Interviewing older people by telephone following initial contact by postal survey.
Although the use of the telephone for interviewing has become a commonly used and largely accepted research method, the literature on this subject makes it clear that certain reservations remain. Some of these relate to problems encountered when interviewing older adults by telephone and others concern the use of the telephone in interviews where there has been no prior face-to-face contact. The conclusions of others who have studied these two sets of problems in combination are that special difficulties exist. These conclusions are examined with reference to researchers' experiences of conducting a study on continence care, in which a postal survey (as opposed to face-to-face contact) preceded telephone interviews. Interviews were conducted with adults of all ages, including a high proportion of older people. Researchers encountered few major difficulties and were satisfied with both response rate and response quality. Research to compare the effects of a variety of initial contact modes on telephone interviews with both younger and older adults is recommended.


Optimization of orders in multichannel fractional Fourier-domain filtering circuits and its application to the synthesis of mutual-intensity distributions.
Owing to the nonlinear nature of the problem, the transform orders in fractional Fourier-domain filtering configurations have usually not been optimized but chosen uniformly. We discuss the optimization of these orders for multi-channel-filtering configurations by first finding the optimal filter coefficients for a larger number of uniformly chosen orders, and then maintaining the most important ones. The method is illustrated with the problem of synthesizing desired mutual-intensity distributions. The method we propose allows those fractional Fourier domains, which add little benefit to the filtering process but increase the overall cost, to be pruned, so that comparable performance can be attained with less cost, or higher performance can be obtained with the same cost. The method we propose is more likely to be useful when confronted with low-cost rather than high-performance applications, because larger improvements are obtained when the use of a smaller number of filters is desired.


Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2 (1 × 10(6) IU/m(2)) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rose >fivefold (P < .001) and >fourfold (P < .001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg:Tcon ratio rose >fivefold (P < .001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P = .005; 249 vs 461 days after cGVHD onset; P = .03). Treg:Tcon ratios ≥0.07 at baseline and ≥0.2 at week 1 also predicted clinical response (P = .003; P = .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg:Tcon ratio gradually normalized. Low-dose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated.


Cloning and functional characterization of seed-specific LEC1A promoter from peanut (Arachis hypogaea L.).
LEAFY COTYLEDON1 (LEC1) is a HAP3 subunit of CCAAT-binding transcription factor, which controls several aspects of embryo and postembryo development, including embryo morphogenesis, storage reserve accumulation and skotomorphogenesis. Herein, using the method of chromosomal walking, a 2707bp upstream sequence from the ATG initiation codon site of AhLEC1A which is a homolog of Arabidopsis LEC1 was isolated in peanut. Its transcriptional start site confirmed by 5' RACE was located at 82 nt from 5' upstream of ATG. The bioinformatics analysis revealed that there existed many tissue-specific elements and light responsive motifs in its promoter. To identify the functional region of the AhLEC1A promoter, seven plant expression vectors expressing the GUS (β-glucuronidase) gene, driven by 5' terminal series deleted fragments of AhLEC1A promoter, were constructed and transformed into Arabidopsis. Results of GUS histochemical staining showed that the regulatory region containing 82bp of 5' UTR and 2228bp promoter could facilitate GUS to express preferentially in the embryos at different development periods of Arabidopsis. Taken together, it was inferred that the expression of AhLEC1A during seed development of peanut might be controlled positively by several seed-specific regulatory elements, as well as negatively by some other regulatory elements inhibiting its expression in other organs. Moreover, the GUS expression pattern of transgenic seedlings in darkness and in light was relevant to the light-responsive elements scattered in AhLEC1A promoter segment, implying that these light-responsive elements harbored in the AhLEC1A promoter regulate skotomorphogenesis of peanut seeds, and AhLEC1A expression was inhibited after the germinated seedlings were transferred from darkness to light.


Mouse beta defensin-1 is a functional homolog of human beta defensin-1.
Defensin are 3-4 kDa antimicrobial peptides of which three distinct families have been identified; alpha-defensin, beta-defensins, and insect defensins. Recent investigations have shown that beta-defensins are present in the human airways and may be relevant to the pathogenesis of cystic fibrosis (CF) lung disease. We report here the further characterization of a recently identified mouse beta-defensin gene, Defb1, sometimes referred to as mBD-1, which is homologous to the human airway beta defensin hBD-1. We report that Defb1 is expressed in a variety of tissues including the airways and, similar to hBD-1, is not upregulated by lipopolysaccharide (LPS). Defb1 was found to consist of two small exons separated by a 16-kb intron and cytogenetic, and physical mapping linked it to the alpha defensin gene cluster on mouse Chromosome (Chr) 8. Functional studies demonstrate that, like hBD-1, Defb1 demonstrates a salt-sensitive antimicrobial activity against Pseudomonas aeruginosa. Of relevance to CF lung disease is the fact that neither the hBD-1 nor the mBD-1 peptides are active against Burkholderia cepacia.


Dynamic postprandial hepatic stiffness augmentation assessed with MR elastography in patients with chronic liver disease.
MR elastography (MRE) is an MRI-based technique for quantitatively assessing tissue stiffness by studying shear wave propagation through tissue. The goal of this study was to test the hypothesis that hepatic MRE performed before and after a meal will result in a postprandial increase in hepatic stiffness among patients with hepatic fibrosis because of transiently increased portal pressure. Twenty healthy volunteers and 25 patients with biopsyproven hepatic fibrosis were evaluated. Preprandial MRE measurements were performed after overnight fasting. A liquid test meal was administered, and 30 minutes later a postprandial MRE acquisition was performed. Identical imaging parameters and analysis regions of interest were used for pre- and postprandial acquisitions. The results in the 20 subjects without liver disease showed a mean stiffness change of 0.16 ± 0.20 kPa (range, -0.12 to 0.78 kPa) or 8.08% ± 10.33% (range, -5.36% to 41.7%). The hepatic stiffness obtained in the 25 patients with hepatic fibrosis showed a statistically significant increase in postprandial liver stiffness, with mean augmentation of 0.89 ± 0.96 kPa (range, 0.17-4.15 kPa) or 21.24% ± 14.98% (range, 7.69%-63.3%). MRE-assessed hepatic stiffness elevation in patients with chronic liver disease has two major components: a static component reflecting structural change or fibrosis and a dynamic component reflecting portal pressure that can increase after a meal. These findings will provide motivation for further studies to determine the potential value of assessing postprandial hepatic stiffness augmentation for predicting the progression of fibrotic disease and the development of portal hypertension. The technique may also provide new insights into the natural history and pathophysiology of chronic liver disease.


Implementation of Patient Engagement Tools in Electronic Health Records to Enhance Patient-Centered Communication: Protocol for Feasibility Evaluation and Preliminary Results.
Patient-physician communication during clinical encounters is essential to ensure quality of care. Many studies have attempted to improve patient-physician communication. Incorporating patient priorities into agenda setting and medical decision-making are fundamental to patient-centered communication. Efficient and scalable approaches are needed to empower patients to speak up and prepare physicians to respond. Leveraging electronic health records (EHRs) in engaging patients and health care teams has the potential to enhance the integration of patient priorities in clinical encounters. A systematic approach to eliciting and documenting patient priorities before encounters could facilitate effective communication in such encounters. In this paper, we report the design and implementation of a set of EHR tools built into clinical workflows for facilitating patient-physician joint agenda setting and the documentation of patient concerns in the EHRs for ambulatory encounters. We engaged health information technology leaders and users in three health care systems for developing and implementing a set of EHR tools. The goal of these tools is to standardize the elicitation of patient priorities by using a previsit "patient important issue" questionnaire distributed through the patient portal to the EHR. We built additional EHR documentation tools to facilitate patient-staff communication when the staff records the vital signs and the reason for the visit in the EHR while in the examination room, with a simple transmission method for physicians to incorporate patient concerns in EHR notes. The study is ongoing. The anticipated completion date for survey data collection is November 2021. A total of 34,037 primary care patients from three health systems (n=26,441; n=5136; and n=2460 separately recruited from each system) used the previsit patient important issue questionnaire in 2020. The adoption of the digital previsit questionnaire during the COVID-19 pandemic was much higher in one health care system because it expanded the use of the questionnaire from physicians participating in trials to all primary care providers midway through the year. It also required the use of this previsit questionnaire for eCheck-ins, which are required for telehealth encounters. Physicians and staff suggested anecdotally that this questionnaire helped patient-clinician communication, particularly during the COVID-19 pandemic. EHR tools have the potential to facilitate the integration of patient priorities into agenda setting and documentation in real-world primary care practices. Early results suggest the feasibility and acceptability of such digital tools in three health systems. EHR tools can support patient engagement and clinicians' work during in-person and telehealth visits. They could potentially exert a sustained influence on patient and clinician communication behaviors in contrast to prior ad hoc educational efforts targeting patients or clinicians. ClinicalTrials.gov NCT03385512; https://clinicaltrials.gov/ct2/show/NCT03385512. DERR1-10.2196/30431.


The rights of man and animal experimentation.
Since emotions give contradictory signals about animal experimentation in medical science, man's relationship to animals must be based upon reason. Thomas Aquinas argues that man is essentially different from animals because man's intellectual processes show evidence of an abstract mechanism not possessed by animals. Man's rights arise in association with this essential difference. The consequence is that only man possesses true rights by Aquinas's definition; animals have them only by analogy. However, cruelty to animals is illicit and they should be protected, principally not because they have rights, but because he who is cruel to animals is more likely to be cruel to his fellowman. If there is a need for animal experimentation in science for the good of man, this approach gives philosophical justification for experimentation, since man's well-being must come before that of animals because of his unique possession of rights. However, those experiments should be carried out in the kindest way possible, to promote kindness towards man. To see man as solely part of a biological continuum in competition for rights with those beings close to him biologically, detracts from man's dignity.


