Prevalence and Factors Associated with the Use of Eye Care Services in South Korea: Korea National Health and Nutrition Examination Survey 2010-2012.
To estimate the factors and prevalence of eye care service utilization in the South Korean population. This cross-sectional, population-based study included data from 22,550 Koreans aged ≥5 years who participated in the Korea National Health and Nutrition Examination Survey from 2010 to 2012. For people aged 5 to 11 years (young children), information was based on self-reports of contact with eye care service in the past year; for people aged ≥12 years (older population), the information was based on the self-reported lifetime contact with eye care service. Univariate and multivariate logistic regression analyses of the complex sample survey data were performed. The prevalence of eye care service use in young children during the past year was 61.1% (95% confidence interval, 58.1%-64.1%), while that in the older population during their lifetime was 73.5%. Subjects aged 7 to 11 years were more likely to have had an eye examination in the past year than subjects aged 5 to 6 years (odds ratio, 3.83; 95% confidence interval, 2.37-6.19). Multivariate logistic regression analysis indicated that higher monthly household income, being a National Health Insurance holder, and having private health insurance were related to more frequent use of eye care services in young children. For the older population and women, those living in an urban area and those with a best-corrected visual acuity less than 20 / 40 in the worse-seeing eye were more likely to have had an eye examination during their lifetime. Low education level was associated with low lifetime use of eye care services in the older population. There are sociodemographic disparities with use of eye care services in South Korea. This population-based study provides information that is useful for determining different intervention programs based on sociodemographic disparities to promote eye care service utilization in South Korea.


Neural correlates of rewarded and unrewarded eye movements in the primate caudate nucleus.
The prospect of immediate reward elicits goal-oriented behavior. However, animals often have to perform actions that do not immediately lead to reward in the pursuit of a long-term goal. Here we identify neural activity in monkey caudate nucleus that specifically correlates with rewarded and unrewarded eye movements. The monkey performed a visually guided saccade task in which only one position was associated with positive reinforcement. To advance in the experimental session, however, the monkey had no choice but to complete a saccade to an unrewarded position as well as to a rewarded position. Some caudate saccadic neurons showed enhanced activity around the time of the saccade in rewarded trials (rewarded-saccade neurons). Another subset of neurons discharged selectively around the execution of the saccade in unrewarded trials (unrewarded-saccade neurons). In both rewarded and unrewarded trials, stronger activity of these neurons was associated with reduced saccade latency. These results suggest that both rewarded and unrewarded saccades are facilitated by caudate saccadic activity. The neuronal activity of unrewarded-saccade neurons might reflect the required execution of unrewarded eye movements on the way to future reward.


Na-Ca exchange in a smooth muscle plasma membrane-enriched fraction.
Na-Ca exchange in the plasma membrane-enriched fraction N1 isolated from rat myometrium has been demonstrated as Ca gain or loss depending on the direction of the [Na+] gradient [Grover et al., Am. J. Physiol. 240 (Cell Physiol. 9): C175-C182, 1981]. In this study, the [Na+]gradient-dependent Ca uptake by this membrane fraction was demonstrated to occur optimally at pH 6.67; and 7.0 +/- 2.2 microMs Ca2+ was required for the half-maximal uptake. Such Ca uptake occurred in vesicles previously loaded with a [Ca] that was the same as or higher than the one present in the Ca-uptake medium, i.e., as an uphill Ca-transport process. The Na-Ca exchange-dependent Ca uptake was abolished by the Ca ionophore A23187 or by the monovalent cation (Na+) ionophore monensin. It was not influenced by the presence of KC1, KC1 plus valinomycin, or the proton uncouplers carbonyl cyanine p-trifluoromethoxyphenyl hydrazone or 5'-chloro-3-t-butyl-2'-chloronitrosalicylanilide in the Ca-uptake medium. The properties of the Na-Ca exchange are compared with those of passive and ATP-dependent Ca uptake by this membrane fraction, and physiological implications of this process are discussed.


Optimal acetabular orientation for hip resurfacing.
Pseudotumours are a rare complication of hip resurfacing. They are thought to be a response to metal debris which may be caused by edge loading due to poor orientation of the acetabular component. Our aim was to determine the optimal acetabular orientation to minimise the risk of pseudotumour formation. We matched 31 hip resurfacings revised for pseudotumour formation with 58 controls who had a satisfactory outcome from this procedure. The radiographic inclination and anteversion angles of the acetabular component were measured on anteroposterior radiographs of the pelvis using Einzel-Bild-Roentgen-Analyse software. The mean inclination angle (47 degrees, 10 degrees to 81 degrees) and anteversion angle (14 degrees, 4 degrees to 34 degrees) of the pseudotumour cases were the same (p = 0.8, p = 0.2) as the controls, 46 degrees (29 degrees to 60 degrees) and 16 degrees (4 degrees to 30 degrees) respectively, but the variation was greater. Assuming an accuracy of implantation of +/- 10 degrees about a target position, the optimal radiographic position was found to be approximately 45 degrees of inclination and 20 degrees of anteversion. The incidence of pseudotumours inside the zone was four times lower (p = 0.007) than outside the zone. In order to minimise the risk of pseudotumour formation we recommend that surgeons implant the acetabular component at an inclination of 45 degrees (+/- 10) and anteversion of 20 degrees (+/- 10) on post-operative radiographs. Because of differences between the radiographic and the operative angles, this may be best achieved by aiming for an inclination of 40 degrees and an anteversion of 25 degrees.


Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.
The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).


Significance of myocardial contusion following blunt chest trauma.
A prospective study was undertaken at a regional trauma unit (RTU) to determine the significance of cardiac complications in patients with blunt chest trauma. Radionuclide angiographic (RNA) imaging was performed as soon as possible after admission and Holter monitors were applied for 72 hours. Routine investigations included serial cardiac enzyme measurements and 12-lead electrocardiograms. Dysrhythmias were classified and ventricular dysrhythmias were stratified by ventricular ectopic score (VES) as ventricular tachycardia (4) or greater than 100 premature ventricular contractions (PVCs)/hour (3). Three hundred twelve patients were entered into the study. Analysis of dysrhythmias revealed 18 patients with a VES of 4 and nine patients with a VES of 3; there were no serious consequences. The most significant dysrhythmia as a marker of outcome was atrial fibrillation (n = 9); five of these patients died, but all of associated noncardiac injuries. A review of abnormal RNAs revealed that all associated mortalities were attributed to noncardiac injuries. A review of postmortem reports and hospital records revealed that no deaths were attributed to cardiac failure or dysrhythmia. Thus the incidence of clinically significant dysrhythmias or other cardiac complications resulting from blunt trauma to the heart may be overestimated.


Management of renal cell carcinoma presenting as inflammatory renal mass.
Renal cell carcinoma (RCC) can have a wide spectrum of clinical presentations. In the immunocompromised patient fever and an inflammatory renal mass can harbor RCC. We reviewed the charts of patients who were managed at our department during 1998-2008 as renal abscess or perinephric collection. Renal ultrasound and subsequently abdominal CT was done. Medical treatment in the form of antibiotics, control of diabetes and drainage was done. Percutaneous or open biopsy, pus cultures, and histopathology were used to guide therapy. With a positive biopsy radical surgery was considered, while with a negative result a follow up CT was planned. We identified 11 patients who had high fever, a renal abscess (in 4), or a suspicious mass with perinephric collection (in 7), and were eventually diagnosed to have RCC. Mean patient age was 66 years (53-82). 8 patients had uncontrolled diabetes. Five patients had a percutaneous drainage biopsy; of those two had a positive histopathology, the other three patients had a persistent enhancing mass on follow-up CT scan. Of this group three patients underwent radical nephrectomy. Another five patients had open drainage and biopsy, four patients had very poor performance status. One patient had radical surgery without the need for biopsy. In the elderly and immunocompromised patient renal cancer may present as renal abscess or perinephric collection. Histopathology and bacteriology are the mainstay of diagnosis. If biopsy was negative, follow up should include a CT scan to exclude any residual enhancing masses.


Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia.
Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone marrow samples from 133 consecutive patients with acute myeloid leukemia and 198 controls for variations in TERT and TERC genes. An additional 89 patients from a second cohort, selected based on cytogenetic status, and 528 controls were further examined for mutations. A third cohort of 372 patients and 384 controls were specifically tested for one TERT gene variant. In the first cohort, 11 patients carried missense TERT gene variants that were not present in controls (P < 0.0001); in the second cohort, TERT mutations were associated with trisomy 8 and inversion 16. Mutation germ-line origin was demonstrated in 5 patients from whom other tissues were available. Analysis of all 3 cohorts (n = 594) for the most common gene variant (A1062T) indicated a prevalence 3 times higher in patients than in controls (n = 1,110; P = 0.0009). Introduction of TERT mutants into telomerase-deficient cells resulted in loss of enzymatic activity by haploinsufficiency. Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability.


Changes in Marital and Partner Relationships in the Aftermath of Hurricane Katrina: An Analysis With Low-Income Women.
Little is known about the impact of natural disasters on marital and partner relationships. In this study, the authors aimed to fill this gap by investigating the changes in such relationships in a sample of 40 low-income, mostly African American women who survived Hurricane Katrina. Through in-depth interviews, participants described how the hurricane affected their intimate relationships. The authors found that, although many participants reported negative changes in their relationships, others reported that their relationships grew stronger, often despite initial strain. As a framework for understanding the processes underlying participants' negative and positive outcomes, the authors drew on the family stress model. Consistent with the model, participants reported that the hurricane led to external stressors, including unemployment and prolonged separations, and that these stressors, in turn, undermined both individual functioning and relational processes (e.g., communication and support). Conversely, participants reporting positive changes experienced new employment opportunities, a greater sense of perspective, and high levels of effective communication and support in their relationships. Based on the findings, policies that reduce the economic strain of low-income families in the aftermath of disasters and empirically supported, culturally sensitive, clinical interventions for individuals and couples are recommended.


