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Background:The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. Methods:In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. Findings:156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30–44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3(IQR 349–828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2–9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. Interpretation:Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital.

PURPOSE: Financial reimbursement programs (FRPs) offset out-of-pocket (OOP) expenses from therapeutic clinical trial (TCT) participation. The study explores patients' experience in TCTs after enrollment in a FRP at two academic medical centers, including barriers and opportunities to improve trial participation. METHODS: From May 2019 to January 2020, adults diagnosed with cancer and eligible for TCTs and FRP were recruited from the Improving Patient Access to Cancer Clinical Trials randomized trial at the University of California San Francisco and University of Southern California. Patients with income ≤ 700% of national poverty guidelines were eligible. Semistructured interviews were conducted in patients' preferred language. Qualitative analysis was performed by site and preferred language by two independent coders. RESULTS: Of 65 trial patients, 53 participated (38%, University of California San Francisco; 62%, USC). The median age was 59 (IQR, 46-65) years, and 58% were female. Nearly half (49%) identified as Latinx/Hispanic compared with 32% non-Hispanic White, 10% Asian, 4% Black, 1% Native American, and 4% Others. A third were non-English speakers, 42% had college education or more, and 55% were retired/unemployed. Most common malignancies were gastrointestinal (42%), breast (19%), and genitourinary (13%), and 66% had metastatic disease. Patients experienced long travel time (1-4.5 hours) among 57% and financial toxicity from OOP costs (68%). High acceptability of the FRP was reported (81%). Although 30% of patients reported willingness to discuss finances of cancer treatment/trial with physicians, majority (87%) preferred discussion with social workers or TCT staff. Proposed modifications to TCTs included decentralization, recruitment strategies, voucher structure, and established rates for OOP expenses. CONCLUSION: Patients' experience with TCTs reveal financial and logistical stressors that may be lessened by the Improving Patient Access to Cancer Clinical Trial reimbursement program. FRPs may address inequities in clinical trial access among low-income and diverse populations.

Purpose: The main aim of this study was to examine and analyse the body composition of young soccer players across different age groups. Methods: A cross-sectional study was carried out among 126 young soccer players divided into age categories: U15 – 53 players (age=14.68±0.47); U17 – 51 players (age=16.47±0.50); U19 – 22 players (age=18.05±0.38). The subjects’ height was measured using an anthropometer, while their body composition was measured using the TANITA BC-420MA digital scale. Results: On average, soccer players in the U15 group had significantly lower body height, weight, body mass index and fat free mass than U17 and U19 players, but had a higher percentage of body fat (p < 0.05). In addition to the percent of body fat mass, which tends to significantly decrease with age, the results also demonstrate significant non-linear increases in body height, weight, and lean body composition concurrent with the players’ ages. Conclusion: These results indicate that younger soccer players have lower absolute values of morphological characteristics compared to senior players.

PurposeFollett's relational process theory illuminates key aspects of interdependence among organizations in the field of education that are essential to fostering capacities for interorganizational resilience. The article argues for the necessity of developing mutualism in systems of education as essential preparation for times of instability and crisis, as demonstrated through recent experiences with the COVID-19 pandemic.Design/methodology/approachThis article provides an introduction to the relational process theory of Mary Parker Follett, a foundational theorist of organizing and administration. This theoretical review uses worked examples drawn from a collaborative, continuous improvement partnership focused on educational leadership preparation and development.FindingsThe author identifies four aspects of Follett's theory that connect most directly to collaborative, continuous improvement partnerships. These include mutualism as circular response, coactive power, embrace of difference through constructive conflict and integrating experience through learning. The article discusses how these offer an integrated framework of foundational concepts for nurturing and sustaining educational systems capable of adaptive change in the face of complex challenges.Originality/valueFollett's relational process theory offers a perspective on partnering as a dynamic and evolving constellation of interactions and activity. The implications of Follett's core ideas for education resonate beyond improvement partnerships and offer guidance at all levels of educational systems seeking to orient towards an evolutionary logic.

The COVID-19 pandemic posed significant risk to the health of cancer patients, compromised standard cancer care and interrupted clinical cancer trials, prompting dramatic streamlining of services. From this health crisis has emerged the opportunity to carry forward an unexpected legacy of positive reforms to clinical cancer research, where conventionally convoluted approvals processes, inefficient trial design, procedures and data gathering could benefit from the lessons in rationalisation learned during the pandemic.

