Multiparametric whole-body MRI of patients with neurofibromatosis type I: spectrum of imaging findings.

Neurofibromatosis (NF) type I is a neuroectodermal and mesodermal dysplasia caused by a mutation of the neurofibromin tumor suppressor gene. Phenotypic features of NF1 vary, and patients develop benign peripheral nerve sheath tumors and malignant neoplasms, such as malignant peripheral nerve sheath tumor, malignant melanoma, and astrocytoma. Multiparametric whole-body MR imaging (WBMRI) plays a critical role in disease surveillance. Multiparametric MRI, typically used in prostate imaging, is a general term for a technique that includes multiple sequences, i.e. anatomic, diffusion, and Dixon-based pre- and post-contrast imaging. This article discusses the value of multiparametric WBMRI and illustrates the spectrum of whole-body lesions of NF1 in a single imaging setting. Examples of lesions include those in the skin (tumors and axillary freckling), soft tissues (benign and malignant peripheral nerve sheath tumors, visceral plexiform, and diffuse lesions), bone and joints (nutrient nerve lesions, non-ossifying fibromas, intra-articular neurofibroma, etc.), spine (acute-angled scoliosis, dural ectasia, intraspinal tumors, etc.), and brain/skull (optic nerve glioma, choroid plexus xanthogranuloma, sphenoid wing dysplasia, cerebral hamartomas, etc.). After reading this article, the reader will gain knowledge of the variety of lesions encountered with NF1 and their WBMRI appearances. Timely identification of such lesions can aid in accurate diagnosis and appropriate patient management.

Correlation Between Traditional Anteroposterior Radiographic Measurements With Lateral Radiographic Measurements Following Triplanar Correction of Hallux Valgus and With Patient-Reported Outcomes From a Prospective Multicenter Trial.

Hallux valgus (HV) is a common condition in which the first ray is deformed, leading to pain and altered joint mechanics. A variety of radiographic measurements are used to evaluate HV. Little is known about measurements used in the assessment of HV on lateral radiographs compared to anteroposterior (AP) radiographs. The primary aim of this study was to correlate lateral measurements with AP measurements pre and postoperatively. The secondary aim was to correlate lateral measurements with patient-reported outcome measures (PROMs) pre and postoperatively. One hundred eighty-three patients were initially enrolled in the study. Two fellowship-trained musculoskeletal radiologists independently performed all measurements. On AP radiographs, hallux valgus angle (HVA) and intermetatarsal angle (IMA) were measured. On lateral radiographs, sagittal IMA, Meary's angle, and sagittal first ray length were measured. Measurements were recorded at baseline and 6, 12, and 24 months postoperatively. Intraclass correlation coefficients (ICCs) were used for inter-reader analysis. ICCs were moderate to very strong among readers. There were significant but weak correlations between lateral measurements and AP measurements. For at least 1 timepoint, IMA correlated with sagittal IMA, sagittal first ray length, and Meary's angle. HVA only correlated with sagittal first ray length. These correlations were all weak in magnitude. There were a few significant but weak correlations between the measurements in the study and PROMs. This study showed that sagittal IMA, sagittal first ray length, and Meary's angle are not predictive of AP measurements or patient outcomes and are not useful in preoperative assessment of HV.

Glenohumeral osteoarthritis: what the surgeon needs from the radiologist.

Glenohumeral osteoarthritis (GHOA) is a widely prevalent disease with increasing frequency due to population aging. Both clinical manifestations and radiography play key roles in the initial diagnosis, staging, and management decisions. Radiographic disease progression evaluation is performed using validated staging systems, such as Kellgren and Lawrence, Samilson, and Hamada. For young patients with mild to moderate GHOA and failed conservative treatment, arthroscopic preservation surgery (APS) is usually considered. Older patients and those with severe GHOA benefit from different types of arthroplasties. Preoperative magnetic resonance imaging (MRI) is essential for APS surgical planning, as it maps repairable labral, cartilage, and rotator cuff lesions. For arthroplasty planning, the status of glenoid cartilage and intactness of rotator cuff as well as glenoid morphology represent key factors guiding the decision regarding the most suitable hardware design, whether resurfacing, partial, total, or reverse joint replacement. Pre-surgical MRI or alternatively computed tomography arthrogram is employed to evaluate the cartilage and rotator cuff. Finally, three-dimensional computed tomography (3D CT) is indicated to optimally assess the glenoid morphology (to determine Walch classification, version, inclination, and bone loss) and analyze the necessity for glenoid osteotomy or graft augmentation to correct the glenoid structural abnormalities for future success and longevity of the shoulder implants or chosen constructs. Understanding the purpose of each imaging and treatment modality allows more efficient image interpretation. This article reviews the above concepts and details what a surgeon needs from a radiologist and could benefit from accurate reporting of preoperative imaging studies.