[Factors associated with the non-utilization of healthcare services among venezuelan migrants in Peru].
To estimate the prevalence and determine the factors associated with the non-utilization of healthcare facilities (NUHCF) among adult Venezuelan migrants in Peru. An analytical cross-sectional study of the "Survey of the Venezuelan Population Residing in Peru" 2018. We calculated the proportion of immigrants with NUHCF (immigrants with some symptom or malaise, illness, relapse of chronic illness, accident and discomfort, or other problem such as depression, fear, anger, anxiety, and stress, and who did not consider that it was serious or that they needed to visit a healthcare facility). Raw and adjusted (PRa) prevalence ratios (PR) for presenting NUHCF were estimated using generalized linear models. The study included 2,144 Venezuelan migrants: 57.2% presented NUHCF, reporting reasons such as: not having money (64.5%), lack of health insurance (24.3%), self-medication (12.8%), and not having time (8.4%). Living in Arequipa (PRa: 0.69; 95% CI: 0.57-0.83) or Trujillo (PRa: 0.87; 95% CI: 0.76-0.99), suffering from a chronic disease (PRa: 0.83; 95% CI: 0.71-0.97), and being enrolled in the Seguro Integral de Salud (SIS) insurance (PRa: 0.28; 95% CI: 0.13-0.61) was associated with a lower probability of NUHCF. Belonging to an age group under 60 years was associated with a higher probability of NUHCF. One out of two Venezuelan migrants in Peru presents NUHCF. Having SIS increases the likelihood of Venezuelan migrants in Peruvian territory seeking medical attention. Increasing public health insurance for this population, which is currently low, could increase the utilization of health services.


Optical compensation for night myopia based on dark focus and CA/C ratio.
To determine whether individual differences in dark focus and convergence accommodation to convergence (CA/C) ratio can be used to prescribe the best optical correction for night myopia. The best correction for night myopia was obtained by measuring visual acuity and contrast sensitivity across a range of lens powers and luminances. Dark focus was measured with an infrared optometer, and CA/C ratio was measured with an infrared optometer and eyetracker. Only young subjects were used (mean age = 25.4 years). Optimal lens power was significantly correlated with dark focus, regardless of CA/C ratio. However, the slope of the regression line relating lens power to dark focus was steeper for subjects with CA/C ratios less than 0.4 diopters/meter angle (D/MA, n = 7) than for subjects with CA/C ratios greater than 0.4 D/MA (n = 9). The mean CA/C ratio for the entire sample (n = 16) was 0.59 D/MA. The mean optimal lens power and dark focus were -0.79 and 0.74 D, respectively, for the low CA/C group, and -0.60 and 0.91 D, respectively, for the high CA/C group. Visual performance in night myopia can be optimized by taking into account intersubject differences in dark focus and CA/C ratio. Best visual performance was found with a lens roughly equaling the full dark focus for subjects with low CA/C ratios and half the dark focus for subjects with high CA/C ratios.


General anesthetic exposure in adolescent rats causes persistent maladaptations in cognitive and affective behaviors and neuroplasticity.
Accumulating evidence indicates that exposure to general anesthetics during infancy and childhood can cause persistent cognitive impairment, alterations in synaptic plasticity, and, to a lesser extent, increased incidence of behavioral disorders. Unfortunately, the developmental parameters of susceptibility to general anesthetics are not well understood. Adolescence is a critical developmental period wherein multiple late developing brain regions may also be vulnerable to enduring general anesthetic effects. Given the breadth of the adolescent age span, this group potentially represents millions more individuals than those exposed during early childhood. In this study, isoflurane exposure within a well-characterized adolescent period in Sprague-Dawley rats elicited immediate and persistent anxiety- and impulsive-like responding, as well as delayed cognitive impairment into adulthood. These behavioral abnormalities were paralleled by atypical dendritic spine morphology in the prefrontal cortex (PFC) and hippocampus (HPC), suggesting delayed anatomical maturation, and shifts in inhibitory function that suggest hypermaturation of extrasynaptic GABAA receptor inhibition. Preventing this hypermaturation of extrasynaptic GABAA receptor-mediated function in the PFC selectively reversed enhanced impulsivity resulting from adolescent isoflurane exposure. Taken together, these data demonstrate that the developmental window for susceptibility to enduring untoward effects of general anesthetics may be much longer than previously appreciated, and those effects may include affective behaviors in addition to cognition.


Human survival in volcanic eruptions: Thermal injuries in pyroclastic surges, their causes, prognosis and emergency management.
This study of burns patients from two eruptions of Merapi volcano, Java, in 1994 and 2010, is the first detailed analysis to be reported of thermal injuries in a large series of hospitalised victims of pyroclastic surges, one of the most devastating phenomena in explosive eruptions. Emergency planners in volcanic crises in populated areas have to integrate the health sector into disaster management and be aware of the nature of the surge impacts and the types of burns victims to be expected in a worst scenario, potentially in numbers and in severity that would overwhelm normal treatment facilities. In our series, 106 patients from the two eruptions were treated in the same major hospital in Yogyakarta and a third of these survived. Seventy-eight per cent were admitted with over 40% TBSA (total body surface area) burns and around 80% of patients were suspected of having at least some degree of inhalation injury as well. Thirty five patients suffered over 80% TBSA burns and only one of these survived. Crucially, 45% of patients were in the 40-79% TBSA range, with most suspected of suffering from inhalation injury, for whom survival was most dependent on the hospital treatment they received. After reviewing the evidence from recent major eruptions and outlining the thermal hazards of surges, we relate the type and severity of the injuries of these patients to the temperatures and dynamics of the pyroclastic surges, as derived from the environmental impacts and associated eruption processes evaluated in our field surveys and interviews conducted by our multi-disciplinary team. Effective warnings, adequate evacuation measures, and political will are all essential in volcanic crises in populated areas to prevent future catastrophes on this scale.


Long telomere length and a TERT-CLPTM1 locus polymorphism association with melanoma risk.
Telomere length has been associated with the development of cancer. Studies have shown that shorter telomere length may be related to a decreased risk of cutaneous melanoma. Furthermore, deregulation of the telomere-maintaining gene complexes, has been related to this oncogenic process. Some variants in these genes seem to be correlated with a change in telomerase expression. We examined the effect of 10 single nucleotide polymorphisms (SNPs) in the TERT gene (encoding telomerase), one SNP in the related TERT-CLPTM1L locus and one SNP in the TRF1 gene with telomere length, and its influence on melanoma risk in 970 Spanish cases and 733 Spanish controls. Genotypes were determined using KASP technology, and telomere length was measured by quantitative polymerase chain reaction (PCR) on DNA extracted from peripheral blood leucocytes. Our results demonstrate that shorter telomere length is associated with a decreased risk of melanoma in our population (global p-value, 2.69×10(-11)), which may be caused by a diminution of proliferative potential of nevi (melanoma precursor cells). We also obtained significant results when we tested the association between rs401681 variant (TERT-CLPTM1L locus) with melanoma risk (Odds ratio, OR; 95% confidence interval, CI=1.24 (1.08-1.43); p-value, 3×10(-3)). This is the largest telomere-related study undertaken in a Spanish population to date. Furthermore, this study represents a comprehensive analysis of some of the most relevant telomere pathway genes in relation to cutaneous melanoma susceptibility.


Genetic susceptibility loci of idiopathic interstitial pneumonia do not represent risk for systemic sclerosis: a case control study in Caucasian patients.
Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were also risk loci for SSc overall or severity of ILD in SSc. A total of 2571 SSc patients and 4500 healthy controls were investigated from the US discovery GWAS and additional US replication cohorts. Thirteen IIP-related selected single nucleotide polymorphisms (SNPs) were genotyped and analyzed for their association with SSc. We found an association of SSc with the SNP rs6793295 in the LRRC34 gene (OR = 1.14, CI 95 % 1.03 to 1.25, p value = 0.009) and rs11191865 in the OBFC1 gene (OR = 1.09, CI 95 % 1.00 to 1.19, p value = 0.043) in the discovery cohort. Additionally, rs7934606 in MUC2 (OR = 1.24, CI 95 % 1.01 to 1.52, p value = 0.037) was associated with SSc-ILD defined by imaging. However, these associations failed to replicate in the validation cohort. Furthermore, SNPs rs2076295 in DSP (β = -2.29, CI 95 % -3.85 to -0.74, p value = 0.004) rs17690703 in SPPL2C (β = 2.04, CI 95 % 0.21 to 3.88, p value = 0.029) and rs1981997 in MAPT (β = 2.26, CI 95 % 0.35 to 4.17, p value = 0.02) were associated with percent predicted forced vital capacity (FVC%) even after adjusting for the anti-topoisomerase (ATA)-positive subset. However, these associations also did not replicate in the validation cohort. Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities.


Search for Scalar Charm Quark Pair Production in pp Collisions at sqrt[s]=8 TeV with the ATLAS Detector.
The results of a dedicated search for pair production of scalar partners of charm quarks are reported. The search is based on an integrated luminosity of 20.3 fb^{-1} of pp collisions at sqrt[s]=8 TeV recorded with the ATLAS detector at the LHC. The search is performed using events with large missing transverse momentum and at least two jets, where the two leading jets are each tagged as originating from c quarks. Events containing isolated electrons or muons are vetoed. In an R-parity-conserving minimal supersymmetric scenario in which a single scalar-charm state is kinematically accessible, and where it decays exclusively into a charm quark and a neutralino, 95% confidence-level upper limits are obtained in the scalar-charm-neutralino mass plane such that, for neutralino masses below 200 GeV, scalar-charm masses up to 490 GeV are excluded.


