It has long been demonstrated that a subset of patients with Sjogren's syndrome (SS) develop ectopic lymphoid structures (ELS) in the salivary glands (SG). These structures are characterised by periductal clusters of T and B lymphocytes, development of high endothelial venules and differentiation of follicular dendritic cells (FDC) networks. Evidence in patients with and animal models of SS demonstrated that the formation and maintenance of ELS in the SG is critically dependent on the ectopic expression of lymphotoxins (LT) and lymphoid chemokines CXCL13, CCL19, CCL21 and CXCL12. Several cell types, including resident epithelial, stromal and endothelial cells as well as different subsets of infiltrating immune cells, have been shown to be capable of producing some of these factors during chronic inflammation in SS. In this review we focus on the cellular and molecular mechanisms regulating the formation of ELS in SS SG, with particular emphasis on the role of lymphoid chemokines. In addition, we summarise accumulating data in support of the notion that ELS in SS represent functional niches whereby autoreactive B cells undergo affinity maturation, clonal selection and differentiation into autoantibody producing cells, thus contributing to autoimmunity over and above secondary lymphoid organs. Furthermore, we review the emerging role of ELS and lymphoid chemokines in driving extranodal B cell lymphomagenesis in SS and we focus on recent evidence suggesting that ELS identify subsets of SS patients at increased risk of developing systemic manifestations and lymphoma.

Control of trabecular bone volume is mediated by local events. Recently, it has been shown that the cytokines interleukin-1 (IL-1), tumor necrosis factor alpha (TNF alpha), and TNF beta [also called lymphotoxin (LT)] produced by immune cells all stimulate osteoclast activity, whereas the lymphokine interferon-gamma (IFN gamma) inhibits osteoclast activity stimulated by these agents. We report here the effects of each of these cytokines on bone collagen content measured as incorporation of proline into collagen and noncollagen protein in 20-day-old fetal rat calvariae. We found that IL-1, LT, and TNF decreased bone collagen synthesis and, to a lesser degree, noncollagen protein synthesis when the bones were exposed continuously to these agents. In addition, these cytokines stimulated DNA synthesis in the calvariae. In contrast to its action on bone resorption, where it opposed the resorptive effects of IL-1, TNF, and LT, IFN gamma inhibited bone collagen synthesis and had an additive effect with TNF and LT when bones were exposed to both. However, unlike the other cytokines, IFN gamma also decreased DNA synthesis in the calvariae. These data indicate that cytokines released by immune cells in the bone marrow microenvironment may work in concert to affect osteoblast activity in vitro.

<A<em>b</em>stractText>It has <em>b</em>een reported that the triglyceride-glucose (TyG) index may serve as a simple and credi<em>b</em>le surrogate marker of insulin resistance (IR). However, its association with macrovascular and microvascular damage is unclear. Accordingly, the o<em>b</em>jective of the present study is to investigate the association of macrovascular and microvascular damage with the TyG index.</A<em>b</em>stractText><A<em>b</em>stractText>A total of 2830 elderly participants from the Northern Shanghai Study (NSS) were enrolled. The TyG index was calculated as ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Parameters of vascular damage, including carotid-femoral pulse wave velocity (cf-PWV), <em>b</em>rachial-ankle pulse wave velocity (<em>b</em>a-PWV), ankle-<em>b</em>rachial index (ABI), carotid intima-media thickness (CMT), carotid plaque, estimated glomerular fi<em>lt</em>ration rate (eGFR) and the urine al<em>b</em>umin-to-creatinine ratio (UACR), were measured and calculated.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>In univariate logistic regression, an increased TyG index was associated with a higher risk of cf-PWV > 10 m/s, <em>b</em>a-PWV > 1800 cm/s, ABI &<em>lt</em>; 0.9, microal<em>b</em>uminuria (MAU) and chronic kidney disease (CKD). In mu<em>lt</em>ivaria<em>b</em>le logistic regression, there was a significant increase in the risk of cf-PWV > 10 m/s (OR = 1.86, 95% confidence interval [95% CI] 1.37-2.53, P<su<em>b</em>)for trend</su<em>b</em>) &<em>lt</em>; 0.001), <em>b</em>a-PWV > 1800 cm/s (OR = 1.39, [95% CI] 1.05-1.84, P<su<em>b</em>)for trend</su<em>b</em>)= 0.02), MAU (OR = 1.61, [95% CI] 1.22-2.13, P<su<em>b</em>)for trend</su<em>b</em>) &<em>lt</em>; 0.001) and CKD (OR = 1.67, [95% CI] 1.10-1.50, P<su<em>b</em>)for trend</su<em>b</em>)= 0.02) after adjustment for age, sex, BMI, waist circumference, smoking ha<em>b</em>it, hypertension, family history of premature CVD, dia<em>b</em>etes, HDL-C, LDL-C, insulin therapy and statin therapy. However, no significant relationship was o<em>b</em>served <em>b</em>etween the TyG index and lower extremity atherosclerosis, carotid hypertrophy or carotid plaque.</p><A<em>b</em>stractText>An elevated TyG index was significantly associated with a higher risk of arterial stiffness and nephric microvascular damage. This conclusion lends support to the clinical significance of the TyG index for the assessment of vascular damage.</A<em>b</em>stractText>

