Development of a Musculoskeletal Ultrasound Protocol to Evaluate Hand Pain in Systemic Sclerosis Patients.

Hand impairment is a frequently reported complaint in systemic sclerosis (SSc) patients and a leading cause of disability and diminished quality of life. Managing hand pain can be particularly challenging due to the coexistence of non-inflammatory arthralgias, inflammatory arthritis, acro-osteolysis, tenosynovitis, joint contractures, tendon friction rubs, nerve entrapment, Raynaud's phenomenon (RP), digital ulcers (DU), sclerodactyly, calcinosis, and chronic pain. While physical examination and radiographs are the first line methods for evaluating hand pain, they are limited in scope and miss many underlying etiologies of hand impairment. We propose a joint ultrasound (US) hand protocol to differentiate between various articular, periarticular, ischemic, skin, and nerve pathologies and to assist in targeted treatment strategies.

Giant cell arteritis associated with intravenous zoledronic acid administration.

Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association between aminobisphosphonates, such as alendronate and zoledronic acid, and rheumatologic and/or immune-mediated syndromes (RIMS) has been described. Herein we report 2 patients, one with a prior history of rheumatic disease and one without, who developed giant cell arteritis meeting the American College of Rheumatology 2022 criteria following zoledronic acid infusion. We subsequently review existing mechanistic and clinical literature supporting this link. The duration of symptoms and elevation of inflammatory markers may serve as indicators for differentiating between the more common ACR and less frequent but potentially morbid RIMS. Although the benefit of bisphosphonates will outweigh the risk of RIMS for most patients with high fracture risk, clinicians should be aware of this phenomenon to assist earlier diagnosis and treatment in affected individuals.

The role of comprehensive stress cardiac MRI in autoimmune rheumatic disease: A review.

Cardiovascular disease is the leading cause of morbidity and mortality in patients with autoimmune rheumatic diseases. Much of this may be attributed to systemic inflammation resulting in coronary atherosclerosis and myocarditis. Cardiac magnetic resonance imaging is the gold standard for the evaluation of cardiac structure and function, including tissue characterization, which allows for detection of myocardial edema, inflammation, and fibrosis. Advances in parametric mapping and coronary flow reserve measurement techniques have the potential to change the diagnosis, risk stratification, and management of patients with autoimmune rheumatic diseases. We provide an overview of the current evidence and suggest potential future roles for the use of comprehensive cardiac magnetic resonance in patients with autoimmune rheumatic diseases in the field of cardio-rheumatology.

Primary Cardiac Involvement in Systemic Sclerosis: Best Approach to Diagnosis.

Primary cardiac involvement in systemic sclerosis (SSc) is an important cause of morbidity and mortality. Abnormalities of cardiac structure and function can be detected on routine cardiopulmonary screening that is the standard of care for SSc monitoring. Cardiovascular magnetic resonance-extracellular volume (indicating diffuse fibrosis) and cardiac biomarkers may identify at-risk patients who would benefit from further evaluation including screening for atrial and ventricular arrhythmias with implantable loop recorders. The role of algorithm-based cardiac evaluation both before and after therapeutic initiation is one of the many unmet needs for SSc clinical care.

Evaluation of hypertension in systemic sclerosis and systemic lupus erythematosus overlap.

Patients with systemic sclerosis and systemic lupus erythematosus serologies present a unique challenge to the clinician when hypertension is detected in the outpatient setting. Treatment choices for non-renal crisis hypertension are different for systemic sclerosis versus systemic lupus erythematosus. Urgent laboratory studies and, in the presence of certain symptoms, imaging assessment are indicated in systemic sclerosis and systemic lupus erythematosus overlap patients with systemic hypertension. Long-term assessment of systemic hypertension may be enhanced by advances in non-contrast imaging that serve as valuable biomarkers for progressive vasculopathy. In this review, the diagnostic approach to systemic sclerosis and systemic lupus erythematosus overlap patients presenting with hypertension is discussed.

