Observational designs in clinical multiple sclerosis research: Particulars, practices and potentialities.
Observational studies investigate a wide range of topics in multiple sclerosis research. This paper presents an overview of the various observational designs and their applications in clinical studies. Observational studies are well suited for making discoveries and assessing new explanations of phenomena, but less so for establishing causal relationships, due to confounding by indication (selection bias), co-morbidity, socio-economic or other factors. Whether observational findings are demonstrative, indicative or only suggestive, depends on the research question, whether and how the design fits this question, analytical techniques, and the quality of data. Observational studies may be cross-sectional vs. longitudinal, and prospective vs. retrospective. The term 'retrograde' is proposed to explicate that cross-sectional studies may obtain data that cover (long) preceding periods. Case reports and case series are usually based on accidental observations or routinely collected data. Cross-sectional studies, by simultaneously assessing clinical phenomena and external factors, enable the discovery and quantification of associations. In ecological studies the unit of analysis is population or group, and relationships on patient level cannot be established. A cohort study is a longitudinal study that investigates patients with a defining characteristic, e.g. diagnosis or specific treatment, by analyzing data acquired at various intervals. Prospective cohort studies use (some) data that are not yet available at the time the research is conceived, whereas in retrospective studies the data already exist. In a case-control study a representative group of patients with a specific clinical feature is compared with controls, and the frequencies at which an external factor, e.g. infection, has occurred in each group is compared; in a nested case-control study controls are drawn from a fully known cohort. Randomized controlled trial (RCT)-extension studies are informative because, due to RCT randomization, they are free from confounding by indication. Patient or disease registries are organised systems for the long-term collection of uniform data on a population that is defined by a particular disease, condition or exposure, with the purpose to study changes over time. In pharmacotherapeutic research, accidental observations of unexpected beneficial effects may lead to further research into a drug's efficacy in other conditions. Uncontrolled phase 1 studies investigate safety and dosing aspects. Observational studies are alternatives to RCTs when these are not feasible for ethical or practical reasons. Phase 4 observational studies play a crucial role in the evaluation of the effectiveness of treatments in daily practice, the validation of RCT-based side effect profiles, and the discovery of late occurring or rare, potentially life-threatening side effects. Combinations of multidisciplinary longitudinal data bases into large data sets enable the development of algorithms for personalized treatments. To improve the reporting of observational findings on treatment effectiveness, it is proposed that abstracts define the research question(s) the study was meant to answer, study design and analytical methods, and identify and quantify the patient population, treatment of interest, relevant outcomes and the study's strengths and limitations. The development of guidelines for Strengthening the Reporting of Observational Studies in Effectiveness Research (STROBER), as an extension of the guidelines used in epidemiology, is wanted.


Seasonal distribution of psychiatric births in England.
There is general consensus that season of birth influences the risk of developing psychiatric conditions later in life. We aimed to investigate whether the risk of schizophrenia (SC), bipolar affective disorder (BAD) and recurrent depressive disorder (RDD) is influenced by month of birth in England to a similar extent as other countries using the largest cohort of English patients collected to date (n = 57,971). When cases were compared to the general English population (n = 29,183,034) all diseases showed a seasonal distribution of births (SC p = 2.48E-05; BAD p = 0.019; RDD p = 0.015). This data has implications for future strategies of disease prevention.


Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome.
There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.


Impact of short-term cycle ergometer training on quality of life, cognition and depressive symptomatology in multiple sclerosis patients: a pilot study.
In this pilot study, we investigate whether a routine cycle ergometry training programme has therapeutic potential in individuals with multiple sclerosis (MS) by improving quality of life (QOL) and depressive symptomatology, while ameliorating cognitive disturbances. Healthy volunteers and MS patients cycled for 30 min at 65-75% age-predicted maximal heart rate on a recumbent ergometer, with this session repeated twice a week for 8 weeks. QOL, depressive symptomatology and cognitive function were assessed pre- and post-exercise using the MS Quality of Life-54 (MSQOL-54) questionnaire, 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) questionnaire and the Cambridge Neuropsychological Test Automated Battery (CANTAB), respectively. We determined that QOL was lower in MS patients, compared to healthy subjects, with a reduction in physical and mental health summary scores observed. Exercise improved both physical and mental health scores in MS patients. In support of this, exercise was shown to reduce depressive symptomatology in MS patients. Exercise was also associated with an improvement in visual sustained attention, executive function/cognitive flexibility and hippocampal-dependent visuospatial memory in patients. Overall, this study identifies a short-term exercise programme that improves physical and mental health, while reducing depressive symptomatology and cognitive dysfunction in MS.


Aerobic fitness, maturation, and training experience in youth basketball.
Relationships among chronological age (CA), maturation, training experience, and body dimensions with peak oxygen uptake (VO2max) were considered in male basketball players 14-16 y of age. Data for all players included maturity status estimated as percentage of predicted adult height attained at the time of the study (Khamis-Roche protocol), years of training, body dimensions, and VO2max (incremental maximal test on a treadmill). Proportional allometric models derived from stepwise regressions were used to incorporate either CA or maturity status and to incorporate years of formal training in basketball. Estimates for size exponents (95% CI) from the separate allometric models for VO2max were height 2.16 (1.23-3.09), body mass 0.65 (0.37-0.93), and fat-free mass 0.73 (0.46-1.02). Body dimensions explained 39% to 44% of variance. The independent variables in the proportional allometric models explained 47% to 60% of variance in VO2max. Estimated maturity status (11-16% of explained variance) and training experience (7-11% of explained variance) were significant predictors with either body mass or estimated fat-free mass (P ≤ .01) but not with height. Biological maturity status and training experience in basketball had a significant contribution to VO2max via body mass and fat-free fat mass and also had an independent positive relation with aerobic performance. The results highlight the importance of considering variation associated with biological maturation in aerobic performance of late-adolescent boys.


The Use of Functional Data Analysis to Evaluate Activity in a Spontaneous Model of Degenerative Joint Disease Associated Pain in Cats.
Accelerometry is used as an objective measure of physical activity in humans and veterinary species. In cats, one important use of accelerometry is in the study of therapeutics designed to treat degenerative joint disease (DJD) associated pain, where it serves as the most widely applied objective outcome measure. These analyses have commonly used summary measures, calculating the mean activity per-minute over days and comparing between treatment periods. While this technique has been effective, information about the pattern of activity in cats is lost. In this study, functional data analysis was applied to activity data from client-owned cats with (n = 83) and without (n = 15) DJD. Functional data analysis retains information about the pattern of activity over the 24-hour day, providing insight into activity over time. We hypothesized that 1) cats without DJD would have higher activity counts and intensity of activity than cats with DJD; 2) that activity counts and intensity of activity in cats with DJD would be inversely correlated with total radiographic DJD burden and total orthopedic pain score; and 3) that activity counts and intensity would have a different pattern on weekends versus weekdays. Results showed marked inter-cat variability in activity. Cats exhibited a bimodal pattern of activity with a sharp peak in the morning and broader peak in the evening. Results further showed that this pattern was different on weekends than weekdays, with the morning peak being shifted to the right (later). Cats with DJD showed different patterns of activity from cats without DJD, though activity and intensity were not always lower; instead both the peaks and troughs of activity were less extreme than those of the cats without DJD. Functional data analysis provides insight into the pattern of activity in cats, and an alternative method for analyzing accelerometry data that incorporates fluctuations in activity across the day.


Diagnostic approach to chronic constipation in adults.
Constipation is traditionally defined as three or fewer bowel movements per week. Risk factors for constipation include female sex, older age, inactivity, low caloric intake, low-fiber diet, low income, low educational level, and taking a large number of medications. Chronic constipation is classified as functional (primary) or secondary. Functional constipation can be divided into normal transit, slow transit, or outlet constipation. Possible causes of secondary chronic constipation include medication use, as well as medical conditions, such as hypothyroidism or irritable bowel syndrome. Frail older patients may present with nonspecific symptoms of constipation, such as delirium, anorexia, and functional decline. The evaluation of constipation includes a history and physical examination to rule out alarm signs and symptoms. These include evidence of bleeding, unintended weight loss, iron deficiency anemia, acute onset constipation in older patients, and rectal prolapse. Patients with one or more alarm signs or symptoms require prompt evaluation. Referral to a subspecialist for additional evaluation and diagnostic testing may be warranted.


Long-range conformational transition of a photoswitchable allosteric protein: molecular dynamics simulation study.
A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E, which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligand-bound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and trans states of the photoswitch, in explicit water were conducted. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein.


Linear time delay methods and stability analyses of the human spine. Effects of neuromuscular reflex response.
Linear stability methods were applied to a biomechanical model of the human musculoskeletal spine to investigate effects of reflex gain and reflex delay on stability. Equations of motion represented a dynamic 18 degrees-of-freedom rigid-body model with time-delayed reflexes. Optimal muscle activation levels were identified by minimizing metabolic power with the constraints of equilibrium and stability with zero reflex time delay. Muscle activation levels and associated muscle forces were used to find the delay margin, i.e., the maximum reflex delay for which the system was stable. Results demonstrated that stiffness due to antagonistic co-contraction necessary for stability declined with increased proportional reflex gain. Reflex delay limited the maximum acceptable proportional reflex gain, i.e., long reflex delay required smaller maximum reflex gain to avoid instability. As differential reflex gain increased, there was a small increase in acceptable reflex delay. However, differential reflex gain with values near intrinsic damping caused the delay margin to approach zero. Forward-dynamic simulations of the fully nonlinear time-delayed system verified the linear results. The linear methods accurately found the delay margin below which the nonlinear system was asymptotically stable. These methods may aid future investigations in the role of reflexes in musculoskeletal stability.


