Two translocations of chromosome 15q associated with dyslexia.
Developmental dyslexia is characterised by difficulties in learning to read. As reading is a complex cognitive process, multiple genes are expected to contribute to the pathogenesis of dyslexia. The genetics of dyslexia has been a target of molecular studies during recent years, but so far no genes have been identified. However, a locus for dyslexia on chromosome 15q21 (DYX1) has been established in previous linkage studies. We have identified two families with balanced translocations involving the 15q21-q22 region. In one family, the translocation segregates with specific dyslexia in three family members. In the other family, the translocation is associated with dyslexia in one family member. We have performed fluorescence in situ hybridisation (FISH) studies to refine the position of the putative dyslexia locus further. Our results indicate that both translocation breakpoints on 15q map within an interval of approximately 6-8 Mb between markers D15S143 and D15S1029, further supporting the presence of a locus for specific dyslexia on 15q21.


Suicide Ideation and Thwarted Interpersonal Needs among Psychiatric Inpatients: A Network Approach.
We aimed to demonstrate the utility of an item-level network analysis approach to suicide risk by testing the interpersonal psychological theory of suicide (IPTS) among 402 psychiatric inpatients. We hypothesized specific thwarted belongingness (TB) or perceived burdensomeness (PB; Interpersonal Needs Questionnaire items) facets would positively relate to passive or active suicide ideation, and these facets would positively relate to each other and form distinct clusters. We also tested TB and PB facets central to the networks as predictors of suicide ideation compared to the full TB and PB subscales. Face-valid items congruent with latent constructs proposed by the IPTS (i.e., feelings of burden on society, feeling that one does not belong) were the only two facets uniquely predictive of passive and active suicide ideation. Facets of TB and PB did not form distinct clusters. Item-level network analysis may have important conceptual, assessment, predictive, and clinical implications for understanding suicide risk.


Publication Rates of Abstracts Presented at the Society of General Internal Medicine Annual Meeting.
Abstracts accepted at scientific meetings are often not subsequently published. Data on publication rates are largely from subspecialty and surgical studies. The aims of this study were to 1) determine publication rates of abstracts presented at a general internal medicine meeting; 2) describe research activity among academic general internists; 3) identify factors associated with publication and with the impact factor of the journal of publication; and 4) evaluate for publication bias. Retrospective cohort study. All scientific abstracts presented at the Society of General Internal Medicine 2009 Annual Meeting. Publication rates were determined by searching for full-text publications in MEDLINE. Data were abstracted regarding authors' institution, research topic category, number of study sites, sample size, study design, statistical significance (p value and confidence interval) in abstract and publication, journal of publication, publication date, and journal impact factor. Of the 578 abstracts analyzed, 274 (47.4%) were subsequently published as a full article in a peer-reviewed journal indexed in MEDLINE. In a multivariable model adjusting for institution site, research topic, number of study sites, study design, sample size, and abstract results, publication rates for academic general internists were highest in the areas of medical education (52.5%, OR 5.05, 95% CI 1.57-17.25, reference group Veterans Affairs (VA)-based research, publication rate 36.7%), mental health/substance use (67.7%, OR 4.16, 95% CI 1.39-13.06), and aging/geriatrics/end of life (65.7%, OR 3.31, 95% CI 1.15-9.94, p = 0.01 across topics). Publication rates were higher for multicenter studies than single-institution studies (52.4% vs. 40.4%, OR 1.66, 95% CI 1.10-2.52, p = 0.04 across categories). Randomized controlled trials had higher publication rates than other study designs (66.7% vs. 45.9%, OR 2.72, 95% CI 1.30-5.94, p = 0.03 across study designs). Studies with positive results did not predict higher publication rates than negative studies (OR 0.89, 95% CI 0.6-1.31, p = 0.21). This study demonstrated that 47.4% of abstracts presented at a general internal medicine national conference were subsequently published in a peer-reviewed journal indexed in MEDLINE.


Detection of the abnormal isoform of the prion protein associated with chronic wasting disease in the optic pathways of the brain and retina of Rocky Mountain elk (Cervus elaphus nelsoni).
Eyes and nuclei of the visual pathways in the brain were examined in 30 Rocky Mountain elk (Cervus elaphus nelsoni) representing 3 genotypes of the prion protein gene PRNP (codon 132: MM, ML, or LL). Tissues were examined for the presence of the abnormal isoform of the prion protein associated with chronic wasting disease (PrP(CWD)). Nuclei and axonal tracts from a single section of brain stem at the level of the dorsal motor nucleus of the vagus nerve were scored for intensity and distribution of PrP(CWD) immunoreactivity and degree of spongiform degeneration. This obex scoring ranged from 0 (elk with no PrP(CWD) in the brain stem) to 10 (representing elk in terminal stage of disease). PrP(CWD) was detected in the retina of 16 of 18 (89%) elk with an obex score of > 7. PrP(CWD) was not detected in the retina of the 3 chronic wasting disease-negative elk and 9 elk with an obex score of < 6. PrP(CWD) was found in the nuclei of the visual pathways in the brain before it was found in the retina. Within the retina, PrP(CWD) was first found in the inner plexiform layer, followed by the outer plexiform layer. Intracytoplasmic accumulation of PrP(CWD) was found in a few neurons in the ganglion cell layer in the PRNP 132ML elk but was a prominent feature in the PRNP 132LL elk. Small aggregates of PrP(CWD) were present on the inner surface of the outer limiting membrane in PRNP 132LL elk but not in PRNP 132MM or 132ML elk. This study demonstrates PrP(CWD) accumulation in nuclei of the visual pathways of the brain, followed by PrP(CWD) in the retina.


P53 overexpression in gastric adenocarcinoma with Helicobacter pylori infection.
Gastric carcinogenesis has been studied in various aspects. Helicobacter pylori (Hp) infection and mutation of the p53 tumor suppressor gene have recently been argued to be important factors of gastric carcinogenesis. There have been many studies to determine the precise mechanism of how Hp is related to gastric cancer, but it is so far still unknown. We studied the relationship of Hp infection and p53 overexpression and tried to discover some significance in clinicopathologic factors such as age, sex, stage, site, differentiation and gross morphology. Ninety-six patients who were diagnosed with gastric cancer at Severance Hospital, Yonsei University Medical College from November 1995 to March 1996, and 96 control patients of non-ulcer dyspepsia (NUD) were studied by endoscopic biopsy of normal gastric tissue and cancer tissue. They also underwent the CLO (Delta West, Melbourne, Western Australia) test for Hp positivity and p53 immunohistochemical stain for p53 positivity. These data were analyzed for comparison with the clinicopathologic characteristics of gastric cancers. In conclusion, the differentiated group cancer had a significantly high Hp positivity and p53 positivity. There is a possibility that Hp infection and p53 tumor suppressor gene mutation might be significantly related in the gastric carcinogenic process of well- and moderately-differentiated adenocarcinomas, but further study is necessary to determine more direct clues on the carcinogenic roles of these factors.


ACURATE neo2 versus SAPIEN 3 Ultra for transcatheter aortic valve implantation.
No comparative data exist with the latest generation self-expanding ACURATE neo2 (Neo2) and the balloon-expandable SAPIEN 3 Ultra (Ultra) transcatheter heart valves (THV). We aimed to compare the outcomes after transcatheter aortic valve implantation (TAVI) using the Neo2 and the Ultra THV. A total of 1,356 patients at 4 centres were treated either with the Neo2 (n=608) or the Ultra (n=748). The primary endpoint was device success according to the latest Valve Academic Research Consortium definitions. The association of the THV used and the primary endpoint was assessed using inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM), which identified 472 matched pairs. Results: After PSM, there were no relevant differences between the groups. While rates of moderate to severe paravalvular leakage (PVL) were overall low (0.6% vs 1.1%; p=0.725), elevated transvalvular gradients (≥20 mmHg) were less frequent with the Neo2 (2.4% vs 7.7%; p<0.001), which translated into a significantly higher rate of device success with the Neo2 compared with the Ultra (91.9% vs 85.0%; p<0.001). Consistently, the Neo2 was associated with higher rates of device success in the IPTW analysis (odds ratio [OR] 1.961, 95% confidence interval [CI]: 1.269-3.031; p=0.002). Rates of mild PVL were significantly lower with the Ultra compared with the Neo2 (20.0% vs 32.8%; p<0.001). Clinical events at 30 days were comparable between the 2 groups. Short-term outcomes after TAVI using the Neo2 or Ultra THV were excellent and, overall, comparable. However, transvalvular gradients were lower with the Neo2, which translated into higher rates of device success. Rates of mild PVL were significantly lower with the Ultra THV.


Perspectives from the other side of the screen: how clinicians and radiologists communicate about diagnostic errors.
Background Miscommunication amongst providers is a major factor contributing to diagnostic errors. There is a need to explore the current state of communications between clinicians and diagnostic radiologists. We compare and contrast the perceptions, experiences, and other factors that influence communication behaviors about diagnostic errors between clinicians and radiologists. Methods A survey with questions addressing (1) communication around diagnostic error, (2) types of feedback observed, (3) the manner by which the feedback is reported, and (4) length of time between the discovery of the diagnostic error and disclosing it was created and distributed through two large academic health centers and through listservs of professional societies of radiologists and clinicians. Results A total of 240 individuals responded, of whom 58% were clinicians and 42% diagnostic radiologists. Both groups of providers frequently discover diagnostic errors, although radiologists encounter them more frequently. From the qualitative analysis, feedback around diagnostic error included (1) timeliness of error, (2) specificity in description or terminology, (3) collegial in delivery, and (4) of educational value through means such as quality improvement. Conclusions Clinicians and radiologists discover diagnostic errors surrounding the interpretation of radiology images, although radiologists discover them more frequently. There is significant opportunity for improvement in education and practice regarding how radiologists and clinicians communicate as a team and, importantly, how feedback is given when an error is discovered. Educators and clinical leaders should consider designing, implementing, and evaluating strategies for improvement.


Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation.
Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid-liquid mixing must be achieved quickly by appropriate arrangement of transport and kneading elements in the granulator screw allowing the production of granules with a size distribution appropriate for tableting. The distribution of residence time and granulation liquid is governed by the field conditions (such as location and length of mixing zones) in the twin-screw granulator, thus contain interesting information on granulation time, mixing and resulting sub-processes such as wetting, aggregation and breakage. In this study, the impact of process (feed rate, screw speed and liquid-to-solid ratio) and equipment parameters (number of kneading discs and stagger angle) on the residence time (distribution), the granulation liquid-powder mixing and the resulting granule size distributions during twin-screw granulation were investigated. Residence time and axial mixing data was extracted from tracer maps and the solid-liquid mixing was quantified from moisture maps, obtained by monitoring the granules at the granulator outlet using near infra-red chemical imaging (NIR-CI). The granule size distribution was measured using the sieving method. An increasing screw speed dominantly reduced the mean residence time. Interaction of material throughput with the screw speed and with the number of kneading discs led to most variation in the studied responses including residence time and mixing capacity. At a high screw speed, granulation yield improved due to high axial mixing. However, increasing material throughput quickly lowers the yield due to insufficient mixing of liquid and powder. Moreover, increasing liquid-to-solid ratio resulted in more oversized granules, and the fraction of oversized granules further increased at higher throughput. Although an increasing number of kneading discs was found to be critical for achieving a uniform distribution of the granulation liquid, the granulation performance was hampered due to insufficient solid-liquid mixing capacity of the current kneading discs which is essential for wet granulation. Thus, a balance between material throughput and screw speed should be strived for in order to achieve a specific granulation time and solid-liquid mixing for high granulation yield. Additionally, more efforts are needed both in modification of the screw configuration as well as the geometry of the mixing elements to improve the mixing capacity of the twin-screw granulator. The results from the current experimental study improved the understanding regarding the interplay between granulation time and the axial and solid-liquid mixing responsible for the granulation performance in twin-screw wet granulation.


Collaborative Quality Improvement Strategy in Secondary Prevention of Cardiovascular Disease in India: Findings from a Multi-Stakeholder, Qualitative Study using Consolidated Framework for Implementation Research (CFIR).
Cardiovascular disease (CVD) is highly prevalent in India, and little is known about the perception of patients and providers about a package of collaborative quality improvement (C-QIP) strategies consisting of provider-focused electronic health records-decision support system (EHR-DSS), non-physician health workers (NPHW), and patient-facing text messages to enhance the CVD care. To explore the barriers and enablers of the C-QIP strategy from the perspective of providers, health administrators, patients, and care givers in India. We conducted a qualitative study using the consolidated framework for implementation research (CFIR) to understand the challenges and facilitators of implementing C-QIP strategy to enhance CVD care in the Indian context. A diverse sample of 38 physicians, 14 non-physician health workers (nurses, pharmacists), 4 health administrators, and 16 patients and their caregivers participated in semi-structured interviews. All interviews were audio-recorded, transcribed, translated, anonymised, and coded using MAXQDA software. We used the framework method and CFIR domains to analyze the qualitative data. Barriers perceived from providers' and health administrators' perspectives in providing quality CVD care were high patient volume, physician burnout, lack of robust communication or referral system, paucity of electronic health records, lack of patient counsellors, polypharmacy, poor patient adherence to medications, and lack of financial incentives. Low health literacy, high cost of treatment, misinformation bias, and difficulty in maintaining lifestyle changes were barriers from patients' perspectives. The CFIR identified key enablers for the implementation of C-QIP such as standardized treatment protocol, reduced medication errors, improved physician-patient relationships, and enhanced patient self-care through trained and supported NPHW. Barriers included: heterogenous healthcare settings, diverse patient groups and comorbidities, associated costs of care and interoperability, confidentiality, and data privacy issues around the use of EHR-DSS. Strategies to enhance CVD care must be low-cost, culturally acceptable, and integrated into existing care pathways.


Early Predictors of Trajectories of Tobacco Use Level from Adolescence to Young Adulthood: A 16-Year Follow-Up of the TEMPO Cohort Study (1999-2015).
Individual and family characteristics early on in life are associated with adolescent smoking; however, their role with regard to long-term tobacco smoking trajectories into young adulthood is not well-known, which is what we set out to study using data from a longitudinal community-based cohort. We used data from 2,025 youths in France (12-26 years at baseline, 16 years of follow-up), participating in the longitudinal TEMPO cohort study. First, we modeled smoking trajectories from adolescence onwards using Group-Based Trajectory Modeling, by using the declared consumption of cigarettes at different ages. Second, among trajectories of smokers, associations with individual and family characteristics in childhood and adolescence were studied using multinomial logistic regression. We observed 5 smoking trajectories: non-smokers (62.3%), 3 groups of persistent smokers with different levels of tobacco use (low, intermediate, high), and a group characterized by high-level smoking followed by cessation. Among participants who were lifetime smokers (n = 763), the trajectory of tobacco use was associated with early substance use initiation, academic attainment, grade retention, and parental smoking. Early tobacco and cannabis use initiation predicted high-level tobacco use, whether it persisted (OR 2.29, 95% CI 1.23-4.28) or not (OR 2.99, 95% CI 1.59-5.63). Grade retention and parental smoking predicted persistent smoking of intermediate (respectively OR 1.53, 95% CI 1.03-1.92; OR 1.74, 95% CI 1.03-2.92) or high level use (respectively OR 1.74, 95% CI 1.07-2.85; OR 1.70, 95% CI 0.91-3.18). Poor academic attainment predicted all 3 smoking trajectories, especially persistent high-level smoking (no high school degree: OR 5.29, 95% CI 1.65-16.97, vocational degree: OR 1.94, 95% CI 0.99-3.80). Tobacco smoking trajectories from adolescence to adulthood are associated with early substance use initiation, parental smoking, and academic difficulties.


Independent processing of the temporal and ordinal structure of movement sequences.
We investigated if the temporal and ordinal structures of sequences can be represented and learned independently. In Experiment 1, subjects learned three rhythmic sequences of key presses with the right index finger: Combined consisted of nine key presses with a corresponding temporal structure of eight intervals; Temporal had the temporal structure of Combined but was performed on one key; Ordinal had the ordinal structure of Combined but an isochronous rhythm. Subjects were divided into two groups. Group 1 first learned Combined, then Temporal and Ordinal; Group 2 first learned Temporal and Ordinal, then Combined. Strong transfer effects were seen in both groups. In Group 1, having learned combined facilitated the learning of the temporal (Temporal) or ordinal (Ordinal) sequence alone; in Group 2, having learned Temporal and Ordinal facilitated the learning of Combined, where the two are combined. This supports that subjects had formed independent temporal and ordinal representations. In Experiment 2, we investigated if these can be learned independently. Subjects repeatedly reproduced sequences with fixed temporal and random ordinal structure; random temporal and fixed ordinal structure; and random temporal and ordinal structures. Temporal and ordinal learning was seen only in the first and second sequences, respectively. In summary, we provide evidence for the existence of independent systems for learning and representation of ordinal and temporal sequences and for implicit learning of temporal sequences. This may be important for fast learning and flexibility in motor control.


Tuberculous pyomyositis of the thigh masquerading as malignancy with concomitant tuberculous flexor tenosynovitis and dactylitis of the hand.
Multifocal involvement of the skeleton is extremely rare, with tuberculous pyomyositis and tenosynovitis of the wrist being uncommon presentations of skeletal tuberculosis (TB). We present an immunocompetent 68-year-old woman with concomitant presentation of these uncommon forms of extrapulmonary TB heralded by tuberculous pyomyositis. Tuberculous pyomyositis can often masquerade as malignancy, leading to misdiagnosis and patients being mistakenly referred to oncologists for management. This delayed the institution of appropriate drug therapy. Similarly, because of its rarity, tuberculous tenosynovitis may be overlooked as a cause of chronic tenosynovitis. In the absence of pathognomonic imaging findings, the diagnosis ultimately rests on histopathological and microbiological confirmation. This case highlights the importance of maintaining a high index of suspicion of the protean manifestations of extrapulmonary TB, not only in high-risk populations, but in immunocompetent individuals as well. It also illustrates the advantage of a clinically-directed multidisciplinary approach in early recognition and treatment of this entity.


2021 GRAPPA Trainee Symposium: A Summary of Oral and Poster Presentations.
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held a trainee symposium at its 2021 virtual meeting. Dermatology and rheumatology trainees presented their work on psoriasis and psoriatic arthritis (PsA). This report briefly reviews 5 oral presentations: prediction of cardiovascular events in psoriatic disease (PsD), correlation between spine abnormalities and clinical findings, biomechanical stress as a trigger for PsA, differences in DNA methylation among twins with PsD, and critical proteins associated with induction of PsD. In addition, we highlight 22 posters broadly discussing clinical and molecular implications of PsD.


Loudness and auditory steady-state responses in normal-hearing subjects.
This study evaluated the use of multiple auditory steady-state responses (ASSRs) to estimate the growth of loudness in listeners with normal hearing. Individual intensity functions were obtained from measures of loudness growth using the contour test and from the electrophysiological amplitude measures of multiple amplitude-modulated (77-105 Hz) tones (500, 1000, 2000, and 4000 Hz) simultaneously presented to both ears and recorded over the scalp. Slope analyses for the behavioural and electrophysiological intensity functions were separately performed. Response amplitudes of the ASSRs and loudness sensation judgements increase as the stimulus intensity increases for the four frequencies studied. A significant relationship was obtained between loudness and the ASSRs. The results of this study suggest that the amplitude of the ASSRs may be used to estimate loudness growth at least for individuals with normal hearing.


Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer.
LINE-1 and Alu elements are non-LTR retrotransposons, constituting together over 30% of the human genome and they are frequently hypomethylated in human tumors. A relationship between global hypomethylation and genomic instability has been shown, however, there is little evidence to suggest active role for hypomethylation-mediated reactivation of retroelements in human cancer. In our study, we examined by Pyrosequencing the methylation levels of LINE-1 and Alu sequences in 48 primary nonsmall cell carcinomas and their paired adjacent tissues. We demonstrate a significant reduction of the methylation levels of both elements (p = 7.7 x 10(-14) and 9.6 x 10(-7), respectively). The methylation indices of the 2 elements correlated (p = 0.006), suggesting a possible common mechanism for their methylation maintenance. Genomic instability was measured utilizing 11 fluorescent microsatellite markers located on lung cancer hot-spot regions such as 3p, 5q 9p, 13q and 17p. Hypomethylation of both transposable elements was associated with increased genomic instability (LINE, p = 7.1 x 10(-5); Alu, p = 0.008). The reduction of the methylation index of LINE-1 and Alu following treatment of 3 lung cell lines with 5-aza-2'-deoxycitidine, consistently resulted in increased expression of both elements. Our study demonstrates the strong link between hypomethylation of transposable elements with genomic instability in non-small cell lung cancer and provides early evidence for a potential active role of these elements in lung neoplasia. As demethylating agents are now entering lung cancer trials, it is imperative to gain a greater insight into the potential reactivation of silent retrotransposons in order to advance for the clinical utilization of epigenetics in cancer therapy.


"Ultrashort" control of hypothalamic hormones secretion: a brief history.
Some 30 years ago we proposed that the synthesis of the hypothalamic releasing factors (RFs) might be influenced by changes of their own titers in the general circulation and in the hypothalamus. At that time the dominating concept was that there were two different hypothalamic RFs controling respectively follicle-stimulating hormone (FSHRF) and luteinizing hormone (LHRF). The possible existence of the first "ultrashort" feedback system was proposed on the basis of the observation that in male rats castrated, to eliminate the "long" feedback effect of testosterone, and then hypophysectomized, to abolish the possible "short" feedback effect of pituitary hormones on the hypothalamus, the intrahypothalamic levels of FSHRF resulted to be higher than in controls. Following a treatment with an hypothalamic extract, the intrahypothalamic stores of FSHRF returned to pre-operation levels, suggesting that a factor present in the hypothalamic extract might exert an inhibitory influence on the synthesis of FSHRF. In 1987, we confirmed these findings using an in vitro perfusion system of rat hypothalamic tissue, where the amount of gonadotropin-releasing hormone (GnRH) released was measured in the effluent. When a GnRH analog was added to the perfusion medium, both the spontaneous and the stimulated release of GnRH were totally obliterated. The presence of specific binding sites for GnRH has been clearly demonstrated in GnRH neurons. It is becoming consequently attractive the hypothesis that paracrine interactions might occur among GnRH neurons, entertaining an "ultrashort" feedback control of GnRH secretion.


Changes in serum levels of perfluoroalkyl substances during a 10-year follow-up period in a large population-based cohort.
Poly- and perfluoroalkyl substances (PFASs) are a group of man-made fluorinated chemicals which have, at background levels, been associated with negative health effects in humans. Thus far, most human biomonitoring studies have evaluated the general change in PFAS concentration over time by continuously testing various individuals. This is one of the few studies to report the longitudinal trend of a range of PFAS concentrations in humans. In addition, this is the first known longitudinal study to include a large background level exposed cohort of both men and women with the same age and location who were repeatedly sampled from 2001 to 2014. The longitudinal change in concentration of eight PFASs detected in serum collected from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort were determined and compared to results from general population studies. The sex-dependent changes in PFAS concentrations over time were also assessed. Serum was sampled from the same individuals at ages 70 (collection period 2001-2004), 75 (2006-2009) and 80 (2011-2014,). Eight (C6-11) of fourteen (C4-13) analyzed PFASs were usually detected in over 75% of individuals and assessed using a random effects (mixed) model. In the 579 individuals attending all three examinations, PFOSA and PFOS concentrations significantly decreased, while the remaining six PFASs significantly increased between ages 70 and 75. However, between ages 75 and 80 all PFAS concentrations significantly decreased. Overall from age 70 to 80, concentrations of PFHxS, PFUnDA, PFNA, and PFDA showed a significant increase (7% to 34%), whereas concentrations of PFOSA, PFHpA, PFOS, and PFOA (-75% to -27%) significantly decreased. Over time PFHxS concentrations increased more among women, while PFHpA concentrations showed a greater decrease among men. From age 70 to age 80, spanning from 2001-2004 to 2011-2014, the PIVUS cohort showed decreases in circulating levels of some PFASs phased out of production with the exception of PFHxS and C>8 PFASs. Contrary to other studies, PFHxS concentrations showed the greatest overall increase, which is likely attributed to a local drinking water contamination incident.


Health insurance for Americans approaching age sixty-five: an analysis of options for incremental reform.
This article provides a systematic evaluation of the options for incremental health insurance reforms aimed at older Americans nearing age sixty-five. It presents three basic arguments for giving special consideration to this age group: (1) early retirement and its effect on access to employer insurance; (2) changes in health and health care expenses associated with increasing age; (3) the vulnerability to unexpected economic or health "shocks" that will affect people throughout their retirement. The analysis of policy options begins by specifying criteria for evaluating alternative approaches to reform. The proposed criteria emphasize that reforms for this age group should be designed to fit with other financial plans and decisions made during such a transitional stage of life. Policy options should be judged according to fundamental goals such as equity and efficiency, not simply ranked according to the number of uninsured who will gain coverage. After offering a comprehensive catalog and evaluation of available options, the analysis identifies and discusses a preferred approach-which preserves choices while offering universal and subsidized access to Medicare before age sixty-five.


Incidence of active tuberculosis in individuals with latent tuberculosis infection in rural China: follow-up results of a population-based, multicentre, prospective cohort study.
The management of latent Mycobacterium tuberculosis infection is a new priority action for the WHO End Tuberculosis (TB) Strategy. However, national guidelines on latent tuberculosis infection testing and treatment have not yet been developed in China. Here, we present the results from the 2-year follow-up of a study that aimed to track the development of active disease in individuals with latent tuberculosis infection, identify priority populations for latent infection management, and explore the most suitable latent infection diagnostic approach. A population-based multicentre prospective study was done in four sites in rural China, between 2013 and 2015. The baseline survey in 2013 measured the prevalence of latent tuberculosis infection using QuantiFERON-TB Gold In-Tube (QFT) and tuberculin skin test (TST) in eligible participants. During the follow-up phase between 2014-15, we assessed individuals who had tuberculosis infection at baseline (QFT-positivity or TST tuberculin reaction size [induration] of ≥10 mm) for the development of active disease through active case finding. Eligible participants included in follow-up survey had a birth date before June 1, 2008 (5 years or older in 2013), and continuous residence at the study site for 6 months or longer in the past year. Participants with current active tuberculosis at baseline survey were excluded. Between Sept 1, 2013, and Aug 31, 2015, 7505 eligible participants (aged 5 years or older) were included in tuberculosis infection test positive cohorts (4455 were QFT positive, 6404 had TST induration ≥10 mm, and 3354 were positive for both tests) after baseline examination. During the 2-year follow-up period, 84 incident cases of active tuberculosis were diagnosed. Of participants who developed active tuberculosis, 75 were diagnosed with latent infection by QFT, 62 were diagnosed by TST, and 53 were diagnosed by both tests. An incidence rate of 0·87 (95% CI 0·68-1·07) per 100 person-years was observed for individuals who tested positive with QFT, 0·50 (0·38-0·63) per 100 person-years for those who tested positive with TST (p<0·0001), and 0·82 (0·60-1·04) per 100 person-years for those who tested positive with both tests. Male sex and a history of tuberculosis were significantly associated with increased risk of disease development with adjusted hazard ratios of 2·36 (95% CI 1·30-4·30) for male sex and 5·40 (3·34-8·71) for a history of tuberculosis. Our results suggest that high-risk populations in communities in rural China, such as individuals at a high risk of disease reactivation from previous tuberculosis, should be targeted for latent infection screening and treatment with an interferon-γ releasing assay rather than a TST. National Science and Technology Major Project of China, Program for Changjiang Scholars and Innovative Research Team in University of China, CAMS Innovation Fund for Medical Sciences, and Sanming Project of Medicine in Shenzhen.


Glutamate decreases mitochondrial size and movement in primary forebrain neurons.
Mitochondria are essential to maintain neuronal viability. In addition to the generation of ATP and maintenance of calcium homeostasis, the effective delivery of mitochondria to the appropriate location within neurons is also likely to influence their function. In this study we examined mitochondrial movement and morphology in primary cultures of rat forebrain using a mitochondrially targeted enhanced yellow fluorescent protein (mt-eYFP). Mt-eYFP-labeled mitochondria display a characteristic elongated phenotype and also move extensively. Application of glutamate to cultures results in a rapid diminution of movement and also an alteration from elongated to rounded morphology. This effect required the entry of calcium and was mediated by activation of the NMDA subtype of glutamate receptor. Treatment of cultures with an uncoupler or blocking ATP synthesis with oligomycin also stopped movement but did not alter morphology. Interestingly, application of glutamate together with the uncoupler did not prevent the changes in movement or shape but facilitated recovery after washout of the stimuli. This suggests that the critical target for calcium in this paradigm is cytosolic. These studies demonstrate that in addition to altering the bioenergetic properties of mitochondria, neurotoxins can also alter mitochondrial movement and morphology. We speculate that neurotoxin-mediated impairment of mitochondrial delivery may contribute to the injurious effects of neurotoxins.