Purpose: Many children with communication disorders (CDs) experience lengthy gaps between parental reporting of concerns and formal identification by professionals. This means that children with CDs are denied access to early interventions that may help support the development of communication skills and prevent possible negative sequelae associated with long-term outcomes. This may be due, in part, to the lack of assessment instruments available for children younger than 3 years of age. This study therefore reports on promising preliminary data from a novel set of valid dynamic assessment (DA) measures designed for infants. Method: We recruited 53 low-risk children and two groups of children considered to be at high risk for CDs ( n = 17, social high risk, and n = 22, language high risk) due to family members with language and social communication difficulties. The children were between 1 and 2 years of age and were assessed using a battery of five DA tasks related to receptive vocabulary, motor imitation, response to joint attention, turn taking, and social requesting. A set of standardized measures were also used. Results: The DA tasks showed high levels of interrater reliability and relationships with age across a cross-sectional sample of children from the low-risk group. Three tasks showed moderate to strong correlations with standardized measures taken at the same age, with particularly strong correlations between the DA of receptive vocabulary and other receptive language measures. The DA of receptive vocabulary was also the only task to discriminate between the three risk groups, with the social high risk group scoring lower. Conclusions: These results provide preliminary information about early DA tasks, forming the basis for further research into their utility. DA tasks might eventually facilitate the development of new methods for detecting CDs in very young children, allowing earlier intervention and support.

Background: Disruption of circadian processes has been linked to cancer initiation, progression, metastasis, resistance, and mortality. Clock proteins are an emerging target for therapy in breast cancer. Circadian rhythms are controlled by a network of transcription/translation feedback loops primarily driven by BMAL and CLOCK and the transcriptional repressors period (PER1-3) and cryptochrome (CRY1-2). We investigated the molecular and clinical associations of clock genes in breast cancer. Methods: A total of 9563 breast tumors underwent molecular profiling (Caris Life Sciences). Analyses included next-generation sequencing of DNA (592 genes-NextSeq, WES-NovaSeq) and RNA (NovaSeq). Clock gene Score (CS) was determined using expression of clock pathway gene Z scores (positives of BMAL, CLOCK and negatives of PER1/2 and CRY1/2) and then stratified into quartiles. xCell was used to quantify immune cell infiltration in the tumor microenvironment (TME). ER/PR was tested by IHC and HER2 was tested by either IHC or CISH. Significance was determined as P values adjusted for multiple comparison (Q) of < 0.05. Real-world survival information was obtained from insurance claims data and was calculated from either tissue collection to last contact or time on treatment (TOT); comparison was done by Kaplan-Meier test. Results: TNBC had the highest median CS score, while HR+/HER2- had the lowest CS (0.96 vs 0.26 q Citation Format: Priya Jayachandran, Yasmine Baca, Joanne Xiu, Yuanzhong Pan, Phil Walker, Francesca Battaglin, Hiroyuki Arai, Moh’d Khushman, Janice Lu, Darcy Spicer, Shannon Mumenthaler, Richard Goldberg, Benjamin Weinberg, Emil Lou, Michael Hall, Arielle L. Heeke, W. Michael Korn, Steve A. Kay, Heinz-Josef Lenz, Evanthia T. Roussos Torres. Clock Genes in Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-06.

What is this summary about? In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in The New England Journal of Medicine in 2022. The goal of CheckMate 816 was to find out if nivolumab, an immunotherapy that activates a person's immune system (the body's natural defense system) to fight cancer, plus chemotherapy works better than chemotherapy alone when given before surgery in people with non–small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC). What happened in the study? Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive nivolumab plus chemotherapy, and 179 people were randomly assigned to receive chemotherapy alone. The researchers assessed whether people who received nivolumab plus chemotherapy lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe. What were the results? Researchers found that people who took nivolumab plus chemotherapy lived longer without the cancer getting worse or coming back compared with those who took chemotherapy alone. More people in the nivolumab plus chemotherapy group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took nivolumab plus chemotherapy instead of chemotherapy alone had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries. Adding nivolumab to chemotherapy did not lead to an increase in the rate of side effects compared with chemotherapy alone, and side effects were generally mild and manageable. What do the results of the study mean? Results from CheckMate 816 support the benefit of using nivolumab plus chemotherapy before surgery for people with resectable NSCLC. Clinical Trial Registration: NCT02998528 ( ClinicalTrials.gov )

