs seeded onto TCP controls over all time points and consistently higher than that of hMSCs seeded onto 2D-Ti scaffolds. However, when ALP activity was normalized to protein content, no statistical differences were found between all scaffolds tested and TCP controls. 3D-pTi provides a scaffold for bone formation that structurally mimics cancellous bone and improves hMSC adhesion and proliferation compared to 2D-Ti and PEEK.


Health care providers' perspectives regarding the use of chlorhexidine gel for cord care in neonates in rural Kenya: implications for scale-up.
This paper explores the perspectives of health care providers regarding the use of 7.1% Chlorhexidine Digluconate (CHX) gel that releases 4% chlorhexidine for newborn umbilical cord care under a managed access program (MAP) implemented in Bungoma County of Kenya. Understanding the perspectives of providers regarding CHX is important since they play a key role in the health system and the fact that their views could be influenced by prior beliefs and inconsistent practices regarding umbilical cord care. Data are from in-depth interviews conducted between April and June 2016 with 39 service providers from 21 facilities that participated in the program. The data were transcribed, typed in Word and analyzed for content. Analysis entailed identifying recurring themes based on the interview guides. Use of CHX gel for cord care in neonates was acceptable to the health care providers, with all of them supporting scaling up its use throughout the country. Their views were largely influenced by positive outcomes of the medication including fast healing of the cord as reported by mothers, minimal side effects, reduced newborn infections based on what their records showed and mothers' reports, ease of use that made it simple for them to counsel mothers on how to apply it, positive feedback from mothers which demonstrated satisfaction with the medication, and general acceptance of the medication by the community. They further noted that successful scale-up of the medication required community sensitization, adequate follow-up mechanisms to ensure mothers use the medication correctly, addressing issues of staffing levels and staff training, developing guidelines and protocols for provision of the medication, adopting appropriate service delivery approaches to ensure all groups of mothers are reached, and ensuring constant supply of the medication. Use of CHX gel for cord care in neonates is likely to be acceptable to health care workers in settings with high prevalence of neonatal morbidity and mortality arising from cord infections. In scaling up the use of the medication in such settings, some of the health systems requirements for successful roll-out can be addressed by programs while others are likely to be a persistent challenge.


The expression of the secreted aspartyl proteinases Sap4 to Sap6 from Candida albicans in murine macrophages.
Medically important yeasts of the genus Candida secrete aspartyl proteinases (Sap), which are of particular interest as virulence factors. Six closely related gene sequences, SAP1 to SAP6, for secreted proteinases are present in Candida albicans. The methylotrophic yeast Pichia pastoris was chosen as an expression system for preparing substantial amounts of each Sap isoenzyme. Interestingly, Sap4, Sap5 and Sap6, which have not yet been detected in C. albicans cultures in vitro, were produced as active recombinant enzymes. Different Sap polyclonal antibodies were raised in rabbits and tested before further application by enzyme-linked immunosorbent assay (ELISA) against each recombinant Sap. Two antisera recognized only Sap4 to Sap6. Using these antisera, together with sap null mutants obtained by targeted mutagenesis, we could demonstrate a high production of Sap4, Sap5 and Sap6 by C. albicans cells after phagocytosis by murine peritoneal macrophages. Furthermore, a delta sap4,5,6 null mutant was killed 53% more effectively after contact with macrophages than the wild-type strain. These results support a role for Sap4 to Sap6 in pathogenicity.


A Transcriptional Activator of Ascorbic Acid Transport in Streptococcus pneumoniae Is Required for Optimal Growth in Endophthalmitis in a Strain-Dependent Manner.
Streptococcus pneumoniae is among the top causes of bacterial endophthalmitis, an infectious disease of the intraocular fluids. The mechanisms by which S. pneumoniae grows and thrives in the intraocular cavity are not well understood. We used a bacterial genome-wide assessment tool (transposon insertion site sequencing) to determine genes essential for S. pneumoniae growth in vitreous humor. The results indicated that an ascorbic acid (AA) transport system subunit was important for growth. We created an isogenic gene deletion mutant of the AA transcriptional activator, ulaR2, in 2 strains of S. pneumoniae. Growth curve analysis indicated that ulaR2 deletion caused attenuated growth in vitro for both strains. However, in vivo vitreous humor infection in rabbits with either strain determined that ulaR2 was necessary for growth in one strain but not the other. These results demonstrate that ulaR2 may be important for fitness during S. pneumoniae endophthalmitis depending on the background of the strain.


Occurrence and trends in ski injuries in Norway.
To provide an overview of ski injuries in Norway and to describe the changes between 1990 and 1996. All ski injuries (7966) treated at four hospitals providing health care to a defined population of about 11% of the Norwegian population were registered prospectively from 1990 to 1996. For this study, 6462 injuries sustained in cross country skiing, downhill skiing, telemark skiing, and snowboarding were selected for further analysis. The relative distribution of ski injuries by type of skiing changed significantly from 1990 to 1996 (p<0.001). Injuries from snowboarding showed the highest relative increase, and those sustained during downhill skiing showed a decline. The proportion of fractures in all types of skiing increased during the study period (p=0.001). The proportion of injuries to knee/lower leg decreased and the proportion to the forearm/wrist/hand increased during the study period (p=0.03). The mean age of the injured skiers differed significantly among the different types of skiing activity (p<0.001): cross country skiers were the oldest followed by telemark skiers, downhill skiers, and snowboarders. Ski injury surveillance results in early detection of changes in temporal injury trends, allowing timely adjustment of injury prevention strategies. Injuries from snowboarding are on the increase in Norway, warranting more effective injury prevention measures.


Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast.
Metaplastic carcinomas are distinct invasive breast carcinomas with aberrant nonglandular differentiation, which may be spindle, squamous, or chondroid. The limited effective treatments result from the lack of knowledge of its molecular etiology. Given the role of the Wnt pathway in cell fate and in the development of breast cancer, we hypothesized that defects in this pathway may contribute to the development of metaplastic carcinomas. In 36 primary metaplastic carcinomas, we comprehensively determined the prevalence of and mechanism underlying beta-catenin and Wnt pathway deregulation using immunohistochemistry for beta-catenin expression and localization and mutational analysis for CTNNB1 (encoding beta-catenin), APC, WISP3, AXIN1, and AXIN2 genes. By immunohistochemistry, normal beta-catenin was seen as membrane staining, and it was aberrant when >5% of tumor cells had nuclear or cytoplasmic accumulation or reduced membrane staining. By immunohistochemistry, aberrant beta-catenin was present in 33 of 36 (92%) cases, revealing deregulation of the Wnt pathway. CTNNB1 missense mutations were detected in 7 of 27 (25.9%) tumors available for mutation analyses. All mutations affected the NH(2)-terminal domain of beta-catenin, presumably rendering the mutant protein resistant to degradation. Two of 27 (7.4%) tumors had mutations of APC, and 5 (18.5%) carried a frame shift mutation of WISP3. No AXIN1 or AXIN2 mutations were found. Activation of the Wnt signaling pathway is common in this specific subtype of breast carcinoma. The discovery of CTNNB1, APC, and WISP3 mutations may result in new treatments for patients with metaplastic carcinomas of the breast.


Validity of Two Awake Wear-Time Classification Algorithms for activPAL in Youth, Adults, and Older Adults.
The authors assessed agreement between participant diaries and two automated algorithms applied to activPAL (PAL Technologies Ltd, Glasgow, United Kingdom) data for classifying awake wear time in three age groups. Study 1 involved 20 youth and 23 adults who, by protocol, removed the activPAL occasionally to create nonwear periods. Study 2 involved 744 older adults who wore the activPAL continuously. Both studies involved multiple assessment days. In-bed, out-of-bed, and nonwear times were recorded in the participant diaries. The CREA (in PAL processing suite) and ProcessingPAL (secondary application) algorithms estimated out-of-bed wear time. Second- and day-level agreement between the algorithms and diary was investigated, as were associations of sedentary variables with self-rated health. The overall accuracy for classifying out-of-bed wear time as compared with the diary was 89.7% (Study 1) to 95% (Study 2) for CREA and 89.4% (Study 1) to 93% (Study 2) for ProcessingPAL. Over 90% of the nonwear time occurring in nonwear periods >165 min was detected by both algorithms, while <11% occurring in periods ≤165 min was detected. For the daily variables, the mean absolute errors for each algorithm were generally within 0-15% of the diary mean. Most Spearman correlations were very large (≥.81). The mean absolute errors and correlations were less favorable for days on which any nonwear time had occurred. The associations between sedentary variables and self-rated health were similar across processing methods. The automated awake wear-time classification algorithms performed similarly to the diary information on days without short (≤2.5-2.75 hr) nonwear periods. Because both diary and algorithm data can have inaccuracies, best practices likely involve integrating diary and algorithm output.


