Patient Perspectives on the Risk-Based NLST Outcomes Tool for Lung Cancer Screening.

Researchers at the NCI have developed the Risk-Based NLST Outcomes Tool (RNOT), an online tool that calculates risk of lung cancer diagnosis and death with and without lung cancer screening, and false-positive risk estimates. This tool has the potential to facilitate shared decision making for screening. The objective of this study was to examine how current heavy and former smokers understand and respond to personalized risk estimates from the RNOT. Individuals who were eligible for lung cancer screening and were visiting Walter Reed National Military Medical Center were invited to participate in a semi-structured interview to assess their experiences with and perceptions of the RNOT. Results were analyzed using template analysis. Participants found their risk of lung cancer death to be lower than anticipated and were confused by changes in risk for lung cancer diagnosis with and without screening. Most participants indicated that the RNOT would be helpful in making screening decisions, despite reporting that there was no maximum risk for a false positive that would lead them to forgo lung cancer screening. Participants provided actionable needs and recommendations to optimize this tool. Risk-based screening tools may enhance shared decision making. The RNOT is being updated to incorporate these findings.

Ultra-high field magnetic resonance imaging parameter mapping in the posterior horn of ex vivo human menisci.

OBJECTIVE: To investigate the relationship between meniscus magnetic resonance (MR) relaxation parameters and meniscus degradation through quantitative imaging of ex vivo posterior horns of menisci from subjects with and without knee osteoarthritis (OA). DESIGN: We sampled medial and lateral menisci from ten medial compartment knee OA patients (mean age 63 years) undergoing total knee replacement and from ten deceased donors (references, mean age 51 years). MR relaxation parameters T2*, T2 and T1 of the posterior horn were measured at a 9.4 T scanner. Comparisons were made between OA patients and references (with adjustment for age) as well as between medial and lateral menisci from the same knees. RESULTS: Mean values (standard deviation) of mean T2* were 13 (3.8), 6.9 (2.3), 7.2 (1.9) and 7.2 (1.7) ms for the medial and lateral patient menisci and the medial and lateral reference menisci, respectively. Corresponding values were 17 (3.7), 9.0 (2.2), 12 (4) and 9.0 (1.3) ms for T2 and 1810 (150), 1630 (30), 1580 (90) and 1560 (50) ms for T1. All three relaxation times were significantly longer in medial OA menisci compared to the other groups. Among medial reference menisci, relaxation times (mainly T1) tended to increase with age. CONCLUSIONS: MR relaxation times T2*, T2 and T1 in the posterior horn are longer in the medial menisci of patients with end-stage medial compartment knee OA compared to the corresponding lateral menisci and to reference menisci. The meniscus seems to undergo intrasubstance alterations related to both OA and ageing.

Persisting CAM deformity is associated with early cartilage degeneration after Slipped Capital Femoral Epiphysis: 11-year follow-up including dGEMRIC.

OBJECTIVE: Slipped capital femoral epiphysis (SCFE) in adolescence is associated with increased risk of future osteoarthritis (OA). The purpose of this study was to study clinical and radiographic risk factors for early cartilage degeneration after SCFE. DESIGN: 22 patients (44 hips) (mean age 24 years, range 18-27) treated with in situ fixation (The Hansson hook-pin) for stable SCFE on average 11 years previously were investigated. Cartilage status was assessed with delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC). The alpha angle, reflecting femoroacetabular impingement (FAI), and the original slip angle were measured. Clinical outcome was assessed with the Copenhagen hip and groin outcome score (HAGOS) and clinical examination. RESULTS: The dGEMRIC index was lower in SCFE hips than unaffected hips 456 ms (CI 419-493) vs 521 ms (CI 476-567) (P = 0.03). The difference was larger (mean 21 ms) in anterior than posterior regions of the hip (P = 0.038). The alpha angle was higher in SCFE hips, 61.5° (CI 53.9-69.1) vs 45.6° (CI 43.6-47.6), (P < 0.001). The alpha angle, but not the original slip angle, correlated negatively with the dGEMRIC index (R = -0.40, P = 0.046). There was a positive correlation between HAGOS and the dGEMRIC-index (R = 0.41, P = 0.012). CONCLUSIONS: Early cartilage degeneration after SCFE seems related to persisting FAI in adulthood, rather than the initial slip severity. The correlation between dGEMRIC and HAGOS indicates a clinical relevance of the MRI findings. Our results suggest that FAI after SCFE should be evaluated already after physeal closure in order to predict and possibly prevent future OA development.