Interreader reliability assessment of hallux valgus evaluation on dorsoplantar weightbearing radiographs from a prospective multi-center trial and correlation with patient-reported outcome measures.

OBJECTIVE: To determine inter-reader reliability (IRR) of hallux valgus (HV) related parameters, i.e. intermetatarsal angle (IMA), hallux valgus angle (HVA), lateral round sign of the first metatarsal, tibial sesamoid position (TSP), metatarsus adductus angle (MAA), transverse osseous foot width, 1st MT length, MTP osteoarthritis (OA), and distal metatarsal articular angle (DMAA). These were correlated with patient-reported outcome measures (PROMs). MATERIALS AND METHODS: A prospective single-arm Level 3 multicenter clinical trial in which standardized radiographs and PROMs were collected at the time of the initial patient visit for pre-operative assessment. Two musculoskeletal radiologists performed measurements blinded to each other's reads and clinical information. Intraclass coefficient and kappa were obtained for inter-reader analysis. A partial spearman rank order was used to correlate the measurements with PROMs. RESULTS: The final cohort size of 183 patients had mean age of 40.77 years, mean body mass index was 26.11 kg/m2, with 91.2% females and 8.7% males. There was excellent IRR for HVA (0.96, CI: [0.94,0.97]), IMA (0.92, CI: [0.89,0.94]), transverse osseous foot width (0.99, CI: [0.98,1.00]), and DMAA (0.80, CI: [0.74, 0.85]), good agreement for TSP (0.73, CI:[0.67,0.79]) and MAA (0.67, CI: [0.16, 0.84]), fair agreement for MTP OA (0.48, CI: [0.36,0.59]), and poor agreement for lateral round sign (0.32, CI: [0.11, 0.52]. The negative correlation of increasing transverse osseous foot width with worsening PROMIS physical but better MOxFQ and VAS scores is likely spurious. CONCLUSION: Good to excellent inter-reader reliability was observed for the most often used measurements for HV assessment without major trends in their correlations with PROMs. Lateral round sign is not a reliable finding in HV deformity.

General Anxiety Is Associated with Problematic Initial Recovery After Carpal Tunnel Release.

BACKGROUND: Carpal tunnel release can stop the progression of idiopathic median neuropathy at the wrist (carpal tunnel syndrome). Intermittent symptoms tend to resolve after surgery, but loss of sensibility can be permanent. Both pathophysiology (severe neuropathy) and mental health (symptoms of despair or worry) contribute to problematic recovery after carpal tunnel release, but their relative associations are unclear. QUESTION/PURPOSE: Is problematic initial recovery after carpal tunnel release associated with psychologic distress rather than with disease severity? METHODS: We retrospectively studied 156 patients who underwent in-office carpal tunnel release between November 2017 and February 2020, and we recorded their symptoms of anxiety (Generalized Anxiety Disorder-7 [GAD]) and depression (Patient Health Questionnaire), signs of severe median neuropathy (loss of sensibility, thenar muscle atrophy, and palmar abduction weakness), and problematic recovery. The initial recovery (first 2 weeks) was categorized as problematic if the patient was upset about persistent numbness, experienced unsettling postoperative pain, developed hand stiffness, or experienced wound issues-all of which are routinely recorded in the medical record by the treating surgeon along with signs of severe median neuropathy. Twenty-four percent (38 of 156) of patients had a problematic initial recovery characterized by distress regarding persistent numbness (16% [25 of 156]), unsettling pain (8% [12 of 156]), hand stiffness (5% [8 of 156]), or wound issues (1% [2 of 156]); 6% (9 of 156) of patients had more than one issue. Associations between problematic initial recovery and age, gender, symptoms of anxiety and depression, disease severity, specific exam findings, and insurance were evaluated using t-tests, Mann-Whitney tests, and chi-square tests, with the plan to perform logistic regression if at least two variables had an association with p < 0.10. RESULTS: The only factor associated with problematic initial recovery was greater symptoms of anxiety (median GAD score 1.5 [interquartile range 0 to 7.8] for problematic initial recovery compared with a median score of 0 [IQR 0 to 2] for nonproblematic recovery; p = 0.04), so we did not perform a logistic regression. Physical examination findings consistent with severe median neuropathy were not associated with problematic initial recovery. CONCLUSION: The finding that problematic initial recovery after carpal tunnel release was related to symptoms of anxiety and not to the severity of median neuropathy highlights the need to study the ability of efforts to ameliorate anxiety symptoms before carpal tunnel release as an effective intervention to reduce unplanned visits and additional tests, therapy, and repeat surgery, while improving patient-reported outcomes and experience. LEVEL OF EVIDENCE: Level III, therapeutic study.

