Movement-related skin strain associated with goal-oriented lip actions.
It is generally accepted that sensory input contributes to the generation of natural movements. In most motor systems, muscle spindles, tendon organs, joint receptors, and cutaneous mechanoreceptors may provide proprioceptive information. However, the perioral area of the human face lacks muscle spindles, tendon organs, and joint receptors and is therefore a model system for the study of cutaneous afferent contributions to proprioception. This investigation examined a series of skin strains associated with lower-lip movements in human subjects to determine if such strains, which serve as stimuli for cutaneous mechanoreceptors, may underlie proprioception in the face. The results suggested that strains associated with lower-lip movements were of sufficient magnitude to elicit cutaneous mechanoreceptor discharge, as shown in recent human microneurographic studies. Further, the magnitude of multiple strains was predictive of lower-lip movement endpoints. These results highlight the potential importance of cutaneous mechanoreceptors as putative proprioceptors.


A randomized, double-blinded, placebo-controlled, crossover, add-on study of CoEnzyme Q10 in the prevention of pediatric and adolescent migraine.
To evaluate the efficacy of Coenzyme Q10 (CoQ10) supplementation in the prevention of migraine in children using a placebo-controlled, double-blinded, crossover, add-on trial. CoQ10 has been demonstrated to have efficacy in migraine prevention in adults but lacks pediatric research with more rigorous methodology. CoQ10 has been observed to be deficient in a significant number of children and adolescents presenting to tertiary headache centers. CoQ10 has the potential to modify both the inflammatory changes that occur during recurrent migraine and the alteration of mitochondrial function. A deficit of CoQ10 could thus affect the response to treatment and clinical characteristics of migraine in children and adults. One-hundred-and-twenty children and adolescents with migraine headache were randomized in a crossover, double-blind, placebo-controlled, randomized, add-on study to receive a placebo or CoQ10 (100 mg) supplement for 224 days. Data for 76 patients were available at the crossover point and 50 were analysed at the endpoint. Response to treatment, overall headache improvement, and headache disability were assessed. Both the placebo and CoQ10 groups showed reduced migraine frequency [F(1, 60)=15.68, p<0.001], severity [F(1, 54)=8.09, p=0.006], and duration [F(1, 45)=6.27, p=0.016] over time. CoQ10 treated patients had a significantly greater improvement in frequency from subject reported baseline starting within 4 weeks of initiation. No group differences comparing the first 4 weeks of treatment with the last 4 weeks of treatment were found in migraine frequency [F(1, 60)=2.34, p>0.05], severity [F(1, 54)=0.06, p>0.05], or duration [F(1, 45)=0.14, p>0.05]. Overall, results of the study demonstrate that children and adolescents with migraine improved over time with multidisciplinary, standardized treatment regardless of supplementation with CoQ10 or placebo. There was no difference in headache outcomes between the CoQ10 and placebo groups at day 224. Due to the improvements seen in weeks 1-4, CoQ10 may lead to earlier improvement in headache severity, but given the sample size this conclusion warrants further investigation with a larger sample.


Class I malocclusion with anterior crossbite and severe crowding.
This article reports the orthodontic diagnosis and treatment planning carried out with a 14-year and 5-month-old female patient with esthetic and functional complaints. She presented an Angle Class I malocclusion, anterior crossbite and severe crowding in both maxillary and mandibular arches, in addition to a lightly concave straight facial profile. Orthodontic treatment did not require extraction. Crossbite was corrected by protrusion of upper teeth, which contributed to alignment and leveling of teeth, in addition to improving the patient's facial profile. The case was presented to the Brazilian Board of Orthodontics and Dentofacial Orthopedics (BBO) as a requirement for the BBO certification.


Craniofacial disorders caused by mutations in homeobox genes MSX1 and MSX2.
The molecular biology of the homeobox genes MSX1 and MSX2 is reviewed. In a selective type of tooth agenesis, an MSX1 G --> C transversion results in a missense mutation Arg31Pro. The phenotype is due to haploinsufficiency. Boston-type craniosynostosis involves an MSX2 C --> A transversion, resulting in a missense mutation Pro7His. Three different mutations on MSX2 cause parietal foramina by haploinsufficiency. These mutations, which result in decreased parietal ossification, are in marked contrast to the gain-of-function mutation for Boston-type craniosynostosis, which results in increased sutural ossification.


[Roaming through methodology. V. The prevention paradox: few with a high risk versus many with a moderate risk].
With a good primary prevention programme a number of healthy individuals will never know that they had a narrow escape from disease and maybe even death. Large numbers of individuals participate in such a programme, while only a few of those would have fallen ill without it. Nevertheless such a population approach often will yield a larger health benefit (on a population level) than an intervention that only aims at the high risk group in the population. That has been called the prevention paradox. The choice between a population or a high risk approach has prompted lengthy debates in the Netherlands. Epidemiology offers a methodology to estimate the effects of different approaches. The health impact will be determined by the distribution of exposure in the population and the risk function of exposure. In the final decision on a prevention strategy other considerations such as cost-effectiveness of interventions, negative side effects, possibilities of identification of high risk groups and ethical issues can play a part.


Manufacturing Large-scale Materials with Structural Color.
Living organisms frequently use structural color for coloration as an alternative mechanism to chemical pigmentation. Recently there has been a growing interest to translate structural color into synthetic materials as a more durable and less hazardous alternative to conventional pigments. Efforts to fabricate structurally colored materials take place in different fronts, from 3D printing to spray-coating and roll-to-roll casting. Stability, performance, and quality of the color, the environmental impact of the materials or their manufacturing methods are some of the heavily researched topics we discuss. First, we highlight recent examples of large-scale manufacturing technologies to fabricate structurally colored objects. Second, we discuss the current challenges to be tackled to create perfect appearances which aim at the full color gamut while caring for environmental concerns. Finally, we discuss possible scenarios that could be followed in order to involve other manufacturing methods for creating structurally colored objects.


[The effect of long-term hyperbarism on pregnant guinea pigs and their progeny].
The effect of hyperbarism has been investigated on 1-3-, 4-5- and 8-10-week pregnant rats and their offsprings. It was found that the mortality rate of pregnant rats is two times higher after hyperbaric exposures than in control animals. The animals exhibit the highest sensitivity at a stage of 8-10 weeks. Hyperbaric conditions significantly affect offsprings. Only 53% of newborn puppies were found to be normal, whereas 35% were born dead and 12% revealed various abnormalities. The highest sensitivity was observed during organogenesis (4-5 weeks), the mortality rate during this period reached 70%. The body mass in newborn puppies was significantly lower than in control animals. The most significant retardation in the development was observed in animals which were subjected to the effect of hyperbarism at the 4-5-th week of intrauterine life.


Electrospinning of bovine serum albumin-based nano-fibers: From synthesis to medical prospects; Challenges and future directions.
Bovine serum albumin (BSA) is a globular non-glycoprotein that has gotten a lot of attention because of its unique properties like biocompatibility, biodegradability, non-immunogenicity, non-toxicity, and strong resemblance to the natural extracellular matrix (ECM). Given its robust mechanical properties, such as interfacial tension, conductivity, swelling resistance, and viscoelasticity, it can be concluded that it is an appropriate matrix for producing novel BSA-based nanoconstructs. Thus, simple analytic methods are required for accurately detecting BSA as a model protein in medical sciences and healthcare. Furthermore, the characteristics mentioned above aid BSA in the electrospinning process, which results in fibers conjugated with other polymers. Electrospun synthesis has recently received much attention for its ability to produce stable, biomimicking, highly porous, 3D BSA-derived nano-fibers. As a result, BSA-based nano-fibers have achieved exclusive developments in the medical sector, such as tissue engineering for the remodeling of damaged tissue or organ repair by creating artificial ones. Meanwhile, they could be used as drug delivery systems (DDS) for target-specific drug delivery, wound dressings, and so on. This study illustrates the structural and physicochemical properties of BSA and the determination of BSA using various methods, by citing recent reports and current developments in the medical field. Furthermore, current challenges and future directions are also highlighted.


[Exposure to chloroprene as an occupational hazard (a cohort epidemiologic study)].
A cancer epidemiological study was conducted in chloroprene workers in Yerevan. In a cohort of male workers, the total morbidity rates for all tumor patterns were significantly lower (32%) than expected, which was attributed to the effect of "the healthy worker". Risk for hepatic tumor was 3.83 times the expected level among male operators of the chloroprene production equipment. A direct "dose-effective" correlation was established between liver cancer risk and length of record for occupational exposure to chloroprene. The highest risk was among males who came into contact with the substance under the age of 30.


Nucleobase-modified nucleosides and nucleotides: Applications in biochemistry, synthetic biology, and drug discovery.
. DNA is often referred to as the "molecule of life" since it contains the genetic blueprint for all forms of life on this planet. The core building blocks composing DNA are deoxynucleotides. While the deoxyribose sugar and phosphate group are ubiquitous, it is the composition and spatial arrangement of the four natural nucleobases, adenine (A), cytosine (C), guanine (G), and thymine (T), that provide diversity in the coding information present in DNA. The ability of DNA to function as the genetic blueprint has historically been attributed to the formation of proper hydrogen bonding interactions made between complementary nucleobases. However, recent chemical and biochemical studies using nucleobase-modified nucleotides that contain "non-hydrogen bonding" functional groups have challenged many of the dogmatic views for the necessity of hydrogen-bonding interactions for DNA stability and function. Based on years of exciting research, this area has expanded tremendously and is thus too expansive to provide a comprehensive review on the topic. As such, this review article provides an opinion highlighting how nucleobase-modified nucleotides are being applied in diverse biomedical fields, focusing on three exciting areas of research. The first section addresses how these analogs are used as mechanistic probes for DNA polymerase activity and fidelity during replication. This section outlines the synthetic logic and medicinal chemistry approaches used to replace hydrogen-bonding functional groups to examine the contributions of shape/size, nucleobase hydrophobicity, and pi-electron interactions. The second section extends these mechanistic studies to provide insight into how nucleobase-modified nucleosides are used in synthetic biology. One example is through expansion of the genetic code in which changing the composition of DNA makes it possible to site-specifically incorporate unnatural amino acids bearing unique functional groups into enzymes and receptors. The final section describes results of pre-clinical studies using nucleobase-modified nucleosides as potential therapeutic agents against diseases such as cancer.