Reorganisation of the microtubular cytoskeleton by embryonic microtubule-associated protein 2 (MAP2c).
Microtubule-associated protein 2c (MAP2c) is one of a set of embryonic MAP forms that are expressed during neuronal differentiation in the developing nervous system. We have investigated its mode of action by expressing recombinant protein in non-neuronal cell lines using cell cDNA transfection techniques. At every level of expression, all the MAP2c was bound to cellular microtubules. At low MAP2c levels, the microtubules retained their normal arrangement, radiating from the centrosomal microtubule-organising centre (MTOC) but at higher levels an increasing proportion of microtubules occurred independently of the MTOC. In most cells, radially oriented microtubules still attached to the MTOC co-existed with detached microtubules, suggesting that the primary effect of MAP2 is to increase the probability that tubulin polymerisation will occur independently of the MTOC. The MTOC-independent microtubules formed bundles whose distribution depended on their length in relation to the diameter of the transfected cell. Short bundles were attached to the cell cortex at one end and followed a straight course through the cytoplasm, whereas longer bundles followed a curved path around the periphery of the cell. By comparing these patterns to those produced by two chemical agents that stabilise microtubules, taxol and dimethyl sulphoxide, we conclude that effects of MAP2c arise from two sources. It stabilises microtubules without providing assembly initiation sites and as a result produces relatively few, long microtubule bundles. These bend only when they encounter the restraining influence of the cortical cytoskeleton of the cell, indicating that MAP2c also imparts stiffness to them. By conferring these properties of stability and stiffness to neuronal microtubules MAP2c contributes to supporting the structure of developing neurites.


Correlation of pelvic orientation with adult scoliosis.
Prospective analysis of elderly volunteers with adult scoliosis. To analyze the correlation between the sagittal pelvic parameters and adult scoliosis. There are little data on the relationship between the sagittal pelvic parameters and adult scoliosis. The study group comprised 108 elderly volunteers (21 men and 87 women). All underwent anteroposterior and lateral radiographs of whole spine including hip joints. The participants were classified into 3 groups: normal (Cobb angle <10 degrees), low grade (Cobb angle 10 to 19 degrees), and high grade (Cobb angle ≥20 degrees). The radiographic parameters were magnitude, location and direction of curves, sacral slope, pelvic tilting, pelvic incidence, S1 overhang, thoracic kyphosis, lumbar lordosis, and C7 plumbline. Statistical analysis was performed to identify the significant differences between the groups. Analysis of variance and Pearson correlation coefficient were used to determine the significance. The mean age and Cobb angle of the participants was 73 years (range: 61 to 87 y), and 11.2 degrees (range: 0.3 to 36.3 degrees), respectively. There were no significant differences in the sacral slope, thoracic kyphosis, and lumbar lordosis between the 3 groups (P>0.05, analysis of variance). The mean pelvic tilting of the high-grade or low-grade groups was significantly higher than that of the normal group (P<0.0001, P=0.003, Tukey HSD post hoc test). The high-grade group had significantly higher pelvic incidence than either the low-grade or normal groups (P=0.016, P<0.0001), and the low-grade group had higher pelvic incidence than the normal group (P<0.0001). The high-grade or low-grade groups had a significantly higher S1 overhang than the normal groups (P<0.0001, P=0.002). Comparing the C7 plumbline, high-grade or low-grade groups had a significantly higher value than normal groups (P<0.0001, P=0.012). The pelvic incidence, pelvic tilting, and S1 overhang were significantly correlated with the magnitude of curvature (r=0.592, P=0.0001; r=0.434, P=0.0001; and r=0.461, P=0.0001, respectively). There was a significant correlation between the sagittal pelvic parameters and adult scoliosis in elderly volunteers. There was a significant difference in the pelvic incidence between the normal, low-grade, high-grade adult scoliosis groups. The pelvic tilting and S1 overhang of the high-grade or low-grade groups were significantly higher than the normal group. These 3 parameters were also associated with the magnitude of curvature.


Biomarkers in Sporadic and Familial Alzheimer's Disease.
Most forms of Alzheimer's disease (AD) are sporadic (sAD) or inherited in a non-Mendelian fashion, and less than 1% of cases are autosomal-dominant. Forms of sAD do not exhibit familial aggregation and are characterized by complex genetic and environmental interactions. Recently, the expansion of genomic methodologies, in association with substantially larger combined cohorts, has resulted in various genome-wide association studies that have identified several novel genetic associations of AD. Currently, the most effective methods for establishing the diagnosis of AD are defined by multi-modal pathways, starting with clinical and neuropsychological assessment, cerebrospinal fluid (CSF) analysis, and brain-imaging procedures, all of which have significant cost- and access-to-care barriers. Consequently, research efforts have focused on the development and validation of non-invasive and generalizable blood-based biomarkers. Among the modalities conceptualized by the systems biology paradigm and utilized in the "exploratory biomarker discovery arena", proteome analysis has received the most attention. However, metabolomics, lipidomics, transcriptomics, and epigenomics have recently become key modalities in the search for AD biomarkers. Interestingly, biomarker changes for familial AD (fAD), in many but not all cases, seem similar to those for sAD. The integration of neurogenetics with systems biology/physiology-based strategies and high-throughput technologies for molecular profiling is expected to help identify the causes, mechanisms, and biomarkers associated with the various forms of AD. Moreover, in order to hypothesize the dynamic trajectories of biomarkers through disease stages and elucidate the mechanisms of biomarker alterations, updated and more sophisticated theoretical models have been proposed for both sAD and fAD.


A comparative analysis of metabarcoding and morphology-based identification of benthic communities across different regional seas.
In a world of declining biodiversity, monitoring is becoming crucial. Molecular methods, such as metabarcoding, have the potential to rapidly expand our knowledge of biodiversity, supporting assessment, management, and conservation. In the marine environment, where hard substrata are more difficult to access than soft bottoms for quantitative ecological studies, Artificial Substrate Units (ASUs) allow for standardized sampling. We deployed ASUs within five regional seas (Baltic Sea, Northeast Atlantic Ocean, Mediterranean Sea, Black Sea, and Red Sea) for 12-26 months to measure the diversity and community composition of macroinvertebrates. We identified invertebrates using a traditional approach based on morphological characters, and by metabarcoding of the mitochondrial cytochrome oxidase I (COI) gene. We compared community composition and diversity metrics obtained using the two methods. Diversity was significantly correlated between data types. Metabarcoding of ASUs allowed for robust comparisons of community composition and diversity, but not all groups were successfully sequenced. All locations were significantly different in taxonomic composition as measured with both kinds of data. We recovered previously known regional biogeographical patterns in both datasets (e.g., low species diversity in the Black and Baltic Seas, affinity between the Bay of Biscay and the Mediterranean). We conclude that the two approaches provide complementary information and that metabarcoding shows great promise for marine monitoring. However, until its pitfalls are addressed, the use of metabarcoding in monitoring of rocky benthic assemblages should be used in addition to classical approaches rather than instead of them.


Clinical and economic burden of HPV-related cancers in the US veteran population.
Human papillomavirus (HPV) is one of the most common sexually transmitted infection in the United States and can lead to cervical, vulvovaginal, anal, penile, and oropharyngeal cancers. Compared with the general population, US military members are at a higher risk of HPV-related conditions, yet vaccination rates are relatively low in this population. As many service members may not be diagnosed with HPV-related cancers until after they leave active service, the objective of this study was to determine the incidence, prevalence, and economic burden of HPV-related cancers among US veterans. The study used the 2014-2018 Veterans Health Administration (VHA) database to identify newly diagnosed adult patients (cases) with HPV-related cancers, including cervical, vulvovaginal, anal, penile, and oropharyngeal cancers. Cases were matched by age, race, and sex to patients without HPV related cancer (controls). Outcome measures included annual incidence, prevalence, health care resource utilization (HCRU), and costs. These outcomes were calculated from the index date (first cancer diagnosis) through the earliest of 24 months, death, or end of study period. Adjusted results were examined using generalized linear models. The annual prevalence and incidence rates of HPV-related cancers ranged from 43 (anal) to 790 (oropharyngeal) cases per million (CPM), and four (anal) to 131 (cervical) CPM, respectively. Compared with controls, cases had significantly higher annual HCRU. Mean numbers of annual inpatient hospitalizations were several times higher compared to controls (cervical: 6.7-times (×); vulvovaginal: 2.7×; penile: 6.6×; oropharyngeal: 10.2×; and anal: 14.9×; all p < 0.01). Similarly, cases had significantly higher all-cause healthcare costs vs. matched controls across all cancer types: cervical ($24,252 vs. $10,402), vulvovaginal ($34,801 vs. $10,913), penile ($42,772 vs. $9,139), oropharyngeal ($82,763 vs. $10,017), and anal ($98,146 vs. $8,339); (all p < 0.01). HPV-related cancers may cause significant clinical and economic burden within the VHA system. Given the consequences of HPV-related cancers among veterans who did not have access to the vaccine, HPV vaccination of active military and eligible veterans should be considered a healthcare priority.


