Practices and perspectives on advanced diagnostic and interventional bronchoscopy among pediatric pulmonologists in the United States.

INTRODUCTION: Advanced diagnostic bronchoscopy includes endobronchial ultrasound (EBUS) guided transbronchial lung and lymph node biopsies, CT navigation and robotic bronchoscopy. Interventional bronchoscopy refers to procedures performed for therapeutic purposes such as balloon dilation of the airway, tissue debulking, cryotherapy, removal of foreign bodies and insertion of endobronchial valves [1]. For adult patients, these procedures are standard of care [2, 3]. Despite a lack of formalized training, there are numerous case reports and case series describing the use of advanced diagnostic and interventional bronchoscopy techniques in children. The safety and feasibility of EBUS-TBNA, cryotherapy techniques, endobronchial valves among other techniques have been demonstrated in these publications [1, 4-9]. METHODS: We sought to better understand the current practices and perspectives on interventional and advanced bronchoscopy among pediatric pulmonologists through surveys sent to pediatric teaching hospitals across the United States. RESULTS: We received 43 responses representing 28 programs from 25 states. The highest bronchoscopy procedure volume occurred in the 0-5 years age group. Among our respondents, 31% self-identified as a pediatric interventional/advanced bronchoscopist. 79% believe that advanced and interventional training is feasible in pediatric pulmonology and 77% believe it should be offered to pediatric pulmonary fellows. DISCUSSION: This is the first study to characterize current practices and perspectives regarding advanced diagnostic and interventional bronchoscopy procedures among pediatric pulmonologists in the United States. Pediatric interventional pulmonology (IP) is in its infancy and its beginnings echo those of the adult IP where only certain centers were performing these procedures.

Eye Tracking Effort Expenditure and Autonomic Arousal to Social and Circumscribed Interest Stimuli in Autism Spectrum Disorder.

The social communicative deficits and repetitive behaviours seen in Autism Spectrum Disorder (ASD) may be affected by altered stimulus salience and reward attribution. The present study used eye tracking and a behavioural measure to index effort expenditure, arousal, and attention, during viewing of images depicting social scenes and subject-specific circumscribed interests in a group of 10 adults with ASD (mean age 25.4 years) and 19 typically-developing controls (mean age 20.7 years) Split-plot and one-way repeated measures ANOVAs were used to explore results. A significant difference between the ASD and control group was found in the amount of effort expended to view social and circumscribed images. The ASD group also displayed significant differences in pupillary response to social and circumscribed images, indicative of changes in autonomic arousal. Overall, the results support the social motivation hypothesis in ASD (Chevallier et al., Trends Cogn Sci 16(4):231-239, 2012) and suggest a role for autonomic arousal in the ASD symptom dyad.

Anomalous left coronary artery from the pulmonary artery (ALCAPA) diagnosed in adulthood: Varied clinical presentation, therapeutic approach and outcome.

INTRODUCTION: The diagnosis of ALCAPA syndrome is sporadic in adulthood, of the limited cases in the literature most are incidental or without symptoms. There is a broad spectrum of clinical manifestations of ALCAPA syndrome however, including sudden cardiac death. CASES: We present herewith a series of 12 consecutive patients with ALCAPA, all diagnosed in adulthood (between 18 and 73 years of age). Five patients developed symptoms (breathlessness) after the fourth decade of life, 3 were undiagnosed despite a history of previous mitral valve repair, one presented with heart failure, one with resuscitated cardiac arrest, whereas two patients were asymptomatic. We review in this paper, the clinical history, diagnostic approach and therapeutic choices of ALCAPA syndrome. CONCLUSION: ALCAPA syndrome is not confined to childhood, late diagnosis in adulthood has a varied clinical presentation. ALCAPA syndrome should be particularly considered as a potential, albeit uncommon cause of mitral regurgitation and/or dilated cardiomyopathy.

Reliability of the sliding scale for collecting affective responses to words.