<A<em>b</em>stractText>Radiomics has emerged as a new approach that can help identify imaging information associated with tumor pathophysiology. We developed and validated a radiomics nomogram for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC).</A<em>b</em>stractText><p><div>(<em>b</em>)Methods</<em>b</em>)</div>Two hundred and eight patients with pathologically confirmed HCC (training cohort: <i>n</i> = 146; validation cohort: <i>n</i> = 62) who underwent preoperative gadoxetic acid-enhanced magnetic resonance (MR) imaging were included. Least a<em>b</em>solute shrinkage and selection operator logistic regression was applied to select features and construct signatures derived from MR images. Univariate and mu<em>lt</em>ivariate analyses were used to identify the significant clinicoradiological varia<em>b</em>les and radiomics signatures associated with MVI, which were then incorporated into the predictive nomogram. The performance of the radiomics nomogram was evaluated <em>b</em>y its cali<em>b</em>ration, discrimination, and clinical utility.</p><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>Higher α-fetoprotein level (<i>p</i> = 0.046), nonsmooth tumor margin (<i>p</i> = 0.003), arterial peritumoral enhancement (<i>p &<em>lt</em>;</i> 0.001), and the radiomics signatures of hepato<em>b</em>iliary phase (HBP) T1-weighted images (<i>p &<em>lt</em>;</i> 0.001) and HBP T1 maps (<i>p &<em>lt</em>;</i> 0.001) were independent risk factors of MVI. The predictive model that incorporated the clinicoradiological factors and the radiomic features derived from HBP images outperformed the com<em>b</em>ination of clinicoradiological factors in the training cohort (area under the curves [AUCs] 0.943 vs. 0.850; <i>p</i> = 0.002), though the validation did not have a statistical significance (AUCs 0.861 vs. 0.759; <i>p</i> = 0.111). The nomogram <em>b</em>ased on the model exhi<em>b</em>ited C-index of 0.936 (95% CI 0.895-0.976) and 0.864 (95% CI 0.761-0.967) in the training and validation cohort, fitting well in cali<em>b</em>ration curves (<i>p</i> > 0.05). Decision curve analysis further confirmed the clinical usefulness of the nomogram.</p><A<em>b</em>stractText>The nomogram incorporating clinicoradiological risk factors and radiomic features derived from HBP images achieved satisfactory preoperative prediction of the individualized risk of MVI in patients with HCC.</A<em>b</em>stractText>

(<em>b</em>)Rationale:</<em>b</em>) Symptom su<em>b</em>types have <em>b</em>een descri<em>b</em>ed in clinical and population samples of patients with o<em>b</em>structive sleep apnea (OSA). It is unclear whether these su<em>b</em>types have different cardiovascular consequences.(<em>b</em>)O<em>b</em>jectives:</<em>b</em>) To characterize OSA symptom su<em>b</em>types and assess their association with prevalent and incident cardiovascular disease in the Sleep Heart Hea<em>lt</em>h Study.(<em>b</em>)Methods:</<em>b</em>) Data from 1,207 patients with OSA (apnea-hypopnea index ≥ 15 events/h) were used to evaluate the existence of symptom su<em>b</em>types using latent class analysis. Associations <em>b</em>etween su<em>b</em>types and prevalence of overall cardiovascular disease and its components (coronary heart disease, heart failure, and stroke) were assessed using logistic regression. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate whether su<em>b</em>types were associated with incident events, including cardiovascular mortality.(<em>b</em>)Measurements and Main Resu<em>lt</em>s:</<em>b</em>) Four symptom su<em>b</em>types were identified (distur<em>b</em>ed sleep [12.2%], minimally symptomatic [32.6%], excessively sleepy [16.7%], and moderately sleepy [38.5%]), similar to prior studies. In adjusted models, a<em>lt</em>hough no significant associations with prevalent cardiovascular disease were found, the excessively sleepy su<em>b</em>type was associated with more than threefold increased risk of prevalent heart failure compared with each of the other su<em>b</em>types. Symptom su<em>b</em>type was also associated with incident cardiovascular disease (<i>P</i> &<em>lt</em>; 0.001), coronary heart disease (<i>P</i> = 0.015), and heart failure (<i>P</i> = 0.018), with the excessively sleepy again demonstrating increased risk (hazard ratios, 1.7-2.4) compared with other su<em>b</em>types. When compared with individuals without OSA (apnea-hypopnea index &<em>lt</em>; 5), significantly increased risk for prevalent and incident cardiovascular events was o<em>b</em>served mostly for patients in the excessively sleepy su<em>b</em>type.(<em>b</em>)Conclusions:</<em>b</em>) OSA symptom su<em>b</em>types are reproduci<em>b</em>le and associated with cardiovascular risk, providing important evidence of their clinical relevance.

