Disease Progression In People Research Articles

419-P: Association of Remnant Cholesterol (rem-C) with Kidney Disease Progression in People with Type 2 Diabetes (T2D)

419-P: Association of Remnant Cholesterol (rem-C) with Kidney Disease Progression in People with Type 2 Diabetes (T2D)

Mpox in people with HIV: A narrative review.

The 2022 global mpox outbreak disproportionately impacted people living with HIV. This review explores recent evidence on mpox in this group, focusing on clinical presentation, complications, treatment modalities and vaccine strategies. Recent studies have suggested that people with HIV diagnosed with mpox have a greater risk of proctitis and hospitalization compared with people without HIV. In addition, those with advanced immunosuppression face an elevated risk of severe mpox infection, which can lead to mortality. Comprehensive and prompt supportive care using antiretrovirals and mpox antivirals is crucial in this group. Although results from randomized clinical trials are still forthcoming, recent studies suggest that early initiation of tecovirimat can prevent disease progression in people with HIV. The non-replicative attenuated smallpox vaccine is well tolerated and effective in preventing monkeypox virus infections in people with HIV. Further studies are needed regarding long-term vaccine effectiveness for this population. Evaluating the risk of severe mpox in people living with HIV requires assessing the level of immune suppression and viral control. Universal access to vaccination is imperative to prevent the resurgence of future outbreaks.

Clinical implications of innate immune exhaustion in cystic fibrosis

ObjectivesThe lung disease progression in people with cystic fibrosis (pwCF) varies from one individual to another. Different immunological characteristics have been suggested to explain this variation, and we hypothesized that lung capacity may be associated with the innate immune response in pwCF. In an exploratory study, we aimed to investigate potential links between the innate immune response and lung function in pwCF using the standardized immune function assay TruCulture.MethodsIn a single-centre study with combined cross-sectional and longitudinal data before and after intravenous antibiotics, blood was sampled fromPseudomonas aeruginosainfected pwCF. Whole blood was analysed by TruCulture to reveal the unstimulated and stimulated cytokine release. Tobit regressions and Spearman's correlations were used to estimate the associations between lung function and cytokine release.ResultsWe included 52 pwCF in the cross-sectional study and 24 in the longitudinal study. In the cross-sectional study, we found that compared to a healthy population the release of toll-like receptor (TLR)3, −4 and −7/8 stimulated IFN-γ, and IL-12p40 were reduced. Although TLR3-stimulated IL-1β and IL-6 release increased with lung function, overall, cytokine release did not correlate well with lung function. In the longitudinal study, the cytokine release was modified by antibiotic treatment, but the cytokine release before antibiotic treatment did not associate with changes in lung function after treatment.ConclusionThe stimulated cytokine release could not predict lung function levels or changes in pwCF, but our data indicate that pwCF experience exhaustion in the innate immune response after years of chronic bacterial infection.

Spatiotemporal changes in imaging features associated with diffuse idiopathic skeletal hyperostosis (DISH)

ObjectivesThe purpose of our study was to characterise spatiotemporal features of disease progression in people with diffuse idiopathic skeletal hyperostosis (DISH), early-phase DISH, and those not meeting either criterion who...

Predictors of liver disease progression in people living with HIV-HBV co-infection on antiretroviral therapy

In people living with HIV-HBV, liver fibrosis progression can occur even with suppressive antiretroviral therapy (ART). We investigated the relationship between liver fibrosis and biomarkers of inflammation, apoptosis, and microbial translocation. In this observational cohort study adults living with HIV-HBV already on effective ART were recruited in Australia and Thailand and followed for 3 years including 6 monthly clinical review and blood tests and annual transient elastography. Differences in clinical and laboratory predictors of liver fibrosis progression were tested followed by regression analysis adjusted for CD4+ T-cells at study entry. A linear mixed model was fitted to longitudinal data to explore changes over time. 67 participants (85% male, median age 49y) were followed for 175 person-years. Median duration of ART was 10 years (interquartile range (IQR) 8-16 years). We found 11/59 (19%) participants during 3-years follow-up (6/100 person-years) met the primary endpoint of liver disease progression, defined as increased Metavir stage from baseline to final scan. In regression analysis, progressors compared to non-progressors had higher levels of high mobility group box 1 protein (HGMB1), (median (IQR) 3.7 (2.6-5.0) and 2.4ng/mL (1.5-3.4) respectively, adjusted relative risk 1.47, 95% CI [1.00, 2.17]) and lower nadir CD4+ T-cell percentage (median 4% (IQR 2-8) and 11% (4-15) respectively (relative risk 0.93, 95% CI [0.88, 0.98]). Progression in liver fibrosis occurs in people with HIV-HBV on suppressive ART. Fibrosis progression was associated with higher HMGB1 and lower percentage nadir CD4+ T-cell count, highlighting the importance of early initiation of HBV-active ART. This work was supported by NHMRC project grant 1101836; NHMRC practitioner fellowship 1138581 and NHMRC program grant 1149990. The funder had no role in study design, data collection, data analysis, interpretation, writing of this manuscript or decision to submit for publication.

