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This paper examines the impact of mobile money account ownership on farmers' participation in farmer‐based organisations (FBOs), structured market and off‐farm work. Relying on recursive bivariate probit model, our results reveal that owning a mobile money account increases the likelihood of farmers' participating in an FBO, structured market and off‐farm work by 15.4%, 33.3% and 37.5%, respectively. Furthermore, mobile money account ownership is influenced by socioeconomic and institutional factors as well as the presence of mobile money vendors within a community. Our finding calls for sustained efforts to deepen digital financial inclusion for increased participation in FBOs, structured market and off‐farm work. [ABSTRACT FROM AUTHOR]

Objectives: To describe the outcome and complications associated with the use of caudal superficial epigastric axial pattern flaps in dogs and cats. Material and Methods: Multicentre retrospective review and descriptive study of clinical records of dogs and cats having undergone caudal superficial epigastric axial pattern flaps between 2007 and 2020. Data retrieved included signalment, aetiology of surgical defect, tumour type, presence/absence of clean surgical margins, presence/absence of post‐operative wound infection, use of peri‐ and post‐operative antibiotics, duration of anaesthesia, duration of surgery, presence and duration of hypothermia, presence and duration of hypotension, presence/absence of post‐operative surgical drain and length of caudal superficial epigastric axial pattern flap. The incidence of complications and outcomes were documented. Results: Seventy cases met the inclusion criteria; 51 dogs and 19 cats. In dogs, 67% of cases developed complications (59% minor, 8% major) and 33% had uneventful wound healing. In cats, 53% of cases developed complications, (47% minor, 5% major) and 47% had uneventful wound healing. In dogs, the percentage of cases experiencing dehiscence, necrosis, seroma, oedema and post‐operative infection was 31%, 29%, 26%, 26% and 16% respectively. In cats, this was 26%, 16%, 11%, 0% and 5% respectively. A good overall outcome was seen in 77% of dogs and 79% of cats. A poor overall outcome was seen in 4% of dogs and 0% of cats. Clinical Significance: Caudal superficial epigastric axial pattern flaps are traditionally thought more robust than other flaps, yet complication rates remain high, despite a high overall success rate. [ABSTRACT FROM AUTHOR]

Around 42% of individuals with cancer experience distress. Acceptance and commitment therapy (ACT) can reduce distress, but effects are small, and mechanisms unclear. This review aimed to identify associations between ACT processes and distress in cancer. Search terms included cancer, ACT processes, self-compassion, and distress. Six online databases and grey literature were searched until March 2022. Of 6555 papers screened, 108 studies were included with 17,195 participants. Five meta-analyses of 77 studies were conducted. Random effects meta-analyses of correlations revealed higher scores on flexible processes (acceptance, present moment awareness, self-compassion) were associated with lower distress ( r pooled  = -0.24, -0.39, -0.48, respectively); whilst higher scores on inflexible processes (experiential avoidance, cognitive fusion) were associated with higher distress ( r pooled  = 0.58, 0.57, respectively). Meta-analyses displayed moderate-to-high heterogeneity with most studies assessed as low risk of bias. Meta-regressions revealed no significant moderators (stage, time since diagnosis, gender and age). This review provides a theoretically aligned evidence base for associations between ACT processes and distress in cancer, supporting elements of ACT theory and providing targeted directions for intervention development. Due to limited evidence, future research should focus on self-as-context, values and committed action and conduct mediation analysis in controlled trials of ACT processes on distress in cancer.

