Citations

What is the agreement of commercial SARS-CoV-2 immunoglobulin G (IgG) assays during a time of low coronavirus disease 2019 (COVID-19) prevalence and no vaccine availability? Serological tests produced concordant results in a time of low SARS-CoV-2 prevalence and no vaccine availability, driven largely by the proportion of samples that were negative by two immunoassays. The CDC recommends two sequential tests for positivity for future pandemic preparedness.

Objective We investigated prolonged COVID-19 symptom duration, defined as lasting 28 days or longer, among people with systemic autoimmune rheumatic diseases (SARDs). Methods We analysed data from the COVID-19 Global Rheumatology Alliance Vaccine Survey (2 April 2021–15 October 2021) to identify people with SARDs reporting test-confirmed COVID-19. Participants reported COVID-19 severity and symptom duration, sociodemographics and clinical characteristics. We reported the proportion experiencing prolonged symptom duration and investigated associations with baseline characteristics using logistic regression. Results We identified 441 respondents with SARDs and COVID-19 (mean age 48.2 years, 83.7% female, 39.5% rheumatoid arthritis). The median COVID-19 symptom duration was 15 days (IQR 7, 25). Overall, 107 (24.2%) respondents had prolonged symptom duration (≥28 days); 42/429 (9.8%) reported symptoms lasting ≥90 days. Factors associated with higher odds of prolonged symptom duration included: hospitalisation for COVID-19 vs not hospitalised and mild acute symptoms (age-adjusted OR (aOR) 6.49, 95% CI 3.03 to 14.1), comorbidity count (aOR 1.11 per comorbidity, 95% CI 1.02 to 1.21) and osteoarthritis (aOR 2.11, 95% CI 1.01 to 4.27). COVID-19 onset in 2021 vs June 2020 or earlier was associated with lower odds of prolonged symptom duration (aOR 0.42, 95% CI 0.21 to 0.81). Conclusion Most people with SARDs had complete symptom resolution by day 15 after COVID-19 onset. However, about 1 in 4 experienced COVID-19 symptom duration 28 days or longer; 1 in 10 experienced symptoms 90 days or longer. Future studies are needed to investigate the possible relationships between immunomodulating medications, SARD type/flare, vaccine doses and novel viral variants with prolonged COVID-19 symptoms and other postacute sequelae of COVID-19 among people with SARDs.

ObjectiveTo describe people with gout who were diagnosed with coronavirus disease 2019 (COVID‐19) and hospitalized and to characterize their outcomes.MethodsData on patients with gout hospitalized for COVID‐19 between March 12, 2020, and October 25, 2021, were extracted from the COVID‐19 Global Rheumatology Alliance registry. Descriptive statistics were used to describe the demographics, comorbidities, medication exposures, and COVID‐19 outcomes including oxygenation or ventilation support and death.ResultsOne hundred sixty‐three patients with gout who developed COVID‐19 and were hospitalized were included. The mean age was 63 years, and 85% were male. The majority of the group lived in the Western Pacific Region (35%) and North America (18%). Nearly half (46%) had two or more comorbidities, with hypertension (56%), cardiovascular disease (28%), diabetes mellitus (26%), chronic kidney disease (25%), and obesity (23%) being the most common. Glucocorticoids and colchicine were used pre‐COVID‐19 in 11% and 12% of the cohort, respectively. Over two thirds (68%) of the cohort required supplemental oxygen or ventilatory support during hospitalization. COVID‐19‐related death was reported in 16% of the overall cohort, with 73% of deaths documented in people with two or more comorbidities.ConclusionThis cohort of people with gout and COVID‐19 who were hospitalized had high frequencies of ventilatory support and death. This suggests that patients with gout who were hospitalized for COVID‐19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity.

ObjectiveSome patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID‐19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID‐19 ARDS in this population and to create a simple risk score calculator for use in clinical settings.MethodsData were derived from the COVID‐19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID‐19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier.ResultsThe study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67‐0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%‐83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator.ConclusionWe were able to predict ARDS with good sensitivity using information readily available at COVID‐19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID‐19 disease progression.