Improved measurement of disease progression in people living with early Parkinson’s disease using digital health technologies

BackgroundDigital health technologies show promise for improving the measurement of Parkinson’s disease in clinical research and trials. However, it is not clear whether digital measures demonstrate enhanced sensitivity to disease progression compared to traditional measurement approaches.MethodsTo this end, we develop a wearable sensor-based digital algorithm for deriving features of upper and lower-body bradykinesia and evaluate the sensitivity of digital measures to 1-year longitudinal progression using data from the WATCH-PD study, a multicenter, observational digital assessment study in participants with early, untreated Parkinson’s disease. In total, 82 early, untreated Parkinson’s disease participants and 50 age-matched controls were recruited and took part in a variety of motor tasks over the course of a 12-month period while wearing body-worn inertial sensors. We establish clinical validity of sensor-based digital measures by investigating convergent validity with appropriate clinical constructs, known groups validity by distinguishing patients from healthy volunteers, and test-retest reliability by comparing measurements between visits.ResultsWe demonstrate clinical validity of the digital measures, and importantly, superior sensitivity of digital measures for distinguishing 1-year longitudinal change in early-stage PD relative to corresponding clinical constructs.ConclusionsOur results demonstrate the potential of digital health technologies to enhance sensitivity to disease progression relative to existing measurement standards and may constitute the basis for use as drug development tools in clinical research.

Increased platelet-CD8+ T-cell aggregates displaying high activation, exhaustion, and tendency to death correlate with disease progression in people with HIV-1.

Platelets engage in HIV-1 infection by interacting with immune cells, which has been realized broadly. However, the potential interaction between platelets and CD8+ T cells remains unidentified. Here, treatment-naive individuals with HIV-1, complete immunological responders to antiretroviral therapy, and healthy controls were enrolled. First, we found that treatment-naive individuals with HIV-1 had low platelet numbers and high CD8+ T-cell counts when compared with complete immunological responders to antiretroviral therapy and healthy controls, leading to a low platelet/CD8+ T-cell ratio in peripheral blood, which could effectively differentiate the status of HIV-1 infection. Moreover, cytokines that may have been derived from platelets were higher in the plasma of people with HIV-1 despite viral suppression. Furthermore, we demonstrated that platelet-CD8+ T-cell aggregates were elevated in treatment-naive individuals with HIV-1, which positively correlated with HIV-1 viral load but negatively correlated with CD4+ T-cell count and CD4/CD8 ratio. Finally, we revealed that platelet-CD8+ T-cell aggregates correlate with enhanced activation/exhaustion and pyroptosis/apoptosis compared with free CD8+ T cells. Moreover, platelet-induced caspase 1 activation of CD8+ T cells correlated with IL-1β and IL-18 plasma levels. In brief, we reveal the importance of platelets in HIV-1 infection, which might secrete more cytokines and mediate CD8+ T-cell phenotypic characteristics by forming platelet-CD8+ T-cell aggregates, which are related to poor prognosis.

Real-world use of ofatumumab to treat multiple sclerosis 9 months post-FDA approval during COVID-19 pandemic.