Cellular and proteomics analysis of the endomembrane system from the unicellular Entamoeba histolytica.
Entamoeba histolytica is the protozoan parasite agent of amoebiasis, an infectious disease of the human intestine and liver. Specific active pathogenic factors are secreted toward the external milieu upon interaction of the parasite with human tissue. Trafficking dynamics and secretion of these factors is not known and characterization of the dynamics interplay of subcellular compartments such as the ER or Golgi apparatus is still pending. In this work, we took advantage of cell fractionation and a wide proteomic analysis to search for principal components of the endomembrane system in E. histolytica. Over 1500 proteins were identified and the two top categories contained components of trafficking machinery and GTPases. Trafficking related proteins account for over 100 markers from the ER, Golgi, MVB, and retromers. The lack of important components supporting Golgi polarization was also highlighted. The data further describe principal components of the endosomal traffic highlighting Alix in isolated vesicles and during parasite division. This work represents the first in-depth proteomics analysis of subcellular compartments in E. histolytica and allows a detailed map of vesicle traffic components in an ancient single-cell organism that lacks a stereotypical ER and Golgi apparatus to be established.


Spectral organization of the eye of a butterfly, Papilio.
This review outlines our recent studies on the spectral organization of butterfly compound eyes, with emphasis on the Japanese yellow swallowtail butterfly, Papilio xuthus, which is the most extensively studied species. Papilio has color vision when searching for nectar among flowers, and their compound eyes are furnished with six distinct classes of spectral receptors (UV, violet, blue, green, red, broadband). The compound eyes consist of many ommatidia, each containing nine photoreceptor cells. How are the six classes of spectral receptors arranged in the ommatidia? By studying their electrophysiology, histology, and molecular biology, it was found that the Papilio ommatidia can be divided into three types according to the combination of spectral receptors they contain. Different types of ommatidia are distributed randomly over the retina. Histologically, the heterogeneity appeared to be related to red or yellow pigmentation around the rhabdom. A subset of red-pigmented ommatidia contains 3-hydroxyretinol in the distal portion, fluorescing under UV epi-illumination. The red, yellow and fluorescing pigments all play crucial roles in determining the spectral sensitivities of receptors. Spectral heterogeneity and random array of ommatidia have also been found in other lepidopteran species. Similarities and differences between species are also discussed.


Timing of anticoagulation therapy in patients with acute ischaemic stroke and atrial fibrillation.
In patients with acute stroke and atrial fibrillation (AF), the risk of early recurrence has been reported to range between 0.1 % and 1.3 % per day. Anticoagulants are the most effective therapy for the prevention of recurrent ischaemic stroke in these patients, but randomised clinical trials have failed to produce any evidence supporting the administration of heparin within 48 hours from stroke onset as it has been associated with a non-significant reduction in the recurrence of ischaemic stroke, no substantial reduction in death and disability, and an increase in intracranial bleeding. As early haemorrhagic transformation is a major concern in the acute phase of stroke patients with AF, determining the optimal time to start anticoagulant therapy is essential. This review which focuses on the epidemiology of recurrent ischaemic stroke and haemorrhagic transformation in patients with acute ischaemic stroke and AF, proposes a model for decision making on optimal timing for initiating anticoagulation, based on currently available evidence.


Expression and distribution of ion transport mRNAs in human nasal mucosa and nasal polyps.
Our results indicate that the electrogenic kidney Na(+)/HCO(3)(-) cotransporter (kNBC), KCl cotransporter (KCC1 and -4) and Ca(2+)-activated Cl(-) channel (CaCC1, -2, -3) mRNAs are expressed in normal nasal mucosa and nasal polyp, suggesting that altered expression of all CaCC mRNAs in nasal polyp may cause impaired electrolyte and water transport across the epithelial cells. Electrolyte transport by nasal epithelia has been suggested to be important for controlling the quantity and composition of the nasal fluid and may play an important role in the development of nasal polyps. Transepithelial transport of ions and water in various fluid-transporting epithelia is strictly dependent on the localization of specific membrane proteins in the polarized epithelial cells. In this study we investigated the expression and distribution of mRNA transcripts for kNBC, pancreatic NBC, KCC1, -2, -3, -4 and CaCC1, -2, -3 gene families in human nasal mucosa and nasal polyp. The expression and localization of these gene families were investigated in inferior turbinate tissues and nasal polyp using reverse transcriptase polymerase chain reaction (RT-PCR), semiquantitative RT-PCR and in situ hybridization. mRNAs for kNBC, KCC1 and -4 and all the CaCC families (CaCC1, -2 and -3) are expressed in human turbinate mucosa and nasal polyp. The expression levels of kNBC and KCC1 and -4 mRNAs did not differ between nasal mucosa and nasal polyp. However, the expression levels of all the CaCC genes were significantly decreased in nasal polyp. In situ hybridization revealed that the expression of these genes was mainly localized in the epithelial layer and submucosal glands of inferior turbinate mucosa and in the epithelial layer of nasal polyp.


Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.
The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.


Gender differences in the relation between depression and social support in later life.
Prevalence of depression is twice as high in women as in men, also in older adults. Lack of social support is a risk factor for late-life depression. The relation between depression and social support may be different for men and women. Data from the Longitudinal Aging Study Amsterdam were used to investigate gender differences in the relation between social support and depression in a population-based sample aged 55-85 years, with n = 2,823 at baseline and using the 13-year follow-up data on onset of depression. Respondents without a partner in the household, with a small network, and with low emotional support were more often depressed, with men showing higher rates of depression than women. A high need for affiliation was associated with depression in women but not in men. Lack of a partner in the household and having a small network predicted onset of depression in men but not in women. In respondents with high affiliation need and low social support, depression rates were higher, with men being more often depressed than women. Low social support and a high need for affiliation were related to depression in later life, with men being more vulnerable for depression than women. Considering the serious consequences of depression, especially in older people, it is important to identify the persons with low social support and a high need for affiliation, and to help them to increase their social support or to adjust their needs.


Carbon Chain Growth by Sequential Reactions of CO and CO2 with [W(CO)6] and an Aluminum(I) Reductant.
The formation of carbon chains by the coupling of CO x ( x = 1 or 2) units on transition metals is a fundamental step relevant to Fischer-Tropsch catalysis. Fischer-Tropsch catalysis produces energy dense liquid hydrocarbons from synthesis gas (CO and H2) and has been a mainstay of the energy economy since its discovery nearly a century ago. Despite detailed studies aimed at elucidating the steps of catalysis, experimental evidence for chain growth (C n → C n+1; n ≥ 2) from the coupling of CO units on metal complexes is, to the best of our knowledge, unprecedented. In this paper, we show that carbon chains can be grown from sequential reactions of CO or CO2 with a transition metal carbonyl complex. By exploiting the cooperative effect of transition and main group metals, we document the first example of chain propagation from sequential coupling of CO units (C1 → C3 → C4), along with the first example of incorporation of CO2 into the growing carbon chain.


Occurrence of other cancers among patients with prior basal cell and squamous cell skin cancer.
Epidemiological studies suggest that individuals with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are more likely to develop other malignancies; however, the factors responsible for this are unknown. To clarify the risk of other cancers following the occurrence of BCC and SCC, we followed participants in a multicenter skin cancer prevention trial for subsequent malignancies. The study group consisted of 1805 BCC and SCC patients who had enrolled in a trial testing the efficacy of oral beta-carotene. Medical confirmation was sought for all cancers (other than BCC or SCC), which were reported by participants or their next-of-kin over a follow-up period of 10 years. We computed the rate ratio (RR) and 95% confidence interval (CI) of time to first new, primary cancer in relation to history of BCC and SCC, using a proportional hazards model. A total of 235 participants had a new primary invasive cancer during 13,887 person-years of follow up. The risk of other cancers was modestly elevated in patients with one or more previous SCCs compared with those who only had a history of BCC (adjusted RR, 1.37; 95% CI, 0.91-2.07). Risk of other cancers also appeared to be increased among those who had multiple prior BCCs relative to those who had only one prior BCC (adjusted RR, 1.21; 95% CI, 0.91-1.61). Further adjustment for smoking history, Quetelet index, radiotherapy, extent of actinic skin damage, treatment assignment, or baseline beta-carotene concentrations did not appreciably alter the results. Cancer of the respiratory system was most strongly related to previous SCC or multiple BCC [RRs (95% CI), 2.20 (1.05-4.62) and 2.34 (1.14-4.83), respectively]. Our data suggest that unidentified exposures or inherited risk factors may play a common etiological role in the pathogenesis of nonmelanoma skin cancer and other cancers, especially respiratory cancers, although larger studies would be necessary to exclude the role of chance in these findings.


