The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

The provisional OMERACT ultrasonography score for giant cell arteritis.

OBJECTIVES: To develop an Outcome Measures in Rheumatology (OMERACT) ultrasonography score for monitoring disease activity in giant cell arteritis (GCA) and evaluate its metric properties. METHODS: The OMERACT Instrument Selection Algorithm was followed. Forty-nine members of the OMERACT ultrasonography large vessel vasculitis working group were invited to seven Delphi rounds. An online reliability exercise was conducted using images of bilateral common temporal arteries, parietal and frontal branches as well as axillary arteries from 16 patients with GCA and 7 controls. Sensitivity to change and convergent construct validity were tested using data from a prospective cohort of patients with new GCA in which ultrasound-based intima-media thickness (IMT) measurements were conducted at weeks 1, 3, 6, 12 and 24. RESULTS: Agreement was obtained (92.7%) for the OMERACT GCA Ultrasonography Score (OGUS), calculated as follows: sum of IMT measured in every segment divided by the rounded cut-off values of IMTs in each segment. The resulting value is then divided by the number of segments available. Thirty-five members conducted the reliability exercise, the interrater intraclass correlation coefficient (ICC) for the OGUS was 0.72-0.84 and the median intrareader ICC was 0.91. The prospective cohort consisted of 52 patients. Sensitivity to change between baseline and each follow-up visit up to week 24 yielded standardised mean differences from -1.19 to -2.16, corresponding to large and very large magnitudes of change, respectively. OGUS correlated moderately with erythrocyte sedimentation rate, C reactive protein and Birmingham Vasculitis Activity Score (corrcoeff 0.37-0.48). CONCLUSION: We developed a provisional OGUS for potential use in clinical trials.

Nationwide racial/ethnic disparities in US emergency department visits and hospitalizations for gout.

OBJECTIVES: Gout prevalence is reportedly ∼20% higher in US Black adults than Whites, but racial differences in emergency department (ED) visits and hospitalizations for gout are unknown. We evaluated the latest US national utilization datasets according to racial/ethnic groups. METHODS: Using 2019 US National Emergency Department Sample and National Inpatient Sample databases, we compared racial/ethnic differences in annual population rates of ED visits and hospitalizations for gout (primary discharge diagnosis) per 100 000 US adults (using 2019 age- and sex-specific US census data). We also examined rates of ED visits and hospitalizations for gout among all US ED visits/hospitalizations and mean costs for each gout encounter. RESULTS: Compared with White patients, the per capita age- and sex-adjusted rate ratio (RR) of gout primary ED visits for Black patients was 5.01 (95% CI 4.96, 5.06), for Asian patients 1.29 (1.26, 1.31) and for Hispanic patients 1.12 (1.10, 1.13). RRs for gout primary hospitalizations were 4.07 (95% CI 3.90, 4.24), 1.46 (1.34, 1.58) and 1.06 (0.99, 1.13), respectively. Corresponding RRs among total US hospitalizations were 3.17 (95% CI 2.86, 3.50), 3.23 (2.71, 3.85) and 1.43 (1.21, 1.68) and among total ED visits were 2.66 (95% CI, 2.50, 2.82), 3.28 (2.64, 4.08), and 1.14 (1.05, 1.24), respectively. RRs were largest among Black women. Costs for ED visits and hospitalizations experienced by race/ethnicity showed similar disparities. CONCLUSIONS: These first nationwide data found a substantial excess in both gout primary ED visits and hospitalizations experienced by all underserved racial/ethnic groups, particularly by Black women, revealing an urgent need for improved care to eliminate inequities in gout outcomes.

Temporal Trends and Outcomes Among Patients Admitted for Immune-Related Adverse Events: A Single-Center Retrospective Cohort Study from 2011 to 2018.