Relapsing multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disease of the central nervous system that causes episodes of neurological dysfunction (relapse) alternating with variable intervals of stability. Disease-modifying therapies (DMTs) aim to reduce the rate of relapse and slow disease progression in people with MS, particularly in those with relapsing MS. Ofatumumab is a fully human anti-CD20 monoclonal antibody approved to treat patients with relapsing forms of MS. This study describes the demographics, clinical characteristics, and prior DMT use of patients with at least one ofatumumab prescription claim following approval by the United States (US) Food and Drug Administration (FDA). Understanding ofatumumab utilization patterns and patient characteristics can help define the journey of patients with MS and aid future clinical decision-making. This retrospective study is based on data from IQVIA's Longitudinal Prescription Data (LRx) and Medical Claims (Dx) databases in the US, collected between August 01, 2019 and May 31, 2021. The index date was defined as the date of the first ofatumumab prescription. The pre-index period was defined as the 12 months prior to the index date. Adult patients (aged ≥18 years) with a diagnosis of MS and at least one prescription for ofatumumab between August 2020 and May 2021 in the LRx database were included. Only patients with at least one medical claim in the Dx database and a diagnosis of MS 24 months prior to the index date were included. Descriptive analyses were conducted 3, 6, and 9 months after FDA approval. Overall, 3,600 patients with a prescription for ofatumumab were identified in the LRx claims database, and 2,101 patients remained in the study after inclusion and exclusion criteria had been applied. At the 9-month post-approval time point, patients with ofatumumab claims were characterized as primarily female (74%) and middle-aged (median age: 48 years); two-thirds (64.7%) had a mild MS disability level. Patients were otherwise generally healthy with limited comorbid conditions. Most patients (81.7%) in the study did not experience relapse during the pre-index period. DMT-naïve patients who were prescribed ofatumumab at 3, 6, and 9 months post-approval accounted for 46.9%, 54.8%, and 58.4% of the study population, respectively. Over time, this increase in DMT-naïve ofatumumab initiators was statistically significant (p=0.0003). Among patients who had been treated with DMTs during the previous year, most had taken them orally (50.6%), some had received them via intravenous infusion (32.2%), and some via subcutaneous/intramuscular injection (21.1%). Intravenous ocrelizumab was the most common DMT switch observed (n=205, 23.4%) among these patients. This real-world study is the first to describe patients treated with ofatumumab since FDA approval during the COVID-19 pandemic. The majority of patients in this study were middle-aged women with mild MS symptoms. Ofatumumab was increasingly used as a first-line DMT. Additionally, a number of patients aged ≥55 years (beyond the trial population) used ofatumumab, which may suggest expanding clinician confidence in the safety and clinical utility of ofatumumab therapy. However, future long-term observational studies are needed to confirm these results.

Impact of adherence to disease modifying therapies on long-term clinical and economic outcomes in multiple sclerosis: A claims analysis of real-world data.

Multiple sclerosis (MS) is a chronic neurodegenerative inflammatory disease that requires long-term commitment to treatment for optimal outcomes. A variety of disease-modifying therapies (DMTs) are now available that reduce relapses and delay disease progression in people with MS. However, adherence remains a significant issue, with a variety of mental, physical, and emotional factors contributing to non-adherence. In a large number of studies, non-adherence has been associated with worse clinical outcomes (relapses and disease severity), a higher economic burden, and loss of work productivity. However, many of these studies were short-term (1-2 years) or cross-sectional studies; thus, more data are needed on the long-term clinical and economic impacts of DMT non-adherence. The objective of this study was to determine the longer-term impact of adherence to DMTs on disease activity and healthcare resource utilization (HCRU) in people with MS. The study hypothesis was that non-adherence to DMTs would be associated long-term with worse clinical outcomes and a higher economic burden. A retrospective administrative claims analysis of the US MarketScan® Commercial database (2011-2017) in individuals (18-65 years) with MS (based on International Classification of Disease coding) was conducted. Adherence was classified by proportion of days covered (PDC) ≥0.8 and non-adherence by PDC <0.8; sensitivity analyses helped further categorize as moderately (PDC ≥0.6-<0.8) or highly (PDC <0.6) non-adherent. Cohorts were matched using propensity score matching. Time to first relapse, annualized relapse rate (ARR), time to use of assistive devices (cane/walker or wheelchair), and annual HCRU (inpatient, emergency room [ER], outpatient, and MRI visits and costs) were compared between cohorts. 10,248 MS cases were identified; 58% met adherence criteria, and 42% met non-adherence criteria. Mean follow-up from diagnosis or first DMT claim was 5.3 years. Adherent individuals had a longer time to first relapse (hazard ratio [HR] 0.83; 95% confidence interval [CI]: 0.77-0.90; p<0.0001), a lower ARR (0.13vs. 0.18, respectively; rate ratio [RR] 0.75 [95% CI: 0.71-0.79]; p<0.0001), and longer lag times to cane/walker use (HR 0.79 [95% CI: 0.66-0.94]; p=0.0067) and wheelchair use (HR 0.68 [95% CI: 0.55-0.83]; p=0.0002) than non-adherent individuals. Adherent individuals had fewer annual inpatient and ER visits and lower total costs than those who were non-adherent (p<0.0001). Sensitivity analyses showed that differences in disease activity and HCRU were generally more pronounced between matched adherent and highly non-adherent pairs than between matched adherent and moderately non-adherent pairs. Significant differences in MS disease activity and HCRU were observed based on adherence to DMTs. Our study underscores the negative impact of non-adherence to DMTs on long-term clinical and economic outcomes in MS.

Vascular disease risk factors in multiple sclerosis: Effect on metabolism and brain volumes.