Incest versus abstinence: reproductive trade-offs between mate limitation and progeny fitness in a self-incompatible invasive plant.
Plant mating systems represent an evolutionary and ecological trade-off between reproductive assurance through selfing and maximizing progeny fitness through outbreeding. However, many plants with sporophytic self-incompatibility systems exhibit dominance interactions at the S-locus that allow biparental inbreeding, thereby facilitating mating between individuals that share alleles at the S-locus. We investigated this trade-off by estimating mate availability and biparental inbreeding depression in wild radish from five different populations across Australia. We found dominance interactions among S-alleles increased mate availability relative to estimates based on individuals that did not share S-alleles. Twelve of the sixteen fitness variables were significantly reduced by inbreeding. For all the three life-history phases evaluated, self-fertilized offspring suffered a greater than 50% reduction in fitness, while full-sib and half-sib offspring suffered a less than 50% reduction in fitness. Theory indicates that fitness costs greater than 50% can result in an evolutionary trajectory toward a stable state of self-incompatibility (SI). This study suggests that dominance interactions at the S-locus provide a possible third stable state between SI and SC where biparental inbreeding increases mate availability with relatively minor fitness costs. This strategy allows weeds to establish in new environments while maintaining a functional SI system.


Should First-line Empiric Treatment Strategies for Neonates Cover Coagulase-negative Staphylococcal Infections in Kenya?
Neonatal mortality remains high in sub-Saharan Africa, and a third of deaths are estimated to result from infection. While coagulase-negative staphylococci (CoNS) are leading neonatal pathogens in resource-rich settings, their role, and the need for early anti-Staphylococcal treatment in empiric antibiotic guidelines, is unknown in sub-Saharan Africa. We examined systematic clinical and microbiologic surveillance data from all neonatal admissions to Kilifi County Hospital (1998-2013) to determine associated case fatality and/or prolonged duration of admission associated with CoNS in neonates treated according to standard World Health Organization guidelines. CoNS was isolated from blood culture in 995 of 9552 (10%) neonates. Case fatality among neonates with CoNS isolated from blood did not differ from other neonatal admissions (P = 0.2), and duration of admission was not prolonged [odds ratio (OR) = 0.9 (0.7-1.0), P = 0.040]. Neonates with CoNS were more likely to have convulsions [OR = 1.4 (1.0-1.8), P = 0.031] but less likely to have impaired consciousness or severe indrawing [OR = 0.8 (0.7-0.9), P = 0.025; OR = 0.9 (0.7-1.0), P = 0.065]. CoNS isolation in blood cultures at admission was not associated with adverse clinical outcomes in neonates treated according to standard World Health Organization guidelines for hospital care in this setting. There is no evidence that first-line antimicrobial treatment guidelines should be altered to increase cover for CoNS infections in neonates in this setting.


Mini-open transpedicular corpectomies with expandable cage reconstruction. Technical note.
Transpedicular corpectomies are frequently used to perform anterior surgery from a posterior approach. Minimally invasive thoracolumbar corpectomies have been previously described, but these are performed through a unilateral approach. Bilateral access must be obtained for a circumferential decompression when using such techniques. The authors describe a technique that allows for a mini-open transpedicular corpectomy, 360° decompression, and expandable cage reconstruction through a single posterior approach. This is performed using percutaneous pedicle screws, the trap-door rib-head osteotomy, and a single midline fascial exposure. The authors describe this technique with intraoperative photos and a video demonstrating the technique.


Construction and expression of immunogenic hybrid enterotoxigenic Escherichia coli CFA/I and CS2 colonization fimbriae for use in vaccines.
Enterotoxigenic Escherichia coli (ETEC) are an important cause of diarrheal morbidity in developing countries, especially in children and also of traveler's diarrhea. Colonization factors (CFs) of ETEC, like CFA/I and CS2 which are genetically and structurally related, play a substantial role in pathogenicity, and since intestinal-mucosal immune responses against CFs appear to be protective, much effort has focused on the development of a CF-based ETEC vaccine. We have constructed hybrid operons in which the major CS2 subunit-encoding cotA gene was inserted into the CFA/I operon, either replacing (hybrid I) or being added to the major CFA/I subunit-encoding cfaB gene (hybrid II). Using specific monoclonal antibodies against the major subunits of CFA/I and CS2, high levels of surface expression of both fimbrial subunits were shown in E. coli carrying the hybrid II operon. Oral immunization of mice with formalin-killed bacteria expressing hybrid II fimbriae induced strong CFA/I- and CS2-specific serum IgG + IgM and fecal IgA antibody responses, which were higher than those achieved by similar immunization with the reference strains. Bacteria expressing hybrid fimbriae are potential candidate strains in an oral-killed CF-ETEC vaccine, and the approach represents an attractive and novel means of producing a broad-spectrum ETEC vaccine.


Designing Nanostructured Ti6Al4V Bioactive Interfaces with Directed Irradiation Synthesis toward Cell Stimulation to Promote Host-Tissue-Implant Integration.
A new generation of biomaterials are evolving from being biologically inert toward bioactive surfaces, which can further interact with biological components at the nanoscale. Here, we present directed irradiation synthesis (DIS) as a novel technology to selectively apply plasma ions to bombard any type of biomaterial and tailor the nanofeatures needed for in vitro growth stimulation. In this work, we demonstrate for the first time, the influence of physiochemical cues (e.g., self-organized topography at nanoscale) of medical grade Ti6Al4V results in control of cell shape, adhesion, and proliferation of human aortic smooth muscle stem cells. The control of surface nanostructures was found to be correlated to ion-beam incidence angle linked to a surface diffusive regime during irradiation synthesis with argon ions at energies below 1 keV and a fluence of 2.5 × 1017 cm-2. Cell viability and cytoskeleton morphology were evaluated at 24 h, observing an advance cell attachment state on post-DIS surfaces. These modified surfaces showed 84% of cell biocompatibility and an increase in cytoplasmatic protusions ensuring a higher cell adhesion state. Filopodia density was promoted by a 3-fold change for oblique incidence angle DIS treatment compared to controls (e.g., no patterning) and lamellipodia structures were increased more than a factor of 2, which are indicators of cell attachment stimulation due to DIS modification. In addition, the morphology of the nanofeatures were tailored, with high fidelity control of the main DIS parameters that control diffusive and erosive regimes of self-organization. We have correlated the morphology and the influence in cell behavior, where nanoripple formation is the most active morphology for cell stimulation.


Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study.
Stereotactic ablative body radiotherapy (SABR) is increasingly being used to treat oligometastatic cancers, but high-level evidence to provide a basis for policy making is scarce. Additional evidence from a real-world setting is required. We present the results of a national study of patients with extracranial oligometastases undergoing SABR, representing the largest dataset, to our knowledge, on outcomes in this population so far. In 2015, National Health Service (NHS) England launched a Commissioning through Evaluation scheme that funded a prospective, registry-based, single-arm, observational, evaluation study of patients with solid cancer and extracranial oligometastases treated with SABR. Prescribed doses ranged from 24-60 Gy administered in three to eight fractions. The study was done at 17 NHS radiotherapy centres in England. Patients were eligible for the scheme if aged 18 years or older with confirmed primary carcinoma (excluding haematological malignancies), one to three extracranial metastatic lesions, a disease-free interval from primary tumour development to metastases of longer than 6 months (with the exception of synchronous colorectal liver metastases), a WHO performance status of 2 or lower, and a life expectancy of at least 6 months. The primary outcome was overall survival at 1 year and 2 years from the start of SABR treatment. The study is now completed. Between June 15, 2015, and Jan 30, 2019, 1422 patients were recruited from 17 hospitals in England. The median age of the patients was 69 years (IQR 62-76), and the most common primary tumour was prostate cancer (406 [28·6%] patients). Median follow-up was 13 months (IQR 6-23). Overall survival was 92·3% (95% CI 90·5-93·9) at 1 year and 79·2% (76·0-82·1) at 2 years. The most common grade 3 adverse event was fatigue (28 [2·0%] of 1422 patients) and the most common serious (grade 4) event was increased liver enzymes (nine [0·6%]). Notreatment-related deaths were reported. In patients with extracranial oligometastatic cancer, use of SABR was associated with high overall survival and low toxicity. 'The study findings complement existing evidence from a randomised, phase 2 trial, and represent high-level, real-world evidence supporting the use of SABR in this patient cohort, with a phase 3 randomised, controlled trial to confirm these findings underway. Based on the selection criteria in this study, SABR was commissioned by NHS England in March, 2020, as a treatment option for patients with oligometastatic disease. NHS England Commissioning through Evaluation scheme.


Ingestion of gelatinized potato starch containing a high level of phosphorus decreases serum and liver lipids in rats.
Potato starch is known to have a higher concentration of phosphate than other starches. The presence of phosphate groups in amylopectin results in resistance to digestion by amylase. Therefore, there is a possibility that potato starch is slowly digested, inducing a physiological effect similar to that of resistant starch and indigestible oligosaccharides. The amount of phosphate group in starch differs with potato cultivar. In the present study, we investigated the effects of gelatinized potato starch containing a high level of phosphorus on lipid metabolism in rats. For this purpose, we determined lipid levels in the serum and liver in rats fed two kinds of gelatinized potato starches with different phosphorus contents. Four groups of male Sprague-Dawley rats were fed a 60% sucrose diet (control) or one of three diets containing cornstarch (CS), Benimaru (BM) potato starch or Hokkaikogane (HK) potato starch. Fat pad weight was slightly decreased in the HK diet group compared with that in the other groups. Free fatty acids in serum were significantly lowered by dietary HK starch compared with control, and serum triglyceride in rats fed the HK diet was also decreased. In the BM and HK diet groups, triglyceride levels in the liver were decreased compared with that in the control and CS groups. As for hepatic total cholesterol level, there were no significant differences among three starch diet groups. Fecal bile acid excretion was greater in the two potato starch groups than in the control group. On the other hand, there were no significant differences in cecal short-chain fatty acid content or pH. Thus, we conclude that dietary gelatinized potato starch reduces free fatty acid and triglyceride in serum and hepatic triglyceride, but does not affect cecal fermentation.