<A<em>b</em>stractText>As lenalidomide <em>b</em>ecomes increasingly esta<em>b</em>lished for upfront treatment of mu<em>lt</em>iple myeloma, patients refractory to this drug represent a population with an unmet need. The com<em>b</em>ination of pomalidomide, <em>b</em>ortezomi<em>b</em>, and dexamethasone has shown promising resu<em>lt</em>s in phase 1/2 trials of patients with relapsed or refractory mu<em>lt</em>iple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory mu<em>lt</em>iple myeloma who previously received lenalidomide.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>We did a randomised, open-la<em>b</em>el, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of mu<em>lt</em>iple myeloma and measura<em>b</em>le disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to <em>b</em>ortezomi<em>b</em> and dexamethasone with or without pomalidomide using a permutated <em>b</em>locked design in <em>b</em>locks of four, stratified according to age, num<em>b</em>er of previous regimens, and concentration of <em>β</em><su<em>b</em>)2</su<em>b</em>) microglo<em>b</em>ulin at screening. Bortezomi<em>b</em> (1·3 mg/m²) was administered intravenously until protocol amendment 1 then either intravenously or su<em>b</em>cutaneously on days 1, 4, 8, and 11 for the first eight cycles and su<em>b</em>sequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as <em>b</em>ortezomi<em>b</em> and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed <em>b</em>y an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, num<em>b</em>er NCT01734928; patients are no longer <em>b</em>eing enrolled.</p><A<em>b</em>stractText>Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, <em>b</em>ortezomi<em>b</em>, and dexamethasone and 278 were allocated <em>b</em>ortezomi<em>b</em> and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, <em>b</em>ortezomi<em>b</em>, and dexamethasone significantly improved progression-free survival compared with <em>b</em>ortezomi<em>b</em> and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p&<em>lt</em>;0·0001). 278 patients received at least one dose of pomalidomide, <em>b</em>ortezomi<em>b</em>, and dexamethasone and 270 patients received at least one dose of <em>b</em>ortezomi<em>b</em> and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had fe<em>b</em>rile neutropenia), infections (86 [31%] vs 48 [18%]), and throm<em>b</em>ocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, <em>b</em>ortezomi<em>b</em>, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received <em>b</em>ortezomi<em>b</em> and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]).</A<em>b</em>stractText><A<em>b</em>stractText>Patients with relapsed or refractory mu<em>lt</em>iple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, <em>b</em>ortezomi<em>b</em>, and dexamethasone compared with <em>b</em>ortezomi<em>b</em> and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, <em>b</em>ortezomi<em>b</em>, and dexamethasone. This study supports use of pomalidomide, <em>b</em>ortezomi<em>b</em>, and dexamethasone as a treatment option in patients with relapsed or refractory mu<em>lt</em>iple myeloma who previously received lenalidomide.</A<em>b</em>stractText><A<em>b</em>stractText>Celgene.</A<em>b</em>stractText>

OBJECTIVE

The goal of this study was to characterize the role of inflammatory macrophages in the induction of the vascular smooth muscle cell (VSMC)-mediated formation of aortic tertiary lymphoid organs (TLOs).

RESULTS

Mouse bone marrow-derived M1 macrophages acted as lymphoid tissue inducer cells. Indeed, they expressed high levels of tumour necrosis factor (TNF)-α and membrane-bound lymphotoxin (LT)-α, two inducing cytokines that triggered expression of the chemokines CCL19, CCL20, and CXCL16, as did M1 supernatant. The blockade of LTβR signalling with LTβR-Ig had no effect, whereas that of TNFR1/2 signalling reduced chemokine expression by VSMCs in both wild-type (WT) and LTβR KO mice, demonstrating that LTβR signalling is dispensable for the M1-inducing effect. This effect was corroborated by the development of TLOs observed in LTβR KO>>apolipoprotein E knockout (ApoE KO) aortic segments after orthotopic transplantation. Furthermore, treatment of ApoE KO mice with anti-TNF-α antibody decreased the number and incidence of aortic TLOs. Finally, lymphoid nodules composed of T and B cells formed in in vivo-implanted scaffolds seeded with VSMCs previously stimulated ex vivo by M1-conditioned medium.