Relations between urban bird and plant communities and human well-being and connection to nature.
By 2050, 70% of the world's population will live in urban areas. In many cases urbanization reduces the richness and abundance of native species. Living in highly modified environments with fewer opportunities to interact directly with a diversity of native species may adversely affect residents' personal well-being and emotional connection to nature. We assessed the personal well-being, neighborhood well-being (a measure of a person's satisfaction with their neighborhood), and level of connection to nature of over 1000 residents in 36 residential neighborhoods in southeastern Australia. We modeled these response variables as a function of natural features of each neighborhood (e.g., species richness and abundance of birds, density of plants, and amount of vegetation cover) and demographic characteristics of surveyed residents. Vegetation cover had the strongest positive relations with personal well-being, whereas residents' level of connection to nature was weakly related to variation in species richness and abundance of birds and density of plants. Demographic characteristics such as age and level of activity explained the greatest proportion of variance in well-being and connection to nature. Nevertheless, when controlling for variation in demographic characteristics (examples were provided above), neighborhood well-being was positively related to a range of natural features, including species richness and abundance of birds, and vegetation cover. Demographic characteristics and how well-being was quantified strongly influenced our results, and we suggest demography and metrics of well-being must be considered when attempting to determine relations between the urban environment and human well-being.


The characteristic of patulous eustachian tube patients diagnosed by the JOS diagnostic criteria.
The objective is to describe characteristics of patients diagnosed with patulous Eustachian tube (PET) using the Diagnostic Criteria proposed by Japan Otological Society, and to evaluate the efficiency of objective tests to determine patent Eustachian tube. Retrospective. Tertiary referral center. A retrospective survey of medical records in Sen-En Rifu Hospital identified 78 ears of 56 patients with "Definite PET" diagnosed by the JOS Diagnostic Criteria between January 2017 and December 2017. Initial diagnosis, aural symptoms (voice autophony, aural fullness and breathing autophony), tubal obstruction procedures (posture change and pharyngeal orifice obstruction) and objective findings (tympanic membrane movement, Tubo-Tympano-Aerodynamic Graphy (TTAG) and sonotubometry) were evaluated. In addition, sonotubometry with postural change (Ohta's method), sitting CT and a newly devised PHI-10 score were also examined. Voice autophony, aural fullness, and breathing autophony were observed in 93.6%, 87.2%, 78.2%, respectively. In 91% of the ears, PET symptoms improved by postural change from sitting to the lying / forward-bending position. Synchronous movement of the TM upon respiration was observed in 69.1% of the ears. Positive findings of TTAG were observed in 75.6% of ears. Positive findings of sonotubometry were found in 55.1% of ears. Sonotubometry with postural change (Ohta's method), when the cut-off value of over 10dB was used, was positive in 45.2% of ears. Newly devised PHI-10 score representing severity of subjective symptoms classifying patients into no handicap, mild handicap, moderate handicap and severe handicap were observed in 12.2%, 10.8%, 18.9% and 58.1% of ears, respectively. The evaluation of the extent of patency of the ET by sitting CT indicated completely open, closed-short, and closed-long, in 68.6%, 11.4% and 21.4% of ears, respectively. Compared to the closed group, the completely open group had a significantly higher frequency of positive breathing autophony, positive sonotubometry, and positive Ohta's method. The characteristics of main symptoms and the efficiency of various tests in PET diagnosis were analyzed based on data obtained from "Definite PET" patients diagnosed by the JOS Diagnostic Criteria. The greater the availability of tests to evaluate PET, the greater the opportunities to diagnose "Definite PET". In particular, tests measuring pressure transmission between the nasopharynx and middle ear, such as TM observation and TTAG, are more sensitive than sonotubometry measuring sound transmission.


Expression of non-neuronal cholinergic system in maxilla of rat in vivo.
Acetylcholine (ACh) is known to be a key neurotransmitter in the central and peripheral nervous systems, which is also produced in a variety of non-neuronal tissues and cell. The existence of ACh in maxilla in vivo and potential regulation role for osteogenesis need further study. Components of the cholinergic system (ACh, esterase, choline acetyltransferase, high-affinity choline uptake, n- and mAChRs) were determined in maxilla of rat in vivo, by means of Real-Time PCR and immunohistochemistry. Results showed RNA for CarAT, carnitine/acylcarnitine translocase member 20 (Slc25a20), VAChT, OCTN2, OCT1, OCT3, organic cation transporter member 4 (Slc22a4), AChE, BChE, nAChR subunits α1, α2, α3, α5, α7, α10, β1, β2, β4, γ and mAChR subunits M1, M2, M3, M4, M5 were detected in rat's maxilla. RNA of VAChT, AChE, nAChR subunits α2, β1, β4 and mAChR subunits M4 had abundant expression (2(-ΔCt) > 0.03). Immunohistochemical staining was conducted for ACh, VAChT, nAChRα7 and AChE. ACh was expressed in mesenchymal cells, chondroblast, bone and cartilage matrix and bone marrow cells, The VAChT expression was very extensively while ACh receptor α7 was strongly expressed in newly formed bone matrix of endochondral and bone marrow ossification, AchE was found only in mesenchymal stem cells, cartilage and bone marrow cells. ACh might exert its effect on the endochondral and bone marrow ossification, and bone matrix mineralization in maxilla.


Magnetodielectric Effect in Crystals of the Noncentrosymmetric CaOFeS at Low Temperature.
Single crystals of the stoichiometric iron calcium oxysulfide CaOFeS have been grown by a solid-state reaction. Structural analysis of CaOFeS at room temperature by combining single-crystal X-ray diffraction data and transmission electron microscopy leads to a stoichiometric hexagonal noncentrosymmetric P63mc layered structure isostructural to CaOZnS. It is built from alternating layers made of FeOS3 tetrahedra sharing sulfur apexes and stacked with Ca(2+) planes. All Fe-O bonds are parallel to the stacking axis; this breaks the centrosymmetry, leading to a polar structure. The dielectric measurements reveal the existence of a magnetodielectric effect near 33 K in good agreement with the Neel temperature, as evidenced near 35 K by specific heat measurements reported by a different group.


Use of the Columbia-Suicide Severity Rating Scale (C-SSRS) in a large sample of Veterans receiving mental health services in the Veterans Health Administration.
To evaluate the associations of self-reports of suicidal ideation and behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS) in a survey of patients receiving mental health services in the Veterans Health Administration (VHA) with reports of attempts documented in medical records and administrative data. The C-SSRS was administered to 15,373 Veterans in the Veterans Outcome Assessment (VOA) survey. Concurrent validity was evaluated by comparing self-reports from the past 3 months with VHA records. Predictive validity was evaluated by logistic regression models using attempts over the subsequent 3 months as the outcome. Tests of concurrent validity found strong associations between self-reports and attempts documented in VHA records, but there were substantial numbers of discordant responses. In tests of predictive validity, area under the ROC curve for predicting future attempts was >0.8. There were differences in the distribution of responses and of psychometric properties across VHA mental health programs. Findings support the value of screening and the validity of the self-reports based on the C-SSRS, but limitations in concordance with medical records and variability across programs suggest the need for clinical judgment in interpreting responses.


Yersinia pestis, the cause of plague, is a recently emerged clone of Yersinia pseudotuberculosis.
Plague, one of the most devastating diseases of human history, is caused by Yersinia pestis. In this study, we analyzed the population genetic structure of Y. pestis and the two other pathogenic Yersinia species, Y. pseudotuberculosis and Y. enterocolitica. Fragments of five housekeeping genes and a gene involved in the synthesis of lipopolysaccharide were sequenced from 36 strains representing the global diversity of Y. pestis and from 12-13 strains from each of the other species. No sequence diversity was found in any Y. pestis gene, and these alleles were identical or nearly identical to alleles from Y. pseudotuberculosis. Thus, Y. pestis is a clone that evolved from Y. pseudotuberculosis 1,500-20,000 years ago, shortly before the first known pandemics of human plague. Three biovars (Antiqua, Medievalis, and Orientalis) have been distinguished by microbiologists within the Y. pestis clone. These biovars form distinct branches of a phylogenetic tree based on restriction fragment length polymorphisms of the locations of the IS100 insertion element. These data are consistent with previous inferences that Antiqua caused a plague pandemic in the sixth century, Medievalis caused the Black Death and subsequent epidemics during the second pandemic wave, and Orientalis caused the current plague pandemic.


