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The title compound, C13H9ClO2, exhibits a non-planar geometry; the furan ring being inclined to the benzene ring by 50.52 (16)°. In the crystal, molecules stack along the a axis; however, there are no significant intermolecular interactions present.

As of May 2023, the public health emergency of COVID-19 was lifted across the globe. However, SARS-CoV-2 infections continue to be recorded worldwide. This situation has been attributed to the ability of the virus to evade host immune responses including neutralizing antibody-derived Immunity. The vast majority of antibody escape mutations have been associated with the S1 subunit of the spike protein, especially the Receptor Binding Domain (RBD) but also the N-terminal Domain (NTD). The other region of the spike, the S2 subunit, is the most conserved region amongst coronaviruses. We hypothesized that S2-specific antibody responses are suboptimal in vaccinated and SARS-CoV-2 infected patients resulting in an ineffective neutralization of distant coronaviruses. Here, we analyzed S2-specific antibody responses SARS-CoV-2-infected individuals, including a mixed cohort of those with and without immunosuppression and prior vaccination. We found that S2-specific antibody responses are generally lower than S1-specific antibody responses. Furthermore, we observed in immunocompetent individuals that S1 and S2-specific antibody responses are both positively correlated with Wuhan, Omicron, SARS-CoV and W1V1-CoV pseudovirus neutralization. Among the immunocompromised patients, S1-specific antibody responses were rarely correlated with pseudovirus neutralization in contrast to S2-specific antibody responses which frequently correlated with pseudovirus neutralization. These data highlight the potential of the S2-subunit as an ideal target for induction of cross-neutralizing antibody immunity against divergent coronaviruses., Competing Interests: The authors declare no competing interests. J.Z.L has consulted for Abbvie and received a grant from Merck but none of these activities impacted nor influenced the design, performance and conclusions of this study. J.A.S. has received research support from Boehringer Ingelheim and Bristol Myers Squibb unrelated to this work. He has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB unrelated to this work.Additional Declarations: No competing interests reported.

In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of nirmatrelvir-ritonavir near the time of symptom onset, coupled with incomplete viral clearance, appear to be the main factors leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. Finally, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment, in particular to a 10-day regimen, may greatly diminish the risk for rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2., Competing Interests: Competing interests: ASP owns stock in Pfizer. He was also on a Pfizer advisory committee and received an honorarium. The other authors declare that they have no competing interests.

Background: Social prescribing connects patients with community resources to improve their health and well-being. It is gaining momentum globally due to its potential for addressing non-medical causes of illness while building on existing resources and enhancing overall health at a relatively low cost. The COVID-19 pandemic further underscored the need for policy interventions to address health-related social issues such as loneliness and isolation., Aim: This paper presents evidence of the conceptualisation and implementation of social prescribing schemes in twelve countries: Australia, Austria, Canada, England, Finland, Germany, Portugal, the Slovak Republic, Slovenia, the Netherlands, the United States and Wales., Methods: Twelve countries were identified through the Health Systems and Policy Monitor (HSPM) network and the EuroHealthNet Partnership. Information was collected through a twelve open-ended question survey based on a conceptual model inspired by the WHO's Health System Framework., Results: We found that social prescribing can take different forms, and the scale of implementation also varies significantly. Robust evidence on impact is scarce and highly context-specific, with some indications of cost-effectiveness and positive impact on well-being., Conclusions: This paper provides insights into social prescribing in various contexts and may guide countries interested in holistically tackling health-related social factors and strengthening community-based care. Policies can support a more seamless integration of social prescribing into existing care, improve collaboration among sectors and training programs for health and social care professionals., Competing Interests: Declaration of competing interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024. Published by Elsevier B.V.)

Naturally occurring T cells that recognize microbial peptides via HLA-E, a nonpolymorphic HLA class Ib molecule, could provide the foundation for new universal immunotherapeutics. However, confidence in the biological relevance of putative ligands is crucial, given that the mechanisms by which pathogen-derived peptides can access the HLA-E presentation pathway are poorly understood. We systematically interrogated the HIV proteome using immunopeptidomic and bioinformatic approaches, coupled with biochemical and cellular assays. No HIV HLA-E peptides were identified by tandem mass spectrometry analysis of HIV-infected cells. In addition, all bioinformatically predicted HIV peptide ligands (>80) were characterized by poor complex stability. Furthermore, infected cell elimination assays using an affinity-enhanced T cell receptor bispecific targeted to a previously reported HIV Gag HLA-E epitope demonstrated inconsistent presentation of the peptide, despite normal HLA-E expression on HIV-infected cells. This work highlights the instability of the HIV HLA-E peptidome as a major challenge for drug development., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Z.W., T.H., R.L.P., R.J.S., T.G., M.D., J.D., J.B., J.L., W.B., D.G.-H., D.P.K., D.B.L., L.F.G., A.W., P.K.S., A.K., S.L., and L.D. were/are employees of Immunocore Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This manuscript assesses the incidence of Pneumocystis jiroveci pneumonia (PJP) among patients receiving contemporary treatment regimens for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and adverse events associated with PJP prophylaxis., Methods: Incident users of rituximab or cyclophosphamide for AAV were identified in the TriNetX electronic health records database from 2011 to 2022. The incidence rates (IRs) of PJP in the first 6 months of induction therapy with rituximab and/or cyclophosphamide and during postinduction maintenance therapy with rituximab were calculated. Cox proportional hazard models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) for the risk of adverse events commonly associated with PJP prophylaxis., Results: We identified 1,461 AAV cases who received induction therapy with rituximab (69.7%), cyclophosphamide (18.9%), or both (11.4%). Prophylaxis prescribed within 30 days of induction included trimethoprim-sulfamethoxazole (30.7%), atovaquone (5.4%), dapsone (3.8%), and pentamidine (0.8%). During induction therapy, 10 cases of PJP were identified (IR 15.0 cases per 1,000 patient-years); no deaths occurred. In adjusted analyses, those who received prophylaxis had a higher risk of leukopenia (HR 3.1; 95% CI 1.1-8.6), rash (HR 1.9; 95% CI 1.0-3.6), and nephropathy (HR 2.6; 95% CI 1.3-5.1) than those who did not. During rituximab maintenance therapy (n = 709), five cases of PJP were identified (IR 2.1 cases per 1,000 person-years), one of whom died during the hospitalization associated with a PJP diagnosis., Conclusion: Rates of PJP in patients with AAV were lower than previously observed, and few cases occurred during rituximab maintenance therapy. PJP prophylaxis was associated with adverse events., (© 2023 American College of Rheumatology.)

