BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. METHODS: Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1-12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. RESULTS: Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01-2.41; aOR 2.43, 95% CI 1.48-4.02) and ICU admission (aOR 2.30, 95% CI 0.98-5.39; aOR 3.93, 95% CI 1.56-9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07) and ICU admission (aOR 2.55, 95% CI 1.49-4.36; aOR 4.32, 95% CI 2.27-8.23), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13-3.07; aOR 2.88, 95% CI 1.68-4.92) and ICU admission (aOR 2.13, 95% CI 0.85-5.35; aOR 3.23, 95% CI 1.17-8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71-17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. DISCUSSION: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.

Background: Extended interval dosing of natalizumab is associated with significantly lower progressive multifocal leukoencephalopathy risk compared with every-4-week (Q4W) dosing in patients with relapsing-remitting multiple sclerosis. Previous studies have suggested that natalizumab effectiveness is maintained in patients who switch from Q4W to extended interval dosing but have been limited by a lack of well-matched patient cohorts. Methods: Tysabri Observational Program (TOP) data as of November 2019 were used to identify patients with relapsing-remitting multiple sclerosis treated with natalizumab Q4W and those with a single physician-indicated dosing change from Q4W to every-6-week (Q6W) dosing after ⩾1 year of Q4W treatment. Patients were propensity score matched at the time of the switch from Q4W to Q6W dosing. Clinical outcomes (annualized relapse rate and probability of remaining relapse free or free of 24-week confirmed disability worsening) and safety outcomes were assessed for the two cohorts. Results: This study included 219 pairs of propensity score-matched Q6W and Q4W patients. Annualized relapse rates were similar for Q6W (0.150) and Q4W (0.157) patients. The probability of remaining relapse free [hazard ratio = 1.243 (95% confidence interval = 0.819-1.888); p = 0.307] and of remaining free of 24-week confirmed disability worsening [hazard ratio = 0.786 (95% confidence interval = 0.284-2.176); p = 0.644] did not differ significantly between Q6W and Q4W patients. Summarized safety results for the matched Q6W and Q4W patients are also presented. Conclusion: These real-world findings in well-matched patient cohorts from TOP demonstrate that natalizumab effectiveness is maintained in patients who switch to Q6W dosing after ⩾1 year of Q4W dosing. ClinicalTrialsgov identifier: NCT00493298.

Whilst some of the diversity in management of women with ductal carcinoma in situ (DCIS) may be explained by tumour characteristics, the role of patient preference and the factors underlying those preferences have been less frequently examined. We have used a descriptive qualitative study to explore treatment decisions for a group of Australian women diagnosed with DCIS through mammographic screening. Semi-structured telephone interviews were performed with 16 women diagnosed with DCIS between January 2012 and December 2018, recruited through the LifePool dataset (a subset of BreastScreen participants who have agreed to participate in research). Content analysis using deductive coding identified three themes: participants did not have a clear understanding of their diagnosis or prognosis; reported involvement in decision making about management varied; specific factors including the psychosexual impact of mastectomy and perceptions of radiotherapy, could act as barriers or facilitators to specific decisions about treatment. The treatment the women received was not simply determined by the characteristics of their disease. Interaction with the managing clinician was pivotal, however many other factors played a part in individual decisions. Recognising that decisions are not purely a function of disease characteristics is important for both women with DCIS and the clinicians who care for them.

Anal cancer is a rare disease that has doubled in incidence over the last four decades. Current treatment and survival of patients with this disease has not changed substantially over this period of time, due, in part, to a paucity of preclinical models to assess new therapeutic options. To address this hiatus, we set-out to establish, validate and characterise a panel of human anal squamous cell carcinoma (ASCC) cell lines by employing an explant technique using fresh human ASCC tumour tissue. The panel of five human ASCC cell lines were validated to confirm their origin, squamous features and tumourigenicity, followed by molecular and genomic (whole-exome sequencing) characterisation. This panel recapitulates the genetic and molecular characteristics previously described in ASCC including phosphoinositide-3-kinase (PI3K) mutations in three of the human papillomavirus (HPV) positive lines and TP53 mutations in the HPV negative line. The cell lines demonstrate the ability to form tumouroids and retain their tumourigenic potential upon xenotransplantation, with varied inducible expression of major histocompatibility complex class I (MHC class I) and Programmed cell death ligand 1 (PD-L1). We observed differential responses to standard chemotherapy, radiotherapy and a PI3K specific molecular targeted agent in vitro, which correlated with the clinical response of the patient tumours from which they were derived. We anticipate this novel panel of human ASCC cell lines will form a valuable resource for future studies into the biology and therapeutics of this rare disease.

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection. This was accompanied by a reduction in the proportion of KLRG1- memory precursor cells and a transcriptional bias toward terminal differentiation. Of note, forced expression of KLRG1 was sufficient to impede TRM cell formation. Normalizing memory precursor frequencies by transferring equal numbers of KLRG1- cells restored TRM generation, demonstrating that Ptpn2 impacted skin seeding with precursors rather than downstream TRM cell differentiation. Importantly, Ptpn2-deficient TRM cells augmented skin autoimmunity but also afforded superior protection from HSV-1 infection. Our results emphasize that KLRG1 repression is required for optimal TRM cell formation in skin and reveal an important role of Ptpn2 in regulating TRM cell functionality.

