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BackgroundThe advent of antibody-drug conjugates (ADCs) represents a landmark advance in cancer therapy, permitting targeted delivery of a potent cytotoxic agent to tumor cells with minimal damage to surrounding cells. Although ADCs can induce sustained therapeutic responses in heavily pretreated patients, they can also cause significant toxicity and thus require careful monitoring. The prototype ADC, ado-trastuzumab emtansine (T-DM1) is comprised of a humanized, monoclonal human epidermal growth factor receptor 2 (HER2)-directed antibody, trastuzumab, linked to the cytotoxic agent, DM1, and is used for the treatment of early-stage and advanced HER2-positive breast cancer. Liver toxicities, including transaminitis and nodular regenerative hyperplasia resulting in portal hypertension have been described. We report a case series of four patients who developed hepatopulmonary syndrome (HPS) during treatment with T-DM1. HPS is characterized by hypoxemia, portal hypertension, and intrapulmonary shunting, and it can be associated with severe hypoxic respiratory failure. HPS secondary to noncirrhotic portal hypertension occurring with long-term exposure to T-DM1 has not previously been reported.Case series presentationFour patients who received T-DM1 in our institutional cohort (n=230) developed HPS, which can be associated with severe hypoxic respiratory failure. Each patient diagnosed with HPS received >50 doses of T-DM1. Only one patient at diagnosis had resting hypoxia, while the other three patients became hypoxic with exertion only. Discontinuation of T-DM1 led to clinical improvement in hypoxia in three of the four patients. The spectrum of liver injury that occurs with long-term use of T-DM1 remains incompletely defined.ConclusionsAs T-DM1 is approved for use in the management of early-stage operable and advanced breast cancer, awareness of HPS as a potential complication of long-term administration of T-DM1 is necessary. The emergence of dyspnea alone or combined with low oxygen saturation and signs of hypoxemia (clubbing or elevated hemoglobin) should raise clinical suspicion and prompt evaluation for HPS. Cancer care team members should be vigilant regarding the potential for new and serious side effects associated with novel targeted therapies, which may emerge years beyond initial regulatory approval.

BackgroundEarly intervention services (EIS) for psychosis have proven highly effective in treating first episode psychosis. Yet, retention or “engagement” in EIS remains highly variable. Dis/engagement as a contested concept and fluid process involving relationships between service providers and service users remains poorly understood. This study aimed to critically evaluate and explain the dynamic interplay of service provider-user relationships in effecting dis/engagement from an early intervention program for psychosis.MethodsForty study participants, 16 service providers and 24 service users (19 current and 5 disengaged) from a Canadian EIS program, were administered semi-structured interviews. Qualitative analysis was conducted using grounded theory methods, with findings captured and reconceptualized in a novel explanatory model.FindingsA model of engagement with eight major domains of engagement in EIS positioned along a control-autonomy spectrum was developed from the findings, with Clinical engagement (attendance) and Life engagement (life activities) at opposite ends of the spectrum, interspersed by six intermediate domains: Medication/treatment, Symptoms/illness, Mental health, Physical health/wellness, Communication, and Relationships, each domain bearing uniquely on engagement.ConclusionsAn examination of service user and service provider perspectives on the various domains identified in the spectrum model, and their dynamic interplay, reveals the complexity of choices faced by service users in engaging and not engaging with services.

Background: Psychosocial interventions, crucial for recovery in patients with schizophrenia, have often been developed and tested in high income countries. We aimed at developing and validating home-based a booklet based psycho-social intervention with inputs from stakeholders: patients, families, and mental health professionals (MHP) for patients with schizophrenia and related disorders in low resource settings. Methods: We developed a preliminary version of psychosocial intervention booklets based on six themes derived from focus group discussions conducted with patients, families, and MHP. Initially, quantitative assessment of content validity was done by MHP on overall and Content Validity Index of individual items of the specific booklets, followed by in-depth interviews about their views. The booklets were modified based on their inputs. Further, pilot testing of manuals was done on the users - nine pairs of patients and caregivers followed by development of a final version of psycho-social intervention. Results: The percentage content validity of individual modules and overall booklets was ≥78.5% indicating good validity. Most MHP reported that the manuals were relevant and easy to use but were text-heavy, and lengthy. On pilot testing of modified manuals with patients and their family caregivers, majority (77.8%) of them found booklets useful and suggested that there should be separate booklets for both patients and caregivers for providing information and entering separate response for the activities, integrating helpful tips. Language should be simple. Finally, two sets of booklets (“info book” and “workbook”) named ‘Saksham’ (meaning empowered) were created with specific modules (viz., ‘Medicine adherence’, ‘Daily routine’, ‘Eating right’, ‘Physical activity’, ‘Physical health monitoring’, ‘Self-reliance’, and ‘Psychoeducation’) for patients and caregivers each, in two languages (Hindi and English). Conclusion: Booklets with modules for psychosocial interventions for patients with schizophrenia and their caregivers were developed after establishing content validity and pilot testing.