BACKGROUND: The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death. METHODS: Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected. RESULTS: In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA-4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA-4 plus PD-1 combination therapy recipients (OR, 1.88; p < .001), relative to PD-1/PD-L1 monotherapy recipients, and patients with multiple toxicity had a 5-fold increase in inpatient mortality. CONCLUSION: This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA-4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi-organ involvement is common and those patients are at highest risk of inpatient mortality. IMPLICATIONS FOR PRACTICE: The number of patients admitted to Massachusetts General Hospital for immune-related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.

Comprehensive evaluation of published gene expression prognostic signatures for biomarker-based lung cancer clinical studies.

Background: A more accurate prognosis for non-small-cell lung cancer (NSCLC) patients could aid in the identification of patients at high risk for recurrence. Many NSCLC mRNA expression signatures claiming to be prognostic have been reported in the literature. The goal of this study was to identify the most promising mRNA prognostic signatures in NSCLC for further prospective clinical validation. Experimental design: We carried out a systematic review and meta-analysis of published mRNA prognostic signatures for resected NSCLC. The prognostic performance of each signature was evaluated via a meta-analysis of 1927 early stage NSCLC patients collected from 15 studies using three evaluation metrics (hazard ratios, concordance scores, and time-dependent receiver-operating characteristic curves). The performance of each signature was then evaluated against 100 random signatures. The prognostic power independent of clinical risk factors was assessed by multivariate Cox models. Results: Through a literature search, we identified 42 lung cancer prognostic signatures derived from genome-wide expression profiling analysis. Based on meta-analysis, 25 signatures were prognostic for survival after adjusting for clinical risk factors and 18 signatures carried out significantly better than random signatures. When analyzing histology types separately, 17 signatures and 8 signatures are prognostic for adenocarcinoma and squamous cell lung cancer, respectively. Despite little overlap among published gene signatures, the top-performing signatures are highly concordant in predicted patient outcomes. Conclusions: Based on this large-scale meta-analysis, we identified a set of mRNA expression prognostic signatures appropriate for further validation in prospective clinical studies.

Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility.

BACKGROUND: Cancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatic analyses, The Cancer Genome Atlas (TCGA) project has identified panels of somatic mutations that contributed to the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these significantly mutated genes (SMGs) and lung cancer susceptibility. PATIENTS AND METHODS: We comprehensively evaluated 1655 tagged single nucleotide polymorphisms (SNPs) located in 127 SMGs identified by TCGA, and test their association with lung cancer risk in large-scale case-control study. Functional effect of the validated SNPs, gene mutation frequency and pathways were analyzed. RESULTS: We found 11 SNPs in 8 genes showed consistent association (P < 0.1) and 8 SNPs significantly associated with lung cancer risk (P < 0.05) in both discovery and validation phases. The most significant association was rs10412613 in PPP2R1A, with the minor G allele associated with a decreased risk of lung cancer [odds ratio = 0.91, 95% confidence interval (CI): 0.87-0.96, P = 2.3 × 10-4]. Cumulative analysis of risk score built as a weight sum of the 11 SNPs showed consistently elevated risk with increasing risk score (P for trend = 9.5 × 10-9). In stratified analyses, the association of PPP2R1A:rs10412613 and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The expression quantitative trait loci analysis indicated that rs10412613, rs10804682, rs635469 and rs6742399 genotypes significantly correlated with the expression of PPP2R1A, ATR, SETBP1 and ERBB4, respectively. From TCGA data, expression of the identified genes was significantly different in lung tumors compared with normal tissues, and the genes' highest mutation frequency was found in lung cancers. Integrative pathway analysis indicated the identified genes were mainly involved in AKT/NF-κB regulatory pathway suggesting the underlying biological processes. CONCLUSION: This study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.

The Suicide Paradigm: Insights from Ancient Hindu Scriptures.

The world religions in general promote peace and happiness. They strongly discourage all sorts of violence in society including suicide. Religious commitments toward life-saving value are known to prevent suicide attempts since all world religions promote unity, reducing interpersonal hostilities. Therefore, understanding the basics on what religious scriptures narrate on life and death including suicide is essential. This paper highlights the seldom discussed topic on the concept and consequences of suicide portrayed in the ancient Hindu religious scriptures.