The long non-coding RNA NEAT1 is elevated in polyglutamine repeat expansion diseases and protects from disease gene-dependent toxicities.

Polyglutamine (polyQ) repeat diseases are a class of neurodegenerative disorders caused by CAG-repeat expansion. There are diverse cellular mechanisms behind the pathogenesis of polyQ disorders, including transcriptional dysregulation. Interestingly, we find that levels of the long isoform of nuclear paraspeckle assembly transcript 1 (Neat1L) are elevated in the brains of mouse models of spinocerebellar ataxia types 1, 2, 7 and Huntington's disease (HD). Neat1L was also elevated in differentiated striatal neurons derived from HD knock-in mice and in HD patient brains. The elevation was mutant Huntingtin (mHTT) dependent, as knockdown of mHTT in vitro and in vivo restored Neat1L to normal levels. In additional studies, we found that Neat1L is repressed by methyl CpG binding protein 2 (MeCP2) by RNA-protein interaction but not by occupancy of MeCP2 at its promoter. We also found that NEAT1L overexpression protects from mHTT-induced cytotoxicity, while reducing it enhanced mHTT-dependent toxicity. Gene set enrichment analysis of previously published RNA sequencing data from mouse embryonic fibroblasts and cells derived from HD patients shows that loss of NEAT1L impairs multiple cellular functions, including pathways involved in cell proliferation and development. Intriguingly, the genes dysregulated in HD human brain samples overlap with pathways affected by a reduction in NEAT1, confirming the correlation of NEAT1L and HD-induced perturbations. Cumulatively, the role of NEAT1L in polyQ disease model systems and human tissues suggests that it may play a protective role in CAG-repeat expansion diseases.

Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo.

The neuronal ceroid lipofuscinoses are a class of inherited neurodegenerative diseases characterized by the accumulation of autofluorescent storage material. The most common neuronal ceroid lipofuscinosis has juvenile onset with rapid onset blindness and progressive degeneration of cognitive processes. The juvenile form is caused by mutations in the CLN3 gene, which encodes the protein CLN3. While mouse models of Cln3 deficiency show mild disease phenotypes, it is apparent from patient tissue- and cell-based studies that its loss impacts many cellular processes. Using Cln3 deficient mice, we previously described defects in mouse brain endothelial cells and blood-brain barrier (BBB) permeability. Here we expand on this to other components of the BBB and show that Cln3 deficient mice have increased astrocyte endfeet area. Interestingly, this phenotype is corrected by treatment with a commonly used GAP junction inhibitor, carbenoxolone (CBX). In addition to its action on GAP junctions, CBX has also been proposed to alter lipid microdomains. In this work, we show that CBX modifies lipid microdomains and corrects membrane fluidity alterations in Cln3 deficient endothelial cells, which in turn improves defects in endocytosis, caveolin-1 distribution at the plasma membrane, and Cdc42 activity. In further work using the NIH Library of Integrated Network-based Cellular Signatures (LINCS), we discovered other small molecules whose impact was similar to CBX in that they improved Cln3-deficient cell phenotypes. Moreover, Cln3 deficient mice treated orally with CBX exhibited recovery of impaired BBB responses and reduced autofluorescence. CBX and the compounds identified by LINCS, many of which have been used in humans or approved for other indications, may find therapeutic benefit in children suffering from CLN3 deficiency through mechanisms independent of their original intended use.

Cis-acting single nucleotide polymorphisms alter MicroRNA-mediated regulation of human brain-expressed transcripts.