Abstract Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30 ‐associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9‐year‐old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9‐year‐old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30 ‐associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.

2583 Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.

Abstract Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.

Abstract Objective The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled “Developing a Clinical Genomic Informatics Research Agenda”. The meeting’s goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings. Materials and Methods Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to develop a genomic-based clinical informatics research strategy. Results Outcomes from the meeting included identifying short-term research needs, such as designing and implementing standards-based interfaces between laboratory information systems and electronic health records, as well as long-term projects, such as identifying and addressing barriers related to the establishment and implementation of genomic data exchange systems that, in turn, the research community could help address. Discussion Discussions centered on identifying gaps and barriers that impede the use of GCIT in genomic medicine. Emergent themes from the meeting included developing an implementation science framework, defining a value proposition for all stakeholders, fostering engagement with patients and partners to develop applications under patient control, promoting the use of relevant clinical workflows in research, and lowering related barriers to regulatory processes. Another key theme was recognizing pervasive biases in data and information systems, algorithms, access, value, and knowledge repositories and identifying ways to resolve them.

AbstractMigraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before the emergence of pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress is a common migraine trigger that engages hypothalamic dynorphin/kappa opioid receptor (KOR) signalling and increases circulating prolactin. Prolactin acts at both long and short prolactin receptor isoforms that are expressed in trigeminal afferents. Following downregulation of the prolactin receptor long isoform, prolactin signalling at the prolactin receptor short isoform sensitizes nociceptors selectively in females. We hypothesized that stress may activate the kappa opioid receptor on tuberoinfundibular dopaminergic neurons to increase circulating prolactin leading to female-selective sensitization of trigeminal nociceptors through dysregulation of prolactin receptor isoforms.A mouse two-hit hyperalgesic priming model of migraine was used. Repeated restraint stress promoted vulnerability (i.e. first-hit priming) to a subsequent subthreshold (i.e. second-hit) stimulus from inhalational umbellulone, a TRPA1 agonist. Periorbital cutaneous allodynia served as a surrogate of migraine-like pain. Female and male KORCre; R26lsl-Sun1-GFP mice showed a high percentage of KORCre labelled neurons co-localized in tyrosine hydroxylase-positive cells in the hypothalamic arcuate nucleus. Restraint stress increased circulating prolactin to a greater degree in females. Stress-primed, but not control, mice of both sexes developed periorbital allodynia following inhalational umbellulone. Gi-DREADD activation (i.e. inhibition through Gi-coupled signalling) in KORCre neurons in the arcuate nucleus also increased circulating prolactin and repeated chemogenetic manipulation of these neurons primed mice of both sexes to umbellulone. Clustered regularly interspaced short palindromic repeats–Cas9 deletion of the arcuate nucleus KOR prevented restraint stress-induced prolactin release in female mice and priming from repeated stress episodes in both sexes. Inhibition of circulating prolactin occurred with systemic cabergoline, a dopamine D2 receptor agonist, blocked priming selectively in females. Repeated restraint stress downregulated the prolactin receptor long isoform in the trigeminal ganglia of female mice. Deletion of prolactin receptor in trigeminal ganglia by nasal clustered regularly interspaced short palindromic repeats–Cas9 targeting both prolactin receptor isoforms prevented stress-induced priming in female mice.Stress-induced activation of hypothalamic KOR increases circulating prolactin resulting in trigeminal downregulation of prolactin receptor long and pain responses to a normally innocuous TRPA1 stimulus. These are the first data that provide a mechanistic link between stress-induced hypothalamic activation and the trigeminal nociceptor effectors that produce trigeminal sensitization and migraine-like pain. This sexually dimorphic mechanism may help to explain female prevalence of migraine. KOR antagonists, currently in phase II clinical trials, may be useful as migraine preventives in both sexes, while dopamine agonists and prolactin/ prolactin receptor antibodies may improve therapy for migraine, and other stress-related neurological disorders, in females.