Background: Individuals with transfusion-dependent β-thalassemia (TDT) experience symptoms and functional impacts that reduce their health-related quality of life. However, EQ-5D-derived health utility index scores in TDT often indicate good HRQoL, suggesting the EQ-5D may not adequately capture the impact of TDT. This study explored the disease and treatment burden of TDT and examined the appropriateness of the EQ-5D-5L descriptive system (DS) in measuring HRQoL in TDT., Methods: Adults with TDT in the United Kingdom, United States, and France completed a background questionnaire and EQ-5D-5L DS, followed by 60-minute semi-structured interviews on symptoms and HRQoL impacts of TDT (concept elicitation) and appropriateness of EQ-5D-5L DS (cognitive debrief). Transcribed interviews were analyzed using thematic and content analyses. The relationship between TDT symptoms and impacts were summarized in a conceptual model. EQ-5D-5L DS was mapped to concepts identified in the qualitative data to assess its capture of HRQoL concepts. Participants' EQ-5D-5L DS scores were compared to their qualitative descriptions for each dimension to assess their concordance., Results: Thirty participants in the United States (n = 14 [46.7%]), United Kingdom. (n = 12 [40.0%]), and France (n = 4 [13.3%]) completed the study (73.3% female; mean age = 28.4 years [standard deviation (SD) = 5.1]; mean annual red blood cell transfusion [RBCT] frequency = 18.4 [SD = 7.6]). Participants reported TDT symptoms and impacts on HRQoL, all fluctuating across the RBCT cycle. EQ-5D-5L DS did not fully capture 11 of 16 (68.8%) HRQoL concepts reported. Most participants (n = 20/27 [74.1%]) reported that EQ-5D-5L DS did not capture important aspects of living with TDT, and 42.9% (n = 12/28) reported negative/neutral overall impressions of EQ-5D-5L DS. The highest degree of discordance between participants' qualitative data and EQ-5D-5L DS dimension scores was observed with mobility (42.3%) and self-care (34.6%), where the qualitative descriptions relating to these dimensions were worse than their quantitative scores., Conclusion: Current findings suggest that EQ-5D-5L DS lacks content validity and the derived health utility index score may not fully represent the burden of disease in TDT., (© 2024. The Author(s).)

Niraparib was recently funded in Canada for the maintenance treatment of ovarian cancer following platinum-based chemotherapy. However, the drug's safety profile in the real world remains uncertain. We conducted a cohort study to describe the patient population using niraparib and the proportion that experienced adverse events between June 2019 and December 2022 in four Canadian provinces (Ontario, Alberta, British Columbia [BC], and Quebec). We used administrative data and electronic medical records from Ontario Health, Alberta Health Services, and BC Cancer, and registry data from Exactis Innovation. We summarized baseline characteristics using descriptive statistics and reported safety outcomes using cumulative incidence. We identified 514 patients receiving niraparib. Mean age was 67 years and most were initiated on a daily dose of 100 or 200 mg/day. Grade 3/4 anemia, neutropenia, and thrombocytopenia occurred in 11-16% of the cohort. In Ontario, the three-month cumulative incidence of grade 3/4 thrombocytopenia was 11.6% (95% CI, 8.3-15.4%), neutropenia was 7.1% (95% CI, 4.6-10.4%), and anemia was 11.3% (95% CI, 8.0-15.2%). Cumulative incidences in the remaining provinces were similar. Initial daily dose and proportions of hematological adverse events were low in the real world and may be related to cautious prescribing and close monitoring by clinicians.

Competing Interests: K.S.-F. is the owner of CellTrend producing ELISA kits for the determination of antibodies against GPCR.

Background and Aims: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear., Methods: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation., Results: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model., Conclusions: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dysautonomia tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined before and six months after first-time SARS-CoV-2 vaccination of healthy controls ( N = 89; 71 females; mean/median age: 39/49 years) were compared with corresponding values of PACVS-affected persons ( N = 191; 159 females; mean/median age: 40/39 years) exhibiting chronic fatigue/dysautonomia (≥three symptoms for ≥five months after the last SARS-CoV-2 mRNA vaccination) not due to SARS-CoV-2 infection and/or confounding diseases/medications. Normal vaccination response encompassed decreases in 11 receptor antibodies (by 25-50%, p < 0.0001), increases in two receptor antibodies (by 15-25%, p < 0.0001) and normal IL-6. In PACVS, serological vaccination-response appeared significantly ( p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p < 0.0001) by increased Angiotensin II type 1 receptor antibodies (cut-off ≤ 10.7 U/mL, ROC-AUC = 0.824 ± 0.027), decreased alpha-2B adrenergic receptor antibodies (cut-off ≥ 25.2 U/mL, ROC-AUC = 0.828 ± 0.025) and increased IL-6 (cut-off ≤ 2.3 pg/mL, ROC-AUC = 0.850 ± 0.022). PACVS is thus indicated as a somatic syndrome delineated/detectable by diagnostic blood markers.