CONCLUSIONS

These results are the first to identify M1 macrophages as inducer cells that trigger the expression of chemokines by VSMCs independently of LTβR signalling. We propose that the dialogue between macrophages and VSMCs-established across the vascular wall-contributes to the formation of aortic TLOs.

(<em>b</em>)Rationale:</<em>b</em>) Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in mu<em>lt</em>iple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, <em>b</em>ut the role of eDNA, NETs, and IL-1β in asthma is uncertain. (<em>b</em>)O<em>b</em>jectives:</<em>b</em>) To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation. (<em>b</em>)Methods:</<em>b</em>) We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 hea<em>lt</em>hy control su<em>b</em>jects. We su<em>b</em>divided su<em>b</em>jects with asthma into eDNA-low and -high su<em>b</em>groups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can <em>b</em>e prevented <em>b</em>y DNase. (<em>b</em>)Measurements and Main Resu<em>lt</em>s:</<em>b</em>) We found that 13% of the Severe Asthma Research Program-3 cohort is "eDNA-high," as defined <em>b</em>y sputum eDNA concentrations a<em>b</em>ove the upper 95th percentile value in hea<em>lt</em>h. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all <i>P</i> values &<em>lt</em>;0.05). Sputum eDNA in asthma was associated with airway neutrophilic inflammation, increases in solu<em>b</em>le NET components, and increases in caspase 1 activity and IL-1β (all <i>P</i> values &<em>lt</em>;0.001). In <i>in vitro</i> studies, NETs caused cytotoxicity in airway epithelial cells that was prevented <em>b</em>y disruption of NETs with DNase. (<em>b</em>)Conclusions:</<em>b</em>) High extracellular DNA concentrations in sputum mark a su<em>b</em>set of patients with more severe asthma who have NETs and markers of inflammasome activation in their airways.

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course. We assessed these risks in patients with MS (PwMS).

Objective: The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies.

Methods: The IBM^® Explorys electronic health record database of > 72,000,000 patients from US healthcare networks identified patients with MS or SLE, with and without polymerase chain reaction-confirmed COVID-19. COVID-19 cumulative incidence, hospitalization, and deaths among DMT classes were compared using logistic regression (adjusted for age, sex, body mass index, comorbidities, and race/ethnicity). As a secondary data source to assess safety data, COVID-19 reports for Biogen MS therapies were extracted and described from Biogen's Global Safety Database.

Results: 30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score ≥ 1, body mass index ≥ 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p &lt; 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p &lt; 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine.

Conclusions: Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach.

<A<em>b</em>stractText>Here, we report resu<em>lt</em>s of the first phase I study of erdafitini<em>b</em>, a potent, oral pan-FGFR inhi<em>b</em>itor.</A<em>b</em>stractText><p><div>(<em>b</em>)PATIENTS AND METHODS</<em>b</em>)</div>Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating <i>FGFR</i> genomic a<em>lt</em>erations. In patients with such a<em>lt</em>erations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously pu<em>b</em>lished (Ta<em>b</em>ernero JCO 2015;33:3401-8)] were tested.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were o<em>b</em>served in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversi<em>b</em>le after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitini<em>b</em>, with o<em>b</em>jective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evalua<em>b</em>le patients with <i>FGFR</i> mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitini<em>b</em> carried <i>FGFR</i> mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were &<em>lt</em>;10%.</p><A<em>b</em>stractText>Erdafitini<em>b</em> shows tolera<em>b</em>ility and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.</A<em>b</em>stractText>

(<em>b</em>)Background</<em>b</em>) - COVID-19 has led to over 1 million deaths worldwide and has <em>b</em>een associated with cardiac complications including cardiac arrhythmias. The incidence and pathophysiology of these manifestations remain elusive. In this worldwide survey of patients hospitalized with COVID-19 who developed cardiac arrhythmias, we descri<em>b</em>e clinical characteristics associated with various arrhythmias, as well as glo<em>b</em>al differences in modulations of routine electrophysiology practice during the pandemic. (<em>b</em>)Methods</<em>b</em>) - We conducted a retrospective analysis of patients hospitalized with COVID-19 infection worldwide with and without incident cardiac arrhythmias. Patients with documented atrial fi<em>b</em>rillation (AF), atrial flutter (AFL), supraventricular tachycardia (SVT), non-sustained or sustained ventricular tachycardia (VT), ventricular fi<em>b</em>rillation (VF), atrioventricular <em>b</em>lock (AVB), or marked sinus <em>b</em>radycardia (HR&<em>lt</em>;40<em>b</em>pm) were classified as having arrhythmia. De-identified data was provided <em>b</em>y each institution and analyzed. (<em>b</em>)Resu<em>lt</em>s</<em>b</em>) - Data was collected for 4,526 patients across 4 continents and 12 countries, 827 of whom had an arrhythmia. Cardiac comor<em>b</em>idities were common in patients with arrhythmia: 69% had hypertension, 42% dia<em>b</em>etes mellitus, 30% had heart failure and 24% coronary artery disease. Most had no prior history of arrhythmia. Of those who did develop an arrhythmia, the majority (81.8%) developed atrial arrhythmias, 20.7% developed ventricular arrhythmias, and 22.6% had <em>b</em>radyarrhythmia. Regional differences suggested a lower incidence of AF in Asia compared to other continents (34% vs. 63%). Most patients in in North America and Europe received hydroxychloroquine, though the frequency of hydroxychloroquine therapy was constant across arrhythmia types. Forty-three percent of patients who developed arrhythmia were mechanically ventilated and 51% survived to hospital discharge. Many institutions reported drastic decreases in electrophysiology procedures performed. (<em>b</em>)Conclusions</<em>b</em>) - Cardiac arrhythmias are common and associated with high mor<em>b</em>idity and mortality among patients hospitalized with COVID-19 infection. There were significant regional variations in the types of arrhythmias and treatment approaches.