Vascular disease risk factors (VDRF) such as hypertension, hyperlipidemia, obesity, diabetes and heart disease likely play a role in disease progression in people with multiple sclerosis (PwMS) (Marrie, Rudick etal. 2010). Studies exploring the mechanistic connection between vascular disease and MS disease progression are scant. We hypothesized that phosphate energy metabolism impairment in PwMS with VDRFs (VDRF+) will be greater compared to PwMS without VDRFs (VDRF-) and is related to increased brain atrophy in VDRF+. To test this hypothesis, we planned to study the differences in the high energy phosphate (HEP) metabolites in cerebral gray matter as assessed by 31P magnetic resonance spectroscopic imaging (MRSI) and MRI brain volumetric in the VDRF+ and VDRF- PwMS at four different timepoints over a 3 yearlong period using a 7T MR system. We present here the results from the cross-sectional evaluation of HEP metabolites and brain volumes. We also evaluated the differences in clinical impairment, blood metabolic biomarkers and quality of life in VDRF+ and VDRF- PwMS in this cohort. Group differences in high energy phosphate metabolites were assessed from a volume of interest in the occipital region using linear mixed models. Brain parenchymal and white matter lesion volumes were determined from MR anatomic images. We present here the cross-sectional analysis of the baseline data collected as part of a longitudinal 3 yearlong study where we obtained baseline and subsequent 6-monthly clinical and laboratory data and annual 7T MRI volumetric and 31P MR spectroscopic imaging (MRSI) data on 52 PwMS with and without VDRF. Key clinical and laboratory outcomes included: body mass index (BMI), waist and thigh circumferences and disability [Expanded Disability Status Scale (EDSS)], safety (complete blood count with differential, complete metabolic), lipid panel including total cholesterol and HbA1C. We analyzed clinical and laboratory data for the group differences using student's t or χ2 test. We investigated relationship between phosphate metabolites and VDRF using mixed effect linear regression. Complete MRI data were available for 29 VDRF+, age 56.3 (6.8) years [mean (SD)] (83% female), and 23 VDRF-, age 52.5 (7.5) years (57% female) individuals with MS. The mean value of normalized adenosine triphosphate (ATP) (calculated as the ratio of ATP to total phosphate signal in a voxel) was decreased by 4.5% (p < .05) in VDRF+ compared to VDRF- MS group. White matter lesion (WML) volume fraction in VDRF+ individuals {0.007 (0.007)} was more than doubled compared to VDRF- participants {0.003 (0.006), p= .02}. We found significantly lower brain ATP and higher inorganic phosphate (Pi) in those PwMS with VDRFs compared to those without. ATP depletion may reflect mitochondrial dysfunction. Ongoing longitudinal data analysis from this study, not presented here, will evaluate the relationship of phosphate metabolites, brain atrophy and disease progression in PwMS with and without vascular disease.

P184 Sex differences in annual pulmonary exacerbations in people with cystic fibrosis

Pulmonary exacerbations (PEx) are a major contributor to disease progression in people with cystic fibrosis (CF). While studies have demonstrated that females with CF experiencing PEx have worse clinical outcomes compared to males, there is currently a lack of epidemiologic studies comparing the frequency of PEx in the current era. We therefore utilized the Cystic Fibrosis Foundation Patient Registry (CFFPR) to evaluate whether the burden of PEx differs between females and males with CF.

