Evidence-informed stakeholder consultations to promote rights-based approaches for children with disabilities.

Purpose: To strengthen the translation of evidence to actionable policy, stakeholder engagement is necessary to synthesize, prioritize and contextualize the academic research content into accessible language. In this manuscript we describe a multi-level evidence-based stakeholder consultation process and related outcomes proposed to promote awareness of and foster cross-sectorial collaborations towards human rights-based approaches for children with disabilities. Methods: Mixed-methods participatory action research done in three steps: (1) A literature review of peer-reviewed evidence on rights-based approaches in childhood disabilities; (2) Consultation with researchers in diverse fields, grassroot organizations, caregivers, and youth with disabilities; (3) A constructive dialogue with decision makers at federal and provincial levels in Canada to discuss consultations results. Results: Stakeholders value human rights approaches that can have a direct impact on practical aspects of their daily living. Organizations give high importance to adopting rights-based approaches to measure policy outcomes, while parents value service provision and youth emphasize accessibility. Conclusion: The implementation of rights-based approaches in childhood disabilities can support policy, services, and daily lives of children with disabilities and the ecosystems around them. It can also guide research priorities, and create a common language to foster collaborations across sectors and interested parties.

Haemophagocytic Lymphohistiocytosis Following the anti-PD-1 Nivolumab in a Patient with Gastric Cancer and Ankylosing Spondylitis.

Background: Autoimmune diseases are not contraindications for immune checkpoint inhibitors (ICI) therapy in patients with cancer. However, immune-related adverse events (irAEs) are frequently observed in patients receiving ICIs including dermatitis, thyroiditis, colitis, and pneumonitis. Thrombocytopenic purpura, aplasia, and haemophagocytic lymphohistiocytosis (HLH) are rarely observed during ICIs. Case description: We report the case of a male patient with pre-existing untreated HLA B27 and ankylosing spondylitis with gastric cancer and liver metastases. The 79-year-old man was treated with anti-HER2 trastuzumab and anti-PD-1 nivolumab. Seventeen days after the seventh cycle of treatment, he presented at the emergency department with acute fever, confusion, and hypotension. Laboratory results showed pancytopenia, and elevation of ferritin and triglyceride. No infections were detected. Although not seen in a bone marrow biopsy, clinical presentation, and absence of infection, together with an H-score of 263, indicated HLH. The patient was treated with dexamethasone for four days and discharged on a tapering dose of steroids. At the two-month follow-up, clinical presentation was normal and blood test almost normalised. At 8 months, no liver metastases were observed. Conclusions: In a patient with a pre-existing autoimmune condition, immunotherapy led to the development of HLH, which was controlled by glucocorticoid. Absence of the feature of haemophagocytosis in the bone marrow biopsy did not exclude the diagnosis, as HLH can occur in the spleen or in the liver. Glucocorticoid therapy did not prevent the anti-cancer effect of ICIs, and liver metastases disappeared 8 months post-HLH. This case warrants further research on the interplay between autoimmunity and ICI response, as well as ICI-induced irAEs. LEARNING POINTS: Haemophagocytic lymphohistiocytosis (HLH) post seventh cycle of trastuzumab (anti-HER2) and nivolumab (anti-PD-1) was controlled with glucocorticoid.Breach of tolerance was due to immunotherapy-induced HLH in a patient with pre-existing autoimmune condition (HLA B27- positive ankylosing spondylitis).There was a complete disappearance of liver metastases 8 months post-HLH.

The dermatopathologist-patient consultation program: A pilot study on patient perspectives and interest.