Measurement of Minimal Disease Activity in Psoriatic Arthritis Using the Patient-Reported Outcomes Measurement Information System-Physical Function or the Health Assessment Questionnaire Disability Index.

OBJECTIVE: To assess the interchangeability of the Health Assessment Questionnaire disability index (HAQ DI) with the Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF) in the calculation of minimal disease activity (MDA) in psoriatic arthritis (PsA). METHODS: Comprehensive PsA disease activity was collected concomitantly with the HAQ DI and the PROMIS-PF measures in a PsA cohort. The PROMIS-PF-based MDA definitions were built using the existing cross-walk between the scores: HAQ DI ≤0.5 equivalent to a PROMIS-PF T score of ≥41.3. We assessed agreement between MDA (MDA HAQ DI) and the PROMIS-PF MDA definitions (MDA PROMIS-PF short form 4a and MDA PROMIS-PF bank) at each visit and longitudinally (MDA state changes between consecutive visits) through the kappa statistic. The predictive value of the MDA PROMIS-PF for the MDA HAQ DI was assessed using receiver operator characteristic (ROC) curve analysis. RESULTS: A total of 100 participants contributed 352 observations with up to 5 visits. The mean ± SD age was 52 ± 12 years, 60% were female, and 43% were in MDA at baseline. The kappa statistic for the PROMIS-PF-based MDA reflected excellent agreement with the HAQ DI MDA: κ = 0.94 (95% confidence interval [95% CI] 0.90-0.97) for MDA PROMIS-PF bank, and κ = 0.90 (95% CI 0.80-0.95) for MDA PROMIS-PF4a. Higher longitudinal agreement was seen between the MDA HAQ DI and the MDA PROMIS-PF bank versus the MDA PROMIS-PF4a between consecutive visits: κ values ranged between 0.81 and 0.94 versus a range between 0.72 and 0.84, respectively. The area under the ROC curve for predicting the MDA HAQ DI was 0.97 for the MDA PROMIS-PF bank and 0.95 for the MDA PROMIS-PF4a. CONCLUSION: Excellent agreement was seen between the HAQ DI and the PROMIS-based MDA definitions both cross-sectionally and longitudinally. The PROMIS-PF bank and PROMIS-PF4a are accurate replacements for the HAQ DI in calculating MDA state in PsA.

Evaluating the Revised American Society for Gastrointestinal Endoscopy Guidelines for Common Bile Duct Stone Diagnosis.

BACKGROUND/AIMS: The American Society for Gastrointestinal Endoscopy (ASGE) revised its guidelines for risk stratification of patients with suspected choledocholithiasis. This study aimed to assess the diagnostic performance of the revision and to compare it to the previous guidelines. METHODS: We conducted a retrospective cohort study of 267 patients with suspected choledocholithiasis. We identified high-risk patients according to the original and revised guidelines and examined the diagnostic accuracy of both guidelines. We measured the association between individual criteria and choledocholithiasis. RESULTS: Under the original guidelines, 165 (62%) patients met the criteria for high risk, of whom 79% had confirmed choledocholithiasis. The categorization had a sensitivity and specificity of 68% and 55%, respectively, for the detection of choledocholithiasis. Under the revised guidelines, 86 (32%) patients met the criteria for high risk, of whom 83% had choledocholithiasis. The revised categorization had a lower sensitivity and higher specificity of 37% and 80%, respectively. The positive predictive value of the high-risk categorization increased with the revision, reflecting a potential decrease in diagnostic endoscopic retrograde cholangiopancreatograpies (ERCPs). Stone visualized on imaging had the greatest specificity for choledocholithiasis. Gallstone pancreatitis was not associated with the risk for choledocholithiasis. CONCLUSION: The 2019 revision of the ASGE guidelines decreases the utilization of ERCP as a diagnostic modality and offers an improved risk stratification tool.

Inflammatory hypothesis of atherogenesis: Will colchicine be added to the armamentarium in the prevention of coronary artery disease?