Association Between Depression and Physical Conditions Requiring Hospitalization

Depression is associated with an increased risk of physical illness, but the most common causes of hospitalization among people with depression are unclear. To examine the association of depression with an array of physical conditions requiring hospital treatment. In this outcomewide prospective multicohort study, primary analysis was based on data from the UK Biobank, a population-based study in the United Kingdom. Analyses were repeated in an independent data set of 2 cohorts in Finland, a population-based study and an occupational cohort. Data analysis was conducted between April and September 2022. Self-reported depression, recurrent severe major depression, recurrent moderate major depression, and a single major depressive episode. A total of 77 common health conditions ascertained from linkage data to national hospital and mortality registries. The analytical sample of UK Biobank participants consisted of 130 652 individuals (71 565 women [54.8%]; 59 087 men [45.2%]; mean [SD] age at baseline, 63.3 [7.8] years). The pooled data from the Finnish replication cohorts included 109 781 participants (82 921 women [78.6%]; 26 860 men [21.4%]; mean [SD] age, 42 [10.8] years). In the main analysis, severe/moderately severe depression was associated with the incidence of 29 nonoverlapping conditions requiring hospital treatment during a 5-year follow-up. Twenty-five of these associations remained after adjustment for confounders and multiple testing (adjusted hazard ratio [HR] range, 1.52-23.03) and were confirmed in the analysis of the Finnish cohorts. These included sleep disorders (HR, 5.97; 95% CI, 3.27-10.89), diabetes (HR, 5.15; 95% CI, 2.52-10.50), ischemic heart disease (HR, 1.76; 95% CI, 1.36-2.29), chronic obstructive bronchitis (HR, 4.11; 95% CI, 2.56-6.60), bacterial infections (HR, 2.52; 95% CI, 1.99-3.19), back pain (HR, 3.99; 95% CI, 2.96-5.38), and osteoarthritis (HR, 1.80; 95% CI, 1.46-2.20). The highest cumulative incidence was observed for endocrine and related internal organ diseases (245 per 1000 persons with depression; risk difference relative to unaffected individuals: 9.8%), musculoskeletal diseases (91 per 1000 persons; risk difference, 3.7%), and diseases of the circulatory system and blood (86 per 1000 persons; risk difference, 3.9%). The cumulative incidence was lower for hospital-treated mental, behavioral, and neurological disorders (20 in 1000 persons; risk difference, 1.7%). Depression was also associated with disease progression in people with prevalent heart disease or diabetes, and for 12 conditions, there was evidence of a bidirectional relationship. In this study, the most common causes of hospitalization in people with depression were endocrine, musculoskeletal, and vascular diseases, not psychiatric disorders. These findings suggest that depression should be considered as a target for the prevention of physical and mental disease.

Evaluating the Effect of a Bruton’s Tyrosine Kinase Inhibitor in a Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis (P2-3.012)

<h3>Objective:</h3> To characterize a central nervous system (CNS)-penetrant, tolebrutinib-like Bruton’s tyrosine kinase inhibitor (BTKi) in murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) for its potential to modulate disease progression and expression of genes linked to disease-associated microglia (DAM). <h3>Background:</h3> BTK inhibition may slow disease progression in people with MS by targeting microglia-driven neuroinflammation in the CNS. We previously showed that a structural analogue of the BTKi tolebrutinib can reduce BTK-dependent inflammatory signalling in microglia in the mouse brain, using the cuprizone-mediated model of demyelination. <h3>Design/Methods:</h3> Female C57BL/6 mice were immunized with MOG_35–55 peptide (250 μg/mouse; two subcutaneous injections in the lower back) to induce EAE. Animals were randomized to receive vehicle (n=15) or oral BTKi (15 mg/kg; n=15), starting at clinical score of 1.0–1.5. Treatment groups were blinded until after final data analysis. Cohorts were monitored daily for development and severity of disease symptoms. After 10 days of treatment, spinal cord and plasma samples were taken for transcriptome analysis and neurofilament heavy chain (NfH) concentration measurement, respectively. <h3>Results:</h3> BTK inhibition significantly reduced the clinical score in the EAE mice, with significant differences between treatment groups starting after two days of treatment and continuing until end of study (Day 10). BTK inhibition significantly reduced plasma Nfh concentrations. A BTK-dependent transcriptional signature was identified, with BTK inhibition found to modulate pathways relevant to MS pathology. BTK inhibition modulated mRNA expression of genes that had previously been linked to DAM and/or are associated with BTK-signalling. <h3>Conclusions:</h3> We extended our previous <i>in vivo</i> findings from a demyelination model by demonstrating that dosing with a BTKi halted disease progression in an immune-mediated model of MS. This therapeutic benefit was accompanied by modulated expression of genes associated with activated microglia, which could abrogate microglia-driven neuroinflammation implicated in disease progression in MS. <b>Disclosure:</b> Dr. Gruber has received personal compensation for serving as an employee of Sanofi. Dr. Gruber has received stock or an ownership interest from Sanofi. Dr. Blazier has received personal compensation for serving as an employee of Sanofi. Lan Lee has nothing to disclose. Dr. Ryan has nothing to disclose. Dr. Cheong has received personal compensation for serving as an employee of Sanofi. Ms. Havari has received personal compensation for serving as an employee of sanofi. Timothy J. Turner has received personal compensation for serving as an employee of Sanofi. Timothy J. Turner has received stock or an ownership interest from Sanofi. Timothy J. Turner has received intellectual property interests from a discovery or technology relating to health care. Dimitry Ofengeim has received personal compensation for serving as an employee of Sanofi. Dimitry Ofengeim has received stock or an ownership interest from Sanofi. Dimitry Ofengeim has received personal compensation in the range of $500-$4,999 for serving as a Study Section Reveiwer with NIH.