Introduction: Bile has long been considered sterile. Recent studies show that bacteria can frequently be detected in bile and certain bacterial species are associated with bile duct-associated liver disease., Objectives: To detect bacterial species and antibiotic resistance in bile in bile duct-associated liver disease., Methodology: To evaluate microbiological findings of bile samples obtained during ERCP at a tertiary center from 2009 to 2019., Results: There were 1885 bile samples from 992 patients examined by cultural microbiological analysis. Germs were detected in 91% of the samples. Most bile samples (n) were obtained from patients who had undergone liver transplantation (LTX; n = 556), followed by patients with primary sclerosing cholangitis (PSC; n = 287). Enterococci were detected in 67% of samples, followed by E. coli (32.2%) and Klebsiella (28.2%). Of 1151 enterococci detected, 13.1% were vancomycin (VRE)s and of 216 staphylococci detected, 10% were ORSA. The proportion of VRE increased with the number of tests performed during ERCPs ( P  < 0.01; chi-square) and increased 2.5-fold over 10 years, whereas the detection of ORSA remained stable. Patients with cholecystolithiasis were significantly more likely to have evidence of VRE in bile compared to LTX and PSC patients ( P  = 0.02, P  < 0.01; chi-square). The most abundant bacterial genera showed highly statistically significant differences in their levels of liver enzymes and c-reactive protein ( P  < 0.001)., Conclusion: Knowledge of the bacterial composition of bile in various bile duct-associated liver diseases may allow more targeted antibiotic use in the future., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The rapid evolution of new SARS-CoV-2 variants poses a continuing threat to human health. Vaccination has become the primary therapeutic intervention. The goal of the current work was the construction of immunogenic virus-like particles (VLPs). Here, we describe a human cell line for cost-efficient and scalable production of immunogenic SARS-CoV-2 VLPs. The modular design of the VLP-production platform facilitates rapid adaptation to new variants. Methods: The N, M-, and E-protein genes were integrated into the genome of Expi293 cells (ExpiVLP&#95;MEN). Subsequently, this cell line was further modified for the constitutive expression of the SARS-CoV-2 spike protein. The resulting cell line (ExpiVLP&#95;SMEN) released SARS-CoV-2 VLP upon exposure to doxycycline. ExpiVLP&#95;SMEN cells were readily adapted for VLP production in a 5 L bioreactor. Purified VLPs were quantified by Western blot, ELISA, and nanoparticle tracking analysis and visualized by electron microscopy. Immunogenicity was tested in mice. Results: The generated VLPs contained all four structural proteins, are within the size range of authentic SARS-CoV-2 virus particles, and reacted strongly and specifically with immunoserum from naturally infected individuals. The VLPs were stable in suspension at 4 °C for at least 10 weeks. Mice immunized with VLPs developed neutralizing antibodies against lentiviruses pseudotyped with the SARS-CoV-2 spike protein. The flexibility of the VLP-production platform was demonstrated by the rapid switch of the spike protein to a new variant of concern (BA.1/Omicron). The present study describes an efficient, scalable, and adaptable production method of immunogenic SARS-CoV-2 VLPs with therapeutic potential.

Objective: To describe the clinical presentation, diagnostic imaging findings, surgical technique, histopathological diagnosis, and postoperative outcome in 3 cats with extensive vaginal masses., Animals: Medical records of cats diagnosed with vaginal masses that had a bilateral pubic and ischial osteotomy and vaginectomy between 2004 and 2022 were retrospectively reviewed. Three cats met the inclusion criteria., Clinical Presentation: Histopathological diagnosis included T-cell-rich B-cell lymphoma (n = 1), mycetoma (1), and vaginal polyp (1). Diagnostic imaging included CT (n = 2) and MRI (1), and tumor length/width/height percentages in relation to the pelvic dimensions were 53% X 62% X 63% (case 1), 50% X 100% X 60% (case 2), and 150% X 120% X 120% (case 3). A bilateral pubic and ischial osteotomy was performed in all 3 cases., Results: All 3 cases developed mild pelvic-limb splaying postoperatively; all resolved within 8 weeks, and 2 cases fully resolved within 14 days. Two of the 3 cases presented with mild stranguria postoperatively, which resolved fully in both cases., Clinical Relevance: Vaginal neoplasia, either malignant or benign, is infrequently reported in cats in the veterinary literature. Bilateral pubic and ischial osteotomy for resection of vaginal masses in cats is a successful surgical approach, offering good exposure for resection of large vaginal masses, with minimal postoperative complications.

