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Background Despite availability of effective screening and treatment for Hepatitis C (HCV), the uptake remains suboptimal. Immigrants from HCV endemic countries comprise 35% of cases in Canada. There is an average 10-year diagnosis delay, causing poor health outcomes and high healthcare system costs. Therefore, we aimed to understand immigrants’ perceptions and beliefs about HCV, as well as the barriers and enablers to HCV care among immigrants, with a focus on individuals from Egypt, given the country’s high endemic rates of HCV infection and the large Egyptian community in Canada. Methods We established a Community Advisory Group to provide advice at all stages. We used a qualitative-descriptive design guided by the Common-Sense Self-Regulation Model and Theoretical Domains Framework to perform semi-structured interviews with adult immigrants from Egypt (with or without HCV) in Ottawa, Canada. Sampling continued until thematic saturation was achieved. The interviews were double-coded and key findings were identified. Results We conducted interviews with 18 individuals (eight females, ten males), including 12 who had undergone HCV screening. Among them, seven had tested positive, and all had received treatment. While all participants were aware of HCV, misconceptions and a lack of knowledge regarding its symptoms, modes of transmission, and treatment options were prevalent. Many stated that they would not seek screening in the absence of significant symptoms. Perceived stigma associated with HCV and experiences of ethnocultural discrimination discouraged some individuals from seeking care. Additionally, challenges such as limited access to family doctors and long wait times were frequently cited as barriers. However, those who had received HCV treatment reported positive experiences and remained engaged in follow-up care. Conclusion There is an urgent need to improve access to care for immigrants from endemic countries to eliminate HCV in Canada. We took a systematic, theory-informed approach to understand lived experiences and views among Egyptian immigrants in Canada. We identified key factors contributing to the low uptake of HCV screening and treatment. These findings will inform a theory-based intervention to optimize HCV care in immigrant communities.

Background Routine seeking of imaging for patients with low back pain is not concordant with the evidence-based recommendation that imaging is rarely of diagnostic value. Inappropriate imaging is a waste of resources and can lead to undesirable downstream effects for individuals and health systems. To develop effective strategies to reduce unwarranted referrals for imaging in primary care, we must understand the drivers for, and barriers to, guideline-adherent practice. We explored clinicians’ views to identify the dominant influences on clinicians as they choose to pursue, or avoid, imaging for their patients with low back pain. Methods We interviewed a purposeful sample of 47 primary care clinicians (14 physiotherapists, 18 chiropractors, 15 physicians) throughout Ontario, Canada, with a guide based on the Theoretical Domains Framework (TDF). We investigated clinicians’ views about their use of imaging in the management of low back pain. Interviews were recorded and transcribed verbatim. We analysed transcripts, then identified themes within TDF domains. Results Most clinicians reported that, for most clinical encounters, they adhered to guideline recommendations about imaging. Many clinicians across disciplines expressed the following themes: (1) imaging may result in an incidental finding or otherwise cause harm to patients, and drive up health system costs (TDF domain Beliefs about consequences ); (2) clinicians were confident in their abilities to diagnose, to explain to patients the rationale for not recommending imaging, and to respond to their needs (domains Beliefs about capabilities; Skills) . Many clinicians identified that patients occasionally want the validation that imaging provides (domain S ocial influences). Some clinicians described the value of imaging to corroborate a diagnosis (domain Beliefs about consequences) . Conclusions This study is the first to examine influences on imaging behaviours of a large interprofessional sample of primary care clinicians in Canada. Even among knowledgeable, skilled, confident clinicians who reported mostly adhering to guideline recommendations, there are potential influences on deviating from guideline-adherent care.