Harvesting river water through small dams promote positive environmental impact.

While deliberations relating to negative consequences of large dams on the environment continue to dominate world attention, positive benefits provided by small dams, also known as check dams, go unobserved. Besides, little is known about the potential of check dams in mitigating global warming impacts due to less data availability. Small dams are usually commissioned to private contractors who do not have clear mandate from their employers to post their work online for public scrutiny. As a result, statistics on the design, cost, and materials used to build check dams are not available in public domain. However, this review paper presents data for the first time on the often ignored potential of check dams mitigating climate-induced hydrological threats. We hope that the scientific analysis presented in this paper will promote further research on check dams worldwide to better comprehend their eco-friendly significance serving society.

Non-Maternal Infant Handling in Wild Formosan Macaques of Mount Longevity, Taiwan.

In this paper, we present quantitative data on how the social network and sex of infants influence allomothering behaviour among wild Formosan macaques, Macaca cyclopis. Using long-term field data collected from the Mount Longevity study site in Kaohsiung (Taiwan), we have tested relevant hypotheses incorporating data on age, rank and reproductive state of infant handlers, and the relationship between handlers and infants. The results support 2 major hypotheses, i.e. those of reciprocity and alliance formation. Nevertheless, neither could account for the observed occurrences of unrelated infant handling by dominant females.

Living on the Societal Edge: India's Transgender Realities.

The transgendered people have played an important role in ancient Indian culture over millennia. They were portrayed in famous Hindu religious scriptures such as Ramayana and Mahabharata. They were given imperative roles in the royal courtyards of Mughal emperors. Their downfall came only at the onset of British rule during the eighteenth century when they were blacklisted and treated as criminal elements in society. Only in 2014, India's Supreme Court has made a landmark ruling by declaring that the transgendered people must have access to equal opportunity in society. In spite of this legal recognition, transgenders at large have been forced to live on the fringes of the contemporary Indian society. This article explores their past glories, present struggles and future ambitions in the world's largest democracy.

Serum urate change among gout patients treated with sodium-glucose cotransporter type 2 inhibitors vs. sulfonylurea: A comparative effectiveness analysis.

OBJECTIVE: To investigate the serum urate (SU) change among gout patients initiating SGLT2i, and to compare with sulfonylurea, the second-most widely used glucose-lowering medication after metformin. METHODS: We conducted a cohort study of patients with gout and baseline SU >6 mg/dL who had SU measured within 90 days before and after SGLT2i or sulfonylurea initiation. Using multivariable linear regression, we compared SU change among SGLT2i initiators between those with and without diabetes and then compared SU change between SGLT2i and sulfonylurea. RESULTS: We identified 28 patients with gout initiating SGLT2i (including 16 with diabetes) and 28 patients initiating sulfonylurea (all with diabetes). Among SGLT2i initiators, the mean within-group SU change was -1.8 (95 % CI, -2.4 to -1.1) mg/dL, including -1.2 (-1.8 to -0.6) mg/dL and -2.5 (-3.6 to -1.3) mg/dL among patients with and without diabetes, respectively, with an adjusted difference between those with and without diabetes of -1.4 (-2.4 to -0.5) mg/dL. The SU did not change after initiating sulfonylurea (+0.3 [-0.3 to 1.0] mg/dL). The adjusted SU change difference between SGLT2i vs. sulfonylurea initiation was -1.8 (-2.7 to -0.9) mg/dL in all patients. The SU reduction persisted regardless of urate-lowering therapy or diuretic use and the presence of diabetes, chronic kidney disease, or heart failure. CONCLUSION: Among patients with gout, SGLT2i was associated with a notable reduction in SU compared with sulfonylurea, with a larger reduction among patients without diabetes. With their proven cardiovascular-kidney-metabolic benefits, adding SGLT2i to current gout management could provide streamlined benefits for gout and its comorbidities.

Use of a computerized order set to increase prescription of calcium and vitamin D supplementation in patients receiving glucocorticoids.