Development and evaluation of a portable sham transcranial magnetic stimulation system.
Transcranial magnetic stimulation (TMS) is a relatively noninvasive brain stimulation technology that can focally stimulate the human cortex. One significant limitation of much of the TMS research to date concerns the nature of the placebo or sham conditions used. When TMS pulses are delivered repetitively (especially prefrontal TMS), it is often experienced as painful. Most sham TMS techniques produce identical sounds to active TMS, but they do not cause much, if any, scalp or facial sensation or discomfort. This is a serious problem when investigators are attempting to evaluate the effects of TMS by using traditional sham techniques because of unintended systematic differences between real and sham TMS groups (ie, confounds). As long as traditional approaches to sham TMS are used, the validity of the inferences regarding the efficacy of TMS will be limited. Although some other sophisticated systems have been developed to address these concerns, they tend to be expensive and lack portability. Portability will likely become more and more important as TMS applications expand into different clinical areas (eg, TMS in the postanesthesia care unit after surgery). This study describes a portable electrical TMS sham system (eSham system) modeled after the James Long System that was designed to produce similar scalp sensations as real TMS. Preliminary results are presented on 9 healthy adults who received both real and eSham 10 Hz repetitive TMS (rTMS) (at 80%, 100%, and 120% of resting motor threshold) over the prefrontal cortex and rated the sensation quality (pain, tingling, sharpness, piercing, electric, tugging, pinching), tolerability, and location. Real TMS and eSham TMS were rated similarly across all seven sensory dimensions examined. Real and eSham TMS were also rated similarly with respect to tolerability and perceived location of the TMS-induced sensations. The eSham system may be a simple, affordable, and portable approach to providing convincing sham TMS for future clinical trials. This study provides preliminary evidence supporting the use of the eSham system. Future larger-scale studies are warranted.


Local-global interaction and the emergence of scale-free networks with community structures.
Understanding complex networks in the real world is a nontrivial task. In the study of community structures we normally encounter several examples of these networks, which makes any statistical inferencing a challenging endeavor. Researchers resort to computer-generated networks that resemble networks encountered in the real world as a means to generate many networks with different sizes, while maintaining the real-world characteristics of interest. The generation of networks that resemble the real world turns out in itself to be a complex search problem. We present a new rewiring algorithm for the generation of networks with unique characteristics that combine the scale-free effects and community structures encountered in the real world. The algorithm is inspired by social interactions in the real world, whereby people tend to connect locally while occasionally they connect globally. This local-global coupling turns out to be a powerful characteristics that is required for our proposed rewiring algorithm to generate networks with community structures, power law distributions both in degree and in community size, positive assortative mixing by degree, and the rich-club phenomenon.


Rapid 'mix and read' assay for scalable detection of SARS-CoV-2 antibodies in patient plasma.
The human beta coronavirus SARS-CoV-2, causative virus of COVID-19, has infected more than 15 million people globally and continues to spread. Widespread, population level testing to detect active and past infections is critical to curb the COVID-19 pandemic. Antibody (serological) testing is the only option for detecting past infections outside the narrow window accessible to nucleic acid-based tests. However, currently available serological assays commonly lack scalability. Here, we describe the development of a rapid homogenous serological assay for the detection of antibodies to SARS-CoV-2 in patient plasma. We show that the fluorescence-based assay accurately detects seroconversion in COVID-19 patients from less than 1 microliter of plasma. Using a cohort of samples from COVID-19 infected or healthy individuals, we demonstrate detection with 100% sensitivity and specificity. This assay addresses an important need for a robust, low barrier to implementation, and scalable serological assay with complementary strengths to currently available serological platforms.


Integrated biogas upgrading and hydrogen utilization in an anaerobic reactor containing enriched hydrogenotrophic methanogenic culture.
Biogas produced by anaerobic digestion, is mainly used in a gas motor for heat and electricity production. However, after removal of CO(2) , biogas can be upgraded to natural gas quality, giving more utilization possibilities, such as utilization as autogas, or distant utilization by using the existing natural gas grid. The current study presents a new biological method for biogas upgrading in a separate biogas reactor, containing enriched hydrogenotrophic methanogens and fed with biogas and hydrogen. Both mesophilic- and thermophilic anaerobic cultures were enriched to convert CO(2) to CH(4) by addition of H(2) . Enrichment at thermophilic temperature (55°C) resulted in CO(2) and H(2) bioconversion rate of 320 mL CH(4) /(gVSS h), which was more than 60% higher than that under mesophilic temperature (37°C). Different dominant species were found at mesophilic- and thermophilic-enriched cultures, as revealed by PCR-DGGE. Nonetheless, they all belonged to the order Methanobacteriales, which can mediate hydrogenotrophic methanogenesis. Biogas upgrading was then tested in a thermophilic anaerobic reactor under various operation conditions. By continuous addition of hydrogen in the biogas reactor, high degree of biogas upgrading was achieved. The produced biogas had a CH(4) content, around 95% at steady-state, at gas (mixture of biogas and hydrogen) injection rate of 6 L/(L day). The increase of gas injection rate to 12 L/(L day) resulted in the decrease of CH(4) content to around 90%. Further study showed that by decreasing the gas-liquid mass transfer by increasing the stirring speed of the mixture the CH(4) content was increased to around 95%. Finally, the CH(4) content around 90% was achieved in this study with the gas injection rate as high as 24 L/(L day).


A comparison of endogenous digoxin-like immunoreactivity and sodium transport inhibitory activity in umbilical arterial and venous serum.
1. Endogenous digoxin-like immunoreactivity (EDLI) was measured by radioimmunoassay for digoxin in 13 paired samples of arterial and venous umbilical cord serum. EDLI was present in vein and artery, but was higher in the venous samples (P less than 0.025). 2. The venous cord serum inhibited the ouabain-sensitive sodium efflux rate constant of a normal mixed leucocyte population when compared with the effect of arterial cord serum (P less than 0.005). 3. It is suggested that the placenta may be involved in the production or metabolism of neonatal EDLI and of the inhibitor of sodium transport.


Telomere length is a determinant of emphysema susceptibility.
Germline mutations in the enzyme telomerase cause telomere shortening, and have their most common clinical manifestation in age-related lung disease that manifests as idiopathic pulmonary fibrosis. Short telomeres are also a unique heritable trait that is acquired with age. We sought to understand the mechanisms by which telomerase deficiency contributes to lung disease. We studied telomerase null mice with short telomeres. Although they have no baseline histologic defects, when mice with short telomeres are exposed to chronic cigarette smoke, in contrast with controls, they develop emphysematous air space enlargement. The emphysema susceptibility did not depend on circulating cell genotype, because mice with short telomeres developed emphysema even when transplanted with wild-type bone marrow. In lung epithelium, cigarette smoke exposure caused additive DNA damage to telomere dysfunction, which limited their proliferative recovery, and coincided with a failure to down-regulate p21, a mediator of cellular senescence, and we show here, a determinant of alveolar epithelial cell cycle progression. We also report early onset of emphysema, in addition to pulmonary fibrosis, in a family with a germline deletion in the Box H domain of the RNA component of telomerase. Our data indicate that short telomeres lower the threshold of cigarette smoke-induced damage, and implicate telomere length as a genetic susceptibility factor in emphysema, potentially contributing to its age-related onset in humans.


Newborn chickens generate invariant object representations at the onset of visual object experience.
To recognize objects quickly and accurately, mature visual systems build invariant object representations that generalize across a range of novel viewing conditions (e.g., changes in viewpoint). To date, however, the origins of this core cognitive ability have not yet been established. To examine how invariant object recognition develops in a newborn visual system, I raised chickens from birth for 2 weeks within controlled-rearing chambers. These chambers provided complete control over all visual object experiences. In the first week of life, subjects' visual object experience was limited to a single virtual object rotating through a 60° viewpoint range. In the second week of life, I examined whether subjects could recognize that virtual object from novel viewpoints. Newborn chickens were able to generate viewpoint-invariant representations that supported object recognition across large, novel, and complex changes in the object's appearance. Thus, newborn visual systems can begin building invariant object representations at the onset of visual object experience. These abstract representations can be generated from sparse data, in this case from a visual world containing a single virtual object seen from a limited range of viewpoints. This study shows that powerful, robust, and invariant object recognition machinery is an inherent feature of the newborn brain.


Catalase-peroxidase activity is decreased in a Caulobacter crescentus rho mutant.
A Caulobacter crescentus rho::Tn5 mutant strain presenting a partially functional transcription termination factor Rho is highly sensitive to hydrogen peroxide in both exponential and stationary phases. The mutant was shown to be permanently under oxidative stress, based on fluorophore oxidation, and also to be sensitive to tert-butyl hydroperoxide and paraquat. However, the results showed that the activities of superoxide dismutases CuZnSOD and FeSOD and the alkylhydroperoxide reductase ahpC mRNA levels in the rho mutant were comparable to the wild-type control in the exponential and stationary phases. In contrast, the KatG catalase activity of the rho mutant strain was drastically decreased and did not show the expected increase in the stationary phase compared with the exponential phase. Transcription of the katG gene was increased in the rho mutant and the levels of the immunoreactive KatG protein do not differ considerably compared with the wild type in the stationary phase, suggesting that KatG activity is affected in a translational or a post-translational step.