Innovation of a syringe needle auto-detaching device for clinicians.
Needle-stick injuries accounts for a great proportion of all medical accidents in developing and undeveloped countries. The main cause of needle-stick accident injuries is the medical personnel's ``recovering'' the needle action after injection. This study applies an electronic technique to the needling instrument for the purpose of automatically detaching the needle. The proposed method can effectively avoid needle-stick accident injury when ``recovering'' the needle. The syringe needle auto-detaching device includes an abutment on which there is a turntable mechanism composed of a pedestal, a turn-table and a driving unit. A photo interrupter on the pedestal detects the rotational angle of the turntable and controls the stepping motor through a control circuit. An optical sensor is located on the upper end of the sensing mechanism. When the syringe is inserted into the syringe plughole the exposed portion of the needle will be detected by the optical sensor. After the syringe is placed into the plughole, its needle will be detected by the sensor. At this time the needle will be detached from the syringe and automatically fall down into the needle collection box. The syringe needle auto-detaching device was fatigue tested for an extensive period of time (A group: 1000 times/day for 3 ml, B group: 1000 times/day for 5 ml, C group: 1000 times/day for 3 ml and 5 ml staggered, D group: 1000 times/day for 3 ml and 5 ml randomized). The needle and syringe detachment rates were 100% in all test groups. The syringe needle auto-detaching device developed in this study, in that the clinician performs only one step to dispose a needle. Six syringe needle sets can be managed sequence second by second. The proposed device without all of the risk factors of the traditional syringe needle detachment device.


Postoperative sensitivity in Class V composite restorations: Comparing soft start vs. constant curing modes of LED.
One of the major disadvantages associated with using composites is polymerization shrinkage; stresses are generated at the margins, and if these stresses exceed the bond strength, microleakage occurs at the tooth restoration interface which causes ingress of cariogenic bacteria, post-operative sensitivity, and secondary caries. LED offers several curing modes: constant cure, ramped cure, and soft start cure. It is claimed that soft start polymerization mode produces less polymerization shrinkage and consequently less postoperative sensitivity. To compare the postoperative sensitivity in Class V composite restorations using soft start and constant LED curing modes. Using the appropriate burrs cavity was prepared and filled with composite Z 100(3M-ESPE) using a incremental technique. Each increment of 2 mm was cured either with soft start or constant cure. All patients were evaluated at day 2 for postoperative sensitivity. Out of 124 restorations that were placed, only three restorations presented with postoperative sensitivity, each one being in mild, moderate, and severe categories, respectively. No relationship was seen between the sensitivity and tooth type. There was no statistically significant difference in postoperative sensitivity in either of the treatment modalities (constant or soft start). We conclude that restorations placed with the soft start curing technique did not show significant changes in postoperative sensitivity when compared to the constant curing technique.


SF3B1, NRAS, KIT, and BRAF Mutation; CD117 and cMYC Expression; and Tumoral Pigmentation in Sinonasal Melanomas: An Analysis With Newly Found Molecular Alterations and Some Population-Based Molecular Differences.
Sinonasal melanomas encompass melanoma arising in the nasal cavity and paranasal sinuses. Despite recent advances in tumor genomics, correlation between mutational status and protein expression with prognosis and tumor pigmentation has not been carried out in sinonasal melanomas. Ninety-five sinonasal melanomas from 95 patients were included. As per univariate analyses, age was the only variable that significantly correlated with progression-free survival. SF3B1, NRAS, KIT, and BRAF mutations were documented in 7% (5/72), 22% (16/72), 22% (16/72), and 8% (6/72) of cases, respectively. Comutation was detected in 6 cases: NRAS and KIT in 2 cases; NRAS and BRAF in 2 cases; SF3B1, KIT, and BRAF in one case; and SF3B1, NRAS, and KIT in one case. Correlations approaching statistical significance were observed between BRAF mutation status and poorer overall survival and progression-free survival (log-rank P-values=0.054 and 0.061). Increased CD117 expression (33%, 29/88) and decreased nuclear cMYC expression (40%, 39/84) significantly correlated with cytoplasmic pigmentation. Several SF3B1, NRAS, and KIT mutations not previously documented in sinonasal melanomas were detected in our series, suggesting a potential role for targeted therapies. A similar frequency of SF3B1, NRAS, and KIT mutations was noted in Asian cases, whereas NRAS, KIT, and BRAF mutations were predominant in the United States and European cases; however, the number of included cases was small. The significant association between CD117 and cMYC expression with increased cytoplasmic pigmentation in our series suggests that the pigmented morphologic appearance of sinonasal melanomas could be attributed to the underlying oncogenic mutations and metabolic interaction.


Expression of the unique NCAM VASE exon is independently regulated in distinct tissues during development.
During development of the rat central nervous system, neural cell adhesion molecule (NCAM) mRNAs containing in the extracellular domain a 30-bp alternative exon, here named VASE, replace RNAs that lack this exon. The presence of this alternative exon between previously described exons 7 and 8 changes the predicted loop structure of the derived polypeptide from one resembling an immunoglobulin constant region domain to one resembling an immunoglobulin variable domain. This change could have significant effects on NCAM polypeptide function and cell-cell interaction. In this report we test multiple rat tissues for the presence of additional alternative exons at this position and also examine the regulation of splicing of the previously described exon. To sensitively examine alternative splicing, polymerase chain reactions (PCRs) with primers flanking the exon 7/exon 8 alternative splicing site were performed. Four categories of RNA samples were tested for new exons: whole brain from embryonic day 11 to adult, specific brain regions dissected from adult brain, clonal lines of neural cells in vitro, and muscle cells and tissues cultured in vitro and obtained by dissection. Within the limits of the PCR methodology, no evidence for any alternative exon other than the previously identified VASE was obtained. The regulation of expression of this exon was found to be complex and tissue specific. Expression of the 30-bp exon in the heart and nervous system was found to be regulated independently; a significant proportion of embryonic day 15 heart NCAM mRNAs contain VASE while only a very small amount of day 15 nervous system mRNAs contain VASE. Some adult central nervous system regions, notably the olfactory bulb and the peripheral nervous system structures adrenal gland and dorsal root ganglia, express NCAM which contains very little VASE. VASE is undetectable in NCAM PCR products from the olfactory epithelium. Other nervous system regions express significant quantities of NCAM both with and without VASE. Clonal cell lines in culture generally expressed very little VASE. These results indicate that a single alternative exon, VASE, is found in NCAM immunoglobulin-like loop 4 and that distinct tissues and nervous system regions regulate expression of VASE independently both during development and in adult animals.


Trends in food consumption over 30 years: evidence from a British birth cohort.
As populations are ageing, more emphasis is placed on healthy ageing. Over the past decades, food consumption patterns and food availability have also changed drastically, and therefore this study aimed to describe these changes in an ageing population. Food consumption of participants from the Medical Research Council National Survey on Health and Development, a British birth cohort study, was assessed using a 5-day estimated food records at 60-64 years (2006-11), 53 years (1999), 43 years (1989) and 36 years (1982). Only those who recorded ⩾3 days at all four time points were included in the analyses, n=989 (n=438 men and n=551 women); trends were tested using the Friedman test. Consumption of white bread, whole milk, fats and oils, meat and meat products, alcoholic drinks, coffee, sugar, preserves and confectionery decreased (P<0.001), whereas consumption of wholemeal and granary bread, semi-skimmed milk, fish and fruit and vegetables increased (P<0.001) over time. These observed changes in food consumption reflect a healthier diet, for example, replacement of white bread by granary and wholemeal bread, lower consumption of red and processed meats, somewhat higher consumption of fish, higher consumption of vegetables and lower consumption of coffee. This could partly be because of ageing of the cohort or compliance with dietary recommendations, facilitated by greater availability of healthier foods, such as semi-skimmed milk and wholegrain bread, in the UK. The changes in food consumption in this British birth cohort over the past three decades are encouraging and reflect a healthier diet in the later years.


Inhibition of glycolysis in the denervated dog heart.
We measured glucose metabolism in five dogs before and 3 weeks after cardiac denervation; after this time myocardial norepinephrine is depleted. The discharge by the myocardium, of 14CO2 from infused 14C-D-glucose (U), decreased following denervation (P = 0.05). The ratio of 14CO2 to total CO2 production, which measured the proportion of glucose to total substrate oxidized, also decreased following denervation (P = 0.05). The inhibition of glucose oxidation by denervation was not due to an increase in arterial lactate concentration. There was an associated increase in myocardial content of fructose-6-phosphate in an additional seven dogs (P < 0.01). We postulate that myocardial tissue norepinephrine is one of the controllers of the activity of phosphofructokinase.


QT prolongation is an independent predictor of mortality in end-stage renal disease.
Coronary artery disease (CAD) is the predominant cause of sudden cardiac death in the general population, and sudden cardiac death is the leading cause of mortality in end-stage renal disease (ESRD). QT-interval prolongation is an independent prognosticator in ESRD. We reviewed clinical, electrocardiographic, stress test, and coronary angiography data on ESRD patients evaluated for transplantation at our institution between 2000 and 2004 who underwent coronary angiography. The QT interval was corrected for heart rate and QRS duration (QTc). All-cause mortality data were prospectively collected and verified against the Social Security Death Index database. During 40 +/- 28 months of follow-up, 132 of the 280 (47%) patients died prior to renal transplantation. Patients with a prolonged QTc (39%) had 1-, 3-, and 5-year death-rates of 12%, 36%, and 47%, respectively, vs 8%, 24%, and 36% for those with normal QTc (log-rank P = 0.03). In a multivariate Cox regression model that adjusted for age, gender, diabetes mellitus, myocardial infarction, presence and severity of CAD on angiography, left ventricular (LV) hypertrophy, LV ejection fraction (EF), and multiple other variables, QTc remained to be an independent predictor of survival (hazard ratio [HR]: 1.008, 95% confidence interval [CI]: 1.001-1.014, P = 0.016). Female gender, decreasing LVEF, and decreasing severity of CAD on angiography were independent predictors of prolonged QTc. QTc prolongation is an independent predictor of mortality in ESRD patients being evaluated for renal transplantation. The prognostic information gained from the QTc is additive to that provided by the LVEF and the severity of CAD.