G protein-coupled receptors (GPCR) are involved in various physiological and pathophysiological processes. Functional autoantibodies targeting GPCRs have been associated with multiple disease manifestations in this context. Here we summarize and discuss the relevant findings and concepts presented in the biennial International Meeting on autoantibodies targeting GPCRs (the 4th Symposium), held in Lübeck, Germany, 15-16 September 2022. The symposium focused on the current knowledge of these autoantibodies' role in various diseases, such as cardiovascular, renal, infectious (COVID-19), and autoimmune diseases (e.g., systemic sclerosis and systemic lupus erythematosus). Beyond their association with disease phenotypes, intense research related to the mechanistic action of these autoantibodies on immune regulation and pathogenesis has been developed, underscoring the role of autoantibodies targeting GPCRs on disease outcomes and etiopathogenesis. The observation repeatedly highlighted that autoantibodies targeting GPCRs could also be present in healthy individuals, suggesting that anti-GPCR autoantibodies play a physiologic role in modeling the course of diseases. Since numerous therapies targeting GPCRs have been developed, including small molecules and monoclonal antibodies designed for treating cancer, infections, metabolic disorders, or inflammatory conditions, anti-GPCR autoantibodies themselves can serve as therapeutic targets to reduce patients' morbidity and mortality, representing a new area for the development of novel therapeutic interventions., (Copyright © 2023. Published by Elsevier B.V.)

This study measures patient's concordance between clinical reference pathways with survival or cost among a population-based cohort of colon cancer patients applying a continuous measure of concordance. The primary hypothesis is that a higher concordance score with the clinical pathway is significantly associated with longer survival or lower cost. The study informs whether patient's adherence to a defined clinical pathway is beneficial to patients' outcomes or health system. An externally determined clinical pathway for colon cancer was used to identify treatment nodes in colon cancer care. Using observational data up to 2019, the study generated a continuous measure of pathway concordance. The study measured whether incremental improvements in pathway concordance were associated with survival and treatment costs. Concordance between patients' reference pathways and their observed trajectories of care was highly statistically associated with survivorship [hazard ratio: 0.95 (95% confidence interval, CI, 0.95-0.96)], showing that adherence to the clinical pathway was associated with a lower mortality rate. An increase in concordance was statistically significantly associated with a decrease in health system cost. When patients' care followed the clinical pathway, survival outcomes were better and total health system costs were lower in this cohort. This finding creates a compelling case for further research into understanding the barriers to pathway concordance and developing interventions to improve outcomes and help providers implement best practice care where appropriate., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Quality in Health Care.)

Background: Breast cancer is the most common cancer among women, but most cancer registries do not capture recurrences. We estimated the incidence of local, regional, and distant recurrences using administrative data., Methods: Patients diagnosed with stage I-III primary breast cancer in Ontario, Canada from 2013 to 2017 were included. Patients were followed until 31/Dec/2021, death, or a new primary cancer diagnosis. We used hospital administrative data (diagnostic and intervention codes) to identify local recurrence, regional recurrence, and distant metastasis after primary diagnosis. We used logistic regression to explore factors associated with developing a distant metastasis., Results: With a median follow-up 67 months, 5,431/45,857 (11.8%) of patients developed a distant metastasis a median 23 (9, 42) months after diagnosis of the primary tumor. 1086 (2.4%) and 1069 (2.3%) patients developed an isolated regional or a local recurrence, respectively. Patients with distant metastatic disease had a median overall survival of 15.4 months (95% CI 14.4-16.4 months) from the time recurrence/metastasis was identified. In contrast, the median survival for all other patients was not reached. Patients were more likely to develop a distant metastasis if they had more advanced stage, greater comorbidity, and presented with symptoms (p < 0.0001). Trastuzumab halved the risk of recurrence [OR 0.53 (0.45-0.63), p < 0.0001]., Conclusion: Distant metastasis is not a rare outcome for patients diagnosed with breast cancer, translating to an annual incidence of 2132 new cases (17.8% of all breast cancer diagnoses). Overall survival remains high for patients with locoregional recurrences, but was poor following a diagnosis of a distant metastasis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Precise, repeatable genetic access to specific neurons via GAL4/UAS and related methods is a key advantage of Drosophila neuroscience. Neuronal targeting is typically documented using light microscopy of full GAL4 expression patterns, which generally lack the single-cell resolution required for reliable cell type identification. Here, we use stochastic GAL4 labeling with the MultiColor FlpOut approach to generate cellular resolution confocal images at large scale. We are releasing aligned images of 74,000 such adult central nervous systems. An anticipated use of this resource is to bridge the gap between neurons identified by electron or light microscopy. Identifying individual neurons that make up each GAL4 expression pattern improves the prediction of split-GAL4 combinations targeting particular neurons. To this end, we have made the images searchable on the NeuronBridge website. We demonstrate the potential of NeuronBridge to rapidly and effectively identify neuron matches based on morphology across imaging modalities and datasets., Competing Interests: GM, AN, ZD, GD, KF, TG, JH, YH, NI, JJ, LJ, RJ, KL, BM, BY, CZ, JC, CG, HO, KR, RS, YA, GC, BD, EE, JG, MI, DK, WK, LM, RM, SN, GR, GS, TW, OM No competing interests declared, (© 2023, Meissner et al.)