A stable, minimum physiological health status is required for patients to qualify for transplant or artificial organ support eligibility to ensure the recipient has enough reserve to survive the perioperative transplant period. Herein, we present a novel strategy to stabilize and improve patient clinical status through extracorporeal immunomodulation of systemic hyperinflammation with impact on multiple organ systems to increase eligibility and feasibility for transplant/device implantation. This involves treatment with the selective cytopheretic device (SCD), a cell-directed extracorporeal therapy shown to adhere and immunomodulate activated neutrophils and monocytes toward resolution of systemic inflammation. In this overview, we describe a case series of successful transition of pediatric and adult patients with multiorgan failure to successful transplant/device implantation procedures by treatment with the SCD in the following clinical situations: pediatric hemophagocytic lymphohistiocytosis, and adult hepatorenal and cardiorenal syndromes. Application of the SCD in these cases may represent a novel paradigm in increasing clinical eligibility of patients to successful transplant outcomes.

Background: Chemotherapy usually results in the premature shrinkage of thymic cells, often resulting in atrophy. However, in some children, the thymus has the potential to regenerate following the withdrawal of stimulus, resulting in an increase in thymic cells – called rebound/reactive thymic hyperplasia. This phenomenon often appears clinically and radiologically similar to lymphoma in the anterior mediastinum, leading to overtreatment. Case report: We report a 6-year-old boy with T-Lymphoblastic lymphoma (LL) who presented with mediastinal mass. He was treated with high risk ALL protocol and completed treatment uneventfully. Post-treatment PET-CT for routine assessment showed an anterior mediastinal mass with a SUVt of 4.64, highly suggestive of recurrence, however was finally diagnosed with thymic hyperplasia confirmed by biopsy. Conclusion: Pediatric hemato-oncologists and radiologists need to be aware of this phenomenon to avoid misdiagnosis and overtreatment. Relapse should always be confirmed by histopathological examination.

Abstract Psychotic disorders are highly heterogeneous. Understanding relationships between symptoms will be relevant to their underlying pathophysiology. We apply dimensionality-reduction methods across two unique samples to characterize the patterns of symptom organization. We analyzed publicly-available data from 153 participants diagnosed with schizophrenia or schizoaffective disorder (fBIRN Data Repository and the Consortium for Neuropsychiatric Phenomics), as well as 636 first-episode psychosis (FEP) participants from the Prevention and Early Intervention Program for Psychosis (PEPP-Montreal). In all participants, the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) were collected. Multidimensional scaling (MDS) combined with cluster analysis was applied to SAPS and SANS scores across these two groups of participants. MDS revealed relationships between items of SAPS and SANS. Our application of cluster analysis to these results identified: 1 cluster of disorganization symptoms, 2 clusters of hallucinations/delusions, and 2 SANS clusters (asocial and apathy, speech and affect). Those reality distortion items which were furthest from auditory hallucinations had very weak to no relationship with hallucination severity. Despite being at an earlier stage of illness, symptoms in FEP presentations were similarly organized. While hallucinations and delusions commonly co-occur, we found that their specific themes and content sometimes travel together and sometimes do not. This has important implications, not only for treatment, but also for research—particularly efforts to understand the neurocomputational and pathophysiological mechanism underlying delusions and hallucinations.

OBJECTIVES:. Acute kidney injury (AKI) requiring continuous kidney replacement therapy is a significant complication in ICU patients with mortality rates exceeding 50%. A dysregulated immune response can lead to systemic inflammation caused by hyperactivity of pro-inflammatory neutrophils and monocytes leading to tissue damage. The selective cytopheretic device (SCD) is an investigational medical device in a new class of cell-directed extracorporeal therapies distinct from cytokine adsorbers or filters, as it targets activated leukocytes. These leukocytes are the cellular sources driving this hyperinflammatory process. The objective of this report is to summarize the safety experience from clinical studies of the SCD in ICU patients with AKI or acute respiratory distress syndrome (ARDS) and multiple organ dysfunction (MOD). DATA SOURCES AND STUDY SELECTION:. The studies included in this report represent all relevant trials of the SCD conducted in patients with AKI or ARDS and MOD. Adverse event data, clinical laboratory data and mortality rates were described and summarized in this report. DATA EXTRACTION AND DATA SYNTHESIS:. Five clinical studies were included in this report, including four adult studies of AKI and/or ARDS and one pediatric AKI study, which involved 151 patients treated with the SCD in an ICU setting. Over 800 SCD sessions were deployed with an estimated 19,000 exposure hours with no device-related infections or attributable serious adverse events. Furthermore, there were no safety signals of leukopenia, thrombocytopenia, or other indications of immunodepletion or immunosuppression. CONCLUSIONS:. The SCD has shown to be a promising extracorporeal therapy with promising clinical results and a favorable safety profile. These studies support that the SCD can be added as a therapeutic intervention in critically ill AKI patient populations with multiple organ failure without adding additional safety risks.