How antibodies fold.
B cells use unconventional strategies for the production of a seemingly unlimited number of antibodies from a very limited amount of DNA. These methods dramatically increase the likelihood of producing proteins that cannot fold or assemble appropriately. B cells are therefore particularly dependent on 'quality control' mechanisms to oversee antibody production. Recent in vitro experiments demonstrate that Ig domains have evolved diverse folding strategies ranging from robust spontaneous folding to intrinsically disordered domains that require assembly with their partner domains to fold; in vivo experiments reveal that these different folding characteristics form the basis for cellular checkpoints in Ig transport. Taken together, these reports provide a detailed understanding of how B cells monitor and ensure the functional fidelity of Ig proteins.


Signaling pathways for PC12 cell differentiation: making the right connections.
A key issue in signal transduction is how signaling pathways common to many systems-so-called canonical signaling cassettes-integrate signals from molecules having a wide spectrum of activities, such as hormones and neurotrophins, to deliver distinct biological outcomes. The neuroendocrine cell line PC12, derived from rat pheochromocytoma, provides an example of how one canonical signaling cassette-the Raf --> mitogen-activated protein kinase kinase (MEK) --> extracellular signal-regulated kinase (ERK) pathway-can promote distinct outcomes, which in this case include neuritogenesis, gene induction, and proliferation. Two growth hormones, epidermal growth factor (EGF) and nerve growth factor (NGF), use the same pathway to cause PC12 proliferation and differentiation, respectively. In addition, pituitary adenylate cyclase-activating polypeptide (PACAP), a neurotransmitter that also causes differentiation, uses the same canonical cassette as NGF but in a different way. The Connections Map for PC12 Cell Differentiation brings into focus the complex array of specific cellular responses that rely on canonical signal transduction systems.


The influence of pressure on the intrinsic dissolution rate of amorphous indomethacin.
New drug candidates increasingly tend to be poorly water soluble. One approach to increase their solubility is to convert the crystalline form of a drug into the amorphous form. Intrinsic dissolution testing is an efficient standard method to determine the intrinsic dissolution rate (IDR) of a drug and to test the potential dissolution advantage of the amorphous form. However, neither the United States Pharmacopeia (USP) nor the European Pharmacopeia (Ph.Eur) state specific limitations for the compression pressure in order to obtain compacts for the IDR determination. In this study, the influence of different compression pressures on the IDR was determined from powder compacts of amorphous (ball-milling) indomethacin (IND), a glass solution of IND and poly(vinylpyrrolidone) (PVP) and crystalline IND. Solid state properties were analyzed with X-ray powder diffraction (XRPD) and the final compacts were visually observed to study the effects of compaction pressure on their surface properties. It was found that there is no significant correlation between IDR and compression pressure for crystalline IND and IND-PVP. This was in line with the observation of similar surface properties of the compacts. However, compression pressure had an impact on the IDR of pure amorphous IND compacts. Above a critical compression pressure, amorphous particles sintered to form a single compact with dissolution properties similar to quench-cooled disc and crystalline IND compacts. In such a case, the apparent dissolution advantage of the amorphous form might be underestimated. It is thus suggested that for a reasonable interpretation of the IDR, surface properties of the different analyzed samples should be investigated and for amorphous samples the IDR should be measured also as a function of the compression pressure used to prepare the solid sample for IDR testing.


Mucin production by human colonic carcinoma cells correlates with their metastatic potential in animal models of colon cancer metastasis.
Patients with mucinous colorectal cancers characteristically present with advanced disease, however, the relationship between mucin production by colon cancer cells and their metastatic potential remains unclear. We therefore sought to define the relationship between mucin production by human colon cancer cells and metastatic ability by employing animal models of colon cancer metastasis. LS LiM 6, a colon carcinoma cell line with high liver metastasizing ability during cecal growth in nude mice produced twofold more metabolically labeled intracellular mucin and secreted four- to fivefold more mucin into the culture medium compared to poorly metastatic parental line LS174T. This was accompanied by a similar elevation in poly(A)+ RNA detected by blot hybridization with a human intestinal mucin cDNA probe, and increases in mucin core carbohydrate antigens determined immunohistochemically. Variants of LS174T selected for high (HM 7) or low (LM 12) mucin synthesizing capacity also yielded metastases after cecal growth and colonized the liver after splenic-portal injection in proportion to their ability to produce mucin. Inhibition of mucin glycosylation by the arylglycoside benzyl-alpha-N-acetyl-galactosamine greatly reduced liver colonization after splenic-portal injection of the tumor cells. These data suggest that mucin production by human colon cancer cells correlates with their metastatic potential and affects their ability to colonize the liver in experimental model systems.


Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway.
Telomerase is a regulated enzyme and its activity is tightly associated with cell proliferation. The mechanisms of this association are unclear, but specific growth factors may regulate telomerase activity. The present study examines the effect of epidermal growth factor (EGF) on telomerase activity and identifies the signal transduction pathway involved in this process. EGF up-regulated telomerase activity in EGF receptor-positive cells after the activation of telomerase reverse transcriptase (TERT) mRNA expression. This activation was rapid, peaked after 6 or 12 h and was not blocked by the concurrent exposure to cycloheximide, suggesting a direct effect of EGF on TERT transcription. Transient expression assays revealed that EGF activates the hTERT promoter and that the proximal core promoter is responsible for this regulation. The activation of hTERT mRNA expression by EGF was specifically blocked by MEK inhibitor, and in vitro kinase assays demonstrated that ERK is activated in response to EGF. Transient expression assays using mutant reporter plasmids revealed that an ETS motif located in the core promoter of hTERT is required for the EGF-induced transactivation of hTERT. Overexpression of wild type Ets in cells enhanced the EGF effect on hTERT transcription, while that of dominant negative Ets significantly repressed EGF action. These findings suggest that EGF activates telomerase through the direct activation of TERT transcription, in which the Ras/MEK/ERK pathway and Ets factor play major roles. Our data support the notion that growth factors directly regulate telomerase via specific signal transduction pathways.


The entangled triplet pair state in acene and heteroacene materials.
Entanglement of states is one of the most surprising and counter-intuitive consequences of quantum mechanics, with potent applications in cryptography and computing. In organic materials, one particularly significant manifestation is the spin-entangled triplet-pair state, which mediates the spin-conserving fission of one spin-0 singlet exciton into two spin-1 triplet excitons. Despite long theoretical and experimental exploration, the nature of the triplet-pair state and inter-triplet interactions have proved elusive. Here we use a range of organic semiconductors that undergo singlet exciton fission to reveal the photophysical properties of entangled triplet-pair states. We find that the triplet pair is bound with respect to free triplets with an energy that is largely material independent (∼30 meV). During its lifetime, the component triplets behave cooperatively as a singlet and emit light through a Herzberg-Teller-type mechanism, resulting in vibronically structured photoluminescence. In photovoltaic blends, charge transfer can occur from the bound triplet pairs with >100% photon-to-charge conversion efficiency.


A comparison of exercise interventions from bed rest studies for the prevention of musculoskeletal loss.
Musculoskeletal loss in actual or simulated microgravity occurs at a high rate. Bed rest studies are a reliable ground-based spaceflight analogue that allow for direct comparison of intervention and control participants. The aim of this review was to investigate the impact of exercise compared to no intervention on bone mineral density (BMD) and muscle cross-sectional area (muscle CSA) in bed rest studies relative to other terrestrial models. Eligible bed rest studies with healthy participants had an intervention arm with an exercise countermeasure and a control arm. A search strategy was implemented for MEDLINE. After screening, eight studies were identified for inclusion. Interventions included resistive exercise (RE), resistive vibration exercise (RVE), flywheel resistive exercise, treadmill exercise with lower body negative pressure (LBNP) and a zero-gravity locomotion simulator (ZLS). Lower limb skeletal sites had the most significant BMD losses, particularly at the hip which reduced in density by 4.59% (p < 0.05) and the tibial epiphysis by 6% (p < 0.05). Exercise attenuated bone loss at the hip and distal tibia compared to controls (p < 0.05). Muscle CSA changes indicated that the calf and quadriceps were most affected by bed rest. Exercise interventions significantly attenuated loss of muscle mass. ZLS, LBNP treadmill and RE significantly attenuated bone and muscle loss at the hip compared to baseline and controls. Despite exercise intervention, high rates of bone loss were still observed. Future studies should consider adding bisphosphonates and pharmacological/nutrition-based interventions for consideration of longer-duration missions. These findings correlate to terrestrial bed rest settings, for example, stroke or spinal-injury patients.


Long-term functional outcomes after replacement of the esophagus with gastric, colonic, or jejunal conduits: a systematic literature review.
It is generally recognized that in patients with an intact stomach diagnosed with esophageal cancer, gastric tubulization and pull-up shall always be the preferred technique for reconstruction after an esophageal resection. However, in cases with extensive gastroesophageal junction (GEJ) cancer with aboral spread and after previous gastric surgery, alternative methods for reconstruction have to be pursued. Moreover, in benign cases as well as in those with early neoplastic lesions of the esophagus and the GEJ that are associated with long survival, it is basically unclear which conduit should be recommended. The aim of this study is to determine the long-term functional outcomes of different conduits used for esophageal replacement, based on a comprehensive literature review. Eligible were all clinical studies reporting outcomes after esophagectomy, which contained information on at least three years of follow-up after the operation in patients who were older than 18 years of age at the time of the operation. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic web-based search using MEDLINE, the Cochrane Library, and EMBASE databases was performed, reviewing medical literature published between January 2006 and December 2015. The scientific quality of the data was generally low, which allowed us to incorporate only 16 full text articles for the final analyses. After a gastric pull-up, the proportion of patients who suffered from dysphagia varied substantially but seemed to decrease over time with a mild dysphagia remaining during long-term follow-up. When reflux-related symptoms and complications were addressed, roughly two third of patients experienced mild to moderate reflux symptoms a long time after the resection. Following an isoperistaltic colonic graft, the functional long-term outcomes regarding swallowing difficulties were sparsely reported, while three studies reported reflux/regurgitation symptoms in the range of 5% to 16%, one of which reported the symptom severity as being mild. Only one report was available after the use of a long jejunal segment, which contained only six patients, who scored the severity of dysphagia and reflux as mild. Very few if any data were available on a structured assessment of dumping and disturbed bowel functions. Few high-quality data are available on the long-term functional outcomes after esophageal replacement irrespective of the use of a gastric tube, the right or left colon or a long jejunal segment. No firm conclusions regarding the advantages of one graft over the other can presently be drawn.