An oral cavity profile in illicit- Drug abusers?
The aim of this study is to shed the light on the oral cavity profile assessing teeth and periodontal tissues in previously illicit drug abusers of cannabis and heroin with different drug addiction circumstances. Study population included 100 inmates, aged 21-64 years, incarcerated for previous addiction to cannabis or heroin. Personal information and drug circumstances of addiction were registered with dental and periodontal parameters including daily teeth brushing frequency, decayed missed filled teeth (DMFT), plaque index (PI), gingival index (GI), bleeding on probing (BOP), recession, and clinical attachment loss (CAL). Half of the population were illiterate, and 70% were married. Heroin was the most previously abused drug and more than 70% of the participants had been addicted for more than 12 months. Low teeth brushing activity profile dominated with higher values for DMFT and BOP in the heroin group compared with the cannabis (after age adjustment) (DMFT = 22.6 ± 7.9, 18.5 ± 9.8, respectively, P = 0.03) (BOP = 60% ± 30%, 66.6% ± 32%, respectively). In addition, higher values of BOP were recorded in the heroin injecting group compared with both of heroin fumes inhalation and cannabis smoking (BOP = 76.41% ± 27.7%, 59.12% ± 33.6%, 60.05% ± 31.8% P = 0.04, respectively), whereas PI, GI, Reces, and CAL means were comparable among groups regardless of other addiction circumstances. Abused drug type and the way its chemical form being administered would negatively affect, directly or indirectly, the oral cavity concomitantly with the sustained state of self-negligence and less interest in implementing the oral hygiene measurements. Altogether, addiction circumstances synergize leading to a distinctive dental and oral profile which would impose a burden to adapt a more customized treatment approach.


Repair of O6-propylguanine and O6-butylguanine in DNA by O6-alkylguanine-DNA alkyltransferases from rat liver and E. coli.
DNA substrates containing O6-n-butylguanine, O6-iso-butylguanine, O6-n-propylguanine and O6-iso-propylguanine were prepared by reaction of calf thymus DNA with the appropriate N-alkyl-N-nitrosourea. These substrates were used to test the ability of O6-alkylguanine-DNA alkyltransferases from Escherichia coli and rat liver to remove such alkyl groups from the O6-position of guanine. It was found that all of these adducts were removed by the alkyltransferases, but the branched alkyl chain iso-butyl- and iso-propyl adducts were removed very slowly. Also, when tested with a DNA substrate containing both O6-n-propylguanine and O6-iso-propylguanine, the alkyltransferases removed almost all of the n-propyl-adduct before the iso-propyl-adduct was attacked. Both alkyltransferases showed a decreasing rate of reaction as the size of the alkyl group increased, but there was a significant difference between the rat liver and E. coli alkyltransferase in the relative rates. The rat liver alkyltransferase repaired O6-methylguanine more slowly than the E. coli protein, but was considerably more rapid than the bacterial equivalent when acting on n-propyl- and n-butyl-adducts. The relative rates of repair were methyl much greater than ethyl greater than n-propyl greater than n-butyl greater than iso-propyl, iso-butyl for the E. coli alkyl-transferase and methyl greater than ethyl, n-propyl greater than n-butyl greater than iso-propyl, iso-butyl greater than 2-hydroxyethyl for the rat liver protein. These results indicate that differential rates of repair may contribute to the relative risks of carcinogenesis and mutagenesis by exposure to alkylating agents of different size and that rates of repair may be species specific and must be determined from specific measurements rather than extrapolated from data on other organisms.


Protocol for the Cognitive Interventions and Nutritional Supplements (CINS) trial: a randomized controlled multicenter trial of a brief intervention (BI) versus a BI plus cognitive behavioral treatment (CBT) versus nutritional supplements for patients with long-lasting muscle and back pain.
Brief intervention programs are clinically beneficial, and cost efficient treatments for low back pain, when offered at 8-12 weeks, compared with treatment as usual. However, about 30% of the patients do not return to work. The European Guidelines for treatment of chronic low back pain recommends Cognitive Behavioral Therapy (CBT), but conclude that further research is needed to evaluate the effectiveness of CBT for chronic low back pain. The aim of the multicenter CINS trial (Cognitive Interventions and Nutritional Supplements) is to compare the effectiveness of 4 different interventions; Brief Intervention, Brief Intervention and CBT, Brief Intervention and nutritional supplements of seal oil, and Brief Intervention and nutritional supplements of soy oil. All participants will be randomly assigned to the interventions. The nutritional supplements will be tested in a double blind design. 400 patients will be recruited from a population of chronic low back pain patients that have been sick listed for 2-10 months. Four outpatient clinics, located in different parts of Norway, will participate in recruitment and treatment of the patients.The Brief Intervention is a one session cognitive, clinical examination program based on a non-injury model, where return to normal activity and work is the main goal, and is followed by two booster sessions. The CBT is a tailored treatment involving 7 sessions, following a detailed manual. The nutritional supplements consist of a dosage of 10 grams of either soy or seal oil (capsules) per day for 3 months, administered in a double blind design. All patients will be followed up with questionnaires after 3, 6 and 12 months, while sick leave data will be collected up to at least 24 months after randomization. The primary outcome of the study is sick leave and will be based on register data from the National Insurance Administration. Secondary outcomes include self-reported data on disability, pain, and psychological variables. To our knowledge, the CINS trial will be the largest, randomized trial of psychological and nutritional interventions for chronic low back pain patients to date. It will provide important information regarding the effectiveness of CBT and seal oil for chronic low back pain patients. http://www.clinicaltrials.gov, with registration number NCT00463970.


[Swiss veterinary drug compendium as a tool for reconversions].
The new Swiss ordinance on veterinary drugs poses a new challenge to the veterinarians, specially those working with farm animals. A complete overview about the registered veterinary drugs and immunobiologicals is absolutely necessary to cope with these new tasks: the internet version of the Swiss Veterinary Drug Compendium is a versatile tool to satisfy this needs (http://www.tierarzneimittel.ch). Due to the frequent updates and powerful search possibilities, this database is a reliable and comprehensive information system regarding Swiss veterinary drugs. We will demonstrate how this system can be used as a valuable help in the case of reconversions of drugs (e.g. use of small animal drugs in farm animals).


A proposal for an extended dual descriptor: a possible solution when Frontier Molecular Orbital Theory fails.
In this paper, we introduce new local descriptors in the framework of Conceptual Density Functional Theory. They can be considered as an extension of the dual descriptor [Morell et al., J. Phys. Chem. A, 2005, 109, 205]. These indices are particularly suited for the discrimination between electrophilic and nucleophilic sites inside a molecule. They are computed using the densities of the electronic excited states, giving a picture of the polarization of the electron density induced by the approach of a reactant. Links with the linear-response function are discussed, and the first examples of applications are given, highlighting how these new descriptors can be used in practice for reactivity studies. It has been found that this extension of the dual descriptor can handle tricky cases, such as nitrobenzene or isoquinoline, for which Frontier Molecular Orbital Theory fails.


Contribution of cyanobacterial alkane production to the ocean hydrocarbon cycle.
Hydrocarbons are ubiquitous in the ocean, where alkanes such as pentadecane and heptadecane can be found even in waters minimally polluted with crude oil. Populations of hydrocarbon-degrading bacteria, which are responsible for the turnover of these compounds, are also found throughout marine systems, including in unpolluted waters. These observations suggest the existence of an unknown and widespread source of hydrocarbons in the oceans. Here, we report that strains of the two most abundant marine cyanobacteria, Prochlorococcus and Synechococcus, produce and accumulate hydrocarbons, predominantly C15 and C17 alkanes, between 0.022 and 0.368% of dry cell weight. Based on global population sizes and turnover rates, we estimate that these species have the capacity to produce 2-540 pg alkanes per mL per day, which translates into a global ocean yield of ∼ 308-771 million tons of hydrocarbons annually. We also demonstrate that both obligate and facultative marine hydrocarbon-degrading bacteria can consume cyanobacterial alkanes, which likely prevents these hydrocarbons from accumulating in the environment. Our findings implicate cyanobacteria and hydrocarbon degraders as key players in a notable internal hydrocarbon cycle within the upper ocean, where alkanes are continually produced and subsequently consumed within days. Furthermore we show that cyanobacterial alkane production is likely sufficient to sustain populations of hydrocarbon-degrading bacteria, whose abundances can rapidly expand upon localized release of crude oil from natural seepage and human activities.


One- and two-dimensional single-mode differential fiber-optic displacement sensor for submillimeter measurements.
Using the overlap integral method and the Gaussian approximation for the single-mode fiber-optic field, the working principle of one- and two-dimensional differential fiber-optic displacement sensors for submillimeter measurements is demonstrated. The sensors consist of one emitting fiber and two or three receiving fibers, respectively, for the one- and two-dimensional sensors. Sensor responses are intrinsically linear over a wide range of travels. Moreover, for the two-dimensional sensor, each axis of displacement can be measured independently. Sensor responses are simulated experimentally using a highly precise robot. Linearity, travel, and sensitivity are characterized for the different gap distance between the emitting and receiving fibers. A design chart that includes nonlinearity error, travel, sensitivity, and gap is finally proposed.


Peripapillary choroidal thickness variation with age and race in normal eyes.
This study examined the association between peripapillary choroidal thickness (PCT) with age and race in a group of African descent (AD) and European descent (ED) subjects with normal eyes. Optic nerve head images from enhanced depth imaging spectral-domain optical coherence tomography of 166 normal eyes from 84 subjects of AD and ED were manually delineated to identify the principal surfaces of Bruch's membrane (BM), Bruch's membrane opening (BMO), and anterior sclera (AS). Peripapillary choroidal thickness was measured between BM and AS at increasing distance away from BMO. The mean PCT was compared between AD and ED subjects and generalized estimating equation (GEE) regression analysis was used to examine the association between race and PCT overall, in each quadrant, and by distance from BMO. Models were adjusted for age, BMO area, and axial length in the regression analysis. Overall, the mean PCT increased from 63.9 μm ± 18.1 at 0 to 250 μm to 170.3 μm ± 56.7 at 1500 to 2000 μm from BMO. Individuals of AD had a greater mean PCT than those of ED at all distances from BMO (P < 0.05 at each distance) and in each quadrant (P < 0.05 in each quadrant). Results from multivariate regression indicate that ED subjects had significantly lower PCT compared to AD overall and in all quadrants and distances from BMO. Increasing age was also significantly associated with a lower PCT in both ED and AD participants. Peripapillary choroidal thickness varies with race and age, as individuals of AD have a thicker peripapillary choroid than those of ED. (ClinicalTrials.gov number, NCT00221923.).