Warriner, Shore, Schmidt, Imbault, and Kuperman, Canadian Journal of Experimental Psychology, 71; 71-88 (2017) have recently proposed a slider task in which participants move a manikin on a computer screen toward or further away from a word, and the distance (in pixels) is a measure of the word's valence. Warriner, Shore, Schmidt, Imbault, and Kuperman, Canadian Journal of Experimental Psychology, 71; 71-88 (2017) showed this task to be more valid than the widely used rating task, but they did not examine the reliability of the new methodology. In this study we investigated multiple aspects of this task's reliability. In Experiment 1 (Exps. 1.1-1.6), we showed that the sliding scale has high split-half reliability (r = .868 to .931). In Experiment 2, we also showed that the slider task elicits consistent repeated responses both within a single session (Exp. 2: r = .804) and across two sessions separated by one week (Exp. 3: r = .754). Overall, the slider task, in addition to having high validity, is highly reliable.

A single baseline ultrasound assessment of fibroid presence and size is strongly predictive of future uterine procedure: 8-year follow-up of randomly sampled premenopausal women aged 35-49 years.

STUDY QUESTION: How well can a single baseline ultrasound assessment of fibroid burden (presence or absence of fibroids and size of largest, if present) predict future probability of having a major uterine procedure? SUMMARY ANSWER: During an 8-year follow-up period, the risk of having a major uterine procedure was 2% for those without fibroids and increased with fibroid size for those with fibroids, reaching 47% for those with fibroids ≥ 4 cm in diameter at baseline. WHAT IS KNOWN ALREADY: Uterine fibroids are a leading indication for hysterectomy. However, when fibroids are found, there are few available data to help clinicians advise patients about disease progression. STUDY DESIGN, SIZE, DURATION: Women who were 35-49 years old were randomly selected from the membership of a large urban health plan; 80% of those determined to be eligible were enrolled and screened with ultrasound for fibroids ≥ 0.5 cm in diameter. African-American and white premenopausal participants who responded to at least one follow-up interview (N = 964, 85% of those eligible) constituted the study cohort. During follow-up (5822 person-years), participants self-reported any major uterine procedure (67% hysterectomies). Life-table analyses and Cox regression (with censoring for menopause) were used to estimate the risk of having a uterine procedure for women with no fibroids, small (<2 cm in diameter), medium (2-3.9 cm), and large fibroids (≥ 4 cm). Differences between African-American and white women, importance of a clinical diagnosis of fibroids prior to study enrollment, and the impact of submucosal fibroids on risk were investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS: There was a greater loss to follow-up for African-Americans than whites (19 versus 11%). For those with follow-up data, 64% had fibroids at baseline, 33% of whom had had a prior diagnosis. Of those with fibroids, 27% had small fibroids (<2 cm in diameter), 46% had medium (largest fibroid 2-3.9 cm in diameter), and 27% had large fibroids (largest ≥ 4 cm in diameter). Twenty-one percent had at least one submucosal fibroid. MAIN RESULTS AND THE ROLE OF CHANCE: Major uterine procedures were reported by 115 women during follow-up. The estimated risk of having a procedure in any given year of follow-up for those with fibroids compared with those without fibroids increased markedly with fibroid-size category (from 4-fold, confidence interval (CI) (1.4-11.1) for the small fibroids to 10-fold, CI (4.4-24.8) for the medium fibroids, to 27-fold, CI (11.5-65.2) for the large fibroids). This influence of fibroid size on risk did not differ between African-Americans and whites (P-value for interaction = 0.88). Once fibroid size at enrollment was accounted for, having a prior diagnosis at the time of ultrasound screening was not predictive of having a procedure. Exclusion of women with a submucosal fibroid had little influence on the results. The 8-year risk of a procedure based on lifetable analyses was 2% for women with no fibroids, 8, 23, and 47%, respectively, for women who had small, medium or large fibroids at enrollment. Given the strong association of fibroid size with subsequent risk of a procedure, these findings are unlikely to be due to chance. LIMITATIONS, REASONS FOR CAUTION: Despite a large sample size, the number of women having procedures during follow-up was relatively small. Thus, covariates such as BMI, which were not important in our analyses, may have associations that were too small to detect with our sample size. Another limitation is that the medical procedures were self-reported. However, we attempted to retrieve medical records when participants agreed, and 77% of the total procedures reported were verified. Our findings are likely to be generalizable to other African-American and white premenopausal women in their late 30s and 40s, but other ethnic groups have not been studied. WIDER IMPLICATIONS OF THE FINDINGS: Though further studies are needed to confirm and extend the results, our findings provide an initial estimate of disease progression that will be helpful to clinicians and their patients.