INTRODUCTION: Chronic hip pain in middle-aged and older adults is common and disabling. Patient-centred care of chronic hip pain requires a comprehensive understanding of how people with chronic hip pain view their health problem and its care. This paper outlines a protocol to synthesise qualitative evidence of middle-aged and older adults' views, beliefs, expectations and preferences about their chronic hip pain and its care. METHODS AND ANALYSIS: We will perform a qualitative evidence synthesis using a framework approach. We will conduct this study in accord with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement and the Enhancing Transparency in Reporting the synthesis of Qualitative research checklist. We will search MEDLINE, CINAHL, The Cochrane Central Register of Controlled Trials, EMBASE and PsycINFO using a comprehensive search strategy. A priori selection criteria include qualitative studies involving samples with a mean age over 45 and where 80% or more have chronic hip pain. Two or more reviewers will independently screen studies for eligibility, assess methodological strengths and limitations using the Critical Appraisal Skills Programme qualitative studies checklist, perform data extraction and synthesis and determine ratings of confidence in each review finding using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research approach. Data extraction and synthesis will be guided by the Common-Sense Model of Self-Regulation. All authors will contribute to interpreting, refining and finalising review findings. This protocol is registered on PROSPERO and reported according to the PRISMA Statement for Protocols (PRISMA-P) checklist. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review as primary data will not be collected. The findings of the review will be disseminated through publication in an academic journal and scientific conferences. PROSPERO REGISTRATION NUMBER: PROSPERO registration number: CRD42021246305.

BACKGROUND: Strong evidence supports the proximal combined with quadriceps strengthening for patellofemoral pain (PFP) rehabilitation. However, most reported rehabilitation programs do not follow specific exercise prescription recommendations or do not provide adequate details for replication in clinical practice. Furthermore, people with PFP have power deficits in hip and knee muscles and it remains unknown whether the addition of power exercises would result in superior or more consistent outcomes. Therefore, this study is designed to verify whether the benefits of a rehabilitation program addressing proximal and knee muscles comprising power and strength exercises are greater than those of a program consisting of strength exercises only. METHOD: This study will be a randomized controlled trial that will be conducted at university facilities. A minimum of 74 people with PFP between the ages of 18 and 45 years will be included. The experimental group will engage in a 12-week resistance training program focusing on proximal and knee muscles using power and strength exercises. The control group will engage in a 12-week resistance training program focusing on proximal and knee muscles using strength exercises only. Primary outcomes will be pain intensity and physical function; and secondary outcomes will be kinesiophobia, self-reported improvement, quality of life, peak hip and knee torque, and hip and knee rate of force development. The primary outcomes will be evaluated at baseline, and after 6 weeks, 12 weeks, 3 months, 6 months, and 1 year. The secondary outcomes will be evaluated at baseline and immediately after the interventions. Therapists and participants will not be blinded to group allocation. DISCUSSION: This randomized clinical trial will investigate if adding power exercises to a progressive resistance training may lead to more consistent outcomes for PFP rehabilitation. The study will provide additional knowledge to support rehabilitation programs for people with PFP. TRIAL REGISTRATION: ClinicalTrials.gov NCT03985254. Registered on 26 August 2019.

Osteochondral (OC) defects are debilitating joint injuries characterized by the loss of full thickness articular cartilage along with the underlying calcified cartilage through to the subchondral bone. While current surgical treatments can provide some relief from pain, none can fully repair all the components of the OC unit and restore its native function. Engineering OC tissue is challenging due to the presence of the three distinct tissue regions. Recent advances in additive manufacturing provide unprecedented control over the internal microstructure of bioscaffolds, the patterning of growth factors and the encapsulation of potentially regenerative cells. These developments are ushering in a new paradigm of 'multiphasic' scaffold designs in which the optimal micro-environment for each tissue region is individually crafted. Although the adoption of these techniques provides new opportunities in OC research, it also introduces challenges, such as creating tissue interfaces, integrating multiple fabrication techniques and co-culturing different cells within the same construct. This review captures the considerations and capabilities in developing 3D printed OC scaffolds, including materials, fabrication techniques, mechanical function, biological components and design.

INTRODUCTION: Addressing disparities in arthritis care is an important yet unmet health need for Aboriginal and Torres Strait Islander people in Australia (respectfully Aboriginal people herewith). Despite the significant prevalence and burden of arthritis within Aboriginal communities, access to care for arthritis is low. One means to reduce existing disparities in health care is to address current challenges relating to the appropriateness and acceptability of health care information resources for Aboriginal people. Health information sources can help to empower patients and their families to have greater involvement in their care and to engage in self-management of their condition. Despite an extensive range of arthritis information resources being available, currently no resources have been culturally adapted and developed in collaboration with Aboriginal consumers with arthritis. This paper outlines the processes that will be undertaken within the Staying Moving, Staying Strong project. This project aims to develop culturally secure arthritis information for Aboriginal people with osteoarthritis, rheumatoid arthritis, lupus and gout. METHODS AND ANALYSIS: The overarching principle guiding this project is cultural security, referring to the incorporation of processes such that the research will not compromise the cultural rights, values and expectations of Aboriginal people. This project will prioritise partnerships, community engagement, community benefit, sustainability, transferability, and capacity building and therefore uphold the cultural rights and values of Aboriginal people. In this six-phase project we will; 1) Establish a community reference group and advisory committee; 2) Explore the health information needs and preferences of Aboriginal people with arthritis; 3) Synthesise the existing key recommendations in high quality clinical practice guidelines on arthritis care; 4) Culturally adapt key clinical recommendations; 5) Develop culturally appropriate arthritis resources and; 6) Qualitatively evaluate the developed resources.