Background: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir-ritonavir (N-R) and virologic rebound (VR)., Objective: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19., Design: Observational cohort study., Setting: Multicenter health care system in Boston, Massachusetts., Participants: Ambulatory adults with acute COVID-19 with and without use of N-R., Intervention: Receipt of 5 days of N-R treatment versus no COVID-19 therapy., Measurements: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log 10 copies/mL that were also at least 1.0 log 10 copies/mL higher than a prior viral load below 4.0 log 10 copies/mL., Results: Compared with untreated persons ( n = 55), those taking N-R ( n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) ( P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected., Limitations: Observational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission., Conclusion: Virologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus., Primary Funding Source: National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1756.

Imidacloprid (IM) has emerged as a contaminant of concern in several areas within the United States due to its frequent detection in aquatic ecosystems and its pseudo-persistence, which pose potential risks to nontarget species. We evaluated the sublethal toxicity of IM to fathead minnow larvae following chronic exposure beginning just after fertilization. Our in silico analysis and in vivo bioassays suggest that IM has a low binding affinity for the vertebrate nicotinate acetylcholine receptor (nAChR), as expected. However, chronic exposure to ≥0.16 µg IM/L reduced survival by 10%, and exposure to ≥18 µg IM/L reduced survival by approximately 20%-40%. Surviving fish exposed to ≥0.16 µg IM/L showed reduced growth, altered embryonic motor activity, and premature hatching. Furthermore, a significant proportion of fish exposed to ≥0.16 µg IM/L were slower to respond to vibrational stimuli and slower to swim away, indicating that chronic exposure to IM has the potential to impair the ability of larvae to escape predation. The adverse health effects we observed indicate that chronic exposure to environmentally relevant concentrations of IM may elicit sublethal responses that culminate in a significant increase in mortality during early life stages, ultimately translating to reduced recruitment in wild fish populations. Environ Toxicol Chem 2023;42:2184-2192. © 2023 SETAC., (© 2023 SETAC.)

Background: Due to geographic isolation and border controls Aotearoa New Zealand (AoNZ) attained high levels of population coronavirus disease-19 (COVID-19) vaccination before widespread transmission of COVID-19. We describe outcomes of SARS-CoV-2 infection (Omicron variant) in people with inflammatory rheumatic diseases in this unique setting., Methods: This observational study included people with inflammatory rheumatic disease and SARS-CoV-2 infection in AoNZ between 1 February and 30 April 2022. Data were collected via the Global Rheumatology Alliance Registry including demographic and rheumatic disease characteristics, and COVID-19 vaccination status and outcomes. Multivariable logistic regression was used to explore associations of demographic and clinical factors with COVID-19 hospitalisation and death., Findings: Of the 1599 cases included, 96% were from three hospitals that systematically identified people with inflammatory rheumatic disease and COVID-19. At time of COVID-19, 1513 cases (94.6%) had received at least two COVID-19 vaccinations. Hospitalisation occurred for 104 (6.5%) cases and 10 (0.6%) patients died. Lower frequency of hospitalisation was seen in cases who had received at least two vaccinations (5.9%), compared to the unvaccinated (20.6%) or those with a single vaccine dose (10.7%). In multivariable adjusted models, people with gout or connective tissue diseases (CTD) had increased risk of the combined outcome of hospitalisation/death, compared to people with inflammatory arthritis. Glucocorticoid and rituximab use were associated with increased rates of hospitalisation/death. All patients who died had three or more co-morbidities or were over 60 years old., Interpretation: In this cohort with inflammatory rheumatic diseases and high vaccination rates, severe outcomes from SARS-CoV-2 Omicron variant were relatively infrequent. The outcome of Omicron variant infection among vaccinated but SARS-CoV-2 infection-naive people with inflammatory rheumatic disease without other known risk factors were favourable., Funding: Financial support from the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) included management of COVID-19 Global Rheumatology Alliance funds., Competing Interests: JB has no conflicts of interest to declare. AM has no conflicts of interest to declare. ND reports personal fees from AstraZeneca, Dyve Biosciences, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs, Hikma outside the submitted work. MS reports speaking fees from Novartis. RNK has no conflicts of interest to declare. AC has no conflicts of interest to declare. VQ has no conflicts of interest to declare. SB reports consulting fees from AbbVie, Horizon, Novartis, and Pfizer. SB is an employee of Pfizer, Inc. MGM has no conflicts of interest to declare. JH has research grants from the Rheumatology Research Foundation and the Childhood Arthritis and Rheumatology Research Foundation. JH reports speaking fees from Novartis, Fresenius Kabi, Pfizer, and Biogen. JL has a research grant from Pfizer. PMM has received consulting/speaker's fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartisg, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, and is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC). PS reports an honorarium from the COVID-19 Global Rheumatology Alliance. ES reports grants from the COVID-19 Global Rheumatology Alliance, Canada's drug and health technology agency, the Canadian Institute for Health Research, and McMaster University. ES reports honoraria from the Canadian Rheumatology Association and the Canadian Arthritis Patient's Alliance. PR was unable to report his conflicts of interest as he is deceased. ZW reports research grants from BMS, Sanofi, the National Institute of Health and the Rheumatology Research Foundation. ZW reports royalties from the IgG4 symptom severity score and consulting fees from Sanofi, Horizon, MedPace, Viela Bio, Zenas, and Shionogi. ZW reports participation on data monitoring boards for Sanofi, Horizon, Novartis, Visterra/Otsuka, and Shinogi. JY is supported by NIH/NIAMS K24 AR07534 and AHRQ R01HS028024. She has received research grants from Gilead, Aurinia, BMS Foundation and Astra Zeneca and performed consultation for Astra Zeneca, Pfizer, and Aurinia. RG reports personal and/or speaking fees from AbbVie, Janssen, Novartis, Pfizer, Cornerstones and travel assistance from Pfizer (all < $10,000). The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology (ACR), the European Alliance of Associations for Rheumatology (EULAR), the (UK) National Health Service (NHS), the National Institute for Health Research (NIHR), or the (UK) Department of Health, or any other organisation., (© 2023 The Author(s).)