A ticket for the live show: microtubules in male gametophyte development.
Microtubule-reporter plants expressing green fluorescent protein-α-TUBULIN fusion protein (GFP-TUA6) in male gametophytic cells of tobacco and Arabidopsis provide new tools for studying the native organization of microtubule (MT) arrays during reproductive development. These plants reveal unique features of gametophytic MT arrays including a basket-like cortical MT array in polarized microspores at interphase, an asymmetric spindle and curved phragmoplast MTs at microspore division and an assembly of bundled cortical MTs during germ cell morphogenesis. The application of these MT-reporter plants has been demonstrated by RNAi-mediated knockdown of the microtubule-associated protein TMBP200, the tobacco orthologue of the conserved MAP215/Dis1 family protein. The double transgenic lines display defects in nuclear positioning, division asymmetry and cytokinesis that are associated with striking defects in spindle and phragmoplast position and organization. This study reveals native and altered MT arrays in unprecedented detail and clarifies the essential functions of MAP215/Dis1 protein function in successive steps in male germline establishment. Such gametophytic MT-reporter lines should accelerate studies of the dynamic regulation of MT arrays by microtubule associated proteins and other effectors during male gametophyte development.


cAMP/protein kinase A activates cystic fibrosis transmembrane conductance regulator for ATP release from rat skeletal muscle during low pH or contractions.
We have shown that cystic fibrosis transmembrane conductance regulator (CFTR) is involved in ATP release from skeletal muscle at low pH. These experiments investigate the signal transduction mechanism linking pH depression to CFTR activation and ATP release, and evaluate whether CFTR is involved in ATP release from contracting muscle. Lactic acid treatment elevated interstitial ATP of buffer-perfused muscle and extracellular ATP of L6 myocytes: this ATP release was abolished by the non-specific CFTR inhibitor, glibenclamide, or the specific CFTR inhibitor, CFTR(inh)-172, suggesting that CFTR was involved, and by inhibition of lactic acid entry to cells, indicating that intracellular pH depression was required. Muscle contractions significantly elevated interstitial ATP, but CFTR(inh)-172 abolished the increase. The cAMP/PKA pathway was involved in the signal transduction pathway for CFTR-regulated ATP release from muscle: forskolin increased CFTR phosphorylation and stimulated ATP release from muscle or myocytes; lactic acid increased intracellular cAMP, pCREB and PKA activity, whereas IBMX enhanced ATP release from myocytes. Inhibition of PKA with KT5720 abolished lactic-acid- or contraction-induced ATP release from muscle. Inhibition of either the Na(+)/H(+)-exchanger (NHE) with amiloride or the Na(+)/Ca(2+)-exchanger (NCX) with SN6 or KB-R7943 abolished lactic-acid- or contraction-induced release of ATP from muscle, suggesting that these exchange proteins may be involved in the activation of CFTR. Our data suggest that CFTR-regulated release contributes to ATP release from contracting muscle in vivo, and that cAMP and PKA are involved in the activation of CFTR during muscle contractions or acidosis; NHE and NCX may be involved in the signal transduction pathway.


DogMATIC--A Remote Biospecimen Collection Kit for Biobanking.
Canine tumors are valuable comparative oncology models. This research was designed to create a sustainable biobank of canine mammary tumors for breast cancer research. The aim was to provide a well-characterized sample cohort for specimen sharing, data mining, and long-term research aims. Canine mammary tumors are most frequently managed at a local veterinary clinic or hospital. We adopted a biobank framework based on a large number of participating veterinary hospitals and clinics acting as collection centers that were serviced by a centralized storage facility. Recruitment was targeted at rural veterinary clinics. A tailored, stable collection kit (DogMATIC) was designed that was used by veterinarians in remote or rural locations to collect both fresh and fixed tissue for submission to the biobank. To validate this methodology the kit design, collection rate, and sample quality were analyzed. The Australian Veterinary Cancer Biobank was established as a network of 47 veterinary clinics and three veterinary pathology laboratories spanning over 200,000 km(2). In the first 12 months, 30 canine mammary tumor cases were submitted via the DogMATIC kit. Pure intact RNA was isolated in over 80% of samples with an average yield of 14.49 μg. A large network biobank, utilizing off-site collection with the DogMATIC kit, was successfully coordinated. The creation of the Australian Veterinary Cancer Biobank has established a long-term, sustainable, comparative oncology research resource in Australia. There are broader implications for biobanking with this very different form of collection and banking.


An assessment of diagnostic performance of a filter-based antibody-independent peripheral blood circulating tumour cell capture paired with cytomorphologic criteria for the diagnosis of cancer.
Circulating tumour cells (CTCs) are reported to be predictive for prognosis and response to treatment in advanced lung cancer. However, the clinical utility of the CTCs detection remains unknown for early stage lung cancer as the number of CTCs is reported as low, providing challenges in identification. We have evaluated diagnostic performance of filtration-based technology using cytomorphologic criteria in patients undergoing surgery for lung cancer. We processed blood from 76 patients undergoing surgery for known or suspected lung cancer using ScreenCell(®) Cyto filter devices. Captured cells were stained using haematoxylin and eosin and independently assessed by two pathologists for the presence of atypical cells suspicious for cancer. Diagnostic performance was evaluated against pathologist reported diagnoses of cancer from surgically obtained specimens. Cancer was diagnosed in 57 patients (77.0%), including 32 with primary lung cancer (56.1%). The proportion of patients with early stage primary lung cancer in which CTCs were identified was 18 and 21 (56.3% and 65.6%, respectively) as reported by two pathologists. The agreement between the pathologists was 77.0% corresponding to a kappa-statistic of 53.7% indicating moderate agreement. No significant differences were found for the percentage of CTCs for primary and metastatic cancer as well as for cancer stages. On sensitivity weighted analysis, a sensitivity and specificity were 71.9% (95% CI 60.5-83.0) and 52.9% (95% CI 31.1-77.0), respectively. On specificity weighted analysis, a sensitivity and specificity were 50.9% (95% CI 39.3-64.4) and 82.4% (60.4-96.2), respectively. The performance of the tested filter-based antibody-independent technology to capture CTCs using standard cytomorphologic criteria provides the potential of a diagnostic blood test for lung cancer.


Cost-effectiveness considerations in critical care.
The ICU, perhaps more than any other area in modern medicine, brings the conflicting issues of high cost and life-saving technology into stark relief. Cost-effectiveness analysis offers a quantitative method for selecting among treatments to optimize outcomes for any given financial outlay. Impediments to developing and using cost-effectiveness analysis to guide medical care decisions include the lack of accurate estimates or treatment effectiveness and reliable cost measures; variations in assumptions used in different cost-effectiveness analyses; and lack of an ethical or regulatory construct to ensure that the decisions will be carried out fairly. Recently, standards for performing cost-effectiveness analyses have been proposed which should enhance the quality and comparability of studies. A detailed understanding of the methods and limitations of economic analyses is essential to clinicians challenged by a growing number of articles and manufacturers' claims regarding the cost-effectiveness of critical care.


Normal infant brain anatomy: correlated real-time sonograms and brain specimens.
An investigation of the identifiable real-time sonographic features of the normal infant brain in the horizontal, coronal, inclined coronal, and midsagittal planes was undertaken. Correlations were made of sonograms of intact brains in vitro, corresponding brain sections, and sonograms in vivo. A large number of anatomic structures could be consistently depicted including cisterns, fissures, faix cerebri, tentorium cerebelli, ventricles, brainstem, cerebellum, basal ganglia, thalami, and corpus callosum. Pulsations of intracranial arteries, visible by real-time sonography, were of considerable help in identifying various structures. The investigation provides a reference of sonographic anatomy of the brain displayed in four clinically useful imaging planes.


HLA expression in hemopoietic development. Class I and II antigens are induced in the definitive erythroid lineage and differentially modulated by fetal liver cytokines.
We investigated the expression of HLA Ag on hemopoietic progenitors (burst-forming unit E, CFU-E, and CFU-granulocyte-macrophage) and precursors from human embryonic fetal liver (FL) and peripheral blood at 5 to 9 wk postconception. The expression on progenitors was evaluated by complement-mediated cytotoxicity followed by assay of residual progenitors in clonogenic culture; immunofluorescence and RIA were used for differentiated precursors. HLA Class I and II Ag are not expressed on the primitive erythroid lineage, i.e., on yolk sac-derived megaloblasts circulating in 5- to 6-wk peripheral blood. However, they are gradually induced on the definitive erythroid lineage in FL. Their expression on progenitors is first detected at 6 wk and shows a progressive increase through 9 wk, up to greater than or equal to 50% of adult values. A similar expression pattern is observed for FL erythroblasts. Incubation of 6-wk FL erythroid cells with IFN-alpha, -beta, or -gamma, or TNF-alpha induces a sharp rise of the expression of HLA class I, but not HLA class II Ag on both progenitors and precursors. In contrast, incubation with PHA-stimulated adult leukocyte-conditioned medium causes a marked increase of both HLA-ABC and HLA class II Ag expression. We hence investigated the effect of cytokines present in leukocyte-conditioned medium on the expression of HLA class II Ag: although IL-1 alpha, IL-2, and granulocyte-macrophage-CSF do not exert a significant action, IL-1 beta and IL-4 induce a marked increase of HLA class II, but not class I, Ag expression on 6-wk FL progenitors and precursors. Low amounts of IFN-gamma, TNF-alpha, and IL-1 beta were detected in the supernatants and extracts of 6-wk FL cells. The concentrations of these cytokines in both supernatants and extracts sharply increase in the 7- to 8-wk period, particularly for TNF-alpha and IL-1 beta, thus indicating a direct correlation with the rise of HLA Ag expression on FL erythroid cells in the same period. In conclusion, the expression of HLA class I and II Ag is not detected on primitive megaloblasts, but is gradually induced on definitive FL progenitors and precursors, possibly via production of specific cytokines in the FL microenvironment, i.e., IFN-gamma and TNF-alpha for class I Ag and IL-1 beta for class II Ag.


Genome rearrangements and phylogeny reconstruction in Yersinia pestis.
Genome rearrangements have played an important role in the evolution of Yersinia pestis from its progenitor Yersinia pseudotuberculosis. Traditional phylogenetic trees for Y. pestis based on sequence comparison have short internal branches and low bootstrap supports as only a small number of nucleotide substitutions have occurred. On the other hand, even a small number of genome rearrangements may resolve topological ambiguities in a phylogenetic tree. We reconstructed phylogenetic trees based on genome rearrangements using several popular approaches such as Maximum likelihood for Gene Order and the Bayesian model of genome rearrangements by inversions. We also reconciled phylogenetic trees for each of the three CRISPR loci to obtain an integrated scenario of the CRISPR cassette evolution. Analysis of contradictions between the obtained evolutionary trees yielded numerous parallel inversions and gain/loss events. Our data indicate that an integrated analysis of sequence-based and inversion-based trees enhances the resolution of phylogenetic reconstruction. In contrast, reconstructions of strain relationships based on solely CRISPR loci may not be reliable, as the history is obscured by large deletions, obliterating the order of spacer gains. Similarly, numerous parallel gene losses preclude reconstruction of phylogeny based on gene content.