Background: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee. Purpose: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis. Results: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, −1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation ( P = .03; 6.4 points in favor of ACI; 95% CI, −0.4 to 13.1). More participants experienced a serious adverse event with ACI ( P = .02). Conclusion: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI. Registration: International Standard Randomised Controlled Trial Number: 48911177

Exploring the relationship between various neurotransmitters and breast cancer cell growth has revealed their likely centrality to improving breast cancer treatment. Neurotransmitters play a key role in breast cancer biology through their effects on the cell cycle, epithelial mesenchymal transition, angiogenesis, inflammation, the tumor microenvironment and other pathways. Neurotransmitters and their receptors are vital to the initiation, progression and drug resistance of cancer and progress in our biological understanding may point the way to lower-cost and lower-risk antitumor therapeutic strategies. This review discusses multiple neurotransmitters in the context of breast cancer. It also discusses risk factors, repurposing of pharmaceuticals impacting neurotransmitter pathways, and the opportunity for better integrated models that encompass exercise, the intestinal microbiome, and other non-pharmacologic considerations. Neurotransmitters’ role in breast cancer should no longer be ignored; it may appear to complicate the molecular picture but the ubiquity of neurotransmitters and their wide-ranging impacts provide an organizing framework upon which further understanding and progress against breast cancer can be based.

Microphthalmia transcription factor (MITF) regulates melanocyte development and is the "lineage-specific survival" oncogene of melanoma. MITF is essential for melanoma initiation, progression, and relapse and has been considered an important therapeutic target; however, direct inhibition of MITF through small molecules is considered impossible, due to the absence of a ligand-binding pocket for drug design. Here, our structural analyses show that the structure of MITF is hyperdynamic because of its out-of-register leucine zipper with a 3-residue insertion. The dynamic MITF is highly vulnerable to dimer-disrupting mutations, as we observed that MITF loss-of-function mutations in human Waardenburg syndrome type 2 A are frequently located on the dimer interface and disrupt the dimer forming ability accordingly. These observations suggest a unique opportunity to inhibit MITF with small molecules capable of disrupting the MITF dimer. From a high throughput screening against 654,650 compounds, we discovered compound TT-012, which specifically binds to dynamic MITF and destroys the latter's dimer formation and DNA-binding ability. Using chromatin immunoprecipitation assay and RNA sequencing, we showed that TT-012 inhibits the transcriptional activity of MITF in B16F10 melanoma cells. In addition, TT-012 inhibits the growth of high-MITF melanoma cells, and inhibits the tumor growth and metastasis with tolerable toxicity to liver and immune cells in animal models. Together, this study demonstrates a unique hyperdynamic dimer interface in melanoma oncoprotein MITF, and reveals a novel approach to therapeutically suppress MITF activity.

Protein N-termini provide uniquely reactive motifs for single site protein modification. A comprehensive comparative study of the most promising modification reagents is performed, finding that there is no ‘one size fits all’ approach.

Peptide retention time (RT) prediction algorithms are tools to study and identify the physicochemical properties that drive the peptide-sorbent interaction. Traditional RT algorithms use multiple linear regression with manually curated parameters to determine the degree of direct contribution for each parameter and improvements to RT prediction accuracies relied on superior feature engineering. Deep learning led to a significant increase in RT prediction accuracy and automated feature engineering via chaining multiple learning modules. However, the significance and the identity of these extracted variables are not well understood due to the inherent complexity when interpreting “relationships-of-relationships” found in deep learning variables. To achieve both accuracy and interpretability simultaneously, we isolated individual modules used in deep learning and the isolated modules are the shallow learners employed for RT prediction in this work. Using a shallow convolutional neural network (CNN) and gated recurrent unit (GRU), we find that the spatial features obtained via the CNN correlate with real-world physicochemical properties namely cross-collisional sections (CCS) and variations of assessable surface area (ASA). Furthermore, we determined that the discovered parameters are “micro-coefficients” that contribute to the “macro-coefficient” – hydrophobicity. Manually embedding CCS and the variations of ASA to the GRU model yielded an R2 = 0.981 using only 525 variables and can represent 88% of the ∼110,000 tryptic peptides used in our dataset. This work highlights the feature discovery process of our shallow learners can achieve beyond traditional RT models in performance and have better interpretability when compared with the deep learning RT algorithms found in the literature.