Rituximab is Associated with Limiting Progression in Individuals with Stiff Person Syndrome Spectrum Disorders (S40.002)

<h3>Objective:</h3> To assess if rituximab minimizes disease progression in people with Stiff Person Syndrome Spectrum Disorders (SPSD). <h3>Background:</h3> Rituximab has been used to treat many autoimmune conditions including SPSD. However, there is a lack of long-term data assessing rituximab in a large cohort of people with SPSD. We previously analyzed the effects of rituximab in a small group of people with SPSD and focused on improvement of function. The purpose of this study was to evaluate the effects of rituximab in a larger cohort of patients over a longer duration of time and assess how this therapy minimizes disease progression. <h3>Design/Methods:</h3> Demographic and clinical data from 235 SPSD patients evaluated at the Johns Hopkins SPS Center were obtained as part of an ongoing longitudinal observational study. Data analysis was performed in patients who met the following inclusion criteria: confirmed diagnosis of SPSD, exposure to rituximab therapy, and &gt;1 follow-up visit with adequate clinical information for outcome measure comparisons. The main outcomes were change in relevant symptoms, objective findings, and global score (combined subjective and objective data). <h3>Results:</h3> Of 69 SPSD patients with rituximab exposure (81% female, age M±SD=49y±13.6y), data analysis was performed in 63 patients who met the inclusion criteria. The median (IQR) years between symptom onset and rituximab exposure was 9.17y (4.46y, 13.26y). At baseline, 97% self-reported gait difficulties, 88% had objective gait abnormalities, and mean (SD) modified Rankin score was 3.0 (0.83). The median and maximum follow-up times were 1.1y and 9.4y, respectively. Based on global scores over the follow-up period, 37 (58.7%) improved, 21 (33.3%) stabilized, and 5 (7.9%) worsened after rituximab exposure. <h3>Conclusions:</h3> The findings of this study suggest that many patients with SPSD may experience plateauing of worsening disability with chronic rituximab treatment. Specific factors associated with treatment response remain unclear and warrant further studies. <b>Disclosure:</b> The institution of Dr. Harrison has received research support from National MS Society. Miss Hu has nothing to disclose. Dr. Aljarallah has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Aljarallah has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Aljarallah has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Sanofi Genzyme. The institution of Dr. Wang has received research support from Genentech. The institution of Dr. Fitzgerald has received research support from NIH. The institution of Dr. Fitzgerald has received research support from National MS Society. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Newsome has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Greenwich Biosciences. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon Therapeutics. The institution of Dr. Newsome has received research support from Biogen. The institution of Dr. Newsome has received research support from Genentech/Roche. The institution of Dr. Newsome has received research support from Department of Defense. The institution of Dr. Newsome has received research support from Patient Centered Outcomes Research Institute. The institution of Dr. Newsome has received research support from National MS Society. The institution of Dr. Newsome has received research support from The Stiff Person Syndrome Research Foundation. Dr. Newsome has received personal compensation in the range of $5,000-$9,999 for serving as a Clinical adjudication committee member for clinical trial with medDay Pharmaceuticals. Dr. Newsome has received personal compensation in the range of $10,000-$49,999 for serving as a Lead PI for Clinical Trial with Roche.

Association of Oxygen Therapy with the Natural Disease Progression of Cystic Fibrosis: A Multi-State Model of the European Cystic Fibrosis Society Patient Registry.

Association between dependence on oxygen therapy (OT) and natural disease progression in people with cystic fibrosis (pwCF) has not been estimated yet. The aim of this study is to understand the prognosis for pwCF on OT, evaluating how the transition probabilities from being alive without lung transplantation (LTx) to LTx and to death, and from being alive after LTx to death change in pwCF with and without OT. We used 2008-2017 data from the 35-country European CF Society Patient Registry. A multi-state model was fitted to assess the effects of individual risk factors on transition probabilities. We considered 48,343 pwCF aged from 6 to 50 years. OT (HR 5.78, 95% CI: 5.32-6.29) and abnormal FEV1 (HR 6.41, 95% CI: 5.28-7.79) were strongly associated with the probability of having LTx; chronic infection with Burkholderia cepacia complex (HR 3.19, 95% CI: 2.78-3.67), abnormal FEV1 (HR 5.00, 95% CI: 4.11-6.08) and the need for OT (HR 4.32, 95% CI: 3.93-4.76) showed the greatest association with the probability of dying without LTx. Once pwCF received LTx, OT (HR 1.75, 95% CI: 1.41-2.16) and abnormal FEV1 (HR 1.63, 95% CI: 1.18-2.25) were the main factors associated with the probability of dying. An association of gross national income with the probability of receiving LTx and with the probability of dying without LTx was also found. Oxygen therapy is associated with poor survival in pwCF with and without LTx; harmonization of CF care throughout European countries and minimization of the onset of pulmonary gas exchange abnormalities using all available means remains of paramount importance.

