New Insights into LINC00346 and its Role in Disease

Accumulating evidence has shown that long intergenic non-protein-coding RNA 346 (LINC00346) functions as an oncogene in the tumorigenesis of several cancers. The expression level of LINC00346 has been shown to be obviously correlated with prognosis, lymphoma metastasis, histological grade, TNM stage, tumor size and pathologic stage. LINC00346 has been found to regulate specific cellular functions by interacting with several molecules and signaling pathways. In this review, we summarize recent evidence concerning the role of LINC00346 in the occurrence and development of diseases. We also discuss the potential clinical utility of LINC00346, thereby providing new insight into the diagnosis and treatment of diseases. In addition, we further discuss the potential clinical utility of LINC00346 in the diagnosis, prognostication, and treatment of diseases.

Choice Bundling Increases Valuation of Delayed Losses More Than Gains in Cigarette Smokers

Choice bundling, in which a single choice produces a series of repeating consequences over time, increases valuation of delayed monetary and non-monetary gains. Interventions derived from this manipulation may be an effective method for mitigating the elevated delay discounting rates observed in cigarette smokers. No prior work, however, has investigated whether the effects of choice bundling generalize to reward losses. In the present study, an online panel of cigarette smokers (N = 302), recruited using survey firms Ipsos and InnovateMR, completed assessments for either monetary gains or losses (randomly assigned). In Step 1, participants completed a delay-discounting task to establish Effective Delay 50 (ED50), or the delay required for an outcome to lose half of its value. In Step 2, participants completed three conditions of an adjusting-amount task, choosing between a smaller, sooner (SS) adjusting amount and a larger, later (LL) fixed amount. The bundle size (i.e., number of consequences) was manipulated across conditions, where a single choice produced either 1 (control), 3, or 9 consequences over time (ascending/descending order counterbalanced). The delay to the first LL amount in each condition, as well as the intervals between all additional SS and LL amounts (where applicable), were set to individual participants’ ED50 values from Step 1 to control for differences in discounting of gains and losses. Results from Step 1 showed significantly higher ED50 values (i.e., less discounting) for losses compared to gains (p < 0.001). Results from Step 2 showed that choice bundling significantly increased valuation of both LL gains and losses (p < 0.001), although effects were significantly greater for losses (p < 0.01). Sensitivity analyses replicated these conclusions. Future research should examine the potential clinical utility of choice bundling, such as development of motivational interventions that emphasize both the bundled health gains associated with smoking cessation and the health losses associated with continued smoking.

The use of ultrasonography as a tool to evaluate the quadriceps muscle in patients with chronic obstructive pulmonary disease: a systematic review

The aim of this review is to understand the feasibility and potential clinical utility of US in measurements of the quadriceps muscles in patients with COPD. A total of 217 studies were identified and after applying the inclusion criteria, 12 were selected. The data were systematically searched by two independent reviewers. Of the included articles, five evaluated the maximal voluntary contraction of the quadriceps muscle and the Transverse Section Area (TSA) measured by US, of these, 4 found a remarkably reduced strength in COPD and in one article, it was described that this reduction occurs in all grades of the disease. Moreover, the greater the thickness of the quadriceps, the greater the maximum voluntary contraction of this musculature, however, the TSA is reduced in these patients when compared to healthy individuals. Thus, it is suggested that the AST, evaluated by US, can be used to assess the presence and/or severity of musculoskeletal dysfunction in these patients. The sonographic evaluation of the quadriceps in patients with COPD may provide a safe, effective, low-cost, reliable and reproducible evaluation, allowing the identification and monitoring of peripheral muscle dysfunction in this population, even when compared with other strategies.

GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism

Context Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism (FIHP) and sporadic PHPT. However, as these previously-reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. Objective Determine the frequency of GCM2 variants-of-interest among patients with sporadic multigland or familial parathyroid disease, and assess their penetrance. Design and Patients DNA encoding PHPT-associated GCM2 germline-variants were PCR-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. Results GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and three (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33%, 1.04% respectively). Conclusions Observed in vitro activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared with the general population, yet penetrance values are very low i.e. most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.