Differentiated thyroid carcinoma. Follow-up of 264 patients from one institution for up to 25 years.
The optimum treatment for differentiated thyroid carcinoma (DTC) is still debated. Results obtained using a selective treatment strategy for papillary (PTC) and follicular (FTC) thyroid carcinoma over 25 years in one institution are reported. 149 patients (mean age 46 yrs) had PTC in TNM stages I-IV in 58%, 26%, 15% and 1% respectively. Total thyroidectomy and remnant 131I ablation (43%) were carried out in TNM high-risk patients (stages III and IV) and in low-risk patients (I and II) at risk for a (curable) recurrence (stages pN1 and/or pT4). Hemi- or total thyroidectomy, without radioiodine, was used in 76% of pT1-3 N0 tumours (68%). Central and/or lateral lymphadenectomy was performed in 42% of patients (electively in the last 4 years). The mean follow-up was 7 years. 6 patients died of PTC and 8/143 patients treated for cure had a recurrence (6 nodal, 1 contralateral, 1 local). In low-risk patients--including 68% of patients aged > or = 45 yrs--the cause specific 25-year survival rate was 100%, vs. 62% (at 15 years) (p < 0.0001) in high-risk patients. In stage I and stage II the recurrence-free survival rates at 25 years were 95% and 100% respectively. Risk factors for recurrence were macroscopic (p < 0.0001) but not microscopic local invasion (pT4); stage pN1 (p = 0.0004). Only 1/107 patients initially judged node-negative had a nodal recurrence. FTC (n = 115; mean age 56 yrs; mean follow-up 8 yrs): Cause-related death (n = 8) or serious recurrence (n = 3) occurred in 10/53 grossly invasive FTC, in 1/45 minimally invasive FTC with vascular invasion, and in none of 17 FTC with capsular invasion (CI) alone, under radical treatment (131I) in 75%, 33%, and 12% respectively. 20-year disease-free survival in grossly and in minimally invasive FTC was 78% and 95.5% respectively (p = 0.0007). Patients aged < 45 yrs and patients with minimally invasive FTC with CI alone (all ages) had 100% 20-year disease-free survival vs. 80% (p = 0.013) in the remainder. There was no curable recurrence in FTC. The ratio of grossly invasive FTC decreased (p < 0.0001) during the study period. Risk-0 groups may be defined and selected for a reduced extent of treatment (PTC pT1-3 N0; FTC < 45 yrs, or CI alone). Older (> or = 45 yrs) patients with PTC in stages I and II have an excellent prognosis (risk 0). With selective (therapeutic) lymphadenectomy the risk of nodal recurrence may be very low in node negative tumours, without use of radioiodine. Meticulous lymphadenectomy is indicated in pN1 tumours with nodal recurrences despite 131I (5/36 patients). The technique of capsular dissection for extracapsular total uni- or bilateral thyroidectomy provides excellent oncological and surgical results. A decrease in the incidence of FTC parallels a decrease in endemic goitre in Switzerland.


Glass formation via structural fragmentation of a 2D coordination network.
The structure of a glass obtained by the melt quenching of a two-dimensional (2D) coordination network was examined. X-ray analyses disclosed a 2D-to-0D structural transformation before and after glass formation. The mechanism is unique to coordination compounds, as it is characterized by labile and flexible coordination bonds.


Electronic and optical properties of nanostructured MoS2 materials: influence of reduced spatial dimensions and edge effects.
We theoretically study the electronic and optical properties of nanostructured MoS2 systems focusing on the influence of reduced spatial dimensions and edge effects, which lead to the change in character from semiconducting to metallic. For nanowires, we identify edge types which lead to the creation of a bandgap, reflecting the effect of confinement: with increasing the size of the wire in lateral direction and/or number of MoS2 layers, the gap reduces. For nanodisks, we identify features in electronic properties that are universal; specifically, our calculations reveal presence of a local maximum in electronic density of states, insensitive on nanodisk's geometrical properties. By manipulating with sulfur and molybdenum atoms at the edges we tune position of Fermi energy with respect to the local maximum. We discuss total electronic density and partial electronic density for energy levels below Fermi energy, that could be used for mapping to STM images under negative bias. Our findings are extracted from a tight-binding (TB) model that includes non-orthogonal sp3d5 orbitals and spin-orbit coupling. We benchmark our TB model by comparing our results to those extracted from density functional theory and quasiparticle self-consistent GW, test different TB parameter sets, establishing the range of their validity, and discuss limitations of our model.


Effect of color shading procedures and cyclic loading on the biaxial flexural strength of zirconia.
Zirconia is the most preferred ceramic restoration in posterior areas because of its flexural strength. The aim of the study is the evaluation of biaxial flexural strength of different colored zirconium oxide core materials after cyclic loading. Zirconia discs (12 mm diameter and 1.2 mm thickness) were divided into 6 groups of 12 discs each. Groups were colored according to the Vita Classic shade guide: A3 and D4. One group was not colored and left as control. Each group was randomly divided into subgroups and subjected to mechanical cycling prior to biaxial flexural strength test. Cyclic loading was applied as 50 N loads for 20,000 times for the loaded groups. Samples were subjected to biaxial flexural strength test in a universal testing machine with a crosshead speed of 1 mm/min. Two-way analysis of variance (ANOVA) and Tukey's HSD tests were used for comparisons of the groups. Biaxial flexural strength values did not vary significantly depending on coloring procedure or loading process tested (p>.05). XRD analysis displayed that the monoclinic volume fraction of zirconia was highest in cyclic loaded D4 and was lowest in non-loaded control group. The SEM image revealed that A3 color solution created metallic coloring pigments at grain boundaries. Coloring procedures and cyclic loading did not affect the biaxial flexural strength of zirconia core material; however, microstructural analysis displays changes, which may weaken the zirconia structure on the long term.


Functionally significant, rare transcription factor variants in tetralogy of Fallot.
Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF). We sequenced the coding, 5'UTR, and 3'UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1) in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network. This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3-13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.


Self-reporting and refoldable profluorescent single-chain nanoparticles.
We pioneer the formation of self-reporting and refoldable profluorescent single-chain nanoparticles (SCNPs) via the light-induced reaction (λmax = 320 nm) of nitroxide radicals with a photo-active crosslinker. Whereas the tethered nitroxide moiety in these polymers fully quenches the luminescence (i.e. fluorescence) of the aromatic backbone, nitroxide trapping of a transient C-radical leads to the corresponding closed shell alkoxyamine thereby restoring luminescence of the folded SCNP. Hence, the polymer in the folded state is capable of emitting light, while in the non-folded state the luminescence is silenced. Under oxidative conditions the initially folded SCNPs unfold, resulting in luminescence switch-off and the reestablishment of the initial precursor polymer. Critically, we show that the luminescence can be repeatedly silenced and reactivated. Importantly, the self-reporting character of the SCNPs was followed by size-exclusion chromatography (SEC), dynamic light scattering (DLS), fluorescence, electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR) and diffusion ordered NMR spectroscopy (DOSY).


Assessing the Mortality Impact of the COVID-19 Pandemic in Florida State Prisons.
The increased risk of COVID-19 infection among incarcerated individuals due to environmental hazards is well known and recent studies have highlighted the higher rates of infection and mortality prisoners in the United States face due to COVID-19. However, the impact of COVID-19 on all-cause mortality rates in incarcerated populations has not been studied. Using data reported by the Florida Department of Corrections on prison populations and mortality events we conducted a retrospective cohort study of all individuals incarcerated in Florida state prisons between 2015 and 2020. We calculated excess deaths by estimating age-specific expected deaths from mortality trends in 2015 through 2019 and taking the difference between observed and expected deaths during the pandemic period. We calculated life table measures using standard demographic techniques and assessed significant yearly changes using bootstrapping. The Florida Department of Corrections reported 510 total deaths from March 1, 2020 to December 31, 2020 among the state prison population. This was 42% higher (rate ratio 1.42, 95% CI 1.15 to 1.89) than the expected number of deaths in light of mortality rates for previous years. Reported COVID-19 deaths in a month were positively correlated with estimated excess deaths (80.4%, p <.01). Using age-specific mortality estimates, we found that life expectancy at age 20 declined by 4 years (95% CI 2.06-6.57) between 2019 and 2020 for the Florida prison population. The Florida prison population saw a significant increase in all-cause mortality during the COVID-19 pandemic period, leading to a decrease in life expectancy of more than four years. Life years lost by the Florida prison population were likely far greater than those lost by the general United States population, as reported by other studies. This difference in years lost highlights the need for increased interventions to protect vulnerable incarcerated populations during pandemics. Vital Projects Fund, Arnold Ventures, US Centers for Disease Control, Eunice Kennedy Shriver National Institute of Child Health and Human Development.


Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers.
Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibition have shown promising results in GC, but key questions remain regarding which GC subclass may respond best. In other cancers, expression of the PD-1 ligand PD-L1 has been shown to identify cancers with greater likelihood of response to PD-1 blockade. We here show with immunohistochemistry that Epstein-Barr Virus (EBV)+ GCs (n = 32) have robust PD-L1 expression not seen in other GCs. In EBV+ GC, we observed PD-L1 staining in tumor cells in 50% (16/32) and immune cells in 94% (30/32) of cases. Among EBV-negative GCs, PD-L1 expression within tumors cells was observed only in cases with microsatellite instability (MSI), although 35% of EBV-/MSS GCs possessed PD-L1 expression of inflammatory cells. Moreover, distinct classes of GC showed different patterns of PD-L1+ immune cell infiltrations. In both EBV+ and MSI tumors, PD-L1+ inflammatory cells were observed to infiltrate the tumor. By contrast, such cells remained at the tumor border of EBV-/MSS GCs. Consistent with these findings, we utilized gene expression profiling of GCs from The Cancer Genome Atlas study to demonstrate that an interferon-γ driven gene signature, an additional proposed marker of sensitivity to PD-1 therapy, were enriched in EBV+ and MSI GC. These data suggest that patients with EBV+ and MSI GC may have greater likelihood of response to PD-1 blockade and that EBV and MSI status should be evaluated as variables in clinical trials of these emerging inhibitors.


Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial.
Interleukin-6 (IL-6) contributes to atherosclerotic plaque destabilization and is involved in myocardial injury during ischaemia-reperfusion. Interleukin-6 is therefore a potential therapeutic target in myocardial infarction (MI). We hypothesized that the IL-6 receptor antagonist tocilizumab would attenuate inflammation, and secondarily reduce troponin T (TnT) release in non-ST-elevation MI (NSTEMI). In a two-centre, double-blind, placebo-controlled trial, 117 patients with NSTEMI were randomized at a median of 2 days after symptom onset to receive placebo (n = 59) or tocilizumab (n = 58), administered as a single dose prior to coronary angiography. High sensitivity (hs) C-reactive protein and hsTnT were measured at seven consecutive timepoints between Days 1 and 3. The area under the curve (AUC) for high-sensitivity C-reactive protein was the primary endpoint. The median AUC for high-sensitivity C-reactive protein during hospitalization was 2.1 times higher in the placebo than in the tocilizumab group (4.2 vs. 2.0 mg/L/h, P < 0.001). Also, the median AUC for hsTnT during hospitalization was 1.5 times higher in the placebo group compared with the tocilizumab group (234 vs. 159 ng/L/h, P = 0.007). The differences between the two treatment groups were observed mainly in (i) patients included ≤2 days from symptom onset and (ii) patients treated with percutaneous coronary intervention (PCI). No safety issues in the tocilizumab group were detected during 6 months of follow-up. Tocilizumab attenuated the inflammatory response and primarily PCI-related TnT release in NSTEMI patients.


[A study of relapse/recurrence cases after surgical treatment for patients with pulmonary nontuberculous mycobacteriosis].
This is a retrospective study on relapse/recurrence of surgical cases of pulmonary nontuberculous mycobacteriosis (NTM). Surgical treatment was performed at one hospital and by one surgeon. Fifty patients had undergone surgical treatment from August 2004 to July 2011 in hospital. From this group, 37 patients were selected after one year, and of these, 9 patients had a relapse/recurrence (group A) and the others (28 patients without relapse/recurrence, group B). Data was recorded about their age, gender, pre-operative image score, cavernous lesions, residual lesions after operation, drugs of pre-operative chemotherapy, the duration of pre-operative chemotherapy, the duration of any follow-up after operation, type of mycobacteria, the results of bacterial cultivation of surgical specimens, type of mycobacterium and operative procedure. Three factors, the result of bacterial cultivation of surgical specimens, duration of chemotherapy before operation and existence of residual lesions, showed a significant difference statistically. No case with major surgical complication and hospital death was recognized. The visible foci should be removed as thoroughly as possible. Pre-operative chemotherapy should not be continued unnecessarily, and surgical treatment should be chosen at an early stage. The results of bacterial cultures of surgical specimens could be very useful for predicting the possibility of relapse/recurrence after operation. Surgical treatments of our patients were carried out safely. However, as the patients have a risk of relapse/recurrence, they require careful monitoring and post-operative chemotherapy over along period.


Comparative analyses of song complexity and song-control nuclei in fourteen oscine species.
Most studies on the relationship between measures of song behavior and the sizes of song control nuclei have focused on one or two oscine species, and often show inconsistent results. To address this issue, we first measured four variables for song complexity, i.e., song repertoire size, syllable repertoire size, the mean number of syllables per phrase (MNS) and the number of syllables in the longest phrase (NSLP), and the sizes of three song control nuclei, i.e., HVC, RA (the robust nucleus of the arcopallium), and Area X in 14 oscine species from eight families. To tackle the problem of statistical non-independence that probably existed among the closely related species, we reconstructed the phylogeny of the species studied using mitochondrial cytochrome b DNA sequences from GenBank. By using the methods adopted in most previous reports, we tested the relationship between song complexity and the sizes of the song control nuclei. We found that: 1) the absolute sizes of RA and Area X, but not of HVC, were positively correlated to the three measures of song complexity, but that only the residual size of RA in regard to telencephalon size was significantly correlated to the song measures; 2) independent contrasts analysis showed RA and Area X to be significantly associated with NSLP. Our results indicated that the relationship between song behavior and its neural structures varied among song nuclei, suggesting that each song control nucleus may play a different role in song behavior.


Associations between signs of sleep bruxism and insomnia: A polysomnographic study.
Sleep bruxism (SB) is a repetitive jaw-muscle activity characterised by clenching or grinding of the teeth and/or by bracing or thrusting of the mandible. Sleep bruxism has been linked with insomnia symptoms. Moreover, it has been suggested that there is a positive association between distress and the occurrence of sleep bruxism. However, the occurrence of sleep bruxism and its association with distress have not been studied in patients with insomnia. Therefore, we hypothesised that: (1) the occurrence of sleep bruxism is higher in patients with insomnia than in healthy controls; and (2) the occurrence of sleep bruxism in insomnia patients with moderate to high distress (IMHD) is higher than that in insomnia patients with slight distress (ISD). A total of 44 controls (34 females, 10 males, mean ± SD age = 46.8 ± 14.4 years) and 42 participants with insomnia (35 females, 7 males, mean ± SD age = 51.3 ± 12.1 years) were enrolled in this study. Among 42 participants with insomnia, 20 participants were subtyped as IMHD, 17 participants as ISD. Another five participants were not subtyped due to insufficient information. Group differences in rhythmic masticatory muscle activity (RMMA), a biomarker of sleep bruxism, were evaluated with Mann-Whitney U tests. The medians and interquartile ranges of the RMMA indices were 0.8|1.8|3.3 in controls, 1.1|1.6|2.3 in IMHD and 1.2|1.9|2.9 in ISD. There was no significant difference in the RMMA index, neither between participants with insomnia and controls (P = 0.514) nor between IMHD versus ISD (P = 0.270). The occurrence of RMMA indicators of possible sleep bruxism is not significantly different between individuals with insomnia and controls, nor between IMHD versus ISD.


Molecular basis for proofreading by the unique exonuclease domain of Family-D DNA polymerases.
Replicative DNA polymerases duplicate entire genomes at high fidelity. This feature is shared among the three domains of life and is facilitated by their dual polymerase and exonuclease activities. Family D replicative DNA polymerases (PolD), found exclusively in Archaea, contain an unusual RNA polymerase-like catalytic core, and a unique Mre11-like proofreading active site. Here, we present cryo-EM structures of PolD trapped in a proofreading mode, revealing an unanticipated correction mechanism that extends the repertoire of protein domains known to be involved in DNA proofreading. Based on our experimental structures, mutants of PolD were designed and their contribution to mismatch bypass and exonuclease kinetics was determined. This study sheds light on the convergent evolution of structurally distinct families of DNA polymerases, and the domain acquisition and exchange mechanism that occurred during the evolution of the replisome in the three domains of life.


Photostick: a method for selective isolation of target cells from culture.
Sorting of target cells from a heterogeneous pool is technically difficult when the selection criterion is complex, e.g. a dynamic response, a morphological feature, or a combination of multiple parameters. At present, mammalian cell selections are typically performed either via static fluorescence (e.g. fluorescence activated cell sorter), via survival (e.g. antibiotic resistance), or via serial operations (flow cytometry, laser capture microdissection). Here we present a simple protocol for selecting cells based on any static or dynamic property that can be identified by video microscopy and image processing. The "photostick" technique uses a cell-impermeant photochemical crosslinker and digital micromirror array-based patterned illumination to immobilize selected cells on the culture dish. Other cells are washed away with mild protease treatment. The crosslinker also labels the selected cells with a fluorescent dye and a biotin for later identification. The photostick protocol preserves cell viability, permits genetic profiling of selected cells, and can be performed with complex functional selection criteria such as neuronal firing patterns.


Identification of the ER-resident E3 ubiquitin ligase RNF145 as a novel LXR-regulated gene.
Cellular cholesterol metabolism is subject to tight regulation to maintain adequate levels of this central lipid molecule. Herein, the sterol-responsive Liver X Receptors (LXRs) play an important role owing to their ability to reduce cellular cholesterol load. In this context, identifying the full set of LXR-regulated genes will contribute to our understanding of their role in cholesterol metabolism. Using global transcriptional analysis we report here the identification of RNF145 as an LXR-regulated target gene. We demonstrate that RNF145 is regulated by LXRs in both human and mouse primary cells and cell lines, and in vivo in mice. Regulation of RNF145 by LXR depends on a functional LXR-element in its proximal promotor. Consistent with LXR-dependent regulation of Rnf145 we show that regulation is lost in macrophages and fibroblasts from Lxrαβ(-/-) mice, and also in vivo in livers of Lxrα(-/-) mice treated with the LXR synthetic ligand T0901317. RNF145 is closely related to RNF139/TRC8, an E3 ligase implicated in control of SREBP processing. However, silencing of RNF145 in HepG2 or HeLa cells does not impair SREBP1/2 processing and sterol-responsive gene expression in these cells. Similar to TRC8, we demonstrate that RNF145 is localized to the ER and that it possesses intrinsic E3 ubiquitin ligase activity. In summary, we report the identification of RNF145 as an ER-resident E3 ubiquitin ligase that is transcriptionally controlled by LXR.


