Ketorolac Injections for Musculoskeletal Conditions: A Narrative Review.

Musculoskeletal conditions of the upper and lower extremities are commonly treated with corticosteroid injections. Ketorolac, a parenteral nonsteroidal anti-inflammatory drug, represents an alternative injectant for common shoulder, hip, and knee conditions. A review of the current literature was conducted on the efficacy of ketorolac injection in musculoskeletal diseases. Several studies support the use and efficacy of ketorolac injection in subacromial bursitis, adhesive capsulitis, and hip and knee osteoarthritis. Given the systemic effects of glucocorticoid injections, ketorolac may be a safe and effective alternative in patients with musculoskeletal disease. However, more evidence is required to better understand the effects ketorolac has on the human body during inflammatory processes.

Ultrasound Measurement of Femoral Articular Cartilage Thickness Before and After Marathon Running.

OBJECTIVE: The purpose of this study was to use ultrasonography to measure femoral articular cartilage thickness changes during marathon running, which could support MRI studies showing that deformation of knee cartilage during long-distance running is no greater than that for other weight-bearing activities. MATERIALS AND METHODS: Participants included 38 marathon runners with no knee pain or history of knee injury, aged 18-39. Ultrasound images of the femoral articular cartilage were taken two hours before and immediately after the race. Femoral articular cartilage thickness was measured at both the medial and lateral femoral condyles. RESULTS: The maximum change in femoral articular cartilage thickness, measured at the left outer lateral femoral condyle, was 6.94% (P=.006). All other femoral articular cartilage thickness changes were not significant. CONCLUSION: A change in femoral articular cartilage thickness of 6.94% supports our hypothesis that long-distance running does not induce deformational changes greater than that of regular daily activities. This study using ultrasonography supports MRI evidence that knee cartilage tolerates marathon running well.

Do physicians know when to refer patients for genetic testing?

Primary care physicians (PCPs) are commonly approached with concerns involving patient genetics. This is a challenge because most PCPs lack expertise in genetic testing compared to their genetic counselor counterparts. Currently, the recommended best practice is to refer patients for genetic testing based on cancer-related family history questionnaires with a genetic counseling referral to discuss their results and any implications. However, the extent to which PCPs are using these questionnaires for this purpose remains poorly understood. In this cross-sectional study, PCPs were presented with the American Cancer Society's seven recommended family history questions to determine the percentage who consider each to be an indicator for referral to a genetics specialist. Questionnaires were completed by 88 of 260 attending PCPs at a national primary care review conference. The main outcome was the percentage of PCPs who identified each question as a trigger for genetic testing. Secondary outcomes included correlations with years of practice, genetics training, and methods used to obtain patient family history. Only two of the seven questions were considered triggers by most PCPs (range, 76-83%). The remaining five had lower percentages (range, 22-55%). Years of practice did not influence the number of triggers identified (Spearman correlation coefficient test: r = 0.05, p = 0.68). Few PCPs (3.4%) felt they had good to excellent genetics training during residency. Only 44.3% had genetics specialists available for referral. Overall, low percentages of PCPs consider the American Cancer Society questions to be triggers for genetic testing referrals. Furthermore, many do not have a genetics specialist or counselor available for referral. Addressing these concerns may help PCPs understand the basics of genetic testing and use standardized questionnaires to make appropriate referrals to genetic specialists, thereby reducing inappropriate referrals and improving appointment access to this precious resource for those who truly need it.

Genomics combined with a protein informatics platform to assess a novel pathogenic variant c.1024 A>G (p.K342E) in OPA1 in a patient with autosomal dominant optic atrophy.

BACKGROUND: Autosomal Dominant Optic Atrophy (ADOA) is caused by mutations in the Optic Atrophy 1 Gene which disrupts the OPA1 protein. This disruption affects the normal function of the protein; impairs fusion of the mitochondrial inner membrane; and prevents normal OPA1 protein degradation. These events cause damage in retinal ganglion cells that could affect the patients with symptoms ranging from none to legally blind. MATERIALS AND METHODS: Our study identifies a missense variant mutation, c.1024 A > G (p.K342E), in OPA1 gene causing ADOA. Diagnosed clinically in three family members and the presence of this mutation was confirmed in two members by genetic testing. Pathogenic variants in OPA1 impact the secondary protein structure and function by causing non-conservative amino acid substitutions. We also modeled this mutation and compared it to the wild type using statistical mechanics. RESULTS AND CONCLUSIONS: The proband's pathogenic variant, c.1024 A > G (p.K342E), is located in the GTPase domain of OPA1 and causes changes in the protein structure by affecting the oligomerization pattern thus resulting in ADOA. Identifying the pathogenic potential of the missense mutations in the OPA1 gene using neoteric protein modeling techniques would help in the early detection of ADOA in patients who have family history of blindness. This action would help in providing early follow up, possible treatment in the future, and genetic counseling. Abbreviations: ADOA: Autosomal Dominant Optic Atrophy; CYCS: Caspase Activator Cytochrome C; OPA1: Optic Atrophy Gene 1; RGC: Retinal Ganglion Cells; VUS: Variant of Uncertain Significance.