Pancreas volume and fat fraction in children with Type 1 diabetes.

AIMS: People with Type 1 diabetes have smaller pancreases than healthy individuals. Several diseases causing pancreatic atrophy are associated with pancreatic steatosis, but pancreatic fat in Type 1 diabetes has not been measured. This cross-sectional study aimed to compare pancreas size and fat fraction in children with Type 1 diabetes and controls. METHODS: The volume and fat fraction of the pancreases of 22 children with Type 1 diabetes and 29 controls were determined using magnetic resonance imaging. RESULTS: Pancreas volume was 27% smaller in children with diabetes (median 34.9 cm(3) ) than in controls (47.8 cm(3) ; P < 0.001). Pancreas volume correlated positively with age in controls (P = 0.033), but not in children with diabetes (P = 0.649). Pancreas volume did not correlate with diabetes duration, but it did correlate positively with units of insulin/kg body weight/day (P = 0.048). A linear model of pancreas volume as influenced by age, body surface area and insulin units/kg body weight/day found that insulin dosage correlated with pancreas volume after controlling for both age and body surface area (P = 0.009). Pancreatic fat fraction was not significantly different between the two groups (1.34% vs. 1.57%; P = 0.891). CONCLUSIONS: Our findings do not indicate that pancreatic atrophy in Type 1 diabetes is associated with an increased pancreatic fat fraction, unlike some other diseases featuring reduced pancreatic volume. We speculate that our results may support the hypotheses that much of pancreatic atrophy in Type 1 diabetes occurs before the clinical onset of the disease and that exogenous insulin administration decelerates pancreatic atrophy after diabetes onset.

Evaluation and recommendations of the oral health, oral function, and orofacial aesthetics-related measures of the ICHOM Standard Set for Cleft Lip and Palate.

This study was performed to evaluate the efficacy of outcome measures for the orofacial domain included in the International Consortium for Health Outcomes Measurement Standard Set for Cleft Lip and Palate (ICHOM-SCS). In this multicentre study involving two cleft centres, suggestions to optimize the type and timing of outcome measures were made based on data and clinical experience. Patient-reported outcome measures (PROMs) (CLEFT-Q Jaw, Teeth, Eating/Drinking; Child Oral Health Impact Profile-Oral Symptoms Scale (COHIP-OSS)) and clinical outcome measures (caries experience and dental occlusion) data were collected retrospectively for age 5, 8, 10, 12, 19, and 22 years. The data were categorized by cleft type and analysed within and between age groups using Spearman correlation, the distribution of responses per item, a two-sample test for equality of proportions, and effect plots. Most correlations between PROMs and clinical outcome measures were weak (r < 0.5), suggesting PROMs and clinical outcome measures complement each other. The COHIP-OSS and CLEFT-Q Eating/Drinking barely detected problems in any patient category and are no longer recommended. A suitable alternative appears complex to find; outcomes of this study and the recent literature doubt an added value. Similar problems were found in the CLEFT-Q Jaw at time-point 12 years. Therefore, time-points 15 and 17 years are currently suggested.

Anti-cytokine autoantibodies preceding onset of autoimmune polyendocrine syndrome type I features in early childhood.

PURPOSE: Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-ω and IFN-α2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients. METHODS: Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles. RESULTS: Antibody titers were already high against IFN-α2 and IFN-ω at age 6 months in one sibling-8 months before onset of APS-I-and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-ω and/or IL-22 when first tested, but only modestly positive against IFN-ω in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects. CONCLUSION: This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad-specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization.

Anti-cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a recessive disorder resulting from mutations in the autoimmune regulator (AIRE). The patients' autoantibodies recognize not only multiple organ-specific targets, but also many type I interferons (IFNs) and most T helper type 17 (Th17) cell-associated cytokines, whose biological actions they neutralize in vitro. These anti-cytokine autoantibodies are highly disease-specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE. Moreover, autoantibodies against Th17 cell-associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin (Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN-ω, IFN-α2a, interleukin (IL)-17A and IL-22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 without IgE, possibly implicating regulatory T cell responses and/or epithelia in their initiation in these AIRE-deficiency states. The epitopes on IL-22 and IFN-α2a appeared mainly conformational. We also found mainly IgG1 neutralizing autoantibodies to IL-17A in aged AIRE-deficient BALB/c mice - the first report of any target shared by these human and murine AIRE-deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation.

Positional cloning of the APECED gene.

Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markers D21S49 and D21S171 by linkage studies. We have isolated a novel gene from this region, AIRE (autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription factor including two zinc-finger (PHD-finger) motifs, a proline-rich region and three LXXLL motifs. Two mutations, a C-->T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A-->G substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swiss and Finnish APECED patients. The Arg257stop (R257X) is the predominant mutation in Finnish APECED patients, accounting for 10/12 alleles studied. These results indicate that this gene is responsible for the pathogenesis of APECED. The identification of the gene defective in APECED should facilitate the genetic diagnosis and potential treatment of the disease and further enhance our general understanding of the mechanisms underlying autoimmune diseases.

Correlation of 24-hour urinary protein quantification with spot urine protein:creatinine ratio in lupus nephritis.

OBJECTIVES: Twenty-four hour urine collection has been the foundation for monitoring patients with lupus nephritis. However, the use of protein to creatinine ratios in spot urine samples is now widely used. We aimed to evaluate the validity of this method cross-sectionally and longitudinally. METHODS: A cross-sectional retrospective study was conducted. Records of 486 lupus nephritis patients were searched for paired results of 24-h quantification of urinary protein and a random spot urine protein to creatinine ratio and were examined over a three-year period. RESULTS AND CONCLUSIONS: Ninety-five lupus nephritis patients had paired results and were included in the final analysis, male/female 14/81, mean age 36.5 years. Over a three-year period there were a total of 137 samples from 95 patients. For the entire dataset, there was a significant correlation between protein:creatinine ratio and 24-h urine collection protein (mg), Spearman Rho correlation coefficient was 0.869, p < 0.0001 with (R (2 )= 0.504). There was also a strong correlation for longitudinal data, n = 14 at two-years Rho 0.910, p < 0.0001 with (R (2 )= 0.878), n = 8 at three-years Rho 0.909, p < 0.0001 and (R (2 )= 0.73). We have shown for the first time in a UK population of lupus nephritis patients, well trained in producing 24-h collection, that the spot protein:creatinine ratio correlates well with 24-h urinary total protein excretion. Having a simple, reliable, reproducible and cost-effective test such as the spot urine protein:creatinine ratio is therefore a valuable tool with which to monitor disease progression.

Extreme compression for extreme conditions: pilot study to identify optimal compression of CT images using MPEG-4 video compression.

This study aims to evaluate the utility of compressed computed tomography (CT) studies (to expedite transmission) using Motion Pictures Experts Group, Layer 4 (MPEG-4) movie formatting in combat hospitals when guiding major treatment regimens. This retrospective analysis was approved by Walter Reed Army Medical Center institutional review board with a waiver for the informed consent requirement. Twenty-five CT chest, abdomen, and pelvis exams were converted from Digital Imaging and Communications in Medicine to MPEG-4 movie format at various compression ratios. Three board-certified radiologists reviewed various levels of compression on emergent CT findings on 25 combat casualties and compared with the interpretation of the original series. A Universal Trauma Window was selected at -200 HU level and 1,500 HU width, then compressed at three lossy levels. Sensitivities and specificities for each reviewer were calculated along with 95 % confidence intervals using the method of general estimating equations. The compression ratios compared were 171:1, 86:1, and 41:1 with combined sensitivities of 90 % (95 % confidence interval, 79-95), 94 % (87-97), and 100 % (93-100), respectively. Combined specificities were 100 % (85-100), 100 % (85-100), and 96 % (78-99), respectively. The introduction of CT in combat hospitals with increasing detectors and image data in recent military operations has increased the need for effective teleradiology; mandating compression technology. Image compression is currently used to transmit images from combat hospital to tertiary care centers with subspecialists and our study demonstrates MPEG-4 technology as a reasonable means of achieving such compression.

External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer.

BACKGROUND: Data for selpercatinib [a selective REarranged during Transfection (RET) inhibitor] from a single-arm trial (LIBRETTO-001, NCT03157128) in RET-fusion-positive advanced/metastatic non-small-cell lung cancer (NSCLC) were used in combination with external data sources to estimate comparative efficacy [objective response rate (ORR), progression-free survival, and overall survival (OS)] in first- and second-line treatment settings. METHODS: Patient-level data were obtained from a de-identified real-world database. Patients diagnosed with advanced/metastatic NSCLC with no prior exposure to a RET inhibitor and one or more prior line of therapy were eligible. Additionally, individual patient-level data (IPD) were obtained from the pemetrexed + platinum arm of KEYNOTE-189 (NCT03950674, first line) and the docetaxel arm of REVEL (NCT01168973, post-progression). Patients were matched using entropy balancing, doubly robust method, and propensity score approaches. For patients with unknown/negative RET status, adjustment was made using a model fitted to IPD from a real-world database. RESULTS: In first-line unadjusted analyses of the real-world control, ORR was 87.2% for LIBRETTO-001 versus 66.7% for those with RET-positive NSCLC (P = 0.06). After adjustment for unknown RET status and other patient characteristics, selpercatinib remained significantly superior versus the real-world control for all outcomes (all P < 0.001 except unadjusted RET-fusion-positive cohort). Similarly, outcomes were significantly improved versus clinical trial controls (all P < 0.05). CONCLUSIONS: Findings suggest improvement in outcomes associated with selpercatinib treatment versus the multiple external control cohorts, but should be interpreted with caution. Data were limited by the rarity of RET, lack of mature OS data, and uncertainty from assumptions to create control arms from external data.