Global analysis of protein localization in budding yeast.
A fundamental goal of cell biology is to define the functions of proteins in the context of compartments that organize them in the cellular environment. Here we describe the construction and analysis of a collection of yeast strains expressing full-length, chromosomally tagged green fluorescent protein fusion proteins. We classify these proteins, representing 75% of the yeast proteome, into 22 distinct subcellular localization categories, and provide localization information for 70% of previously unlocalized proteins. Analysis of this high-resolution, high-coverage localization data set in the context of transcriptional, genetic, and protein-protein interaction data helps reveal the logic of transcriptional co-regulation, and provides a comprehensive view of interactions within and between organelles in eukaryotic cells.


Coupling a nano-particle with isothermal fluctuating hydrodynamics: Coarse-graining from microscopic to mesoscopic dynamics.
We derive a coarse-grained description of the dynamics of a nanoparticle immersed in an isothermal simple fluid by performing a systematic coarse graining of the underlying microscopic dynamics. As coarse-grained or relevant variables, we select the position of the nanoparticle and the total mass and momentum density field of the fluid, which are locally conserved slow variables because they are defined to include the contribution of the nanoparticle. The theory of coarse graining based on the Zwanzing projection operator leads us to a system of stochastic ordinary differential equations that are closed in the relevant variables. We demonstrate that our discrete coarse-grained equations are consistent with a Petrov-Galerkin finite-element discretization of a system of formal stochastic partial differential equations which resemble previously used phenomenological models based on fluctuating hydrodynamics. Key to this connection between our "bottom-up" and previous "top-down" approaches is the use of the same dual orthogonal set of linear basis functions familiar from finite element methods (FEMs), both as a way to coarse-grain the microscopic degrees of freedom and as a way to discretize the equations of fluctuating hydrodynamics. Another key ingredient is the use of a "linear for spiky" weak approximation which replaces microscopic "fields" with a linear FE interpolant inside expectation values. For the irreversible or dissipative dynamics, we approximate the constrained Green-Kubo expressions for the dissipation coefficients with their equilibrium averages. Under suitable approximations, we obtain closed approximations of the coarse-grained dynamics in a manner which gives them a clear physical interpretation and provides explicit microscopic expressions for all of the coefficients appearing in the closure. Our work leads to a model for dilute nanocolloidal suspensions that can be simulated effectively using feasibly short molecular dynamics simulations as input to a FEM fluctuating hydrodynamic solver.


Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.
Mannitol (M) and deferoxamine (DFO) can each protect against myohemoglobinuric acute renal failure (MH-ARF). This study assessed M-DFO interactions during MH-ARF to help discern mechanisms of renal injury, and to define whether M + DFO exerts additive or synergistic antioxidant/cytoprotective effects. Rats subjected to the glycerol model of MH-ARF were treated with (a) M; (b) DFO; (c) M + DFO; or (d) no protective agents. Relative degrees of protection (24-h plasma urea/creatinine concentrations) were M + DFO greater than M greater than DFO greater than or equal to no therapy. To assess whether catalytic Fe is generated during MH-ARF, the bleomycin assay was applied to plasma/urine samples obtained 0-2 h post-glycerol injection. Although striking plasma and urinary increments were noted, excess renal hydroxyl radical (.OH) production was not apparent (gauged by the salicylate trap method). M increased catalytic Fe excretion (four times), whereas DFO eliminated its urinary (but not plasma) activity. To determine direct M/DFO effects on proximal tubular cell oxidant injury, isolated rat proximal tubular segments (PTS) were incubated with toxic dosages of FeSO4 or H2O2. Despite inducing cell injury (lactic dehydrogenase release), Fe caused no .OH production. DFO conferred dose-dependent cytoprotection, correlating with increased, not decreased, .OH generation. Although M scavenged this .OH excess, it had no additive or independent, protective effect. H2O2 cytotoxicity correlated with increased catalytic Fe (but not .OH) generation. The fact that DFO (but not .OH scavengers [M and dimethylthiourea]) blocked H2O2 toxicity implied Fe-dependent, .OH-independent cell killing. In conclusion, (a) striking catalytic Fe generation occurs during MH-ARF, but augmented intrarenal .OH production may not develop; (b) DFO can block Fe toxicity despite a prooxidant effect; (c) H2O2 PTS toxicity is Fe, but possibly not .OH, dependent; and (d) M does not mitigate oxidant PTS injury, either in the presence or absence of DFO, suggesting that its additive benefit with DFO in vivo occurs via a diuretic, not antioxidant effect.


Long-term ethanol exposure causes human liver cancer cells to become resistant to mitomycin C treatment through the inactivation of bad-mediated apoptosis.
The aim of this study was to test whether long-term ethanol consumption confers therapeutic resistance to human liver cancer patients infected with hepatitis B virus (HBV). Chronic ethanol-treated cells were established by consecutively culturing a human hepatocellular carcinoma cell line, Hep 3B, which contains integrated HBV sequences, for 20-40 passages with or without 10 mM ethanol (designated as E20-E40 and C20-C40, respectively). Flow cytometry analysis demonstrated that a growth promoting effect of long-term ethanol treatment was induced in the E40 cells through preferential acceleration of S-phase in these cells. Lower protein expression levels of p16, p21/Cip1, and p27/Kip1 were detected in the ethanol-treated E40 cells. We further demonstrated that long-term ethanol-treated E40 cells develop drug resistance in response to mitomycin C (MMC) treatment (>8 microM). Immunoblot analysis revealed that caspase-8-mediated mitochondrial apoptotic signals (such as Bad) were inactivated in the MMC-resistant E40 cells. Immunoprecipitation experiments demonstrated that the sequestration of phosphorylated Bad (Ser-112) through its binding with 14-3-3 was detected more profoundly in the MMC-resistant E40 cells. Next, we examined the therapeutic efficacy of MMC (10 mg MMC/kg body weight, three times per week) in severe combined immunodeficient (SCID) mice bearing E40- and C40-xenografted tumors. Significant reductions (>3-fold) in tumor growth were detected in MMC-treated C40-xenografted mice. In vivo and in vitro studies demonstrated that AKT- and extracellular signal-regulated kinase (ERK)-mediated survival factors inhibited the Bad-induced mitochondrial apoptotic signals that were involved in E40 tumor cells and that conferred resistance to MMC.


Advances in microbial ecosystem concepts and their consequences for ruminant agriculture.
Microbial transformations in the rumen ecosystem have a major impact on our ability to meet the challenge of reducing the environmental footprint of ruminant livestock agriculture, as well as enhancing product quality. Current understanding of the rumen microbial ecosystem is limited, and affects our ability to manipulate rumen output. The view of ruminal fermentation as the sum of activities of the dominant rumen microbiota is no longer adequate, with a more holistic approach required. This paper reviews rumen functionality in the context of the microbiota of the rumen ecosystem, addressing ruminal fermentation as the product of an ecosystem while highlighting the consequences of this for ruminant agriculture. Microbial diversity in the rumen ecosystem enhances the resistance of the network of metabolic pathways present, as well as increasing the potential number of new pathways available. The resulting stability of rumen function is further promoted by the existence of rumen microbiota within biofilms. These protected, structured communities offer potential advantages, but very little is currently known about how ruminal microorganisms interact on feed-surfaces and how these communities develop. The temporal and spatial development of biofilms is strongly linked to the availability of dietary nutrients, the dynamics of which must also be given consideration, particularly in fresh-forage-based production systems. Nutrient dynamics, however, impact not only on pathway inputs but also the turnover and output of the whole ecosystem. Knowledge of the optimal balance of metabolic processes and the corresponding microbial taxa required to provide a stable, balanced ecosystem will enable a more holistic understanding of the rumen. Future studies should aim to identify key ecosystem processes and components within the rumen, including microbial taxa, metabolites and plant-based traits amenable to breeding-based modification. As well as gaining valuable insights into the biology of the rumen ecosystem, this will deliver realistic and appropriate novel targets for beneficial manipulation of rumen function.


Big Five Personality Traits and the General Factor of Personality as Moderators of Stress and Coping Reactions Following an Emergency Alarm on a Swiss University Campus.
We conducted an online survey including 306 participants aged 18-64 years to assess the general factor of personality (GFP) and Big Five personality traits in relation to individual stress and coping reactions following a shooting emergency alarm at a Swiss university campus. Although the emergency eventually turned out to be a false alarm, various witnesses showed pronounced distress owing to a vast police operation. The GFP structure was replicated using two alternative modelling approaches. Neuroticism related substantially to acute fear and traumatic distress as well as to more enduring maladaptive coping. Agreeableness was negatively associated with the coping strategy of medication use, whereas both agreeableness and conscientiousness related positively to social activity following the emergency. The GFP related moderately to peri-traumatic distress and showed a substantial negative association with medication use and a strong positive association with social activity. In conclusion, both the GFP and Big Five traits significantly moderate stress responses following a stressful life event. The GFP predominantly relates to socially adaptive coping, whereas in particular neuroticism accounts for acute stress reactions such as fear and traumatic distress. These findings support the notion that personality influences how persons react in the face of adversity. Copyright © 2016 John Wiley & Sons, Ltd.