Examination of Molecular Effects of MYLK Deletion in a Patient with Extensive Aortic, Carotid, and Abdominal Dissections That Underlie the Genetic Dysfunction.

We describe the phenotype of a patient with extensive aortic, carotid, and abdominal dissections. The proband was found to have a heterozygous deletion of exons 21-34 in MYLK, which is a rare finding, as deletions in this gene have been infrequently reported. We describe this finding following detection in a proband with an extensive history of aortic, carotid, and abdominal dissections. Neoteric molecular modeling techniques to help determine the impact of this deletion on protein function indicated loss of function due to lack of any kinase domain. We also provide the electrostatics calculations from the wild type and mutant variant. Through a combined multiomic approach of clinical, functional, and protein informatics, we arrive at a data fusion for determination of pathogenicity embedded within the genetic code for this particular genetic variant, which, as a platform, continues to broaden its scope across the field of variants of uncertain significance classification.

Psychosocial and Financial Burden of Therapy in USA Patients with Pulmonary Arterial Hypertension.

Abstract: Pulmonary arterial hypertension (PAH) is a devastating disease with significant morbidity and mortality. There are many psychosocial and financial implications of this disease; however, little is known how this affects the treatment of PAH patients. A questionnaire-based prospective cohort study was performed on 106 PAH patients from a Pulmonary Hypertension Center and the Pulmonary Hypertension Association national conference in 2018. The demographic, treatment, psychosocial, employment, financial impact on treatment data was obtained. The majority of patients had cardiopulmonary symptoms despite treatment. The symptoms affected their social and work lives, with about one in three applying for disability because of their PAH. The majority of PAH patients had insurance coverage, but still noted a significant financial burden of the disease, with nearly a half who needed financial assistance to pay for their PAH medications. Thirty (28.3%; 95% CI, 20.6-37.5%) patients mentioned they changed their medication regimen, with some skipping doses outright (28 [26.4%; 95% CI, 19-35.6%]) in order to save money. PAH continues to cause significant psychosocial and financial burden on patients despite advances in medications. This impact ranged from dissatisfaction with quality of life, to unemployment, to altering their medication regimen to save money.

Acute pulmonary embolism in patients with obstructive sleep apnea: frequency, hospital outcomes, and recurrence.

STUDY OBJECTIVES: The objectives of this study were to assess the effect of obstructive sleep apnea (OSA) on the risk of acute pulmonary embolism (PE), hospital outcomes including mortality, and PE recurrence. METHODS: We retrospectively enrolled adult patients, admitted to Mayo Clinic Hospital in Rochester, Minnesota, within a 5-year period (2009-2013). We compared frequency of PE, hospital mortality, and secondary outcomes in patients with OSA versus patients without OSA. We assessed risk of PE recurrence in relation to compliance with OSA therapy. RESULTS: Of 25,038 patients, 3,184 (13%) had OSA and 283 (1.1%) experienced PE. Frequency of PE in patients with and without OSA was 2.4% versus 0.9% (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.9-3.3; P < .001). OSA was independently associated with increased risk of PE after adjusting for demographics and comorbidities (OR, 1.44; 95% CI, 1.07-1.9; P = .017). Adjusted hospital mortality was increased in patients with PE (OR, 2.88; 95% CI, 1.7-4.9; P < .001) but not in patients with OSA (OR, 0.98; 95% CI, 0.7-1.4, P = .92). OSA was not a significant determining factor for mortality in patients who experienced a PE (OR, 0.56; 95% CI, 0.1.1-2.78; P = .47), adjusting for demographics, PE severity, and Charlson comorbidity index. Adjusted risk of PE recurrence was greater in patients with OSA compared with patients without OSA (OR, 2.21; 95% CI, 1.05-4.68; P < .04). The patients compliant with OSA therapy had a lower rate of PE recurrence (16% vs 32%; P = not significant). CONCLUSIONS: Although OSA significantly increases risk of acute PE occurrence and recurrences, related hospital mortality was not greater in patients with OSA compared with those without OSA. OSA therapy might have a modifying effect on PE recurrence.