Background and Study Aim. Musculoskeletal disorders (MSD) are incredibly common and are often related to work load. For any occupational or public health intervention, injury prevention is preferred to injury treatment. Occupational health and injury prevention research has the potential to help mitigate MSD in the workplace. The aim of this study was to determine how the work demands of ski instructors may affect the health of their musculoskeletal system. Material and Methods. A cross-sectional study involved the participation of 87 ski instructors (age = 34.61 ±10.67) in Bosnia and Herzegovina (ATUS in Bosnia and Herzegovina). Observed variables were the prevalence of MSD measured using a modified Nordic questionnaire about injuries during the previous ski season (neck, shoulders, elbows, wrist, upper back, lower back, one or both hips, one or both knees, and ankle). Means and standard deviations for each of the variables were calculated, and differences between genders were examined using an independent sample t-test. Results. Prevalence of MSDs in ski instructors was most common in neck (13.8%), shoulders (12.6%), elbows (4.6%), wrist (9.2%), upper back (10.3%), lower back (46.0%), one or both hips (9.2%), one or both knees (29.9%), and ankle (9.2%). The results showed statistically significant differences in MSD between genders in the neck (p=.034); shoulders (p=.017); upper back (p=.027); one or both knees (p=.003) and in the ankle joint (p=.011). Conclusions. MSD’s are common in ski instructors, especially in the low back and knees of female employees. Future research or injury prevention programs would benefit these populations., Передумови та мета дослідження. Захворювання опорно-рухового апарату (ЗОРА) надзвичайно поширені та часто пов’язані з робочим навантаженням. Для будь-якого втручання на виробництві чи охорони здоров’я запобігання травматизму є кращим, ніж лікування травм. Дослідження з питань гігієни праці та запобігання травматизму можуть допомогти пом’якшитиЗОРА на робочому місці. Метою цього дослідження було визначити, як робочі вимоги лижних інструкторів можуть вплинути на здоров’я їх опорно-рухового апарату.Матеріал і методи. Перехресне дослідження включало участь 87 лижних інструкторів (вік = 34,61 ±10,67) у Боснії та Герцеговині (ATUS у Боснії та Герцеговині). Перемінними, що спостерігалися, були поширеністьЗОРА, виміряна за допомогою модифікованого скандинавського опитувальника щодо травм під час попереднього лижного сезону (шиї, плечей, ліктів, зап’ястя, верхньої частини спини, нижньої частини спини, одного або обох стегон, одного або обох колін і щиколотки). Було розраховано середні значення та стандартні відхилення для кожної зі змінних, а відмінності між статями досліджено за допомогою t-критерію незалежної вибірки.Результати. ПоширеністьЗОРА у лижних інструкторів була найбільш поширеною в шиї (13,8%), плечах (12,6%), ліктях (4,6%), зап’ястях (9,2%), верхній частині спини (10,3%), нижній частині спини (46,0%), одному або обидва стегна (9,2%), одне або обидва коліна (29,9%) і щиколотки (9,2%). Результати показали статистично значущі відмінності вЗОРА між статями в області шиї (p=0,034); плечі (p=0,017); верхня частина спини (p=0,027); одного або обох колін (p=0,003) і в гомілковостопному суглобі (p=0,011).Висновки.ЗОРА поширені у лижних інструкторів, особливо в нижній частині спини та колінах працівників. Майбутні дослідження або програми запобігання травмам принесуть користь цим групам населення.

Genetic datasets lack diversity and include very few data from Indigenous populations. Research models based on equitable partnership have the potential to increase Indigenous participation and have led to successful collaborations. We report here on a meeting of participants in four Indigenous community-university partnerships pursuing research on precision medicine. The goal of the meeting was to define values and practices that strengthen opportunities for genetic research. The group accorded the highest priority to developing trusting relationships, ensuring respect for Indigenous community authority, and pursuing research that has the potential to lead to community benefit. Supporting priorities included incorporation of Indigenous expertise in research planning, transparent communication, and development of community capacity, including capacity to participate in formulating research questions, informing research methodology, and leading research projects. Participants also noted the importance of attention to social determinants of health so that genetic contributors to health are evaluated in the appropriate context.