ASE in thin disk lasers: theory and experiment.

We derive equations for the ASE intensity, decay time, and heat load. The crux of our development is frequency integration over the gain lineshape followed by a spatial integration over the emitters. These integrations result in a gain length that is determined from experiment. We measure the gain as a function of incident pump power for a multi-pass pumped Yb:YAG disk doped at 9.8 at.% with an anti-ASE cap. The incident pump powers are up to 3kW. Our fit to the measured gain is within 10% of the measured gain up to pump powers where the gain starts to flatten out and roll over. In this comparison we extract the gain length that turns out to be 43% of the pump spot size of 7mm.

Application of regularized Richardson-Lucy algorithm for deconvolution of confocal microscopy images.

Although confocal microscopes have considerably smaller contribution of out-of-focus light than widefield microscopes, the confocal images can still be enhanced mathematically if the optical and data acquisition effects are accounted for. For that, several deconvolution algorithms have been proposed. As a practical solution, maximum-likelihood algorithms with regularization have been used. However, the choice of regularization parameters is often unknown although it has considerable effect on the result of deconvolution process. The aims of this work were: to find good estimates of deconvolution parameters; and to develop an open source software package that would allow testing different deconvolution algorithms and that would be easy to use in practice. Here, Richardson-Lucy algorithm has been implemented together with the total variation regularization in an open source software package IOCBio Microscope. The influence of total variation regularization on deconvolution process is determined by one parameter. We derived a formula to estimate this regularization parameter automatically from the images as the algorithm progresses. To assess the effectiveness of this algorithm, synthetic images were composed on the basis of confocal images of rat cardiomyocytes. From the analysis of deconvolved results, we have determined under which conditions our estimation of total variation regularization parameter gives good results. The estimated total variation regularization parameter can be monitored during deconvolution process and used as a stopping criterion. An inverse relation between the optimal regularization parameter and the peak signal-to-noise ratio of an image is shown. Finally, we demonstrate the use of the developed software by deconvolving images of rat cardiomyocytes with stained mitochondria and sarcolemma obtained by confocal and widefield microscopes.

Utilizing Participatory Research to Engage Underserved Populations to Improve Health-Related Outcomes in Delaware.

Cooperative Extension is a community outreach program. Despite its large reach, there is a need for the evaluation of changes in health-related outcomes for individuals engaged with Cooperative Extension. A team-based challenge was developed using community-engaged participatory research integrated with Cooperative Extension to encourage healthy eating and physical activity behaviors through Cooperative Extension programming. Thus, the primary purpose of this secondary analysis was to (1) evaluate changes in anthropometric outcomes and (2) evaluate changes in health behavior outcomes. Associations of anthropometric changes and health behavior changes with engagement in the three-month team-based challenge were explored. Anthropometrics were measured using standard procedures, and intake of fruits and vegetables and physical activity were self-reported. Of the 145 participants in the community-engaged participatory research portion of the study, 52.4% (n = 76) had complete anthropometrics before and after the team-based challenge and were included in this study. At 3 months, there was a significant reduction in body mass index (-0.3 kg/m2, p = 0.024) and no significant change in waist circumference (p = 0.781). Fruit and vegetable intake significantly increased (+0.44 servings/day, p = 0.018). Physical activity did not significantly change based on (1) the number of days 30 or more minutes of physical activity was conducted (p = 0.765) and (2) Godin Leisure-Time Exercise Questionnaire scores (p = 0.612). Changes in anthropometrics and health behaviors were not associated with engagement in the team-based challenge. Using community-engaged participatory research with community outreach programs, such as Cooperative Extension, can improve health-related outcomes in underserved populations. However, despite a participatory approach, changes in anthropometrics and health behaviors were not associated with engagement in the developed team-based challenge.