Social insurance literacy: a scoping review on how to define and measure it.
Sickness insurance and workers' compensation systems decide on peoples' eligibility for benefits, and are commonly based on medical certificates and assessments of work ability. Systems differ in the extent to which they preserve clients' dignity and right to fair assessments. In this article, we define a new concept for studying interactions between individuals and systems: social insurance literacy, which concerns how well people understand the different procedures and regulations in social insurance systems, and how well systems communicate with clients in order to help them understand the system. The concept was defined through a scoping literature review of related concepts, a conceptual re-analysis in relation to the social insurance field, and a following workshop. Five related concepts were reviewed for definitions and operationalizations: health literacy, financial/economic literacy, legal capability/ability, social security literacy, and insurance literacy. Social insurance literacy is defined as the extent to which individuals can obtain, understand and act on information in a social insurance system, related to the comprehensibility of the information provided by the system. This definition is rooted in theories from sociology, social medicine and public health. In the next step, a measure for the concept will be developed based on this review.Implications for rehabilitationSocial insurance literacy is a new concept that is based on theories in sociology, social medicine and public health.It provides conceptual orientation for analyzing factors that may influence different outcomes of peoples' contacts with social insurance systems.The concept is of relevance for rehabilitation professionals since it focuses on how interactions between individuals and systems can influence the rehabilitation process.The study will in the next step develop a measure of social insurance literacy which will have practical applications for rehabilitation professionals.


Oxidative folding of peptides with cystine-knot architectures: kinetic studies and optimization of folding conditions.
Bioactive peptides often contain several disulfide bonds that provide the main contribution to conformational rigidity and structural, thermal, or biological stability. Among them, cystine-knot peptides-commonly named "knottins"-make up a subclass with several thousand natural members. Hence, they are considered promising frameworks for peptide-based pharmaceuticals. Although cystine-knot peptides are available through chemical and recombinant synthetic routes, oxidative folding to afford the bioactive isomers still remains a crucial step. We therefore investigated the oxidative folding of ten protease-inhibiting peptides from two knottin families, as well as that of an HIV entry inhibitor and of aprotinin, under two conventional sets of folding conditions and by a newly developed procedure. Kinetic studies identified folding conditions that resulted in correctly folded miniproteins with high rates of conversion even for highly hydrophobic and aggregation-prone peptides in concentrated solutions.


Mechanical evaluation of posterior wiring as a supplement to anterior cervical plate fixation.
An in vitro experimental study was performed to examine 3-dimensional biomechanical stability of cervical fixations. To determine whether posterior interspinous wiring contributes to the rigidity of a single-level motion segment that has been plated anteriorly, and to determine the effects of this combined fixation on intradiscal pressure and spinal motion at the adjacent segments. Combined anterior and posterior column fixation is being increasingly used in a variety of clinical situations that do not involve complete disruption of the motion segment. The biomechanical validity of combined anterior posterior fixation in the absence of overt posterior ligamentous disruption has not been studied. Six human fresh-frozen cadaveric cervical spines (C3-T1) were used. Three-dimensional intersegmental motion and intradiscal pressure were measured while the spine was loaded in flexion, extension, lateral bending, and torsion (up to 2.5 Nm). Fixation stability at the operative level (C5-C6) and influence of the fixation on adjacent segments were evaluated after an anterior plating procedure and combined anterior plating and posterior wiring. Comparing the combined approach with anterior plating alone, significant reductions in C5-C6 motion was noted: 49% in flexion (P <0.05), 48% in extension (P <0.003), and 33% and 39%, respectively, in left and right torsion (P <0.05). Reduction in the left and right lateral bending was not significant (18% and 12%, respectively). The improved fixation had minimal influence on the adjacent segments. Combined anterior posterior fixation further reduces the segmental motion by almost 50% in flexion and extension, 33% and 39% in torsion, and does not significantly alter intradiscal pressure and spinal motion at adjacent segments.


Plastic litter colonization in a brackish water environment.
Transitional waters, including coastal ponds, represent unique environments. These distinct ecosystems are often among the most severely polluted systems due to intensive human activities. Our study marks the first evaluation of aquatic invertebrates associated with plastic litter in two brackish ponds. We collected 43 items of plastic litter (including bottles and disposable plastics) during the winter and spring of 2022. Most of plastic litter (76.8 %) was colonized by aquatic invertebrates. A total of 495 individuals were observed on the plastic litter, with the number of individuals ranging from 1 to 54 (average = 13.4). The most abundant taxa were from the families Gammaridae, Serpulidae, and Sphaeromatidae. Invertebrates colonized both the external and internal surfaces of the plastic bottles. Plastic bottles trapped 25 % of the total biota. The internal entrapped taxa were mainly represented by gammarids, molluscs egg mass, and sphaeromatids. Open bottles could potentially serve as temporary or permanent traps for invertebrates colonizing their internal surfaces. We argue that the dispersal of species driven by plastics is possible but limited, just as water exchanges with the seas are limited. These brackish lakes could be transit areas, but more importantly, they could be hotspots for plastic litter.


Comparison of monocyte with high density lipoprotein cholesterol ratio in dipper and nondipper hypertensive patients.
Aim: We aimed to compare the monocyte to HDL-cholesterol ratio (MHR) of nondipper hypertension (NDHT) and dipper hypertension patients. Patients & methods: A total of 162 patients were included in the study. Patients were grouped as dipper and nondipper according to 24-h ambulatory blood pressure recordings. Results: The MHR was significantly higher in nondipper hypertension group compared with control (p < 0.001) and dipper hypertension groups (p = 0.03). MHR, hs-CRP and red-cell distribution width (RDW) were independent predictors of nondipper hypertension. Area under the curve was 0.62 (p = 0.034) for MHR and 0.61 (p = 0.012) for hs-CRP in the ROC analysis. Conclusion: MHR has elevated levels in NDHT patients. Increased levels of MHR may evaluate as increased risk of cardiovascular events in NDHT patients.


Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches.
Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core-rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late-onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1-RM. Finally, perspectives for future approaches to treatment development are broached.


Postinfectious encephalomyelitis.
Postinfectious forms of encephalomyelitis, also termed acute disseminated encephalomyelitis (ADEM), form one of several categories of inflammatory demyelinating disorders of the central nervous system (CNS). Recent large, retrospective case series have refined our understanding of the clinical, laboratory, and neuroimaging characteristics of ADEM. The differences between childhood and adult ADEM, risks of development of multiple sclerosis, and the contributions of recent studies to refining the nosology of CNS demyelinating syndromes are discussed.


Nonclinical safety profile of telbivudine, a novel potent antiviral agent for treatment of hepatitis B.
Telbivudine is a novel nucleoside drug recently approved for the treatment of patients with chronic hepatitis B. Its nonclinical safety was evaluated in a comprehensive program of studies, including safety pharmacology, acute and chronic toxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity. There were no test article-related effects observed in an in vitro hERG assay or in a core battery of safety pharmacology studies (central nervous system, respiratory, and cardiovascular safety pharmacology studies). Telbivudine was well tolerated in rats and in monkeys following single oral doses up to 2,000 mg/kg/day. Except for equivocal axonopathic findings in monkeys and occasional incidences of emesis, soft feces, and minor changes in body weight and food consumption, there was no target organ toxicity observed in mice, rats, or monkeys following oral administration for up to 3, 6, or 9 months, respectively, at doses up to 3,000 mg/kg/day. Axonopathy in the sciatic nerves and in the spinal cords of monkeys dosed at 1,000 mg/kg/day observed in a 9-month study was considered equivocal, as the role of telbivudine in the injury could not be determined. Slightly higher incidences of abortion and premature delivery observed in rabbits dosed at 1,000 mg/kg/day were considered secondary to maternal toxicity. There was no evidence of genotoxicity or carcinogenicity. These results suggest that telbivudine has a favorable safety profile and support its use in patients with chronic compensated hepatitis B viral infection.


Incorporating an immunization certificate program into the pharmacy curriculum.
To describe the method of incorporating an immunization certificate training program, such as the American Pharmacists Association's (APhA) Pharmacy-Based Immunization Delivery into a pharmacy curriculum. The program was delivered over 3 weeks in the spring semester of the third professional year (P3) as part of a required Pharmacy Care Lab sequence. Student response surveys and faculty input were used to evaluate the placement of the program in the curriculum. Optional comments yielded more than 44% of students providing positive open-ended feedback regarding the course while almost 10% felt the course should not be mandated in the curriculum.


A family-centered prevention ameliorates the associations of low self-control during childhood with employment income and poverty status in young African American adults.
Children with low self-control who grow up in poverty are at elevated risk for living in poverty when they are adults. The purpose of this study was to further understanding of the intergenerational continuity of poverty by (a) examining the likelihood that children with low levels of self-control at age 11 earn less employment income and are more likely to live in poverty 14 years later, at age 25; and (b) determining, via a preventive intervention, whether enhancing supportive parenting during childhood will ameliorate these associations. Parents and their 11-year-old children from 381 families participated in the Strong African American Families (SAAF) program or a control condition. Teachers assessed children's self-control at 11 years; parents reported their use of supportive parenting when children were 11 and 13 years; emerging adults provided data on cognitive and emotional self-control at 19, 20, and 21 years; and young adults indicated their employment income at 25 years. Significant two-way interactions were detected between children's self-control and prevention condition for employment income (b = -183.18, 95% CI [-363.82, -2.53], p < .05) and poverty status (b = 0.257, 95% CI [0.018, 0.497], p < .05). Low self-control at age 11 forecast less employment income and a greater likelihood of living in poverty among children in the control condition, but not among low self-control SAAF participants. Mediated moderation analyses confirmed that enhanced supportive parenting accounted for SAAF's effects on employment income (indirect effect = 63.057, 95% BCA [19.385, 124.748]) and poverty status (indirect effect = -0.071, 95% BCA [-0.165, -0.016]). This study is unique in using a randomized controlled trial to show that preventive interventions designed to enhance parenting and strengthen families can buffer the long-term economic consequences of low self-control.