BACKGROUND: Despite the integral contribution of dermatopathologists in diagnosing skin lesions, their role often remains unclear to patients, likely due to little face-to-face interaction. More healthcare systems have begun introducing patient-pathologist consultation programs that allow patients to discuss results with a pathologist and view tissue under a microscope. To our knowledge, only one study has been published exploring patient perspectives of these programs and no studies exist regarding interest in dermatopathology. METHODS: An anonymous survey was distributed via online support groups for various dermatologic diagnoses. RESULTS: Patients demonstrated a high level of interest in the dermatopathologist-patient consultation program, with 81.3% expressing at least moderate interest in discussing their diagnosis with a dermatopathologist and 79.2% expressing at least moderate interest in examining their tissue under the microscope with a dermatopathologist. The rationale for interest included various themes: (1) knowledge/understanding, (2) empowerment, (3) emotional support, (4) general interest, and (5) improved trust. CONCLUSIONS: Patients with cancerous and non-cancerous dermatologic diagnoses demonstrate high interest in a dermatopathologist-patient consultation program. Efforts to pilot this type of program can build upon the infrastructure of current pathologist consultation programs. Future efforts should be taken by hospital leadership, clinicians, and dermatopathologists to determine physician interest and address logistical challenges to the implementation of these programs.

The Pediatric Autism Research Cohort (PARC) Study: protocol for a patient-oriented prospective study examining trajectories of functioning in children with autism.

INTRODUCTION: The developmentally variable nature of autism poses challenges in providing timely services tailored to a child's needs. Despite a recent focus on longitudinal research, priority-setting initiatives with stakeholders highlighted the importance of studying a child's day-to-day functioning and social determinants of health to inform clinical care. To address this, we are conducting a pragmatic multi-site, patient-oriented longitudinal investigation: the Pediatric Autism Research Cohort (PARC) Study. In young children (<7 years of age) newly diagnosed with autism, we will: (1) examine variability in trajectories of adaptive functioning from the point of diagnosis into transition to school; and (2) identify factors associated with trajectories of adaptive functioning. METHODS AND ANALYSIS: We aim to recruit 1300 children under 7 years of age with a recent (within 12 months) diagnosis of autism from seven sites: six in Canada; one in Israel. Participants will be followed prospectively from diagnosis to age 8 years, with assessments at 6-month intervals. Parents/caregivers will complete questionnaires administered via a customized online research portal. Following each assessment timepoint, families will receive a research summary report describing their child's progress on adaptive functioning and related domains. Analysis of the longitudinal data will map trajectories and examine child, family and service characteristics associated with chronogeneity (interindividual and intraindividual heterogeneity over time) and possible trajectory turning points around sensitive periods like the transition to school. ETHICS AND DISSEMINATION: Ethics approvals have been received by all sites. All parents/respondents will provide informed consent when enrolling in the study. Using an integrated knowledge translation approach, where stakeholders are directly engaged in the research process, the PARC Study will identify factors associated with trajectories of functioning in children with autism. Resulting evidence will be shared with government policy makers to inform provincial and national programs. Findings will be disseminated at conferences and published in peer-reviewed journals.

Placental metastasis from maternal NUT carcinoma: diagnostic pitfalls and challenges.

We report a young pregnant woman with large midline thoracic mass and markedly elevated serum alpha-fetoprotein (AFP) levels. Initially suspected as a germ cell tumour (GCT) due to age, site, and high AFP levels, a biopsy unveiled a high-grade malignant tumour characterised by undifferentiated monotonous cells. Although tumour cells exhibited positive AFP, the overall immunoprofile did not provide additional evidence to support GCT. Further work-up showed positive for NUT (nuclear protein in testis) immunostaining and the presence of BRD4-NUT1 fusion, confirming the diagnosis of NUT carcinoma. On radiology, there were extensive metastases to lungs, liver, vertebrae, and placenta. Despite aggressive chemotherapy, radiotherapy and immunotherapy, she did not respond to the therapies. Fortunately, her child was not affected by the carcinoma. This is the first case highlighting that thoracic lung primary NUT carcinoma can spread to the placenta and manifest with elevated serum AFP levels, potentially leading to misdiagnosis as GCT both clinically and pathologically.

Generation and Study of Antibodies against Two Triangular Trimers Derived from Aß.