Albizia, a diverse tree genus, occupies monsoonal warm, humid rain forests in tropical and subtropical regions. We recovered a well-preserved compound fossil leaf and two fossil fruits of Albizia (Fabaceae) from the latest Neogene (Rajdanda Formation: Pliocene) sediments of Jharkhand of Chotanagpur Plateau, eastern India. On the basis of the architectural features of the fossil leaf, a new species is established as A. mahuadanrensis Hazra, Hazra and Khan, n. sp., characterised by a bipinnate, compound leaf having a rachis bearing opposite, asymmetrically ovate to sub-rhomboid leaflets, pulvinus on leaflet petiolule and brochiodromous secondary veins. Based on both morphological and anatomical characters of the fossil fruits, A. palaeoprocera Hazra, Hazra and Khan, n. sp. is erected, characterised by flattened to broadly linear shaped, wingless fruits; ovate-elliptic shaped seed chambers having ellipsoidal seeds in one series; irregularly polygonal to rectangular epidermal cells with oblique end walls and randomly oriented, scattered, paracytic stomata. Analysis of Albizia fossil occurrences indicates that the legume taxon was common in Neogene forests of India and elsewhere. The present-day distribution of the closely affiliated modern species of the fossil taxa indicates a warm and humid tropical environment during the time of deposition. We also review the biogeographic history of Albizia in India and other Asian countries.

The problem Medical students graduate underprepared for postgraduate medical training despite years of classroom and clinical training. In this article, a medical student shares her personal perspectives on three factors contributing to this problem in undergraduate medical education: students’ peripheral roles in the clinical environment impede learning, students receive inadequate feedback, and assessments do not measure desired learning outcomes. A solution The authors describe how using entrustable professional activities (EPAs) could address these issues and promote students’ clinical engagement by clarifying their roles, providing them with frequent and actionable feedback, and aligning their assessments with authentic work. These factors combined with grading schemes rewarding improvement could contribute to a growth mindset that reprioritizes clinical skill acquisition. The authors explore how medical schools have begun implementing the EPA framework, highlight insights from these efforts, and describe barriers that must be addressed. The future Incorporating EPAs into medical school curricula could better prepare students for postgraduate training while also alleviating issues that contribute to student burnout by defining students’ roles, improving feedback, and aligning assessments with desired learning outcomes.

Background Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker. Methods We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay. Results Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the tumour. sFRα levels decreased alongside concurrent tumour burden in patients receiving standard therapies. High concentrations of sFRα partly reduced anti-FRα antibody tumour cell killing, an effect overcome by increased antibody doses. Conclusions sFRα may present a non-invasive marker for tumour FRα expression, with the potential for monitoring patient response to treatment. Larger, prospective studies should evaluate FRα for assessing disease burden and response to systemic treatments.

Background: We have recently reported a 35% drop in new lung cancer diagnoses and a 64% drop in lung cancer surgeries during the first year of the pandemic. Methods: The target population was divided into three cohorts: pre-COVID-19 (2019), first year of COVID-19 (2020), and second year of COVID-19 (2021). Results: The number of new lung cancer diagnoses during the second year of the pandemic increased by 75%, with more than 50% being in the advanced/metastatic stage. There was a significant increase in cases with multiple extrathoracic sites of metastases during the pandemic. During the first year of the pandemic, significantly more patients were treated with radiosurgery compared to the pre-COVID-19 year. During the second year, the number of radiosurgery and surgical cases returned to pre-COVID-19 levels. No significant changes were observed in systemic chemotherapy and targeted therapy. No statistical difference was identified in the mean wait time for diagnosis and treatment during the three years of observation. However, the wait time for surgery was prolonged compared to the pre-COVID-19 cohort. Conclusions: The significant drop in new diagnoses of lung cancer during the first year of the pandemic was followed by an almost two-fold increase in the second year, with the increased rate of metastatic disease with multiple extra-thoracic site metastases. Limited access to surgery resulted in the more frequent use of radiosurgery.