An exploration looking at the impact of domiciliary and day hospital delivery of stroke rehabilitation on informal carers.
To explore the impact of two methods of post-hospital stroke rehabilitation on both carers' perceptions of the health services offered and their quality of life. East Dorset Health Authority. Forty-six informal carers were recruited from a sample of 106, initially identified from stroke patients participating in a larger randomized controlled trial. Qualitative methods. Semi-structured interviews were used at baseline and six months to explore carers' perception of a good therapy, the advantages and disadvantages of the different services and their fulfilment with the services. In-depth thematic analysis was carried out to explore the impact of the two different methods of service delivery on carers' quality of life. Day hospitals provided carers with respite opportunities, whilst domiciliary stroke teams provided carers with better educational opportunities to be involved in therapy. No qualitative difference was found in the impact that the different services had on carers' quality of life, which were influenced by factors such as the degree of disruption that caring had on their lives, the loss of a shared life and the availability of social support. Ultimately, carers saw the services as providing benefit for survivors and not themselves. Domiciliary stroke teams provided informal stroke carers with skills that could help improve postdischarge stroke rehabilitation amongst stroke survivors. Informal carers also benefited from the respite elements of day hospital. A mixed model using both domiciliary care and day hospital care, could provide carers with the benefits of education, convenience and respite.


Whole muscle length-tension properties vary with recruitment and rate modulation in areflexive cat soleus.
The length-tension relationship is a fundamental property of muscle. In its classic form, which is used in muscle models incorporated into studies of motor control, the length-tension relationship is measured during maximal activation via tetanic electrical stimulation in whole muscles or during high intracellular calcium levels in single muscle fibers. In this study, we measured the length-tension relationship of the cat soleus muscle during different levels of natural activation consisting of recruitment and rate modulation of motor units generated by the crossed extension reflex. The ipsilateral dorsal roots were cut to eliminate sensory feedback from the soleus. Length-tension was measured by large shortening steps that transiently allowed force to drop to zero. Force then recovered to a new steady value as the shorter length was maintained for several seconds. The effects of various levels of crossed extension activation on length-tension were compared with direct electrical stimulation of the muscle at 5, 10, 20, and 100 Hz. At all levels of crossed extension, the slope of the length-tension function was much steeper than the slope for tetanic stimulation at 100 Hz. Most slopes for crossed extension fell between the slopes seen with electrical stimulation at 10 and 20 Hz. There was a modest overall tendency for slope to decrease with the level of crossed extension activation. Because much of the normal movement repertoire requires submaximal activation, muscle models based on the tetanic length tension relationship will greatly underestimate the contribution of this relationship to force modulation at different muscle lengths.


Comparison of Health Care Expenditures Among U.S. Older Adults With Pain Who Reported Frequent Exercise Versus Nonfrequent Exercise.
This cross-sectional study included a nationally representative sample of U.S. adults aged ≥50 years with self-reported pain in the past 4 weeks from the 2018 Medical Expenditure Panel Survey. Adjusted linear regression analyses accounted for the complex survey design and assessed differences in several types of annual health care expenditures between individuals who reported frequent exercise (≥30 min of moderate-vigorous intensity physical activity ≥5 times per week) and those who did not. Approximately 23,940,144 of 56,979,267 older U.S. adults with pain reported frequent exercise. In adjusted analyses, individuals who reported frequent exercise had 15% lower annual prescription medication expenditures compared with those who did not report frequent exercise (p = .007). There were no statistical differences between frequent exercise status for other health care expenditure types (p > .05). In conclusion, adjusted annual prescription medication expenditures were 15% lower among older U.S. adults with pain who reported frequent exercise versus those who did not.


Gynecomastia - a difficult diagnostic problem.
Gynecomastia is a benign, abnormal, growth of the male breast gland which can occur unilaterally or bilaterally, resulting from a proliferation of glandular, fibrous and adipose tissue. Gynecomastia is characterised by the presence of soft, 2-4 cm in diameter, usually discusshaped enlargement of tissues under the nipple. It is estimated that this pathology occurs in 32-65% of men over the age of 17. Gynecomastia is a psychosocial problem and may lead to a perceived lowering of quality of life. The main cause of gynecomastia is a loss of equilibrium between oestrogens and androgens. Increased sensitivity for oestrogens of the breast gland, or local factors (e.g. an excessive synthesis of oestrogens in breast tissues or changes in oestrogen and androgen receptors) may cause gynecomastia. Also, prolactin, thyroxine, cortisol, human chorionic gonadotropin, leptin and receptors for human chorionic gonadotropin, prolactin and luteinizing hormone localised in tissues of the male breast may participate in the etiopathogenesis of gynecomastia. Usually three types of gynecomastia are distinguished: physiological, idiopathic and pathological gynecomastia. The latter is the consequence of relative or absolute excess of oestrogens. In this paper, frequent as well as casuistic causes of gynecomastia will be described. A diagnosis of gynecomastia is usually possible after a palpation examination. Ultrasonographic, mammographic or histopathological examinations are useful in aiding diagnosis. The five degree scale devised by Tanner and Marshall is useful in estimating disease progression.


A study of synthetic-aperture imaging with virtual source elements in B-mode ultrasound imaging systems.
We propose an all point transmit and receive focusing method based on transmit synthetic focusing combined with receive dynamic focusing in a linear array transducer. In the method, on transmit, a virtual source element is assumed to be located at the transmit focal depth of conventional B-mode imaging systems, and transmit synthetic focusing is used in two half planes, one before and the other after the transmit focal depth, using the RF data of each scanline, together with all other relevant RF scanline data previously stored. The proposed new method uses the same data acquisition scheme as the conventional focusing method while maintaining the same frame rate via high-speed signal processing, but it is not suitable for imaging moving objects. It improves upon the lateral resolution and sidelobe level at all imaging depths. Also, it increases the transmit power and image signal-to-noise ratio (SNR), due to transmit field synthesis, and extends the image penetration depth as well. Evaluations with simulation and experimental data show much improvement in resolution and SNR at all imaging depths.


Investigation of six selected bacterial species in endo-periodontal lesions.
To investigate and determine possible associations of six tested bacteria belonging to 'orange' and 'green' complexes, in endo-periodontal lesions: Parvimonas micra, Fusobacterium nucleatum, Campylobacter rectus, Eubacterium nodatum, Eikenella corrodens and Capnocytophaga sputigena. Forty-six patients presenting with different types of endo-periodontal lesions were investigated. Clinical examinations, periapical radiographs and microbiological sampling from the canal system (endo) and periodontal pockets (perio) were performed. Qualitative and semiquantitative evaluation of bacteria was performed by polymerase chain reaction (PCR) and DNA-DNA hybridization (micro-IDent plus; Hain Lifescience, Germany). Extremely high bacterial loads in endodontic samples were recorded for P. micra, F. nucleatum and C. sputigena, while periodontal samples were often colonized by the same species, plus C. rectus. Significant association was recorded between F. nucleatum-endo and P. micra-endo (P = 0.03, Fisher's exact test). There was marginal evidence of associations between: (i) C. sputigena-endo and C. sputigena-perio (P = 0.06, Fisher's exact test); (ii) P. micra-endo and P. micra-perio (P = 0.05, Fisher's exact test). Sensitivity to percussion was associated with an increased chance of cases with P. micra-endo (P = 0.03, Pearson chi-square test). The findings suggest that F. nucleatum, P. micra and C. sputigena may play a role in the pathogenesis of endo-periodontal lesions.


Comparison of manual and automated AmpliSeq™ workflows in the typing of a Somali population with the Precision ID Identity Panel.
The Precision ID Identity Panel was used to type 109 Somali individuals in order to obtain allele frequencies for the Somali population. These frequencies were used to establish a Somali HID-SNP database, which will be used for the biostatistic calculations in family and immigration cases. Genotypes obtained with the Precision ID Identity Panel were found to be almost in complete concordance with genotypes obtained with the SNPforID PCR-SBE-CE assay. In seven SNP loci, silent alleles were identified, of which most were previously described in the literature. The project also set out to compare different AmpliSeq™ workflows to investigate the possibility of using automated library building in forensic genetic case work. In order to do so, the SNP typing of the Somalis was performed using three different workflows: 1) manual library building and sequencing on the Ion PGM™, 2) automated library building using the Biomek®3000 and sequencing on the Ion PGM™, and 3) automated library building using the Ion Chef™ and sequencing on the Ion S5™. AmpliSeq™ workflows were compared based on coverage, locus balance, noise, and heterozygote balance. Overall, the Ion Chef™/Ion S5™ workflow was found to give the best results and required least hands-on time in the laboratory. However, the Ion Chef™/Ion S5™ workflow was also the most expensive. The number of libraries that may be constructed in one Ion Chef™ library building run was limited to eight, which is too little for high throughput workflows. The Biomek®3000/Ion PGM™ workflow was found to perform similarly to the manual/Ion PGM™ workflow. This argues for the use of automated library building in forensic genetic case work. Automated library building decreases the workload of the laboratory staff, decreases the risk of pipetting errors, and simplifies the daily workflow in forensic genetic laboratories.


Drug-food Interactions in the Era of Molecular Big Data, Machine Intelligence, and Personalized Health.
The drug-food interaction brings forth changes in the clinical effects of drugs. While favourable interactions bring positive clinical outcomes, unfavourable interactions may lead to toxicity. This article reviews the impact of food intake on drug-food interactions, the clinical effects of drugs, and the effect of drug-food in correlation with diet and precision medicine. Emerging areas in drug-food interactions are the food-genome interface (nutrigenomics) and nutrigenetics. Understanding the molecular basis of food ingredients, including genomic sequencing and pharmacological implications of food molecules, helps to reduce the impact of drug-food interactions. Various strategies are being leveraged to alleviate drug-food interactions; measures including patient engagement, digital health, approaches involving machine intelligence, and big data are a few of them. Furthermore, delineating the molecular communications across dietmicrobiome- drug-food-drug interactions in a pharmacomicrobiome framework may also play a vital role in personalized nutrition. Determining nutrient-gene interactions aids in making nutrition deeply personalized and helps mitigate unwanted drug-food interactions, chronic diseases, and adverse events from their onset. Translational bioinformatics approaches could play an essential role in the next generation of drug-food interaction research. In this landscape review, we discuss important tools, databases, and approaches along with key challenges and opportunities in drug-food interaction and its immediate impact on precision medicine.