Patients as Front-Line Owners and Partners in Improving Quality and Safety.
As patient partners, we are pleased by the success of the front-line ownership (FLO) approach in advancing safe care in a variety of initiatives and settings. The FLO underlying principles and approach deeply resonate with us as illustrated in the following quotes from the paper: "Nothing about me without me," "Most passionate change agents are not in roles that typically get invited to participate," "Inviting anybody who is interested in the problem at hand," "FLO creates a way to break down hierarchies, increase positive dialogue between diverse players in organizations, and encourage people who may not have felt empowered previously to come forward and problem-solve." It is not described in the article if and how patients and/or patient partners were involved; therefore, we call on the authors to follow up with that information because it can provide valuable lessons to others who will be looking at implementing FLO in their organizations. Based on our decade-long experience as patient partners at all system levels, on literature and leading practices (key references included) we argue that patients have an important role to play in improvement initiatives and recommend partnering with patients in all improvement efforts.


Calcium currents in a fast-twitch skeletal muscle of the rat.
Slow ionic currents were measured in the rat omohyoid muscle with the three-microelectrode voltage-clamp technique. Sodium and delayed rectifier potassium currents were blocked pharmacologically. Under these conditions, depolarizing test pulses elicited an early outward current, followed by a transient slow inward current, followed in turn by a late outward current. The early outward current appeared to be a residual delayed rectifier current. The slow inward current was identified as a calcium current on the basis that (a) its magnitude depended on extracellular calcium concentration, (b) it was blocked by the addition of the divalent cations cadmium or nickel, and reduced in magnitude by the addition of manganese or cobalt, and (c) barium was able to replace calcium as an inward current carrier. The threshold potential for inward calcium current was around -20 mV in 10mM extracellular calcium and about -35 mV in 2 mM calcium. Currents were net inward over part of their time course for potentials up to at least +30 mV. At temperatures of 20-26 degrees C, the peak inward current (at approximately 0 mV) was 139 +/- 14 microA/cm2 (mean +/- SD), increasing to 226 +/- 28 microA/cm2 at temperatures of 27-37 degrees C. The late outward current exhibited considerable fiber-to-fiber variability. In some fibers it was primarily a time-independent, nonlinear leakage current. In other fibers it was primarily a time-independent, nonlinear leakage current. In other fibers it appeared to be the sum of both leak and a slowly activated outward current. The rate of activation of inward calcium current was strongly temperature dependent. For example, in a representative fiber, the time-to-peak inward current for a +10-mV test pulse decreased from approximately 250 ms at 20 degrees C to 100 ms at 30 degrees C. At 37 degrees C, the time-to-peak current was typically approximately 25 ms. The earliest phase of activation was difficult to quantify because the ionic current was partially obscured by nonlinear charge movement. Nonetheless, at physiological temperatures, the rate of calcium channel activation in rat skeletal muscle is about five times faster than activation of calcium channels in frog muscle. This pathway may be an important source of calcium entry in mammalian muscle.


Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis.
High levels of vascular endothelial growth factor (VEGF), a key angiogenic factor, are present in patients with systemic sclerosis (SSc), but its role in the pathogenesis of fibrosis and its contribution to the disturbed angiogenesis of SSc remains hypothetical. Mono (+/-) and double (+/+) VEGF transgenic (tg) mice and their wildtype (wt) controls were analysed. The bleomycin model was applied to VEGF tg mice to evaluate effects of VEGF under proinflammatory conditions. Additionally, tight skin (TSK) 1/VEGF+/+ mice were generated to mimic later non-inflammatory stages of SSc. VEGF+/+, but not VEGF+/- tg mice, spontaneously developed significant skin fibrosis, indicating profibrotic effect of VEGF in a gene-dosing manner. In the proinflammatory bleomycin model, the profibrotic effect became more pronounced with induction of skin fibrosis in VEGF+/- tg mice and even more enhanced fibrosis in VEGF+/+ tg mice. Analysis in TSK1/VEGF+/+ mice showed similar profibrotic effects of VEGF also under non-inflammatory in vivo conditions. In vitro analysis revealed that VEGF is able to directly induce collagen synthesis in dermal fibroblasts. Additionally, there was an inverse gene-dosing effect on the efficacy of angiogenesis in that a higher number of microvessels was observed in VEGF+/- tg mice than in VEGF+/+ tg mice. These data provide the first evidence for VEGF as a novel molecular link between fibrosis and vasculopathy in the pathogenesis of SSc. They suggest that high levels of VEGF potently induce fibrosis in inflammatory and non-inflammatory stages, and also contribute to the relatively insufficient angiogenesis characteristic for SSc.


Risks and Benefits of Live Surgical Broadcast: A Systematic Review.
Live surgical broadcast (LSB), also known as live surgery, has become a popular format for many types of surgical education meetings. However, concerns have been raised in relation to patient safety, ethical issues, and the actual educational value of LSB. To summarize current evidence on LSB with a focus on the risks of complications and the educational impact. We performed a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies up to December 2020. We identified original articles reporting on patient outcomes, educational value, current use, and development of LSB. We also interrogated surgical society guidelines for position statements on LSB. Our literature search identified 46 studies spanning six surgical specialties, with urology being the most frequent. Approximately half of the studies reported on outcomes of surgical procedures during LSB. In urology, the few comparative studies available did not suggest higher complication rates in LSB, whereas data for other surgical fields highlighted evidence of worse outcomes. Four studies assessed the educational value of LSB via survey administration, for which the evidence is limited and of low quality. Thirteen guidelines and position statements on live surgery were identified among major surgical societies, including the European Association of Urology (EAU). Some surgical societies have expressly prohibited the use of LSB at their major meetings. The perspective of surgeons performing and/or attending live surgical sessions was evaluated in six studies, and four studies looked at urologists' perception of LSB compared to semi-LSB. Limitations of this systematic review include the limited number of studies available, the low quality of the evidence, and data heterogeneity. Evidence regarding outcomes of LSB is limited. Almost all the studies do not show a higher risk of complications or worse outcomes for patients undergoing a procedure during LSB. Only one study on gastrointestinal surgery reported that LSB outcomes were worse. Ongoing concerns have led to specific guidelines by several scientific societies, including the EAU, with the ultimate aim of minimizing surgical risks and maximizing patient safety. Live surgery events are often part of surgical conferences. Data in the literature show mixed outcomes for operations performed during live surgery events, but with no increase in complication rates. Safety and ethical concerns remain. Other educational tools, such as prerecorded videos and live surgery transmission from the home institution of the operating surgeon might become preferred options in the future. This review was prospectively registered on the PROSPERO website (www.crd.york.ac.uk/PROSPERO, registration number CRD42020194023).


Twisting with a twist: supramolecular helix fluctuations in chiral nematics.
Most theoretical descriptions of lyotropic cholesteric liquid crystals to date focus on homogeneous systems in which the rod concentration, as opposed to the rod orientation, is uniform. In this work, we build upon the Onsager-Straley theory for twisted nematics and study the effect of weak concentration gradients, generated by some external potential, on the cholesteric twist. We apply our theory to chiral nematics of nanohelices in which the supramolecular helix sense is known to spontaneously change sign upon variation of particle concentration, passing through a so-called compensation point at which the mesoscopic twist vanishes. We show that the imposed field offers exquisite control of the handedness and magnitude of the helicoidal director field, even at weak field strengths. Within the same framework we also quantify the director fluctuation spectrum and find evidence for a correlation length diverging at the compensation point.


Factors associated with eating performance for long-term care residents with moderate-to-severe cognitive impairment.
The aim of this study was to examine the association of specific personal and environmental factors with eating performance among long-term care residents with moderate-to-severe cognitive impairment. Eating is the one of the most basic and easiest activities of daily living to perform. While multilevel factors can be associated with eating performance, the evidence among those with dementia was insufficient. A secondary analysis of baseline data collected between March and September in 2012 from 199 residents in eight long-term care facilities. Eating performance was conceptualized using the single self-care 'feeding' item in the Barthel Index and was scored based on four levels of dependence and assistance required. Binary logistic regression was used to examine the adjusted association of specific factors with eating performance. Almost one-third of the residents needed help with eating. After adjusting the type of facility, number of comorbidities, chair-sitting balance, agitation and depression, compromised eating performance was associated with severe cognitive impairment and low physical capability. This study supported the association of eating performance with cognitive impairment and physical capability among long-term care residents with moderate-to-severe cognitive impairment. Targeted interventions should be implemented to reduce the impact of cognitive decline on eating performance and promote physical capability to optimize eating performance. Future work need to use validated multiple-item measures for eating performance and test the association of personal and environmental factors with eating performance among a larger heterogeneous group of long-term care residents to enhance understanding of the factors.


