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ObjectivesTo explore experiences of physiotherapists working with adults living with Long COVID in Canada.DesignCross-sectional descriptive qualitative study involving online semi-structured interviews.ParticipantsWe recruited physiotherapists in Canada who self-identified as having clinically treated one or more adults living with Long COVID in the past year.Data collectionUsing an interview guide, we inquired about physiotherapists’ knowledge of Long COVID, assessment and treatment experiences, perspectives on physiotherapists’ roles, contextual and implementation factors influencing rehabilitative outcomes, and their recommendations for Long COVID rehabilitation. Interviews were audio-recorded, transcribed verbatim and analysed using a group-based thematic analytical approach. We administered a demographic questionnaire to describe sample characteristics.Results13 physiotherapists from five provinces participated; most were women (n=8; 62%) and practised in urban settings (n=11; 85%). Participants reported variable amounts of knowledge of existing guidelines and experiences working with adults living with Long COVID in the past year. Physiotherapists characterised their experiences working with adults living with Long COVID as a dynamic process involving: (1) a disruption to the profession (encountering a new patient population and pivoting to new models of care delivery), followed by (2) a cyclical process of learning curves and evolving roles of physiotherapists working with persons living with Long COVID (navigating uncertainty, keeping up with rapidly emerging evidence, trial and error, adapting mindset and rehabilitative approaches and growing prominence of roles as advocate and collaborator). Participants recommended the need for education and training, active and open-minded listening with patients, interdisciplinary models of care, and organisational- and system-level improvements to foster access to care.ConclusionsPhysiotherapists’ experiences involved a disruption to the profession followed by a dynamic process of learning curves and evolving roles in Long COVID rehabilitation. Not all participants demonstrated an in-depth understanding of existing Long COVID rehabilitation guidelines. Results may help inform physiotherapy education in Long COVID rehabilitation.

Study designQualitative exploratoryObjectivesRehabilitation following spinal cord injury (SCI) is a life-long process involving healthcare in a variety of settings, including facilities lacking SCI-specific services (i.e., non-SCI-specialized centers). Activity-based therapy (ABT) is a neurorestorative approach involving intensive, task-specific movement practice below the injury level. This study explored the existing knowledge, perceptions, and implementation of ABT among physical and occupational therapists working in non-SCI-specialized centers.SettingCanadian hospitals and community clinicsDesign/methodsSemi-structured interviews were conducted with Canadian therapists who worked at non-SCI-specialized centers and treated at least one patient with SCI within the last 18 months. The Theoretical Domains Framework was used to develop interview questions that queried therapists’ experiences in delivering SCI rehabilitation, their understanding of ABT and experience with its implementation. Interviews were audio-recorded, transcribed verbatim and analyzed using interpretive description.ResultsFour physical therapists and three occupational therapists, from diverse settings (i.e., acute care, inpatient rehabilitation, long-term care, outpatient rehabilitation, rural outpatient clinic) participated. Three themes were identified: (1) Available knowledge, resources and therapy time in non-SCI-specialized centers challenge ABT implementation, (2) How current therapy practices in non-SCI-specialized centers align with ABT and (3) Desire for ABT knowledge. Although participants were not familiar with the term ABT, it was identified that they were unknowingly incorporating some components of ABT into their practice. Participants expressed a keenness to learn more about ABT.ConclusionCurrent knowledge and implementation of ABT in non-SCI-specialized centers is limited. Tailoring ABT education to therapists at non-SCI-specialized centers may increase ABT implementation.

Background/ObjectiveRehabilitation after spinal cord injury (SCI) is a life-long process with individuals accessing care in a variety of settings, including centres without SCI-specific services (i.e., non-SCI-specialized centres). Activity-based Therapy (ABT) is a relatively new neurorestorative approach that involves intensive, task-specific movement practice below the level of injury. This study aimed to understand current knowledge, perceptions, and use of ABT by physical and occupational therapists at non-SCI-specialized centres.Design/MethodsA qualitative exploratory study using semi-structured interviews was conducted. The Theoretical Domains Framework was used to develop an interview guide that queried therapists’ experiences providing SCI rehabilitation, perceptions of ABT and ABT implementation. Canadian therapists who worked with at least one SCI patient in the last 18 months and practiced at non-SCI-specialized centres participated. Interviews were audio-recorded, transcribed verbatim and analyzed using interpretive description.ResultsFour physical and three occupational therapists from acute, inpatient, long-term care and outpatient settings participated. Three themes were determined: 1) Perceived challenges of working with SCI in non-SCI-specialized centres, 2) Current therapy techniques used and 3) Desire for ABT knowledge and implementation strategies specific to non-SCI-specialized centres. It was identified that participants were unknowingly incorporating some components of ABT in their practice. Participants emphasized challenges to ABT implementation, such as knowledge gaps, and expressed a keenness to learn more about ABT.ConclusionsCurrent implementation of ABT in non-SCI-specialized centres is limited, with a variety of challenges and therapist needs identified. Tailoring ABT education to therapists at non-SCI-specialized centres may increase implementation of ABT at these centres.