An observational study of salivary C-reactive protein as a potential novel non-invasive biomarker of neonatal sepsis

Objectives: Serial C-reactive protein (CRP) monitoring helps to rule out and prognosticate sepsis. Small blood volumes in neonates make it difficult for repeated blood draws for serial CRP monitoring. Hence, the need of the hour is a non-invasive method such as CRP estimation in saliva. This study aims to correlate salivary CRP with serum CRP levels and establish the potential clinical utility of salivary CRP in diagnosing neonatal sepsis. Materials and Methods: Twenty-three consecutive neonates diagnosed with clinically suspected sepsis and admitted to the NICU were the study subjects. Demographics such as gestational age and weight at birth, sex and detailed clinical features, and comorbidities were noted. Blood samples for CRP estimation and blood culture were collected as soon as clinical suspicion of sepsis arose. Saliva samples were collected for CRP estimation within 1 h of blood sample collection. The saliva was collected in a 2 mL syringe using low suction. Salivary and serum CRP were estimated by the particle enhanced immunoturbidimetric assay. Results: In our study, the CRP levels in saliva correlated moderately well with CRP levels in serum (Spearman correlation coefficient r = 0.582, P = 0.004). The sensitivity and specificity of salivary CRP to predict a serum level of ≥10 mg/L were observed to be 0.75 and 0.93, respectively. Conclusion: Our study shows the promise of salivary CRP as a potential clinically meaningful biomarker of neonatal sepsis and warrants the need for larger studies to validate the utility of salivary CRP to serially monitor neonatal sepsis.

Anti-virulence Bispecific Monoclonal Antibody Mediated Protection Against Pseudomonas aeruginosa Ventilator-Associated Pneumonia in a Rabbit Model

Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa . We characterized the correlates of protection of MEDI3902, a bispecific human IgG1 mAb that targets the P. aeruginosa type-3-secretion PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal volume mechanical ventilation. Rabbits infused with MEDI3902 prophylactically were protected, whereas those pretreated with irrelevant isotype-control IgG (c-IgG) succumbed between 12 and 44 hours post infection [100% (8/8) vs. 0% (8/8) survival, P <0.01 by log-rank test]. Lungs from rabbits pretreated with c-IgG, but not those with MEDI3902, had bilateral, multifocal areas of marked necrosis, hemorrhage, neutrophilic inflammatory infiltrate, diffuse fibrinous edema in alveolar spaces. All rabbits pretreated with c-IgG developed worsening bacteremia that peaked at the time of death, whereas only 38% (3/8) rabbits pretreated with MEDI3902 developed such high-grade bacteremia (two-sided Fisher’s exact test, P =0.026). Biomarkers associated with acute respiratory distress syndrome were evaluated longitudinally in blood samples collected every 2-4 hours to assess systemic pathophysiological changes in rabbits pretreated with MEDI3902 or c-IgG. Biomarkers were sharply increased or decreased in rabbits pretreated with c-IgG, but not those pretreated with MEDI3902, including ratio of arterial oxygen partial pressure to fractional inspired oxygen PaO 2 /FiO 2 <300, hypercapnia or hypocapnia, severe lactic acidosis, leukopenia and neutropenia. Cytokines and chemokines associated with ARDS were significantly downregulated in lungs from rabbits pretreated with MEDI3902 compared with c-IgG. These results suggest that MEDI3902 prophylaxis could have potential clinical utility for decreasing severity of P. aeruginosa ventilator-associated pneumonia.

Is kallikrein-8 a blood biomarker for detecting amnestic mild cognitive impairment? Results of the population-based Heinz Nixdorf Recall study

Background Kallikrein-8 (KLK8) might be an early blood-biomarker of Alzheimer’s disease (AD). We examined whether blood KLK8 is elevated in persons with amnestic mild cognitive impairment (aMCI) which is a precursor of AD, compared to cognitively unimpaired (CU) controls. Methods Forty cases and 80 controls, matched by sex and age (± 3years), were participants of the longitudinal population-based Heinz Nixdorf Recall study (baseline: 2000–2003). Standardized cognitive performance was assessed 5 (T1) and 10 years after baseline (T2). Cases were CU at T1 and had incidental aMCI at T2. Controls were CU at T1 and T2. Blood KLK8 was measured at T2. Using multiple logistic regression the association between KLK8 in cases vs. controls was investigated by estimating odds ratios (OR) and 95% confidence intervals (95%CI), adjusted for inter-assay variability and freezing duration. Using receiver operating characteristic (ROC) analysis, the diagnostic accuracy of KLK8 was determined by estimating the area under the curve (AUC) and 95%CI (adjusted for inter-assay variability, freezing duration, age, sex). Results Thirty-seven participants with aMCI vs. 72 CU (36.7%women, 71.0±8.0 (mean±SD) years) had valid KLK8 measurements. Mean KLK8 was higher in cases than in controls (911.6±619.8 pg/ml vs.783.1±633.0 pg/ml). Fully adjusted, a KLK8 increase of 500pg/ml was associated with a 2.68 (1.05–6.84) higher chance of having aMCI compared to being CU. With an AUC of 0.92 (0.86–0.97), blood KLK8 was a strong discriminator for aMCI and CU. Conclusion This is the first population-based study to demonstrate the potential clinical utility of blood KLK8 as a biomarker for incipient AD.