[A bronchogenic cervical cyst. A case report].
The bronchogenic cyst is a tracheobronchial tree congenital malformation, normally intrathoracic. Usually presenting as an acute respiratory insufficiency (especially during infancy) or as recurrent respiratory infections or may be an accidental finding in asymptomatic patients. We present a rare case of cervical localization which began as an acute respiratory distress following a tonsilar infection.


Crash severity along rural mountainous highways in Malaysia: An application of a combined decision tree and logistic regression model.
Traffic crashes along mountainous highways may lead to injuries and fatalities more often than along highways on plain topography; however, research focusing on the injury outcome of such crashes is relatively scant. The objective of this study was to investigate the factors affecting the likelihood that traffic crashes along rural mountainous highways result in injuries. This study proposes a combination of decision tree and logistic regression techniques to model crash severity (injury vs. noninjury), because the combined approach allows the specification of nonlinearities and interactions in addition to main effects. Both a scobit model and a random parameters logit model, respectively accounting for an imbalance response variable and unobserved heterogeneities, are tested and compared. The study data set contains a total of 5 years of crash data (2008-2012) on selected mountainous highways in Malaysia. To enrich the data quality, an extensive field survey was conducted to collect detailed information on horizontal alignment, longitudinal grades, cross-section elements, and roadside features. In addition, weather condition data from the meteorology department were merged using the time stamp and proximity measures in AutoCAD-Geolocation. The random parameters logit model is found to outperform both the standard logit and scobit models, suggesting the importance of accounting for unobserved heterogeneity in crash severity models. Results suggest that proportion of segment lengths with simple curves, presence of horizontal curves along steep gradients, highway segments with unsealed shoulders, and highway segments with cliffs along both sides are positively associated with injury-producing crashes along rural mountainous highways. Interestingly, crashes during rainy conditions are associated with crashes that are less likely to involve injury. It is also found that the likelihood of injury-producing crashes decreases for rear-end collisions but increases for head-on collisions and crashes involving heavy vehicles. A higher order interaction suggests that single-vehicle crashes involving light and medium-sized vehicles are less severe along straight sections compared to road sections with horizontal curves. One the other hand, crash severity is higher when heavy vehicles are involved in crashes as single vehicles traveling along straight segments of rural mountainous highways. In addition to unobserved heterogeneity, it is important to account for higher order interactions to have a better understanding of factors that influence crash severity. A proper understanding of these factors will help develop targeted countermeasures to improve road safety along rural mountainous highways.


Validated risk score predicts the development of congestive heart failure after presentation with unstable angina or non-ST-elevation myocardial infarction: results from OPUS-TIMI 16 and TACTICS-TIMI 18.
Few data are available about development of congestive heart failure (CHF) in patients with unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI). We developed and validated a risk score to predict which patients will develop CHF. A subset of 4681 patients from the Orbofiban in Patients With Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction (OPUS-TIMI 16) trial with UA/NSTEMI and without a history of CHF were included in this analysis and stratified according to the development of CHF at 10 months. A risk score was created from significant variables and validated in the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI 18) trial. B-type natriuretic peptide (BNP) was then added to the initial multivariate analysis and validated in the TACTICS-TIMI 18 trial. The incidence of CHF at 30 days was 4.9%, and at 10 months it was 5.6%. Significant variables on multivariate analysis included age >65 years, heart rate >100 beats/min, history of diabetes mellitus, lateral electrocardiographic changes, and history of angiographically confirmed coronary artery disease. The risk of CHF increased 10-fold across the number of risk factors (P <.001). When validated in the TACTICS-TIMI 18 trial, the risk score was significantly associated with CHF at 6 months (P =.01). The median BNP value doubled across the number of risk factors (P <.001 for trend). The addition of BNP to the risk score improved its discriminatory capacity. In patients with UA/NSTEMI, a simple clinical risk score can aid in assessing the risk of developing CHF. BNP adds to the predictive capacity of this risk score. This score may assist in identifying patients who warrant more careful monitoring and therapy for CHF prevention inhospital and during follow-up.


Acute recurrent pancreatitis: a possible clinical manifestation of ampullary cancer.
Acute recurrent pancreatitis still poses diagnostic difficulties. The coexistence or moreover the causative relationship of carcinoma of the ampulla of Vater and acute recurrent pancreatitis is fairly rare. We present a case of carcinoma of the ampulla of Vater that presented with acute recurrent necrotizing pancreatitis complicated with pseudocysts. A diagnosis of malignancy in the ampulla was only made after several ERCP attempts due to residual inflammation at the periampullary area. Malignancy at the ampulla of Vater causing recurrent episodes of pancreatitis represents a realistic risk and attempts to diagnose the underlying cause should always take into account the possibility of cancer.


Lessons from 8 years' experience of hypothalamic stimulation in cluster headache.
Neuroimaging studies in cluster headache (CH) patients have increased understanding of attack-associated events and provided clues to the pathophysiology of the condition. They have also suggested stimulation of the ipsilateral posterior inferior hypothalamus as a treatment for chronic intractable CH. After 8 years of experience, stimulation has proved successful in controlling the pain attacks in almost 60% of chronic CH patients implanted at various centres. Although hypothalamic implant is not without risks, it has generally been performed safely. Implantation affords an opportunity to perform microrecordings of individual posterior hypothalamic neurons. These studies are at an early stage, but suggest the possibility of identifying precisely the target site by its electrophysiological characteristics. Autonomic studies of patients undergoing posterior hypothalamic stimulation provide further evidence that long-term stimulation is safe, revealing that it can cause altered modulation of the mechanisms of orthostatic adaptation without affecting the baroreflex, cardiorespiratory interactions or efferent sympathetic and vagal functions. Chronically stimulated patients have an increased threshold for cold pain at the site of the first trigeminal branch ipsilateral to the stimulated side; when the stimulator is switched off, changes in sensory and pain thresholds do not occur immediately, suggesting that long-term stimulation is required to induce sensory and nociceptive changes. Posterior inferior hypothalamic stimulation is now established as a treatment for many chronic CH patients. The technique is shedding further light on the pathophysiology of the disease, and is also providing clues to functioning of the hypothalamus itself.


Testing the association between the incidence of schizophrenia and social capital in an urban area.
Social capital has been considered aetiologically important in schizophrenia but the empirical evidence to support this hypothesis is absent. We tested whether social capital, measured at the neighbourhood level, was associated with the incidence of schizophrenia (ICD-10 F20). MethodWe administered a cross-sectional questionnaire on social capital to 5% of the adult population in 33 neighbourhoods (wards) in South London (n=16 459). The questionnaire contained items relating to two social capital constructs: social cohesion and trust (SC&T) and social disorganization (SocD). Schizophrenia incidence rates, estimated using data from the Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP) study, provided the outcome. We used multi-level Poisson regression to test our hypothesis while controlling for individual- and neighbourhood-level characteristics. We identified 148 cases during 565 576 person-years at-risk. Twenty-six per cent of the variation in incidence rates was attributable to neighbourhood-level characteristics. Response from the social capital survey was 25.7%. The association between SC&T and schizophrenia was U-shaped. Compared with neighbourhoods with medial levels of SC&T, incidence rates were significantly higher in neighbourhoods with low [incidence rates ratio (IRR) 2.0, 95% confidence interval (CI) 1.2-3.3] and high (IRR 2.5, 95% CI 1.3-4.8) levels of SC&T, independent of age, sex, ethnicity, ethnic density, ethnic fragmentation and socio-economic deprivation. ConclusionNeighbourhood variation in SC&T was non-linearly associated with the incidence of schizophrenia within an urban area. Neighbourhoods with low SC&T may fail to mediate social stress whereas high SC&T neighbourhoods may have greater informal social control or may increase the risk of schizophrenia for residents excluded from accessing available social capital.


Median artery revisited.
This study confirms that the median artery may persist in adult life in 2 different patterns, palmar and antebrachial, based on their vascular territory. The palmar type, which represents the embryonic pattern, is large, long and reaches the palm. The antebrachial type,which represents a partial regression of the embryonic artery is slender, short, and terminates before reaching the wrist. These 2 arterial patterns appear with a different incidence. The palmar pattern was studied in the whole sample (120 cadavers) and had an incidence of 20%, being more frequent in females than in males (1.3:1), occurring unilaterally more often than bilaterally (4:1) and slightly more frequently on the right than on the left (1.1:1). The antebrachial pattern was studied in only 79 cadavers and had an incidence of 76%, being more frequent in females than in males (1.6:1); it was commoner unilaterally than bilaterally (1.5:1) and was again slightly more prevalent on the right than on the left (1.2:1). The origin of the median artery was variable in both patterns. The palmar type most frequently arose from the caudal angle between the ulnar artery and its common interosseous trunk (59%). The antebrachial pattern most frequently originated from the anterior interosseous artery (55%). Other origins, for both patterns, were from the ulnar artery or from the common interosseous trunk. The median artery in the antebrachial pattern terminated in the upper third (74%) or in the distal third of the forearm (26%). However, the palmar pattern ended as the 1st, 2nd or 1st and 2nd common digital arteries (65%) or joined the superficial palmar arch (35%). The median artery passed either anterior (67%) or posterior (25%) to the anterior interosseous nerve. It pierced the median nerve in the upper third of the forearm in 41% of cases with the palmar pattern and in none of the antebrachial cases. In 1 case the artery pierced both the anterior interosseous and median nerves.