Objective: To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound., Design: Observational cohort study., Setting: Multicenter healthcare system in Boston, Massachusetts., Participants: We enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir., Exposures: Receipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy., Main Outcome and Measures: The primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads ≥4.0 log 10 copies/milliliter after a prior reduction in viral load to <4.0 log 10 copies/milliliter., Results: Compared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvir-ritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and ≥2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene., Conclusions and Relevance: Virologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.

Objective: To describe obstetric outcomes based on COVID-19 vaccination status, in women with rheumatic and musculoskeletal diseases (RMDs) who developed COVID-19 during pregnancy., Methods: Data regarding pregnant women entered into the COVID-19 Global Rheumatology Alliance registry from 24 March 2020-25 February 2022 were analysed. Obstetric outcomes were stratified by number of COVID-19 vaccine doses received prior to COVID-19 infection in pregnancy. Descriptive differences between groups were tested using the chi-squared or Fisher's exact test., Results: There were 73 pregnancies in 73 women with RMD and COVID-19. Overall, 24.7% (18) of pregnancies were ongoing, while of the 55 completed pregnancies, 90.9% (50) of pregnancies resulted in livebirths. At the time of COVID-19 diagnosis, 60.3% (n = 44) of women were unvaccinated, 4.1% (n = 3) had received one vaccine dose while 35.6% (n = 26) had two or more doses. Although 83.6% (n = 61) of women required no treatment for COVID-19, 20.5% (n = 15) required hospital admission. COVID-19 resulted in delivery in 6.8% (n = 3) of unvaccinated women and 3.8% (n = 1) of fully vaccinated women. There was a greater number of preterm births (PTB) in unvaccinated women compared with fully vaccinated 29.5% (n = 13) vs 18.2% (n = 2)., Conclusions: In this descriptive study, unvaccinated pregnant women with RMD and COVID-19 had a greater number of PTB compared with those fully vaccinated against COVID-19. Additionally, the need for COVID-19 pharmacological treatment was uncommon in pregnant women with RMD regardless of vaccination status. These results support active promotion of COVID-19 vaccination in women with RMD who are pregnant or planning a pregnancy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To compare the risk of SARS-CoV-2 infection and its related severe sequelae between patients with systemic lupus erythematosus (SLE) and the general population according to COVID-19 vaccination status., Methods: We performed cohort studies using data from The Health Improvement Network to compare the risks of SARS-CoV-2 infection and severe sequelae between patients with SLE and the general population. Individuals aged 18-90 years with no previously documented SARS-CoV-2 infection were included. We estimated the incidence rates and HRs of SARS-CoV-2 infection and severe sequelae between patients with SLE and the general population according to COVID-19 vaccination status using exposure score overlap weighted Cox proportional hazards model., Results: We identified 3245 patients with SLE and 1 755 034 non-SLE individuals from the unvaccinated cohort. The rates of SARS-CoV-2 infection, COVID-19 hospitalisation, COVID-19 death and combined severe outcomes per 1000 person-months were 10.95, 3.21, 1.16 and 3.86 among patients with SLE, and 8.50, 1.77, 0.53 and 2.18 among general population, respectively. The corresponding adjusted HRs were 1.28 (95% CI: 1.03 to 1.59), 1.82 (95% CI: 1.21 to 2.74), 2.16 (95% CI: 1.00 to 4.79) and 1.78 (95% CI: 1.21 to 2.61). However, no statistically significant differences were observed between vaccinated patients with SLE and vaccinated general population over 9 months of follow-up., Conclusion: While unvaccinated patients with SLE were at higher risk of SARS-CoV-2 infection and its severe sequelae than the general population, no such difference was observed among vaccinated population. The findings indicate that COVID-19 vaccination provides an adequate protection to most patients with SLE from COVID-19 breakthrough infection and its severe sequelae., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the association between race/ethnicity and COVID-19 outcomes in individuals with systemic lupus erythematosus (SLE)., Methods: Individuals with SLE from the US with data entered into the COVID-19 Global Rheumatology Alliance registry between March 24, 2020 and August 27, 2021 were included. Variables included age, sex, race, and ethnicity (White, Black, Hispanic, other), comorbidities, disease activity, pandemic time period, glucocorticoid dose, antimalarials, and immunosuppressive drug use. The ordinal outcome categories were: not hospitalized, hospitalized with no oxygenation, hospitalized with any ventilation or oxygenation, and death. We constructed ordinal logistic regression models evaluating the relationship between race/ethnicity and COVID-19 severity, adjusting for possible confounders., Results: We included 523 patients; 473 (90.4%) were female and the mean ± SD age was 46.6 ± 14.0 years. A total of 358 patients (74.6%) were not hospitalized; 40 patients (8.3%) were hospitalized without oxygen, 64 patients (13.3%) were hospitalized with any oxygenation, and 18 (3.8%) died. In a multivariable model, Black (odds ratio [OR] 2.73 [95% confidence interval (95% CI) 1.36-5.53]) and Hispanic (OR 2.76 [95% CI 1.34-5.69]) individuals had higher odds of more severe outcomes than White individuals., Conclusion: Black and Hispanic individuals with SLE experienced more severe COVID-19 outcomes, which is consistent with findings in the US general population. These results likely reflect socioeconomic and health disparities and suggest that more aggressive efforts are needed to prevent and treat infection in this population., (© 2022 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