Prevalence and prognostic implication of restenosis or dilatation at the aortic coarctation repair site assessed by cardiovascular MRI in adult patients late after coarctation repair.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is ideal for assessing patients with repaired aortic coarctation (CoA). Little is known on the relation between long-term complications of CoA repair as assessed by CMR and clinical outcome. We examined the prevalence of restenosis and dilatation at the repair site and the long-term outcome in patients with repaired CoA. METHODS AND RESULTS: CMR imaging and clinical data for adult CoA patients (247 patients aged 33.0 ± 12.8 years, 60% male), were analyzed. The diameter of the aorta at the repair site was measured on CMR and its ratio to the aortic diameter at the diaphragm (repair site-diaphragm ratio, RDR) was calculated. Restenosis (RDR≤70%) was present in 31% of patients (and significant in 9% [RDR<50%]), and dilatation (RDR>150%) in 13.0%. A discrete aneurysm at the repair site was observed in 9%. Restenosis was more likely after resection and end-end anastomosis, whereas dilatation after patch repair. Systemic hypertension was present in 69% of patients. Of the hypertensive patients, blood pressure (133 ± 20/73 ± 10 mm Hg) was well controlled in 93% with antihypertensive therapy. Mortality rate over a median length of 5.9 years was low (0.69% per year, 95% CI: 0.33-1.26), but significantly higher than age-matched healthy controls (standardised mortality ratio 2.86, CI 1.43-5.72, p<0.001). CONCLUSION: Restenosis or dilatation at the CoA repair site as assessed by CMR is not uncommon. Medium term survival remains good, however, albeit lower than in the general population. Life-long follow-up and optimal blood pressure control are likely to secure a good longer term outlook in these patients.

Incidence of non-lung solid cancers in Czech uranium miners: a case-cohort study.

OBJECTIVES: Uranium miners are chronically exposed to radon and its progeny, which are known to cause lung cancer and may be associated with leukemia. This study was undertaken to evaluate risk of non-lung solid cancers among uranium miners in Príbram region, Czech Republic. METHODS: A retrospective stratified case-cohort study in a cohort of 22,816 underground miners who were employed between 1949 and 1975. All incident non-lung solid cancers were ascertained among miners who worked underground for at least 12 months (n=1020). A subcohort of 1707 subjects was randomly drawn from the same population by random sampling stratified on age. The follow-up period lasted from 1977 to 1996. RESULTS: Relative risks comparing 180 WLM (90th percentile) of cumulative lifetime radon exposure to 3 WLM (10th percentile) were 0.88 for all non-lung solid cancers combined (95% CI 0.73-1.04, n=1020), 0.87 for all digestive cancers (95% CI 0.69-1.09, n=561), 2.39 for gallbladder cancer (95% CI 0.52-10.98, n=13), 0.79 for larynx cancer (95% CI 0.38-1.64, n=62), 2.92 for malignant melanoma (95% CI 0.91-9.42, n=23), 0.84 for bladder cancer (95% CI 0.43-1.65, n=73), and 1.13 for kidney cancer (95% CI 0.62-2.04, n=66). No cancer type was significantly associated with radon exposure; only malignant melanoma and gallbladder cancer showed elevated but non-significant association with radon. CONCLUSIONS: Radon was not significantly associated with incidence of any cancer of interest, although a positive association of radon with malignant melanoma and gallbladder cancer cannot be entirely ruled out.

The crystal structure of CD8 in complex with YTS156.7.7 Fab and interaction with other CD8 antibodies define the binding mode of CD8 alphabeta to MHC class I.