Substantial variability exists in the presentation of complex neurological disorders, and the study of single nucleotide polymorphisms (SNPs) has shed light on disease mechanisms and pathophysiological variability in some cases. However, the vast majority of disease-linked SNPs have unidentified pathophysiological relevance. Here, we tested the hypothesis that SNPs within the miRNA recognition element (MRE; the region of the target transcript to which the miRNA binds) can impart changes in the expression of those genes, either by enhancing or reducing transcript and protein levels. To test this, we cross-referenced 7,153 miRNA-MRE brain interactions with the SNP database (dbSNP) to identify candidates, and functionally assessed 24 SNPs located in the 3'UTR or the coding sequence (CDS) of targets. For over half of the candidates tested, SNPs either enhanced (4 genes) or disrupted (10 genes) miRNA binding and target regulation. Additionally, SNPs causing a shift from a common to rare codon within the CDS facilitated miRNA binding downstream of the SNP, dramatically repressing target gene expression. The biological activity of the SNPs on miRNA regulation was also confirmed in induced pluripotent stem cell (iPSC) lines. These studies strongly support the notion that SNPs in the 3'UTR or the coding sequence of disease-relevant genes may be important in disease pathogenesis and should be reconsidered as candidate modifiers.

Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion in the gene-encoding Huntingtin (HTT). Transcriptome dysregulation is a major feature of HD pathogenesis, as revealed by a large body of work on gene expression profiling of tissues from human HD patients and mouse models. These studies were primarily focused on transcriptional changes affecting steady-state overall gene expression levels using microarray based approaches. A major missing component, however, has been the study of transcriptome changes at the post-transcriptional level, such as alternative splicing. Alternative splicing is a critical mechanism for expanding regulatory and functional diversity from a limited number of genes, and is particularly complex in the mammalian brain. Here we carried out a deep RNA-seq analysis of the BA4 (Brodmann area 4) motor cortex from seven human HD brains and seven controls to systematically discover aberrant alternative splicing events and characterize potential associated splicing factors in HD. We identified 593 differential alternative splicing events between HD and control brains. Using two expanded panels with a total of 108 BA4 tissues from patients and controls, we identified four splicing factors exhibiting significantly altered expression levels in HD patient brains. Moreover, follow-up molecular analyses of one splicing factor PTBP1 revealed its impact on disease-associated splicing patterns in HD. Collectively, our data provide genomic evidence for widespread splicing dysregulation in HD brains, and suggest the role of aberrant alternative splicing in the pathogenesis of HD.

Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.

Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how the loss of CFTR function first disrupts airway host defence has remained uncertain. To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, we interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed from the lung and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO(3)(-) transport. Without CFTR, airway epithelial HCO(3)(-) secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions.

SYVN1, NEDD8, and FBXO2 Proteins Regulate ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation.

We previously reported that delivery of a microRNA-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (ΔF508/ΔF508) airway epithelia partially restored ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated cAMP-stimulated Cl- conductance. We hypothesized that dissecting this microRNA-138/SIN3A-regulated gene network would identify individual proteins contributing to the rescue of ΔF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia. We found that depletion of the ubiquitin ligase SYVN1, the ubiquitin/proteasome system regulator NEDD8, or the F-box protein FBXO2 partially restored ΔF508-CFTR-mediated Cl- transport in primary cultures of human cystic fibrosis airway epithelia. Moreover, knockdown of SYVN1, NEDD8, or FBXO2 in combination with corrector compound 18 further potentiated rescue of ΔF508-CFTR-mediated Cl- conductance. This study provides new knowledge of the CFTR biosynthetic pathway. It suggests that SYVN1 and FBXO2 represent two distinct multiprotein complexes that may degrade ΔF508-CFTR in airway epithelia and identifies a new role for NEDD8 in regulating ΔF508-CFTR ubiquitination.

Adherens junction protein nectin-4 is the epithelial receptor for measles virus.

Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths. Although it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously. How and where the virus crosses back into the airways has remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, here we identify nectin-4 (ref. 8; also called poliovirus-receptor-like-4 (PVRL4)) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains measles virus entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is downregulated in infected epithelial cells, including those of macaque tracheae. Although other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that measles virus targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer, which has implications for ongoing measles-virus-based clinical trials of oncolysis.

Newborn Cystic Fibrosis Pigs Have a Blunted Early Response to an Inflammatory Stimulus.