Chronic inflammation promotes the development and progression of atherosclerosis. Despite aggressive risk reduction, patients with coronary artery disease have a significant residual risk of myocardial infarction and cardiovascular death related in part to ongoing inflammation within coronary vasculature. In this review, we summarize the clinical trials that provide evidence for the inflammatory hypothesis of atherogenesis. Additionally, we describe studies suggesting colchicine may be able to reduce residual inflammatory risk via the NLRP3 pathway. Given its tolerable side effect profile, safety, and low cost, colchicine holds promise as an anti-inflammatory agent in primary and secondary prevention of coronary disease.

Communicating COVID-19 health information to culturally and linguistically diverse communities: insights from a participatory research collaboration.

OBJECTIVE: To consider the challenges of communicating COVID-19 directives to culturally and linguistically diverse (CALD) communities in Australia, and present evidence-based solutions to influence policy and practice on promoting relevant health behaviours; to advance participatory research methodologies for health behaviour change. Type of program or service: We present a case study of a participatory research collaboration between CALD community leaders and health behaviour change scientists during the COVID-19 crisis. The goal was to better understand the role of community leaders in shaping health behaviours in their communities and how that role might be leveraged for better health outcomes. METHODS: This article is the culmination of a series of dialogues between CALD community and advocacy leaders, and health behaviour change scientists in July 2020. The academic authors recruited 12 prominent CALD community leaders, conducted five semi-structured dialogues with small groups, and worked with all participants to develop insights that were applicable to the many different CALD communities represented in the research collaboration. RESULTS: Three key findings emerged: 1) partnerships between CALD leaders, communities and government are critical for effective health communication; 2) shifting behaviour requires moving beyond disseminating information to designing tailored solutions; and 3) the diverse needs and circumstances of people and communities must be at the centre of health communication and behaviour change strategies. LESSONS LEARNT: The collaborative process we undertook in this study enabled us to identify key challenges experienced and solutions offered by CALD leaders in communicating health information throughout the COVID-19 pandemic. Partnering with communities that are subject to health messaging can reduce inequalities in healthcare communication by enabling the development of strategies that help align human behaviour with the recommendations of health experts. This - along with sustained partnership and collaboration with CALD communities, understanding the cultural context, and the appropriate tailoring and delivery of communications - will ensure health-related messages are not lost in translation. The lessons provided in this paper are applicable not only to the current pandemic but also to post-pandemic social and economic recovery.

Importance of the triglyceride level in identifying patients with a Type III Hyperlipoproteinemia phenotype using the ApoB algorithm.

BACKGROUND: Hyperlipoproteinemia Type III (HLP3), also known as dysbetalipoproteinemia, is defined by cholesterol and triglyceride (TG) enriched remnant lipoprotein particles (RLP). The gold standard for diagnosis requires demonstration of high remnant lipoprotein particle cholesterol (RLP-C) by serum ultracentrifugation (UC), which is not readily available in daily practice. The apoB algorithm can identify HLP3 using total cholesterol (TC), plasma triglyceride (TG), and apoB. However, the optimal TG cutoff is unknown. OBJECTIVE: We analyzed apoB algorithm defined HLP3 at different TG levels to optimize the TG cutoff for the algorithm. METHODS: 128,485 UC lipid profiles in the Very Large Database of Lipids (VLDbL) were analyzed. RLP-C was assessed at TG ≥ 133 mg/dL, ≥175 mg/dL, ≥200 mg/dL, and ≥ 250 mg/dL. Sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and prevalence adjusted and bias-adjusted kappa (PABAK) were calculated against UC Criterion (VLDL-C/TG ≥ 0.25) for HLP3. RESULTS: The median age (IQR) was 57 years (46-68). 45% were men, 20.1% had diabetes, and 25.5% had hypertension. The median RLP-C level for the TG cutoffs (mg/dL) of ≥ 133, ≥ 175, ≥ 200, and ≥ 250 were 34, 43, 50, and 62 mg/dL, respectively, compared to 67 mg/dL in UC defined HLP3. TG ≥ 133 mg/dL yielded optimal results (Sn 29.5%, Sp 98.5%, PABAK 0.96, PPV 13.6%, NPV 99.4%). CONCLUSION: TG ≥ 133 mg/dL allows for high sensitivity in screening for HLP3. Higher TG cutoffs may identify more severe HLP3 phenotypes, but with a large loss in sensitivity for HLP3.