[Epidemiology and prevention of anaphylactoid reactions in heart surgery patients].
A retrospective analysis of the incidence, severity, and causes of anaphylactoid reactions (AR) in 1504 cardiosurgical patients operated on at Research Center of Surgery in 1995-1999 showed that AR occurred in 109 (7.4%) patients: 60% during aortocoronary bypass operations, 27.2% during correction of acquired heart diseases, and 12.8% during correction of congenital heart diseases. Skin symptoms predominated in the structure of AR (59.7%); cardiovascular episodes ranked second (38.5%), and the incidence of pulmonary reactions was lowest (1.8%). The causes of AR during anesthesia and surgery were platelet-rich plasma and fresh-frozen plasma (35.3%), antibiotics (12.1%), protamine (12.1%), myorelaxants (9.9%), colloid plasma substitutes (8.8%), dioxidine (3.3%), heparin (2.2%), aprotinin (1.1%), diazepam (2.2%), and other agents (7.6%). A history of AR and repeated interventions are risk factors of AR. The protocol of AR prevention in cardiosurgical patients includes determination of risk factors, selection of the least hazardous agents, strict adherence to the rate of infusion of histamine-releasing drugs, minimum utilization of donor blood components (platelets and plasma), use of H1 and H2 blockers, corticosteroids (celestone) during premedication and operation. Such treatment helped decrease the severity and incidence of AR in cardiosurgical patients to 4.7%.


Prophylactic PPI help reduce marginal ulcers after gastric bypass surgery: a systematic review and meta-analysis of cohort studies.
Marginal ulceration after gastric bypass surgery is a recognized complication and has been reported in 1-16% of patients. There is evidence that acidity may play a role in the disease pathophysiology and it is a common practice for bariatric surgeons to begin a prophylactic course of proton pump inhibitors (PPI), postoperatively. MEDLINE, EMBASE, CINAHL, and the Cochrane Controlled Trials Register were searched using the most comprehensive timeline for each database up to January 2012. Studies that included patients undergoing gastric bypass who received a prophylactic course of PPI postoperatively were eligible. Two reviewers independently selected trials and extracted data. The primary outcome was the incidence of marginal ulcers diagnosed on the basis of endoscopic findings. Inverse variance random effects models were used to estimate odds ratio (OR) and weighted proportion of ulcers. Odds ratio and weighted pooled proportion with corresponding 95% confidence intervals (CI) are reported. The strategic search identified 167 citations. A total of seven studies involving 2,917 participants were eligible for inclusion and 2,114 were used for analysis. The weighted pooled proportion of ulcer formation in PPI groups including all seven studies (four single group cohort studies and PPI arm of three cohort studies) was 5.0% [95% CI 2-10%] (N = 1,407). The OR of marginal ulcer formation comparing PPI to no PPI for three comparative cohort studies was 0.50 [95% CI 0.28-0.90, p = 0.02] (N = 1,022) with low heterogeneity (I(2) = 12%) showing that the PPI group significantly experienced twice less ulceration with PPI treatment compared to no PPI treatment. This finding suggests a significant incremental benefit of prophylactic PPI in reducing marginal ulcer after gastric bypass surgery. Prospective randomized trials are needed to further define the role of PPI following gastric bypass surgery.


Bovine taste bud cyclic adenosine 3', 5' monophosphate phosphodiesterase is inhibited by divalent metal ions.
Two fractions from bovine taste buds, the soluble S4 fraction and the membrane P4B fraction, were used to evaluate the effects of divalent metal ions on cyclic adenosine 3', 5' monophosphate (cAMP) phosphodiesterase (PDE) activity. Zn++, Ni++, Cu++, Fe++, Sn++ and Hg++, in the presence of 5mM Mg++, inhibited cAMP PDE activity whereas these divalent metal ions alone did not affect enzyme activity if Mg++ were absent. Zn++ inhibited cAMP PDE activity in S4 and P4B taste bud fractions with Ki values of 100 microM and 90 microM, respectively; this inhibition was noncompetitive with substrate activity but competitive with Mg++. In the presence of Mg++, Zn++ inhibited taste bud cAMP PDE more effectively than any other metal ion studied. Inhibition of taste bud cAMP PDE by divalent metal ions, particularly Zn++, suggests a role for these substances in the taste process through regulation of intracellular concentration of taste bud cAMP.


Nutritional and metabolic assessment of critically ill children.
In a prospective study, with the objective of determining the metabolic profile, response to nutrient supply, and role of nutritional and metabolic assessment parameters in children admitted to a pediatric ICU, 11 patients in the age group 2-12 were studied. The assessment was carried out during the first 72 hours of admission, and again seven days later, and included the following parameters; caloric supply; nitrogen supply; prealbumin serum level; urinary urea nitrogen; nitrogen balance and creatinine-height index. The evolution of the parameters in the two stages of the study showed the following results: The urinary urea nitrogen median value at admission was 7.5 g/m2 of corporeal surface, and did not present significant changes seven days later. There was a significant increase in caloric supply from 42.9 to 70.3 kcal/kg, and in nitrogen supply, from 4.7 to 10.2 g/m2 of corporeal surface p 0.01. The level of nitrogen balance rose from -5.6 to 2.5 g/24 h (p < 0.03), and that of prealbumin, from 16.7 to 26.3 mg/dl (p < 0.03). There was a significant reduction in the creatinine-height index, from 86.2 percent to 55.0 percent p 0.01. The magnitude of urinary urea nitrogen excretion at admission varied 2.5-13.8 g/m2 of corporeal surface. Based on this parameter, it was not possible to establish a characteristic metabolic profile for the conditions studied. Notwithstanding an increase in the protein and caloric supply, prealbumin level and nitrogen balance observed in the second stage of the study, the patients lost muscle mass and entered into a malnutrition process, probably due to intense protein catabolism and the poor response to nutrition supply that occurs in metabolic stress.


Involvement of ALAD-20S Proteasome Complexes in Ubiquitination and Acetylation of Proteasomal α2 Subunits.
The ubiquitin-proteasome pathway has gained attention as a potential chemotherapeutic target, owing to its importance in the maintenance of protein homeostasis and the observation that cancer cells are more dependent on this pathway than normal cells. Additionally, inhibition of histone deacetylases (HDACs) by their inhibitors like Vorinostat (SAHA) has also proven a useful strategy in cancer therapy and the concomitant use of proteasome and HDAC inhibitors has been shown to be superior to either treatment alone. It has also been reported that delta-aminolevulinic acid dehydratase (ALAD) is a proteasome-associated protein, and may function as an endogenous proteasome inhibitor. While the role of ALAD in the heme biosynthetic pathway is well characterized, little is known about its interaction with, and the mechanism by which it inhibits, the proteasome. In the present study, this ALAD-proteasome complex was further characterized in cultured prostate cancer cells and the effects of SAHA treatment on the regulation of ALAD were investigated. ALAD interacts with the 20S proteasomal core, but not the 19S regulatory cap. Some ubiquitinated species were detected in ALAD immunoprecipitates that have similar molecular weights to ubiquitinated proteasomal α2 subunits, suggesting preferred binding of ALAD to ubiquitinated α2. Additionally, SAHA treatment increases levels of ALAD protein and an acetylated protein with a molecular weight similar to the ubiquitinated α2 subunit. Thus, the results of this study suggest that ALAD may play a regulatory role in a previously unreported post-translational modification of proteasomal α subunits.


CRISPR/Cas9 Genome Editing vs. Over-Expression for Fluorescent Extracellular Vesicle-Labeling: A Quantitative Analysis.
Over-expression of fluorescently-labeled markers for extracellular vesicles is frequently used to visualize vesicle up-take and transport. EVs that are labeled by over-expression show considerable heterogeneity regarding the number of fluorophores on single particles, which could potentially bias tracking and up-take studies in favor of more strongly-labeled particles. To avoid the potential artefacts that are caused by over-expression, we developed a genome editing approach for the fluorescent labeling of the extracellular vesicle marker CD63 with green fluorescent protein using the CRISPR/Cas9 technology. Using single-molecule sensitive fluorescence microscopy, we quantitatively compared the degree of labeling of secreted small extracellular vesicles from conventional over-expression and the CRISPR/Cas9 approach with true single-particle measurements. With our analysis, we can demonstrate a larger fraction of single-GFP-labeled EVs in the EVs that were isolated from CRISPR/Cas9-modified cells (83%) compared to EVs that were isolated from GFP-CD63 over-expressing cells (36%). Despite only single-GFP-labeling, CRISPR-EVs can be detected and discriminated from auto-fluorescence after their up-take into cells. To demonstrate the flexibility of the CRISPR/Cas9 genome editing method, we fluorescently labeled EVs using the HaloTag® with lipid membrane permeable dye, JaneliaFluor® 646, which allowed us to perform 3D-localization microscopy of single EVs taken up by the cultured cells.