Keywords: COVID-19; SARS-CoV-2.

Background: Blood-based biomarkers for Alzheimer's disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta_(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity.

Methods: We included individuals with a positive (n = 176: 63 ± 7 years, 87 (49%) females) or negative (n = 76: 61 ± 9 years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET-), mild cognitive impairment (26 PET+, 24 PET-), or AD-dementia (132 PET+). Plasma Abeta_(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald's backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman's correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA).

Results: Abeta_(1-42/1-40) and GFAP independently associated with amyloid PET status (p = 0.009 and p < 0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (p = 0.001 and p = 0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta_(1-42/1-40) and GFAP, alongside age and APOE (AUC = 88% (95% CI 83-93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized β (sβ) = - 0.40 to - 0.26; NfL: range sβ = - 0.35 to - 0.18; all: p < 0.002), whereas Abeta_(1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range sβ = 0.22 - 0.11; all: p < 0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman's rho> 0.33, p < 0.001). Abeta_(1-42/1-40) showed a moderate negative correlation with MTA (Spearman's rho = - 0.24, p = 0.001).

Discussion and conclusions: Combination of plasma Abeta_(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.

Keywords: Alzheimer’s continuum; Amyloid pathology; Blood-based biomarkers; Plasma GFAP; Plasma amyloid beta.

Prostate-specific mem<em>b</em>rane antigen (PSMA) may <em>b</em>e targeted for <em>b</em>oth diagnostic and therapeutic purposes in the management of prostate cancer (PCa). In preclinical models, androgen <em>b</em>lockade (AB) increases expression of PSMA in <em>b</em>oth hormone-sensitive and castrate-resistant xenotypes. The aim of this study was to evaluate the effect of AB treatment on ⁶⁸Ga-PSMA-11 PET imaging in hormone-naive (luteinizing hormone-releasing hormone [LHRH] ± <em>b</em>icalutamide) and in castrate-resistant men (enzalutamide or a<em>b</em>iraterone) with metastatic PCa. (<em>b</em>)Methods:</<em>b</em>) Serial ⁶⁸Ga-PSMA-11 PET was prospectively performed at <em>b</em>aseline and on days 9, 18, and 28 in 8 men with measura<em>b</em>le metastatic hormone-sensitive PCa commencing LHRH ± <em>b</em>icalutamide (cohort 1) and 7 men with castrate-resistant PCa commencing either enzalutamide or a<em>b</em>iraterone (cohort 2). Gleason score, age, time since diagnosis, and prior treatments were documented. Testosterone and prostate-specific antigen (PSA) were measured at <em>b</em>aseline and all imaging time points. PET/CT was quantitatively analyzed for SUV<su<em>b</em>)max</su<em>b</em>), SUV<su<em>b</em>)mean</su<em>b</em>), and total tumor volume. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) In cohort 1, a median 30% (interquartile range [IQR], 5-61) reduction in SUV<su<em>b</em>)max</su<em>b</em>) was recorded <em>b</em>y day 9 after AB. A reduction from <em>b</em>aseline SUV<su<em>b</em>)max</su<em>b</em>) occurred in 86.5% (6/7) men <em>b</em>y day 9 (<i>P</i> &<em>lt</em>; 0.04), with an associated PSA response in 100% men (<i>P</i> &<em>lt</em>; 0.03). Total tumor volume reduced in all men <em>b</em>y 74.5% (IQR, 27-97) (<i>P</i> &<em>lt</em>; 0.02). After day 9, PSMA response heterogeneity was noted, with persistently high or increasing SUV<su<em>b</em>)max</su<em>b</em>) in 37.5% (3/8) and marked reduction in 62.5% (5/8). In cohort 2, a median 45% (IQR, 12.7-66) increase in intensity of PSMA SUV was recorded <em>b</em>y day 9 after AB. All men demonstrated an increase in SUV<su<em>b</em>)max</su<em>b</em>) and SUV<su<em>b</em>)mean</su<em>b</em>) on PSMA PET compared with <em>b</em>aseline (<i>P</i> &<em>lt</em>; 0.04). This increase at day 9 plateaued <em>b</em>y day 28. PSA responses were more delayed in cohort 2 (-15% [IQR, 70-138]), with 2 of 7 men demonstrating PSA progression. (<em>b</em>)Conclusion:</<em>b</em>) There is rapid dichotomous response on ⁶⁸Ga-PSMA PET imaging to AB-dependent on the presence of a hormone-sensitive or castrate-resistant PCa phenotype. This has important implications for interpretation of PSMA PET, and in the timing and sequencing of PSMA-targeted therapy.