In patients with severe #COVID19, increased levels of autoantibodies against PAR1 were found. These might serve as allosteric agonists of PAR1 on endothelial cells and platelets, and thus might contribute to the pathogenesis of microthrombosis in COVID-19. https://bit.ly/3pqM9Vv., Competing Interests: Conflict of Interest: T. Bahmer reports grants from BMBF (unrestricted research grant for the German Center for Lung Research (DZL) and National Pandemic Cohort Network (NAPKON) – Coordinating Study Site for population-based cohort platform); lecture fees from Novartis, AstraZeneca, and Chiesi; support for attending the American Thoracic Society Conference from Chiesi; and advisory board participation with GlaxoSmithKline, Boehringer Ingelheim, Roche and AstraZeneca, outside the submitted work. D. Frank reports grants from DFG (467267736), BMBF and DZHK; consulting fees and support for attending meetings from Edwards Lifesciences and Medtronic; lecture honoraria from Edwards Lifesciences, Medtronic, Astra Zeneca, Pfizer, BMS, Novartis, Bayer and Abbott; and participation on advisory boards with BMS, Boehringer Ingelheim, Daiichi Sankyo, outside the submitted work. A.Z. Rosenberg reports grants from the NIH (NIDDK and NHLBI) outside the submitted work. CellTrend is owned by K. Schulze-Forster; CellTrend produces ELISA kits for the determination of antibodies against GPCR. G. Riemekasten reports consulting fees from CellTrend GmbH outside the submitted work. S. Schreiber reports consulting fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, Prevention Bio, Protagonist and Falk, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

A key in controlling the SARS-CoV-2 pandemic is the assessment of the immune status of the population. We explored the utility of SARS-CoV-2 virus-like particles (VLPs) as antigens to detect specific humoral immune reactions in an enzyme-linked immunosorbent assay (ELISA). For this purpose, SARS-CoV-2 VLPs were produced from an engineered cell line and characterized by Western blot, ELISA, and nanoparticle tracking analysis. Subsequently, we collected 42 serum samples from before the pandemic (2014), 89 samples from healthy subjects, and 38 samples from vaccinated subjects. Seventeen samples were collected less than three weeks after infection, and forty-four samples more than three weeks after infection. All serum samples were characterized for their reactivity with VLPs and the SARS-CoV-2 N- and S-protein. Finally, we compared the performance of the VLP-based ELISA with a certified in vitro diagnostic device (IVD). In the applied set of samples, we determined a sensitivity of 95.5% and a specificity of 100% for the certified IVD. There were seven samples with an uncertain outcome. Our VLP-ELISA demonstrated a superior performance, with a sensitivity of 97.5%, a specificity of 100%, and only three uncertain outcomes. This result warrants further research to develop a certified IVD based on SARS-CoV-2 VLPs as an antigen.