RATIONALE: Studies suggest that inappropriate responses to proinflammatory stimuli might contribute to inflammation in cystic fibrosis (CF) lungs. However, technical challenges have made it difficult to distinguish whether altered responses in CF airways are an intrinsic defect or a secondary effect of chronic disease in their tissue of origin. The CF pig model provides an opportunity to study the inflammatory responses of CF airways at birth, before the onset of infection and inflammation. OBJECTIVES: To test the hypothesis that acute inflammatory responses are perturbed in porcine CF airways. METHODS: We investigated the inflammatory responses of newborn CF and non-CF pig airways following a 4-hour exposure to heat-killed Staphylococcus aureus, in vivo and in vitro. MEASUREMENTS AND MAIN RESULTS: Following an in vivo S. aureus challenge, markers of inflammation were similar between CF and littermate control animals through evaluation of bronchoalveolar lavage and tissues. However, transcriptome analysis revealed genotype-dependent differences as CF pigs showed a diminished host defense response compared with their non-CF counterparts. Furthermore, CF pig airways exhibited an increase in apoptotic pathways and a suppression of ciliary and flagellar biosynthetic pathways. Similar differences were observed in cultured airway epithelia from CF and non-CF pigs exposed to the stimulus. CONCLUSIONS: Transcriptome profiling suggests that acute inflammatory responses are dysregulated in the airways of newborn CF pigs.

Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense.

While pathological and clinical data suggest that small airways are involved in early cystic fibrosis (CF) lung disease development, little is known about how the lack of cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to disease pathogenesis in these small airways. Large and small airway epithelia are exposed to different airflow velocities, temperatures, humidity, and CO2 concentrations. The cellular composition of these two regions is different, and small airways lack submucosal glands. To better understand the ion transport properties and impacts of lack of CFTR function on host defense function in small airways, we adapted a novel protocol to isolate small airway epithelial cells from CF and non-CF pigs and established an organotypic culture model. Compared with non-CF large airways, non-CF small airway epithelia cultures had higher Cl(-) and bicarbonate (HCO3 (-)) short-circuit currents and higher airway surface liquid (ASL) pH under 5% CO2 conditions. CF small airway epithelia were characterized by minimal Cl(-) and HCO3 (-) transport and decreased ASL pH, and had impaired bacterial killing compared with non-CF small airways. In addition, CF small airway epithelia had a higher ASL viscosity than non-CF small airways. Thus, the activity of CFTR is higher in the small airways, where it plays a role in alkalinization of ASL, enhancement of antimicrobial activity, and lowering of mucus viscosity. These data provide insight to explain why the small airways are a susceptible site for the bacterial colonization.

A microRNA network regulates expression and biosynthesis of wild-type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator.

Production of functional proteins requires multiple steps, including gene transcription and posttranslational processing. MicroRNAs (miRNAs) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that miRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with an miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl(-) permeability independent of elevated mRNA levels. An miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, ΔF508, causes protein misfolding, protein degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-ΔF508 and restored Cl(-) transport to cystic fibrosis airway epithelia. This miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process more broadly than recognized previously. This discovery also provides therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation.

A genomic signature approach to rescue ΔF508-cystic fibrosis transmembrane conductance regulator biosynthesis and function.

The most common cystic fibrosis (CF) mutation, ΔF508, causes protein misfolding, leading to proteosomal degradation. We recently showed that expression of miR-138 enhances CF transmembrane conductance regulator (CFTR) biogenesis and partially rescues ΔF508-CFTR function in CF airway epithelia. We hypothesized that a genomic signature approach can be used to identify new bioactive small molecules affecting ΔF508-CFTR rescue. The Connectivity Map was used to identify 27 small molecules with potential to restore ΔF508-CFTR function in airway epithelia. The molecules were screened in vitro for efficacy in improving ΔF508-CFTR trafficking, maturation, and chloride current. We identified four small molecules that partially restore ΔF508-CFTR function in primary CF airway epithelia. Of these, pyridostigmine showed cooperativity with corrector compound 18 in improving ΔF508-CFTR function. There are few CF therapies based on new molecular insights. Querying the Connectivity Map with relevant genomic signatures offers a method to identify new candidates for rescuing ΔF508-CFTR function.

Upper Extremity Surgeon Recommendations for Imaging Do Not Correspond with Imaging Appropriateness Guidelines.