Changes in urinary albumin as a surrogate for kidney disease progression in people with type 2 diabetes.

It remains unclear whether urinary albumin changes can predict subsequent kidney disease progression in people with diabetes. This retrospective cohort study included 4570 Japanese adults with type 2 diabetes (T2D). The exposure was changes in urinary albumin-to-creatinine ratio (UACR) over 3years, categorized into three categories: ≤ -30%, minor change, or ≥ 30%. During the exposure period, eGFR decline was also examined and categorized into two categories: < 30% or ≥ 30% decline. The primary outcome was the composite of eGFR halving or initiation of kidney replacement therapy (KRT). The secondary outcome was the initiation of KRT. In the spline model, the hazard ratio for the primary outcome increased linearly on the log2 scale of UACR changes. When classified into six groups based on the categories of UACR changes and eGFR decline, people with a ≤ -30% UACR change and < 30% eGFR decline had a 38% lower incidence of the outcome compared to those with a minor UACR change and < 30% eGFR decline. Meanwhile, the risk in those with a ≤ -30% UACR change and ≥ 30% eGFR decline was 2.89 times. People with a ≥ 30% UACR change had the higher risk, regardless of whether a ≥ 30% eGFR decline occurred. Similar results were obtained in the secondary outcome. UACR changes can be a useful surrogate for kidney disease progression in people with T2D. However, when setting a decrease in UACR as the surrogate, it may be necessary to simultaneously evaluate kidney function decline.

Reliability and validity of the incremental shuttle walk test in patients with fully ambulatory multiple sclerosis.

Functional exercise capacity evaluation is crucial to monitor treatment effects and disease progression in people with multiple sclerosis (pwMS). Compared to other tests, the incremental shuttle walking test (ISWT), which more accurately reflects cardiovascular responses, may be more useful for assessing exercise capacity. The aim of the study is to investigate the reliability and validity of the ISWT. Thirty-six pwMS with an Expanded Disability Status Scale (EDSS) score<4.5 between the ages of 25 and 65 were included in the study. The subjects underwent practice (ISWT-p) before undergoing the test-retest protocol in order to rule out the ISWT learning effect (ISWT-1 - ISWT-2). ISWT-1 and ISWT-2 were administered with a 3-7 day interval for test-retest reliability. Six-minutes walking test (6MWT) were applied for concurrent validity. The EDSS, pulmonary function tests, Fatigue Impact Scale (FIS), respiratory muscle strength [maximum inspiratory and expiratory pressure (MIP-MEP)] measurements were made for convergent validity. ISWT was found to have excellent test-retest reliability with an ICC value of 0.97. The area under the curve value was 0.904 indicating that ISWT has a good performance for predicting disease severity. The moderate correlation between ISWT and 6MWT (rho: 0.68, p<0,001) proved concurrent validity. It was also moderately correlated with EDSS, MEP (rho: -0.58 and 0.47 respectively), weakly correlated with MIP and FIS (rho:0.37 and -0.36, respectively) while not correlated with pulmonary function tests. The ISWT had excellent test-retest reliability, acceptable criterion and construct validity in ambulatory MS patients.

Factors associated with SARS-CoV-2 infections among migrants in Germany

Abstract Background International research shows increased risks for SARS-CoV-2 infection and severe disease progression in people with migration history. In Germany, data on this topic is scarce. Aim of this contribution is to examine the association between migrant status and risk of SARS-CoV-2 infection and discuss potential explanatory mechanisms. Methods We analysed data from the German COVID-19 Snapshot Monitoring online-survey and performed hierarchical multiple regression models to calculate probabilities for a self-reported SARS-CoV-2 infection. Main predictor variable was the migrant status; besides, the association with gender, age, education, household size, household language (German vs. other), and occupation in the health sector was analysed. Results Of 45,858 participants, 3.5% reported a current or previous infection with SARS-CoV-2, 16% reported own or parental history of migration. The probability of reporting an infection was 3.95 percentage points higher among migrants. The effect of different characteristics on self-reported SARS-CoV-2 infection varied. Higher probabilities were shown for individuals living in bigger households and those not speaking German at home. Stepwise integration decreased the observed association with migrant status. When adding an interaction term of migrant status and occupation in the health sector, the probability to report an infection was 11.5 percentage points higher for migrants working in the health sector. Conclusions People with migration history, health sector employees and particular migrant health workers are at a higher risk of SARS-CoV-2 infection. However, the migrant status itself does not determine the risk of infection, but the living and working conditions. Therefore, targeted and multilingual prevention measures are needed that consider living and working conditions. Key messages • Higher SARS-CoV-2 infection risks are not solely determined by migrant status, but were shown for health care workers, people living in bigger households and those not speaking German at home. • As not the migrant status determines infection risks, multilingual and targeted prevention measures considering the living and working conditions of people are necessary.