New electroablation technique following the first-line stapling method for thoracoscopic treatment of primary spontaneous pneumothorax.
A new tip for the electroablation of pneumocysts was examined clinically as a second-line method for stapled resection of pneumocysts during video-assisted thoracoscopic surgery (VATS). A trial to assess feasibility. National referral hospitals. One hundred seven patients were studied, of whom 99 patients were eligible for the study (85 men and 14 women; age range, 15 to 69 years; median age, 23 years), who had undergone VATS for primary spontaneous pneumothorax between July 1996 and June 1998. Apical pneumocysts were resected employing staplers, and residual pneumocysts, if present, were electroablated employing a new tip for the electrosurgery unit (ball shape, 8 mm in diameter, and made of stainless steel). Thirty-three patients (33%) underwent electroablation only for small (< 2 cm in diameter) pneumocysts (group S), and 11 patients (11%) underwent electroablation for large (>/= 2 cm in diameter) pneumocysts (group L). The remaining 55 patients (56%) did not undergo electroablation because there were no residual pneumocysts (group N). There were no complications during surgery. The duration of the operation was significantly shorter (about 20 min on average) for group N, but there was no significant difference in the amount of blood loss, the number of applied staples, the duration of drainage, and the duration of hospital stay. Group S achieved a 100% relapse-free rate (33 of 33 patients), group L achieved a 64% relapse-free rate (7 of 11 patients), and group N achieved an 89% relapse-free rate (49 of 55 patients) [group S vs group N, p = 0.08; group L vs group N, p = 0.001; and group S vs group L, p = 0.002]. Electroablation with the M-tip is feasible as a second-line method for the treatment of small pneumocysts following the stapling technique during VATS.


Non-accidental salt poisoning.
The clinical features of 12 children who incurred non-accidental salt poisoning are reported. The children usually presented to hospital in the first six months of life with unexplained hypernatraemia and associated illness. Most of the children suffered repetitive poisoning before detection. The perpetrator was believed to the mother for 10 children, the father for one, and either parent for one. Four children had serum sodium concentrations above 200 mmol/l. Seven children had incurred other fabricated illness, drug ingestion, physical abuse, or failure to thrive/neglect. Two children died; the other 10 remained healthy in alternative care. Features are described that should lead to earlier detection of salt poisoning; the importance of checking urine sodium excretion, whenever hypernatraemia occurs, is stressed.


Depressive symptoms in hip fracture patients are associated with reduced monocyte superoxide production.
Ageing is accompanied by reduced functioning of the immune system, termed immunesenescence which is associated with increased risk of infection and mortality. However the immune system does not operate in isolation and can be modified by many environmental factors, including stress. In this study we determined whether physical stress (hip fracture) and psychological distress (depressive symptoms) had additive effects upon the aged immune system, specifically on monocyte numbers and function. We assessed immune function in 101 hip fracture patients (81 female) 6weeks and 6months after injury and 43 healthy age matched controls (28 females). Thirty-eight of the hip fracture group were found to be depressed at the 6week sampling. No differences in peripheral monocyte count, distribution of monocyte subsets or TNFα secretion were observed between hip fracture patients and healthy controls. However we observed significantly reduced superoxide production in response to Escherichia coli in the monocytes of hip fracture patients who developed depressive symptoms compared with non-depressed hip fracture patients (p=0.002) or healthy controls (p=0.008) 6weeks after the fracture which remained decreased 6months following injury. In previous studies we have shown an effect of depression on neutrophil superoxide generation in hip fracture patients, suggesting a particular susceptibility of this aspect of immune cell function to psychological stress.


The earlier the more? Differences in the links between age at first drink and adolescent alcohol use and related problems according to quality of parent-child relationships.
Various studies reported associations between age at first drink (AFD) and later problem behaviors. However, the nature and strength of these associations are less clear. The present study investigates differences in the links between AFD and later alcohol use and the ones between alcohol use and later drinking problems, based on quality of parent-child relationships. Structural equation models were estimated based on a three-wave, 2-year prospective study of 364 adolescents. AFD measured at Time 1 was related to drinking quantity at Time 2, which was related to alcohol-related problems at Time 3. However, the significant links between AFD and later alcohol use existed solely among adolescents who reported high-quality relationships with their parents. More specifically, compared with all other adolescents, only those who had a late AFD and a high-quality relationship with their parents were found to have low levels of alcohol use at Time 2 and low levels of alcohol-related problems at Time 3. By promoting a high-quality relationship, prevention efforts might trigger a spiral of healthy developments during adolescence, including family well-being in early adolescence, late AFDs, lower alcohol-use levels, and eventually fewer alcohol-related problems in late adolescence.


Bone compaction enhances fixation of weightbearing titanium implants.
Implant stability is crucial for implant survival. A new surgical technique, compaction, has increased in vitro implant stability and in vivo fixation of nonweightbearing implants. However, the in vivo effects of compaction on weightbearing implants are unknown. As implants inserted clinically are weightbearing, the effects of compaction on weightbearing implants were examined. The hypothesis was that compaction would increase implant fixation compared with conventional drilling. Porous-coated titanium implants were inserted bilaterally into the weightbearing portion of the femoral condyles of dogs. In each dog, one knee had the implant cavity prepared with drilling, and the other knee was prepared with compaction. Eight dogs were euthanized after 2 weeks, and eight dogs were euthanized after 4 weeks. Femoral condyles from an additional eight dogs represented Time 0. Compacted specimens had higher bone-implant contact and periimplant bone density at 0 and 2 weeks, but not at 4 weeks. A biphasic response of compaction was found with a pushout test, as compaction increased ultimate shear strength and energy absorption at 0 and 4 weeks, but not at 2 weeks. This biphasic response indicates that compaction enhances implant fixation by mechanical and biological mechanisms. Therefore, compaction might have potential value in total joint replacement in the future.


Autocrine Leukemia Inhibitory Factor Promotes Esophageal Squamous Cell Carcinoma Progression via Src Family Kinase-Dependent Yes-Associated Protein Activation.
The IL6 family of cytokines, including IL6 and leukemia-inhibitory factor (LIF), are induced during inflammation and are also expressed in many types of cancer where they play an important role in tumor development. IL6 family cytokines mainly activate the JAK-STAT3 pathway via the coreceptor, gp130, and IL6 is known to activate the Src family kinase (SFK)-Yes-associated protein (YAP) pathway. The current study investigated the role of autocrine LIF in human esophageal squamous cell carcinoma (ESCC) that highly expresses LIF. LIF knockdown had various effects on cancer cells, including profound changes in gene expression, suppression of cell proliferation, migration/invasion and sphere formation, and induction of apoptosis. Similar to IL6, LIF activated the SFK-YAP pathway as well as the JAK-STAT3 pathway. LIF-induced YAP activation was more important for cancer cell proliferation than LIF-induced STAT3 activation, and concomitant YAP and STAT3 activation completely compensated for the role of LIF in human ESCC growth. We also confirmed that SFK activation and LIF expression were correlated with YAP activation in human ESCC clinical samples. Furthermore, simultaneous inhibition of the SFK-YAP and JAK-STAT3 pathways in human ESCC cells was more effective at suppressing cell proliferation than single inhibition, and autocrine LIF signaling promoted human ESCC growth in vivo. Therefore, the LIF-SFK-YAP axis may represent a new therapeutic target for human ESCC. IMPLICATIONS: Autocrine LIF signaling promotes human ESCC progression via SFK-dependent YAP activation and is a new potential target of treatment for human ESCC.


The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G+C Gram-positive bacteria.
The genome of Mycobacterium tuberculosis H37Rv has five copies of a cluster of genes known as the ESAT-6 loci. These clusters contain members of the CFP-10 (lhp) and ESAT-6 (esat-6) gene families (encoding secreted T-cell antigens that lack detectable secretion signals) as well as genes encoding secreted, cell-wall-associated subtilisin-like serine proteases, putative ABC transporters, ATP-binding proteins and other membrane-associated proteins. These membrane-associated and energy-providing proteins may function to secrete members of the ESAT-6 and CFP-10 protein families, and the proteases may be involved in processing the secreted peptide. Finished and unfinished genome sequencing data of 98 publicly available microbial genomes has been analyzed for the presence of orthologs of the ESAT-6 loci. The multiple duplicates of the ESAT-6 gene cluster found in the genome of M. tuberculosis H37Rv are also conserved in the genomes of other mycobacteria, for example M. tuberculosis CDC1551, M. tuberculosis 210, M. bovis, M. leprae, M. avium, and the avirulent strain M. smegmatis. Phylogenetic analyses of the resulting sequences have established the duplication order of the gene clusters and demonstrated that the gene cluster known as region 4 (Rv3444c-3450c) is ancestral. Region 4 is also the only region for which an ortholog could be found in the genomes of Corynebacterium diphtheriae and Streptomyces coelicolor. Comparative genomic analysis revealed that the presence of the ESAT-6 gene cluster is a feature of some high-G+C Gram-positive bacteria. Multiple duplications of this cluster have occurred and are maintained only within the genomes of members of the genus Mycobacterium.