Parentage assignment with genotyping-by-sequencing data.
In this paper, we evaluate using genotype-by-sequencing (GBS) data to perform parentage assignment in lieu of traditional array data. The use of GBS data raises two issues: First, for low-coverage (e.g., <2×) GBS data, it may not be possible to call the genotype at many loci, a critical first step for detecting opposing homozygous markers. Second, the amount of sequencing coverage may vary across individuals, making it challenging to directly compare the likelihood scores between putative parents. To address these issues, we extend the probabilistic framework of Huisman (Molecular Ecology Resources, 2017, 17, 1009) and evaluate putative parents by comparing their (potentially noisy) genotypes to a series of proposal distributions. These distributions describe the expected genotype probabilities for the relatives of an individual. We assign putative parents as a parent if they are classified as a parent (as opposed to e.g., an unrelated individual), and if the assignment score passes a threshold. We evaluated this method on simulated data and found that (a) high-coverage (>2×) GBS data performs similarly to array data and requires only a small number of markers to correctly assign parents and (b) low-coverage GBS data (as low as 0.1×) can also be used, provided that it is obtained across a large number of markers. When analysing the low-coverage GBS data, we also found a high number of false positives if the true parent is not contained within the list of candidate parents, but that this false positive rate can be greatly reduced by hand tuning the assignment threshold. We provide this parentage assignment method as a standalone program called AlphaAssign.


Determining the applicability of threshold of toxicological concern approaches to substances found in foods.
Threshold of Toxicological Concern (TTC) decision-support methods present a pragmatic approach to using data from well-characterized chemicals and protective estimates of exposure in a stepwise fashion to inform decisions regarding low-level exposures to chemicals for which few data exist. It is based on structural and functional categorizations of chemicals derived from decades of animal testing with a wide variety of chemicals. Expertise is required to use the TTC methods, and there are situations in which its use is clearly inappropriate or not currently supported. To facilitate proper use of the TTC, this paper describes issues to be considered by risk managers when faced with the situation of an unexpected substance in food. Case studies are provided to illustrate the implementation of these considerations, demonstrating the steps taken in deciding whether it would be appropriate to apply the TTC approach in each case. By appropriately applying the methods, employing the appropriate scientific expertise, and combining use with the conservative assumptions embedded within the derivation of the thresholds, the TTC can realize its potential to protect public health and to contribute to efficient use of resources in food safety risk management.


Ataxia and ophthalmoplegia: an atypical case of Miller Fisher syndrome (MFS) with anti-GAD antibody.
Miller Fisher syndrome (MFS) is frequently encountered variant of Gillian Barre Syndrome (GBS). It has distinct clinical and serological features. Here we describe an atypical GQ1b seronegative case with significantly elevated anti-glutamic acid decarboxylase antibody (GAD-Ab). A 24-year-old previously healthy Caucasian male presented with rapidly progressive ascending weakness, binocular diplopia and autonomic instability for 2 days. Examination was remarkable for asymmetrical facial weakness (L > R), opthalmoplegia and truncal ataxia without areflexia. MRI brain was normal. CSF analysis showed elevated protein. Electromyography/Nerve Conduction Study (EMG/NCS) within the first week was normal. Antiganglioside antibodies were negative. Extended serological and neoplastic workup revealed negative anti-GQ1b antibody, but significant increase of GAD-Ab, Voltage Gated Calcium Channel (VGCC) Ab, and mild elevation of TPO Ab IgG and Thyroglobulin (Tg) Ab IgG. Clinical diagnosis of partial MFS was made. He received a course of IVIg (2 g/kg over 5 days) and had complete recovery in 3 months. There are incomplete or atypical forms of MFS. Recognition of its various clinical presentations is essential for early diagnosis and optimal management. Further investigation is needed to elucidate the role of anti-GAD-ab and other autoimmune antibodies in the pathogenesis of GQ1b-seronegative MFS patients.


A layered aluminum-based metal-organic framework as a superior trap for nitrobenzene capture via an intercalation role.
Layered materials with porous layers are of great interest due to their intriguing structural topologies and potential applications as new adsorbents. In this study, a layered aluminum-based metal-organic framework, i.e. Al-TCPP, was successfully synthesized via a facile method for the adsorptive removal of nitrobenzene (NB). The as-synthesized Al-TCPP exhibited a typical layered structure and can be stable in water at pH = 5-7. Batch experimental results showed a superior adsorption performance towards NB with a maximum adsorption capability of 1.85 mg mg-1, and an exceptionally rapid equilibrium within 1 min, yielding an overall adsorptive performance superior to the state-of-the-art NB adsorbents reported so far. The morphology and crystallinity of the Al-TCPP adsorbent basically retain the original status after the capture of NB. Importantly, X-ray diffraction patterns of the samples after the NB adsorption revealed that the possible NB intercalation took place in layered Al-TCPP and expanded the interlayer space during the adsorption, which greatly enriched the adsorption sites and thus achieved the outstanding performance. This work highlights new prospects in designing layered materials for use in environmental remediation.


Neuroinvasive properties of herpes simplex virus type 1 glycoprotein variants are controlled by the immune response.
Neuroinvasiveness is a property central to the pathogenesis of herpes simplex virus (HSV) and most isolates demonstrate this property. Exceptions are HSV strains KOS and ANG, for which we have previously shown that the non-neuroinvasive phenotype is referable to single amino acid changes in glycoprotein D for ANG or glycoprotein B for KOS. Because glycoproteins B and D are immunologically significant, the possibility that the phenotype has an immunologic basis was examined. Nonimmunosuppressed mice could not be killed with any dose of these non-neuroinvasive viruses after footpad inoculation, but in cyclophosphamide-suppressed animals, the ratios of plaque-forming units to LD50 decreased by at least four orders of magnitude to levels comparable with that of ANG-path, a neuroinvasive derivative of ANG. KOS and ANG induced a more rapid circulating neutralizing Ab response than did ANG-path, and mice were protected when these agents were co-infected with the neuroinvasive strain. The noninvasive viruses engendered an enhanced mononuclear cell infiltrate in infected spinal ganglia which consisted of increased numbers of CD4+ and CD8+ T cells and an increased production and secretion of IgG. HSV-specific Ab-secreting cells were also observed. In addition, passive transfer of anti-HSV mouse serum protected immunosuppressed mice from lethal HSV challenge. Selective in vivo depletion of T lymphocytes increased the detectable levels of both KOS and ANG viruses in the spinal ganglia at 6 days postinfection, but it did not alter the ratios of plaque-forming units to LD50 or affect the HSV-induced increase in ganglionic IgG. Taken together, these data indicate that in these systems there is an immunologic basis for the control of HSV-1 neuroinvasiveness and that humoral, rather than cell-mediated immunity, is playing the major role.


Mutator transposase is widespread in the grasses.
Although the Mutator (Mu) system is well characterized in maize (Zea mays), very little is known about this highly mutagenic system of transposons in other grasses. Mutator is regulated by the MuDR class of elements, which encodes two genes, one of which, mudrA, has similarity to a number of bacterial transposases. Experiments in our laboratory, as well as database searches, demonstrate that mudrA sequences are ubiquitous and diverse in the grasses. In several species it is clear that multiple paralogous elements can be present in a single genome. In some species such as wheat (Triticum aestivum) and rice (Oryza sativa), mudrA-similar sequences are represented in cDNA databases, suggesting the presence of active Mu transposon systems in these species. Further, in rice and in sorghum, mudrA-like genes are flanked by long terminal inverted repeats, as well as the short host sequence direct repeats diagnostic of insertion. Thus, there is ample evidence that systems related to Mu in maize are at least potentially active in a wide variety of grasses. However, the mudrB gene, though important for Mu activity in maize, is not necessarily a component of Mu elements in other grasses.


Enhancing surgeons' gaze strategies in endoscopic surgery during simulated surgical emergency situations thanks to computer vision.
Deficient visualization in minimally invasive surgery often causes misperceptions, which can lead to an increase of iatrogenic lesions and complications. This is especially critical for novice surgeons, who are prone to adopt inadequate switching gaze strategies, thereby increasing the chance of unforeseen complications. In this paper the use of an additional computer-aided vision system was tested for improvement of the reaction of the surgeons to unforeseen complications. Gaze patterns were analyzed using a gaze tracker, as well as other metrics such as task completion time or reaction time to sudden bleeding. While completion time did not show significant difference between tested modalities (p<0.1), the reaction time showed a downward trend as more auxiliary computer-aided vision systems were added (p<0.005). These results support the benefits of including additional vision systems for minimally invasive surgery processes.Clinical Relevance- This work assesses the advantages of including an additional computer vision system to prevent unforeseen complications during minimally invasive surgeries.


Beneficial effects of melatonin on diaphragmatic contractility and fatigability in Escherichia coli endotoxemic rats.
Sepsis impairs diaphragmatic contractility and endurance capacity and increases diaphragmatic fatigability. Several investigations have shown that administration of a number of free radical scavengers, such as N-acetylcysteine (NAC), protects the diaphragm from the development of endotoxin-mediated diaphragmatic dysfunction. The aim of this study was to evaluate the effects of melatonin (CAS 73-31-4), a naturally occurring potent antioxidant, on diaphragmatic contractility and lipid peroxidation as a marker of oxidative stress in endotoxemic rats. Rats were randomly divided into four groups: control group, endotoxemic group, melatonin group and endotoxemic plus melatonin group. Melatonin was administered by intraperitoneal injection 30 min before endotoxin inoculation to animals. Diaphragmatic function and malondialdehyde (MDA) level analysis as an indicator of lipid peroxidation were assessed 17 h after endotoxin or saline inoculation. Endotoxemia decreased the development of diaphragm fatigue and diaphragmatic MDA levels. The effects of endotoxemia on diaphragmatic contractions and fatigability were reversed and returned to control levels by melatonin administration. However, melatonin did not prevent the increase in muscle MDA content. In conclusion, the present study demonstrated that melatonin attenuated the endotoxin-induced impairment of diaphragm function. This effect of melatonin does not seem to be related to its antioxidant properties.