Hepatic epithelial stem-like cells.
The liver is composed of long-lived hepatocytes and biliary epithelial cells whose replacement ordinarily occurs from the proliferation of residual differentiated cells of each type, obviating the need for stem cells to renew hepatocytic and biliary epithelial lineages. Nevertheless, small epithelial cells that are phenotypically distinct from either hepatocytes or biliary epithelial cells can be isolated from normal and pathological livers and established as cultured cell lines. When transplanted into the livers of syngeneic rats, cells of some cultured hepatic epithelial lines migrate into hepatic plates and differentiate into hepatocytes. The strong differentiation-inducing potency of the liver microenvironment is indicated by intrahepatic hepatocytic differentiation and coordinate suppression of tumorigenicity of some aneuploid, neoplastic hepatic epithelial cells that are highly tumorigenic when transplanted into subcutaneous sites. The liver appears to contain cells that have stem-like potential to differentiate into hepatocytes and biliary epithelial cells.


Examining the generality of children's preference for contingent reinforcement via extension to different responses, reinforcers, and schedules.
Studies that have assessed whether children prefer contingent reinforcement (CR) or noncontingent reinforcement (NCR) have shown that they prefer CR. Preference for CR has, however, been evaluated only under continuous reinforcement (CRF) schedules. The prevalence of intermittent reinforcement (INT) warrants an evaluation of whether preference for CR persists as the schedule of reinforcement is thinned. In the current study, we evaluated 2 children's preference for contingent versus noncontingent delivery of highly preferred edible items for academic task completion under CRF and INT schedules. Children (a) preferred CR to NCR under the CRF schedule, (b) continued to prefer CR as the schedule of reinforcement became intermittent, and (c) exhibited a shift in preference from CR to NCR as the schedule became increasingly thin. These findings extend the generality of and provide one set of limits to the preference for CR. Applied implications, variables controlling preferences, and future research are discussed.


Mannose-binding lectin polymorphisms and pulmonary outcome in premature neonates: a pilot study.
Mannose-binding lectin (MBL2) is a collectin molecule able to activate the complement system and the subsequent inflammatory mechanisms. Several MBL2 genetic variants have been described, including the six variants studied in this report, which are those analyzed in most detail in the medical literature. The present study analyzes the prevalence of MBL2 gene variants in preterm newborns and associates individual genotypes with pulmonary outcome variables. All polymorphisms were analyzed by means of a commercially available reverse dot-blot kit. Tertiary neonatal intensive care unit. Seventy-five consecutive preterm newborns. Two variants were particularly analyzed: -550G > C and R52C. The first one is known to be associated with lower protein synthesis when included in specific haplotypes. The homozygous and heterozygous -550G > C mutations were significantly associated with protective effects regarding different lung outcome variables, including shorter duration of mechanical ventilation, hours of continuous positive airway pressure and lower number of hemotransfusions. In contrast, the heterozygous R52C mutation was associated with unfavorable outcome, including higher bronchopulmonary dysplasia prevalence. Multivariate logistic regression analysis showed that these associations were independent of gestational age and birth weight. In addition, four groups of patients were defined on the basis of haplotype combinations. Those known to be associated with low serum MBL2 levels were linked to a better outcome in terms of factors such as hours of mechanical ventilation, continuous positive airway pressure, number of hemotransfusions and bronchopulmonary disease development. The four haplotype combination groups may have a potential diagnostic use as opposite risk factors for lung disease of prematurity.


Usefulness of a Newly Developed Spirometer to Measure Dynamic Lung Hyperinflation following Incremental Hyperventilation in Patients with Chronic Obstructive Pulmonary Disease.
Objective This study was performed to determine the usefulness of a newly developed spirometer for the quantitative assessment of dynamic lung hyperinflation (DLH) following incremental hyperventilation in chronic obstructive pulmonary disease (COPD). Methods The subjects were 54 patients with COPD and 25 healthy volunteers. Each subject was asked to hyperventilate for 30 seconds with stepwise increments starting at the resting respiration rate and increasing to respiratory rates of 20, 30, and finally 40 breaths/min while using a newly developed spirometer. The relationship between the observed inspiratory capacity (IC) reduction following incremental hyperventilation as an index of DLH and spirometry or the 6-minute walking distance was examined. Results The IC did not decrease significantly from the resting IC, even when the respiratory rate was increased, in the healthy volunteer group. However, in the COPD patient group, the IC decreased with increases in the respiratory rate. Significant correlations were found between all IC parameters and the severity of COPD. A significant negative correlation was also found between the decreased IC and the 6-minute walking distance. Conclusion These findings suggest that the quantitative assessment of DLH following incremental hyperventilation using the newly developed spirometer may be useful for the assessment of pathophysiological impairment in patients with COPD.


Pigment epithelium-derived factor (PEDF) represses the glucose transporter 1 (GLUT1) mRNA expression and may be a potential therapeutic agent in psoriasis: a case-control and experimental study.
We investigated the whole blood GLUT1 mRNA expression and serum pigment epithelium-derived factor (PEDF), interleukin-6 (IL-6), fetuin-A, and pentraxin-3 (PTX3) levels in psoriatic patients and tested their correlations with the severity of psoriasis using the psoriasis area and severity index (PASI) score. Also, we tested the GLUT1 mRNA expression after an in vitro treatment of human skin fibroblast (HSF) cell lines with PEDF. The case-control part of the study recruited 74 participants (44 psoriatic patients and 30 healthy volunteers). Whole blood GLUT1 mRNA fold changes were estimated by RT-PCR, and serum PEDF, IL-6, fetuin-A, and PTX3 levels were measured by ELISA kits. In the experimental part, the HSF cell lines were treated with different concentrations of PEDF for different times to test its effect on the GLUT1 mRNA expression. The whole blood GLUT 1 expression significantly increased in psoriatic patients and correlated positively with serum IL-6, fetuin-A, PTX3 levels and with the severity of psoriasis while negatively with serum PEDF levels. The PEDF-treated HSF cell lines showed a time- and dose-dependent decline in the GLUT 1 mRNA expression. The whole blood GLUT 1 mRNA is a non-invasive biomarker that is associated with the severity of psoriasis. PEDF represses GLUT 1 expression and may be a potential therapeutic agent in psoriasis.Trial registration: ClinicalTrials.gov Identifier: NCT04242082.


The effect of health system factors on outcomes and costs after bariatric surgery in a universal healthcare system: a national cohort study of bariatric surgery in Canada.
Previous data demonstrate that patients who receive bariatric surgery at a Center of Excellence are different than those who receive care at non-accredited centers. Canada provides a unique opportunity to naturally exclude confounders such as insurance status, hospital ownership, and lack of access on comparisons between hospitals and surgeons in bariatric surgery outcomes. The objective of this study was to determine the effect of hospital accreditation and other health system factors on all-cause morbidity after bariatric surgery in Canada. This was a population-based study of all patients aged ≥18 who received a bariatric procedure in Canada (excluding Quebec) from April 2008 until March 2015. The main outcomes for this study were all-cause morbidity and costs during the index admission. All-cause morbidity included any documented complication which extended length of stay by 24 h or required reoperation. Risk-adjusted hierarchical regression models were used to determine predictors of morbidity and cost. Overall, 18,398 patients were identified and the all-cause morbidity rate was 10.1%. Surgeon volume and teaching hospitals were both found to significantly decrease the odds of all-cause morbidity. Specifically, for each increase in 25 bariatric cases per year, the odds of all-cause morbidity was 0.94 times lower (95% CI 0.87-1.00, p = 0.03). Teaching hospitals conferred a 0.75 lower odds of all-cause morbidity (95% CI 0.58-0.95, p < 0.001). Importantly, formal accreditation was not associated with a decrease in all-cause morbidity within a universal healthcare system. No health system factors were associated with significant cost differences. This national cohort study found that surgeon volume and teaching hospitals predicted lower all-cause morbidity after surgery while hospital accreditation was not a significant factor.


Sensitivity of broiler starters to three doses of an enzyme cocktail in maize-based diets.
1. The aim of the present study was to investigate the effect of an enzyme cocktail composed of xylanase, amylase and protease on the performance and nutrient utilisation of broiler starters fed on a maize-based diet. A maize/soy-based control diet was formulated to be marginal in apparent metabolisable energy (AME) and amino acids and this diet was fed without or with two concentrations (250 and 500 g/tonne) of the exogenous enzyme cocktail. 2. Growth performance was measured over a 21-d period after which ileal contents were collected for measurement of digestible energy, nitrogen and dry matter. Excreta were collected from d 17 to 20 post-hatch and used to determine the AME, and retention of nitrogen and dry matter. 3. Supplementation of the control diet with 250 and 500 g/tonne of the enzyme cocktail resulted in enhanced performance of the chicks (1.4 and 8.3%, respectively, for weight gain and 1.2 and 2.2%, respectively, for feed per gain), but the improvements were significant (P < 0.05) only at 500 g/tonne. 4. Addition of both 250 and 500 g/tonne improved AME, nitrogen-corrected AME and dry matter retention compared with the control though the improvements were greater with the higher dose. These effects were also reflected in the apparent ileal digestibility coefficients of dry matter, nitrogen and energy, with 500 g/tonne of the enzyme cocktail improving ileal digestible energy by 3.4%. 5. These results demonstrate that a cocktail of exogenous enzymes containing xylanase, amylase and protease is effective in improving the performance of broiler chicks fed on a maize/soybean-meal-based diet. However, these benefits may be dose-dependent and so an economic analysis involving ingredient and enzyme pricing and the relative performance and digestibility enhancements could allow the end user to select the most economical dose to maximise return on investment.


Fuzzy support vector machines.
A support vector machine (SVM) learns the decision surface from two distinct classes of the input points. In many applications, each input point may not be fully assigned to one of these two classes. In this paper, we apply a fuzzy membership to each input point and reformulate the SVMs such that different input points can make different contributions to the learning of decision surface. We call the proposed method fuzzy SVMs (FSVMs).