Artificial Intelligent Virtual Assistant for Plastic Surgery Patient's Frequently Asked Questions: A Pilot Study.

BACKGROUND: Artificial Intelligent Virtual Assistants (AIVA) is a segment of artificial intelligence that is rapidly developing. However, its utilization to address patients' frequently asked questions remains unexplored. METHODS: We developed an AIVA to answer questions related to 10 frequent topics asked by plastic surgery patients in our institution. Between July 27, 2018, and August 10 of 2018, we recruited subjects with administrative positions at our health care institution to chat with the virtual assistant. They asked, with their own words, 1 question for each topic and filled out a satisfaction questionnaire. Postsurvey analysis of questions and answers allowed assessment of the virtual assistant's accuracy. RESULTS: Thirty participants completed the survey. The majority was female (70%), and the mean age was 27.76 years (SD, 8.68 [19-51] years). The overall accuracy of the plastic surgery AIVA was 92.3% (277/294 questions), and participants considered the answer correct in 83.3% of the time (250/294 answers). Most of the participants considered the AIVA easy to use, answered adequately, and could be helpful for patients. However, when asked if this technology could replace a human assistant, they stayed neutral.

Characterization of a Pathogenic Variant in the ABCD1 Gene Through Protein Molecular Modeling.

BACKGROUND: The ATP-binding cassette, subfamily D, member 1 (ABCD1) protein is a peroxisomal half-transporter that allows for very long chain fatty acid (VLCFA) degradation. Pathogenic variants of ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. METHODS: A newly characterized and suspected pathogenic variant in ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. RESULTS: A case of adult onset adrenomyeloneuropathy (AMN) and a novel ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. CONCLUSIONS: Data fusion from multiple sources was combined in a comprehensive approach yielding an enriched assessment of the patient's disease and prognosis. Molecular modeling was performed on the variant to better characterize its clinical significance and confirm pathogenicity.

Genomic Observations of a Rare/Pathogenic SMAD3 Variant in Loeys⁻Dietz Syndrome 3 Confirmed by Protein Informatics and Structural Investigations.

Background and objectives: Loeys-Dietz syndrome 3, also known as aneurysms--osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-ß signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. Common features include scoliosis, uvula abnormalities, striae, and velvety skin. Materials and Methods: The pathogenicity of a variant of uncertain significance in the SMAD3 gene was evaluated (variant c.220C > T) through personalized protein informatics and molecular studies. Results: The case of a 44-year-old male, who was originally presumed to have Marfan syndrome, is presented. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C > T (p.R74W). His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys-Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity.

Cost-Utility of Routine Testing in Chronic Urticaria/Angioedema: A Cohort Study.

BACKGROUND: Chronic urticaria/angioedema (CUA) guidelines recommend limiting tests to diagnose and assess prognosis, activity, and severity. Routine testing in CUA might substantially increase cost of disease without benefiting outcome. OBJECTIVE: To evaluate the utility of tests in CUA and how they influence the cost of disease. METHODS: We reviewed 725 electronic medical records of patients who were evaluated for CUA between 2010 and 2018 at a tertiary care center. The sample was gathered through the search of International Classification of Diseases Ninth and Tenth Revision codes pertaining to CUA. Analyses were made to evaluate changes in outcome for patients on whom at least 1 test was performed to evaluate CUA, the costs generated by these tests, and the tendencies to order specific tests from 2010 through 2018. RESULTS: Of 725 patients (age median, 47 years; women, 73.1%), 543 (74.8%) had at least 1 test performed. Tests had an elevated percentage of normal results (>90%). Five patients (0.9%) had a change in outcome and 8 patients were given a different diagnosis (0.1% each). Evaluation, management, and tests accounted for most of the costs. Costs remain similar between 2010-2014 (mean, $569) and 2015-2018 (mean, $569). CONCLUSIONS: In CUA, tests rarely uncover underlying conditions or lead to changes in management and outcome, but they substantially increase the costs generated by the disease. Adherence to current recommendations to limit testing might help in reducing the financial burden of CUA and improve delivery of care.

Patient with Marfan Syndrome and a Novel Variant in FBN1 Presenting with Bilateral Popliteal Artery Aneurysm.