Clinical pathways are standardized processes that outline the steps required for managing a specific disease. However, patient pathways often deviate from clinical pathways. Measuring the concordance of patient pathways to clinical pathways is important for health system monitoring and informing quality improvement initiatives. In this paper, we develop an inverse optimization-based approach to measuring pathway concordance in breast cancer, a complex disease. We capture this complexity in a hierarchical network that models the patient's journey through the health system. A novel inverse shortest path model is formulated and solved on this hierarchical network to estimate arc costs, which are used to form a concordance metric to measure the distance between patient pathways and shortest paths (i.e., clinical pathways). Using real breast cancer patient data from Ontario, Canada, we demonstrate that our concordance metric has a statistically significant association with survival for all breast cancer patient subgroups. We also use it to quantify the extent of patient pathway discordances across all subgroups, finding that patients undertaking additional clinical activities constitute the primary driver of discordance in the population., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Older adults with cancer may not receive the same opportunities for treatment as younger patients. In this retrospective population-based cohort study, we explored whether age was an independent predictor of receiving specialist consultation and treatment., Methods: Patients age 45-99 were identified from the Ontario Cancer Registry having a primary solid tumor diagnosed between 01/Jan/2010 and 31/Dec/2019. We used logistic regression adjusted sociodemographic and clinical characteristics to compare the likelihood of consultation or receipt of treatment using linear splines at critical ages of 65, 80, and 90 years., Results: A total 168,232 (42%), 165,205 (41%), 57,360 (14%), and 7810 (2%) patients were diagnosed age 45-64, 65-79, 80-89, and 90-99, respectively. The likelihood of surgical consultation decreased as patients reached 65 years [adjusted odds ratio (aOR) 0.86 (0.84-0.89)], which decreased further among octogenarians [aOR 0.63 (0.59-0.67)]. Similar results were observed for consultation with a medical oncologist and radiation oncologist. Receipt of surgery also decreased with age. Three-month post-operative mortality was higher among older patients [aRR 1.38 (1.26-1.50) per 10 years, p < 0.0001], an effect that remained similar as patients reached age 65 + years of age (p = 0.09 for change). For stage I patients, 3-month post-operative survival was high across all age groups, ranging from 99.8% in 45-64 year-olds, 99.4% in 65-79 year-olds, and 98.1% among octogenarians and nonagenarians (lung, colorectal, breast, cervical cancer patients)., Conclusion: Older patients were less likely to have specialist consultations. More comprehensive data collection on clinical factors and referral patterns is needed to improve care for elderly cancer patients., Competing Interests: Conflicts of interest Dr. Ines B. Menjak has some consultancy/honoraria for companies related to lung cancer: Amgen, Astrazeneca. Honoraria for speaking from BMS and Astrazeneca. Education funding from Takeda, Astrazeneca, BMS. All other coauthors have no conflicts to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS., Competing Interests: The authors declare that HH and KS-F are managing directors of CellTrend. CellTrend holds together with Charité a patent for the diagnostic use of AABs against ADRB2. CS has a consulting agreement with CellTrend. FP reports grants from the Guthy Jackson Charitable Foundation, during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor MD declared a past co-authorship with the author YS., (Copyright © 2022 Sotzny, Filgueiras, Kedor, Freitag, Wittke, Bauer, Sepúlveda, Mathias da Fonseca, Baiocchi, Marques, Kim, Lange, Plaça, Luebber, Paulus, De Vito, Jurisica, Schulze-Forster, Paul, Bellmann-Strobl, Rust, Hoppmann, Shoenfeld, Riemekasten, Heidecke, Cabral-Marques and Scheibenbogen.)

Objective: To determine contributions and functions of autoantibodies (Abs) directed to the angiotensin receptor type 1 (AT1R), which are suggested to be involved in the pathogenesis of AT1R Abs-related diseases such as systemic sclerosis (SSc)., Methods: C57BL/6J mice were immunised with membrane-embedded human AT1R or empty membrane as control. Mice deficient for CD4 + or CD8 + T cells and B cells were immunised with membrane-embedded AT1R or an AT1R peptide proposed to be a dominant T cell epitope. A monoclonal (m)AT1R Ab was generated by hybridoma technique and transferred into C57BL/6J and AT1Ra/b knockout mice. The induced phenotype was examined by histology, immunohistochemistry, immunofluorescence, apoptosis assay and ELISA. In vitro, Abs responses towards AT1R were measured in cells of different origins and species., Results: AT1R-immunised mice developed perivascular skin and lung inflammation, lymphocytic alveolitis, weak lung endothelial apoptosis and skin fibrosis accompanied by Smad2/3 signalling, not present in controls or mice deficient for CD4 + T and B cells. The AT1R peptide 149-172 provoked lung inflammation. Application of the mAT1R Ab induced skin and lung inflammation, not observed in AT1Ra/b knockout mice. In vitro, AT1R Abs activated rat cardiomyocytes and human monocytes, enhanced angiotensin II-mediated AT1R activation in AT1R-transfected HEK293 cells via AT1R binding and mAT1R Ab-activated monocytes mediated the induction of profibrotic markers in dermal fibroblasts., Conclusion: Our immunisation strategy successfully induced AT1R Abs, contributing to inflammation and, possibly, to fibrosis via activation of AT1R. Therefore, AT1R Abs are valuable targets for future therapies of SSc and other AT1R Ab-related diseases., Competing Interests: Competing interests: HH is the owner and GR is an advisor of the company CellTrend GmbH, which produced the ME and the tests for the detection of AT1R Abs. IS and GW are shareholders of Berlin Cures GmbH, where the rat cardiomyocyte assay was performed., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Breast cancer recurrence is an important outcome for patients and healthcare systems, but it is not routinely reported in cancer registries. We developed an algorithm to identify patients who experienced recurrence or a second case of primary breast cancer (combined as a "second breast cancer event") using administrative data from the population of Ontario, Canada. A retrospective cohort study design was used including patients diagnosed with stage 0-III breast cancer in the Ontario Cancer Registry between 1 January 2009 and 31 December 2012 and alive six months post-diagnosis. We applied the algorithm to healthcare utilization data from six months post-diagnosis until death or 31 December 2013, whichever came first. We validated the algorithm's diagnostic accuracy against a manual patient record review ( n = 2245 patients). The algorithm had a sensitivity of 85%, a specificity of 94%, a positive predictive value of 67%, a negative predictive value of 98%, an accuracy of 93%, a kappa value of 71%, and a prevalence-adjusted bias-adjusted kappa value of 85%. The second breast cancer event rate was 16.5% according to the algorithm and 13.0% according to manual review. Our algorithm's performance was comparable to previously published algorithms and is sufficient for healthcare system monitoring. Administrative data from a population can, therefore, be interpreted using new methods to identify new outcome measures.