Amniotic fluid soluble fas levels in intra-amniotic infection.
Membrane Fas can induce apoptosis in sensitive cells. It has been reported that soluble Fas (sFas) is elevated in septicemia. We examined amniotic fluid (AF) sFas levels in patients with and without intra-amniotic infection. Forty-two AF specimens were studied. Intra-amniotic infection was defined as the presence of a positive AF culture. Twenty-one specimens were from patients with intra-amniotic infection and 21 were from patients without intra-ammotic infection. Amniotic fluid sFas was determined by an enzyme immunoassay and normalized by AF creatinine levels. The Mann-Whitney U test, contingency table method, and Spearman's rank correlation test were used for statistical analyses. Data were expressed as median with ranges. There were no significant differences in maternal age, gestational age, parity, and race between the groups. The median AF sFas was significantly higher with intra-amniotic infection than without it (5.07 U/mL, range 0.32-13. 25 compared with 1.95 U/mL, range 0.01-5.35; P =.004). After normalizing to AF creatinine, infected fluids also had significantly higher median sFas/creatinine than uninfected amniotic fluids (289.1 U/mg creatinine, range 16.6-920.5 compared with 126.8 U/mg creatinine, range 0.5-546.2; P =.01). Amniotic fluid sFas and sFas/creatinine were positively correlated with AF leukocytes and negatively correlated with AF glucose. Elevated AF sFas is associated with intra-amniotic infection. High production of AF sFas in intra-amniotic infection may play a role in the inhibition of apoptosis of AF leukocytes, leading to the persistence of inflammation.


[Amenorrhoea after oral contraceptives].
Eleven women with amenorrhoea after taking oral contraceptives were studied. A clomiphene stimulation test was performed in ten, with six also having an LH-RH stimulation test. In most of them there was no reaction or a severely impaired response to both clomiphene and LH-RH, but bleeding episodes could be provoked in most women by continuing clomiphene treatment, and some of these ovulated when HCG was added to the therapeutic scheme. A possible relationship between preexisting psychosomatic disorders and the genesis of postcontraceptive amenorrhoea is discussed.


Dynamic characteristics of groups and individuals that amplify adherence to perceived drinking norms in college club sport teams: A longitudinal multilevel investigation.
Social norms positively predict college students' alcohol use, but it is critical to explore heterogeneity in these patterns to identify which students are most susceptible to normative influences. The current study explored the nature of drinking norms within college student peer sport clubs. We examined the association between self-reported alcohol use (i.e., number of drinks in a typical week) and perceived descriptive/injunctive norms as an indicator of norm adherence and then tested moderating effects of social constructs related to the group: Social identification with one's team, along with social network-derived indices of indegree centrality and network density. We sampled members of 35 intact college club sport teams at 3 timepoints across the school year (N = 1,054; 61% female). Multilevel modeling was employed to estimate moderating effects at within-person, between-person, and between-groups levels. Initial analyses revealed that perceived group norms predicted self-reported alcohol use, and that teams approached consensus on the groups' drinking norms over time. Several significant time-varying moderation patterns were uncovered. At timepoints when students identified more strongly with their team (relative to person-mean levels), they more readily adhered to perceived descriptive and injunctive team drinking norms. Students also adhered more closely to these perceived team drinking norms at timepoints when students were nominated as having relatively lower indegree centrality. Cross-level interactions revealed that neither network density nor team sex moderated these associations. Taken together, the current findings advance our understanding of group processes that may produce more salient social influences on students' alcohol use behaviors within proximal peer groups. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Overcoming obstacles in the implementation of factorial design for assay optimization.
Factorial experimental design (FED) is a powerful approach for efficient optimization of robust in vitro assays-it enables cost and time savings while also improving the quality of assays. Although it is a well-known technique, there can be considerable barriers to overcome to fully exploit it within an industrial or academic organization. The article describes a tactical roll out of FED to a scientist group through: training which demystifies the technical components and concentrates on principles and examples; a user-friendly Excel-based tool for deconvoluting plate data; output which focuses on graphical display of data over complex statistics. The use of FED historically has generally been in conjunction with automated technology; however we have demonstrated a much broader impact of FED on the assay development process. The standardized approaches we have rolled out have helped to integrate FED as a fundamental part of assay development best practice because it can be used independently of the automation and vendor-supplied software. The techniques are applicable to different types of assay, both enzyme and cell, and can be used flexibly in manual and automated processes. This article describes the application of FED for a cellular assay. The challenges of selling FED concepts and rolling out to a wide bioscience community together with recommendations for good working practices and effective implementation are discussed. The accessible nature of these approaches means FED can be used by industrial as well as academic users.


What Results Should Be Returned from Opportunistic Screening in Translational Research?
Increasingly, patients without clinical indications are undergoing genomic tests. The purpose of this study was to assess their appreciation and comprehension of their test results and their clinicians' reactions. We conducted 675 surveys with participants from the Vanderbilt Electronic Medical Records and Genomics (eMERGE) cohort. We interviewed 36 participants: 19 had received positive results, and 17 were self-identified racial minorities. Eleven clinicians who had patients who had participated in eMERGE were interviewed. A further 21 of these clinicians completed surveys. Participants spontaneously admitted to understanding little or none of the information returned to them from the eMERGE study. However, they simultaneously said that they generally found testing to be "helpful," even when it did not inform their health care. Primary care physicians expressed discomfort in being asked to interpret the results for their patients and described it as an undue burden. Providing genetic testing to otherwise healthy patients raises a number of ethical issues that warrant serious consideration. Although our participants were enthusiastic about enrolling and receiving their results, they express a limited understanding of what the results mean for their health care. This fact, coupled the clinicians' concern, urges greater caution when educating and enrolling participants in clinically non-indicated testing.


Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis.
Methylosome protein 50 (MEP50) is a component of methylosome where MEP50 binds protein substrates and activates the oncogenic protein arginine methyl transferase 5 (PRMT5). MEP50 is also a coactivator for androgen receptor (AR) and estrogen receptor (ER), and transforms cells in the presence of androgen or estrogen. To extend the understanding of how MEP50 transforms cells, we investigated whether MEP50 could transform cells independent of AR and ER, and clarified whether PRMT5 could contribute to the MEP50-caused tumor formation. Microarray and Western blot analyses revealed the association of MEP50 with many human cancers including lung cancer. Knockdown of MEP50 retarded cell growth and migration in selected lung cancer cell lines, which expressed very low level of AR and ER and were insensitive to inhibitors of AR and ER. Moreover, overexpression of Myc-MEP50 enhanced cell transforming activities of 293T cells which are known lack of expression of AR and ER. Mechanistic analyses showed that MEP50 controlled G2 progression, upregulated cyclin-dependent kinase 1(CDK1)/cyclin B1, and activated the survival cascade Phosphoinositide 3-kinase (PI3K)/AKT. MEP50 promoted cell migration, and activated the cell migration pathways such as Ras-related C3 botulinum toxin substrate 1 (Rac1)/vasodilator-stimulated phosphoprotein (VASP), and forkhead box protein A2 (FOXA2)/slug/cadherin cascades. Further analyses revealed that MEP50 activated the survival factor PI3K through PRMT5-catalyzed dimethylation of PI3K. Collectively, it is concluded that MEP50 can transform cells independent of AR and ER, and PRMT5 has partial contribution to that process.


Insights on decomposition process of c-C4F8 and c-C4F8/N2 mixture as substitutes for SF6.
In recent years, many scholars have carried out studies on c-C4F8 and its gas mixture and found it has potential to be used as an environment-friendly insulating medium to replace SF6 in medium-voltage equipment. In this paper, the c-C4F8 and c-C4F8/N2 gas mixture models were built to study its decomposition process by the combination of reactive molecular dynamics method and density functional theory. The yield of the main decomposition products, the reaction pathways and enthalpy under different temperatures were explored. It was found that the decomposition of c-C4F8/N2 mainly produces CF2, F, CF3, CF, C, CF4 and C2F4. c-C4F8 can decompose to C2F4 by absorbing 43.28 kcal/mol, which is the main decomposition path and this process easily occurs under high temperature. There is a dynamic equilibrium process among the various produced radicals, which ensures the insulation performance of system to a certain extent. The decomposition performance of c-C4F8/N2 mixture is better than that of pure c-C4F8 at the same temperature. Relevant results provide guidance for engineering application of the c-C4F8/N2 gas mixture.


The financial impact of robotic technology for partial and radical nephrectomy.
We sought to evaluate the financial impact of robotic technology for partial nephrectomy (PN) and radical nephrectomy (RN) in the state of Maryland. The Maryland Health Services Cost Review Commission (HSCRC) documents all acute care hospital charges data. This database was queried for patients who underwent laparoscopic or robot-assisted RN and PN from 2008 to 2012. Total hospital charge, subcharge, and length of stay (LOS) were analyzed separately for RN and PN. Overall, 2834 patients were identified. Of those, 282 were laparoscopic PN (LPN), 1078 robot-assisted PN (RPN), 1098 laparoscopic RN (LRN), and 376 robot-assisted RN (RRN). For PN, the total hospital charge was $19,062 for LPN and $18,255 for RPN (P=0.138), with a charge savings of $807 per case in favor of robotics. For RN, the total hospital charge was $23,391 for RRN and $18,280 for LRN (P=0.004), with a charge premium of $5111 for robotic cases. LOS was shorter for RPN compared with LPN (2.51 vs 2.99 days, P<0.0001) and for RRN compared with LRN (3.52 vs 3.98, P=0.0498). RPN is associated with lower hospital charges than LPN, while RRN is associated with higher hospital charges than LRN. Savings for RPN are driven by decreased room and board charge, while the premium for RRN is driven by higher operating room and supply charges. Because RRN use is increasing, the financial implications of RRN use for routine cases warrants further study.