Developmental regulation of hemoglobin synthesis in the green anole lizard Anolis carolinensis.
Tetrapod vertebrates possess multiple α- and β-like globin genes that are ontogenetically regulated, such that functionally distinct hemoglobin (Hb) isoforms are synthesized during different stages of development. The α- and β-like globin genes of amphibians, birds and mammals are differentially expressed during embryonic development and postnatal life, but little is known about the developmental regulation of globin gene expression in non-avian reptiles. Here we report an investigation into the developmental regulation of Hb synthesis in the green anole lizard Anolis carolinensis. We tested two hypotheses derived from comparative genomic studies of the globin gene clusters in tetrapod vertebrates. First, we tested whether the product of the Anolis α(D)-globin gene is incorporated into embryonic Hb, thereby performing the role that would normally be performed by the embyronic α(E)-globin gene (which has been deleted from the green anole genome). Second, we tested whether two 'lizard-specific' β-globin paralogs have independently evolved a division of labor between an early-expressed embryonic gene and a later-expressed adult gene. Results of a proteomic analysis revealed that α- and β-like globin genes of the anole are differentially expressed during embryonic development. However, the same repertoire of α- and β-chain Hb isoforms was expressed during all stages of development and postnatal life, and the ontogenetic shifts in isoform composition were relatively subtle. In contrast to the pattern that has been documented in other tetrapod vertebrates, it appears that the developmental regulation of Hb synthesis in the green anole lizard does not involve discrete, stage-specific switches in gene activation and gene silencing.


Laparoscopic cholecystectomy does not prevent the postoperative protein catabolic response in muscle.
The authors determined the effect of laparoscopic cholecystectomy on protein synthesis in skeletal muscle. In addition to a decrease in muscle protein synthesis, after open cholecystectomy, the authors previously demonstrated a decrease in insulin sensitivity. This study on patients undergoing laparoscopic and open surgery, therefore, included simultaneous measurements of protein synthesis and insulin sensitivity. Laparoscopy has become a routine technique for several operations because of postoperative benefits that allow rapid recovery. However, its effect on postoperative protein catabolism has not been characterized. Conventional laparotomy induces a drop in muscle protein synthesis, whereas degradation is unaffected. Patients were randomized to laparoscopic or open cholecystectomy, and the rate of protein synthesis in skeletal muscle was determined 24 hours postoperatively by the flooding technique using L-(2H5)phenylalanine, during a hyperinsulinemic normoglycemic clamp to assess insulin sensitivity. The protein synthesis rate decreased by 28% (1.77 +/- 0.11%/day vs. 1.26 +/- 0.08%/day, p < 0.01) in the laparoscopic group and by 20% (1.97 +/- 0.15%/day vs. 1.57 +/- 0.15%/day, p < 0.01) in the open cholecystectomy group. In contrast, the fall in insulin sensitivity after surgery was lower with laparoscopic (22 +/- 2%) compared with open surgery (49 +/- 5%). Laparoscopic cholecystectomy did not avoid a substantial decline in muscle protein synthesis, despite improved insulin sensitivity. The change in the two parameters occurred independently, indicating different mechanisms controlling insulin sensitivity and muscle protein synthesis.


Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells.
To understand the mechanisms leading to trastuzumab resistance in HER2-overexpressing breast tumors, we created trastuzumab-insensitive cell lines (SKBR3/100-8 and BT474/100-2). The cell lines maintain HER2 receptor overexpression and show increase in EGF receptor (EGFR). Upon trastuzumab treatment, SKBR3/100-8 and BT474/100-2 cell lines displayed increased growth rate and invasiveness. The trastuzumab resistance in SKBR3/100-8 and BT474/100-2 was accompanied with activation of the Wnt/β-catenin signaling pathway. Further investigation found that Wnt3 overexpression played a key role toward the development of trastuzumab resistance. The expression of Wnt3 in trastuzumab-resistant cells increased nuclear expression of β-catenin and transactivated expression of EGFR. The increased Wnt3 in the trastuzumab-resistant cells also promoted a partial EMT-like transition (epithelial-to-mesenchymal transition); increased N-cadherin, Twist, Slug; and decreased E-cadherin. Knockdown of Wnt3 by siRNA restored cytoplasmic expression of β-catenin and decreased EGFR expression in trastuzumab-resistant cells. Furthermore, the EMT markers were decreased, E-cadherin was increased, and the cell invasiveness was inhibited in response to the Wnt3 downregulation. Conversely, SKBR3 cells which had been stably transfected with full-length Wnt3 exhibited EMT-like transition. The Wnt3 transfectants, SKBR3/Wnt3-7 and SKBR3/Wnt3-9, showed a significant decrease in E-cadherin and increase in N-cadherin, Twist, and Slug. The cells were less sensitive to trastuzumab than parental SKBR3 and vector-transfected cells. In summary, our data suggest that Wnt3 overexpression activates Wnt/β-catenin signaling pathway that leads to transactivation of EGFR and promotes EMT-like transition. This could be an important mechanism leading to trastuzumab resistance in HER2-overexpressing breast cancer cells.


Engineered Human Induced Pluripotent Cells Enable Genetic Code Expansion in Brain Organoids.
Human induced pluripotent stem cell (hiPSC) technology has revolutionized studies on human biology. A wide range of cell types and tissue models can be derived from hiPSCs to study complex human diseases. Here, we use PiggyBac-mediated transgenesis to engineer hiPSCs with an expanded genetic code. We demonstrate that genomic integration of expression cassettes for a pyrrolysyl-tRNA synthetase (PylRS), pyrrolysyl-tRNA (PylT) and the target protein of interest enables site-specific incorporation of a non-canonical amino acid (ncAA) in response to an amber stop codon. Neural stem cells, neurons and brain organoids derived from the engineered hiPSCs continue to express the amber suppression machinery and produce ncAA-bearing reporter. The incorporated ncAA can serve as a minimal bioorthogonal handle for further modifications by labeling with fluorescent dyes. Site-directed ncAA mutagenesis will open a wide range of applications to probe and manipulate proteins in brain organoids and other hiPSC-derived cell types and complex tissue models.


Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment.
The microtubule (MT) cytoskeleton is essential for cellular morphogenesis, cell migration, and cell division. MT organization is primarily mediated by a variety of MT-associated proteins. Among these proteins, plus-end-tracking proteins (+TIPs) are evolutionarily conserved factors that selectively accumulate at growing MT plus ends. Cytoplasmic linker protein (CLIP)-170 is a +TIP that associates with diverse proteins to determine the behavior of MT ends and their linkage to intracellular structures, including mitotic chromosomes. However, how CLIP-170 activity is spatially and temporally controlled is largely unknown. Here, we show that phosphorylation at Ser312 in the third serine-rich region of CLIP-170 is increased during mitosis. Polo-like kinase 1 (Plk1) is responsible for this phosphorylation during the mitotic phase of dividing cells. In vitro analysis using a purified CLIP-170 N-terminal fragment showed that phosphorylation by Plk1 diminishes CLIP-170 binding to the MT ends and lattice without affecting binding to EB3. Furthermore, we demonstrate that during mitosis, stable kinetochore/MT attachment and subsequent chromosome alignment require CLIP-170 and a proper phosphorylation/dephosphorylation cycle at Ser312. We propose that CLIP-170 phosphorylation by Plk1 regulates proper chromosome alignment by modulating the interaction between CLIP-170 and MTs in mitotic cells and that CLIP-170 activity is stringently controlled by its phosphorylation state, which depends on the cellular context.


Differential susceptibility of human thymic dendritic cell subsets to X4 and R5 HIV-1 infection.
Human thymus can be infected by HIV-1 with potential consequences on immune regeneration and homeostasis. We previously showed that CD4 thymocytes preferentially replicate CXCR4 tropic (X4) HIV-1 dependently on interleukin (IL)-7. Here we addressed the susceptibility of thymic dendritic cells (DC) to HIV-1 infection. We investigated the replication ability of CXCR4 or CCR5 (R5) tropic HIV-1 in thymic micro-explants as well as in isolated thymic CD11clowCD14- DC, CD11chighCD14+ DC and plasmacytoid DC subsets. Thymic tissue was productively infected by both X4 and R5 viruses. However, X4 but not R5 HIV-1 replication was enhanced by IL-7 in thymic micro-explants, suggesting that R5 virus replication occurred in cells other than thymocytes. Indeed, we found that R5 HIV-1 replicated efficiently in DC isolated from thymic tissue. The replicative capacity of X4 and R5 viruses differed according to the different DC subsets. R5 but not X4 HIV-1 efficiently replicated in CD11chighCD14+ DC. In contrast, no HIV-1 replication was detected in CD11clowCD14- DC. Both X4 and R5 viruses efficiently replicated in plasmacytoid DC, which secreted interferon-alpha upon HIV-1 exposure. Productive HIV-1 infection also caused DC loss, consistent with different permissivity of each DC subset. Thymic DC sustain high levels of HIV-1 replication. DC might thus be the first target for R5 HIV-1 infection of thymus, acting as a Trojan horse for HIV-1 spread to thymocytes. Furthermore, DC death induced by HIV-1 infection may affect thymopoiesis.


Screening patients with diabetes mellitus for tuberculosis in China.
There is a high burden of both diabetes (DM) and tuberculosis (TB) in China, and as DM increases the risk of TB and adversely affects TB treatment outcomes, there is a need for bidirectional screening of the two diseases. How this is best performed is not well determined. In this pilot project in China, we aimed to assess the feasibility and results of screening DM patients for TB within the routine healthcare setting of five DM clinics. Agreement on how to screen, monitor and record was reached in May 2011 at a national stakeholders meeting, and training was carried out for staff in the five clinics in July 2011. Implementation started in September 2011, and we report on 7 months of activities up to 31 March 2012. DM patients were screened for TB at each clinic attendance using a symptom-based enquiry, and those positive to any symptom were referred for TB investigations. In the three quarters, 72% of 3174 patients, 79% of 7196 patients and 68% of 4972 patients were recorded as having been screened for TB, resulting in 7 patients found who were already known to have TB, 92 with a positive TB symptom screen and 48 of these newly diagnosed with TB as a result of referral and investigation. All patients except one were started on anti-TB treatment. TB case notification rates in screened DM patients were several times higher than those of the general population, were highest for the five sites combined in the final quarter (774/100 000) and were highest in one of the five clinics in the final quarter (804/100 000) where there was intensive in-house training, special assignment of staff for screening and colocation of services. This pilot project shows that it is feasible to carry out screening of DM patients for TB resulting in high detection rates of TB. This has major public health and patient-related implications.