Background Evidence-based guidelines for low back pain recommend against routine imaging. Despite these guidelines, many patients still seek imaging. We sought to understand why patients with low back pain may want imaging, using a qualitative approach grounded in the Common-Sense Self-Regulation Model (CSSRM), a model that frames how patients’ beliefs and actions are shaped by their past experiences and understanding of an illness. Methods We interviewed 28 patients from a larger study in Ontario, Canada. Participants were recruited by family physicians (n = 8), chiropractors (n = 10), and physiotherapists (n = 10), and most (82.1%) had previous episodes of low back pain. Participants completed intake questionnaires and semi-structured interviews that explored their experiences with low back pain care and perspectives on imaging. We analyzed the interview transcripts using the CSSRM. Results The CSSRM domains were represented in patients’ narratives: Stimuli and Illness Representations , Coping Procedures , and Appraisal of Outcomes . Within Stimuli and Representations , patients described perceptions of the causes of their pain, and they associated obtaining an image with gaining a sense of control over their diagnosis. Within Coping Procedures , Cognitive Reappraisal emerged as the construct with the most discourse, reflecting how patients interpreted and reassessed their low back pain over time. Many patients expressed the belief that imaging would resolve uncertainty, validate their experience, and confirm that nothing serious had been overlooked. Patients emphasized that imaging would “show what’s going on,” or help them “feel taken seriously”. Within Appraisal of Outcomes , patients described the self-limiting nature of their LBP; the limited discourse about emotional outcomes was often linked to frustrations and fears. The beliefs expressed in interviews were not consistent with participants’ questionnaire answers from months previously, suggesting that beliefs may shift over time. Conclusions Many patients believed imaging for low back pain was important to gain certainty in diagnosis and reassurance that treatment was appropriate. However, their beliefs about the value of imaging may not be stable over time, as they are influenced by ongoing experiences and reappraisals. To reduce unwarranted imaging, clinicians should consider providing consistent and contextualized messaging that meets the patient’s ongoing illness experience.

Background Hepatitis C virus (HCV) infection is a significant global health burden, particularly among people who inject drugs. Rapid point-of-care HCV testing has emerged as a promising approach to improve HCV detection and linkage to care in harm reduction organizations such as needle and syringe programs. The objective of this study was to use an intersectionality lens to explore the barriers and enablers to point-of-care HCV testing in a needle and syringe program. Methods A qualitative study was conducted using semi-structured interviews with clients (people who inject drugs) and service providers in a large community organization focused on the prevention of sexually transmitted and blood borne infections and harm reduction in Montreal, Canada. An intersectionality lens was used alongside the Theoretical Domains Framework to guide the formulation of research questions as well as data collection, analysis, and interpretation. Results We interviewed 27 participants (15 clients, 12 providers). For clients, four themes emerged: (1) understanding and perceptions of HCV testing, (2) the role of an accessible and inclusive environment, (3) the interplay of emotions and motivations in decision-making, and (4) the impact of intersectional stigma related to HCV, behaviors, and identities. For providers, five themes emerged: (1) knowledge, skills, and confidence for HCV testing, (2) professional roles and their intersection with identity and lived experience, (3) resources and integration of services, (4) social and emotional factors, and (5) behavioral regulation and incentives for HCV testing. Intersectional stigma amplified access, emotional and informational barriers to HCV care for clients. In contrast, identity and lived experience acted as powerful enablers for providers in the provision of HCV care. Conclusion The application of an intersectionality lens provides a nuanced understanding of multilevel barriers and enablers to point-of-care HCV testing. Findings underscore the need for tailored strategies that address stigma, improve provider roles and communication, and foster an inclusive environment for equitable HCV care. Using an intersectionality lens in implementation research can offer valuable insights, guiding the design of equity-focused implementation strategies.

Abstract Objective Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA). Context Unilateral PA is the most common surgically treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals. Patients and Methods Surgically removed adrenals (n = 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy, and Japan) evaluated the histopathology of hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists. Results Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original HE morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists. Conclusion The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production.

Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery. This paper explores neural network and cellular complexity within human cortical and subcortical fusion organoids. The platform is used to model network dysfunction associated with Rett syndrome and to identify new therapeutic candidates.

Background The T2-FLAIR mismatch sign is an imaging finding highly suggestive of isocitrate dehydrogenase mutated ( IDH- mut) 1p19q non-codeleted (non-codel) gliomas (astrocytomas). In previous studies, it has shown excellent specificity but limited sensitivity for IDH -mut astrocytomas. Whether the mismatch sign is a marker of a clinically relevant subtype of IDH- mut astrocytomas is unknown. Methods We included histopathologically verified supratentorial lower-grade gliomas (LGG) WHO grade II-III retrospectively during the period 2010–2016. In the period 2017–2018, patients with suspected LGG radiologically were prospectively included, and in this cohort other diagnoses than glioma could occur. Clinical, radiological and molecular data were collected. For clinical evaluation we included all patients with IDH -mut astrocytomas. In the 2010–2016 cohort DNA methylation analysis with Infinium MethylationEPIC BeadChip (Illumina) was performed for patients with an IDH -mut astrocytoma with available tissue. We aimed to examine the association of the T2-FLAIR mismatch sign with clinical factors and outcomes. Additionally, we evaluated the diagnostic reliability of the mismatch sign and its relation to methylation profiles. Results Out of 215 patients with LGG, 135 had known IDH- mutation and 1p19q codeletion status. Fifty patients had an IDH -mut astrocytoma and 12 of these (24.0%) showed a mismatch sign. The sensitivity and specificity of the mismatch sign for IDH -mut detection were 26.4 and 97.6%, respectively. There were no differences between patients with an IDH -mut astrocytoma with or without mismatch sign when grouped according to T2-FLAIR mismatch sign with respect to baseline characteristics, clinical outcomes and methylation profiles. The overall interrater agreement between neuroradiologist and clinical neurosurgeons for the T2-FLAIR mismatch sign was significant when all 215 MRI examination assessed (κ = 0.77, p  < 0.001, N  = 215). Conclusion The T2-FLAIR mismatch sign in patients with an IDH -mut astrocytoma is not associated with clinical presentation or outcome. It seems unlikely that the IDH -mut astrocytomas with mismatch sign represent a specific subentity. Finally, we have validated that the T2-FLAIR mismatch sign is a reliable and specific marker of IDH -mut astrocytomas.