T cell exhaustion develops in human immunodeficiency virus (HIV) infection due to chronic viral antigenic stimulation. This adaptive response primarily affects virus-specific CD8 + T cells, which may remain dysfunctional despite viral load-reducing antiretroviral therapy; however, abnormalities may also be evident in non-HIV-specific populations. Both could limit the efficacy of cell therapies against viral reservoirs. Here, we show that bulk (polyclonal) CD8 + T cells from people living with HIV (PLWH) express proposed markers of dysfunctional HIV-specific T cells at high levels yet form lytic immunological synapses (IS) and eliminate primary resting infected (HIV Gag lo ) CD4 + T cells, when redirected by potent bispecific T cell-retargeting molecules, Immune mobilising monoclonal T cell receptors (TCR) Against Virus (ImmTAV). While PLWH CD8 + T cells are functionally impaired when compared to CD8 + T cells from HIV-naïve donors, ImmTAV redirection enables them to eliminate Gag lo CD4 + T cells that are insensitive to autologous HIV-specific cytolytic T cells. ImmTAV molecules may therefore be able to target HIV reservoirs, which represent a major barrier to a cure., (© 2022. The Author(s).)

Objective: To describe people with gout who were diagnosed with coronavirus disease 2019 (COVID-19) and hospitalized and to characterize their outcomes., Methods: Data 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., Results: One 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., Conclusion: This 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., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To investigate factors associated with severe COVID-19 in people with idiopathic inflammatory myopathy (IIM)., Methods: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with IIM were obtained from the COVID-19 Global Rheumatology Alliance physician-reported registry. A 3-point ordinal COVID-19 severity scale was defined: (1) no hospitalisation, (2) hospitalisation (and no death) and (3) death. ORs were estimated using multivariable ordinal logistic regression. Sensitivity analyses were performed using a 4-point ordinal scale: (1) no hospitalisation, (2) hospitalisation with no oxygen (and no death), (3) hospitalisation with oxygen/ventilation (and no death) and 4) death., Results: Of 348 patients, 48% were not hospitalised, 39% were hospitalised (and did not die) and 13% died. Older age (OR=1.59/decade, 95% CI 1.31 to 1.91), high disease activity (OR=3.50, 95% CI 1.25 to 9.83; vs remission), ≥2 comorbidities (OR=2.63, 95% CI 1.39 to 4.98; vs none), prednisolone-equivalent dose >7.5 mg/day (OR=2.40, 95% CI 1.09 to 5.28; vs no intake) and exposure to rituximab (OR=2.71, 95% CI 1.28 to 5.72; vs conventional synthetic disease-modifying antirheumatic drugs only) were independently associated with severe COVID-19. In addition to these variables, in the sensitivity analyses, male sex (OR range: 1.65-1.83; vs female) was also significantly associated with severe outcomes, while COVID-19 diagnosis after 1 October 2020 (OR range: 0.51-0.59; vs on/before 15 June 2020) was significantly associated with less severe outcomes, but these associations were not significant in the main model (OR=1.57, 95% CI 0.95 to 2.59; and OR=0.61, 95% CI 0.37 to 1.00; respectively)., Conclusions: This is the first large registry data on outcomes of COVID-19 in people with IIM. Older age, male sex, higher comorbidity burden, high disease activity, prednisolone-equivalent dose >7.5 mg/day and rituximab exposure were associated with severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with IIM., Competing Interests: Competing interests: S-AY is supported by vs Arthritis, Royal College of Physicians, Rosetrees Trust, University College London Hospitals Biomedical Research Centre and University College London Hospitals Charity, all unrelated to this manuscript. MG is a Pfizer employee as of March 2022. KLH has received support from EULAR for database maintenance and data extraction related to this manuscript, KLH has received grants from Pfizer and BMS for work unrelated to this manuscript, honoraria from Abbvie unrelated to this manuscript, and is supported by the NIHR Manchester Biomedical Research Centre. LC participates on a Data Safety Monitoring Board or Advisory Board of Lilly, and has a leadership or fiduciary role in EULAR, unrelated to this manuscript. CR receives consulting fees from AbbVie, Astra Zeneca, GSK, Novartis, Pfizer, honoraria from AbbVie, Amgen, Astra Zeneca, GSK, Pfizer, Biogen, BMS, Galapagos, Lilly, travel support from Amgen, Celltrion, Galapagos, patents planned, issued or pending by Astra Zeneca, and receipt of equipment, materials, drugs, medical writing, gifts or other services by Biogen and Lilly, all unrelated to this manuscript. GJP-E has received grants from Janssen, consulting fees and honoraria from GSK, Janssen, Pfizer, Werfen, travel support from GSK, Montpellier, Boehringer Ingelheim, and participates on a Data Safety Monitoring Board or Advisory Board of Pfizer, GSK and Janssen, and has received equipment, materials, drugs, medical writing, gifts or other services from Janssen, all unrelated to this manuscript. REV has received grants from BMS, Novartis, Pfizer and honoraria from Hexal, all unrelated to this manuscript. EV has received honoraria from AbbVie, Novartis, Janssen and travel support from AbbVie, Janssen, Pfizer, and participates on a Data Safety Monitoring Board or Advisory Board of AbbVie, Novartis, Janssen, and is President of Asociacion de Rumatologia del Noreste Argentino, all unrelated to this manuscript. ES receives honoraria from the COVID-19 Global Rheumatology Alliance and non-financial support from Canadian Arthritis Patient Alliance, unrelated to this manuscript. JH receives grants from the Rheumatology Research Foundation, salary support from the Childhood Arthritis and Rheumatology Research Alliance, consulting fees from Novartis, Pfizer, Sobi and Biogen, all unrelated to this manuscript. MGM is a patient consultant for Aurinia Pharmaceuticals, Boehringer Ingelheim, Johnson & Johnson, Bristol-Myers Squibb, all unrelated to this manuscript, and receives honoraria from Aurinia Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, all unrelated to this study. RG has received honoraria from Janssen, Pfizer, AbbVie, Cornerstones, Novartis, travel support from Pfizer and Janssen, and is a member of the New Zealand Rheumatology Association executive and ACR Global Engagement Special Committee, all unrelated to this manuscript. SB is a Pfizer employee and has received honoraria from AbbVie, Horizon, Novartis, Pfizer, has received travel support from Pfizer, and owns restricted stock units with Pfizer as a Pfizer employee, all unrelated to this manuscript. PCR has received grants from Pfizer, Novartis, UCB, Janssen, all unrelated to this manuscript, consulting fees from AbbVie, Janssen, UCB, Roche, Lilly, Novartis, Atom Biosciences, Gilead, Kukdong, GSK, all unrelated to this manuscript, honoraria from AbbVie, UCB, Janssen, Novartis, Lilly, GSK, Pfizer, all unrelated to this manuscript, travel support from BMS, UCB, Pfizer, Novartis, all unrelated to this manuscript. PCR reports participation on a Data Safety Monitoring Board or Advisory Board of Atom Biosciences, unrelated to this manuscript, and leadership role in the Australian Rheumatology Association and Arthritis Queensland, unrelated to this manuscript. JY has received support from NIH/NIAMS (grants to UCSF) for the present manuscript, grants from Gilead, Astra Zeneca, BMS Foundation, all unrelated to this manuscript, consulting fees from Astra Zeneca, Aurinia, Pfizer, all unrelated to this manuscript. PMM is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC) and has received consulting fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche, UCB, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunotherapeutic interventions to enhance natural HIV-specific CD8 + T cell responses, such as vaccination or adoptive T cell transfer, have been a major focus of HIV cure efforts. However, these approaches have not been effective in overcoming viral immune evasion mechanisms. Soluble T cell receptor (TCR) bispecifics are a new class of 'off-the-shelf' therapeutic designed to address these limitations. These biologics are built on the Immune mobilising monoclonal TCRs against X disease (ImmTAX) platform, which was pioneered in oncology and recently validated by the FDA's approval of tebentafusp for treatment of metastatic uveal melanoma. ImmTAV® are an application of this technology undergoing clinical development for the elimination of chronic viral infections. ImmTAV molecules comprise an affinity-enhanced virus-specific TCR fused to an anti-CD3 effector domain. Engineering of the TCR confers extraordinary specificity and affinity for cognate viral antigen and the anti-CD3 enables retargeting of non-exhausted cytolytic T cells, irrespective of their specificity. These features enable ImmTAV molecules to detect and kill infected cells, even when expressing very low levels of antigen, bypassing ineffective host immune responses. Furthermore, the modularity of the platform allows for engineering of TCRs that effectively target viral variants. In this review, we discuss the progress made in the development of ImmTAV molecules as therapeutics for functional cure of chronic hepatitis B and HIV, from concept to the clinic., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. ZW, PKS, and LD are employees of Immunocore Ltd., (© 2022 The Authors.)