Diversity of dynamics and morphologies of invasive solid tumors.
Complex tumor-host interactions can significantly affect the growth dynamics and morphologies of progressing neoplasms. The growth of a confined solid tumor induces mechanical pressure and deformation of the surrounding microenvironment, which in turn influences tumor growth. In this paper, we generalize a recently developed cellular automaton model for invasive tumor growth in heterogeneous microenvironments [Y. Jiao and S. Torquato, PLoS Comput. Biol.7, e1002314 (2011)] by incorporating the effects of pressure. Specifically, we explicitly model the pressure exerted on the growing tumor due to the deformation of the microenvironment and its effect on the local tumor-host interface instability. Both noninvasive-proliferative growth and invasive growth with individual cells that detach themselves from the primary tumor and migrate into the surrounding microenvironment are investigated. We find that while noninvasive tumors growing in "soft" homogeneous microenvironments develop almost isotropic shapes, both high pressure and host heterogeneity can strongly enhance malignant behavior, leading to finger-like protrusions of the tumor surface. Moreover, we show that individual invasive cells of an invasive tumor degrade the local extracellular matrix at the tumor-host interface, which diminishes the fingering growth of the primary tumor. The implications of our results for cancer diagnosis, prognosis and therapy are discussed.


Analysis of transmission mode of a matched fiber Bragg grating interrogation scheme.
A detailed investigation has been undertaken into the transmission mode of the matched fiber Bragg grating interrogation scheme with respect to its use in optical fiber sensor applications. Analytical and numerical models of the scheme have been developed. Experimental studies presented include the effect of the spectral characteristics of the gratings on system performance, results of strain and compression calibrations, a scheme to correct for intensity fluctuations, and the correction of temperature-induced shifts by collocating sensor and reference gratings. The results are in good agreement with a simplified model of the transmission mode. The analysis provides quantitative relationships between key sensor design parameters, such as sensitivity and measurement range as a function of grating bandwidth.


Trauma-Induced Conduction Disturbances.
Electrical disturbances following blunt cardiac injuries are rare but can be caused by electrical or structural damage to the heart. We present the case of a patient who had conduction abnormalities following blunt traumatic injury that were incidentally detected on telemetry. A 64-year-old female with no history of cardiac disease was brought to the emergency department after a motor vehicle collision that resulted in chest wall bruising. The patient was found to have L-spine fractures and was admitted for observation. During her hospitalization, the patient had multiple episodes of heart block. A temporary pacemaker was inserted because of the recurrent episodes, and a dual-chamber permanent pacemaker was placed on day 4 of her hospitalization. Heart block as a consequence of blunt cardiac injury is rare; however, it needs to be recognized as early as possible. Permanent pacemaker placement is usually indicated for patients with prolonged or recurrent episodes.


Kinetics of mucosal influx of glycylsarcosine, glycine and leucine into hamster jejunum and ileum in vitro.
1. This paper describes an investigation of the kinetics of influx of the dipeptide glycylsarcosine and the amino acids glycine and L-leucine into rings of everted hamster small intestine in vitro, in proximal and distal small intestine (jejunum and ileum). Results were expressed per unit wet weight of intestine. 2. At all concentrations studied (0.1--100 mmol/l), influx of glycylsarcosine was more rapid in the jejunum than in the ileum. In contrast, at all concentrations studied, influx of glycine and leucine was more rapid in the ileum than the jejunum. 3. Estimates of the simple diffusion component in total influx were made. This component became increasingly large as the substrate concentration was raised. After correction for simple diffusion, transport of all three substrates conformed to Michaelis-Menten kinetics in both jejunum and ileum. Values for simple diffusion, apparent Kt and Vmax, are reported. 4. Possibly physiological implications of the results are discussed, and it is pointed out that under experimental conditions similar to our own, simple diffusion is too large a component in total influx to be ignored.


Drosophila SAF-B links the nuclear matrix, chromosomes, and transcriptional activity.
Induction of gene expression is correlated with alterations in nuclear organization, including proximity to other active genes, to the nuclear cortex, and to cytologically distinct domains of the nucleus. Chromosomes are tethered to the insoluble nuclear scaffold/matrix through interaction with Scaffold/Matrix Attachment Region (SAR/MAR) binding proteins. Identification and characterization of proteins involved in establishing or maintaining chromosome-scaffold interactions is necessary to understand how the nucleus is organized and how dynamic changes in attachment are correlated with alterations in gene expression. We identified and characterized one such scaffold attachment factor, a Drosophila homolog of mammalian SAF-B. The large nuclei and chromosomes of Drosophila have allowed us to show that SAF-B inhabits distinct subnuclear compartments, forms weblike continua in nuclei of salivary glands, and interacts with discrete chromosomal loci in interphase nuclei. These interactions appear mediated either by DNA-protein interactions, or through RNA-protein interactions that can be altered during changes in gene expression programs. Extraction of soluble nuclear proteins and DNA leaves SAF-B intact, showing that this scaffold/matrix-attachment protein is a durable component of the nuclear matrix. Together, we have shown that SAF-B links the nuclear scaffold, chromosomes, and transcriptional activity.


The Association of Opioid Utilization and Patient Satisfaction Following Outpatient Orthopaedic Surgery: More May Not Be Better.
Postoperative analgesia remains an important area of research in orthopaedics. There remains a lack of information on the complex interplay between opioid utilization postoperatively, pain and patient satisfaction. This study aims to describe the relationship between opioid utilization, postoperative pain, and patient satisfaction following outpatient orthopaedic surgery in a multispecialty orthopaedic practice. As a part of an ongoing quality control project at our institution patients were instructed to monitor utilization of postoperative opioids. The results of a convenience sample of 139 patients representing a 53% response rate among eligible patients that completed the survey following outpatient orthopaedic surgery are reported. Among patients undergoing outpatient orthopaedic surgery, there was no clinically significant association between opioid utilization and patient satisfaction. This association appeared largely independent of the patient's actual pain. While lower pain scores were associated with increasing patient satisfaction, this appeared to be independent of opioid utilization. (Journal of Surgical Orthopaedic Advances 29(2):88-93, 2020).


Photon trapping models for x-ray lasers.
Optimum methods for calculating the effects of photon trapping are discussed. An efficient line-transfer algorithm that can calculate trapping when there are overlapping and interacting lines is described. Escape probability formulas are shown to be appropriate for calculating photon trapping for isolated lines and for the highest-energy line in a group of lines in many situations. Major computational savings are achieved by using cylindrical escape probabilities for recombination x-ray laser schemes. For collisional x-ray laser schemes it is shown that the calculation of line transfer in planar geometry is sufficiently fast that one only obtains substantial savings by exploiting the coarser spatial zoning that is possible when using escape probabilities in regions of steep velocity gradients. The use of escape probabilities is shown to be particularly well suited for single-zone parameter studies.


Rate of tree carbon accumulation increases continuously with tree size.
Forests are major components of the global carbon cycle, providing substantial feedback to atmospheric greenhouse gas concentrations. Our ability to understand and predict changes in the forest carbon cycle--particularly net primary productivity and carbon storage--increasingly relies on models that represent biological processes across several scales of biological organization, from tree leaves to forest stands. Yet, despite advances in our understanding of productivity at the scales of leaves and stands, no consensus exists about the nature of productivity at the scale of the individual tree, in part because we lack a broad empirical assessment of whether rates of absolute tree mass growth (and thus carbon accumulation) decrease, remain constant, or increase as trees increase in size and age. Here we present a global analysis of 403 tropical and temperate tree species, showing that for most species mass growth rate increases continuously with tree size. Thus, large, old trees do not act simply as senescent carbon reservoirs but actively fix large amounts of carbon compared to smaller trees; at the extreme, a single big tree can add the same amount of carbon to the forest within a year as is contained in an entire mid-sized tree. The apparent paradoxes of individual tree growth increasing with tree size despite declining leaf-level and stand-level productivity can be explained, respectively, by increases in a tree's total leaf area that outpace declines in productivity per unit of leaf area and, among other factors, age-related reductions in population density. Our results resolve conflicting assumptions about the nature of tree growth, inform efforts to undertand and model forest carbon dynamics, and have additional implications for theories of resource allocation and plant senescence.


Genes, race, and population: avoiding a collision of categories.
A wide array of federal mandates have a profound impact on the use of racial and ethnic categories in biomedical research, clinical practice, product development, and health policy. Current discussions over the appropriate use of racial and ethnic categories in biomedical contexts have largely focused on the practices of individual researchers. By contrast, our discussion focuses on relations between the daily practices of biomedical professionals and federal regulatory mandates. It draws upon the legal doctrine of equal protection to move beyond such debates and to propose guidelines to address the structural forces imposed by federal regulations that mandate how data about race and ethnicity are used in biomedical research. It offers a framework to manage the tension involved in using existing federally mandated categories of race and ethnicity alongside new scientific findings about human genetic variation.