Monoclonal antibodies (mAbs) that target the P-amyloid peptide (Aß) are important Alzheimer's disease research tools and are now being used as Alzheimer's disease therapies. Conformation-specific mAbs that target oligomeric and fibrillar Aß assemblies are of particular interest, as these assemblies are associated with Alzheimer's disease pathogenesis and progression. This paper reports the generation of rabbit mAbs against two different triangular trimers derived from Aß. These antibodies are the first mAbs generated against Aß oligomer mimics in which the high-resolution structures of the oligomers are known. We describe the isolation of the mAbs using single B-cell sorting of peripheral blood mononuclear cells (PBMCs) from immunized rabbits, the selectivity of the mAbs for the triangular trimers, the immunoreactivity of the mAbs with aggregated Aß42, and the immunoreactivity of the mAbs in brain tissue from the 5xFAD Alzheimer's disease mouse model. The characterization of these mAbs against structurally defined trimers derived from Aß enhances understanding of antibody-amyloid recognition and may benefit the development of diagnostics and immunotherapies in Alzheimer's disease.

Design and characterization of protective pan-ebolavirus and pan-filovirus bispecific antibodies.

Monoclonal antibodies (mAbs) are an important class of antiviral therapeutics. MAbs are highly selective, well tolerated, and have long in vivo half-life as well as the capacity to induce immune-mediated virus clearance. Their activities can be further enhanced by integration of their variable fragments (Fvs) into bispecific antibodies (bsAbs), affording simultaneous targeting of multiple epitopes to improve potency and breadth and/or to mitigate against viral escape by a single mutation. Here, we explore a bsAb strategy for generation of pan-ebolavirus and pan-filovirus immunotherapeutics. Filoviruses, including Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV), cause severe hemorrhagic fever. Although there are two FDA-approved mAb therapies for EBOV infection, these do not extend to other filoviruses. Here, we combine Fvs from broad ebolavirus mAbs to generate novel pan-ebolavirus bsAbs that are potently neutralizing, confer protection in mice, and are resistant to viral escape. Moreover, we combine Fvs from pan-ebolavirus mAbs with those of protective MARV mAbs to generate pan-filovirus protective bsAbs. These results provide guidelines for broad antiviral bsAb design and generate new immunotherapeutic candidates.

Management of tinea capitis in infants and children in the United States: A national survey of pediatric dermatologists.

This study aimed to evaluate the current management of tinea capitis in the United States, specifically focusing on patients aged 0-2 months, 2 months to 2 years, and 2 years to 18 years. An online survey, distributed through the Pediatric Dermatology Research Alliance and the Society of Pediatric Dermatology, revealed the following preferences: fluconazole for those under 2 months, griseofulvin for those aged 2 months to 2 years, and terbinafine for those aged 2 years and older. There exists inter-provider variation in tinea capitis treatment regimens within the pediatric dermatology community.

Cardiovascular Outcomes with Intravitreal Anti-Vascular Endothelial Growth Factor Therapy in Patients with Diabetes: A Real-World Data Analysis.

BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is commonly used intravitreally for diabetic proliferative retinopathy, but when used systemically for treating cancers, an excess of cardiovascular disease (CVD) events has been noted. The latter is of concern for people with diabetes, who are at higher risk of CVD. This study aims to explore the relationship between incident CVD and intravitreal anti-VEGF therapy in patients with diabetes, compared to other therapies, using a large real-world global federated dataset. METHODS: Data were analysed using TriNetX, a global electronic medical real-world ecosystem. The study included adults with diabetes and excluded those with a history of CVD prior to the time window of data extraction. Patients were categorised into two cohorts: anti-VEGF therapy or control cohort (laser or steroid therapies). The cohorts were 1:1 propensity score-matched for age, sex, ethnicity, body mass index, systolic blood pressure, HbA1c, and cardiovascular medications. Outcomes analysed at 1, 6 and 12 months were: (1) mortality; (2) acute myocardial infarction (MI); (3) cerebral infarction; and (4) heart failure. Relative risk analyses were performed using the built-in R statistical computing platform on TriNetX. RESULTS: In patients with diabetes (n = 2205; mean age 58.8 ± 15.8, Std diff 0.05; 56% male), anti-VEGF therapy was associated with a numerical but non-statistically significant increased CVD risk over 1, 6, and 12 months: Mortality over 1 month (RR 1; 95% CI 0.42, 2.40), 6 months (RR 1.46; 95% CI 0.72, 2.95) and 12 months (RR 1.41; 95% CI 0.88, 2.27). There was no excess of acute MI over 1 (RR n/a: not applicable; 0/0: 0 events in the anti-VEGF group/0 events in the control group), 6 and 12 months (RR n/a; 0/10 events); cerebral infarction over 1, 6 months (RR n/a; 0/0 events), and 12 months (RR n/a; 0/10); and heart failure over 1 month (RR n/a; 0/0 events), 6 months (RR 1; 95% CI 0.42, 2.40) and 12 months (RR 1; 95% CI 0.42, 2.34). CONCLUSIONS: There was no statistically significant risk of cardiovascular-related events in the short or medium term in patients with diabetes who received intravitreal anti-VEGF therapy, despite a small increase in the number of CVD events. Our study supports the real-world safety of intravitreal anti-VEGF therapy in patients with diabetes free of baseline CVD.

Agony of akathisia: a case of sodium valproate-induced akathisia.

Akathisia is a subjective feeling of restlessness that often results in a compulsion to move. Drug-related causes are the most common aetiologies. It can often be confused with restless legs syndrome (RLS). We describe a case of valproate-induced akathisia that improved with drug cessation. This case reports a rare but treatable adverse effect of sodium valproate and highlights the importance of differentiating akathisia from RLS.

Predictor Variables Associated With Dermatology Referral Completion and the Impact on Surgical Treatment: A Retrospective Cohort Study.

BACKGROUND: Delays or failure to complete a dermatologic referral may affect health care outcomes. Factors associated with these delays remain understudied. OBJECTIVE: This study investigated socioeconomic and demographic factors associated with delays or failure to complete dermatology referrals and potential impact on surgical outcomes. METHODS: A retrospective chart review was performed for 400 patients internally referred to an academic dermatology center from 19 primary-care clinics from July 2018 to June 2019. Only patients referred after an in-person primary-care visit in which the provider documented a specific concerning lesion were included. Multivariate analyses were performed to explore variables associated with delays or failure to complete dermatology referrals. RESULTS: Patients were more likely to complete their referral if they had a personal history (adjusted odds ratio [aOR] = 7.843, 95% CI 1.383-14.304) or family history (aOR = 11.307, 95% CI 2.344-20.27) of skin cancer. Patients were more likely to delay referral completion past 30 days if they were ages 18 to 34 (aOR = 6.665, 95% CI 1.285-12.044) and less likely to delay referral past 30 days if they had a previous history of skin cancer (aOR = 0.531, 95% CI 0.181-0.882). LIMITATIONS: Single institution, retrospective study, limited surgical patients. CONCLUSION: Understanding factors associated with delays in dermatology referral completion can help identify at-risk patient populations.

Effect of exercise interventions on hospital length of stay and admissions during cancer treatment: a systematic review and meta-analysis.