Abstract Background Stigma associated with mental health challenges is a major barrier to service seeking among youth. Understanding how stigma impacts service-seeking decisions from the perspectives of youth remains underexplored. Such research is necessary to inform effective stigma reduction. Objective This study aims to understand how stigma influences service seeking among youth with mental health challenges. Methods Qualitative inquiry was taken using youth engagement, underpinned by pragmatism. Data were collected via 4 virtual focus groups with 22 purposively selected youth participants with lived experience of mental health challenges in Ontario, Canada. Focus group guides were developed collaboratively among research team members, including youth co-researchers. Data were analyzed inductively using reflexive thematic analysis. Results Three main themes were constructed from the data: point of entry into the system, being biomedicalized or trivialized, and paving the way for non-stigmatizing services. Initial contact with the mental healthcare system was seen to be affected by stigma, causing participants to delay contact or be refused services if they do not fit with an expected profile. Participants described a constant negotiation between feeling ‘sick enough’ and ‘not sick enough’ to receive services. Once participants accessed services, they perceived the biomedicalization or trivialization of their challenges to be driven by stigma. Lastly, participants reflected on changes needed to reduce stigma’s effects on seeking and obtaining services. Conclusion A constant negotiation between being ‘sick enough’ or ‘not sick enough’ is a key component of stigma from the perspectives of youth. This tension influences youth decisions about whether to seek services, but also service provider decisions about whether to offer services. Building awareness around the invisibility of mental health challenges and the continuum of wellness to illness may help to break down stigma’s impact as a barrier to service seeking. Early intervention models of care that propose services across the spectrum of challenges may prevent the sense of stigma that deters youth from accessing and continuing to access services.

Abstract Background System-level approaches that target social determinants of health are promising strategies to support substance use prevention, holistic youth development and wellbeing. Yet, the youth services system is largely based on individual-focused programs that do not adequately account for social determinants of health and place the responsibility for wellness on the individual. There is a need to understand how to enhance adoption of complex system-level approaches that support comprehensive youth development. The Icelandic Prevention Model (IPM) represents a collaborative initiative that takes an ecological, system-level approach to prevent substance use and promote wellness in youth. This research was designed to examine key stakeholder perceptions to better understand social motivations and contextual complexities that influence stakeholder support to garner community-level adoption of the IPM in a rural Canadian community. Methods This research applies a case study approach using qualitative interviews to explore strategies to support uptake in the early stages of IPM adoption associated with developing community buy-in and acceptance. A thematic analysis was applied using QSR NVivo. Results Nine interviews were conducted with community partners leading the implementation of the IPM. Three over-arching themes emerged from the data: 1) Motivating influences 2) Strategies to develop buy-in, and 3) Resistance to the adoption of the IPM. Findings reflect issues that affect behaviour change in system transformation in general as well as upstream prevention and the IPM, in particular. Conclusions The findings from this research describe critical insight derived from implementing community-driven initiatives that are designed to support health promotion. It contributes new scientific knowledge related to implementation of complex system-level innovations and practical information that is useful for communities interested in implementing the IPM or following similar approaches to prevent substance use.

Abstract Background While interventions have been developed and tested to help youth who have become disconnected from work and school, there is a paucity of research on young people’s intervention preferences. This study aims to understand young people’s preferred intervention outcomes and approaches for youth who are out of work and school. Methods Thirty youth participated in virtual focus groups. Transcripts were analyzed using thematic analysis. Results Youth want interventions and approaches that support them in (1) vocational readiness, (2) securing a job, and (3) mental health and well-being, while providing them with (4) high-contact, individualized, and integrated support. Conclusions Young people want interventions to be individualized and integrated, providing a high level of support for their educational and employment pursuits as well as their mental health and well-being. Incorporating youth's perspectives when designing interventions can increase intervention relevance and potentially service uptake, helping youth continue to pursue their educational and vocational goals.