Electro-cortical manifestations of common vs. proper name processing during reading.
The main purpose of the present study was to investigate how proper and common nouns are represented in the brain independent of memory retrieval processes. Participants were instructed to perform a lexical decision task while dense-array EEG was continuously recorded. Both ERP components (namely N400 and P300) and swLORETA suggested that proper name processing engaged a more widespread neural network and required more cognitive resources than common noun processing. Overall, our results come down in favor of the hypothesis that specific effects of proper vs. common noun processing exist, and they suggest a possible neuro-functional segregation of proper vs. common noun processing. The difference in proper and common noun processing seems to emerge at the level of storage or representation of lexical knowledge, and it may crucially depend on their semantic characteristics.


Preparing student nurses to be healthy role models: A qualitative study.
There are national and international expectations for nurses to be healthy role models. This study aimed to investigate student nurses', nurse educators' and registered nurses' experiences and perceptions about being healthy role models and to explore whether nurse education prepares students to become healthy role models. The study used an exploratory qualitative design and was based in the south of England. Participants (n = 39) included student nurses, nurse lecturers and registered nurses. Data collection was conducted through focus groups and data were analysed using thematic analysis. The themes highlighted nurses' understanding of the key features of being a healthy role model, and perceptions that working as nurses does not support individuals to be healthy. Participants had varied views about whether they should be healthy role models or mirror society and share the same struggles with their health. Students and registered nurses reported inadequate understanding of health promotion and that there was a lack of healthy lifestyle content within undergraduate nurse education. Participants also considered that role modelling healthy behaviour would not in itself influence behaviour change. In conclusion, there needs to be preparation and support for student nurses to be healthy role models from the outset of nurse education.


Natural Antimicrobial Nano Composite Fibres Manufactured from a Combination of Alginate and Oregano Essential Oil.
Alginate is a linear biodegradable polysaccharide polymer, which is bio-renewable and widely used for various biomedical applications. For the next generation of medical textiles, alginate nanofibres are desirable for their use in wound dressings that are biocompatible, sustainable, and abundantly available. This study has developed a unique manufacturing process for producing alginate nanofibres with exceptional antimicrobial properties of oregano essential oil (OEO) as a natural antimicrobial agent. OEO with varying degrees of concentration was incorporated in an aqueous alginate solution. Appropriate materials and electrospinning process parameter selection allowed us to manufacture alginate fibres with a range of diameters between 38 and 105 nm. A unique crosslinking process for alginate nanofibres using extended water soaking was developed. Mechanical characterisation using micro-mechanical testing of nonwoven electrospun alginate/oregano composite nanofibres revealed that it was durable. An extensive antimicrobial study was carried out on alginate/oregano composite nanofibres using a range of Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA) and Listeria monocytogenes) and Gram-negative bacteria (Klebsiella pneumoniae and Salmonella enterica), which are common wound and food pathogens. The results indicated that increasing the concentration of OEO from 2 to 3 wt % showed improved antimicrobial activity against all pathogens, and activity was significantly improved against MRSA compared to a non-alginate-based control disk containing OEO. Therefore, our research suggests that all-natural alginate/oregano nanofibre composite textiles offer a new generation of medical textiles for advanced wound dressing technology as well as for food packaging applications.


Knee strength and knee adduction moments following arthroscopic partial meniscectomy.
This study investigated the relationship between muscular strength about the knee and knee joint moments during gait in patients who had undergone arthroscopic partial meniscectomy (APM). One hundred and two APM patients and 42 age-matched nonoperated controls underwent strength testing and three-dimensional gait analysis. Patients were divided into weak and normal subgroups and compared with controls for spatiotemporal, kinematic, and kinetic gait parameters. Spatiotemporal parameters, kinematics, and sagittal plane kinetics were similar between APM patients and controls. The APM group displayed weaker concentric knee extension and flexion strength compared with controls. The weak APM subgroup had an increased average and peak knee adduction moments over stance compared with the APM subgroup with normal strength levels and controls. The normal strength APM subgroup had a larger peak knee adduction moment in early stance compared with controls. Achieving normal lower limb muscle strength following APM appears important to resume normal frontal plane loading of the knee while walking.


Mutational definition of the human immunodeficiency virus type 1 Rev activation domain.
Replication of human immunodeficiency virus type 1 requires the functional expression of the virally encoded Rev protein. The binding of this nuclear trans activator to its viral target sequence, the Rev-response element, induces the cytoplasmic expression of unspliced viral mRNAs. Mutation of the activation domain of Rev generates inactive proteins with normal RNA binding capabilities that inhibit wild-type Rev function in a trans-dominant manner. Here, we report that the activation domain comprises a minimum of nine amino acids, four of which are critically spaced leucines. The preservation of this essential sequence in other primate and nonprimate lentivirus Rev proteins indicates that this leucine-rich motif has been highly conserved during evolution. This conclusion, taken together with the observed permissiveness of a variety of eukaryotic cell types for Rev function, suggests that the target for the activation domain of Rev is likely to be a highly conserved cellular protein(s) intrinsic to nuclear mRNA transport or splicing.


Effect of corn silage hybrid on dry matter yield, nutrient composition, in vitro digestion, intake by dairy heifers, and milk production by dairy cows.
Three corn hybrids, Mycogen TMF94, Cargill F337 (which contains a brown midrib trait), and Pioneer 3861 were compared in a plot trial, an intake trial, and a lactation trial. In the plot trial, the three corn hybrids were planted in replicated 15.2 x 385-m plots. Mycogen TMF94 and Cargill F337 had lower yields of dry matter (DM), higher concentrations of neutral detergent fiber, and higher in vitro true DM disappearance compared with Pioneer 3861. Mycogen TMF94 had a higher yield of DM than Cargill F337 despite having a lower plant population. However, Cargill F337 had a higher in vitro true DM disappearance than Mycogen TMF94. In the intake trial, six individually penned Holstein heifers were blocked and assigned randomly to one of three total mixed rations containing 79% (DM basis) Mycogen TMF94, Cargill F337, or Pioneer 3861 corn silages in replicated 3 x 3 Latin squares. Heifers fed the Pioneer 3861-based TMR had lower DMI than heifers fed Mycogen TMF94 and Cargill F337-based TMR. In the lactation trial, 75 midlactation Holstein cows were blocked and assigned randomly to one of three total mixed rations containing 31% (DM basis) Mycogen TMF94, Cargill F337, or Pioneer 3861 corn silages used in the intake trial. Milk production was highest for cows fed Cargill F337-based total mixed rations. It is concluded from this study that Mycogen TMF94 was higher yielding, but less digestible, and resulted in lower milk production by lactating cows than Cargill F337. In addition, Mycogen TMF94 had higher in vitro true DM disappearance, and similar DM yield and milk production by lactating cows when compared with Pioneer 3861.


Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy.
Hepatocellular cancer (HCC) is a highly treatment-refractory cancer and is also highly resistant to adverse cellular stress. Although cell behavior can be modulated by noncoding RNAs (ncRNA) within extracellular vesicles (EV), the contributions of long noncoding RNAs (lncRNAs) are largely unknown. To this end, the involvement and functional roles of lncRNAs contained within EVs during chemotherapeutic stress in human HCC were determined. Expression profiling identified a subset of lncRNAs that were enriched in tumor cell-derived vesicles released from two different cell lines. Of these, lincRNA-VLDLR (linc-VLDLR) was significantly upregulated in malignant hepatocytes. Exposure of HCC cells to diverse anticancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell-cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, subfamily G member 2), whereas overexpression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an EV-enriched lncRNA that contributes to cellular stress responses. These findings provide new insight into the role of EVs and demonstrate the capacity of lncRNAs to mediate chemotherapeutic stress response in HCC.


A "politically robust" experimental design for public policy evaluation, with application to the Mexican universal health insurance program.
We develop an approach to conducting large-scale randomized public policy experiments intended to be more robust to the political interventions that have ruined some or all parts of many similar previous efforts. Our proposed design is insulated from selection bias in some circumstances even if we lose observations; our inferences can still be unbiased even if politics disrupts any two of the three steps in our analytical procedures; and other empirical checks are available to validate the overall design. We illustrate with a design and empirical validation of an evaluation of the Mexican Seguro Popular de Salud (Universal Health Insurance)program we are conducting. Seguro Popular, which is intended to grow to provide medical care, drugs, preventative services, and financial health protection to the 50 million Mexicans without health insurance, is one of the largest health reforms of any country in the last two decades. The evaluation is also large scale, constituting one of the largest policy experiments to date and what may be the largest randomized health policy experiment ever.


Ubiquitin-specific protease 2 regulates hepatic gluconeogenesis and diurnal glucose metabolism through 11β-hydroxysteroid dehydrogenase 1.
Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral-mediated expression of USP2 in the liver promotes hepatic glucose production and exacerbates glucose intolerance in diet-induced obese mice. In contrast, in vivo RNA interference (RNAi) knockdown of this factor improves systemic glycemic control. USP2 is a target gene of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a coactivator that integrates clock and energy metabolism, and is required for maintaining diurnal glucose homeostasis during restricted feeding. At the mechanistic level, USP2 regulates hepatic glucose metabolism through its induction of 11β-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling in the liver. Pharmacological inhibition and liver-specific RNAi knockdown of HSD1 significantly impair the stimulation of hepatic gluconeogenesis by USP2. Together, these studies delineate a novel pathway that links hormonal and circadian signals to gluconeogenesis and glucose homeostasis.


Toxicological effects of emissions from diesel engines.
The 29 papers at this international symposium demonstrate the success of the past decade's research on diesel exhaust emissions. The observations made in different countries which have utilized biological systems ranging from macromolecules to cells and tissues to populations of animals and people are highly complementary. The findings presented here, combined with estimates of diesel exhaust exposure, provide the basis for development of qualitative and, perhaps semi-quantitative, estimates of cancer risk from exposure to diesel exhaust. In addition, the research reported provides valuable insight into the mechanisms by which inhalation of complex mixtures may cause lung cancer.


Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis.
Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.


Racial, gender, and socioeconomic status bias in senior medical student clinical decision-making: a national survey.
Research suggests stereotyping by clinicians as one contributor to racial and gender-based health disparities. It is necessary to understand the origins of such biases before interventions can be developed to eliminate them. As a first step toward this understanding, we tested for the presence of bias in senior medical students. The purpose of the study was to determine whether bias based on race, gender, or socioeconomic status influenced clinical decision-making among medical students. We surveyed seniors at 84 medical schools, who were required to choose between two clinically equivalent management options for a set of cardiac patient vignettes. We examined variations in student recommendations based on patient race, gender, and socioeconomic status. The study included senior medical students. We investigated the percentage of students selecting cardiac procedural options for vignette patients, analyzed by patient race, gender, and socioeconomic status. Among 4,603 returned surveys, we found no evidence in the overall sample supporting racial or gender bias in student clinical decision-making. Students were slightly more likely to recommend cardiac procedural options for black (43.9 %) vs. white (42 %, p = .03) patients; there was no difference by patient gender. Patient socioeconomic status was the strongest predictor of student recommendations, with patients described as having the highest socioeconomic status most likely to receive procedural care recommendations (50.3 % vs. 43.2 % for those in the lowest socioeconomic status group, p < .001). Analysis by subgroup, however, showed significant regional geographic variation in the influence of patient race and gender on decision-making. Multilevel analysis showed that white female patients were least likely to receive procedural recommendations. In the sample as a whole, we found no evidence of racial or gender bias in student clinical decision-making. However, we did find evidence of bias with regard to the influence of patient socioeconomic status, geographic variations, and the influence of interactions between patient race and gender on student recommendations.


Disturbed meningeal lymphatic function associated with malignancy and progression in patients with intracranial malignant tumors.
Meningeal lymphatic vessels (mLVs) have proven to bear a relationship with tumor immunity and therapeutic efficacy of intracranial malignant tumors in pre-clinical animal studies. We aimed to explore the association between mLV function and intracranial malignant tumors in clinical participants. The participants were allocated to a control group or a group of patients with intracranial tumors. Dynamic enhanced magnetic resonance was used to evaluate the wash-in and wash-out functions of mLVs around the superior sagittal sinus and the sigmoid sinus. A total of 246 individuals were recruited for our study. The area under curve and wash-in rate of mLVs in the intracranial tumor group were higher than in the control group (2,749 vs. 2,110, p < 0.001 and 3.72 vs. 2.87, p < 0.001, respectively). The wash-out ratio of mLVs was lower in the intracranial tumor group than in the control group (0.65 vs. 0.73, p < 0.001). Decreased wash-out of mLVs was associated with tumor progression (β = -0.118; p < 0.001). High-grade glioma and isocitrate dehydrogenase wild type were associated with a lower mLV wash-out function (β = -0.057, p = 0.044 and β = -0.069, p = 0.047, respectively). Intracranial malignant tumors were associated with elevated wash-in function and decreased wash-out function of mLVs. High-grade glioma and isocitrate dehydrogenase wild type were associated with low mLV wash-out function, and long-term decreased mLV wash-out function was a risk factor for tumor progression. There was no funding.


[Amyloidosis induced colonic stricture. The first symptom of myeloma multiplex. A case report].
Systemic amyloidosis often involves the gastrointestinal tract and usually presents as ulceration or polypoid lesions. However, annular stricture of the colon due to amyloidosis is very rare. Amyloidosis develops in appr. 10% of multiple myeloma patients with lambda light chain production, it is usually type AL and not a presenting symptom. A 73-year-old female patient appeared at our hospital with anaemia, abdominal pain and hematochezia. Colonoscopy revealed a circular narrowing of the sigmoid colon suggesting malignancy. The patient underwent sigmoid resection and rectosigmoidal anastomosis was prepared to relieve mechanical obstruction. Surprisingly the histological finding from the resected specimen was amyloidosis. Subcutaneous fat tissue biopsy established the diagnosis of systemic AA amyloidosis. Immunoelectrophoresis revealed an elevated gamma-globulin fraction with IgG lambda monoclonal component, as well as a different lambda light chain. Therefore bone marrow biopsy was carried out which confirmed the diagnosis of multiple myeloma. Our case is a rare example of the extraordinary tumor-mimicking colon amyloidosis that led to the diagnosis of multiple myeloma. Beside haematological treatment, strict follow-up of the colon process and reconsideration of surgical therapy or endoscopic stenting is of great importance.


Multirater Validation of Peripapillary Hyperreflective Ovoid Mass-like Structures (PHOMS).
Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are a new retinal optical coherence tomography (OCT) finding. The Optic Disc Drusen Studies Consortium had made recommendations to distinguish PHOMS from true optic disc drusen (ODD) in 2018. While publications on PHOMS have increased since then, the accuracy of the definition of PHOMS and reliability of detection is unknown. In this multi-rater study, we demonstrate that the 2018 definition of PHOMS resulted in a poor multi-rater kappa of 0.356. We performed a Delphi consensus process to develop a consistent and refined definition of PHOMS with clear principles around the nature of PHOMS and how they differ from normal anatomy. Fifty explanatory teaching slides, provided as supplementary material, allowed our expert group of raters to achieve a good level of agreement (kappa 0.701, 50 OCT scans, 21 raters). We recommend adopting the refined definition for PHOMS.


The adherence of human Fc receptor-bearing lymphocytes to antigen-antibody complexes. II. Morphologic alterations induced by the substrate.
The adhesion of human Fc receptor-bearing lymphocytes to immobilized antigen-antibody complexes is accompanied by marked alterations in cell shape, resulting in flattening of greater than 90% of the adherent cells. In addition, about 65% of the adherent cells become elongated, with distinct uropods being present in about 1/3 of these cells. Scanning electron microscopy demonstrates that most of the surface microvilli are lost, while ruffled membranes and long microextensions are formed during the shape change. Time-lapse cinematography shows that the major shape changes occur within a few minutes after contact with the substrate, and that the adherent cells undergo translational motility. Both flattening and elongation of the adherent cells are inhibited by low temperature, chelating agents, cytochalasin B, and vinblastine, while sodium azide selectively inhibits elongation and uropod formation. It is argued that these morphological changes result from an active response of the cell to the immobilized complexes, and that such alterations may be related mechanistically to the ability of the cells to kill antibody-coated target cells.


Asbestos-related mesothelioma: factors discriminating between pleural and peritoneal sites.
Up to the end of 1980, 144 confirmed cases of mesothelioma were identified among employees of an organisation using asbestos in manufacturing and insulation. The primary site was peritoneal in 74 cases, pleural in 66, and undetermined in four. All employees had been exposed to amphibole asbestos, and evidence from different factories confirmed the predominant role of crocidolite in the production of mesothelioma. The ratio of pleural to peritoneal sites showed a continuous change when related to the year of first exposure, varying from 5:1 pleural to peritoneal before 1921 to 1:3 after 1950. The strong temporal relationship appeared to reflect progressive dust suppression, including the non-fibrous dusts present in insulation materials and perhaps also the degree to which the fibres had been opened. Other predisposing factors were related to the degree of individual exposure, the peritoneal site being associated preferentially with longer and heavier exposures.


The effect of using an audience response system on learning, motivation and information retention in the orthodontic teaching of undergraduate dental students: a cross-over trial.
New methods of teaching and learning are constantly being sought in the adult learning environment. Audience Response Systems (ARS) have been used in many different learning environments, especially in the field of medical education. The objective of this investigation was to ascertain the effect of ARS use in undergraduate teaching in a UK dental school. A cross-over clustered randomized educational trial. Leeds Dental Institute. Year 4 undergraduate dental students in orthodontics. Students at Leeds Dental Institute were taught two different topics within the curriculum to test the use of ARS in a cross-over trial. A questionnaire was delivered to the test (ARS) and control (non-ARS) groups. The response rate to the questionnaires was 89·5% (test group) and 82·9% (control group). The ARS enabled students to perform better as shown by knowledge retention (P = 0·013). Students found the seminar more interesting (P = 0·013), easier to concentrate (P = 0·025) and easier to participate in (P = 0·020) when ARS was used. When ARS was used, students were more able to answer questions (P<0·0001), were more likely to prepare for the seminar (P<0·0001) and significantly preferred using ARS (P<0·0001). ARS was found to significantly improve student concentration and participation in small group seminar teaching and significantly improved knowledge retention. ARS may be useful in facilitating orthodontic teaching in the future.


Bromotryptamine and Bromotyramine Derivatives from the Tropical Southwestern Pacific Sponge Narrabeena nigra.
So far, the Futuna Islands located in the Central Indo-Pacific Ocean have not been inventoried for their diversity in marine sponges and associated chemical diversity. As part of the Tara Pacific expedition, the first chemical investigation of the sponge Narrabeena nigra collected around the Futuna Islands yielded 18 brominated alkaloids: seven new bromotryptamine derivatives 1-7 and one new bromotyramine derivative 8 together with 10 known metabolites of both families 9-18. Their structures were deduced from extensive analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) data. In silico metabolite anticipation using the online tool MetWork revealed the presence of a key and minor biosynthetic intermediates. These 18 compounds showed almost no cytotoxic effect up to 10 µM on human neuroblastoma SH-SY5Y and microglia BV2 cells, and some of them exhibited an interesting neuroprotective activity by reducing oxidative damage.