Prehabilitation is well established for improving outcomes in cancer surgery. Combining prehabilitation with neoadjuvant treatments may provide an opportunity to rapidly initiate cancer-directed therapy while improving functional status in preparation for local consolidation. In this proof-of-concept study, we analyzed non-small-cell lung cancer patients who underwent simultaneous prehabilitation and neoadjuvant therapy.We retrospectively analyzed all patients who underwent neoadjuvant treatment for non-small-cell lung cancer followed by curative intent surgery between 2015 and 2021. Patients who were screened for the prehabilitation program were identified. The screening included assessment of physical performance, nutritional status, and signs of anxiety and depression.We identified a total of 141 patients who underwent neoadjuvant therapy. Twenty patients were screened to undergo a prehabilitation program. Four patients did not complete the exercise program (1 surgical intervention too soon, 1 drop-out after the first session, and 2 patients were deemed fit without intervention). The postoperative median length of stay was 2 days (range 1-18). Patients improved their 6-minute-walk test despite undergoing neoadjuvant treatment by a mean of 33 meters (± 50, P = .1). Self-reported functional status (DASI) showed significant improvement by a mean of 10 points (± 11, P = .03), and HADS-anxiety-score was significantly reduced after the prehabilitation program by a mean of 1.5 points (± 1, P = .005).Neoadjuvant prehabilitation therapy is feasible and associated with encouraging results. The performance of all measures remains a logistic challenge. With multimodal strategies for lung cancer treatment becoming key to optimal outcomes, neoadjuvant prehabilitation therapy is a concept worthy of prospective multi-center evaluation.

New drugs that precisely target the immune mechanisms critical for cytotoxic T lymphocyte (CTL) and natural killer (NK) cell driven pathologies are desperately needed. In this perspective, we explore the cytolytic protein perforin as a target for therapeutic intervention. Perforin plays an indispensable role in CTL/NK killing and controls a range of immune pathologies, while being encoded by a single copy gene with no redundancy of function. An immunosuppressant targeting this protein would provide the first-ever therapy focused specifically on one of the principal cell death pathways contributing to allotransplant rejection and underpinning multiple autoimmune and postinfectious diseases. No drugs that selectively block perforin-dependent cell death are currently in clinical use, so this perspective will review published novel small molecule inhibitors, concluding with

Background: A major cost to healthcare delivery in Ontario is hospital visits. Innovations averting unnecessary hospitalizations and emergency department (ED) visits are, therefore, of paramount importance for system sustainability. A multidisciplinary clinic called the London Health Sciences Center Urgent COVID Care Clinic (LUC3) pioneered acute care for community-based COVID19-positive patients via telephone assess-ments paired with in-home pulse oximetry.Objectives: To identify and analyze costs and savings associated with LUC3.Methods: A retrospective observational analysis of all COVID19-positive patients referred to LUC3 between April 23, 2020 and Aug 31, 2020. We compared the cost of operating LUC3 with savings accrued from diverted or averted ambulatory visits and inpatient admissions. Two independent non-LUC3 physicians adjudicated diverted or averted hospital visits.Results: A total of 117 patients were followed for 60 days. LUC3 saved $25,495 by preventing 25 unnecessary ED visits and replacing 228 in-person appointments with telephone assessments. The net savings after accounting for LUC3 operational costs, intentional ED visits, and admissions was $11,759.Conclusions & Implications: Telemedicine clinics can be cost-beneficial when treating community-based patients with acute illnesses, provided there is ready access to physicians and use of appropriate in-home monitoring. These lessons should be applied to other acute patient populations as Canada’s healthcare system seeks resource reallocation opportunities.RésuméContexte: Les visites à l’hôpital représentent un coût important en matière de prestation de soins de santé en Ontario. Les innovations permettant d’éviter les hospitalisations et les visites inutiles à l’urgence sont donc d’une importance capitale pour assurer la viabilité du système. Une clinique multidisciplinaire appelée la Lon-don Health Sciences Centre Urgent COVID Care Clinic (LUC3) a instauré la prestation de soins de courte durée dans la collectivité pour les patients atteints de la COVID-19 au moyen d’évaluations téléphoniques couplées à l’oxymétrie de pouls à domicile. Objectifs: Déterminer et analyser les coûts et les économies associés à la LUC3.Méthodologie: Analyse observationnelle rétrospective de tous les patients atteints de la COVID-19 dirigés vers la LUC3 entre le 23 avril et le 31 août 2020. Nous avons comparé les coûts d’exploitation de la LUC3 aux économies découlant des visites ambulatoires et des admissions à l’hôpital redirigées ou évitées. Deux médecins indépendants ne faisant pas partie de la LUC3 ont jugé les visites à l’hôpital redirigées ou évitées.Résultats: Au total, 117 patients ont été suivis pendant 60 jours. La LUC3 a permis d’économiser 25 495 $ en évitant 25 visites inutiles à l’urgence et en remplaçant 228 rendezvous en personne par des évaluations téléphoniques. Les économies nettes, après avoir tenu compte des coûts d’exploitation de la LUC3, des visites à l’urgence et des hospitalisations intentionnelles, s’élèvent à 11 759 $.Conclusions et répercussions: Les cliniques de télémédecine peuvent être rentables lorsqu’elles traitent dans la collectivité des patients atteints d’une affection médicale aiguë, à condition qu’il y ait un accès facile aux médecins et une surveillance à domicile appropriée. Ces constats devraient être appliqués à d’autres populations de patients atteints d’affections aiguës, car le système de soins de santé du Canada cherche des possibilités de réaffectation des ressources.