Telehealth Decreases Rural Emergency Department Wait Times for Behavioral Health Patients in a Group of Critical Access Hospitals.
Background: Telehealth has been proposed as an important care delivery strategy to increase access to behavioral health care, especially in rural and medically-underserved settings where mental health care provider shortage areas predominate, to speed access to behavioral health care, and reduce health disparities.Introduction: This study was conducted to determine the effects of telehealth-based care delivery on clinical, temporal, and cost outcomes for behavioral health patients in rural emergency departments (EDs) of four Midwestern critical access hospitals (CAHs).Materials and Methods: Observational matched cohort study of adult (age ≥18 years) behavioral health patients treated in participating CAH EDs from 2015 to 2017 (N = 287). Telehealth cases were matched 2:1 retrospectively to nontelehealth control cases based on gender, age ±10 years, diagnosis group, and CAH, before implementation of telehealth in the rural hospitals (2005-2013; N = 153).Results: The greatest number of behavioral health cases evaluated was in the mood, anxiety, and other mental health disorders category. The majority of patients in the telehealth (74%) and nontelehealth (68%) cohorts were 18-44 years. Mean ED wait time for the telehealth cohort was significantly shorter at 12 min (95% CI 11-14 min) (p < 0.001) compared to a mean time of 27 min (95% CI 22-32 min) for the nontelehealth case controls (local provider only). The ED length of stay (LOS) for the telehealth cohort was significantly longer (M = 318 min vs. 147 min, p < 0.001) compared to the nontelehealth cohort. The end of telehealth visit to departure (EOTVtD) from the ED in minutes was evaluated to highlight factors potentially influencing delivery of behavioral health care in the ED. Across three behavioral diagnostic categories, time in minutes from end of telehealth visit to disposition/discharge was significantly longer for suicide and intentional self-injury cases (n = 100; 113 min, 95% CI 88-145; p = 0.004) compared to anxiety, mood, and other mental health disorders (n = 126; 66 min, 95% CI 52-83). There was a clinically meaningful difference in EOTVtD in minutes for substance abuse-related cases, which were shorter in length on average (n = 58; 71 min, 95% CI 54-94). Total ED costs for substance abuse-related cases for the telehealth (n = 58; $4556, 95% CI $3963-$5238) cohort were significantly higher than for the two other behavioral diagnostic groups (p < 0.001).Conclusions: Telehealth consultation in the ED for behavioral health cases was associated with decreased wait time and longer ED LOS. Similar to recent studies, the most common behavioral health cases involved mood and anxiety disorders. Costs related to treatment were highest for substance abuse-related cases, likely due to the additional interventions needed, especially related to resuscitation There are opportunities to improve ED efficiencies and post-telehealth visit protocols related to the timeframe extending from the EOTVtD from the ED, which continues to be a focus of future research. Additional research is also needed to determine if telehealth lends itself more effectively to specific categories of behavioral health cases.


Rubella seroprevalence in children in Dogankent, a rural area of Adana province in Turkey, January-February 2005.
A cross-sectional study was performed to determine the rubella seroprevalence in 331 children aged between 0 and 59 months in Turkey who were not vaccinated for rubella and lived in the area covered by Dogankent Health Center, a rural area with a large proportion of residents of low socioeconomic status. Rubella seropositivity was found to be low, with 17.5%, increased with age and low socioeconomic level, and was particularly high in children who live in a household with one member going to school, and in children of uneducated parents (p<0.05). The asymptomatic infection rate was 98.3%. There was no significant difference in seropositivity with regards to the gender, history of rubella infection, size of the household, or number of children at home (p>0.05). Rubella vaccine has only been included into the national vaccination programme in the form of the measles-mumps-rubella (MMR) vaccine since 2006 and is performed at the age of 12 months, in the first year of primary school and at the age of about 15 years. In order to eliminate rubella and congenital rubella syndrome, it is necessary that use of MMR vaccine is expanded to include the children born before 2006.


The Damaging Effect of Passenger Mutations on Cancer Progression.
Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution; most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human cell lines and immunocompromised mouse models. We found that passengers dramatically reduced proliferative fitness (∼3% per Mb), slowed tumor growth, and reduced metastatic progression. We developed new genomic measures of damaging passenger load that can accurately predict the fitness costs of passengers in cell lines and in human breast cancers. We conclude that genomic instability and an elevated load of DNA alterations in cancer is a double-edged sword: it accelerates the accumulation of adaptive drivers, but incurs a harmful passenger load that can outweigh driver benefit. The effects of passenger alterations on cancer fitness were unrelated to enhanced immunity, as our tests were performed either in cell culture or in immunocompromised animals. Our findings refute traditional paradigms of passengers as neutral events, suggesting that passenger load reduces the fitness of cancer cells and slows or prevents progression of both primary and metastatic disease. The antitumor effects of chemotherapies can in part be due to the induction of genomic instability and increased passenger load. Cancer Res; 77(18); 4763-72. ©2017 AACR.


Evolutionary History of the Hymenoptera.
Hymenoptera (sawflies, wasps, ants, and bees) are one of four mega-diverse insect orders, comprising more than 153,000 described and possibly up to one million undescribed extant species [1, 2]. As parasitoids, predators, and pollinators, Hymenoptera play a fundamental role in virtually all terrestrial ecosystems and are of substantial economic importance [1, 3]. To understand the diversification and key evolutionary transitions of Hymenoptera, most notably from phytophagy to parasitoidism and predation (and vice versa) and from solitary to eusocial life, we inferred the phylogeny and divergence times of all major lineages of Hymenoptera by analyzing 3,256 protein-coding genes in 173 insect species. Our analyses suggest that extant Hymenoptera started to diversify around 281 million years ago (mya). The primarily ectophytophagous sawflies are found to be monophyletic. The species-rich lineages of parasitoid wasps constitute a monophyletic group as well. The little-known, species-poor Trigonaloidea are identified as the sister group of the stinging wasps (Aculeata). Finally, we located the evolutionary root of bees within the apoid wasp family "Crabronidae." Our results reveal that the extant sawfly diversity is largely the result of a previously unrecognized major radiation of phytophagous Hymenoptera that did not lead to wood-dwelling and parasitoidism. They also confirm that all primarily parasitoid wasps are descendants of a single endophytic parasitoid ancestor that lived around 247 mya. Our findings provide the basis for a natural classification of Hymenoptera and allow for future comparative analyses of Hymenoptera, including their genomes, morphology, venoms, and parasitoid and eusocial life styles.


Anti-Leukemic Activity of Shikonin: Role of ERP57 in Shikonin Induced Apoptosis in Acute Myeloid Leukemia.
ER-Stress and activation of unfolded protein response belong to the major factors involved in chemoresistance in cancer cells. In this study we investigated the effect of shikonin on the survival of acute myeloid leukemia cells and the role of ER-stress protein ERP57, a protein disulfide isomerase, in improvement of chemotherapy. Using MTT assay we studied cytotoxic effects of shikonin on HL-60 cells. The flow cytometry was adopted to examine the shikonin induced mode of cell death in HL-60 cells. The overall protein expression alteration resulting from shikonin treatment was investigated using proteomics methods. Western blotting was performed to quantify the alteration in protein expression in HL-60 after shikonin treatment. Silencing and overexpression studies were carried out to highlight the therapeutic role of ERP57 in shikonin effect on AML cells. Shikonin induces apoptosis in HL-60 cells without significant effect on Primary cells from healthy volunteers. The apoptotic effect was dose and time dependent and was accompanied by strong alteration in cell proteome. Among the proteins targeted by shikonin, ERP57 was significantly downregulated in HL-60 after treatment. Compared to healthy control ERP57 was found to be highly expressed in AML cell line HL60 and was downregulated after shikonin treatment. Overexpression of ERP57 protected HL-60 from shikonin induced apoptosis, whereas knockdown of ERP57 expression resulted in increase in shikonin induced apoptosis. Our results demonstrate that ERP57 plays a crucial role in resistance towards shikonin induced apoptosis in AML cells. Targeting of ERP57 might offer a new therapeutic option for the treatment of acute myeloid leukemia.


Epstein-Barr virus immortalization of human B-cells leads to stabilization of hypoxia-induced factor 1 alpha, congruent with the Warburg effect.
Epstein-Barr virus (EBV) encodes six nuclear transformation-associated proteins that induce extensive changes in cellular gene expression and signaling and induce B-cell transformation. The role of HIF1A in EBV-induced B-cell immortalization has not been previously studied. Using Western blotting and Q-PCR, we found that HIF1A protein is stabilized in EBV-transformed lymphoblastoid cells. Western blotting, GST pulldown assays, and immunoprecipitation showed that EBV-encoded nuclear antigens EBNA-5 and EBNA-3 bind to prolylhydroxylases 1 and 2, respectively, thus inhibiting HIF1A hydroxylation and degradation. Immunostaining and Q-PCR showed that the stabilized HIF1A translocates to the nucleus, forms a heterodimer with ARNT, and transactivates several genes involved in aerobic glycolysis. Using biochemical assays and Q-PCR, we also found that lymphoblastoid cells produce high levels of lactate, lactate dehydrogenase and pyruvate. Our data suggest that activation of the aerobic glycolytic pathway, corresponding to the Warburg effect, occurs in EBV-transformed lymphoblastoid cells, in contrast to mitogen-activated B-cells.