Biomarkers of disease progression in people with psoriasis: a scoping review.

Identification of those at risk of more severe psoriasis and/or associated morbidities offers opportunity for early intervention, reduced disease burden and more cost-effective healthcare. Prognostic biomarkers of disease progression have thus been the focus of intense research, but none are part of routine practice. To identify and catalogue candidate biomarkers of disease progression in psoriasis for the translational research community. A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with disease progression. The main outcomes were any measure of skin severity or any prespecified psoriasis comorbidity. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (longitudinal design and/or use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise, and mapped to relevant cellular and molecular pathways. Of 181 included studies, most investigated genomic or proteomic biomarkers associated with disease severity (n = 145) or psoriatic arthritis (n = 30). Methodological and reporting limitations compromised interpretation of findings, most notably a lack of longitudinal studies, and inadequate control for key prognostic factors. The following candidate biomarkers with future potential utility were identified for predicting disease severity: LCE3D, interleukin (IL)23R, IL23A, NFKBIL1 loci, HLA-C*06:02 (genomic), IL-17A, IgG aHDL, GlycA, I-FABP and kallikrein 8 (proteomic), tyramine (metabolomic); psoriatic arthritis: HLA-C*06:02, HLA-B*27, HLA-B*38, HLA-B*08, and variation at the IL23R and IL13 loci (genomic); IL-17A, CXCL10, Mac-2 binding protein, integrin b5, matrix metalloproteinase-3 and macrophage-colony stimulating factor (proteomic) and tyramine and mucic acid (metabolomic); and type 2 diabetes mellitus: variation in IL12B and IL23R loci (genomic). No biomarkers were supported by sufficient evidence for clinical use without further validation. This review provides a comprehensive catalogue of investigated biomarkers of disease progression in psoriasis. Future studies must address the common methodological limitations identified herein to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? The current treatment paradigm in psoriasis is reactive. There is a need to develop effective risk-stratified management approaches that can proactively attenuate the substantial burden of disease. Prognostic biomarkers of disease progression have therefore been the focus of intense research. What does this study add? This review is the first to scope, collate and catalogue research investigating biomarkers of disease progression in psoriasis. The review identifies potentially promising candidate biomarkers for further investigation and highlights common important limitations that should be considered when designing and conducting future studies in this area.

Increased Adipose Tissue Expression of IL-23 Associates with Inflammatory Markers in People with High LDL Cholesterol.

Chronic low-grade inflammation induced by obesity is a central risk factor for the development of metabolic syndrome. High low-density lipoprotein cholesterol (LDL-c) induces inflammation, which is a common denominator in metabolic syndrome. IL-23 plays a significant role in the pathogenesis of meta-inflammatory diseases; however, its relationship with LDL-c remains elusive. In this cross-sectional study, we determined whether the adipose tissue IL-23 expression was associated with other inflammatory mediators in people with increased plasma LDL-c concentrations. Subcutaneous adipose tissue biopsies were collected from 60 people, sub-divided into two groups based on their plasma LDL-c concentrations (<2.9 and ≥2.9 mmol/L). Adipose expression of IL-23 and inflammatory markers were determined using real-time qRT-PCR; plasma concentrations of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c) and LDL-c were determined using the standard method; and adiponectin levels were measured by enzyme-linked immunosorbent assay (ELISA). Adipose IL-23 transcripts were found to be increased in people with high LDL-c, compared to low LDL-c group (H-LDL-c: 1.63 ± 0.10–Fold; L-LDL-c: 1.27 ± 0.09–Fold; p < 0.01); IL-23 correlated positively with LDL-c (r = 0.471, p < 0.0001). Immunochemistry analysis showed that AT IL-23 protein expression was also elevated in the people with H-LDL-c. IL-23 expression in the high LDL-c group was associated with multiple adipose inflammatory biomarkers (p ≤ 0.05), including macrophage markers (CD11c, CD68, CD86, CD127), TLRs (TLR8, TLR10), IRF3, pro-inflammatory cytokines (TNF-α, IL-12, IL-18), and chemokines (CXCL8, CCL3, CCL5, CCL15, CCL20). Notably, in this cohort, IL-23 expression correlated inversely with plasma adiponectin. In conclusion, adipose IL-23 may be an inflammatory biomarker for disease progression in people with high LDL-c.