Abstract Background Individuals with mental health problems have many insufficiently met support needs. Across sociocultural contexts, various parties (e.g., governments, families, persons with mental health problems) assume responsibility for meeting these needs. However, key stakeholders' opinions of the relative responsibilities of these parties for meeting support needs remain largely unexplored. This is a critical knowledge gap, as these perceptions may influence policy and caregiving decisions. Methods Patients with first-episode psychosis (n = 250), their family members (n = 228), and clinicians (n = 50) at two early intervention services in Chennai, India and Montreal, Canada were asked how much responsibility they thought the government versus persons with mental health problems; the government versus families; and families versus persons with mental health problems should bear for meeting seven support needs of persons with mental health problems (e.g., housing; help covering costs of substance use treatment; etc.). Two-way analyses of variance were conducted to examine differences in ratings of responsibility between sites (Chennai, Montreal); raters (patients, families, clinicians); and support needs. Results Across sites and raters, governments were held most responsible for meeting each support need and all needs together. Montreal raters assigned more responsibility to the government than did Chennai raters. Compared to those in Montreal, Chennai raters assigned more responsibility to families versus persons with mental health problems, except for the costs of substance use treatment. Family raters across sites assigned more responsibility to governments than did patient raters, and more responsibility to families versus persons with mental health problems than did patient and clinician raters. At both sites, governments were assigned less responsibility for addressing housing- and school/work reintegration-related needs compared to other needs. In Chennai, the government was seen as most responsible for stigma reduction and least for covering substance use services. Conclusions All stakeholders thought that governments should have substantial responsibility for meeting the needs of individuals with mental health problems, reinforcing calls for greater government investment in mental healthcare across contexts. The greater perceived responsibility of the government in Montreal and of families in Chennai may both reflect and influence differences in cultural norms and healthcare systems in India and Canada.

Abstract Background Individuals with mental health problems have multiple, often inadequately met needs. Responsibility for meeting these needs frequently falls to patients, their families/caregivers, and governments. Little is known about stakeholders' views of who should be responsible for these needs and there are no measures to assess this construct. This study’s objectives were to present the newly designed Whose Responsibility Scale (WRS), which assesses how stakeholders apportion responsibility to persons with mental health problems, their families, and the government for addressing various needs of persons with mental health problems, and to report its psychometric properties. Methods The 22-item WRS asks respondents to assign relative responsibility to the government versus persons with mental health problems, government versus families, and families versus persons with mental health problems for seven support needs. The items were modelled on a World Values Survey item comparing the government’s and people’s responsibility for ensuring that everyone is provided for. We administered English, Tamil, and French versions to 57 patients, 60 family members, and 27 clinicians at two early psychosis programs in Chennai, India, and Montreal, Canada, evaluating test–retest reliability, internal consistency, and ease of use. Internal consistency estimates were also calculated for confirmatory purposes with the larger samples from the main comparative study. Results Test–retest reliability (intra-class correlation coefficients) generally ranged from excellent to fair across stakeholders (patients, families, and clinicians), settings (Montreal and Chennai), and languages (English, French, and Tamil). In the standardization and larger confirmatory samples, internal consistency estimates (Cronbach’s alphas) ranged from acceptable to excellent. The WRS scored average on ease of comprehension and completion. Scores were spread across the 1–10 range, suggesting that the scale captured variations in views on how responsibility for meeting needs should be distributed. On select items, scores at one end of the scale were never endorsed, but these reflected expected views about specific needs (e.g., Chennai patients never endorsed patients as being substantially more responsible for housing needs than families). Conclusions The WRS is a promising measure for use across geo-cultural contexts to inform mental health policies, and to foster dialogue and accountability among stakeholders about roles and responsibilities. It can help researchers study stakeholders’ views about responsibilities, and how these shape and are shaped by sociocultural contexts and mental healthcare systems.

IntroductionMental health problems are common globally, and typically have their onset in adolescence and early adulthood—making youth (aged 11–25) an optimal target for prevention and early intervention efforts. While increasing numbers of youth mental health (YMH) initiatives are now underway, thus far few have been subject to economic evaluations. Here we describe an approach to determining the return on investment of YMH service transformation via the pan-Canadian ACCESS Open Minds (AOM) project, for which a key focus is on improving access to mental health care and reducing unmet need in community settings.ApproachAs a complex intervention package, it is hoped that the AOM transformation will: (i) enable early intervention through accessible, community-based services; (ii) shift care away toward these primary/community settings and away from acute hospital and emergency services; and (iii) offset at least some of the increased costs of primary care/community-based mental health services with reductions in the volume of more resource-intensive acute, emergency, hospital or specialist services utilized. Co-designed with three diverse sites that represent different Canadian contexts, a return on investment analysis will (separately at each site) compare the costs generated by the intervention, including volumes and expenditures associated with the AOM service transformation and any contemporaneous changes in acute, emergency, hospital or service utilization (vs. historical or parallel comparators). Available data from health system partners are being mobilized to assess these hypotheses.Anticipated resultsAcross urban, semi-urban and Indigenous sites, the additional costs of the AOM transformation and its implementation in community settings are expected to be at least partially offset by a reduction in the need for acute, emergency, hospital or specialist care.DiscussionComplex interventions such as AOM aim to shift care “upstream”: away from acute, emergency, hospital and specialist services and toward community-based programming which is more easily accessible, often more appropriate for early-stage presentations, and more resource-efficient. Carrying out economic evaluations of such interventions is challenging given the constraints of available data and health system organization. Nonetheless, such analyses can advance knowledge, strengthen stakeholder engagement, and further implementation of this public health priority.