General Movements trajectories and outcome at 12 months in very preterm infants: An analysis of tendencies and pathological persistence.
Very preterm infants (VPI) < 32 weeks are at increased risk of developmental disorders detectable using the Prechtl General Movements Assessment (GMA) and the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). The aim of this study was to investigate General Movements (GMs) trajectories from preterm to fidgety age including GMs tendencies and their association with cognitive and motor outcome. Retrospective analysis of VPI with GMA at preterm (35 ± 2 weeks postmenstrual age (PMA), T1) and fidgety age (12 ± 3 weeks corrected age CA), T2), and BSID-III (12 ± 3 months CA, T3) is performed. Data are analysed using Pearson χ2-test, Fisher-Freeman-Halton Exact test, and residual analyses. This study found significant associations between (a) GMs (T1) and (b) persistent pathological GMs (T1 + T2) with cognitive outcomes at 12 months (T3) considering the tendencies of GMs in addition to the global character (p = 0.007, p = 0.022, respectively), representing medium-sized effects. There were no significant associations between GMs or persistence of pathological GMs and gross and fine motor outcomes, regardless of GMs tendencies. Findings indicate that considering tendencies of GMs and the persistence of pathological GMs may be important in identifying children at risk of cognitive impairments early. This additional assessment parameter may have the potential for early identification of infants with milder motor and/or cognitive impairments. However, more research is needed using larger sample cohorts to generalise the results and to be able to recommend sequential GMA for clinical routine.


Photocarcinogenesis in the Tg.AC mouse: lomefloxacin and 8-methoxypsoralen.
The Tg.AC mouse is a good predictor of carcinogenic potential when the test article is administered by dorsal painting (Tennant et al. (1995) Environ. Health Perspect. 103, 942). We have used lomefloxacin (LOME) and 8-methoxypsoralen (8-MOP) in combination with UVA to determine whether the Tg.AC transgenic mouse also responds to parenterally administered photocarcinogens. Female Tg.AC mice were given LOME (25 mg/kg intraperitoneal in normal saline) followed by UVA (25 J/cm2) 1-2 h later, five times every 2 weeks on a repetitive schedule. Other groups received LOME, UVA or vehicle alone. After 16 weeks, the mean numbers of papillomas/mouse +/- SD (% responding) were: saline, 0.3 +/- 0.5 (33%); UVA + saline, 1.3 +/- 0.6 (100%); LOME, 1.9 +/- 1.6 (86%) and LOME-UVA, 1.5 +/- 1.9 (64%). Only the 100% incidence of tumors in the UVA group and the maximum tumor yields in the LOME and UVA groups are significant (P < 0.05) when compared with the control. In a second study, Tg.AC mice were administered the classical photocarcinogen 8-MOP (8 mg/kg intragastric in corn oil) followed by 2 J/cm2 UVA 1-2 h later, five times every 2 weeks on a repetitive schedule. The second group received 8-MOP, whereas the third was exposed to UVA alone. Papillomas began to appear at 2 weeks in the 8-MOP-UVA group, and after 17 weeks the mean numbers of papillomas/mouse +/- SD (% responding) were: 8-MOP-UVA, 6.9 +/- 8.6 (93%); UVA + corn oil, 1.1 +/- 1.2 (69%) and 8-MOP, 1.1 +/- 1.6 (50%). The maximum tumor yield in the 8-MOP-UVA group was significantly higher (P < 0.01) than that in the other two groups. Our findings suggest that more studies need to be done before the Tg.AC mouse can be used with confidence to identify parenterally administered photocarcinogens.


Lexical Landscapes as large in silico data for examining advanced properties of fitness landscapes.
In silico approaches have served a central role in the development of evolutionary theory for generations. This especially applies to the concept of the fitness landscape, one of the most important abstractions in evolutionary genetics, and one which has benefited from the presence of large empirical data sets only in the last decade or so. In this study, we propose a method that allows us to generate enormous data sets that walk the line between in silico and empirical: word usage frequencies as catalogued by the Google ngram corpora. These data can be codified or analogized in terms of a multidimensional empirical fitness landscape towards the examination of advanced concepts-adaptive landscape by environment interactions, clonal competition, higher-order epistasis and countless others. We argue that the greater Lexical Landscapes approach can serve as a platform that offers an astronomical number of fitness landscapes for exploration (at least) or theoretical formalism (potentially) in evolutionary biology.


Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review).
It has been shown that epigenetic modifications play an important role in tumorigenesis. Thus, affecting epigenetic tumorigenic alterations can represent a promising strategy for anticancer targeted therapy. Among the key chromatin modifying enzymes which influence gene expression, histone acetyltransferases (HATs) and histone deacetylases (HDACs) have recently attracted interest because of their impact on tumor development and progression. Increased expression of HDACs and disrupted activities of HATs have been found in several tumor types, with a consequent hypoacetylated state of chromatin that can be strictly correlated with low expression of either tumor suppressor or pro-apoptotic genes. Histone deacetylase inhibitors (HDACIs) represent a new and promising class of antitumor drugs that influence gene expression by enhancing acetylation of histones in specific chromatin domains. HDACIs have been shown to exert potent anticancer activities inducing cell cycle arrest and apoptosis. Notably, a high efficacy of these drugs has been selectively revealed in malignant cells rather than in normal cells. Moreover, the therapeutic potential of these agents is also supported by the evidence that HDACIs downregulate genes involved in tumor progression, invasion and angiogenesis. Several HDACIs are currently under clinical investigation, including vorinostat (SAHA), romidepsin (depsipeptide, FK-228), LAQ824/LBH589 and belinostat (PXD101), compounds that have shown therapeutic potential in many types of malignancies including solid tumors. Based on the ability of HDACIs to regulate many signaling pathways, co-treatment of these compounds with molecular targeted drugs is a promising strategy against many types of tumors.


Commonly used adjuvants (liquid soap, foam sanitizer, or ultrasound gel) do not improve strength or curing time of fiberglass cast material.
Bone fractures are one of the most common injuries in the USA. Fiberglass tape is a commonly used casting material, and many medical professionals apply adjuvants including liquid hand soap, foam sanitizers, and ultrasound gel in the hopes of improving outcomes relating to ease of molding and eventual strength, lamination, and smoothness of cast material. However, the efficacy of these agents to improve fiberglass cast mechanics has not been scientifically evaluated. The purpose of this study was to assess the mechanical effects of commonly used adjuvants on fiberglass cast materials. Studies compared regularly shaped samples of water-activated, untreated fiberglass tape (Ossur Techform Premium) to water-activated fiberglass tape treated with one of three commonly used adjuvants (liquid soap, foam hand sanitizer, or ultrasound gel) during lamination. Material stiffness, yield stress, and ultimate load were measured by 3-point bending. These studies demonstrated that that liquid soap and ultrasound gel did not affect fiberglass tape mechanical properties, but alcohol-based foam sanitizer significantly reduced stiffness (- 32.8%), yield stress (- 33.6%), and ultimate load (- 31.0%) of the cast material as compared to the control group. Regression slopes were not significantly different between groups, suggesting that no adjuvants improved material curing time. These data suggest that the application of adjuvants is not beneficial and potentially harmful to fiberglass cast behavior. Despite the widespread practice of adjuvant application by medical professionals during casting, results from the current study suggest that use of these agents for structural enhancement of fiberglass casts is not beneficial and should largely be discouraged.


Interventions Targeting Deep Tissue Lymph Nodes May Not Effectively Reduce the Risk of Salmonellosis from Ground Pork Consumption: A Quantitative Microbial Risk Assessment.
The inclusion of deep tissue lymph nodes (DTLNs) or nonvisceral lymph nodes contaminated with Salmonella in wholesale fresh ground pork (WFGP) production may pose risks to public health. To assess the relative contribution of DTLNs to human salmonellosis occurrence associated with ground pork consumption and to investigate potential critical control points in the slaughter-to-table continuum for the control of human salmonellosis in the United States, a quantitative microbial risk assessment (QMRA) model was established. The model predicted an average of 45 cases of salmonellosis (95% CI = [19, 71]) per 100,000 Americans annually due to WFGP consumption. Sensitivity analysis of all stochastic input variables showed that cooking temperature was the most influential parameter for reducing salmonellosis cases associated with WFGP meals, followed by storage temperature and Salmonella concentration on contaminated carcass surface before fabrication. The input variables were grouped to represent three main factors along the slaughter-to-table chain influencing Salmonella doses ingested via WFGP meals: DTLN-related factors, factors at processing other than DTLNs, and consumer-related factors. The evaluation of the impact of each group of factors by second-order Monte Carlo simulation showed that DTLN-related factors had the lowest impact on the risk estimate among the three groups of factors. These findings indicate that interventions to reduce Salmonella contamination in DTLNs or to remove DTLNs from WFGP products may be less critical for reducing human infections attributable to ground pork than improving consumers' cooking habits or interventions of carcass decontamination at processing.


Angiofibroma of the nasal cavity in 13 dogs.
This case series describes a rare entity, nasal angiofibroma, in 13 dogs that were presented to the University of Wisconsin, School of Veterinary Medicine from 1988 to 2000. All dogs in this case series presented with clinical signs and radiographic changes that were strongly suggestive of a locally invasive neoplasm. However, histopathology completed on transnostral core biopsy samples revealed benign appearing vascular proliferation with secondary lymphosuppurative inflammation was established despite cytologic criteria of malignancy present in five dogs. On the basis of the outcomes in this case series, nasal angiofibroma should be considered a differential for dogs presenting with clinical signs consistent with a malignant nasal tumour.


A Survey on Computational Methods for Investigation on ncRNA-Disease Association through the Mode of Action Perspective.
Molecular and sequencing technologies have been successfully used in decoding biological mechanisms of various diseases. As revealed by many novel discoveries, the role of non-coding RNAs (ncRNAs) in understanding disease mechanisms is becoming increasingly important. Since ncRNAs primarily act as regulators of transcription, associating ncRNAs with diseases involves multiple inference steps. Leveraging the fast-accumulating high-throughput screening results, a number of computational models predicting ncRNA-disease associations have been developed. These tools suggest novel disease-related biomarkers or therapeutic targetable ncRNAs, contributing to the realization of precision medicine. In this survey, we first introduce the biological roles of different ncRNAs and summarize the databases containing ncRNA-disease associations. Then, we suggest a new trend in recent computational prediction of ncRNA-disease association, which is the mode of action (MoA) network perspective. This perspective includes integrating ncRNAs with mRNA, pathway and phenotype information. In the next section, we describe computational methodologies widely used in this research domain. Existing computational studies are then summarized in terms of their coverage of the MoA network. Lastly, we discuss the potential applications and future roles of the MoA network in terms of integrating biological mechanisms for ncRNA-disease associations.