Clinical cancer pathways help standardize healthcare delivery to optimize patient outcomes and health system costs. However, population-level measurement of concordance between standardized pathways and actual care received is lacking. Two measures of pathway concordance were developed for a simplified colon cancer pathway map for Stage II-III colon cancer patients in Ontario, Canada: a cumulative count of concordant events (CCCE) and the Levenshtein algorithm. Associations of concordance with patient survival were estimated using Cox proportional hazards models adjusted for patient characteristics and time-dependent cancer-related activities. Models were compared and the impact of including concordance scores was quantified using the likelihood ratio chi-squared test. The ability of the measures to discriminate between survivors and decedents was compared using the C-index. Normalized concordance scores were significantly associated with patient survival in models for cancer stage-a 10% increase in concordance for Stage II patients resulted in a CCCE score adjusted hazard ratio (aHR) of death of 0.93, 95% CI 0.88-0.98 and a Levenshtein score aHR of 0.64, 95% CI 0.60-0.67. A similar relationship was found for Stage III patients-a 10% increase in concordance resulted in a CCCE aHR of 0.85, 95% CI 0.81-0.88 and a Levenshtein aHR of 0.78, 95% CI, 0.74-0.81. Pathway concordance can be used as a tool for health systems to monitor deviations from established clinical pathways. The Levenshtein score better characterized differences between actual care and clinical pathways in a population, was more strongly associated with survival and demonstrated better patient discrimination., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

We propose Rhythmic Relating for autism: a system of supports for friends, therapists, parents, and educators; a system which aims to augment bidirectional communication and complement existing therapeutic approaches. We begin by summarizing the developmental significance of social timing and the social-motor-synchrony challenges observed in early autism. Meta-analyses conclude the early primacy of such challenges, yet cite the lack of focused therapies. We identify core relational parameters in support of social-motor-synchrony and systematize these using the communicative musicality constructs: pulse ; quality ; and narrative . Rhythmic Relating aims to augment the clarity, contiguity, and pulse-beat of spontaneous behavior by recruiting rhythmic supports (cues, accents, turbulence) and relatable vitality; facilitating the predictive flow and just-ahead-in-time planning needed for good-enough social timing. From here, we describe possibilities for playful therapeutic interaction, small-step co-regulation, and layered sensorimotor integration. Lastly, we include several clinical case examples demonstrating the use of Rhythmic Relating within four different therapeutic approaches (Dance Movement Therapy, Improvisational Music Therapy, Play Therapy, and Musical Interaction Therapy). These clinical case examples are introduced here and several more are included in the Supplementary Material (Examples of Rhythmic Relating in Practice). A suite of pilot intervention studies is proposed to assess the efficacy of combining Rhythmic Relating with different therapeutic approaches in playful work with individuals with autism. Further experimental hypotheses are outlined, designed to clarify the significance of certain key features of the Rhythmic Relating approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daniel, Wimpory, Delafield-Butt, Malloch, Holck, Geretsegger, Tortora, Osborne, Schögler, Koch, Elias-Masiques, Howorth, Dunbar, Swan, Rochat, Schlochtermeier, Forster and Amos.)