International audience

More than a century has passed since Tawara demonstrated the presence of the insulated pathways that extend from the "knoten" at the base of the atrial septum to their ramifications at the ventricular apexes. Having initially doubted the existence of the atrioventricular bundle until reading the monograph produced by Tawara, Keith, together with Flack, soon revealed the presence of the sinus node. Shortly thereafter, Thorel suggested that a special system might be found within the atrial walls, connecting the newly discovered atrial nodes. This prompted the convening of a special session of the German Pathological Society in 1910. The consensus was that no tracts existed within the atrial walls, with Aschoff and Mönckeberg establishing criteria to be met by those proposing recognition of "specialized" atrial conducting pathways. None of those who subsequently proposed the presence of such pathways have discussed their findings on the basis of the criteria established at the meeting of 1910. It remains the case, nonetheless, that drawings continue to be offered by cardiological experts showing narrow pathways within the atrial walls that parallel the arrangement used to show the ventricular conduction pathways. A similar drawing adorns the front cover of Heart Rhythm Journal. We are unaware of any evidence supporting the presence of pathways as illustrated existing within the overall walls of the atrial chambers. In this review, we summarize the evidence that shows, instead, that it is the aggregation of the working atrial cardiomyocytes within the atrial walls that underscores preferential anisotropic interatrial conduction.

The American Society of Breast Surgeons recommends genetic testing (GT) for all women with breast cancer (BC), but implementation and uptake of GT has not been well-described.A retrospective chart review was performed for newly diagnosed BC patients or patients with a newly identified recurrence of BC seen in a multidisciplinary clinic (MDBC) who were offered genetic counseling (GC) and GT.The 138 women attending the MDBC had a median age of 54 years and comprised non-Hispanic whites (46%), Asians (28%), Hispanics (17%), blacks (4%), and other (5%). Of the 105 (76%) patients without prior GT, 100 (95%) accepted GC, with 93 (93%) of these 100 patients undergoing GT. The patients meeting the National Comprehensive Cancer Network (NCCN) guidelines for GT were more likely to undergo GT. Testing was performed with a 67- to 84-gene panel, together with an 8- to 9-gene STAT panel if needed. Among 120 patients with reports available, including 33 patients previously tested, 15 (12%) were positive (1 BLM, 1 BRCA1, 3 BRCA2, 1 BRIP1, 1 CFTR, 1 CHEK2, 1 MUTYH, 1 PALB2, 1 PRSS1, 1 RAD50, 1 RET, and 2 TP53), 44 (37%) were negative, and 61 (51%) had an uncertain variant. The median time to STAT results (n = 50) was 8 days. The STAT results were available before surgery for 47 (98%) of the 48 STAT patients undergoing surgery.New BC patients attending the MDBC demonstrated high rates of acceptance of GC and GT. The combination of GC and GT can offer timely information critical to patient risk assessment and treatment planning.