Objectives: Rates of novel coronavirus disease 2019 (COVID-19) infections have rapidly increased worldwide and reached pandemic proportions. A suite of preventive behaviours have been recommended to minimize risk of COVID-19 infection in the general population. The present study utilized an integrated social cognition model to explain COVID-19 preventive behaviours in a sample from the Iranian general population.

Design: The study adopted a three-wave prospective correlational design.

Methods: Members of the general public (N = 1,718, M_age = 33.34, SD = 15.77, male = 796, female = 922) agreed to participate in the study. Participants completed self-report measures of demographic characteristics, intention, attitude, subjective norm, perceived behavioural control, and action self-efficacy at an initial data collection occasion. One week later, participants completed self-report measures of maintenance self-efficacy, action planning and coping planning, and, a further week later, measures of COVID-19 preventive behaviours. Hypothesized relationships among social cognition constructs and COVID-19 preventive behaviours according to the proposed integrated model were estimated using structural equation modelling.

Results: The proposed model fitted the data well according to multiple goodness-of-fit criteria. All proposed relationships among model constructs were statistically significant. The social cognition constructs with the largest effects on COVID-19 preventive behaviours were coping planning (β = .575, p &lt; .001) and action planning (β = .267, p &lt; .001).

Conclusions: Current findings may inform the development of behavioural interventions in health care contexts by identifying intervention targets. In particular, findings suggest targeting change in coping planning and action planning may be most effective in promoting participation in COVID-19 preventive behaviours. Statement of contribution What is already known on this subject? Curbing COVID-19 infections globally is vital to reduce severe cases and deaths in at-risk groups. Preventive behaviours like handwashing and social distancing can stem contagion of the coronavirus. Identifying modifiable correlates of COVID-19 preventive behaviours is needed to inform intervention. What does this study add? An integrated model identified predictors of COVID-19 preventive behaviours in Iranian residents. Prominent predictors were intentions, planning, self-efficacy, and perceived behavioural control. Findings provide insight into potentially modifiable constructs that interventions can target. Research should examine if targeting these factors lead to changes in COVID-19 behaviours over time.

Keywords: attitude; behaviour change; intention; planning; preventive behaviours.

Objective: Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota-immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT).

Design: Patients with recent-onset (<6 weeks) T1D (18-30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition.

Results: Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=-0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics.

Conclusion: FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D.

Trial registration number: NTR3697.

Keywords: diabetes mellitus.

The advent of tau-targeted PET tracers such as flortaucipir (18F) (flortaucipir, also known as 18F-AV-1451 or 18F-T807) have made it possible to investigate the sequence of development of tau in relationship to age, amyloid-β, and to the development of cognitive impairment due to Alzheimer's disease. Here we report a multicentre longitudinal evaluation of the relationships between baseline tau, tau change and cognitive change, using flortaucipir PET imaging. A total of 202 participants 50 years old or older, including 57 cognitively normal subjects, 97 clinically defined mild cognitive impairment and 48 possible or probable Alzheimer's disease dementia patients, received flortaucipir PET scans of 20 min in duration beginning 80 min after intravenous administration of 370 MBq flortaucipir (18F). On separate days, subjects also received florbetapir amyloid PET imaging, and underwent a neuropsychological test battery. Follow-up flortaucipir scans and neuropsychological battery assessments were also performed at 9 and 18 months. Fifty-five amyloid-β+ and 90 amyloid-β- subjects completed the baseline and 18-month study visits and had valid quantifiable flortaucipir scans at both time points. There was a statistically significant increase in the global estimate of cortical tau burden as measured by standardized uptake value ratio (SUVr) from baseline to 18 months in amyloid-β+ but not amyloid-β- subjects (least squared mean change in flortaucipir SUVr : 0.0524 ± 0.0085, P &lt; 0.0001 and 0.0007 ± 0.0024 P = 0.7850, respectively), and a significant association between magnitude of SUVr increase and baseline tau burden. Voxel-wise evaluations further suggested that the regional pattern of change in flortaucipir PET SUVr over the 18-month study period (i.e. which regions exhibited the greatest change) also varied as a function of baseline global estimate of tau burden. In subjects with lower global SUVr, temporal lobe regions showed the greatest flortaucipir retention, whereas in subjects with higher baseline SUVr, parietal and frontal regions were increasingly affected. Finally, baseline flortaucipir and change in flortaucipir SUVr were both significantly (P &lt; 0.0001) associated with changes in cognitive performance. Taken together, these results provide a preliminary characterization of the longitudinal spread of tau in Alzheimer's disease and suggest that the amount and location of tau may have implications both for the spread of tau and the cognitive deterioration that may occur over an 18-month period.