Microbial communities are essential to the function of virtually all ecosystems and eukaryotes, including humans. However, it is still a major challenge to identify microbial cells active under natural conditions in complex systems. In this study, we developed a new method to identify and sort active microbes on the single-cell level in complex samples using stable isotope probing with heavy water (D ₂O) combined with Raman microspectroscopy. Incorporation of D ₂O-derived D into the biomass of autotrophic and heterotrophic bacteria and archaea could be unambiguously detected via C-D signature peaks in single-cell Raman spectra, and the obtained labeling pattern was confirmed by nanoscale-resolution secondary ion MS. In fast-growing Escherichia coli cells, label detection was already possible after 20 min. For functional analyses of microbial communities, the detection of D incorporation from D ₂O in individual microbial cells via Raman microspectroscopy can be directly combined with FISH for the identification of active microbes. Applying this approach to mouse cecal microbiota revealed that the host-compound foragers Akkermansia muciniphila and Bacteroides acidifaciens exhibited distinctive response patterns to amendments of mucin and sugars. By Raman-based cell sorting of active (deuterated) cells with optical tweezers and subsequent multiple displacement amplification and DNA sequencing, novel cecal microbes stimulated by mucin and/or glucosamine were identified, demonstrating the potential of the nondestructive D ₂O-Raman approach for targeted sorting of microbial cells with defined functional properties for single-cell genomics. Significance Measuring activity patterns of microbes in their natural environment is essential for understanding ecosystems and the multifaceted interactions of microorganisms with eukaryotes. In this study, we developed a technique that allows fast and nondestructive activity measurements of microbial communities on a single-cell level. Microbial communities were amended with heavy water (D ₂O), a treatment that does not change the available substrate pool. After incubation, physiologically active cells are rapidly identified with Raman microspectroscopy by measuring cellular D incorporation. Using this approach, we characterized the activity patterns of two dominant microbes in mouse cecum samples amended with different carbohydrates and discovered previously unidentified bacteria stimulated by mucin and/or glucosamine by combining Raman microspectroscopy and optical tweezer-based sorting.

Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both. We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270). Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13–0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20–0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12–0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (13/101) and shorter modified (9/100) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20–1·83); however, the proportion was higher with ondansetron (16/100) than with placebo (6/101; 3·30, 1·01–10·72; p=0·024). In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen. Chief Scientist Office of the Scottish Government.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) allow investigations in a human cardiac model system, but disorganized mechanics and immaturity of hPSC-CMs on standard two-dimensional surfaces have been hurdles. Here, we developed a platform of micron-scale cardiac muscle bundles to control biomechanics in arrays of thousands of purified, independently contracting cardiac muscle strips on two-dimensional elastomer substrates with far greater throughput than single cell methods. By defining geometry and workload in this reductionist platform, we show that myofibrillar alignment and auxotonic contractions at physiologic workload drive maturation of contractile function, calcium handling, and electrophysiology. Using transcriptomics, reporter hPSC-CMs, and quantitative immunofluorescence, these cardiac muscle bundles can be used to parse orthogonal cues in early development, including contractile force, calcium load, and metabolic signals. Additionally, the resultant organized biomechanics facilitates automated extraction of contractile kinetics from brightfield microscopy imaging, increasing the accessibility, reproducibility, and throughput of pharmacologic testing and cardiomyopathy disease modeling. Investigations of human cardiac disease involving human pluripotent stem cell-derived cardiomyocytes are limited by the disorganized presentation of biomechanical cues resulting in cell immaturity. Here the authors develop a platform of micron-scale 2D cardiac muscle bundles to precisely deliver physiologic cues, improving reproducibility and throughput.