Purpose: This research examines the implementation of the Icelandic Prevention Model (IPM) in Canada to identify opportunities revealed by the COVID-19 pandemic to re-design our social eco-system to promote wellbeing. This paper has two objectives: 1) to provide a conceptual review of research that applies the bioecological model to youth substance use prevention with a focus on the concepts of time and physical space use and 2) to describe a case study that examines the implementation of the IPM in Canada within the context of the COVID-19 pandemic. Method: Study data were collected through semi-structured qualitative interviews with key stakeholders involved in implementing the IPM. Results: Findings are organized within three over-arching themes derived from a thematic analysis: 1) Issues that influence time and space use patterns and youth substance use, 2) Family and community cohesion and influences on developmental context and time use and 3) Opportunities presented by the pandemic that can promote youth wellbeing. Conclusion: We apply the findings to research on the IPM as well as the pandemic to examine opportunities that may support primary prevention and overall youth wellbeing. We use the concepts of time and space as a foundation to discuss implications for policy and practice going forward.

Abstract Objectives There is growing policy impetus for including youth voices in health services research and health system reform. This article examines the perspectives of professionals in a mental healthcare organization charged with engaging young people as advisors in service transformation. Methods An institutional ethnography of a youth mental health services organization in Ontario, Canada, was conducted. Fieldwork consisted of twelve months of observation of meetings, interviews with youth advisors and adult service providers, with subsequent text analysis of engagement training and policy materials. The present article reports data from six adult professionals and related field observations. Results Service providers’ efforts to engage youth were observed in three areas: a) supporting youth's development as advisors, b) retaining and deepening youth participation while waiting for organizational change and c) embedding relationships between youth and adults at various levels within the system of care. This work denotes existing tensions between the values and ideals of youth engagement and the everyday demands of services delivery. Conclusion In this setting, a fundamental dimension of this work consisted of negotiating tensions between the policy enthusiasm for engagement and its realization in a health services context. In describing these contextual challenges, we outline implications for consideration by other youth mental health services. Engagement efforts that are authentic and sustained require resources and flexibility, and leadership commitment to instil service users’ perspectives throughout multiple levels within the organization.

Abstract Background Given high rates of mental health and substance challenges among youth and substantial system access barriers, system innovation is required. Integrated youth services (IYS) models aim to transform youth mental health and substance use services by creating integrative, collaborative models of care in youth-friendly settings. This study examines service provider perspectives on the key service components to include in IYS models. Method A discrete choice experiment modeled service provider preferences for the service components of IYSs. The sample includes 388 service provider/agency leader participants (age 18+) from youth-serving organizations in Ontario. Importance scores and utility values were calculated for 12 attributes represented by four levels each. Latent class analysis identified subgroups of participants with different preferences. Results The majority of participants were direct service providers working in larger organizations in the mental health and/or substance use sectors in large urban centers. Participants strongly endorsed service models that provide rapid access to the widest variety of culturally sensitive service options, with supplementary e-health services, in youth-focused community settings with evening and weekend hours. They prefer caregiver involvement in youth services and treatment decisions and support youth and family engagement. Latent class analyses reveal three segments of service providers: a Youth-Focused Service Accessibility segment representing 62.1% (241/388) of participants, a Service Options segment representing 27.6% (107/388) of participants, and a Caregiver Integration segment representing 10.3% (40/388) of participants. Within these segments, the degree of prioritization of the various service components differ; however, the overall endorsement of the service components remains largely consistent across classes for most attributes. The segments did not differ based on demographic or agency characteristics. Conclusions The core characteristics of IYS settings for youth with mental health and substance use challenges, i.e., rapid access to a wide range of youth-oriented services, are strong priorities of service providers and youth-serving agency leaders. These findings confirm that youth-oriented service providers endorse the importance and relevance of IYS models as a whole; strong service provider buy-in to the model is expected to facilitate development, implementation and scaling of IYS models. Hearing stakeholder perspectives, including those of service providers, youth, and caregivers, is essential to developing, effectively implementing, and scaling effective youth services.