Tremendous efforts have been made in the last decade to advance cutting-edge MRI technology in pursuit of mapping structural connectivity in the living human brain with unprecedented sensitivity and speed. The first Connectom 3T MRI scanner equipped with a 300 mT/m whole-body gradient system was installed at the Massachusetts General Hospital in 2011 and was specifically constructed as part of the Human Connectome Project. Since that time, numerous technological advances have been made to enable the broader use of the Connectom high gradient system for diffusion tractography and tissue microstructure studies and leverage its unique advantages and sensitivity to resolving macroscopic and microscopic structural information in neural tissue for clinical and neuroscientific studies. The goal of this review article is to summarize the technical developments that have emerged in the last decade to support and promote large-scale and scientific studies of the human brain using the Connectom scanner. We provide a brief historical perspective on the development of Connectom gradient technology and the efforts that led to the installation of three other Connectom 3T MRI scanners worldwide – one in the United Kingdom in Cardiff, Wales, another in continental Europe in Leipzig, Germany, and the latest in Asia in Shanghai, China. We summarize the key developments in gradient hardware and image acquisition technology that have formed the backbone of Connectom-related research efforts, including the rich array of high-sensitivity receiver coils, pulse sequences, image artifact correction strategies and data preprocessing methods needed to optimize the quality of high-gradient strength diffusion MRI data for subsequent analyses. Finally, we review the scientific impact of the Connectom MRI scanner, including advances in diffusion tractography, tissue microstructural imaging, ex vivo validation, and clinical investigations that have been enabled by Connectom technology. We conclude with brief insights into the unique value of strong gradients for diffusion MRI and where the field is headed in the coming years.

DUSP22, an atypical dual-specificity phosphatase enzyme, plays a significant role in regulating multiple kinase signaling pathways by dephosphorylation. Our study demonstrated that decreased DUSP22 expression is associated with shorter disease-free survival, advanced TNM (tumor, lymph nodes, and metastasis), cancer stage, and higher tumor grade in lung adenocarcinoma (LUAD) patients. Exogenous DUSP22 expression reduces the colony-forming capacity of lung cancer cells and inhibits xenograft tumor growth primarily by targeting EGFR and suppressing its activity through dephosphorylation. Knockdown of DUSP22 using shRNA enhances EGFR dependency in HCC827 lung cancer cells and increases sensitivity to gefitinib, an EGFR inhibitor. Consistently, genetic deletion of DUSP22 enhances EGFRdel (exon 19 deletion)-driven lung tumorigenesis and elevates EGFR activity. Pharmacological inhibition of DUSP22 activates EGFR, ERK1/2, and upregulates downstream PD-L1 expression. Additionally, lentiviral deletion of DUSP22 by shRNA enhances lung cancer cell migration through EGFR/c-Met and PD-L1-dependent pathways. Gefitinib, an EGFR inhibitor, mechanistically suppresses migration induced by DUSP22 deletion and inhibits c-Met activity. Furthermore, cabozantinib, a c-Met inhibitor, reduces migration and attenuates EGFR activation caused by DUSP22 deletion. Collectively, our findings support the hypothesis that loss of DUSP22 function in lung cancer cells confers a survival advantage by augmenting EGFR signaling, leading to increased activation of downstream c-Met, ERK1/2, and PD-L1 axis, ultimately contributing to the progression of advanced lung cancer.

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell–cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for Ca V 1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease. It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.

Background Pancreatic ductal adenocarcinomas (PDACs) are highly lethal and aggressive with oncogenic KRAS being the main oncogenic driver of the disease. PDACs have been extensively profiled at advanced stages, and in advanced disease the tumor microenvironment is a major determinant that critically shapes patient outcomes. Since the molecular events occurring prior to invasive growth remain poorly understood, we aimed to investigate changes in the precancerous epithelium and its surrounding niche. Methods We acquired time-resolved, single-cell transcriptomic (scRNAseq), and accessible-chromatin data from human pluripotent stem cell-derived pancreatic duct-like organoids (PDLO) inducibly expressing KRAS G12D and from various niche cells. Results Analysis of the pure epithelium already revealed key signatures of matrix remodeling and inflammation-related signaling upon few days of KRAS G12D expression. Machine learning captured KRAS G12D -dependent transcriptomic classifiers with high prediction accuracy and niche preparatory relevance. Various co-culture approaches followed by scRNAseq and functional validation, including T-cell microfluidics, demonstrated that the KRAS G12D -induced PDLO-secretome activates pancreatic stellate cells (PaSCs) and protects precancerous organoids from T cell infiltration. Additional, in silico  approaches reconstructed a virtual pancreatic (pre)cancerous space to profile cell–cell interactions between PDLOs and niche cells. TNFα emerged as a top-ranked ligand and was functionally validated to mediate T-cell shielding and PaSC activation. Cyst fluid from 80 prospectively sampled Intraductal Papillary Mucinous Neoplasm (IPMNs) –well-known cystic PDAC precursor lesions– showed a stepwise TNFα rise across LGD (low-grade), HGD (high-grade), and IC (invasive cancer). Conclusion Our study reveals that oncogenic KRAS orchestrates niche-preparatory programs that precede PDAC formation and highlight a T cell exclusion program governed by epithelial-derived TNFα.