Incorporation of fibronectin to enhance cytocompatibility in multilayer elastin-like protein scaffolds for tissue engineering.
Recombinant, elastin-like protein (ELP) polymers are of significant interest for the engineering of compliant, resilient soft tissues due to a wide range of tunable mechanical properties, biostability, and biocompatibility. Here, we enhance endothelial cell (EC) and mesenchymal stem cell compatibility with ELP constructs by addition of fibronectin (Fn) to the surface or bulk of ELP hydrogels. We find that cell adhesion, proliferation, and migration can be modulated by Fn addition. Adsorption of Fn to the hydrogel surface is more efficient than bulk blending. Surface immobilization of Fn by genipin crosslinking leads to stability without loss of bioactivity. Gels of varying mechanical modulus do not alter cell adhesion, proliferation, and migration in the range we investigate. However, more compliant gels promote an EC morphology suggesting tubulogenesis or network formation, whereas stiffer gels promote cobblestone morphology. Multilayer structures consisting of thin ELP sheets reinforced with collagen microfiber are fabricated and laminated through the culture of MSCs at layer interfaces. High cell viability in the resulting three-dimensional constructs suggests the applicability of Fn to the design of strong, resilient artificial blood vessels and other soft tissue replacements.


Ultrasound Imaging in Radiation Therapy: From Interfractional to Intrafractional Guidance.
External beam radiation therapy (EBRT) is included in the treatment regimen of the majority of cancer patients. With the proliferation of hypofractionated radiotherapy treatment regimens, such as stereotactic body radiation therapy (SBRT), interfractional and intrafractional imaging technologies are becoming increasingly critical to ensure safe and effective treatment delivery. Ultrasound (US)-based image guidance systems offer real-time, markerless, volumetric imaging with excellent soft tissue contrast, overcoming the limitations of traditional X-ray or computed tomography (CT)-based guidance for abdominal and pelvic cancer sites, such as the liver and prostate. Interfractional US guidance systems have been commercially adopted for patient positioning but suffer from systematic positioning errors induced by probe pressure. More recently, several research groups have introduced concepts for intrafractional US guidance systems leveraging robotic probe placement technology and real-time soft tissue tracking software. This paper reviews various commercial and research-level US guidance systems used in radiation therapy, with an emphasis on hardware and software technologies that enable the deployment of US imaging within the radiotherapy environment and workflow. Previously unpublished material on tissue tracking systems and robotic probe manipulators under development by our group is also included.


Vitamin A deficiency following small-bowel bypass surgery for obesity.
Side effects are common in individuals who have undergone small-bowel bypass surgery for morbid obesity. Most of these side effects subside after a few months. More serious complications may require reestablishment of the bypassed loop. Rarely have vitamin deficiencies been observed. Development of vitamin A deficiency in a patient was characterized by phrynoderma and night blindness. This was promptly reversed by oral treatment with vitamin A. There was no improvement in low to subnormal serum levels of fat-soluble vitamins after a course of tetracycline hydrochloride. Studies suggested presence of a malabsorption state probably due to rapid transit time through the small bowel and reduced absorptive surface.


Does calcium supplementation increase cardiovascular risk?
Calcium supplementation is widely used for the prevention of osteoporosis in postmenopausal women and in men. While there has been ongoing debate regarding its effectiveness in fracture prevention, the underlying assumption has been that, even if it was not particularly effective, at least it was safe. The recent finding of the Auckland Calcium Study that myocardial infarctions were more common in women randomised to calcium calls this assumption into question, and consideration of vascular event data from other calcium trials does not refute the Auckland findings. Meta-analyses of these data will be necessary to settle this matter. It is already accepted that calcium supplements increase vascular risk in patients with renal compromise, even in those not yet requiring dialysis. Also, there is substantial epidemiological evidence that serum calcium levels in the upper part of the normal range are a risk factor for vascular disease, and that calcium supplements acutely elevate serum calcium - a combination of findings that lends plausibility to supplementation increasing vascular risk. As there are reasonable grounds for doubting the safety of calcium supplements, and as the evidence for their efficacy in fracture prevention remains marginal, we suggest that there should be a reappraisal of their role in the management of osteoporosis, with a greater emphasis on agents known to prevent fractures.


Differences in Outcomes Reported by Patients With Inflammatory Bowel Diseases vs Their Health Care Professionals.
Inflammatory bowel disease (IBD) scoring systems combine patient-reported data with physicians' observations to determine patient outcomes, but these systems are believed to have limitations. We used real-world data from a large IBD cohort in Switzerland to compare results between patients and healthcare professionals from scoring systems for Crohn's disease (CD) and ulcerative colitis (UC). We collected data from the Swiss IBD cohort, beginning in 2006, using 2453 reports for 1385 patients (52% female, 58% with CD). During office visits, physicians asked patients about signs and symptoms and recorded their answers (health care professional-reported outcomes). On a later date, patients received a questionnaire at home (independently of the medical visit), complete it, and sent it back to the data center. Patients also completed the short form 36 and IBD quality of life (QoL) questionnaires. We calculated Cohen's kappa (κ) statistics to assess the level of agreement in scores between patients and health care professionals (Δt between reports collected less than 2 months apart). We used Spearman correlation coefficients (ρ) to compare general well-being (GWB) and QoL scores determined by patients vs health care professionals. Our primary aim was to investigate the overall and individual level of agreement on signs and symptoms reported by health care professionals vs patients. The best level of agreement (although moderate) was observed for number of stools last week in patients with CD (κ = 0.47), and nocturnal diarrhea in patients with UC (κ = 0.52). Agreement was low on level of abdominal pain (κ = 0.31 for patients with CD and κ = 0.37 for patients with UC) and GWB (κ = 0.23 for patients with CD and κ = 0.26 for patients with UC). Patients reported less severe abdominal pain and worse GWB (CD) or better GWB (UC) than that determined by health care professionals. Patient self-rated GWB correlated with IBD quality of life (ρ = 0.68 for patients with CD and ρ = 0.70 for patients with UC) and SF-36 physical scores (ρ = 0.55 for patients with CD and ρ = 0.60 for patients with UC); there was no correlation between health care professional-rated GWB and QoL. In a comparison of patient vs health care provider-reported outcomes in a Swiss IBD cohort, we found that health care professionals seem to misinterpret patients' complaints. Patients self-rated GWB correlated with QoL scores, indicating that reporting GWB in a single question is possible and relevant, but can vary based on how the data are collected.


The role of proximal dynamic joint stability in the development of exertional medial tibial pain: a prospective study.
To prospectively determine risk factors contributing to the development of exertional medial tibial pain (EMTP). Data were prospectively collected on healthy female students in physical education, who were freshmen in 2010-2011 and 2011-2012. Eighty-six female students aged 19.38±0.85 years, were tested at the beginning of their first academic year. Kinematic parameters in the frontal and transverse plane were measured during a single-leg drop jump (SLDJ). For further analysis, the SLDJ task was divided in two phases: touchdown until maximal knee flexion (MKF) and then MKF until take-off, representing landing and push-off phase, respectively. The injury follow-up of the students was assessed using a weekly online questionnaire and a 3-monthly retrospective control questionnaire. EMTP was diagnosed by an experienced medical doctor. Cox regression analysis was used to identify the potential risk factors for the development of EMTP. During injury follow-up (1-2 years), 22 participants were diagnosed with EMTP. The results of this study identified that increased range of motion (ROM) in the transverse plane of hip and thorax during landing (p=0.010 and 0.026, respectively) and during push off (p=0.019 and 0.045, respectively) are predictive parameters for the development of EMTP in women. Increased ROM values of hip and thorax in the transverse plane, which can be interpreted as impaired ability to maintain dynamic joint stability resulting in increased accessory movements, are significant contributors to the development of EMTP in women.


Automated support for pharmacovigilance: a proposed system.
Governments, manufacturers, and other entities are interested in adverse event surveillance of marketed medical products. FDA's Center for Drug Evaluation and Research redesigned the post-marketing adverse reaction surveillance process to use the advantages of new technology. As part of this effort, a 'Pharmacovigilance Working Group' designed a new strategy for the review and analyses of adverse event reports received by FDA. It created requirements which divided signal detection into five tiers: (1) Single 'urgent' reports would be sent to reviewers' workstations nightly for immediate attention. Reviewers would be able to customize definitions of 'urgent' (events that should not wait for aggregate review). (2) Single urgent reports would be placed in a context matrix containing historical counts of similar events to aid in initial interpretation. (3) In this first level of aggregate review, graphical displays would highlight patterns within all the reports, both urgent and non-urgent, and (4) periodic drug-specific tabled-based reports would display the newly received reports across a pre-defined variety of displays. These four tiers would produce passive and criteria-based results which would be presented to safety reviewers' electronic workstations. (5) Active query capabilities (routine, such as age, sex, and year distributions, as well as ad hoc) would be available for exploring alerted issues. The historical database would be migrated into the new format. All historical and new reaction data would be coded with the new MedDRA (Medical Dictionary for Regulatory Activities) scheme. The strategy was to design a full data capture system which effectively exploits current computing advances and technical performance to automate many aspects of initial adverse event review, supporting more efficient and effective clinical assessment of safety signals.


Caustics caused by refraction in the interface between an isotropic medium and a uniaxial crystal.
In general, a caustic by refraction at an arbitrary surface is commonly known as a diacaustic. We study the formation of the diacaustic in a plane interface between an isotropic medium and a uniaxial crystal, for both ordinary and extraordinary rays, when the crystal axis is perpendicular to the plane of incidence and when it lies in the plane of incidence. For the latter case two special positions of the crystal axis with respect to the normal to the refracting surface for the extraordinary rays are treated.