Opinions of maternity care professionals about integration of care during labor for "moderate risk" indications: a Delphi study in the Netherlands.
The percentage of referrals during labor from primary midwife-led care to obstetrician-led care has increased over the past years in The Netherlands. Most women are referred for indications with a moderate increase in risk and are looked after by clinical midwives. This study aims to provide insight into the opinions of maternity care professionals about integration of care and involvement of primary care midwives in the intrapartum care of women with "moderate risk" factors. A Delphi study consisting of three rounds was conducted. A purposively selected heterogenic panel of 50 professionals, including obstetricians, primary care midwives, clinical midwives, and obstetric nurses, answered questions anonymously. Although primary care midwives would like to expand their responsibilities and tasks with respect to "moderate risk" indications, consensus among panel members was only reached concerning prolonged rupture of membranes for which the primary care midwife could remain the caregiver. This study shows that most participants support more integration of care during labor. The lack of consensus among Dutch maternity care professionals with regard to the distribution of responsibilities and tasks for "moderate risk" indications is a challenge. Further studies should explore how to deal with differences in opinions among professionals when integrating maternity care systems.


Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells.
EGFR/HER2 are frequently expressed in MPM tissues, however, no studies have shown the clinical benefit of using EGFR/HER2-targeting drugs in patients with malignant pleural mesothelioma (MPM). It was reported that the tyrosine kinase inhibitor (TKI) lapatinib enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive breast cancer, suggesting that this combination is a promising strategy for MPM treatment. The aim of the present study was to explore the possibility of a TKI combined with trastuzumab to enhance ADCC in MPM cells. Five MPM cell lines were used to test the effects of TKIs targeting EGFR (gefitinib, afatinib and lapatinib) on cell proliferation and the expression of the HER family receptor. The combined effects of TKI with trastuzumab on ADCC were evaluated using the LDH release assay. Additionally, MPM cells were isolated from patients and evaluated for lapatinib-induced upregulation of HER family receptors and trastuzumab- or cetuximab‑mediated ADCC. In MPM cell lines, HER2 expression was upregulated by lapatinib, downregulated by afatinib and unaffected by gefitinib. As expected, more trastuzumab bound to MPM cells pretreated with lapatinib than untreated cells, resulting in the enhancement of trastuzumab-mediated ADCC in MPM cells. In patient-derived MPM cells, both HER2 and EGFR were upregulated by lapatinib, resulting in the enhancement of both trastuzumab- and cetuximab-mediated ADCC. Of the three TKIs, only lapatinib enhanced trastuzumab-mediated ADCC via the upregulation of HER2 expression in MPM cells, suggesting that sequential combination of lapatinib and trastuzumab may be a promising strategy for MPM treatment.


Medicine against society. Lessons from the Third Reich.
The engagement of German biomedicine in the design and execution of Nazi programs of "racial cleansing" was extensive and was organized by physicians and other professional leaders. In its active involvement and acquiescence, the German medical profession, one of the most sophisticated and respected medical enterprises in the world, dishonored itself and raised profound and persisting questions about the nature, strength, and relevance of the medical ethos and the relationship between medicine and the policies and programs of the state. Efforts to examine the history of German medicine under National Socialism are increasing in scale and number and involve German scholars to an important and expanding extent. Today, many bioethical issues, based on an increasingly sophisticated science and technology, confront medicine. A major lesson from the Nazi era is the fundamental ethical basis of medicine and the importance of an informed, concerned, and engaged profession.


[Human T-cell lymphotropic virus in family members of seropositive blood donors: silent dissemination].
To investigate human T-cell lymphotropic virus transmission among family members of asymptomatic carriers identified through blood donor screening tests; and to determine the most likely direction of transmission in sexual partners having the same (concordant) serological diagnosis. Between March 1997 and June 2003 the relatives and steady sexual partners of seropositive, asymptomatic blood donors were investigated for the presence of human T-cell lymphotropic virus type I and II. Diagnosis was based on enzyme-linked immunoassay and Western blot. To determine the direction of transmission, demographic and behavioral data were obtained through questionnaires. All participants lived in the metropolitan region of Belo Horizonte capital of the state of Minas Gerais, Brazil. The overall prevalence of infection with human T-cell lymphotropic virus type was 25.9% among 352 relatives of 343 seropositive patients. The prevalence rates in mothers, sexual partners, and children of seropositive donors were 36.6% (15/41), 35.9% (42/117), and 17.5% (34/194), respectively. The demographic and behavioral data obtained suggest greater efficiency of male-to-female transmission. The observed prevalence rates suggest there is familial aggregation of human T-cell lymphotropic virus infection. The main transmission mode was horizontal (sexual). It is important to identify the presence of the virus in family members of infected individuals, even if they are asymptomatic. Doing so may lead to a better understanding of how the virus spreads and more efficient measure for preventing disease transmission.


Costs of care for people with dementia just before and after nursing home placement: primary data from eight European countries.
Dementia is the most common cause of functional decline among elderly people and is associated with high costs of national healthcare in European countries. With increasing functional and cognitive decline, it is likely that many people suffering from dementia will receive institutional care in their lifetime. To delay entry to institutional care, many European countries invest in home and community based care services. This study aimed to compare costs for people with dementia (PwD) at risk for institutionalization receiving professional home care (HC) with cost for PwD recently admitted to institutional long-term nursing care (ILTC) in eight European countries. Special emphasis was placed on differences in cost patterns across settings and countries, on the main predictors of costs and on a comprehensive assessment of costs from a societal perspective. Interviews using structured questionnaires were conducted with 2,014 people with dementia and their primary informal caregivers living at home or in an ILTC facility. Costs of care were assessed with the resource utilization in dementia instrument. Dementia severity was measured with the standardized mini mental state examination. ADL dependence was assessed using the Katz index, neuropsychiatric symptoms using the neuropsychiatric inventory (NPI) and comorbidities using the Charlson. Descriptive analysis and multivariate regression models were used to estimate mean costs in both settings. A log link generalized linear model assuming gamma distributed costs was applied to identify the most important cost drivers of dementia care. In all countries costs for PwD in the HC setting were significantly lower in comparison to ILTC costs. On average ILTC costs amounted to 4,491 Euro per month and were 1.8 fold higher than HC costs (2,491 Euro). The relation of costs between settings ranged from 2.4 (Sweden) to 1.4 (UK). Costs in the ILTC setting were dominated by nursing home costs (on average 94%). In the HC setting, informal care giving was the most important cost contributor (on average 52%). In all countries costs in the HC setting increased strongly with disease severity. The most important predictor of cost was ADL independence in all countries, except Spain and France where NPI severity was the most important cost driver. A standard deviation increase in ADL independence translated on average into a cost decrease of about 22%. Transition into ILTC seems to increase total costs of dementia care from a societal perspective. The prevention of long-term care placement might be cost reducing for European health systems. However, this conclusion depends on the country, on the valuation method for informal caregiving and on the degree of impairment.


Epidemiologic features of Vulvovaginal Candidiasis among reproductive-age women in India.
Vulvovaginal candidiasis is characterized by curd-like vaginal discharge and itching, and is associated with considerable health and economic costs. We examined the incidence, prevalence, and risk factors for vulvovaginal candidiasis among a cohort of 898 women in south India. Participants completed three study visits over six months, comprised of a structured interview and a pelvic examination. The positive predictive values for diagnosis of vulvovaginal candidiasis using individual signs or symptoms were low (<19%). We did not find strong evidence for associations between sociodemographic characteristics and the prevalence of vulvovaginal candidiasis. Women clinically diagnosed with bacterial vaginosis had a higher prevalence of vulvovaginal candidiasis (Prevalence 12%, 95% CI 8.2, 15.8) compared to women assessed to be negative for bacterial vaginosis (Prevalence 6.5%, 95% 5.3, 7.6); however, differences in the prevalence of vulvovaginal candidiasis were not observed by the presence or absence of laboratory-confirmed bacterial vaginosis. For correct diagnosis of vulvovaginal candidiasis, laboratory confirmation of infection with Candida is necessary as well as assessment of whether the discharge has been caused by bacterial vaginosis. Studies are needed of women infected with Candida yeast species to determine the risk factors for yeast's overgrowth.