OBJECTIVE

Lipoxin A(4) (LXA(4)) is a lipid mediator involved in the resolution of inflammation. Increased levels of LXA(4) in synovial fluid and enhanced expression of the formyl peptide receptor 2/lipoxin A(4) receptor (FPR2/ALX) in the synovial tissues of rheumatoid arthritis patients have been reported. Endothelins (ETs) play a pivotal pro-inflammatory role in acute articular inflammatory responses. Here, we evaluated the anti-inflammatory role of LXA(4), during the acute phase of zymosan-induced arthritis, focusing on the modulation of ET-1 expression and its effects.

METHODS

The anti-inflammatory effects of LXA(4), BML-111 (agonist of FPR2/ALX receptors) and acetylsalicylic acid (ASA) pre- and post-treatments were investigated in a murine model of zymosan-induced arthritis. Articular inflammation was assessed by examining knee joint oedema; neutrophil accumulation in synovial cavities; and levels of prepro-ET-1 mRNA, leukotriene (LT)B(4), tumour necrosis factor (TNF)-α and the chemokine KC/CXCL1, after stimulation. The direct effect of LXA(4) on ET-1-induced neutrophil activation and chemotaxis was evaluated by shape change and Boyden chamber assays respectively.

RESULTS

LXA(4), BML-111 and ASA administered as pre- or post-treatment inhibited oedema and neutrophil influx induced by zymosan stimulation. Zymosan-induced preproET-1 mRNA, KC/CXCL1, LTB(4) and TNF-α levels were also decreased after LXA(4) pretreatment. In vitro, ET-1-induced neutrophil chemotaxis was inhibited by LXA(4) pretreatment. LXA(4) treatment also inhibited ET-1-induced oedema formation and neutrophil influx into mouse knee joints.

CONCLUSIONS

LXA(4) exerted anti-inflammatory effects on articular inflammation through a mechanism that involved the inhibition of ET-1 expression and its effects.

<A<em>b</em>stractText>Bladder cancer was a malignant disease in patients, our research aimed at discovering the possi<em>b</em>le <em>b</em>iomarkers for the diseases.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>The gene chip GSE31684, including 93samples, was downloaded from the GEO datasets and co-expression network was constructed <em>b</em>y the data. Molecular complex detection(MCODE) was used to identify hu<em>b</em> genes. The most significant cluster including 16 genes: <i>CDH11</i>, <i>COL3A1</i>, <i>COL6A3</i>, <i>COL5A1</i>, <i>AEBP1</i>, <i>COL1A2</i>, <i>NTM</i>, <i>COL11A1</i>, <i>THBS2</i>, <i>COL8A1</i>, <i>COL1A1</i>, <i>BGN</i>, <i>MMP2</i>, <i>PXDN</i>, <i>THY1</i>, and <i>TGFB1I1</i> was identified. After annotated <em>b</em>y BiNGO, they were suggested associated with collagen fi<em>b</em>ril organization and <em>b</em>lood vessel development. In addition, the Kaplan Meier curves were o<em>b</em>tained <em>b</em>y UALCAN. The high expression of <i>THY1</i>, <i>AEBP1</i>, <i>CDH11</i>, <i>COL1A1</i>, <i>COL1A2</i>, <i>COL11A1</i>, <i>MMP2</i>, <i>PXDN</i>, <i>BGN</i>, <i>COL5A1, COL8A1</i>, and <i>TGFB1I1</i> indicated poor prognosis of the patients(<i>P</i> &<em>lt</em>; 0.05). Finally, we examined genes' expression <em>b</em>etween low and high tumor stage <em>b</em>y the Wilcoxon test(P &<em>lt</em>; 0.05), <i>TGFB1I1</i> was excluded.</p><p><div>(<em>b</em>)Conclusion</<em>b</em>)</div><i>THY1, AEBP1, CDH11, COL1A1, COL1A2, COL11A1, MMP2, PXDN, BGN, COL5A1, COL8A1</i> associated with the tumor stage as well as tumor patients' prognosis<i>. COL5A1, COL8A1</i>(<i>P</i> &<em>lt</em>; 0.01) may serve as therapeutic targets for the disease.</p>

BACKGROUND

Chronic cough often lasts for more than 1 year and is associated with airway inflammation. The effect of inhaled corticosteroids on symptom severity and inflammatory mediator levels in these patients is unknown.