Risk factors for oropharynx cancer in a cohort of HIV-infected veterans.

OBJECTIVE: To evaluate HIV-related and other clinical risk factors associated with oropharynx cancer (OPSCC) in HIV-infected U.S. Veterans. METHODS: Retrospective cohort study utilizing Veterans Affairs HIV Clinical Case Registry (CCR) data from 1985 to 2010. Outcome was incident OPSCC as indicated by 1 inpatient or 2 outpatient ICD-9 codes. Cox proportional hazard models were used to determine hazard ratios (HR) and 95% confidence intervals (CI) for each risk factor on the time to OPSCC diagnosis. RESULTS: A total of 40,996 HIV-infected male veterans were included in the cohort with 97 cases of OPSCC. The age adjusted incidence rate was 23.2/100,000 [95% CI 17.8-29.2]. Age>50 (aHR=3.8, 95% CI 1.9-7.8), recent CD4<200 (aHR=3.8, 95% CI 2.0-7.3), and undetectable HIV viral loads 40-79% of the time (aHR=1.8, 95% CI 1.1-3.0) were associated with an increased risk of OPSCC. Era of HIV diagnosis, utilization of cART, nadir CD4 count, race, smoking history, and previous risk of HPV disease, including condyloma or invasive squamous cell carcinoma of the anus (SCCA) were not associated with increased risk of OPSCC. CONCLUSION: Patients who were older at beginning of follow up, had lower CD4 counts around the time of OPSCC diagnosis, and moderate HIV viral control during follow-up had an increased risk of OPSCC. Other HPV-related diseases such as SCCA and condyloma did not increase the risk for OPSCC.

Diagnostic Criteria for Detection of Vestibular Schwannomas in the VA Population.

OBJECTIVE: To investigate the prevalence of vestibular schwannoma (VS) and asymmetric sensorineural hearing loss in the Veterans Administration hospital population and analyze a more efficient method of diagnosing VS in a population with significant noise exposure. STUDY DESIGN: Retrospective review of South Central (VISN 16) Veterans Administration hospitals. METHODS: Record query for ICD-9 codes for asymmetric sensorineural hearing loss or VS between 1999 and 2012. Patient demographics, signs and symptoms at presentation, audiogram and imaging data, and management data were collected and analyzed. Audiograms from tumor patients were compared with controls matched for age, sex, combat experience, and medical comorbidity (2:1 control to case ratio). RESULTS: The prevalence of VS was 1 per 1,145 patients in this population, with average age at diagnosis of 62. Patients with VS presented more commonly with unilateral tinnitus, rollover, and absent acoustic reflexes when compared with matched controls, but positive predictive value was low. Published criteria for defining hearing asymmetry showed variable sensitivity (51-89%) and low specificity (0-42%) for the detection of VS in this population. Criteria meeting the definitions of significant asymmetry with specificity for VS of 80% or greater were as follows: >15 dB threshold difference at 3 kHz and unilateral tinnitus, ≥45 dB threshold difference at 3 kHz regardless of tinnitus, or when the word recognition score difference was ≥80%. With serial audiograms 2.5 years apart or greater, a ≥10 dB threshold increase at any frequency between 0.5 and 4 kHz had a 100% sensitivity for tumor and a ≥10 dB increase at 3 kHz had a specificity of 84%. The majority of patients were observed, whereas only 30% had surgery. Patients who were observed were older than those treated with surgery or radiation (p <0.001). CONCLUSION: Typical audiometric screening criteria should be modified in the veteran population to improve cost efficiency of diagnosis. Observation is the primary management strategy in the veteran population because of age.

Differential effects of cholinergic and noradrenergic neuromodulation on spontaneous cortical network dynamics.