Antihypertensive and hypotensive effects of atrial natriuretic factor in men.
Synthetic atrial natriuretic factor (ANF) was administered in ascending doses (0.03, 0.20, 0.45 microgram/kg/min) to eight mildly essential hypertensive men on high (200 mEq/day) or low (10 mEq/day) sodium diets. Responses of blood pressure, heart rate, urinary volume and electrolyte excretion, renin, and aldosterone were measured. For the entire group, ANF lowered blood pressure and increased heart rate during the 0.20 and 0.45 microgram/kg/min infusions, and the antihypertensive effect of the peptide persisted for at least 2 hours after the infusions ended. Four patients (2 at 0.20 microgram/kg/min and 2 at 0.45 microgram/kg/min) experienced sudden bradycardia and hypotension at the end of or shortly after completion of ANF infusion. Renal excretion of water, sodium, chloride, calcium, and phosphorus increased in a dose-dependent fashion in response to infused ANF. Patients on the 200 mEq/day sodium diet had greater increases in urinary volume (11.1 +/- 2.8 vs 3.0 +/- 2.0 ml/min; p less than 0.05), sodium (870 +/- 134 vs 303 +/- 27 microEq/min; p less than 0.05), and chloride (801 +/- 135 vs 176 +/- 75 microEq/min; p less than 0.02) compared with patients on the low sodium diet. The apparent direct suppressive effect of a 0.03 microgram/kg/min infusion of ANF on renin and aldosterone levels was overcome at higher doses by counterregulation provoked by the depressor action. Renin was slightly (-12%) suppressed during the 0.03 microgram/kg/min infusion of ANF but increased at the 0.20 (+50%) and 0.45 microgram/kg/min (+90%; p less than 0.03) rates. Aldosterone declined significantly during the 0.03 microgram/kg/min infusion (-45%; p less than 0.01) of ANF but not during the two higher dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)


Behavioural and electrophysiological studies of taste discrimination by the maxillary palps of larvae of Locusta migratoria (L.).
1. Behavioural studies show that larvae of Locusta migratoria (L.) can discriminate between certain simple chemicals and between chemicals obtained from plant sources. 2. Electrophysiological tests show that within each sensillum the same neurones respond to different chemicals. 3. The frequency of occurrence of sensilla with enhanced specificity to certain chemicals is investigated. 4. Statistical tests confirm that, despite the variability of response, across-fibre analysis could allow discrimination between chemicals provided an adequate number of senilla are used. 5. The conclusions are discussed in relation to current theories of chemoreceptor functioning.


Removal of Chylomicron Remnants from the Bloodstream is Delayed in Aged Subjects.
Dietary fats absorbed in the intestine are transported in the circulation as chylomicrons and remnants that have atherogenic potential. Although postprandial lipidemia is increased in older subjects, the specific chylomicron metabolism has not been explored in older subjects nor compared to young subjects, which is the focus of this study. After a 12 h fast, artificially-made emulsions similar to lymph chylomicrons and doubly labeled with radioactive cholesteryl esters and triglycerides were intravenously injected in 23 older (66±4 years) and 20 young (24±3 years) subjects. Sequential blood samples were collected to determine fractional clearance rates (FCR, in min-1) by compartmental analysis. Older subjects had higher LDL-cholesterol (p<0.001) and triglycerides (p<0.0001) than young subjects; HDL-cholesterol presented no difference. The emulsion cholesteryl-ester FCR was lower in older subjects compared to the young (p=0.0001). The emulsion triglyceride FCR did not differ in the two groups. Tested in vitro, however, the lipolysis of the emulsion triglycerides was less intense in the older than in the young subjects. As delayed removal of remnants, indicated by the pronouncedly smaller cholesteryl ester FCR, is related to the presence of cardiovascular diseases, this can be a risk factor which could accelerate atherogenic complications occurring in aged subjects.


Polyethyleneimine coating renders polycarbonate resistant to organic solvents.
We propose a method for the modification of surfaces of microchannels in chips fabricated in polycarbonate (PC) that makes the devices resistant to a range of organic solvents. Coating of PC with branched polyethyleneimine (BPEI) with the use of trimethylpropane triglycidyl ether (TTE) as a linker renders the devices resistant to toluene, benzene, acetonitrile, tetrahydrofuran, dioxane and ethylene dichloride. The optimized procedure of modification allows for continuous operation of the chips for several hours without dissolution of PC. Additional modification with the use of Krytox® allows for the use of Fluorinert (FC-40) as the continuous phase and for generation and handling of droplets of organic solvents that are miscible with water.


Influenza-related health care utilization and productivity losses during seasons with and without a match between the seasonal and vaccine virus B lineage.
To assess and compare direct medical costs (incurred by payers) and indirect productivity losses (incurred by employers) associated with influenza seasons with matched or mismatched circulating and vaccine containing influenza B lineages. A retrospective analysis, using two MarketScan databases, for the years 2000-2009. Each influenza season was categorized as matched or mismatched after comparing that season's circulating influenza B lineage and the vaccine influenza B lineage. Patients selected had at least one diagnosis claim for influenza (ICD-9-CM code 487.xx [influenza] or 488.1 [H1N1]) during an influenza season. We assessed the incidence of influenza (overall and influenza B), influenza-related medical utilization and associated costs, and productivity losses for each season. The four matched seasons had lower average influenza incidence (overall incidence per 100,000 plan members: 509; 95% confidence interval [CI]: 505-512) than the five mismatched seasons (748; 95% CI: 745-751). The mismatched seasons had lower influenza B incidence (average incidence per 100,000 plan members: 126; 95% CI: 125-128) than the matched seasons (165; 95% CI: 163-167). The average, per-patient, total influenza-related medical costs in the mismatched seasons ($300.83; range: $245.38-$371.58) were approximately $61.00 higher than in the matched seasons ($239.43; range: $201.49-$264.01). The mismatched seasons had greater average per-patient, influenza-related productivity-loss costs than the matched seasons (mean: $237.31 vs. $175.10). CDC data showed that influenza A was the predominant circulating strain during seasons in which the circulating influenza B lineage did not match the vaccine influenza B lineage. This resulted in lower influenza B incidence during the mismatched seasons. However, the average, per-patient, influenza-related direct medical costs and indirect productivity losses were higher during the mismatched seasons. Additional research is required to determine if these higher costs can be attributed to influenza B infections and if the influenza severity varies during mismatched seasons.


Nurses' and midwives' experiences of providing group antenatal and postnatal care at 18 health centers in Rwanda: A mixed methods study.
The East Africa Preterm Birth Initiative-Rwanda began a cluster randomized controlled trial of group antenatal care (ANC) and postnatal care (PNC) in Rwanda in 2017. That trial will report its primary outcome, gestational length at birth, after data collection concludes in 2019. This nested study includes providers of ANC and/or PNC at the 18 health centers randomized to provide the group model of ANC/PNC and the 18 health centers randomized to continue providing ANC/PNC in the traditional, individual visit model. The objective of this study is to understand the experiences of providers of group ANC/PNC and compare their job satisfaction and perceived stress with individual ANC/PNC providers. We collected both quantitative and qualitative data from providers (nurses and midwives) who were recruited by health center directors to participate as group ANC and PNC facilitators at intervention sites and from a similar number of providers of standard ANC and PNC at control sites. Quantitative data was collected with questionnaires administered at baseline and approximately 9 months later (follow up). Qualitative data was collected in 3 focus groups of group ANC/PNC providers conducted one year after group care began. Eighty-six percent of nurses and midwives surveyed who implemented group ANC and PNC reported that they prefer group care to the traditional individual model of ANC and PNC. Perceived stress levels and job satisfaction results were similar between groups. Mixed focus group discussions among both nurses and midwives experienced in group ANC and PNC suggest that the group model of care has advantages for both service beneficiaries and providers. When providers described implementation challenges, their peers in the focus groups offered them suggestions to cope and improve service delivery. These results are consistent with studies of providers of group ANC and PNC in other LMIC contexts with respect to the perceived benefits of group care. This study adds new insights into the ways peer providers can help one another solve implementation problems. When given the opportunity to meet as a group, these study participants offered one another peer support and shared knowledge about best practices for successful implementation of group ANC/PNC. This trial is registered at clinicaltrials.gov as NCT03154177.


Use of tyramide-fluorescence in situ hybridization and chromosome microdissection for ascertaining homology relationships and chromosome linkage group associations in oats.
The physical mapping of single locus sequences by tyramide-fluorescence in situ hybridization (Tyr-FISH) and the analysis of sequences obtained from microdissected chromosomes were assayed as potential tools for (1) determining homology and homoeology among chromosome regions of Avena species, and (2) establishing associations between linkage groups and specific chromosomes. Low copy number probes, derived from resistance gene analogues (RGAs) and 2.8-4.5 kb long, successfully produced hybridization signals on specific chromosomes. Four sets of homoeologous chromosome regions were identified in the hexaploids using 3 probes that produced 4 single locus markers in A. strigosa and 2 in A. eriantha. Laser capture microdissection of metaphase I cells of A. sativa monosomic lines allowed the isolation of critical univalents. Sequences derived from 2 RGAs were successfully amplified in DNA extracted from univalents. In one instance, it was possible to map a nucleotide polymorphism specific for 1 chromosome. An association was established between this chromosome and its linkage groups in 2 hexaploid genetic maps. The results indicate that Tyr-FISH is useful in the characterization of homoeologous chromosome segments in hexaploids, whereas chromosome microdissection, as employed in this work, needs to be improved before it can routinely be used with meiotic chromosomes.