Dramatic pressure-driven enhancement of bulk skyrmion stability.
The recent discovery of magnetic skyrmion lattices initiated a surge of interest in the scientific community. Several novel phenomena have been shown to emerge from the interaction of conducting electrons with the skyrmion lattice, such as a topological Hall-effect and a spin-transfer torque at ultra-low current densities. In the insulating compound Cu2OSeO3, magneto-electric coupling enables control of the skyrmion lattice via electric fields, promising a dissipation-less route towards novel spintronic devices. One of the outstanding fundamental issues is related to the thermodynamic stability of the skyrmion lattice. To date, the skyrmion lattice in bulk materials has been found only in a narrow temperature region just below the order-disorder transition. If this narrow stability is unavoidable, it would severely limit applications. Here we present the discovery that applying just moderate pressure on Cu2OSeO3 substantially increases the absolute size of the skyrmion pocket. This insight demonstrates directly that tuning the electronic structure can lead to a significant enhancement of the skyrmion lattice stability. We interpret the discovery by extending the previously employed Ginzburg-Landau approach and conclude that change in the anisotropy is the main driver for control of the size of the skyrmion pocket.


Incest, incestuous fantasy & indecency. A clinical catchment area study of normal-weight bulimic women.
This systematic study of 112 consecutive referrals of normal-weight bulimic women from a circumscribed urban catchment area found that eight patients (7%) reported sexual abuse involving physical contact. Four (3.6%) of these described incest, but only in two cases (1.8%) did the incest occur in childhood. Just over 5% of the sample reported unlawful sexual intercourse in childhood or gross indecency. Eighteen additional patients reported incestuous fantasies and two of these were partly acted out. The study indicates that incest and sexual abuse reported by bulimics is usually in those multi-impulsive patients who also abuse alcohol or drugs as well as food. The reported prevalences of incest and indecency in normal-weight bulimic women are only slightly higher than figures derived from general population surveys.


Bladder cancer.
Bladder cancer is a highly prevalent disease and is associated with substantial morbidity, mortality and cost. Environmental or occupational exposures to carcinogens, especially tobacco, are the main risk factors for bladder cancer. Most bladder cancers are diagnosed after patients present with macroscopic haematuria, and cases are confirmed after transurethral resection of bladder tumour (TURBT), which also serves as the first stage of treatment. Bladder cancer develops via two distinct pathways, giving rise to non-muscle-invasive papillary tumours and non-papillary (solid) muscle-invasive tumours. The two subtypes have unique pathological features and different molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers of muscle-invasive bladder cancer (MIBC) as well as subtypes of MIBC with distinct characteristics and therapeutic responses. For non-muscle-invasive bladder cancer (NMIBC), intravesical therapies (primarily Bacillus Calmette-Guérin (BCG)) with maintenance are the main treatments to prevent recurrence and progression after initial TURBT; additional therapies are needed for those who do not respond to BCG. For localized MIBC, optimizing care and reducing morbidity following cystectomy are important goals. In metastatic disease, advances in our genetic understanding of bladder cancer and in immunotherapy are being translated into new therapies.


Melanomacrophage Centers As a Histological Indicator of Immune Function in Fish and Other Poikilotherms.
Melanomacrophage centers (MMCs) are aggregates of highly pigmented phagocytes found primarily in the head kidney and spleen, and occasionally the liver of many vertebrates. Preliminary histological analyses suggested that MMCs are structurally similar to the mammalian germinal center (GC), leading to the hypothesis that the MMC plays a role in the humoral adaptive immune response. For this reason, MMCs are frequently described in the literature as "primitive GCs" or the "evolutionary precursors" to the mammalian GC. However, we argue that this designation may be premature, having been pieced together from mainly descriptive studies in numerous distinct species. This review provides a comprehensive overview of the MMC literature, including a phylogenetic analysis of MMC distribution across vertebrate species. Here, we discuss the current understanding of the MMCs function in immunity and lingering questions. We suggest additional experiments needed to confirm that MMCs serve a GC-like role in fish immunity. Finally, we address the utility of the MMC as a broadly applicable histological indicator of the fish (as well as amphibian and reptilian) immune response in both laboratory and wild populations of both model and non-model vertebrates. We highlight the factors (sex, pollution exposure, stress, stocking density, etc.) that should be considered when using MMCs to study immunity in non-model vertebrates in wild populations.


Immunological characterization of a major transformation-sensitive fibroblast cell surface glycoprotein. Localization, redistribution, and role in cell shape.
The major cell surface glycoprotein of chick embryo fibroblasts, cellular fibronectin (formerly known as CSP or LETS protein), was purified and used to produce monospecific antisera. After affinity purification, the anti-fibronectin was used to investigate fibronectin's localization, its transfer from intracellular to extracellular pools, its antibody-induced redistribution on the cell surface, and its role in cell shape. Anti-fibronectin localizes to extracellular fibrils located under and between sparse cells, and to a dense matrix that surrounds confluent cells. Cellular fibronectin is also present in granular intracytoplasmic structures containing newly synthesized fibronectin before secretion. This intracellular staining disappears 2 h after treatment with cycloheximide or puromycin, and returns after removal of these protein synthesis inhibitors. In pulse-chase experiments using cycloheximide, fibronectin was sequentially transferred from the intracellular to the fibrillar extracellular forms. Transformation of chick fibroblasts results in decreases in both extracellular and intracellular fibronectin, and in altered cell shape. Treatment of untransformed chick fibroblasts with anti-fibronectin results in rapid (30 min) alteration to a rounder cell shape resembling that of many transformed cells. These rapid shape changes are followed by a slow, antibody-induced redistribution of fibronectin to supranuclear caplike structures. This "capping" is inhibited by metabolic inhibitors. Reconstitution of cell surface fibronectin onto transformed cells restores a more normal fibroblastic phenotype. The reconstituted fibronectin on these cells organizes into fibrillar patterns similar to those of untransformed cells. As with untransformed cells, treatment of these reconstituted cells with anti-fibronectin also results in cell rounding and "capping" of fibronectin.


Optimizing the Cell-Nanostructure Interface: Nanoconcave/Nanoconvex Device for Intracellular Recording of Cardiomyocytes.
Nanostructures are powerful components for the development of high-performance nanodevices. Revealing and understanding the cell-nanostructure interface are essential for improving and guiding nanodevice design for investigations of cell physiology. For intracellular electrophysiological detection, the cell-nanostructure interface significantly affects the quality of recorded intracellular action potentials and the application of nanodevices in cardiology research and pharmacological screening. Most of the current investigations of biointerfaces focus on nanovertical structures, and few involve nanoconcave structures. Here, we design both nanoconvex and nanoconcave devices to perform intracellular electrophysiological recordings. The amplitude, signal-to-noise ratio, duration, and repeatability of the recorded intracellular electrophysiological signals provide a multifaceted characterization of the cell-nanostructure interface. We demonstrate that devices based on both convex and concave nanostructures can create tight coupling, which facilitates high-quality and stable intracellular recordings and paves the way for precise electrophysiological study.


Longitudinal Research on Aging Drivers (LongROAD): study design and methods.
As an important indicator of mobility, driving confers a host of social and health benefits to older adults. Despite the importance of safe mobility as the population ages, longitudinal data are lacking about the natural history and determinants of driving safety in older adults. The Longitudinal Research on Aging Drivers (LongROAD) project is a multisite prospective cohort study designed to generate empirical data for understanding the role of medical, behavioral, environmental and technological factors in driving safety during the process of aging. A total of 2990 active drivers aged 65-79 years at baseline have been recruited through primary care clinics or health care systems in five study sites located in California, Colorado, Maryland, Michigan, and New York. Consented participants were assessed at baseline with standardized research protocols and instruments, including vehicle inspection, functional performance tests, and "brown-bag review" of medications. The primary vehicle of each participant was instrumented with a small data collection device that records detailed driving data whenever the vehicle is operating and detects when a participant is driving. Annual follow-up is being conducted for up to three years with a telephone questionnaire at 12 and 36 months and in-person assessment at 24 months. Medical records are reviewed annually to collect information on clinical diagnoses and healthcare utilization. Driving records, including crashes and violations, are collected annually from state motor vehicle departments. Pilot testing was conducted on 56 volunteers during March-May 2015. Recruitment and enrollment were completed between July 2015 and March 2017. Results of the LongROAD project will generate much-needed evidence for formulating public policy and developing intervention programs to maintain safe mobility while ensuring well-being for older adults.


Elucidation of the 14-3-3ζ interactome reveals critical roles of RNA-splicing factors during adipogenesis.
Adipogenesis involves a complex signaling network requiring strict temporal and spatial organization of effector molecules. Molecular scaffolds, such as 14-3-3 proteins, facilitate such organization, and we have previously identified 14-3-3ζ as an essential scaffold in adipocyte differentiation. The interactome of 14-3-3ζ is large and diverse, and it is possible that novel adipogenic factors may be present within it, but this possibility has not yet been tested. Herein, we generated mouse embryonic fibroblasts from mice overexpressing a tandem affinity purification (TAP) epitope-tagged 14-3-3ζ molecule. After inducing adipogenesis, TAP-14-3-3ζ complexes were purified, followed by MS analysis to determine the 14-3-3ζ interactome. We observed more than 100 proteins that were unique to adipocyte differentiation, 56 of which were novel interacting partners. Among these, we were able to identify previously established regulators of adipogenesis (i.e. Ptrf/Cavin1) within the 14-3-3ζ interactome, confirming the utility of this approach to detect adipogenic factors. We found that proteins related to RNA metabolism, processing, and splicing were enriched in the interactome. Analysis of transcriptomic data revealed that 14-3-3ζ depletion in 3T3-L1 cells affected alternative splicing of mRNA during adipocyte differentiation. siRNA-mediated depletion of RNA-splicing factors within the 14-3-3ζ interactome, that is, of Hnrpf, Hnrpk, Ddx6, and Sfpq, revealed that they have essential roles in adipogenesis and in the alternative splicing of Pparg and the adipogenesis-associated gene Lpin1 In summary, we have identified novel adipogenic factors within the 14-3-3ζ interactome. Further characterization of additional proteins within the 14-3-3ζ interactome may help identify novel targets to block obesity-associated expansion of adipose tissues.