Facultative placentotrophy: half-way house or strategic solution?
While yolk is generally the primary source of embryo nutrients in squamates, numerous species supplement this with facultative placentotrophy. We argue that facultative placentotrophy should have selective importance relevant to offspring fitness. In the skink Niveoscincus metallicus, the size of ovulated eggs is unrelated to maternal size but large females produce offspring that are larger than is necessary for survival, providing evidence for facultative placentotrophy. We discuss the circumstances in which facultative placentotrophy might be used to supplement the nutritional support provided by yolk and obligate placentotrophy in this species, and present summary data from experiments designed to investigate these circumstances. Clutch reduction by oviduct removal had no effect on neonate mass or snout-vent length, indicating that the number of embryos does not influence allocation of maternal resources once gestation has commenced. Manipulation of maternal basking opportunity in combination with food intake during pregnancy suggested that an important role of facultative placentotrophy is the optimization of embryonic fat reserves. This hypothesis was supported by the observation that larger neonates have larger abdominal fat bodies. These reserves presumably facilitate survival in the relatively short pre-hibernatory period available to newborn animals. Our data indicate that they also play a vital role in maintaining pre-natal condition if birth is delayed by adverse weather, a common circumstance in this species. In such circumstances the yolk has been used up and the placental membranes have degenerated. Experimental induction of premature ovulation of eggs with reduced yolk, achieved by injecting females with FSH, was followed by fertilization using stored sperm. Gestation length was greatly reduced and the resulting neonates were all < or =75% normal birth mass, with two of the six births being stillborn. Thus facultative placentotrophy does not appear to be a means of compensating for a poor yolk supply. We suggest that facultative placentotrophy in N. metallicus is not a transitional stage en route to greater reliance on obligate placentotrophy, but a uniquely squamate adaptation that provides flexibility in embryonic nutrition, and optimizes offspring fitness in an unpredictable temperate climate.


Monitoring drinking water, sanitation, and hygiene in non-household settings: Priorities for policy and practice.
Inadequate drinking water, sanitation, and hygiene (WaSH) in non-household settings, such as schools, health care facilities, and workplaces impacts the health, education, welfare, and productivity of populations, particularly in low and middle-income countries. There is limited knowledge on the status of WaSH in such settings. To address this gap, we reviewed international standards, international and national actors, and monitoring initiatives; developed the first typology of non-household settings; and assessed the viability of monitoring. Based on setting characteristics, non-household settings include six types: schools, health care facilities, workplaces, temporary use settings, mass gatherings, and dislocated populations. To-date national governments and international actors have focused monitoring of non-household settings on schools and health care facilities with comparatively little attention given to other settings such as workplaces and markets. Nationally representative facility surveys and national management information systems are the primary monitoring mechanisms. Data suggest that WaSH coverage is generally poor and often lower than in corresponding household settings. Definitions, indicators, and data sources are underdeveloped and not always comparable between countries. While not all countries monitor non-household settings, examples are available from countries on most continents suggesting that systematic monitoring is achievable. Monitoring WaSH in schools and health care facilities is most viable. Monitoring WaSH in other non-household settings would be viable with: technical support from local and national actors in addition to international organizations such as WHO and UNICEF; national prioritization through policy and financing; and including WaSH indicators into monitoring initiatives to improve cost-effectiveness. International consultations on targets and indicators for global monitoring of WaSH post-2015 identified non-household settings as a priority. National and international monitoring systems will be important to better understand status, trends, to identify priorities and target resources accordingly, and to improve accountability for progressive improvements in WaSH in non-household settings.


Investigating the stratified efficacy and safety of pharmacological blood pressure-lowering: an overall protocol for individual patient-level data meta-analyses of over 300 000 randomised participants in the new phase of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC).
Previous research from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) and others has shown that pharmacological blood pressure (BP)- lowering substantially reduces the risk of major cardiovascular events, including ischaemic heart disease, heart failure and stroke. In this new phase, the aim is to conduct individual patient-level data (IPD) meta-analyses involving eligible BP-lowering randomised controlled trials (RCTs) to address uncertainties relating to efficacy and safety of BP-lowering treatment. RCTs investigating the effect of pharmacological BP-lowering, with a minimum of 1000 patient-years of follow-up in each trial arm, are eligible. Our systematic review identified 100 potentially eligible trials. We requested their investigators/sponsors to contribute baseline, follow-up and outcomes data. As of June 2018, the collaboration has obtained data from 49 trials (n=315 046 participants), with additional data currently in the process of being transferred from four RCTs (n=34 642 participants). In addition, data harmonisation has commenced. Scientific activities of the collaboration are overseen by the Steering Committee with input from all collaborators. Detailed protocols for individual meta-analyses will be developed and registered on public platforms. Ethics approval has been obtained for this new and extended phase of the BPLTTC, the largest collaboration of de-identified IPD from RCTs. It offers an efficient and ethical manner of re-purposing existing data to answer clinically important questions relating to BP treatment as well as methodological questions relating to IPD meta-analyses. Among the immediate impacts will include reliable quantification of effects of treatment modifiers, such as baseline BP, age and prior disease, on both vascular and non-vascular outcomes. Analyses will further assess the impact of BP-lowering on important, but less well understood, outcomes, such as new-onset diabetes and renal disease. Findings will be published in peer-reviewed medical journals on behalf of the collaboration.


Active, non-spring-like muscle movements in human postural sway: how might paradoxical changes in muscle length be produced?
In humans, during standing the calf muscles soleus and gastrocnemius actively prevent forward toppling about the ankles. It has been generally assumed that these postural muscles behave like springs with dynamic stiffness reflecting their mechanical properties, reflex gain including higher derivatives, and central control. Here, for the first time, we have used an ultrasound scanner and automated image analysis to record the tiny muscular movements occurring in normal standing. This new, non-invasive technique resolves changes in muscle length as small as 10 mum without disturbing the standing process. This technical achievement has allowed us to test the long-established mechano-reflex, muscle spring hypothesis that muscle length changes in a spring-like way during sway of the body. Our results contradict that hypothesis. Muscle length changes in a non-spring-like manner: on average, shortening during forward sway and lengthening during backwards sway (paradoxical movements). This counter-intuitive result is a consequence of the fact that calf muscles generate tension through a series elastic component (SEC, Achilles tendon and foot) which limits maximal ankle stiffness to 92 +/- 20% of that required to balance the body. Paradoxical movements cannot be generated by stretch reflexes with constant intrafusal drive but might be produced by reflex coupling of extrafusal (alpha) and intrafusal (beta, gamma) drive or by positive force feedback. Standing requires the predictive ability to produce the observed muscle movements preceded (110 +/- 50 ms) by corresponding changes in integrated EMG signal. We suggest higher level anticipatory control is more plausible.


The activity and size of the nucleus of comet Hale-Bopp (C/1995 O1) [see comment].
Analysis of Hubble Space Telescope (HST) images of comet Hale-Bopp (C/1995 O1) suggests that the effective diameter of the nucleus is between 27 to 42 kilometers, which is at least three times larger than that of comet P/Halley. The International Ultraviolet Explorer and HST spectra showed emissions from OH (a tracer of H2O) and CS (a tracer of CS2) starting in April 1996, and from the CO Cameron system (which primarily traces CO2) starting in June 1996. The variation of the H2O production rate with heliocentric distance was consistent with sublimation of an icy body near its subsolar point. The heliocentric variation in the production rates of CS2 and dust was different from that of H2O, which implies that H2O sublimation did not control the CS2 or dust production during these observations.


Text-message-based drinking assessments and brief interventions for young adults discharged from the emergency department.
Brief interventions have the potential to reduce heavy drinking in young adults who present to the emergency department (ED), but require time and resources rarely available. Text-messaging (TM) may provide an effective way to collect drinking data from young adults after ED discharge as well as to provide immediate feedback and ongoing support for behavior change. The feasibility of screening young adults in the ED, recruiting them for a TM-based interventional trial, collecting weekly drinking data through TM, and the variance in drinking outcomes remains unknown. Young adults in 3 urban EDs (n = 45; aged 18 to 24 years, 54% women) identified as hazardous drinkers by the Alcohol Use Disorders Identification Test-Consumption score were randomly assigned to weekly TM-based feedback with goal setting (Intervention), weekly TM-based drinking assessments without feedback (Assessment), or control. Participants in the Intervention group who reported ≥5 (for men) and ≥4 (for women) maximum drinks during any one 24-hour period were asked whether they would set a goal to reduce their drinking the following week. We describe the interaction with TM and goal setting. We also describe the heavy drinking days (HDDs), drinks per drinking day (DPDD) using timeline follow-back procedure at baseline and 3 months. We screened 109 young adults over 157 hours across 24 unique days and 52 (48%; 95% CI 38 to 50) screened positive for hazardous drinking. Of these, 45 (87%; 95% CI 74 to 94) met inclusion criteria, were enrolled and randomized, and 6 (13%; 95% CI 5 to 27) did not complete 3-month web-based follow-up; 88% (95% CI 84 to 91) of weekly TM-based drinking assessments were answered, with 77% (95% CI 58 to 90) of participants responding to all 12 weeks. Agreeing to set a goal was associated with a repeat HDD 36% (95% CI 17 to 55) of the time compared with 63% (95% CI 44 to 81) when not willing to set a goal. At 3 months, participants that were exposed to the TM-based intervention had 3.4 (SD 5.4) fewer HDDs in the last month and 2.1 (SD 1.5) fewer DPDD when compared to baseline. TM can be used to assess drinking in young adults and can deliver brief interventions to young adults discharged from the ED. TM-based interventions have the potential to reduce heavy drinking among young adults but larger studies are needed to establish efficacy.