Narrative evidence contained within historical documents and inscriptions provides an important record of climate variability for periods prior to the onset of systematic meteorological data collection. A common approach used by historical climatologists to convert such qualitative information into continuous quantitative proxy data is through the generation of ordinal-scale climate indices. There is, however, considerable variability in the types of phenomena reconstructed using an index approach and the practice of index development in different parts of the world. This review, written by members of the PAGES (Past Global Changes) CRIAS working group – a collective of climate historians and historical climatologists researching Climate Reconstructions and Impacts from the Archives of Societies – provides the first global synthesis of the use of the index approach in climate reconstruction. We begin by summarising the range of studies that have used indices for climate reconstruction across six continents (Europe, Asia, Africa, the Americas, and Australia) as well as the world's oceans. We then outline the different methods by which indices are developed in each of these regions, including a discussion of the processes adopted to verify and calibrate index series, and the measures used to express confidence and uncertainty. We conclude with a series of recommendations to guide the development of future index-based climate reconstructions to maximise their effectiveness for use by climate modellers and in multiproxy climate reconstructions.

Extracellular particles (EPs) including extracellular vesicles (EVs) and exomeres play significant roles in diseases and therapeutic applications. However, their spatiotemporal dynamics in vivo have remained largely unresolved in detail due to the lack of a suitable method. Therefore, a bioluminescence resonance energy transfer (BRET)‐based reporter, PalmGRET, is created to enable pan‐EP labeling ranging from exomeres (<50 nm) to small (<200 nm) and medium and large (>200 nm) EVs. PalmGRET emits robust, sustained signals and allows the visualization, tracking, and quantification of the EPs from whole animal to nanoscopic resolutions under different imaging modalities, including bioluminescence, BRET, and fluorescence. Using PalmGRET, it is shown that EPs released by lung metastatic hepatocellular carcinoma (HCC) exhibit lung tropism with varying distributions to other major organs in immunocompetent mice. It is further demonstrated that gene knockdown of lung‐tropic membrane proteins, solute carrier organic anion transporter family member 2A1, alanine aminopeptidase/Cd13, and chloride intracellular channel 1 decreases HCC‐EP distribution to the lungs and yields distinct biodistribution profiles. It is anticipated that EP‐specific imaging, quantitative assays, and detailed in vivo characterization are a starting point for more accurate and comprehensive in vivo models of EP biology and therapeutic design. PalmGRET, a bioluminescence resonance energy transfer (BRET)‐based reporter for extracellular particles (EPs), enables pan‐EP labeling, including extracellular vesicles and exomeres. PalmGRET allows accurate visualization, tracking, and quantification of EPs from whole animal to nanoscopic resolutions under different imaging modalities, including bioluminescence, BRET, and fluorescence. Using PalmGRET, lung‐tropic EP proteins are identified and dynamically altered biodistributions are revealed under redirected tropism.

BackgroundMyasthenia gravis (MG) is a rare but life-threatening adverse event of immune checkpoint inhibitors (ICI). Given the limited evidence, data from a large cohort of patients is needed to aid in recognition and management of this fatal complication.MethodsWe reviewed our institutional databases to identify patients who had cancer and MG in the setting of ICI. We systematically reviewed the literature through August 2018 to identify all similar reported patients. We collected data on clinical and diagnostic features, management, and outcomes of these cases.ResultsSixty-five patients were identified. Median age was 73 years; 42 (65%) were males, 31 (48%) had metastatic melanoma, and 13 (20%) had a preexisting MG before ICI initiation. Most patients received anti-PD-1 (82%). Sixty-three patients (97%) developed ICI-related MG (new onset or disease flare) after a median of 4 weeks (1 to 16 weeks) of ICI initiation. Twenty-four patients (37%) experienced concurrent myositis, and respiratory failure occurred in 29 (45%). ICI was discontinued in 61 patients (97%). Death was reported in 24 patients (38%); 15 (23%) due to MG complication. A better outcome was observed in patients who received intravenous immunoglobulin (IVIG) or plasmapheresis (PLEX) as first-line therapy than in those who received steroids alone (95% vs 63% improvement of MG symptoms, p = 0.011).ConclusionsMG is a life-threatening adverse event of acute onset and rapid progression after ICI initiation. Early use of IVIG or PLEX, regardless of initial symptoms severity, may lead to better outcomes than steroids alone. Our data suggest the need to reassess the current recommendations for management of ICI-related MG until prospective longitudinal studies are conducted to establish the ideal management approach for these patients.