We present a 43-year-old man with aortic root dilation, mitral valve prolapse, and marfanoid appearance, who presented with acute onset left leg pain. He underwent a Doppler ultrasound that revealed left popliteal artery aneurysm with thrombus. CT angiogram showed bilateral popliteal artery aneurysms. After repairing of his left popliteal artery aneurysm, he was sent for genetic evaluation. He was diagnosed with Marfan syndrome (MFS) based on the revised Ghent criteria and then underwent FBN1 sequencing and deletion/duplication analysis, which detected a novel pathogenic variant in gene FBN1, denoted by c.5872 T>A (p.Cys1958Ser). MFS is a connective tissue disorder with an autosomal dominant inheritance due to pathogenic variants in FBN1 that encodes Fibrillin-1, a major element of the extracellular matrix, and connective tissue throughout the body. MFS involves multiple systems, most commonly the cardiovascular, musculoskeletal, and visual systems. In our case we present a rare finding of bilateral popliteal artery aneurysms in a male patient with MFS.

Early intervention in the management of pulmonary arterial hypertension: clinical and economic outcomes.

Pulmonary arterial hypertension (PAH) has a high morbidity rate and is fatal if left untreated. Increasing evidence supports early intervention, possibly with initial combination therapy. PAH-specific pharmaceuticals, however, are expensive and may have serious adverse effects, particularly when used in combination. The currently dynamic health care economy reinforces the need for a review of early intervention from both outcomes and economic perspectives. We aimed to review the clinical and economic impact of PAH therapy, particularly examining drug cost, hospitalization burden, and health care economics impact, and the effect of early intervention on clinical outcomes. We searched PubMed, Scopus, Ovid, and MEDLINE databases from 2005 to 2017 for studies comparing drug cost, clinical outcomes, and hospitalization burden associated with therapy for PAH. Emerging data indicate that early therapy is effective, but drug therapy is expensive, particularly with combination therapy. Efficacy studies also generally show benefit of combination therapy for patients in World Health Organization functional class II, with a consistent decrease in hospitalization. Pharmacoeconomic studies are limited but indicate that increased pharmacy costs are at least partially offset by decreased health care utilization, particularly inpatient care. Modeling also shows a cost benefit with combination therapy at 2 years. Nonetheless, more rigorously collected health care economic data should be incorporated into future drug efficacy trials to provide a clearer understanding of the impact and the associated cost benefit of early PAH therapy. Increasing evidence in support of early intervention and combination therapy for PAH is associated with rising medication costs that are largely offset by reduced hospitalization, on the basis of the currently available literature. Nonetheless, the studies performed to date have methodologic limitations that highlight the need for prospective studies using more robust economic modeling.

Health IT Usability Focus Section: Data Use and Navigation Patterns among Medical ICU Clinicians during Electronic Chart Review.

Background A detailed understanding of electronic health record (EHR) workflow patterns and information use is necessary to inform user-centered design of critical care information systems. While developing a longitudinal medical record visualization tool to facilitate electronic chart review (ECR) for medical intensive care unit (MICU) clinicians, we found inadequate research on clinician­EHR interactions. Objective We systematically studied EHR information use and workflow among MICU clinicians to determine the optimal selection and display of core data for a revised EHR interface. Methods We conducted a direct observational study of MICU clinicians performing ECR for unfamiliar patients during their routine daily practice at an academic medical center. Using a customized manual data collection instrument, we unobtrusively recorded the content and sequence of EHR data reviewed by clinicians. Results We performed 32 ECR observations among 24 clinicians. The median (interquartile range [IQR]) chart review duration was 9.2 (7.3­14.7) minutes, with the largest time spent reviewing clinical notes (44.4%), laboratories (13.3%), imaging studies (11.7%), and searching/scrolling (9.4%). Historical vital sign and intake/output data were never viewed in 31% and 59% of observations, respectively. Clinical notes and diagnostic reports were browsed ≥10 years in time for 60% of ECR sessions. Clinicians viewed a median of 7 clinical notes, 2.5 imaging studies, and 1.5 diagnostic studies, typically referencing a select few subtypes. Clinicians browsed a median (IQR) of 26.5 (22.5­37.25) data screens to complete their ECR, demonstrating high variability in navigation patterns and frequent back-and-forth switching between screens. Nonetheless, 47% of ECRs begin with review of clinical notes, which were also the most common navigation destination. Conclusion Electronic chart review centers around the viewing of clinical notes among MICU clinicians. Convoluted workflows and prolonged searching activities indicate room for system improvement. Using study findings, specific design recommendations to enhance usability for critical care information systems are provided.