Citations

Abstract The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32–1.67]); Black patients (aOR 1.74; 95 CI 1.24–2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70–6.79) and Other (aOR 2.97; 95 CI 1.71–5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83–12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63–3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20–2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66–3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89–22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701 .

Reactive granulomatous dermatitis (RGD) is an umbrella term to describe a reaction pattern characterized by skin-colored to erythematous papules, plaques, and nodules although other morphologies have been described. RGD has rarely been reported in children, and in this report, we present the case of a 3-year-old girl with acute lymphoblastic leukemia (ALL) who presented with firm, tender nodules, and ulcerated plaques on her extremities. Histopathologic examination showed foci of dense granulomatous inflammatory infiltrates composed of histiocytes, neutrophils, and multinucleate giant cells. The constellation of clinical symptoms, negative infectious workup, and histopathology support the diagnosis of RGD.

AbstractBackgroundChronic pelvic pain is a burdensome condition that involves multiple medical sub‐specialties and is often difficult to treat. Sacral stimulation for functional bladder disease has been well established, but little large‐scale evidence exists regarding utilization of other neuromodulation techniques to treat chronic pelvic pain. Emerging evidence does suggest that neuromodulation is a promising treatment, and we aim to characterize the use and efficacy of such techniques for treating chronic pelvic pain syndromes.Materials and MethodsA systematic review of the literature demonstrating the treatment of chronic pelvic pain syndromes with neuromodulation. Abstracts were reviewed and selected for inclusion, including case series, prospective studies, and randomized controlled trials (RCTs). Case studies and publications in abstract only were not included. The reporting for this systematic review follows Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA). The literature search was performed using MEDLINE, Embase, Cochrane Library, PubMed, CINAHL, and Scopus.ResultsA total of 50 studies were included in this review, three of which were randomized controlled trials, and the remaining were prospective and retrospective case series. The range of pelvic pain conditions treated included interstitial cystitis, peripheral neuralgia, pudendal neuralgia, gastrointestinal pain, urogenital pain, sacroiliac joint pain, and visceral chronic pelvic pain. We reported on outcomes involving pain, functionality, psychosocial improvement, and medication reduction.ConclusionsNeuromodulation is a growing treatment for various chronic pain syndromes. Peripheral nerve stimulation was the least studied form of stimulation. Posterior tibial nerve stimulation appears to offer short‐term benefit, but long‐term results are challenging. Sacral nerve stimulation is established for use in functional bladder syndromes and appears to offer pain improvement in these patients as well. Dorsal root ganglion stimulation and spinal cord stimulation have been used for a variety of conditions with promising results. Further studies of homogeneous patient populations are necessary before strong recommendations can be made at this time, although pooled analysis may also be impactful.

SummaryBackgroundAlpha‐1 antitrypsin deficiency (AATD) is caused by mutations in SERPINA1, which encodes alpha‐1 antitrypsin, a protease inhibitor (Pi). Individuals with AATD and the homozygous Pi*ZZ genotype have variable risk of progressive liver disease but the influence of comorbid lung disease is poorly understood.AimsTo characterise patients with AATD Pi*ZZ and liver disease (AATD‐LD‐Pi*ZZ) with or without lung disease and describe liver disease‐related clinical events longitudinally.MethodsThis was an observational cohort study of patients in the Mayo Clinic Healthcare System (January 2000–September 2021). Patients were identified using diagnosis codes and natural language processing. Fibrosis stage (F0–F4) was assessed using a hierarchical approach at baseline (90 days before or after the index date) and follow‐up. Clinical events associated with liver disease progression were assessed.ResultsAATD‐LD‐Pi*ZZ patients with lung disease had a longer median time from AATD diagnosis to liver disease diagnosis versus those without lung disease (2.2 vs. 0.2 years, respectively). Compared to those without lung disease, patients with lung disease had a longer time to liver disease‐related clinical events (8.5 years and not reached, respectively). AATD‐LD‐Pi*ZZ patients without lung disease were more likely to undergo liver transplantation compared with those with lung disease.ConclusionIn patients with AATD and lung disease, there is a delay in the diagnosis of comorbid liver disease. Our findings suggest that liver disease may progress more rapidly in patients without comorbid lung disease.