Structural stability and energetics of grain boundary triple junctions in face centered cubic materials.
We present a systematic study to elucidate the role of triple junctions (TJs) and their constituent grain boundaries on the structural stability of nanocrystalline materials. Using atomistic simulations along with the nudge elastic band calculations, we explored the atomic structural and thermodynamic properties of TJs in three different fcc materials. We found that the magnitude of excess energy at a TJ was directly related to the atomic density of the metal. Further, the vacancy binding and migration energetics in the vicinity of the TJ were examined as they play a crucial role in the structural stability of NC materials. The resolved line tension which takes into account the stress buildup at the TJ was found to be a good measure in predicting the vacancy binding tendency near the TJ. The activation energy for vacancy migration along the TJ was directly correlated with the measured excess energy. Finally, we show that the resistance for vacancy diffusion increased for TJs with larger excess stored energy and the defect mobility at some TJs is slower than their constituent GBs. Hence, our results have general implications on the diffusional process in NC materials and provide new insight into stabilizing NC materials with tailored TJs.


Evolutionary lines of cysteine peptidases.
The proteolytic enzymes that depend upon a cysteine residue for activity have come from at least seven different evolutionary origins, each of which has produced a group of cysteine peptidases with distinctive structures and properties. We show here that the characteristic molecular topologies of the peptidases in each evolutionary line can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. Clan CA contains the families of papain (C1), calpain (C2), streptopain (C10) and the ubiquitin-specific peptidases (C12, C19), as well as many families of viral cysteine endopeptidases. Clan CD contains the families of clostripain (C11), gingipain R (C25), legumain (C13), caspase-1 (C14) and separin (C50). These enzymes have specificities dominated by the interactions of the S1 subsite. Clan CE contains the families of adenain (C5) from adenoviruses, the eukaryotic Ulp1 protease (C48) and the bacterial YopJ proteases (C55). Clan CF contains only pyroglutamyl peptidase I (C15). The picornains (C3) in clan PA have probably evolved from serine peptidases, which still form the majority of enzymes in the clan. The cysteine peptidase activities in clans PB and CH are autolytic only. In conclusion, we suggest that although almost all the cysteine peptidases depend for activity on catalytic dyads of cysteine and histidine, it is worth noting some important differences that they have inherited from their distant ancestral peptidases.


Unique regulation of the active site of the serine esterase S-formylglutathione hydrolase.
S-Formylglutathione hydrolases (SFGHs) are highly conserved thioesterases present in prokaryotes and eukaryotes, and form part of the formaldehyde detoxification pathway, as well as functioning as xenobiotic-hydrolysing carboxyesterases. As defined by their sensitivity to covalent modification, SFGHs behave as cysteine hydrolases, being inactivated by thiol alkylating agents, while being insensitive to inhibition by organophosphates such as paraoxon. As such, the enzyme has been classified as an esterase D in animals, plants and microbes. While SFGHs do contain a conserved cysteine residue that has been implicated in catalysis, sequence analysis also reveals the classic catalytic triad of a serine hydrolase. Using a combination of selective protein modification and X-ray crystallography, AtSFGH from Arabidopsis thaliana has been shown to be a serine hydrolase rather than a cysteine hydrolase. Uniquely, the conserved reactive cysteine (Cys59) previously implicated in catalysis lies in close proximity to the serine hydrolase triad, serving a gate-keeping function in comprehensively regulating access to the active site. Thus, any covalent modification of Cys59 inhibited all hydrolase activities of the enzyme. When isolated from Escherichia coli, a major proportion of recombinant AtSFGH was recovered with the Cys59 forming a mixed disulfide with glutathione. Reversible disulfide formation with glutathione could be demonstrated to regulate hydrolase activity in vitro. The importance of Cys59 in regulating AtSFGH in planta was demonstrated in transient expression assays in Arabidopsis protoplasts. As determined by fluorescence microscopy, the Cys59Ser mutant enzyme was shown to rapidly hydrolyse 4-methylumbelliferyl acetate in paraoxon-treated cells, while the native enzyme was found to be inactive. Our results clarify the classification of AtSFGHs as hydrolases and suggest that the regulatory and conserved cysteine provides an unusual redox-sensitive regulation to an enzyme functioning in both primary and xenobiotic metabolism in prokaryotes and eukaryotes.


A review on organophosphate Ester (OPE) flame retardants and plasticizers in foodstuffs: Levels, distribution, human dietary exposure, and future directions.
Given the ongoing studies on the adverse effects of organophosphate ester (OPE) flame retardants and plasticizers on human health, there is an increasing scientific interest in the risk of exposure to OPEs via dietary intake. Using peer-reviewed literature published up to 2018, this review surveyed and compiled the available and reported data on the concentrations and distributions of 30 OPEs based on their occurrence in various food samples from around the world. Regardless of sampling locations or food categories, 22 OPEs were detectable in at least one of analyzed sample, and there were clear variations in OPE levels among samples from different locations or food categories. For instance, cereals and fats/oils were the most contaminated by OPEs in China and Belgium, whereas fats/oils and desserts were the main polluted products in Sweden. In contrast, vegetables, fruits, fluid dairy products, and cereals were reported as the primary categories of food polluted by OPEs in Australia. Animal-based food categories such as eggs, fish and meat were the least contaminated, whereas the highest median OPE concentrations were found in meat and fish from the United State. The levels and distribution patterns of OPEs in foodstuffs demonstrated a tremendous difference even when collected from the same country and the same food item. Rice from China had the highest tris(2‑chloroethyl) phosphate (TCEP, mean: 29.8 ng/g dw) levels, whereas 2‑ethylhexyl‑diphenyl phosphate (EHDPP, mean: 4.17 ng/g ww), triphenyl phosphate (TPHP, mean: 26.14 ng/g ww), tris(2-chloroisopropyl) phosphate (TCIPP, mean: 0.87 ng/g ww) and tributyl phosphate (TNBP, median: 0.55 ng/g ww) concentrations were the highest in the same food category from Sweden, Belgium, Australia, and the United States, respectively. These discrepancies may be due to a variety of reasons such as differences in OPE physico-chemical properties, extent of usage, uptake, metabolic pathways, industrial food manufacturing processes, OPE level differences as a function of habitat, and accumulation and degradability of OPEs in different species. It is worth noting that, due to its worldwide usage in food packaging materials, EHDPP was more prominently found in processed food compared to non-processed food. Based on reported OPE levels in various foods, this review conducted a preliminary assessment of human exposure to OPEs through dietary intake, which suggested that the OPE estimated daily intake (EDI) for humans was around 880 ng/kg bw/day (95th percentile). This value was well below the corresponding OPE health reference dose given by the U.S. EPA (≥15,000 ng/kg bw/day). Even so, dietary exposure to OPEs via food intake may be not negligible based on some important factors such as dilution effects, cooking processes, and the contribution of as yet unknown means of OPE exposure. Overall, this review highlights several gaps in our understanding of OPEs in foodstuffs: 1) the investigation of contamination levels of OPEs in foodstuffs should be extended to other regions, especially North America and European countries, where OPEs are widely used and frequently detected in environmental samples, and 2) newly identified OPE derivatives/by-products, e.g., OP diesters and hydroxylated metabolites, which have been reported as end-products of OPE enzymatic metabolism or degradation through aqueous hydrolysis, and which may co-exist with parent OPEs, could also be screened with precursor OPEs in foodstuffs in future studies.


Double Hyperautofluorescence Rings as a Sign of CFAP410-related Retinopathy.
Variants in CFAP410 have been reported to cause retinal dystrophy with or without systemic symptoms. This study was designed to characterize the fundus changes of patients with biallelic variants in CFAP410. Variants in CFAP410 were identified through whole exome sequencing and targeted exome sequencing of 10,530 probands. Biallelic variants in CFAP410 were evaluated by comprehensive in silico analysis and confirmed by Sanger sequencing and segregation analysis. Ocular phenotypes including fundus photographs, scanning laser ophthalmoscopy, autofluorescence images, ERG, and optical coherence tomography were characterized. Nine patients from eight families were homozygotes or compound heterozygotes for a total of four variants in CFAP410, including c.144-6_159del (novel), c.340_351dup, c.347C>T, and c.545+1G>A. Three patients were diagnosed with cone-rod dystrophy, and the remaining six patients with RP. Among eight patients performed with ultra-wide scanning laser ophthalmoscopy, double hyperautofluorescence rings inside and outside of the macular vascular arcades were observed in six patients, and the remaining two older patients demonstrated single hyperautofluorescence ring surrounded by pigmentation. CFAP410-associated retinopathy in early stage was generally tapetoretinal degeneration without noticeable bone spicule pigmentation, with more severe degeneration in the inferior nasal retina. ERG recordings delineated a severely reduced cone response and mildly to severely reduced rod response. Posterior staphyloma was seen in seven patients who underwent optical coherence tomography examinations. The present study demonstrates the fundus characteristics of patients with biallelic variants in CFAP410 and expands the genotype-phenotype spectrum of CFAP410-related retinal degeneration, in which posterior staphyloma together with double hyperautofluorescence rings might be common peculiar signs.


Mood as Representation of Momentum.
Experiences affect mood, which in turn affects subsequent experiences. Recent studies suggest two specific principles. First, mood depends on how recent reward outcomes differ from expectations. Second, mood biases the way we perceive outcomes (e.g., rewards), and this bias affects learning about those outcomes. We propose that this two-way interaction serves to mitigate inefficiencies in the application of reinforcement learning to real-world problems. Specifically, we propose that mood represents the overall momentum of recent outcomes, and its biasing influence on the perception of outcomes 'corrects' learning to account for environmental dependencies. We describe potential dysfunctions of this adaptive mechanism that might contribute to the symptoms of mood disorders.