Objective: While COVID-19 vaccination prevents severe infections, poor immunogenicity in immunocompromised people threatens vaccine effectiveness. We analysed the clinical characteristics of patients with rheumatic disease who developed breakthrough COVID-19 after vaccination against SARS-CoV-2., Methods: We included people partially or fully vaccinated against SARS-CoV-2 who developed COVID-19 between 5 January and 30 September 2021 and were reported to the Global Rheumatology Alliance registry. Breakthrough infections were defined as occurring ≥14 days after completion of the vaccination series, specifically 14 days after the second dose in a two-dose series or 14 days after a single-dose vaccine. We analysed patients' demographic and clinical characteristics and COVID-19 symptoms and outcomes., Results: SARS-CoV-2 infection was reported in 197 partially or fully vaccinated people with rheumatic disease (mean age 54 years, 77% female, 56% white). The majority (n=140/197, 71%) received messenger RNA vaccines. Among the fully vaccinated (n=87), infection occurred a mean of 112 (±60) days after the second vaccine dose. Among those fully vaccinated and hospitalised (n=22, age range 36-83 years), nine had used B cell-depleting therapy (BCDT), with six as monotherapy, at the time of vaccination. Three were on mycophenolate. The majority (n=14/22, 64%) were not taking systemic glucocorticoids. Eight patients had pre-existing lung disease and five patients died., Conclusion: More than half of fully vaccinated individuals with breakthrough infections requiring hospitalisation were on BCDT or mycophenolate. Further risk mitigation strategies are likely needed to protect this selected high-risk population., Competing Interests: Competing interests: KLH reports she has received non-personal speaker’s fees from AbbVie and grant income from BMS, UCB and Pfizer, all unrelated to this manuscript; KLH is supported by the NIHR Manchester Biomedical Research Centre. LG reports personal consultant fees from AbbVie, Amgen, BMS, Biogen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis and UCB, and grants from Amgen, Lilly, Janssen, Pfizer, Sandoz, Sanofi and Galapagos, all unrelated to this manuscript. AS reports research grants from a consortium of 14 companies (among them AbbVie, BMS, Celltrion, Fresenius Kabi, Gilead/Galapagos, Lilly, Mylan/Viatris, Hexal, MSD, Pfizer, Roche, Samsung, Sanofi-Aventis and UCB) supporting the German RABBIT register and personal fees from lectures for AbbVie, MSD, Roche, BMS, Lilly and Pfizer, all unrelated to this manuscript. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as AbbVie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi-Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal and UCB Pharma. EF-M reports personal consultant fees from Boehringer Ingelheim Portugal and that LPCDR received support for specific activities: grants from AbbVie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal, MSD, Celgene, Medac, Pharmakern and GAfPA; grants and non-financial support from Pfizer; and non-financial support from Grünenthal, outside the submitted work. IB reports personal consultant fees from AbbVie, Novartis, Pfizer and Janssen, all unrelated to this manuscript. JZ reports speaker fees from AbbVie, Novartis and Janssen/Johnson & Johnson, all unrelated to this manuscript. GR-C reports personal consultant fees from Eli Lilly and Novartis, all unrelated to this manuscript. JS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers: R01 AR077607, P30 AR070253 and P30 AR072577), and the R Bruce and Joan M Mickey Research Scholar Fund. JS has received research support from Amgen and Bristol Myers Squibb and performed consultancy for Bristol Myers Squibb, Gilead, Inova, Janssen and Optum, unrelated to this work. LW receives speaker’s bureau fees from Aurinia Pharma, unrelated to this manuscript. SB reports no competing interests related to this work. He reports non-branded consulting fees for AbbVie, Horizon and Novartis (all <$10 000). MGM has no competing interests related to this work. She serves as a patient consultant for BMS, BI JNJ and Aurinia (all <$10 000). RG reports no competing interests related to this work. Outside of this work she reports personal and/or speaking fees from AbbVie, Janssen, Novartis, Pfizer and Cornerstones and travel assistance from Pfizer (all <$10 000). JH reports no competing interests related to this work. He is supported by grants from the Rheumatology Research Foundation and has salary support from the Childhood Arthritis and Rheumatology Research Alliance. He has performed consulting for Novartis, Sobi and Biogen, all unrelated to this work (<$10 000). ESi reports non-financial support from Canadian Arthritis Patient Alliance, outside the submitted work. PS reports personal fees from the American College of Rheumatology/Wiley Publishing, outside the submitted work. ZW reports grant support from Bristol Myers Squibb and Principia/Sanofi and performed consultancy for Viela Bio and MedPace, outside the submitted work. His work is supported by grants from the National Institutes of Health. PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this study. PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). PCR reports no competing interests related to this work. Outside of this work PCR reports personal fees from AbbVie, Atom Bioscience, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Kukdong, Novartis, UCB, Roche and Pfizer; meeting attendance support from BMS, Pfizer and UCB; and grant funding from Janssen, Novartis, Pfizer and UCB Pharma (all <$10 000). JY reports no competing interests related to this work. Her work is supported by grants from the National Institutes of Health (K24 AR074534 and P30 AR070155). Outside of this work, she has received research grants or performed consulting for Gilead, BMS Foundation, Pfizer, Aurinia and AstraZeneca., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Problem Considered: K-12 schools have shown minimal spread of COVID-19 when mitigation measures are employed. This study sought to determine baseline asymptomatic COVID-19 rates in secondary schools as students returned to full-time in-person learning with universal masking in place and to evaluate the logistical obstacles of implementing surveillance testing., Methods: An observational cohort study lasting 11 weeks during spring 2021 included 2,288 students and staff in Wood County, Wisconsin. SARS-CoV-2 nasal polymerase chain reaction testing was done on consenting students and staff to determine baseline disease burden. Teacher surveys collected data on student masking compliance and classroom distancing. Information about percent positivity, secondary transmission, quarantine and distancing policies, screening participation, costs, and volunteer hour requirements were obtained. Modified quarantine for fully masked in-classroom exposures was evaluated., Results: Percent positivity averaged 3.0% (0%-16.2% weekly) among students and 1.72% (0%-6.9% weekly) among staff. Two cases of secondary transmission were suspected out of 163 individuals quarantined. An average of 15.6% of the school population consented to participate each week. Minimum classroom distance between students ranged from 2.7 to 5.5 feet. Student masking compliance was greater than 87%. The cost of the program was $106,400 and required approximately 300 volunteer hours. The modified quarantine policy, where students were allowed to continue to attend in-person school after exposure to a case of COVID-19 if the infected and exposed parties were masking, did not result in additional transmission., Conclusions: In the setting of relatively high student masking compliance and limited distance between students, weekly secondary school screening of students and staff in an area of high community disease spread was found to be low yield, costly, and burdensome for the school district. Surveillance participation was low. A modified quarantine policy was not associated with increased in-school transmission. School funding may be better spent on targeted testing or other school expenses, especially with increasing vaccination rates., (Copyright© Board of Regents of the University of Wisconsin System and The Medical College of Wisconsin, Inc.)