Enabling strategies for step efficient syntheses.
The field of natural product total synthesis has reached the point where synthetic efficiency has become more important than merely defining a viable (yet less ideal) route to the target molecule. Synthetic efficiency is best represented by the number of steps it takes to finish the target molecule from readily available starting materials, as by reducing the number of steps, all other factors of synthetic efficiency are influenced positively. By comparing several total syntheses from the recent years, the most successful strategies for step efficient syntheses will be highlighted. Each synthesis will be presented using a color-coded synthetic flowchart, in which each step is categorized by a colored box. Five categories of transformations are defined and rated according to their synthetic value. Each class will be signified by different colors so that the reader can quickly see which parts of the synthesis are productive and those that are not.


Bck2 is a phase-independent activator of cell cycle-regulated genes in yeast.
During the cell division cycle of the yeast Saccharomyces cerevisiae, the G1-to-S transition depends upon the activation of two transcription factors (SBF and MBF), which are responsible for the cell cycle-regulated expression of more than 200 genes. Bck2 becomes essential in the absence of Cln3, the most upstream activator of this transcriptional program. Here we have used a genome-wide approach to elucidate the targets of Bck2. Our data indicate that Bck2 activates a selection of cell cycle-regulated genes from all cell cycle stages. In contrast, Cln3 activates only G1/S phase genes. Furthermore, Bck2 activates many genes independently of Swi6, the common component of SBF and MBF. Comparison of Bck2 targets with those of other transcription factors suggests that, in addition to SBF and MBF, Bck2 may elicit gene expression via Ste12 and Mcm1. We propose that Bck2 activates its targets by a mechanism fundamentally different from that of Cln3, and that it may be a necessary cofactor for the full expression of a subset of cell cycle-regulated genes.


Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose-positron emission tomography.
Thyroid incidentalomas detected by 2-deoxy-2-18F-fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) have been reported in 1% to 4% of the population, with a risk of malignancy of 27.8% to 74%. We performed a retrospective review of FDG-avid thyroid incidentalomas in cancer screening subjects and patients with nonthyroid cancer. The risk of malignancy in thyroid incidentaloma and its association with the maximal standardized uptake value (SUVmax) in 18F-FDG PET/CT were evaluated to define the predictor variables in assessing risk of malignancy. A total of 2,584 subjects underwent 18F-FDG PET/CT for metastatic evaluation or cancer screening from January 2005 to January 2010. Among them, 36 subjects with FDG-avid thyroid incidentalomas underwent further diagnostic evaluation (thyroid ultrasonography-guided fine needle aspiration cytology [FNAC] or surgical resection). We retrospectively reviewed the database of these subjects. Of the 2,584 subjects who underwent 18F-FDG PET/CT (319 for cancer screening and 2,265 for metastatic evaluation), 52 (2.0%) were identified as having FDG-avid thyroid incidentaloma and cytologic diagnosis was obtained by FNAC in 36 subjects. Of the subjects, 15 were proven to have malignant disease: 13 by FNAC and two by surgical resection. The positive predictive value of malignancy in FDG-avid thyroid incidentaloma was 41.7%. Median SUVmax was higher in malignancy than in benign lesions (4.7 [interquartile range (IQR), 3.4 to 6.0] vs. 2.8 [IQR, 2.6 to 4.0], P=0.001). Thyroid incidentalomas found on 18F-FDG PET/CT have a high risk of malignancy, with a positive predictive value of 41.7%. FDG-avid thyroid incidentalomas with higher SUVmax tended to be malignant.


Network analysis of randomized controlled trials in multiple sclerosis.
The optimal treatment of multiple sclerosis (MS) is not yet well-defined. To estimate the relative effectiveness of treatments in MS, we performed a network of multiple-treatments meta-analysis of randomized controlled trials (RCTs) for relapsing MS using three main efficacy outcomes: relapse-free patients, patients without disease progression, and patients without magnetic resonance imaging progression. We systematically searched PubMed and the Cochrane Central Register of Controlled Trials to identify English-language articles with RCTs that compared pharmaceutical treatments using the terms multiple sclerosis and randomized controlled trial. All RCTs that involved patients with definite relapsing MS and provided data for calculating the odds ratios for the main outcomes were considered. First, comparative effectiveness relative to placebo was assessed using direct analysis. Then, each therapy was compared with interferon beta-1b (250 μg)* in direct and indirect analyses. Effect sizes were estimated by applying a random-effects model. We identified 4165 titles; after screening, 109 articles were eligible for inclusion. In total, 26,828 patients were included. The network consisted of 145 treatments involving 59 direct comparisons with placebo and 8 direct comparisons with interferon beta-1b (250 μg). Two treatments showed better response compared with placebo (direct analysis) for all three efficacy outcomes: natalizumab (300 mg)(†) and fingolimod (0.5 mg). In comparing treatments with interferon beta-1b (250 μg), the network analysis revealed that no therapy shows better response for all 3 efficacy outcomes and alemtuzumab, 12 and 24 mg, have better response for 2 of the outcomes (relapse-free patients and patients without disease progression). Although some treatments seem to have better efficacy, the results should be interpreted with caution because the network was dominated by indirect comparisons. Data from the selected studies included in the network cannot be extrapolated beyond them. Large RCTs that make head-to-head comparisons between treatments are needed to draw safe conclusions for the optimal treatment of MS.


Composite recurrent hodgkin lymphoma and diffuse large B-cell lymphoma: one clone, two faces.
We describe a composite lymphoma with recurrent Hodgkin lymphoma and diffuse large B-cell lymphoma components manifesting as a single, perforated small intestinal tumor in a 56-year-old man with a history of classical Hodgkin lymphoma and recent relapse in the bone marrow. The resected mass had 2 morphologically and immunophenotypically distinct components; 1 showed a pleomorphic cellular infiltrate with fibrosis and contained numerous, large Hodgkin/Reed-Sternberg-like cells and variants. The tumor cells were CD30+ and focally positive for CD15 but CD20-, CD79a-, and PAX-5-. In situ hybridization for Epstein-Barr virus (EBV) was strongly positive in the large pleomorphic tumor cells. The adjacent component displayed sheets of relatively uniform, large lymphoid cells with typical morphologic features of diffuse large cell lymphoma. The tumor cells showed uniform expression of tested B-cell antigens, absence of CD30 or CD15, and complete absence of EBV-encoded RNA. Separate molecular studies with immunoglobulin heavy and k light chain gene rearrangements clearly demonstrated an identical rearrangement pattern, indicating derivation from the same clone, which was confirmed by direct DNA sequencing analysis. Such distinctly different morphology, immunophenotype, and EBV status in different components within a clonally related single tumor mass is striking.


Tailored expectant management in couples with unexplained infertility does not influence their experiences with the quality of fertility care.
Do couples who were eligible for tailored expectant management (TEM) and did not start treatment within 6 months after the fertility work-up, have different experiences with the quality of care than couples that were also eligible for TEM but started treatment right after the fertility work-up? Tailored expectant management of at least 6 months in couples with unexplained infertility is not associated with the experiences with quality of care or trust in their physician. In couples with unexplained infertility and a good prognosis of natural conception within 1 year, expectant management for 6-12 months does not compromise ongoing birth rates and is equally as effective as starting medically assisted reproduction immediately. Therefore, TEM is recommended by various international clinical guidelines. Implementation of TEM is still not optimal because of existing barriers on both patient and professional level. An important barrier is the hesitance of professionals to counsel their patients for TEM because they fear that patients will be dissatisfied with care. However, if and how adherence to TEM actually affects the couples' experience with care is unknown. Experiences with the quality care can be measured by evaluating the patient-centredness of care and the patients' trust in their physician. This is a retrospective cross-sectional study. A survey with written questionnaires was performed among all couples who participated in the retrospective audit of guideline adherence on TEM in 25 Dutch clinics. Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis (>30%) of natural conception within 1 year based on the Hunault prediction model. We used patient's questionnaires to collect data on the couples' experience with the quality of care and possible confounders for their experiences other than having undergone TEM or not. Multilevel regression analyses were performed to investigate case-mix adjusted association of TEM with the patient-centredness of care (PCQ-Infertility) and the patients' trust in their physician (Wake Forest Trust Scale). Couples who adhered to TEM experienced the quality of care on the same level as couples who were exposed to early treatment, i.e. started fertility treatment within 6 months after fertility work-up. There were no associations between adherence to TEM and the patient-centredness of care or the patients' trust in their physician. Because this study is retrospective, recall bias might occur. Furthermore, we were unable to measure the difference in experience with care over time. Therefore, our results have to be interpreted carefully. Prospective research on couples undergoing TEM have to be performed to provide more detailed insight in the patients' experiences with the decision making process and subsequently the expectant period. Tackling the barriers surrounding TEM, i.e. better counselling and more patient information material, could further improve patient experiences with the quality of care for couples who are advised TEM. Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. www.trialregister.nl NTR3405.


Art for Ages: The Effects of Group Music Making on the Wellbeing of Nursing Home Residents.
In many countries, life expectancy has increased considerably in past years, and the importance of finding ways to ensure good levels of wellbeing through aging has become more important than ever. Arts based interventions are promising in this respect, and the literature suggests that musical activities can reduce isolation and anxiety and foster feelings of achievement and self-confidence. The present study examined the effects of group music making programs on the health and wellbeing of nursing home residents in Southern Switzerland. A team of professional and student musicians delivered 10 weekly music sessions in four nursing homes, focusing on singing, rhythm-based activities with percussion instruments, and listening to short, live performances. 22 participants (16 women and 6 men, aged 72-95 years, mean 83.6, SD ± 6.9) were recruited to take part in the study and were interviewed after the last music session. The data were analyzed with thematic analysis to investigate how residents experienced group music making and its effects. The findings show that the music programs were beneficial for residents' wellbeing. Music plays an important role in their lives, both in their pasts and presently, and being involved in musical activities offers engagement and novelty in daily life, providing learning opportunities and facilitating interpersonal relationships. Moreover, these results were due to interactions with the musicians involved. Residents particularly appreciated the opportunity to listen to live performances as part of the sessions. This study suggests that nursing home residents value music and that music based interventions play an important and direct role in enhancing their wellbeing.