Abstract Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is the main cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA2/3 scores correlate with resistance to treatment and higher NRM. We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T-cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA2/3 GVHD. Seventy-five patients who were evaluable were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events in >10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared with 150 well-matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and those treated with corticosteroids alone (60% vs 58%; P = .67% and 48% vs 48%; P = 1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival at 12 months in patients treated with natalizumab plus corticosteroids compared with controls treated with corticosteroids alone (38% vs 39%; P = .80% and 46% vs 54%; P = .48, respectively). In this multicenter biomarker–based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high-risk GVHD. This trial was registered at www.clinicaltrials.gov as # NCT02133924.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Traditional ice storage has been the historic standard for preserving donor’s hearts. However, this approach provides variability in cooling, increasing risks of freezing injury. To date, no preservation technology has been reported to improve survival after transplantation. The Paragonix SherpaPak Cardiac Transport System (SCTS) is a controlled hypothermic technology clinically used since 2018. Real-world evidence on clinical benefits of SCTS compared to conventional ice cold storage (ICS) was evaluated. Between October 2015 and January 2022, 569 US adults receiving donor hearts preserved and transported either in SCTS (n = 255) or ICS (n = 314) were analyzed from the Global Utilization And Registry Database for Improved heArt preservatioN (GUARDIAN-Heart) registry. Propensity matching and a subgroup analysis of >240 minutes ischemic time were performed to evaluate comparative outcomes. Overall, the SCTS cohort had significantly lower rates of severe primary graft dysfunction (PGD) ( p = 0.03). When propensity matched, SCTS had improving 1-year survival ( p = 0.10), significantly lower rates of severe PGD ( p = 0.011), and lower overall post-transplant MCS utilization ( p = 0.098). For patients with ischemic times >4 hours, the SCTS cohort had reduced post-transplant MCS utilization ( p = 0.01), reduced incidence of severe PGD ( p = 0.005), and improved 30-day survival ( p = 0.02). A multivariate analysis of independent risk factors revealed that compared to SCTS, use of ice results in a 3.4-fold greater chance of severe PGD ( p = 0.014). Utilization of SCTS is associated with a trend toward increased post-transplant survival and significantly lower severe PGD and MCS utilization. These findings fundamentally challenge the decades-long status quo of transporting donor hearts using ice.

Abstract Objectives ANCA-associated vasculitis (AAV) is currently categorized under the small vessel vasculitides. There is limited knowledge about large vessel involvement in AAV (L-AAV), mainly described in case reports and small series. L-AAV can involve temporal arteries (TA-AAV), aorta (A-AAV), and periaortic soft tissue (PA-AAV). We sought to characterize the features of patients with L-AAV. Methods Patients older than 18 years at diagnosis of TA-AAV, A-AAV and PA-AAV seen at the Mayo Clinic, Rochester between 1 January 2000 and 31 December 2021 were identified through a proprietary medical text search algorithm. Patients were included if diagnosed with L-AAV, fulfilled 2022 ACR/EULAR classification criteria for GPA, MPA or EGPA, had positive ANCA test results, and had more than one outpatient or inpatient visit. Results The study cohort consists of 36 patients with L-AAV. Of those, 23 had p-ANCA and/or MPO-ANCA, and 13 had c-ANCA and/or PR3-ANCA. Mean (s.d.) age at AAV diagnosis was 63.4 (12.79) years; 20 (56%) were male. Seventeen patients had TA-AAV, 10 had A-AAV and 9 had PA-AAV. Most patients (n = 25, 69%) were diagnosed with large vessel vasculitis and AAV within a 1-year timespan. Twenty-five (69%) patients had histopathological confirmation of AAV diagnosis in a location other than temporal artery, aorta or periaortic soft tissue. Glucocorticoids (36/36), rituximab (19/36) and methotrexate (18/36) were the most frequent treatments. Conclusion This is the largest single-centre cohort of patients with L-AAV to date. AAV can involve large arteries, albeit infrequent. AAV-targeted therapy should be considered in patients with L-AAV.