Respiratory disorders, being one of the leading causes of disability worldwide, account for constant evolution in management technologies, resulting in the incorporation of artificial intelligence (AI) in the recording and analysis of lung sounds to aid diagnosis in clinical pulmonology practice. Although lung sound auscultation is a common clinical practice, its use in diagnosis is limited due to its high variability and subjectivity. We review the origin of lung sounds, various auscultation and processing methods over the years and their clinical applications to understand the potential for a lung sound auscultation and analysis device. Respiratory sounds result from the intra-pulmonary collision of molecules contained in the air, leading to turbulent flow and subsequent sound production. These sounds have been recorded via an electronic stethoscope and analyzed using back-propagation neural networks, wavelet transform models, Gaussian mixture models and recently with machine learning and deep learning models with possible use in asthma, COVID-19, asbestosis and interstitial lung disease. The purpose of this review was to summarize lung sound physiology, recording technologies and diagnostics methods using AI for digital pulmonology practice. Future research and development in recording and analyzing respiratory sounds in real time could revolutionize clinical practice for both the patients and the healthcare personnel.

BackgroundUniversity students are reporting concerning levels of mental health distress and challenges. University mental health service provider initiatives have been shown to be effective in supporting students’ mental health, but these services are often resource-intensive. Consequently, new approaches to service delivery, such as web-based and peer support initiatives, have emerged as cost-effective and efficient approaches to support university students. However, these approaches have not been sufficiently evaluated for effectiveness or acceptability in university student populations. ObjectiveThus, the overarching goal of this study was to evaluate a mental health service provider–presented versus peer-presented web-based mental health resilience–building video outreach program against a wait-list comparison group. MethodsParticipants were 217 undergraduate students (mean age 20.44, SD 1.98 years; 171/217, 78.8% women) who were randomly assigned to one of the intervention groups (mental health service provider–presented: 69/217, 31.8%; peer-presented: 73/217, 33.6%) or the wait-list comparison group (75/217, 34.6%). Participants in the intervention groups were asked to watch 3 brief skill-building videos addressing strategies for building mental health resilience, whereas the comparison group was wait-listed. The mental health service provider–presented and peer-presented video series were identical in content, with presenters using a script to ensure consistency across delivery methods, but the videos differed in that they were either presented by mental health service providers or university students (peers). All participants were asked to complete web-based self-report measures of stress, coping self-efficacy, social support, social connectedness, mindfulness, and quality of life at baseline (time 1), 6 weeks later (time 2, after the intervention), and 1-month follow-up (time 3). ResultsResults from a series of 2-way ANOVAs found no significant differences in outcomes among any of the 3 groups. Surprisingly, a main effect of time revealed that all students improved on several well-being outcomes. In addition, results for program satisfaction revealed that both the mental health service provider–presented and peer-presented programs were rated very highly and at comparable levels. ConclusionsThus, findings suggest that a web-based mental health resilience–building video outreach program may be acceptable for university students regardless of it being mental health service provider–presented or peer-presented. Furthermore, the overall increases in well-being across groups, which coincided with the onset and early weeks of the COVID-19 pandemic, suggest an unexpected pattern of response among university students to the early period of the pandemic. Limitations and barriers as well as research implications are discussed. Trial RegistrationClinicalTrials.gov NCT05454592; https://clinicaltrials.gov/ct2/show/NCT05454592

Abstract Background The management of an outbreak of endophthalmitis associated with intravitreal bevacizumab represents a challenging real-time process involving identification of cases, treatment and mitigation measures during the outbreak. We summarize the clinical presentation and management of a cluster of endophthalmitis cases from contaminated bevacizumab, in addition to mathematical probabilistic assessment of the number of cases that define an outbreak. Methods A retrospective study was conducted to assess the management of an endophthalmitis outbreak after intravitreal bevacizumab (IVB) administration. Demographic data, clinical information, individual patient management and public health reporting measures were reviewed. Outcomes of patients who received prophylactic antibiotics for endophthalmitis prevention were also reviewed. Binomial tail probability calculations were performed to determine the likelihood of clusters of endophthalmitis that could inform when an outbreak was evolving that would warrant more public health notification measures and communication. Results Forty-five eyes of 42 patients who received IVB from a single batch were reviewed. Four cases of endophthalmitis from Granulicatella adiacens, a nutritionally-variant Streptococcus species, were treated successfully with intravitreal antibiotics ± vitrectomy. Thirty-four of the remaining 41 eyes were treated with prophylactic intravitreal vancomycin with no additional cases of endophthalmitis. Outbreak management also included CDC, ASRS and public health authority notification. Binominal tail probabilities demonstrated the rarity of clusters from a single batch (i.e. ~ 1/10,000 for 2 cases; 1/2 million for 3 cases). However, given the U.S. scale of IVB administration, there is an 87% chance of a cluster ≧ 2 and a 1% chance of a cluster ≧ 3 cases annually, which may guide outbreak management. A process diagram was developed to incorporate patient management and public health measures when an outbreak is suspected. Conclusion Intravitreal antibiotics and vitrectomy were effective in the individual management of cases of endophthalmitis, and no serious adverse events occurred with prophylactic intravitreal vancomycin for at-risk eyes. Best practices for outbreaks should be evaluated, given their likelihood within the U.S. and the sight-threatening consequences of endophthalmitis.