BACKGROUND: American College of Rheumatology guidelines recommend that patients taking glucocorticoids also take calcium and vitamin D supplements, regardless of the dose or intended duration of glucocorticoid use, to decrease their risk of glucocorticoid-induced osteopenia or osteoporosis (GIOP). OBJECTIVE: To increase the number of prescriptions made for calcium and vitamin D in patients who receive a prescription for glucocorticoids using an automated, computerized order set. DESIGN: Pre-post test design. PATIENTS: A total of 1,041 outpatients receiving care at a single VA medical center. INTERVENTION/MAIN MEASURES: We developed an automated order set in which calcium and vitamin D were automatically co-ordered with glucocorticoid prescriptions of at least 2-week duration. We tested the impact of the order set by comparing the number of calcium and vitamin D prescriptions in patients taking glucocorticoids during a 12-month period before (T1) and after (T2) implementation. The automated order set could be modified by the treating physician, and it was not generated for patients with hypercalcemia. KEY RESULTS: A total of 535 patients during T1 and 506 patients during T2 had a glucocorticoid prescription of at least 2-week duration. The percent of co-prescriptions for calcium increased from 37 to 49% and vitamin D from 38 to 53% (both p < 0.0001) after the new automated order set was implemented. CONCLUSIONS: Implementation of an automatic prescription for calcium and vitamin D supplementation modestly increases the number of patients on glucocorticoids who are prescribed calcium and vitamin D supplementation.

Temporal Artery Ultrasound for the Diagnosis of Giant Cell Arteritis in the Emergency Department.

Giant cell arteritis (GCA), known as temporal arteritis, is a serious condition requiring immediate treatment to prevent complications. GCA can be difficult to diagnose, especially in emergency department (ED) settings where ophthalmology and rheumatology services may be unavailable. Temporal artery ultrasound (TAUS) is a valuable tool for diagnosing GCA. In the ED, TAUS can be used to quickly rule out GCA and avoid unindicated steroid treatment, which can cause serious morbidity in elderly patients. This article discusses the use of TAUS for evaluating patients with suspected GCA in the ED and its potential to expedite treatment and ensure appropriate, timely follow-up for patients with this potential vision and life-threatening condition.

Imaging Features of Calcium Pyrophosphate Deposition Disease: Consensus Definitions From an International Multidisciplinary Working Group.

OBJECTIVE: To develop definitions for imaging features being considered as potential classification criteria for calcium pyrophosphate deposition (CPPD) disease, additional to clinical and laboratory criteria, and to compile example images of CPPD on different imaging modalities. METHODS: The American College of Rheumatology and European Alliance of Associations for Rheumatology CPPD classification criteria Imaging Advisory Group (IAG) and Steering Committee drafted definitions of imaging features that are characteristic of CPPD on conventional radiography (CR), conventional computed tomography (CT), dual-energy CT (DECT), and magnetic resonance imaging (MRI). An anonymous expert survey was undertaken by a 35-member Combined Expert Committee, including all IAG members. The IAG and 5 external musculoskeletal radiologists with expertise in CPPD convened virtually to further refine item definitions and voted on example images illustrating CR, CT, and DECT item definitions, with ≥90% agreement required to deem them acceptable. RESULTS: The Combined Expert Committee survey indicated consensus on all CR definitions. The IAG and external radiologists reached consensus on CT and DECT item definitions, which specify that calcium pyrophosphate deposits appear less dense than cortical bone. The group developed an MRI definition and acknowledged limitations of this modality for CPPD. Ten example images for CPPD were voted acceptable (4 CR, 4 CT, and 2 DECT), and 3 images of basic calcium phosphate deposition were voted acceptable to serve as contrast against imaging features of CPPD. CONCLUSION: An international group of rheumatologists and musculoskeletal radiologists defined imaging features characteristic of CPPD on CR, CT, and DECT and assembled a set of example images as a reference for future clinical research studies.

Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.

As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.