Objective: The aim was to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the clinical experiences, research opportunities and well-being of rheumatology trainees., Methods: A voluntary, anonymous, Web-based survey was administered in English, Spanish or French from 19 August 2020 to 5 October 2020. Adult and paediatric rheumatology trainees were invited to participate via social media and email. Using multiple-choice questions and Likert scales, the perceptions of trainees regarding the impact of the COVID-19 pandemic on patient care and redeployment, learning and supervision, research and well-being were assessed., Results: There were 302 respondents from 33 countries, with 83% in adult rheumatology training. An increase in non-rheumatology clinical work was reported by 45%, with 68% of these having been redeployed to COVID-19. Overall, trainees reported a negative impact on their learning opportunities during rheumatology training, including outpatient clinics (79%), inpatient consultations (59%), didactic teaching (55%), procedures (53%), teaching opportunities (52%) and ultrasonography (36%). Impacts on research experiences were reported by 46% of respondents, with 39% of these reporting that COVID-19 negatively affected their ability to continue their pre-pandemic research. Burnout and increases in stress were reported by 50% and 68%, respectively. Physical health was negatively impacted by training programme changes in 25% of respondents., Conclusion: The COVID-19 pandemic has had a substantial impact on rheumatology training and trainee well-being. Our study highlights the extent of this impact on research opportunities and clinical care, which are highly relevant to future curriculum planning and the clinical learning environment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To evaluate the impact of telemedicine use during the coronavirus disease 2019 (COVID-19) pandemic on rheumatology trainees., Methods: A voluntary, anonymous, web-based survey was administered in English, Spanish, or French from August 19 to October 5, 2020. Adult and pediatric rheumatology trainees were invited to participate via social media and email. Using multiple-choice questions and Likert scales, the survey assessed prior and current telemedicine use, impact on training, and supervision after COVID-19 prompted rapid telemedicine implementation., Results: Surveys were received from 302 trainees from 33 countries, with 83% in adult rheumatology training programs. Reported telemedicine use increased from 13% before the pandemic to 82% during the pandemic. United States trainees predominantly used video visits, whereas outside the United States telemedicine was predominantly audio only. Most (65%) evaluated new patients using telemedicine. More respondents were comfortable using telemedicine for follow-up patients (69%) than for new patients (25%). Only 39% of respondents reported receiving telemedicine-focused training, including instruction on software, clinical skills, and billing, whereas more than half of United States trainees (59%) had training. Postconsultation verbal discussion was the most frequent form of supervision; 24% reported no supervision. Trainees found that telemedicine negatively impacted supervision (50%) and the quality of clinical teaching received (70%), with only 9% reporting a positive impact., Conclusions: Despite widespread uptake of telemedicine, a low proportion of trainees received telemedicine training, and many lacked comfort in evaluating patients, particularly new patients. Inadequate supervision and clinical teaching were areas of concern. If telemedicine remains in widespread use, ensuring appropriate trainee supervision and teaching should be prioritized., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The coronavirus disease 2019 (COVID-19) pandemic has disrupted in-person learning in the United States, with approximately one half of all students receiving online-only instruction since March 2020.* Discontinuation of in-person schooling can result in many hardships (1) and disproportionately affects families of lower socioeconomic status (2). Current evidence suggests that transmission of SARS-CoV-2, the virus that causes COVID-19, in kindergarten through grade 12 (K-12) schools might not significantly contribute to COVID-19 spread nationwide (3). During August 31-November 29, 2020, COVID-19 cases, spread, and compliance with mask use were investigated among 4,876 students and 654 staff members who participated in in-person learning in 17 K-12 schools in rural Wisconsin. School-attributable COVID-19 case rates were compared with rates in the surrounding community. School administration and public health officials provided information on COVID-19 cases within schools. During the study period, widespread community transmission was observed, with 7%-40% of COVID-19 tests having positive results. Masking was required for all students and staff members at all schools, and rate of reported student mask-wearing was high (>92%). COVID-19 case rates among students and staff members were lower (191 cases among 5,530 persons, or 3,453 cases per 100,000) than were those in the county overall (5,466 per 100,000). Among the 191 cases identified in students and staff members, one in 20 cases among students was linked to in-school transmission; no infections among staff members were found to have been acquired at school. These findings suggest that, with proper mitigation strategies, K-12 schools might be capable of opening for in-person learning with minimal in-school transmission of SARS-CoV-2., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Objective: Wrong drug product errors occurring in community pharmacies often originate at the transcription stage. Electronic prescribing and automated product selection are strategies to reduce product selection errors. However, it is unclear how often automated product selection succeeds in outpatient pharmacy platforms., Materials and Methods: The intake of over 800 e-prescriptions was observed at baseline and after intervention to assess the rate of automated product selection success. A dispensing accuracy audit was performed at baseline and postintervention to determine whether enhanced automated product selection would result in greater accuracy; data for both analyses were compared by 2x2 Chi square tests. In addition, an anonymous survey was sent to a convenience sample of 60 area community pharmacy managers., Results: At baseline, 79.8% of 888 e-prescriptions achieved automated product selection. After the intervention period, 84.5% of 903 e-prescriptions achieved automated product selection (P = .008). Analysis of dispensing accuracy audits detected a slight but not statistically significant improvement in accuracy rate (99.3% versus 98.9%, P = .359). Fourteen surveys were returned, revealing that other community pharmacies experience similar automated product selection failure rates., Discussion: Our results suggest that manual product selection by pharmacy personnel is required for a higher than anticipated proportion of e-prescriptions received and filled by community pharmacies, which may pose risks to both medication safety and efficiency., Conclusion: The question of how to increase automated product selection rates and enhance interoperability between prescriber and community pharmacy platforms warrants further investigation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine the potential association between physician gender and academic advancement among US rheumatologists., Methods: We performed a nationwide, cross-sectional study of all rheumatologists practicing in the US in 2014 using a comprehensive database of all licensed physicians. Among academic rheumatologists, we estimated gender differences in faculty rank, adjusting for differences in physician age, years since residency graduation, publications, National Institutes of Health (NIH) grants, registered clinical trials, and appointment at a top 20 medical school using a multivariate logistic regression model. We also estimated gender differences in leadership positions (i.e., division director and fellowship program director)., Results: Among 6,125 total practicing rheumatologists, 941 (15%) had academic faculty appointments in 2014. Women academic rheumatologists (41.4%) were younger and had completed residency more recently than men. Women had fewer total publications, publications on which they were the first or last author, and NIH grants. In fully adjusted analyses, women were less likely to be full or associate professors than men, with an adjusted odds ratio (OR) of 0.78 (95% confidence interval [95% CI] 0.62-0.99]). Women in rheumatology had similar odds as men of being a fellowship program director or division director (adjusted OR 0.99 [95% CI 0.69-1.43] and adjusted OR 0.96 [95% CI 0.66-1.41], respectively)., Conclusion: Among academic rheumatologists, women are less likely than men to be full or associate professors but have similar odds of being fellowship program directors or division directors, when adjusting for several factors known to influence faculty promotion. These differences suggest barriers to academic promotion despite representation in leadership positions within rheumatology divisions., (© 2020, American College of Rheumatology.)