The CD8alphabeta heterodimer interacts with class I pMHC on antigen-presenting cells as a co-receptor for TCR-mediated activation of cytotoxic T cells. To characterize this immunologically important interaction, we used monoclonal antibodies (mAbs) specific to either CD8alpha or CD8beta to probe the mechanism of CD8alphabeta binding to pMHCI. The YTS156.7 mAb inhibits this interaction and blocks T cell activation. To elucidate the molecular basis for this inhibition, the crystal structure of the CD8alphabeta immunoglobulin-like ectodomains were determined in complex with mAb YTS156.7 Fab at 2.7 A resolution. The YTS156.7 epitope on CD8beta was identified and implies that residues in the CDR1 and CDR2-equivalent loops of CD8beta are occluded upon binding to class I pMHC. To further characterize the pMHCI/CD8alphabeta interaction, binding of class I tetramers to CD8alphabeta on the surface of T cells was assessed in the presence of anti-CD8 mAbs. In contrast to YTS156.7, mAb YTS105.18, which is specific for CD8alpha, does not inhibit binding of CD8alphabeta to class I tetramers, indicating the YTS105.18 epitope is not occluded in the pMHCI/CD8alphabeta complex. Together, these data indicate a model for the pMHCI/CD8alphabeta interaction similar to that observed for CD8alphaalpha in the CD8alphaalpha/pMHCI complex, but in which CD8alpha occupies the lower orientation (membrane proximal to the antigen presenting cell), and CD8beta occupies the upper position (membrane distal). The implication of this molecular assembly for the function of CD8alphabeta in T cell activation is discussed.

Crystal structure of the TCR co-receptor CD8alphaalpha in complex with monoclonal antibody YTS 105.18 Fab fragment at 2.88 A resolution.

The CD8 glycoprotein functions as an essential element in the control of T-cell selection, maturation and the TCR-mediated response to peptide antigen. CD8 is expressed as both heterodimeric CD8alphabeta and homodimeric CD8alphaalpha isoforms, which have distinct physiological roles and exhibit tissue-specific expression patterns. CD8alphaalpha has previously been crystallized in complex with class I pMHC and, more recently, with the mouse class Ib thymic leukemia antigen (TL). Here, we present the crystal structure of a soluble form of mouse CD8alphaalpha in complex with rat monoclonal antibody YTS 105.18 Fab fragment at 2.88 A resolution. YTS 105.18, which is commonly used in the blockade of CD8+ T-cell activation in response to peptide antigen, is specific for mouse CD8alpha. The YTS 105.18 Fab is one of only five rat IgG Fab structures to have been reported to date. Analysis of the YTS 105.18 Fab epitope on CD8alpha reveals that this antibody blocks CD8 activity by hydrogen bonding to residues that are critical for interaction with both class I pMHC and TL. Structural comparison of the liganded and unliganded forms of soluble CD8alphaalpha indicates that the mouse CD8alphaalpha immunoglobulin-domain dimer does not undergo significant structural alteration upon interaction either with class I pMHC or TL.

Visuotactile temporal order judgments in ageing.

We report an experiment on the effects of ageing on crossmodal temporal perception. Young (mean age = 21.7 years) and old (mean age = 75.1 years) participants were presented with pairs of visual and vibrotactile stimuli to either hand and required to make unspeeded temporal order judgments (TOJs) regarding which sensory modality appeared to have been presented first. The stimulus onset asynchrony (SOA) between the two stimuli was varied using the method of constant stimuli. Temporal precision, as indexed by the just noticeable difference (JND), was better (i.e., JNDs were lower) when the stimuli were presented from different positions (M = 101 ms) rather than from the same position (M = 120 ms), as has been demonstrated previously. Additionally, older observers required more time (i.e., their JNDs were larger) to accurately perceive the temporal order (M = 131 ms) as compared to younger observers (M = 98 ms). Our results confirm that ageing deleteriously affects crossmodal temporal processing even when the spatial confound inherent in previous research has been ruled out.

Multiple interactions in Sir protein recruitment by Rap1p at silencers and telomeres in yeast.