Subband coding systems incorporating quantizer models.
A new method for dealing with the effects of quantization in a subband system is proposed. It uses the "gain plus additive noise" linear model for the Lloyd-Max quantizer. Based on this, it is demonstrated how, by an appropriate choice of synthesis filters, one can cancel all signal-dependent errors at the output of the system. The only remaining error is random in nature and not correlated with the input signal. We therefore have a tradeoff between the error being only random or having signal-dependent components as well (since the error variances in both cases are comparable). As a result of having only a random error, it is possible to reduce this error using, for example, a noise removal technique. The result is then extended to the case where the input is a multidimensional signal, and arbitrary sampling lattices are used, as well as to the QMF (alias cancellation) case. To demonstrate the validity of the proposed approach, two types of experiments on images are carried out: In a toy example, it is shown that using noise removal could be beneficial. For a more realistic coding scheme, however, it is demonstrated that even in the case when the model is no longer valid (when some of the subbands are discarded), the output error is still much less correlated with the input signal as opposed to the commonly used subband system, while visually, the reconstructed images look very similar.


XFKH2, a Xenopus HNF-3 alpha homologue, exhibits both activin-inducible and autonomous phases of expression in early embryos.
We have isolated the Xenopus fork head (fkh) box-containing gene XFKH2. XFKH2 appears to be most similar to the rat liver transcription factor HNF-3 alpha, with 64% amino acid identity throughout the protein and 96% amino acid identity within the fkh box. Dissection experiments demonstrate that XFKH2 is present in the vegetal pole and marginal zone but not the animal pole of gastrulae and in equal levels in the dorsal and ventral halves of both gastrulae and neurulae. By in situ hybridization, we know that the dorsal component of expression is concentrated in the notochord in neurulae. In tailbud embryos, XFKH2 is detected in the foregut, the brain, and in two lines of cells just dorsal and ventral to the notochord, the hypochord and the floor plate of the spinal cord. Finally, although explanted animal caps will turn on XFKH2 autonomously at midneurula stage, activin induces early expression at gastrula stage. The early, growth factor-dependent expression does occur in the presence of the protein synthesis inhibitor cycloheximide, suggesting that XFKH2 expression during gastrula stage may be an immediate early response to mesoderm induction.


Music therapy versus treatment as usual for refugees diagnosed with posttraumatic stress disorder (PTSD): study protocol for a randomized controlled trial.
Meta-analyses of studies on psychological treatment of refugees describe highly varying outcomes, and research on multi-facetted and personalized treatment of refugees with post-traumatic stress disorder (PTSD) is needed. Music therapy has been found to affect arousal regulation and emotional processing, and a pilot study on the music therapy method Trauma-focused Music and Imagery (TMI) with traumatized refugees resulted in significant changes of trauma symptoms, well-being and sleep quality. The aim of the trial is to test the efficacy of TMI compared to verbal psychotherapy. A randomized controlled study with a non-inferiority design is carried out in three locations of a regional outpatient psychiatric clinic for refugees. Seventy Arabic-, English- or Danish-speaking adult refugees (aged 18-67 years) diagnosed with PTSD are randomized to 16 sessions of either music therapy or verbal therapy (standard treatment). All participants are offered medical treatment, psychoeducation by nurses, physiotherapy or body therapy and social counseling as needed. Outcome measures are performed at baseline, post therapy and at 6 months' follow-up. A blind assessor measures outcomes post treatment and at follow-up. Questionnaires measuring trauma symptoms (HTQ), quality of life (WHO-5), dissociative symptoms (SDQ-20, DSS-20) and adult attachment (RAAS) are applied, as well as physiological measures (salivary oxytocin, beta-endorphin and substance P) and participant evaluation of each session. The effect of music therapy can be explained by theories on affect regulation and social engagement, and the impact of music on brain regions affected by PTSD. The study will shed light on the role of therapy for the attainment of a safe attachment style, which recently has been shown to be impaired in traumatized refugees. The inclusion of music and imagery in the treatment of traumatized refugees hopefully will inform the choice of treatment method and expand the possibilities for improving refugee health and integration. ClinicalTrials.gov ID number NCT03574228, registered retrospectively on 28 June 2016.


Role of Anti-Cancer Peptides as Immunomodulatory Agents: Potential and Design Strategy.
The usage of peptide-based drugs to combat cancer is gaining significance in the pharmaceutical industry. The collateral damage caused to normal cells due to the use of chemotherapy, radiotherapy, etc. has given an impetus to the search for alternative methods of cancer treatment. For a long time, antimicrobial peptides (AMPs) have been shown to display anticancer activity. However, the immunomodulatory activity of anti-cancer peptides has not been researched very extensively. The interconnection of cancer and immune responses is well-known. Hence, a search and design of molecules that can show anti-cancer and immunomodulatory activity can be lead molecules in this field. A large number of anti-cancer peptides show good immunomodulatory activity by inhibiting the pro-inflammatory responses that assist cancer progression. Here, we thoroughly review both the naturally occurring and synthetic anti-cancer peptides that are reported to possess both anti-cancer and immunomodulatory activity. We also assess the structural and biophysical parameters that can be utilized to improve the activity. Both activities are mostly reported by different groups, however, we discuss them together to highlight their interconnection, which can be used in the future to design peptide drugs in the field of cancer therapeutics.


Effects of a home-based walking intervention on mobility and quality of life in people with diabetes and peripheral arterial disease: a randomized controlled trial.
Determine the efficacy of a home-based walking intervention to improve walking ability and quality of life in people with diabetes and peripheral arterial disease (PAD). We conducted a randomized, controlled, single-blind trial within university-affiliated clinics in our local community. We randomized 145 participants (45 women) with diabetes and PAD to our intervention--a 6-month behavioral intervention targeting levels of readiness to engage in routine walking for exercise--versus attention control. Our primary outcome was 6-month change in maximal treadmill walking distance. Secondary outcomes included 3-month change in maximal walking distance, lower limb function (i.e., walking impairment scores), quality of life (Medical Outcomes Short Form Survey), exercise behaviors, depressive symptoms, and self-efficacy at 3 and 6 months. The mean age of participants was 66.5 (SD 10.1) years. Intervention and control groups did not differ significantly in 6-month change in maximal treadmill walking distance (average [SE] 24.5 [19.6] meters vs. 39.2 [19.6] meters; P = 0.60). Among secondary outcomes, for the intervention and control groups, respectively, average walking speed scores increased by 5.7 [2.2] units and decreased by 1.9 [2.8] units (P = 0.03); the mental health quality of life subscale score increased by 3.2 [1.5] and decreased by 2.4 [1.5] units (P = 0.01). A home-based walking intervention did not improve walking distance but did improve walking speed and quality of life in people with diabetes and PAD. Clinicians should consider recommending home-based walking therapy for such patients.


Severe Acute Malnutrition: The Potential of Non-Peanut, Non-Milk Ready-to-Use Therapeutic Foods.
This review provides information on the prospect and effectiveness of ready-to-use therapeutic foods (RUTFs) produced locally without the addition of milk and peanut. The foods used in fighting malnutrition in the past decades contributed little to the success of the alleviation program due to their non-effectiveness. Hence, RUTFs are introduced to fight malnutrition. The peanut allergies, the high cost of milk, and the high production cost of peanut RUTF have made its distribution, treatment spread, and accessibility very slow, especially in areas where it is highly needed. There is a need, therefore, for a low-cost RUTF that is acceptable and effective in treating severe acute malnutrition among under-5 children. This review shows both the success and failure of reported studies on the use of non-peanut and non-milk RUTF, including their cost of production as compared to the standard milk and peanut-based RUTF. It was hypothesised that replacing the milk ingredient component with legumes like soybeans can reduce the cost of production of RUTFs while also delivering an effective product in managing and treating severe acute malnutrition (SAM). Consumers generally accept them better because of their familiarity with the raw materials.


An open-pore MFI zeolite nanosheet-modified separator with Li-ion flux regulation for lithium-metal batteries.
Separator modification has become one of the most facile and promising methods to inhibit Li dendrite formation. Herein, an open-pore MFI zeolite nanosheet-modified polyacrylonitrile (open-pore MFI NSs@PAN) separator was prepared via the combination of vacuum filtration and the electrospinning technique. The straight channels in the MFI NSs, the fluid channels formed by the stacking of the MFI NSs and the interconnected network channels formed by the interweaving of the PAN nanofibers jointly constructed a micro/nano pore structure, which provides sufficient Li+ transport channels and enables uniform Li+ flux. Consequently, the open-pore MFI NSs@PAN separator-based cell delivers a stable and uniform Li deposition, demonstrating a more stable cycle-life and better rate capability. Redistributing Li+ flux through straight channel zeolite nanosheets provides a powerful method for suppressing Li dendrites, presenting enormous potential for promoting the commercial application of lithium metal batteries.


Development of an electronic instruction system to promote multidisciplinary teams.
While the provision of medical care incorporating safety measures, etc. that can earn the trust of the people, patients in particular, is required, the content of instruction is diverse, complex and rapidly increasing in volume along with the sophistication and specialization of medical care. However, until now, the development of electronic instruction systems has lagged behind in the development of HIS. All instructions must be linked to orders and the input of the implementation of instructions in the electronic instruction system incorporated into medical accounting. The system must aim at integrating physician and nursing records and be of a specification that can ensure reliability and efficiency. We report on the efforts at Kagoshima University Hospital to systematize instruction in order to promote multidisciplinary teams.


Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system.
In an attempt to identify prognostic factors for survival and leukemic transformation, 235 untreated patients with primary myelodysplastic syndromes (MDS) were analyzed in a single center retrospective study. To the well known FAB classification of MDS a supplementary group of patients with pure sideroblastic anemia (PSA) was added, characterized by the absence of dysplastic features of non-erythroid cells. Accordingly, the morphological subtypes were refractory anemia (RA), n = 55; PSA, n = 40; RA with ring sideroblasts (RARS), n = 33; RA with excess of blasts (RAEB), n = 53; RAEB in transformation (RAEB/T) n = 29; and chronic myelomonocytic leukemia (CMML), n = 25. Having screened 28 clinical, cytological, and laboratory parameters by univariate analysis, multiple regression analysis identified six variables with independent prognostic value: percentage of bone marrow blasts, serum LDH activity, PSA, hemoglobin concentration, age, and platelet count. If patients with PSA were excluded, the FAB classification no longer contributed independent prognostic information. Based on the results of this multivariate analysis, a simple scoring system was devised for predicting the survival of patients with MDS. A score of unity was allocated to each of the following parameters: bone marrow blasts greater than or equal to 5%, LDH greater than 200 U/I, hemoglobin less than or equal to 9 g/dl, and platelets less than or equal to 100 x 10(9)/I. As a function of their total score, patients were divided into three risk groups (group A, score 0; group B, score 1-2; group C, score 3-4), which differed significantly in both survival and rates of leukemic transformation. The cumulative survival 2 years after diagnosis was 91% in group A, 52% in group B, and 9% in group C (p less than 0.00005). The actuarial risk of transformation to acute myeloid leukemia at 2 years was 0, 19, and 54%, respectively (p less than 0.05). The inclusion of LDH enzyme levels qualified this scoring system for an accurate assessment of patients with CMML whose prognosis is viewed too favorably when rated by other scores. Furthermore, this score was able to identify those patients with RA and RARS who, without showing an excess of marrow blasts, have an unfavorable prognosis.


Evaluation of the accuracy of shoe fitting in older people using three-dimensional foot scanning.
Ill-fitting footwear is a common problem in older people. The objective of this study was to determine the accuracy of shoe fitting in older people by comparing the dimensions of allocated shoes to foot dimensions obtained with a three-dimensional (3D) scanner. The shoe sizes of 56 older people were determined with the Brannock device®, and weightbearing foot scans were obtained with the FotoScan 3D scanner (Precision 3D Ltd, Weston-super-mare, UK). Participants were provided with a pair of shoes (Dr Comfort®, Vista, CA, USA), available in three width fittings (medium, wide and extra wide). The dimensions (length, ball width and ball girth) of the allocated shoes were documented according to the last measurements provided by the manufacturer. Mean differences between last dimensions and foot dimensions obtained with the 3D scanner were calculated to provide an indication of shoe fitting accuracy. Participants were also asked to report their perception of shoe fit and comfort, using 100 mm visual analogue scales (VAS). Shoe size ranged from US size 7 to 14 for men and 5.5 to 11 for women. The allocated shoes were significantly longer than the foot (mean 23.6 mm, 95% confidence interval [CI] 22.1 to 25.2; t55 = 30.3, p < 0.001), however there were no significant differences in relation to ball width (mean 1.4 mm, 95% CI -0.1 to 2.9 mm; t55 = 1.9, p = 0.066) or ball girth (mean -0.7 mm, 95% CI -6.1 to 4.8 mm; t55 = -0.2, p = 0.810). Participants reported favourable perceptions of shoe fit (mean VAS = 90.7 mm, 95% CI 88.4 to 93.1 mm) and comfort (mean VAS = 88.4 mm, 95% CI 85.0 to 91.8 mm). Shoe size selection using the Brannock device® resulted in the allocation of shoes with last dimensions that were well matched to the dimensions of the foot. Participants also considered the shoes to be well fitted and comfortable. Older people with disabling foot pain can therefore be dispensed with appropriately-fitted shoes using this technique, provided that the style and materials used are suitable and extra width fittings are available.


Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.
Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism. To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism. Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002. Patients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0. Recurrent venous thromboembolism, bleeding, and mortality. Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], -1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, -1.0%; 95% CI, -2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, -1.1%; 95% CI, -2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients). Oral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.


Tyrosine 192 in apolipoprotein A-I is the major site of nitration and chlorination by myeloperoxidase, but only chlorination markedly impairs ABCA1-dependent cholesterol transport.
High density lipoprotein (HDL) isolated from human atherosclerotic lesions and the blood of patients with established coronary artery disease contains elevated levels of 3-nitrotyrosine and 3-chlorotyrosine. Myeloperoxidase (MPO) is the only known source of 3-chlorotyrosine in humans, indicating that MPO oxidizes HDL in vivo. In the current studies, we used tandem mass spectrometry to identify the major sites of tyrosine oxidation when lipid-free apolipoprotein A-I (apoA-I), the major protein of HDL, was exposed to MPO or peroxynitrite (ONOO(-)). Tyrosine 192 was the predominant site of both nitration and chlorination by MPO and was also the major site of nitration by ONOO(-). Electron paramagnetic spin resonance studies of spin-labeled apoA-I revealed that residue 192 was located in an unusually hydrophilic environment. Moreover, the environment of residue 192 became much more hydrophobic when apoA-I was incorporated into discoidal HDL, and Tyr(192) of HDL-associated apoA-I was a poor substrate for nitration by both myeloperoxidase and ONOO(-), suggesting that solvent accessibility accounted in part for the reactivity of Tyr(192). The ability of lipid-free apoA-I to facilitate ATP-binding cassette transporter A1 cholesterol transport was greatly reduced after chlorination by MPO. Loss of activity occurred in concert with chlorination of Tyr(192). Both ONOO(-) and MPO nitrated Tyr(192) in high yield, but unlike chlorination, nitration minimally affected the ability of apoA-I to promote cholesterol efflux from cells. Our results indicate that Tyr(192) is the predominant site of nitration and chlorination when MPO or ONOO(-) oxidizes lipid-free apoA-I but that only chlorination markedly reduces the cholesterol efflux activity of apoA-I. This impaired biological activity of chlorinated apoA-I suggests that MPO-mediated oxidation of HDL might contribute to the link between inflammation and cardiovascular disease.


Enhanced protein stability through minimally invasive, direct, covalent, and site-specific immobilization.
Bioconjugating protein to nonbiological surfaces is an essential component of many promising biotechnologies impacting diverse applications such as medical diagnostics, biocatalysis, biohazard detection, and proteomics. However, to enable the widespread economical use of immobilized-protein technologies, long-term stability, and reusability is essential. To enhance protein stability in harsh conditions, herein we report a minimally invasive and covalent bioconjugation that enables precise control of the immobilization location at potentially any surface-accessible location where the incorporated unnatural amino acid does not impact protein structure and function. Specifically, the PRECISE system is introduced where a uniquely reactive unnatural amino acid was incorporated site-specifically at a prespecified location in GFP using cell-free protein synthesis. The GFP was then directly and covalently attached to superparamagnetic beads by the unnatural amino acid in a single click reaction. The immobilized GFP was probed for retained activity and stability under harsh conditions including freeze-thaw cycling and incubation in urea at elevated temperatures. The immobilized GFP was more stable compared to unattached protein in all cases and for all durations observed. The enhanced stability of the immobilized protein is a promising step towards long-term protein stability for biocatalysis and other immobilized-protein applications.


"What took you so long?" The impact of PEPFAR on the expansion of HIV testing and counseling services in Africa.
HIV testing and counseling services in Africa began in the early 1990s, with limited availability and coverage. Fears of stigma and discrimination, complex laboratory systems, and lack of available care and treatment services hampered expansion. Use of rapid point-of-care tests, introduction of services to prevent mother-to-child transmission, and increasing provision of antiretroviral drugs were key events in the late 1990s and early 2000s that facilitated the expansion of HIV testing and counseling services. Innovations in service delivery included providing HIV testing in both clinical and community sites, including mobile and home testing. Promotional campaigns were conducted in many countries, and evolutions in policies and guidance facilitated expansion and uptake. Support from President's Emergency Plan for AIDS Relief and national governments, other donors, and the Global Fund for AIDS, Tuberculosis, and Malaria contributed to significant increases in the numbers of persons tested in many countries. Quality of both testing and counseling, limited number of health care workers, uptake by couples, and effectiveness of linkages and referral systems remain challenges. Expansion of antiretroviral treatment, especially in light of the evidence that treatment contributes to prevention of transmission, will require greater yet strategic coverage of testing services, especially in clinical settings and in combination with other high-impact HIV prevention strategies. Continued support from President's Emergency Plan for AIDS Relief, governments, and other donors is required for the expansion of testing needed to achieve international targets for the scale-up of treatment and universal access to knowledge of HIV status.


[Modification of family expressed emotion after a psychosocial intervention: stability in time].
There is some controversy about whether expressed emotion (EE) tends to remain stable or fluctuates in time and there are very few studies on EE evolution and its subscales once a family intervention has been performed. Better knowledge about its behavior in time would have important theoretical and clinical implications. We have studied changes in EE and its subscales that are produced in a cohort of 37 relatives of schizophrenic patients to whom a familiar intervention orientated to reducing environmental stress was performed. Changes were analyzed according to three cross-sectional moments of evaluation: one moment previous to intervention, another one when it was finished and finally, one at five years of finishing it. In this work, the EE levels tend to vary in time. These changes are mainly produced in the period when the family intervention is carried out, at the expense of decreasing the levels of emotional overinvolvement. Between the end of therapy and the analysis carried out five years later, levels remain stable. The few changes that take place in this period, if any, are associated to variables of clinical severity and social adjustment. Family intervention appears as the determining factor for reducing EE levels, whereas productive clinical severity and the patient's social adjustment condition increases in their levels.