OBJECTIVE: To assess the effect of participating in an exercise intervention compared with no exercise during cancer treatment on the duration and frequency of hospital admissions. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, PEDro and Cochrane Central Registry of Randomized Controlled Trials. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised studies published until August 2023 evaluating exercise interventions during chemotherapy, radiotherapy or stem cell transplant regimens, compared with usual care, and which assessed hospital admissions (length of stay and/or frequency of admissions). STUDY APPRAISAL AND SYNTHESIS: Study quality was assessed using the Cochrane Risk-of-Bias tool and Grading of Recommendations Assessment, Development and Evaluation assessment. Meta-analyses were conducted by pooling the data using random-effects models. RESULTS: Of 3918 screened abstracts, 20 studies met inclusion criteria, including 2635 participants (1383 intervention and 1252 control). Twelve studies were conducted during haematopoietic stem cell transplantation regimens. There was a small effect size in a pooled analysis that found exercise during treatment reduced hospital length of stay by 1.40 days (95% CI: -2.26 to -0.54 days; low-quality evidence) and lowered the rate of hospital admission by 8% (difference in proportions=-0.08, 95% CI: -0.13 to -0.03, low-quality evidence) compared with usual care. CONCLUSION: Exercise during cancer treatment can decrease hospital length of stay and admissions, although a small effect size and high heterogeneity limits the certainty. While exercise is factored into some multidisciplinary care plans, it could be included as standard practice for patients as cancer care pathways evolve.

Revolutionizing the Management of Large-Core Ischaemic Strokes: Decoding the Success of Endovascular Therapy in the Recent Stroke Trials.

Endovascular therapy (EVT) has revolutionized the management of acute ischaemic strokes with large vessel occlusion, with emerging evidence suggesting its benefit also in large infarct core volume strokes. In the last two years, four randomised controlled trials have been published on this topic-RESCUE-Japan LIMIT, ANGEL-ASPECT, SELECT2 and TENSION, with overall results showing that EVT improves functional and neurological outcomes compared to medical management alone. This review aims to summarise the recent evidence presented by these four trials and highlight some of the limitations in our current understanding of this topic.

Immune microenvironment of basal cell carcinoma and tumor regression following combined PD-1/LAG-3 blockade.

Systemic treatment options for patients with locally advanced or metastatic basal cell carcinoma (BCC) are limited, particularly when tumors are refractory to anti-programmed cell death protein-1 (PD-1). A better understanding of immune checkpoint expression within the BCC tumor microenvironment may inform combinatorial treatment strategies to optimize response rates. CD3, PD-1, programmed death ligand-1 (PD-L1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3)+ cell densities within the tumor microenvironment of 34 archival, histologically aggressive BCCs were assessed. Tumor infiltrating lymphocyte (TIL) expression of PD-1, PD-L1, and LAG-3, and to a lesser degree TIM-3, correlated with increasing CD3+ T-cell densities (Pearson's r=0.89, 0.72, 0.87, and 0.63, respectively). 100% of BCCs (34/34) demonstrated LAG-3 and PD-1 expression in >1% TIL; and the correlation between PD-1 and LAG-3 densities was high (Pearson's r=0.89). LAG-3 was expressed at ~50% of the level of PD-1. Additionally, we present a patient with locally-advanced BCC who experienced stable disease during and after 45 weeks of first-line anti-PD-1 (nivolumab), followed by a partial response after the addition of anti-LAG-3 (relatlimab). Longitudinal biopsies throughout the treatment course showed a graduated increase in LAG-3 expression after anti-PD-1 therapy, lending support for coordinated immunosuppression and suggesting LAG-3 as a co-target for combination therapy to augment the clinical impact of anti-PD-(L)1.

Demographics, Cutaneous Manifestations, and Comorbidities Associated with Progressive Cutaneous Sarcoidosis: A Retrospective Cohort Study.

Background: Sarcoidosis is a multisystem granulomatous disease with a wide variety of presentations and clinical courses. Cutaneous manifestations and comorbidities associated with sarcoid prognosis remain understudied. Methods: An EPIC query was run for patients age 18+ at the Johns Hopkins Hospital with a diagnosis of sarcoidosis of the skin according to the ICD-10-CM code D86.3. Data were obtained from a population-based sample of 240 patients from 2015 to 2020. Results: A total of 240 patients were included in the cohort study. The mean (SD) age was 43.76 (11.72) years, and 30% of participants were male; 76.25% of patients identified as black, 19.58% as white, and 4.17% as other. The average age of onset in remissive patients was significantly higher than progressive (47 ± 12 vs. 40 ± 10, p = 0.0005); 49% of black patients experienced progressive sarcoid compared to 32.6% of white patients (p = 0.028). Progressive disease was associated with the presence of lupus pernio (aOR = 3.29, 95% CI, 1.60-6.77) and at least one autoimmune comorbidity (aOR 6.831, 95% CI 1.819-11.843). Conclusions: When controlling for patient demographics, lupus pernio and the presence of at least one autoimmune condition were associated with progressive cutaneous sarcoidosis.