Initiation of transcriptional silencing at mating type loci and telomeres in Saccharomyces cerevisiae requires the recruitment of a Sir2/3/4 (silent information regulator) protein complex to the chromosome, which occurs at least in part through its association with the silencer- and telomere-binding protein Rap1p. Sir3p and Sir4p are structural components of silent chromatin that can self-associate, interact with each other, and bind to the amino-terminal tails of histones H3 and H4. We have identified a small region of Sir3p between amino acids 455 and 481 that is necessary and sufficient for association with the carboxyl terminus of Rap1p but not required for Sir complex formation or histone binding. SIR3 mutations that delete this region cause a silencing defect at HMR and telomeres. However, this impairment of repression is considerably less than that displayed by Rap1p carboxy-terminal truncations that are defective in Sir3p binding. This difference may be explained by the ability of the Rap1p carboxyl terminus to interact independently with Sir4p, which we demonstrate by in vitro binding and two-hybrid assays. Significantly, the Rap1p-Sir4p two-hybrid interaction does not require Sir3p and is abolished by mutation of the carboxyl terminus of Rap1p. We propose that both Sir3p and Sir4p can directly and independently bind to Rap1p at mating type silencers and telomeres and suggest that Rap1p-mediated recruitment of Sir proteins operates through multiple cooperative interactions, at least some of which are redundant. The physical separation of the Rap1p interaction region of Sir3p from parts of the protein required for Sir complex formation and histone binding raises the possibility that Rap1p can participate directly in the maintenance of silent chromatin through the stabilization of Sir complex-nucleosome interactions.

Telomere formation by rap1p binding site arrays reveals end-specific length regulation requirements and active telomeric recombination.

Rap1p, the major telomere repeat binding protein in yeast, has been implicated in both de novo telomere formation and telomere length regulation. To characterize the role of Rap1p in these processes in more detail, we studied the generation of telomeres in vivo from linear DNA substrates containing defined arrays of Rap1p binding sites. Consistent with previous work, our results indicate that synthetic Rap1p binding sites within the internal half of a telomeric array are recognized as an integral part of the telomere complex in an orientation-independent manner that is largely insensitive to the precise spacing between adjacent sites. By extending the lengths of these constructs, we found that several different Rap1p site arrays could never be found at the very distal end of a telomere, even when correctly oriented. Instead, these synthetic arrays were always followed by a short ( approximately 100-bp) "cap" of genuine TG repeat sequence, indicating a remarkably strict sequence requirement for an end-specific function(s) of the telomere. Despite this fact, even misoriented Rap1p site arrays promote telomere formation when they are placed at the distal end of a telomere-healing substrate, provided that at least a single correctly oriented site is present within the array. Surprisingly, these heterogeneous arrays of Rap1p binding sites generate telomeres through a RAD52-dependent fusion resolution reaction that results in an inversion of the original array. Our results provide new insights into the nature of telomere end capping and reveal one way by which recombination can resolve a defect in this process.

Attentional set modulates visual areas: an event-related potential study of attentional capture.

The present experiment offers event-related potential evidence suggesting that modulation of neural activity in the visual cortex underlies top-down attentional capture by irrelevant cues. Participants performed a covert visual search task where they identified the unique stimulus in a brief, four-location display. Targets defined uniquely by color or onset were run in separate blocks, encouraging observers to adopt different attentional sets in each block. In Experiment 1, a brief, white, abrupt-onset cue highlighted one of the locations 100 or 200 ms prior to the target display. In Experiment 2, the cue display consisted of three white and one red cues simultaneously presented at the four locations. In both experiments, participants were informed that there was no predictive relation between the location of the cue and that of the target. Reaction times were dependent on the location of the preceding cue (i.e. attention was captured), but only in those blocks where the cue shared the uniquely relevant target feature. Evoked potentials over the right hemisphere were modulated during the attention-capturing blocks just prior to the cue's appearance. Additionally, the N1 wave elicited by the cue was enhanced over occipital regions during the attention-capturing blocks. These findings support the notion that attentional capture with peripheral cues is not simply reflexive but is modulated by top-down processes.

Transcriptional silencing: replication redux.

Recent studies indicate that, contrary to long-held belief, DNA replication does not have a direct role in transcriptional silencing, but progression through S phase of the cell cycle is nevertheless required for the establishment of silent chromatin.

Failure to remap visuotactile space across the midline in the split-brain.