Objective: To assess the health care costs and utilization in patients with hereditary hemorrhagic telangiectasia (HHT) in the United States. Patients and Methods: Retrospective analysis of patients with HHT diagnosed between 2007 and 2017 was performed using deidentified administrative claims data from the OptumLabs Data Warehouse. Adult patients with new (incident) diagnosis of HHT between January 1, 2007, and December 31, 2017, were included. Comparisons were made using the Wilcoxon rank sum test. Results: Three thousand nine hundred seventy-seven patients with a first diagnosis of HHT between 2007 and 2017 were identified, of which 3590 were matched 1:1 to non-HHT patients with similar baseline characteristics and comorbidities. These 3590 patients with HHT were 63.1% female and 83.9% white with a mean age of 51.1 ± 18.5 years, and a mean follow-up period of 3.2 ± 2.2 years (range, 1.0-11.7 years). Compared with the control group, the cumulative 5-year median total health care cost for patients with HHT was 41.4% higher ($21,118 vs $14,929; P < .001) in those with private commercial insurance and 31.7% higher ($35,462 vs $26,925; P < .001) in those with Medicare Advantage coverage. The median annual health care costs were significantly higher in patients with HHT with commercial insurance and Medicare Advantage in the first year after diagnosis ($4,333 vs $1,804; P < .001), and ($7,322 vs $5,245; P < .001), respectively, and remained higher throughout the duration of follow-up. Further analysis showed that outpatient clinic visits, hospital admission, imaging rates, invasive procedures, iron infusions, and blood transfusions were all significantly higher in the HHT group. Conclusion: Patients with HHT have significantly higher health care costs compared with a matched control group. A better understanding of the reasons underlying these cost differences will provide opportunities for patients, providers, and other stakeholders to better manage this rare condition.

Abstract Background Research in global mental health (GMH) has previously documented how contextual factors like political instability, poverty and poorly-funded health infrastructure continue to compromise effective and equitable mental health service delivery. There is a need to develop more feasible and evidence-based solutions through implementation research. This paper, one in a series pertaining to implementation in GMH projects worldwide, focuses on implementation factors influencing mental health service delivery. Methods This is a qualitative study carried out as part of a Theory of Change-driven evaluation of Grand Challenges Canada’s (GCC’s) Global Mental Health portfolio. Purposive sampling was used to recruit twenty-nine GCC grantees for interviews. A semi-structured interview schedule was used to guide the interviews which were recorded and subsequently transcribed. Transcripts were double-coded and analyzed in NVivo 11 using framework analysis. This paper reports results related to detection and treatment of mental illness, mental health promotion and prevention of mental illness. Results Key barriers included: lack of appropriate human resources and expertise for service delivery; lack of culturally appropriate screening tools and interventions; and difficulties integrating services with the existing mental health system. Formative research was a key driver facilitating the cultural adaptation of mental health detection, treatment, promotion and preventative approaches. Recruiting local providers and utilizing mHealth for improving screening, monitoring and data management were also found to be successful approaches in reducing workforce burden, improving sustainability, mental health literacy, participant engagement and uptake. Conclusions The study identifies a number of key barriers to and drivers of successful service delivery from the perspective of grantees implementing GMH projects. Findings highlight several opportunities to mitigate common challenges, providing recommendations for strengthening systems- and project-level approaches for delivering mental health services. Further, more inclusive research is required to inform guidance around service delivery for successful implementation, better utilization of funding and improving mental health outcomes among vulnerable populations in low-resource settings.

IntroductionMultiple stakeholders have recently called for greater research on the barriers to citizenship and community belonging faced by people with mental health challenges. Citizenship has been defined as a person’s access to the rights, roles, responsibilities, resources and relationships that help people feel a sense of belonging. Factors that may impact citizenship include financial precarity; intersecting forms of marginalization and oppression (e.g., racism); and the mental health care people receive. Research has yet to examine experiences of citizenship among youth with mental health challenges. To address this gap, this study will examine how youth experience citizenship; predictors of citizenship; how citizenship shapes recovery; and the degree to which youth are receiving citizenship-oriented care.MethodsThe research objectives will be evaluated using a multiphase mixed methods research design. Quantitative data will be collected cross-sectionally using validated self-report questionnaires. Qualitative data will be collected using a hermeneutic phenomenological method using semi-structured interviews and focus groups.AnalysesMultiple stepwise regression analyses will be used to determine predictors of citizenship and if of citizenship predict recovery. Pearson correlations will be computed to determine the relationship between participants’ perceived desire for, and receipt of citizenship-oriented care. Phenomenological analysis will be used to analyze qualitative data. Findings will then be mixed using a weaving method in the final paper discussion section.ConclusionFindings from this study may support the development of citizenship-oriented healthcare in Canada.