Thymic Epithelial Neoplasms: Radiologic-Pathologic Correlation.

Thymic epithelial neoplasms, as classified by the World Health Organization, include thymoma, thymic carcinoma, and thymic carcinoid. They are a rare group of tumors and are often diagnosed incidentally in the work-up of parathymic syndrome, such as myasthenia gravis, or when mass effect or local invasion causes other symptoms. In each of these scenarios, understanding the radiologic-pathologic relationship of these tumors allows clinical imagers to contribute meaningfully to management decisions and overall patient care. Integrating important imaging features, such as local invasion, and pathologic features, such as necrosis and immunohistochemistry, ensures a meaningful contribution by clinical imagers to the care team.

Cardiac MRI for Patients with Increased Cardiometabolic Risk.

Cardiac MRI (CMR) has rich potential for future cardiovascular screening even though not approved clinically for routine screening for cardiovascular disease among patients with increased cardiometabolic risk. Patients with increased cardiometabolic risk include those with abnormal blood pressure, body mass, cholesterol level, or fasting glucose level, which may be related to dietary and exercise habits. However, CMR does accurately evaluate cardiac structure and function. CMR allows for effective tissue characterization with a variety of sequences that provide unique insights as to fibrosis, infiltration, inflammation, edema, presence of fat, strain, and other potential pathologic features that influence future cardiovascular risk. Ongoing epidemiologic and clinical research may demonstrate clinical benefit leading to increased future use. © RSNA, 2021.

The alpha chain gene of H-2O has an unexpected location in the major histocompatibility complex.

A previously unknown major histocompatibility complex class II molecule consisting of the beta chain encoded by the H-2Ob gene and an unknown alpha chain was recently described. We now report that the alpha chain occurs in two allelic forms distinguished by charge difference. Using inbred recombinant mouse strains we were able to map the H-2Oa gene to a location between the A.TL and B10.MBR recombination points. Cosmids covering this region were used to isolate the gene. Sequence analysis revealed that the H-2Oa gene is the murine equivalent of the human HLA-DNA gene. These results indicate that the human HLA-DNA gene, the existence of which has long been known, is indeed coding for DO alpha, the alpha chain pairing with DO beta.

Requirements for peptide-induced T cell receptor downregulation on naive CD8+ T cells.

The requirements for inducing downregulation of alpha/beta T cell receptor (TCR) molecules on naive major histocompatibility complex class I-restricted T cells was investigated with 2C TCR transgenic mice and defined peptides as antigen. Confirming previous results, activation of 2C T cells in response to specific peptides required CD8 expression on the responder cells and was heavily dependent upon costimulation provided by either B7-1 or ICAM-1 on antigen-presenting cells (APC). These stringent requirements did not apply to TCR downregulation. Thus, TCR downregulation seemed to depend solely on TCR/peptide/interaction and did not require either CD8 or B7-1 expression; ICAM-1 potentiated TCR downregulation, but only with limiting doses of peptides. TCR downregulation was most prominent with high affinity peptides and appeared to be neither obligatory nor sufficient for T cell activation. In marked contrast to T cell activation, TCR downregulation was resistant to various metabolic inhibitors. The biological significance of TCR downregulation is unclear, but could be a device for protecting T cells against excessive signaling.

Differing roles for B7 and intercellular adhesion molecule-1 in negative selection of thymocytes.

To ensure self tolerance, immature thymocytes with high binding affinity for self peptides linked to major histocompatibility complex (MHC) molecules are eliminated in situ via apoptosis (negative selection). The roles of two costimulatory molecules, B7-1 and intercellular adhesion molecule-1 (ICAM-1), in negative selection was examined by studying apoptosis of T cell receptor transgenic CD4+8+ thymocytes cultured with specific peptides presented by MHC class I-transfected Drosophila cells. When coexpressed on these cells, B7-1 and ICAM-1 act synergistically and cause strong class 1-restricted negative selection of thymocytes. When expressed separately, however, B7-1 and ICAM-1 display opposite functions: negative selection is augmented by B7-1, but is inhibited by ICAM-1. It is notable that B7-1 is expressed selectively in the thymic medulla, whereas ICAM-1 is expressed throughout the thymus. Because of this distribution, the differing functions of B7-1 and ICAM-1 may dictate the sites of positive and negative selection. Thus, in the cortex, the presence of ICAM-1, but not B7-1, on the cortical epithelium may preclude or reduce negative selection and thereby promote positive selection. Conversely, the combined expression of B7-1 and ICAM-1 may define the medulla as the principal site of negative selection.