Surgical Repair of Abdominal Aortic and Renal Artery Aneurysms in Takayasu's Arteritis.
Takayasu's arteritis is a large vessel vasculitis that can be a challenging diagnosis to make and has a varied clinical presentation. Management largely depends on affected vessel disease severity and individual patient considerations. The diagnosis must be considered in a young patient with large vessel aneurysms. We present a case of a 30 year-old woman of Pacific Islander descent who presented to the Tripler Army medical Center Vascular Surgery Department in Honolulu, Hawai'i seeking repair of her abdominal aortic and renal artery aneurysms prior to conception. A 30 year-old Pacific Islander woman with a history of a saccular abdominal aortic aneurysm and renal artery aneurysms presented to our clinic seeking vascular surgery consultation prior to a planned pregnancy. She had a renal artery stent placed at an outside institution for hypertension. She met the diagnosis of Takayasu's arteritis by Sharma's criteria. Physical exam was significant for a palpable, pulsatile, abdominal mass and CT angiography revealed a saccular irregular-appearing infra-renal abdominal aortic aneurysm, extending to the aortic bifurcation, with a maximum diameter of 3.3 cm. A right renal artery aneurysm was also identified proximally, contiguous with the aorta, with a maximal transverse diameter of 1.7 cm. The patient underwent a supraceliac bypass to the right renal artery with a 7 mm Dacron graft, as well as excision of the right renal artery aneurysm. The abdominal aortic aneurysm was replaced using a Hemashield Dacron bifurcated 14 mm x 7 mm bypass graft. Intraoperative measurements of the renal artery aneurysm were 1.5 x 1.5 cm and the saccular appearing distal abdominal aortic aneurysm measured 3.6 x 3.3 cm. The patient was discharged from the hospital 7 days post-operatively. At 1-year follow up, CT scan of the abdominal aorta revealed the repair was without any evidence of aneurysm formation, anastomotic pseudoaneurysm formation, or areas of stenosis. She has remained normotensive with a normal serum creatinine 18 months after her repair. She has since delivered her second child. It is rare for Takayasu's arteritis to present with aneurysmal disease. It is much more common to present with stenosis or occlusion. It has yet to be proven that Takayasu's truly has a higher incidence in those of Asian descent. Takayasu's can be a difficult diagnosis to make but can be aided with the use of Sharma's criteria. Our particular patient posed unique considerations on the effects of the physiology of pregnancy on her aneurysms and repair. Managing the active phases of disease is imperative, and though medical management is first line, surgical intervention may be necessary. Surgical intervention should be performed in a quiescent period of disease if possible given that biological inflammation at the time of intervention increases the complication rate. Repair of aneurysmal disease in a young female should also be considered prior to pregnancy.


A research agenda for radiation oncology: results of the radiation oncology institute's comprehensive research needs assessment.
To promote the rational use of scarce research funding, scholars have developed methods for the systematic identification and prioritization of health research needs. The Radiation Oncology Institute commissioned an independent, comprehensive assessment of research needs for the advancement of radiation oncology care. The research needs assessment used a mixed-method, qualitative and quantitative social scientific approach, including structured interviews with diverse stakeholders, focus groups, surveys of American Society for Radiation Oncology (ASTRO) members, and a prioritization exercise using a modified Delphi technique. Six co-equal priorities were identified: (1) Identify and develop communication strategies to help patients and others better understand radiation therapy; (2) Establish a set of quality indicators for major radiation oncology procedures and evaluate their use in radiation oncology delivery; (3) Identify best practices for the management of radiation toxicity and issues in cancer survivorship; (4) Conduct comparative effectiveness studies related to radiation therapy that consider clinical benefit, toxicity (including quality of life), and other outcomes; (5) Assess the value of radiation therapy; and (6) Develop a radiation oncology registry. To our knowledge, this prioritization exercise is the only comprehensive and methodologically rigorous assessment of research needs in the field of radiation oncology. Broad dissemination of these findings is critical to maximally leverage the impact of this work, particularly because grant funding decisions are often made by committees on which highly specialized disciplines such as radiation oncology are not well represented.


Triode for Magnetic Flux Quanta.
In an electronic triode, the electron current emanating from the cathode is regulated by the electric potential on a grid between the cathode and the anode. Here we demonstrate a triode for single quantum magnetic field carriers, where the flow of individual magnetic vortices in a superconducting film is regulated by the magnetic potential of striae of soft magnetic strips deposited on the film surface. By rotating an applied in-plane field, the magnetic strip potential can be varied due to changes in the magnetic charges at the strip edges, allowing accelerated or retarded motion of magnetic vortices inside the superconductor. Scaling down our design and reducing the gap width between the magnetic stripes will enable controlled manipulation of individual vortices and creation of single flux quantum circuitry for novel high-speed low-power superconducting electronics.


The emergence of the disorganized/disoriented (D) attachment classification, 1979-1982.
This article examines the emergence of the concept of infant disorganized/disoriented attachment, drawing on published and archival texts and interviews. Since this new classification was put forward by Main and Solomon (1986), "disorganized/disoriented attachment" has become an important concept in clinical and social intervention contexts. Yet whereas Main and Solomon have often been misunderstood to have introduced disorganized/disoriented attachment in order to produce an exhaustive, categorical system of infant classifications, this article will suggest quite a different account. Attention will be paid to the emergence of disorganized attachment as a classification out of results and reflections in the late 1970s regarding the limits of an alarmed infant's capacities for maintaining behavioral and attentional avoidance. In contrasting this interpretation of Main and Solomon's work with current, widespread misunderstandings, the article will critically examine tendencies that have supported the reification and misapplication of the concept of disorganized/disoriented attachment.


Multivariate analysis of diaphragm EMG power spectral moments.
A single derived index of the power spectrum of the diaphragm electromyogram (EMG) has been used in detecting fatigue. Additional information in the EMG could be used to study diaphragm function in other respiratory conditions. Diaphragm EMGs and calculated power spectra at 12 frequencies were measured in normal subjects and patients with severe chronic obstructive pulmonary disease during several respiratory maneuvers both before and after treadmill exercise to dyspnea. The power spectra were characterized by the first five moments. Changes in the EMG were similar when assessed by multivariate analysis of variance of the spectral estimates or of the moments. Factor analysis provided two latent variables that correlated with the first and second moment respectively. The first moment was found to be the most sensitive single discriminant of fatigue and is only slightly improved by adding other information. It is concluded that the first and second moments of the EMG power spectra provide a concise, parsimonious description of the changes in the EMG.


NCR3/NKp30 contributes to pathogenesis in primary Sjogren's syndrome.
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity, and they are at markedly increased risk for the development of non- Hodgkin's lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, although the precise etiology remains uncertain. NCR3/NKp30 is a natural killer (NK)-specific activating receptor regulating the cross talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (G>A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were significantly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-γ secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.


Clinical Outcomes of Outpatient Cervical Total Disc Replacement Compared With Outpatient Anterior Cervical Discectomy and Fusion.
A single-center, retrospective study. The aim of this study was to determine the safety and outcomes of total disc replacement (TDR) as an outpatient procedure in the ambulatory surgery center (ASC). Anterior cervical discectomy and fusion (ACDF) has been demonstrated to be safe in the outpatient setting, as the awareness of same-day surgery procedures is on the rise due to better outcome and shorter recovery time. There is a need for motion preservation in a subset of patients TDR provides a solution. Transitioning spine surgery to the outpatient setting including cervical TDR is the next logical step. The medical records of 55 consecutive patients undergoing single level TDR (Group 1) were compared with our control group of 55 patients who had single-level ACDF (Group 2). Outcomes assessed included Visual Analogue Scale (VAS) neck, arm, neck disability index (NDI) scores, and complication rate. Fifty-five patients in Group 1 (TDR, 60%) were male with the group's mean age being 42.6 ± 1.4 years and body mass index (BMI) 24.8 ± 1.2 kg/m. Fifty-five patients in Group 2 (ACDF), 57%, were male with the group's mean age being 53 ± 1.0 years and mean BMI 27.9 ± 0.8 kg/m. There was no statistically significant intergroup difference in 2-year VAS neck, arm and NDI scores. Dysphagia was the most common postoperative compliant in both groups (six patients), with no intergroup significance, P = 0.4. In the ambulatory setting, TDR has shown statistical significant intragroup improvement in VAS neck, arm pain scores, and NDI scores (P < 0.001). In this study, no patients reported serious complications, no incidence of hematoma formation, or worsening postop pain. We conclude that single-level TDR can be safely done in an ASC with satisfactory clinical and patient-reported outcomes. This is comparable to single-level ACDF in the outpatient setting and previous 2-year TDR studies. 3.


Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease.
There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-α) antagonists, or that downregulate the expression of ER-α, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-α pharmacology, that there may already exist among the most recently developed selective estrogen receptor modulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-α conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. The high-affinity SERM bazedoxifene was shown to function as a pure ER-α antagonist in cellular models of breast cancer and effectively inhibited the growth of both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-α that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist efficacy. Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer.


Italian Association of Clinical Endocrinologists (AME) and Italian Chapter of the American Association of Clinical Endocrinologists (AACE) Position Statement: Clinical Management of Vitamin D Deficiency in Adults.
Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25-hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice.


Ovarian stimulation in patients with breast cancer.
Breast cancer is the most prevalent malignancy among women under 50. Improvements in diagnosis and treatment have yielded an important decrease in mortality in the last 20 years. In many cases, chemotherapy and radiotherapy develop side effects on the reproductive function. Therefore, before the anti-cancer treatment impairs fertility, clinicians should offer some techniques for fertility preservation for women planning motherhood in the future. In order to obtain more available oocytes for IVF, the ovary must be stimulated. New protocols which prevent exposure to increased estrogen during gonadotropin stimulation, measurements to avoid the delay in starting anti-cancer treatment or the outcome of ovarian stimulation have been addressed in this review. There is no evidence of association between ovarian stimulation and breast cancer. It seems that there are more relevant other confluent factors than ovarian stimulation. Factors that can modify the risk of breast cancer include: parity, age at full-term birth, age of menarche, and family history. There is an association between breast cancer and exogenous estrogen. Therefore, specific protocols to stimulate patients with breast cancer include anti-estrogen agents such as letrozole. By using letrozole plus recombinant follicular stimulating hormone, patients develop a multifollicular growth with only a mild increase in estradiol serum levels. Controlled ovarian stimulation (COS) takes around 10 days, and we discuss new strategies to start COS as soon as possible. Protocols starting during the luteal phase or after inducing the menses currently prevent a delay in starting ovarian stimulation. Patients with breast cancer have a poorer response to COS compared with patients without cancer who are stimulated with conventional protocols of gonadotropins. Although many centres offer fertility preservation and many patients undergo ovarian stimulation, there are not enough studies to evaluate the recurrence, breast cancer-free interval or mortality rates in these women.