OBJECTIVE

We sought to determine whether inhaled corticosteroids reduce cough severity and sputum mediator concentrations in patients with chronic persistent cough.

METHODS

We performed a double-blind, randomized, placebo-controlled crossover study with inhaled fluticasone, 500 microg twice daily, and placebo for 14 days in 88 patients with cough for more than 1 year, with normal chest radiography and spirometry results. Outcome measures were a daily cough visual analogue scale and induced sputum concentrations of eosinophilic cationic protein (ECP), myeloperoxidase, leukotriene B(4) (LTB(4)), leukotrienes C(4)/D(4)/E(4) (cysteinyl leukotrienes [Cys-LTs]), prostaglandin E(2) (PGE(2)), IL-8, and TNF-alpha. Sputum cell counts, exhaled nitric oxide levels, and carbon monoxide levels were also measured.

RESULTS

There was a significant improvement in the cough visual analogue scale after inhaled fluticasone compared with placebo (mean difference, 1.0; 95% CI, 0.4-1.5; P <.001). LTB(4), Cys-LT, and PGE(2) levels were increased in all causes of cough. Sputum ECP counts, exhaled nitric oxide levels, and carbon monoxide levels decreased significantly after inhaled fluticasone. There was no change in sputum cell counts and other mediator concentrations.

CONCLUSIONS

Cough severity and sputum ECP levels are modestly reduced by inhaled corticosteroids in patients with chronic cough persisting for more than 1 year. LTB(4), Cys-LT, PGE(2), IL-8, myeloperoxidase, and TNF-alpha levels are unaltered by this therapy. This raises the possibility that drugs targeted to reduce the effects of these mediators might be of benefit in chronic persistent cough.

Leukotrienes (LTs) are potent lipid mediators involved in the control of host defense. LTB(4) induces leukocyte accumulation, enhances phagocytosis and bacterial clearance, and increases NO synthesis. LTB(4) is also important in early effector T cell recruitment that is mediated by LTB(4) receptor 1, the high-affinity receptor for LTB(4). The aims of this study were to evaluate whether LTs are involved in the secondary immune response to vaccination in a murine model of Histoplasma capsulatum infection. Our results demonstrate that protection of wild-type mice immunized with cell-free Ags from H. capsulatum against histoplasmosis was associated with increased LTB(4) and IFN-gamma production as well as recruitment of memory T cells into the lungs. In contrast, cell-free Ag-immunized mice lacking 5-lipoxygenase(-/-), a critical enzyme involved in LT synthesis, displayed a marked decrease on recruitment of memory T cells to the lungs associated with increased synthesis of TGF-beta as well as IL-10. Strikingly, these effects were associated with increased mortality to 5-lipoxygenase(-/-)-infected mice. These data establish an important immunomodulatory role of LTs, in both the primary and secondary immune responses to histoplasmosis.

OBJECTIVE

Cardiovascular disease (CVD) is more prevalent and more likely to lead to death in patients with rheumatoid arthritis (RA). Single nucleotide polymorphisms of the genes for lymphotoxin-A (LT-A) and its regulatory protein galectin-2 (LGALS2) have been implicated as genetic risk factors for acute cardiovascular events in the general population: we hypothesised that their risk alleles/genotypes (a) may be more frequent among patients with RA compared with non-RA controls (thus explaining some of the increased CVD in RA), and (b) may be more frequent among patients with RA with prevalent CVD compared with patients with RA without CVD.

METHODS

Genomic DNA samples were collected from 388 patients with RA and 399 local population controls without RA. LT-A gene intron 1 252A>G and LGALS2 intron 1 3279C>T single nucleotide polymorphisms were identified using real-time polymerase chain reaction and melting curve analysis.

RESULTS

LT-A 252GG homozygotes were significantly more prevalent among patients with RA compared with controls (19.8% vs 11.8%, p = 0.002; OR(GG/GA,AA) = 1.85, 95% CI 1.25 to 2.75, p = 0.002). Patients with RA possessing LT-A 252 GG were significantly more likely to have had a myocardial infarction compared with those with LT-A 252 AA or GA (13% vs 5.5%, p = 0.02; adjusted OR(GG/GA,AA) = 3.03, 95% CI 1.2 to 7.68, p = 0.002). The frequency of LGALS2 polymorphisms was similar between RA and controls and was not associated with CVD among patients with RA.

CONCLUSIONS

The LT-A 252GG genotype occurs more frequently among patients with RA than the general population. In RA, this genotype appears to associate with increased likelihood of suffering an myocardial infarction.