We examined the effect of posture change on the representation of visuotactile space in a split-brain patient using a cross-modal congruency task. Split-brain patient J.W. made speeded elevation discrimination responses (up versus down) to a series of tactile targets presented to the index finger or thumb of his right hand. We report congruency effects elicited by irrelevant visual distractors placed either close to, or far from, the stimulated hand. These cross-modal congruency effects followed the right hand as it moved within the right hemispace, but failed to do so when the hand crossed the midline into left hemispace. These results support recent claims that interhemispheric connections are required to maintain an accurate representation of visuotactile space.

Visual prior entry.

It has long been claimed that attended stimuli are perceived prior to unattended stimuli--doctrine of prior entry. Most, if not all, studies on which such claims have been based, however, are open to a nonattentional interpretation involving response bias, leading some researchers to assert that prior entry may not exist. Given this controversy, we introduce a novel methodology to minimize the effect of response bias by manipulating attention and response demands in orthogonal dimensions. Attention was oriented to the left or right (ie., spatially), but instead of reporting on the basis of location, observers reported the order (first or second) of vertical versus horizontal line segments. Although second-order response biases were demonstrated, effects of attention in accordance with the law of prior entry were clearly obtained following both exogenous and endogenous attentional cuing.

A role for Sds3p, a component of the Rpd3p/Sin3p deacetylase complex, in maintaining cellular integrity in Saccharomyces cerevisiae.

The SDS3 gene was identified in a suppressor screen for mutations that enhance position-effect silencing in yeast. Cells that are defective in SDS3 have pleiotropic phenotypes, similar to those seen in the absence of the histone deacetylase components Rpd3p and Sin3p, including meiotic defects and improper regulation of the HO gene. To gain further insight into SDS3 function we undertook an epistasis analysis with other SDS genes. We found that sds3 is synthetically lethal in combination with a deletion of the SWI6 (SDS11) gene, which encodes a cell-cycle regulator. sds3 swi6 double mutants do not display a specific cell-cycle arrest phenotype, but instead die due to cell lysis. Constitutive expression of the G1 cyclin gene CLN2 restores viability to an sds3 swi6 strain, as does overexpression of SKT5/ CHS4, which encodes a regulatory subunit of chitin synthase III, and SSD1, a gene previously implicated in ensuring cell-cycle progression and cellular integrity. Significantly, growth in the presence of 1 M sorbitol or overexpression of PKC1 also partially suppresses the lethal phenotype of the sds3 swi6 strain. This lethality in the absence of SWI6 function most probably reflects an important or essential role for Sds3p in the Rpd3p/Sin3p histone deacetylase complex, since RPD3 and SIN3 mutations are also synthetically lethal in combination with swi6 and these phenotypes are also rescued by elevated dosage of SKT5/CHS4, SSD1, or PCK1. Taken together, these data indicate that the transcription factor Swi6p and the Rpd3p-based deacetylase complex act in parallel pathways to activate genes required for cell wall biosynthesis.

Representation of visuotactile space in the split brain.

Recent neurophysiological research in the monkey has revealed bimodal neuronal cells with both tactile receptive fields on the hand and visual receptive fields that follow the hands as they move, suggesting the existence of a bimodal map of visuotactile space. Using a cross-modal congruency task, we examined the representation of visuotactile space in normal people and in a split-brain patient (J. W.) as the right arm assumed different postures. The results showed that the congruency effects from distracting lights followed the hand around in space in normal people, but failed to do so in the split-brain patient when the hand crossed the midline. This suggests that cross-cortical connections are required to remap visual space to the current hand position when the hand crosses the midline.

Telomeric chromatin: replicating and wrapping up chromosome ends.

Recent advances in our understanding of the specialized chromatin structure at telomeres, the ends of eukaryotic chromosomes, have focused on three separate areas: replication of telomeres through the coordinated action of conventional DNA polymerases and the telomerase enzyme, protection of the chromosome end from DNA damage checkpoint sensors and DNA-repair processes, and the discovery of a novel deacetylase enzyme (Sir2p) required for the establishment and maintenance of telomeric heterochromatin. Although the number of proteins and the complexity of their interactions at telomeres continues to grow, a picture of at least some of the major players and mechanisms underlying telomere replication, end 'capping' and chromatin assembly is beginning to emerge.