The Prevalence of Insomnia Subtypes in Relation to Demographic Characteristics, Anxiety, Depression, Alcohol Consumption and Use of Hypnotics.
The aim of the present study was to examine the prevalence of insomnia subtypes in relation to several demographic characteristics, as well as to investigate the prevalence of possible anxiety and depression, alcohol consumption and use of hypnotics within the different insomnia subtypes. The present study was based on an extensive web-based survey made publicly available in 2012. The data was downloaded in January 2019, after 113 887 people had responded to parts of, or the entire questionnaire. The 64 503 participants who met the criteria for chronic insomnia disorder according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) comprised the study population. The present study divided insomnia into seven subtypes based on type of sleep difficulty reported; sleep onset insomnia (SOL-insomnia), sleep maintenance insomnia (WASO-insomnia), early morning awakening insomnia (EMA-insomnia) and combinations of these. Data were analyzed with chi-square tests and logistic regression analyses adjusted for sex, age, level of education and marital status. More than 60% of the study population met the criteria of either SOL-insomnia or a mixed insomnia subtype consisting of SOL-, WASO- and EMA-insomnia (SOL + WASO + EMA-insomnia). The percentage distribution of insomnia subtypes within the demographic characteristics showed that participants with female sex, high age, low level of education and who were divorced, separated or a widow/widower had a higher prevalence of SOL + WASO + EMA-insomnia compared to their respective demographic counterparts. The prevalence of possible anxiety, possible depression and use of hypnotics were higher among participants with SOL + WASO + EMA-insomnia compared to the other insomnia subtypes. The combination of WASO- and EMA-insomnia (WASO + EMA-insomnia) was associated with the most frequent alcohol consumption. Our findings suggest that there are major differences between the insomnia subtypes, both regarding demographics, but also in terms of how the complaints may affect daily life. Participants with combinations of SOL, WASO and EMA were more likely than participants with the other subtypes to have possible anxiety and possible depression, high alcohol consumption and to use hypnotics.


Biochemical functionality of magnetic particles as nanosensors: how far away are we to implement them into clinical practice?
Magnetic nanosensors have become attractive instruments for the diagnosis and treatment of different diseases. They represent an efficient carrier system in drug delivery or in transporting contrast agents. For such purposes, magnetic nanosensors are used in vivo (intracorporeal application). To remove specific compounds from blood, magnetic nanosensors act as elimination system, which represents an extracorporeal approach. This review discusses principles, advantages and risks on recent advances in the field of magnetic nanosensors. First, synthesis methods for magnetic nanosensors and possibilities for enhancement of biocompatibility with different coating materials are addressed. Then, attention is devoted to clinical applications, in which nanosensors are or may be used as carrier- and elimination systems in the near future. Finally, risk considerations and possible effects of nanomaterials are discussed when working towards clinical applications with magnetic nanosensors.


MAIT cells in immune-mediated tissue injury and repair.
Mucosal-associated invariant T (MAIT) cells are T cells that express a semi-invariant αβ T-cell receptor (TCR), recognizing non-peptide antigens, such as microbial-derived vitamin B2 metabolites, presented by the nonpolymorphic MHC class I related-1 molecule. Like NKT cells and γδT cells, MAIT cells belong to the group of innate-like T cells that combine properties of the innate and adaptive immune systems. They account for up to 10% of the blood T-cell population in humans and are particularly abundant at mucosal sites. Beyond the emerging role of MAIT cells in antibacterial and antiviral defenses, increasing evidence suggests additional functions in noninfectious settings, including immune-mediated inflammatory diseases and tissue repair. Here, we discuss recent advances in the understanding of MAIT cell functions in sterile tissue inflammation, with a particular focus on autoimmunity, chronic inflammatory diseases, and tissue repair.


Viewpoints on driving of individuals with and without autism spectrum disorder.
Understanding the viewpoints of drivers with autism spectrum disorder (ASD) is crucial in the development of mobility support and driver training that is responsive to their needs. Fifty young adults with ASD and fifty seven typically developed adults participated in the study to form a contrasting group. Q-methodology was used to understand viewpoints on driving as a main mode of transportation. Data were analysed using a PQ by-person varimax rotation factor analysis. Although some ASD participants perceived themselves as confident and independent drivers, others preferred other modes of transportation such as public transport and walking. Anxiety was also found to be a barrier to driving. The contrast group revealed consistent viewpoints on their driving ability. They preferred driving as their main mode of transportation and believed that they were competent, safe and independent drivers. These results are important in the planning of transport policies and driver training for individuals with ASD. Driver training manuals can be developed to address anxiety issues, hazard perception and navigation problems in the ASD population. Their use of public transport could be further facilitated through more inclusive transport policies.


On the virome's hidden diversity: lessons from RHDV.
Emerging infectious diseases are a major challenge to human and animal health. While predicting the emergence of pathogens is complex, the advent of high-throughput sequencing technologies has allowed the rapid identification of unknown microbiology diversity within organisms. Here, we discuss an example of a metatranscriptomics output to decipher viral evolution.


Rapid prenatal diagnosis of common numerical chromosomal abnormalities by high-resolution melting analysis of segmental duplications.
Rapid aneuploidy detection (RAD) methods constitute important complements to karyotyping in prenatal diagnosis. We evaluated the effectiveness of a method called high-resolution melting analysis of segmental duplications (SD-HRM) to serve as an alternative RAD method in prenatal diagnosis of common numerical chromosomal abnormalities (NCAs). We designed eight primary SD-HRM assays for the detection of chromosomes 13, 18, 21, X, and Y; 50 chorionic villus, 1105 amniotic fluid, and 395 cord blood samples were examined using these eight assays. For diagnosing samples that could not be diagnosed using primary assays, additional assays were designed for each target chromosome. The success rate of eight primary SD-HRM assays ranged from 99.7% to 100%. For the distinguishable analyses, these eight assays attained high diagnostic sensitivities (100%) and specificities (99.9-100%). We differentiated 53 cases of NCAs from 1550 clinical samples; subsequent reference tests revealed that these assays attained 100% clinical sensitivity and specificity. The mosaic ratio of a 45,X/46,XX sample was also precisely calculated. The SD-HRM method was able to effectively detect common NCAs in 1550 prenatal samples. We propose that SD-HRM could serve as an effective alternative option to the currently used prenatal RAD methods.


Neurological worsening during treatment of HIV-negative cryptococcal meningitis in a patient with Evans syndrome.
A 49-year-old woman with a rare autoimmune hematological disease, Evans syndrome, was admitted to the authors' hospital with immune reconstitution inflammatory syndrome-like reconstitution syndrome after effective antifungal therapy for cryptococcal meningitis. She initially improved after receiving corticosteroid treatment; after prednisone was tapered, her clinical presentation and brain imaging deteriorated but finally improved with the addition of thalidomide. Immune reconstitution inflammatory syndrome-like reconstitution syndrome is a rare complication in cryptococcal meningitis patients receiving immunosuppressive therapy. Thalidomide can be given in addition to corticosteroid therapy to effectively control the paradoxical inflammatory response and improve clinical outcomes.


Assessing the efficiency of RNA interference for maize functional genomics.
A large-scale functional genomics project was initiated to study the function of chromatin-related genes in maize (Zea mays). Transgenic lines containing short gene segments in inverted repeat orientation designed to reduce expression of target genes by RNA interference (RNAi) were isolated, propagated, and analyzed in a variety of assays. Analysis of the selectable marker expression over multiple generations revealed that most transgenes were transmitted faithfully, whereas some displayed reduced transmission or transgene silencing. A range of target-gene silencing efficiencies, from nondetectable silencing to nearly complete silencing, was revealed by semiquantitative reverse transcription-PCR analysis of transcript abundance for the target gene. In some cases, the RNAi construct was able to cause a reduction in the steady-state RNA levels of not only the target gene, but also another closely related gene. Correlation of silencing efficiency with expression level of the target gene and sequence features of the inverted repeat did not reveal any factors capable of predicting the silencing success of a particular RNAi-inducing construct. The frequencies of success of this large-scale project in maize, together with parameters for optimization at various steps, should serve as a useful framework for designing future RNAi-based functional genomics projects in crop plants.


An Epistasis Analysis of recA and recN in Escherichia coli K-12.
RecA is essential for double-strand-break repair (DSBR) and the SOS response in Escherichia coli K-12. RecN is an SOS protein and a member of the Structural Maintenance of Chromosomes family of proteins thought to play a role in sister chromatid cohesion/interactions during DSBR. Previous studies have shown that a plasmid-encoded recA4190 (Q300R) mutant had a phenotype similar to ∆recN (mitomycin C sensitive and UV resistant). It was hypothesized that RecN and RecA physically interact, and that recA4190 specifically eliminated this interaction. To test this model, an epistasis analysis between recA4190 and ∆recN was performed in wild-type and recBC sbcBC cells. To do this, recA4190 was first transferred to the chromosome. As single mutants, recA4190 and ∆recN were Rec+ as measured by transductional recombination, but were 3-fold and 10-fold decreased in their ability to do I-SceI-induced DSBR, respectively. In both cases, the double mutant had an additive phenotype relative to either single mutant. In the recBC sbcBC background, recA4190 and ∆recN cells were very UVS (sensitive), Rec-, had high basal levels of SOS expression and an altered distribution of RecA-GFP structures. In all cases, the double mutant had additive phenotypes. These data suggest that recA4190 (Q300R) and ∆recN remove functions in genetically distinct pathways important for DNA repair, and that RecA Q300 was not important for an interaction between RecN and RecA in vivorecA4190 (Q300R) revealed modest phenotypes in a wild-type background and dramatic phenotypes in a recBC sbcBC strain, reflecting greater stringency of RecA's role in that background.