Utility of the Intelligibility in Context Scale for Predicting Speech Intelligibility of Children with Cerebral Palsy

The Intelligibility in Context Scale (ICS) is a widely used, efficient tool for describing a child’s speech intelligibility. Few studies have explored the relationship between ICS scores and transcription intelligibility scores, which are the gold standard for clinical measurement. This study examined how well ICS composite scores predicted transcription intelligibility scores among children with cerebral palsy (CP), how well individual questions from the ICS differentially predicted transcription intelligibility scores, and how well the ICS composite scores differentiated between children with and without speech motor impairment. Parents of 48 children with CP, who were approximately 13 years of age, completed the ICS. Ninety-six adult naïve listeners provided orthographic transcriptions of children’s speech. Transcription intelligibility scores were regressed on ICS composite scores and individual item scores. Dysarthria status was regressed on ICS composite scores. Results indicated that ICS composite scores were moderately strong predictors of transcription intelligibility scores. One individual ICS item differentially predicted transcription intelligibility scores, and dysarthria severity influenced how well ICS composite scores differentiated between children with and without speech motor impairment. Findings suggest that the ICS has potential clinical utility for children with CP, especially when used with other objective measures of speech intelligibility.

Impact of Immunoscore on the Management of Stage II Colon Cancer Patients: A Physician Survey

Background: Adjuvant chemotherapy use in stage II colon cancer is controversial. Current prognostic risk factors do not take the tumor immune microenvironment into account. Consideration of the Immunoscore, which measures the host immune response at the tumor site, may assist clinicians in reducing adjuvant chemotherapy use in patients who are unlikely to benefit from it. This study sought to determine the potential clinical utility of the Immunoscore, via its effect on medical oncologists’ recommendations for management of patients with stage II colon cancer. Methods: De-identified vignettes of 10 patients with stage II colon cancer were presented to 25 practicing medical oncologists. Each participant completed surveys indicating recommendations for adjuvant chemotherapy and surveillance strategies. An educational session was subsequently conducted, and the same patient profiles were re-presented but included immunoscore results. Participants were again asked to provide their recommendations. A participant was counted as influenced if their responses were altered after immunoscore test results were provided. Results: All but one participant (96%) altered a management recommendation for ≥1 case. For individual cases, a mean of 55% (range, 40–80%) of participants altered their recommendations for adjuvant chemotherapy and/or surveillance. For the immunoscore-high cases (low-risk of recurrence), recommendations for adjuvant chemotherapy use decreased from 60% to 31%. Conclusions: These results indicate a willingness by oncologists to integrate immunoscore information into clinical practice recommendations. Incorporation of immunoscore data resulted in the reduction of nonvalue care in the simulated population. Confirmation in prospective studies is planned.

Rostral Anterior Cingulate Activations Inversely Relate To Reward Payoff Maximation & Predict Depressed Mood

Choice selection strategies and decision making are typically investigated using multiple-choice gambling paradigms that require participants to maximize reward payoff. However, research shows that performance in such paradigms suffers from individual biases towards the frequency of gains to choose smaller local gains over larger longer term gain, also referred to as melioration. Here, we developed a simple two-choice reward task, implemented in 186 healthy human adult subjects across the adult lifespan to understand the behavioral, computational, and neural bases of payoff maximization versus melioration. The observed reward choice behavior on this task was best explained by a reinforcement learning model of differential future reward prediction. Simultaneously recorded and source-localized electroencephalography (EEG) showed that diminished theta-band activations in the right rostral anterior cingulate cortex (rACC) correspond to greater reward payoff maximization, specifically during the presentation of cumulative reward information at the end of each task trial. Notably, these activations (greater rACC theta) predicted self-reported depressed mood symptoms, thereby showcasing a reward processing marker of potential clinical utility.