Cholinergic and noradrenergic neuromodulation play a key role in determining overall behavioral state by shaping the underlying cortical network dynamics. The effects of these systems on synaptic and intrinsic cellular targets are quite diverse and a comprehensive understanding of how these neuromodulators regulate (spontaneous) cortical network activity has remained elusive. Here, we used multielectrode electrophysiology in vitro to investigate the effect of these neuromodulators on spontaneous network dynamics in acute slices of mouse visual cortex. We found that application of Carbachol (CCh) and Norepinephrine (NE) both enhanced the spontaneous network dynamics by increasing (1) the activity levels, (2) the temporal complexity of the network activity, and (3) the spatial complexity by decorrelating the network activity over a wide range of neuromodulator concentrations (1 µM, 10 µM, 50 µM, and 100 µM). Interestingly, we found that cholinergic neuromodulation was limited to the presence of CCh in the bath whereas the effects of NE, in particular for higher concentrations, induced plasticity that caused outlasting effects most prominently in the deep cortical layers. Together, these results provide a comprehensive network-level understanding of the similarities and differences of cholinergic and noradrenergic modulation of spontaneous network dynamics.

Identification of formyl kynurenine formamidase and kynurenine aminotransferase from Saccharomyces cerevisiae using crystallographic, bioinformatic and biochemical evidence.

The essential enzymatic cofactor NAD+ can be synthesized in many eukaryotes, including Saccharomyces cerevisiae and mammals, using tryptophan as a starting material. Metabolites along the pathway or on branches have important biological functions. For example, kynurenic acid can act as an NMDA antagonist, thereby functioning as a neuroprotectant in a wide range of pathological states. N-Formyl kynurenine formamidase (FKF) catalyzes the second step of the NAD+ biosynthetic pathway by hydrolyzing N-formyl kynurenine to produce kynurenine and formate. The S. cerevisiae FKF had been reported to be a pyridoxal phosphate-dependent enzyme encoded by BNA3. We used combined crystallographic, bioinformatic and biochemical methods to demonstrate that Bna3p is not an FKF but rather is most likely the yeast kynurenine aminotransferase, which converts kynurenine to kynurenic acid. Additionally, we identify YDR428C, a yeast ORF coding for an alpha/beta hydrolase with no previously assigned function, as the FKF. We predicted its function based on our interpretation of prior structural genomics results and on its sequence homology to known FKFs. Biochemical, bioinformatics, genetic and in vivo metabolite data derived from LC-MS demonstrate that YDR428C, which we have designated BNA7, is the yeast FKF.

The 1.1-angstrom structure of the spindle checkpoint protein Bub3p reveals functional regions.

Bub3p is a protein that mediates the spindle checkpoint, a signaling pathway that ensures correct chromosome segregation in organisms ranging from yeast to mammals. It is known to function by co-localizing at least two other proteins, Mad3p and the protein kinase Bub1p, to the kinetochore of chromosomes that are not properly attached to mitotic spindles, ultimately resulting in cell cycle arrest. Prior sequence analysis suggested that Bub3p was composed of three or four WD repeats (also known as WD40 and beta-transducin repeats), short sequence motifs appearing in clusters of 4-16 found in many hundreds of eukaryotic proteins that fold into four-stranded blade-like sheets. We have determined the crystal structure of Bub3p from Saccharomyces cerevisiae at 1.1 angstrom and a crystallographic R-factor of 15.3%, revealing seven authentic repeats. In light of this, it appears that many of these repeats therefore remain hidden in sequences of other proteins. Analysis of random and site-directed mutants identifies the surface of Bub3p involved in checkpoint function through binding of Bub1p and Mad3p. Sequence alignments indicate that these surfaces are mostly conserved across Bub3 proteins from diverse species. A structural comparison with other proteins containing WD repeats suggests that these folds may bind partner proteins using similar surface areas on the top and sides of the propeller. The sequences composing these regions are the most divergent within the repeat across all WD repeat proteins and could potentially be modulated to provide specificity in partner protein binding without perturbation of the core structure.