Timing and irreversibility of Müllerian duct inhibition in the embryonic reproductive tract of the human male.
A study was undertaken to determine (1) the effects of endogenous Müllerian inhibiting substance (MIS) on the developing human fetal genital tract; (2) the time in fetal life when MIS is first capable of inhibiting the growth of the embryonic Müllerian ducts; and (3) the reversibility of the effects of MIS on the developing male Müllerian ducts. Human fetal reproductive tracts were transplanted and grown for sustained periods in vivo in athymic nude mice. The genital tracts from 12 male human fetuses, ages 51 to 68 days postovulation, were grafted without their associated gonads into castrated murine hosts and grown for 30 to 70 days. Controls consisted of genital tracts from 8 female human fetuses, ages day 53 to 70 that were grown under identical conditions. Male specimens grew to approximately one-half the size of female specimens and disclosed varying degrees of inhibition of the Müllerian duct system from absence of the Müllerian ducts in older specimens (after Day 63) to poorly segregated segments of stroma as the mildest defect (less than Day 61). It is concluded that (1) MIS secretion by the embryonic testes probably begins before Day 51 of gestation; (2) the effects of MIS are progressive during the so-called critical window; (3) the effects of MIS are permanent; and (4) the mesenchyme is an important target of MIS.


New Therapeutic Approaches for Conjunctival Melanoma-What We Know So Far and Where Therapy Is Potentially Heading: Focus on Lymphatic Vessels and Dendritic Cells.
Conjunctival melanoma (CM) accounts for 5% of all ocular melanomas and arises from malignantly transformed melanocytes in the conjunctival epithelium. Current therapies using surgical excision in combination with chemo- or cryotherapy still have high rates for recurrences and metastatic disease. Lately, novel signal transduction-targeted and immune checkpoint inhibitors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein-1 (PD-1) receptor inhibitors, BRAF- or MEK-inhibitors for systemic treatment of melanoma have improved the outcome even for unresectable cutaneous melanoma, improving patient survival dramatically. The use of these therapies is now also recommended for CM; however, the immunological background of CM is barely known, underlining the need for research to better understand the immunological basics when treating CM patients with immunomodulatory therapies. Immune checkpoint inhibitors activate tumor defense by interrupting inhibitory interactions between tumor cells and T lymphocytes at the so-called checkpoints. The tumor cells exploit these inhibitory targets on T-cells that are usually used by dendritic cells (DCs). DCs are antigen-presenting cells at the forefront of immune response induction. They contribute to immune tolerance and immune defense but in the case of tumor development, immune tolerance is often prevalent. Enhancing the immune response via DCs, interfering with the lymphatic pathways during immune cell migration and tumor development and specifically targeting tumor cells is a major therapeutic opportunity for many tumor entities including CM. This review summarizes the current knowledge on the function of lymphatic vessels in tumor growth and immune cell transport and continues to compare DC subsets in CM with related melanomas, such as cutaneous melanoma and mucosal melanoma.


Two High-Quality Cygnus Genome Assemblies Reveal Genomic Variations Associated with Plumage Color.
As an exemplary model for examining molecular mechanisms responsible for extreme phenotypic variations, plumage color has garnered significant interest. The Cygnus genus features two species, Cygnus olor and Cygnus atratus, that exhibit striking disparities in plumage color. However, the molecular foundation for this differentiation has remained elusive. Herein, we present two high-quality genomes for C. olor and C. atratus, procured using the Illumina and Nanopore technologies. The assembled genome of C. olor was 1.12 Gb in size with a contig N50 of 26.82 Mb, while its counterpart was 1.13 Gb in size with a contig N50 of 21.91 Mb. A comparative analysis unveiled three genes (TYR, SLC45A2, and SLC7A11) with structural variants in the melanogenic pathway. Notably, we also identified a novel gene, PWWP domain containing 2A (PWWP2A), that is related to plumage color, for the first time. Using targeted gene modification analysis, we demonstrated the potential genetic effect of the PWWP2A variant on pigment gene expression and melanin production. Finally, our findings offer insight into the intricate pattern of pigmentation and the role of polygenes in birds. Furthermore, these two high-quality genome references provide a comprehensive resource and perspective for comparative functional and genetic studies of evolution within the Cygnus genus.


Feed-back modulation of cone synapses by L-horizontal cells of turtle retina.
Light stimulation of the periphery of the receptive field of turtle cones can evoke both transient and sustained increases of the cone Ca2+ conductance, which may become regenerative. Such increase in the cone Ca2+ conductance evoked by peripheral illumination results from the activation of a polysynaptic pathway involving a feed-back connexion from the L-horizontal cells (L-HC) to the cones. Thus the hyperpolarization of a L-HC by inward current injection can evoke a Ca2+ conductance increase in neighbouring cones. The cone Ca2+ channels thus activated are likely located at its synaptic endings and probably intervene in the cone transmitter release. Therefore the feed-back connexion between L-HC and cones by modifying the Ca2+ conductance of cones could actually modulate the transmitter release from cone synapses. Such feed-back modulation of cone synapses plays a role in the organization of the colour-coded responses of the chromaticity type-horizontal cells and probably of other second order neurones, post-synaptic to the cones. The mechanisms operating the feed-back connexion from L-HC to cones are discussed.


The static and dynamic structural heterogeneities of B-DNA: extending Calladine-Dickerson rules.
We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence. We characterize the sequence-dependent choreography of backbone and base movements modulating the non-Gaussian or anharmonic effects manifested in the higher moments of the dynamics of the duplex when sampling the equilibrium distribution. Contrary to prior assumptions, such anharmonic deformations are not rare in DNA and can play a significant role in determining DNA conformation within complexes. Polymorphisms in helical geometries are particularly prevalent for certain tetranucleotide sequence contexts and are always coupled to a complex network of coordinated changes in the backbone. The analysis of our simulations, which contain instances of all tetranucleotide sequences, allow us to extend Calladine-Dickerson rules used for decades to interpret the average geometry of DNA, leading to a set of rules with quantitative predictive power that encompass nonlocal sequence-dependence and anharmonic fluctuations.


Antipsychotics prescription and cerebrovascular events in Italian older persons.
Meta-analyses have found conflicting evidence on the link between antipsychotics and cerebrovascular events (CVEs). The primary aim of this study was to evaluate the association between any antipsychotic prescription and CVEs in Italian elderly; second, to compare the effect of typical and atypical antipsychotics on CVEs; and third, to investigate the effect of antipsychotics on CVEs in the subgroup of persons coprescribed with acetylcholinesterase inhibitors (AChEIs). Administrative claims from community-dwelling people aged 65 to 94 years living in Northern Italy were analyzed using a retrospective case-control design, from 2003 to 2005. The primary outcome measure was a hospital discharge diagnosis of CVEs during 2005. Four age-, sex-, and local health unit-matched control subjects were identified for each case. Antihypertensive drugs, anticoagulants, platelet inhibitors, antidiabetic drugs, lipid-lowering drugs, and AChEI were used as covariates in conditional logistic regression models testing the odds ratio (OR) for CVEs due to antipsychotics use. Three thousand eight hundred fifty-five cases of CVEs were identified and matched with 15,420 control subjects. In multiadjusted models, the association of any antipsychotics, typical or atypical with CVEs, was not significant. When antipsychotics were categorized according to the number of boxes prescribed during the observational period, being prescribed with at least 19 boxes of typical antipsychotics was significantly associated with CVEs (OR, 2.4; 95% confidence interval, 1.08-5.5). An interaction was found between any antipsychotic and AChEI coprescription on CVEs (OR, 0.46; 95% confidence interval, 0.23-0.92). In conclusion, only typical antipsychotics were associated with an increased odd of CVEs, but the association was duration dependent. Persons prescribed simultaneously with AChEI and antipsychotics may be at a lower risk of CVEs.


Angle-tolerant linear variable color filter based on a tapered etalon.
We propose and fabricate a linear variable color filter (LVCF) that possesses an enhanced angular tolerance in conjunction with a wide linear filtering range (LFR) by taking advantage of an Ag-TiO2-Ag configuration. The TiO2 cavity is tapered in thickness along the device so that the resonance wavelength can be continuously tuned according to the position. In addition, the metal-dielectric-metal structure is overlaid with a pre-designed graded anti-reflection coating in SiO2 to complete the etalon, thereby maximizing the transmission efficiency across the entire device. The tapered dielectric layers in the proposed filter were fabricated via glancing angle deposition without the help of any mask or moving parts. The center wavelength was scanned from 410 nm to 566 nm, resulting in an LFR of 156 nm, and the overall spectra exhibited an approximate peak transmission of 40% and spectral bandwidth of 68 nm. The angular tolerance was as large as 45°, incurring a fractional wavelength shift below 4.2%. The resonance wavelength was verified to be linearly dependent on the position, providing a linearity beyond 99%. The proposed LVCF will thus be actively utilized in a portable micro-spectrometer and spectral scanning device.