Case report: Creutzfeldt-Jakob disease presenting with anxiety symptoms in a COVID-19 post-infection patient.

Creutzfeldt-Jakob Disease (CJD) is a rare, rapidly progressive, and fatal neurodegenerative disorder. We describe a man whose initial manifestations of CJD occurred shortly after contracting Coronavirus disease 2019 (COVID-19). He first developed anxiety and short-term memory loss a few weeks after a mild COVID-19 infection. He subsequently developed parkinsonism, eventually progressed to akinetic mutism, and passed away 5 months after symptom onset. This case highlights a potential temporal relationship between COVID-19 infection and the onset of neurodegenerative symptoms. Microglia and astrocytes in the central nervous system (CNS) and 'S1' spike proteins on SARS-CoV-2 are potential mediators in neuroinflammation and neurodegeneration.

Fever, Cognitive Decline, and Multifocal T2 Hyperintensities on Brain MRI: A Case Report of Cytokine Release Syndrome.

Cytokine release syndrome (CRS) is a systemic inflammatory response characterized by fever, constitutional symptoms, and multiorgan dysfunction. While most commonly associated with immunotherapy, CRS can also be incited by infections or drugs. This case details the presentation and evaluation of a 71-year-old woman with a history of primary myelofibrosis and breast cancer who presented with acute onset of altered mental status. Initial vital signs were notable for severe hypertension, tachycardia, and fever. The patient was alert and oriented only to self, with little verbal output, and spontaneously moving all extremities. The patient had a submandibular gland abscess that had been diagnosed prior to presentation via a computed tomography scan of the neck. A comprehensive analysis, including blood tests, cerebrospinal fluid (CSF) analysis, electroencephalogram (EEG), and neuroimaging, was performed. Severe leukocytosis was noted and brain MRI demonstrated scattered areas of diffusion restriction and diffuse T2 white matter hyperintensities. Serial imaging demonstrated the progression of T2 hyperintensities. Ultimately, CRS was the most likely diagnosis. In this case, the inciting event was likely an infectious etiology, suspected to be the submandibular gland abscess that was present at the time of admission. It is vital to have a high index of suspicion for CRS in patients with recent infection, drug exposure, or immune dysregulation.

Chikungunya virus cell-to-cell transmission is mediated by intercellular extensions in vitro and in vivo.

Chikungunya virus (CHIKV) has recently emerged to cause millions of human infections worldwide. Infection can induce the formation of long intercellular extensions that project from infected cells and form stable non-continuous membrane bridges with neighbouring cells. The mechanistic role of these intercellular extensions in CHIKV infection was unclear. Here we developed a co-culture system and flow cytometry methods to quantitatively evaluate transmission of CHIKV from infected to uninfected cells in the presence of neutralizing antibody. Endocytosis and endosomal acidification were critical for virus cell-to-cell transmission, while the CHIKV receptor MXRA8 was not. By using distinct antibodies to block formation of extensions and by evaluation of transmission in HeLa cells that did not form extensions, we showed that intercellular extensions mediate CHIKV cell-to-cell transmission. In vivo, pre-treatment of mice with a neutralizing antibody blocked infection by direct virus inoculation, while adoptive transfer of infected cells produced antibody-resistant host infection. Together our data suggest a model in which the contact sites of intercellular extensions on target cells shield CHIKV from neutralizing antibodies and promote efficient intercellular virus transmission both in vitro and in vivo.