Background and Aims: Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV-specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity-enhanced T Cell receptor with an anti-CD3 T Cell-activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus-derived peptides presented by human leukocyte antigen (HLA)., Approach and Results: ImmTAV molecules specific for HLA-A*02:01-restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV-Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging-based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV-Env can redirect T cells from healthy and HBV-infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV-Env redirection of T cells induced cytolysis of antigen-positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA., Conclusions: The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non-HBV-specific T cells, bypassing exhausted HBV-specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials., (© 2020 Immunocore Ltd. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: The antigenic trigger that drives expansion of circulating plasmablasts and CD4 + cytotoxic T cells in patients with IgG 4 -related disease (IgG 4 -RD) is presently unknown., Objective: We sought to sequence immunoglobulin genes from single-cell clones of dominantly expanded plasmablasts and generate recombinant human mAbs to identify relevant antigens in patients with IgG 4 -RD by using mass spectrometry., Methods: Paired heavy and light chain cDNAs from dominant plasmablast clones were expressed as mAbs and used to purify antigens by using immunoaffinity chromatography. Affinity-purified antigens were identified by using mass spectrometry and validated by means of ELISA. Plasma levels of the antigen of interest were also determined by using ELISA., Results: mAbs expressed from the 2 dominant plasmablast clones of a patient with multiorgan IgG 4 -RD stained human pancreatic tissue sections. Galectin-3 was identified as the antigen specifically recognized by both mAbs. Anti-galectin-3 autoantibody responses were predominantly of the IgG 4 isotype (28% of the IgG 4 -RD cohort, P = .0001) and IgE isotype (11% of the IgG 4 -RD cohort, P = .009). No significant responses were seen from the IgG 1 , IgG 2 , or IgG 3 isotypes. IgG 4 anti-galectin-3 autoantibodies correlated with increased plasma galectin-3 levels (P = .001), lymphadenopathy (P = .04), total IgG level increase (P = .05), and IgG 4 level increase (P = .03)., Conclusion: Affinity chromatography using patient-derived mAbs identifies relevant autoantigens in patients with IgG 4 -RD. IgG 4 galectin-3 autoantibodies are present in a subset of patients with IgG 4 -RD and correlate with galectin-3 plasma levels. The marked increases in levels of circulating IgG 4 and IgE observed clinically are, at least in part, caused by the development of IgG 4 - and IgE-specific autoantibody responses., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