Background: Utilization of magnetic resonance imaging (MRI) and computed tomography (CT) increases annually, raising concerns about overuse. Imaging appropriateness guidelines have the potential to standardize decisions regarding imaging based on best evidence, which might reduce unhelpful or potentially misleading imaging. We studied expert use of advanced imaging for musculoskeletal illness compared to published appropriateness recommendations. Methods: First, 15 imaging guidelines with recommendations for advanced imaging of the upper extremity were collated. Next, members of the Science of Variation Group (SOVG) were invited to participate in a survey of 11 patient scenarios of common upper extremity illnesses and asked whether they would recommend MRI or CT. Guideline recommendations for imaging were compared with surgeon recommendations using Fisher's exact tests. We used Fleiss' kappa to measure the interobserver agreement among surgeons. Results: For the 11 scenarios, most imaging appropriateness guidelines suggested that MRI or CT is useful, while most surgeons (n = 108) felt it was not. There was no correlation between surgeons and guidelines recommendations for imaging (ρ = 0.28; p = 0.40). There was slight agreement among surgeons regarding imaging recommendations (kappa: 0.17; 95% confidence interval: 0.023-0.32). Conclusion: The available imaging appropriateness guidelines appear to be too permissive and therefore seem to have limited clinical utility for upper extremity surgeons. The notable surgeon-to-surgeon variation (unreliability) in recommendations for advanced imaging in this and other studies suggests a role for strategies to ensure that patient decisions about imaging are consistent with their values (what matters most to them) and not unduly influenced by patient misconceptions about imaging or by surgeon beliefs and habits. Level Of Evidence: II, diagnostic.

Assessing medical students' confidence in promoting high value care in clinical practice.

Background: Medical students who are exposed to value-based care early in their education may be more likely to practice it. Our study aimed to understand medical students' knowledge of and ability to implement the principles of high-value care in clinical settings. Additionally, we assessed students' confidence in using high-value care practices to both influence care decisions and educate patients. Methods: We surveyed third-year medical students at Texas A&M School of Medicine during their clerkship rotations using a 7-question Likert-scale survey. Students were asked to evaluate their confidence in performing cost-conscious high-value care behaviors. Results: Of the 114 students offered the survey, 34 (30%) completed it fully. The greatest variance in response occurred in students' attitudes toward their role in controlling healthcare costs. Half of respondents agreed or strongly agreed that they played a part in cost control as medical students, with 35% somewhat or strongly disagreeing. A majority of students felt confident initiating a conversation about costs with patients, while 21% somewhat or strongly disagreed that they were confident. Conclusion: Overall, our results reveal that the main area lacking in students' education in value-based care is instilling the belief that they, as medical students, have a role to play in controlling healthcare costs.

Potential Misinformation in the Official Disability Guidelines About the Diagnosis and Treatment of Rotator Cuff Tendinopathy.

OBJECTIVE: We selected statements in the Official Disability Guidelines that had the potential to reinforce misconceptions regarding symptoms from rotator cuff tendinopathy. These statements were revised and presented with the original statement to specialists. METHODS: Twelve statements regarding rotator cuff tendinopathy were identified as deviating from principles based on ethics, values, and the evidence regarding both pathophysiology and human illness behavior. One hundred fifteen upper extremity surgeons reviewed both original and revised versions of the statements and indicated their preference. RESULTS: We found that upper extremity surgeons preferred 3 revised statements, 4 Official Disability Guidelines statements, and 5 were rated as neutral between the 2 statements. CONCLUSIONS: Statements revised for evidence, ethics, and healthy mindset were not preferred by specialists, which may indicate limited awareness about how negative thoughts and distressing symptoms impact human illness.

Post-transcriptional regulation of cystic fibrosis transmembrane conductance regulator expression and function by microRNAs.

MicroRNAs (miRNAs) are increasingly recognized as important posttranscriptional regulators of gene expression, and changes in their actions can contribute to disease states. Little is understood regarding miRNA functions in the airway epithelium under normal or diseased conditions. We profiled miRNA expression in well-differentiated primary cultures of human cystic fibrosis (CF) and non-CF airway epithelia, and discovered that miR-509-3p and miR-494 concentrations were increased in CF epithelia. Human non-CF airway epithelia, transfected with the mimics of miR-509-3p or miR-494, showed decreased cystic fibrosis transmembrane conductance regulator (CFTR) expression, whereas their respective anti-miRs exerted the opposite effect. Interestingly, the two miRNAs acted cooperatively in regulating CFTR expression. Upon infecting non-CF airway epithelial cells with Staphylococcus aureus, or upon stimulating them with the proinflammatory cytokines TNF-α or IL-1ß, we observed an increased expression of both miRNAs and a concurrent decrease in CFTR expression and function, suggesting that inflammatory mediators may regulate these miRNAs. Transfecting epithelia with anti-miRs for miR-509-3p and miR-494, or inhibiting NF-κB signaling before stimulating cells with TNFα or IL-1ß, suppressed these responses, suggesting that the expression of both miRNAs was responsive to NF-κB signaling. Thus, miR-509-3p and miR-494 are dynamic regulators of CFTR abundance and function in normal, non-CF airway epithelia.