Background: In Ontario, patients with breast cancer typically receive their diagnoses through the Ontario Breast Screening Program (OBSP) after an abnormal screen, through screening initiated by a primary care provider or other referring physician, or through follow-up of symptoms by patients' primary care providers. We sought to explore the association of the route to diagnosis (screening within or outside the OBSP or via symptomatic presentation) with use of OBSP-affiliated breast assessment sites (O-BAS), wait times until diagnosis or treatment, health care use and overall survival for patients with breast cancer., Methods: In this retrospective cohort study, we used the Ontario Cancer Registry to identify adults (aged 18-105 yr) who received a diagnosis of breast cancer from 2013 to 2017. We excluded patients if they were not Ontario residents or had missing age or sex, or who died before diagnosis. We used logistic regression to evaluate factors associated with categorical variables (whether patients were or were not referred to an OBAS, whether patients were screened or symptomatic) and Cox proportional hazards regression to identify factors associated with all-cause mortality., Results: Of 51 460 patients with breast cancer, 42 598 (83%) received their diagnoses at an O-BAS. Patients whose cancer was first detected through the OBSP were more likely than symptomatic patients to be given a diagnosis at an O-BAS (adjusted odds ratio 1.68, 95% confidence interval [CI] 1.57 to 1.80). Patients screened by the OBSP were given their diagnoses 1 month earlier than symptomatic patients, but diagnosis at an O-BAS did not affect the time until either diagnosis or treatment. Patients referred to an O-BAS had significantly better overall survival than those who were not referred (adjusted hazard ratio 0.73, 95% CI 0.66 to 0.80)., Interpretation: Patients screened through the OBSP were given their diagnoses earlier than symptomatic patients and were more likely to be referred to an O-BAS, which was associated with better survival. Our findings suggest that individuals with signs and symptoms of breast cancer would benefit from similar referral processes, oversight and standards to those used by the OBSP., Competing Interests: Competing interests: Steven Habbous, Esha Homenauth, Andriana Barisic, Sharmilaa Kandasamy, Vicky Majpruz, Katharina Forster, Marta Yurcan, Anna Chiarelli, Claire Holloway and Andrea Eisen are employees or consultants of Ontario Health (Cancer Care Ontario), which funds the Ontario Breast Screening Program. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Purpose: This literature review examines the provision of an education on pharmacologically active complementary and alternative medicines (CAMs), to people with cancer, their carers and oncology health professionals., Methods: A search of the published literature between 2000 and 2020, in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, was conducted. The search retrieved 1121 studies, 1080 were excluded based on their title or abstract and 26 articles were excluded based on their text. One article was retrieved from the reference lists of the included articles and in total fifteen studies met the inclusion criteria. This review utilised Medical Education Research Quality Instrument (MERSQI) to evaluate the quality of the included studies. Four key outcomes were utilised for analysis and recommendations for future education and/or research were generated. The recommendations were graded according to the Strength of Recommendation Taxonomy (SORT)., Results: This review consistently found that people with cancer, their carers and oncology health professionals derived benefit from a pharmacologically active CAM education and recommends that this population receives one. Conversely, the review found many education formats utilised and no consensus on the most successful methods., Conclusion: Future research should examine who a CAM education should be delivered to, what type of delivery platform is most accessible and useful, and the features of the education that most increase CAM knowledge. The popularity of CAMs amongst people with cancer and the potential dangers associated with their use necessitates further research into how best to communicate CAMs to this population., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity., (© 2022. The Author(s).)

The role of anti-HLA antibodies in transplant rejection is well-known but the injury associated with non-HLA antibodies is now widely discussed. The aim of our study was to investigate a role of non-HLA antibodies in hand allografts rejection. The study was performed on six patients after hand transplantation. The control group consisted of: 12 kidney transplant recipients and 12 healthy volunteers. The following non-HLA antibodies were tested: antibody against angiotensin II type 1 receptor (AT1R-Ab), antibody against endothelin-1 type-A-receptor (ETAR-Ab), antibody against protease-activated receptor 1 (PAR-1-Ab) and anti-VEGF-A antibody (VEGF-A-Ab). Chosen proinflammatory cytokines (Il-1, IL-6, IFNγ) were used to evaluate the post-transplant humoral response. Laboratory markers of endothelial activation (VEGF, sICAM, vWF) were used to assess potential vasculopathy. The patient with the highest number of acute rejections had both positive non-HLA antibodies: AT1R-Ab and ETAR-Ab. The same patient had the highest VEGF-A-Ab and very high PAR1-Ab. All patients after hand transplantation had high levels of laboratory markers of endothelial activation. The existence of non-HLA antibodies together with multiple acute rejections observed in patient after hand transplantation should stimulate to look for potential role of non-HLA antibodies in humoral injury in vascular composite allotransplantation.