HIV cannot be cured by current antiretroviral therapy (ART) because it persists in a transcriptionally silent form in long-lived CD4+ cells. Leading efforts to develop a functional cure have prioritized latency reversal to expose infected cells to immune surveillance, coupled with enhancement of the natural cytolytic function of immune effectors, or "kick and kill." The most clinically advanced approach to improving the kill is therapeutic immunization, which aims to augment or re-focus HIV-specific cytolytic T cell responses. However, no vaccine strategy has enabled sustained virological control after ART withdrawal. Novel approaches are needed to overcome the limitations of natural adaptive immune responses, which relate to their specificity, potency, durability, and access to tissue reservoirs. Adoptive T cell therapy to treat HIV infection was first attempted over two decades ago, without success. Since then, progress in the field of cancer immunotherapy, together with recognition of the similarities in tumor microenvironments and HIV reservoirs has reignited interest in the application of T cell therapies to HIV eradication. Advances in engineering of chimeric antigen receptor (CAR)-transduced T cells have led to improved potency, persistence and latterly, resistance to HIV infection. Immune retargeting platforms have incorporated non-neutralizing and broadly neutralizing antibodies to generate Bispecific T cell Engagers (BiTEs) and Dual-Affinity Re-Targeting proteins (DARTs). T cell receptor engineering has enabled the development of the first bispecific Immune-mobilizing monoclonal T Cell receptors Against Viruses (ImmTAV) molecules. Here, we review the potential for these agents to provide a better "kill" and the challenges ahead for clinical development.

Retroperitoneal fibrosis (RPF) refers to a fibro-inflammatory lesion in the retroperitoneum, often anterolateral to the aorta. Most cases are due to IgG4-related disease (IgG4-RD) or are idiopathic. RPF can lead to severe morbidity. Treatment strategies remain poorly-defined. We evaluated the efficacy and safety of rituximab (RTX) for idiopathic or IgG4-related RPF.We retrospectively reviewed the records of patients who had RPF treated with RTX. Treatment response was determined by assessing changes in both clinical features, including symptoms and laboratory measurements, as well as in the radiographic dimensions of the lesion.Twenty-six patients with IgG4-related (n = 19) or idiopathic RPF (n = 7) were identified. Patients without histopathological evidence of IgG4-RD on either retroperitoneal biopsies or sampling of extra-retroperitoneal organs were considered to have idiopathic RPF. Of the 26 patients, 19 (73%) received RTX without additional glucocorticoids. All 19 patients who presented with pain reported symptomatic improvement following RTX. Among 25 patients with follow-up imaging, 22 (88%) had radiologic improvement. Among 10 patients with ureteral stents and/or percutaneous nephrostomy tubes, 4 (40%) underwent successful stent or tube removal. Responses to treatment were similar among those treated with RTX monotherapy and those treated with RTX and glucocorticoids. RTX was generally well tolerated, but 3 (12%) patients experienced severe infections.In this study, RTX for RPF led to resolution of symptoms in all patients and radiographic improvement in the majority. Prospective studies of RTX for RPF are indicated.

Persistence of human immunodeficiency virus (HIV) in a latent state in long-lived CD4+ T-cells is a major barrier to eradication. Latency-reversing agents that induce direct or immune-mediated cell death upon reactivation of HIV are a possible solution. However, clearance of reactivated cells may require immunotherapeutic agents that are fine-tuned to detect viral antigens when expressed at low levels. We tested the antiviral efficacy of immune-mobilizing monoclonal T-cell receptors against viruses (ImmTAVs), bispecific molecules that redirect CD8+ T-cells to kill HIV-infected CD4+ T-cells. T-cell receptors specific for an immunodominant Gag epitope, SL9, and its escape variants were engineered to achieve supraphysiological affinity and fused to a humanised CD3-specific single chain antibody fragment. Ex vivo polyclonal CD8+ T-cells were efficiently redirected by immune-mobilising monoclonal T-cell receptors against viruses to eliminate CD4+ T-cells from human histocompatibility leukocyte antigen (HLA)-A*0201-positive antiretroviral therapy-treated patients after reactivation of inducible HIV in vitro. The efficiency of infected cell elimination correlated with HIV Gag expression. Immune-mobilising monoclonal T-cell receptors against viruses have potential as a therapy to facilitate clearance of reactivated HIV reservoir cells.