Nearly all young people use the internet daily. Many youth with mental health concerns, especially since the Covid-19 pandemic, are using this route to seek help, whether through digital mental health treatment, illness prevention tools, or supports for mental wellbeing. Videogames also have wide appeal among young people, including those who receive mental health services. This review identifies the literature on videogame interventions for young people, ages 12-29, and maps the data on game use by those with mental health and substance use problems, focusing on evidence for the capacity of games to support treatment in youth mental health services; how stakeholders are involved in developing or evaluating games; and any potential harms and ethical remedies identified. A systematic scoping review methodology was used to identify and assess relevant studies. A search of multiple databases identified a total of 8,733 articles. They were screened, and 49 studies testing 32 digital games retained. An adapted stepped care model, including four levels, or steps, based on illness manifestation and severity, was used as a conceptual framework for organizing target populations, mental health conditions and corresponding digital games, and study results. The 49 selected studies included: 10 studies (20.4%) on mental health promotion/prevention or education for undiagnosed youth (Step 0: 7 games); 6 studies (12.2%) on at-risk groups or suspected mental problems (Step 1: 5 games); 24 studies (49.0%) on mild to moderate mental conditions (Steps 2-3: 16 games); and 9 studies (18.4%) focused on severe and complex mental conditions (Step 4: 7 games). Two interventions were played by youth at more than one level of illness severity: the SPARX game (Steps 1, 2-3, 4) and Dojo (Steps 2-3 and 4), bringing the total game count to 35 with these repetitions. Findings support the potential integration of digital games in youth services based on study outcomes, user satisfaction, relatively high program retention rates and the potential usefulness of most games for mental health treatment or promotion/prevention. Most studies included stakeholder feedback, and involvement ratings were very high for seven games. Potential harms were not addressed in this body of research. This review provides an important initial repository and evaluation of videogames for use in clinical settings concerned with youth mental health.

Bevacizumab is now an emerging treatment option for severe hereditary hemorrhagic telangiectasia–related bleeding including epistaxis and gastrointestinal tract bleeding. The impact of long-term intravenous bevacizumab therapy on cardiac structure and function is unknown. We describe 3 patients receiving intravenous bevacizumab therapy for severe hereditary hemorrhagic telangiectasia–related bleeding who were found to have abnormal mobile masses on the mitral valve (n=2) and aortic valve (n=1). The clinical impact of these findings is unknown and requires further study.

Abstract Background Recurrent joint bleeding in hemophilia results in arthropathy and functional impairment. The relationship of arthropathy development and factor activity (FA) has not been reported in patients with FA levels 10% less than controls; those ≥40 years old with FA 20% less than controls. In the multivariable analysis, subjects with

Abstract Background This study aimed to identify predictors and perceived facilitators of positive change and posttraumatic growth in persons with a first episode of psychosis using a mixed methods convergent design. Methods In the quantitative component, 94 participants completed measures of posttraumatic growth and predictors of posttraumatic growth. The qualitative component involved in-depth interviews with 12 participants. Results Quantitative results revealed that being hospitalized for psychosis, spiritual coping, positive reframing and subjective recovery were significant predictors of posttraumatic growth. Qualitative findings revealed that positive change was perceived to be facilitated by the psychosis itself; receiving mental health services; drawing on personal and social resources and strategies; healing and recovering; a meaning-making and knowledge gaining process; and normative developmental processes. Conclusions Posttraumatic growth following a first episode of psychosis may therefore be facilitated by complex person-environment interactions.

Abstract Background Systems transformation for health promotion, involving engagement from multiple disciplines and levels of influence, requires an investment in partnership development. Integrated youth service is a collaborative model that brings organisations together to provide holistic care for youth. Frayme is an international knowledge translation network designed to support the uptake and scaling of integrated youth service. Social network analysis (SNA) is the study of relationships among social units and is useful to better understand how partners collaborate within a network to achieve major objectives. The purpose of this paper is to apply SNA to the Frayme network in order to (1) examine the level and strength of partnerships, (2) identify the strategies being employed to promote the main objectives and (3) apply the findings to current research in youth mental health and system transformation. Methods The PARTNER tool includes a validated survey and analysis software designed to examine partner interconnections. This tool was used to perform the SNA and 51 of the 75 partners completed the survey (14 researchers, 2 advisory groups and 35 organisations). A network map was created and descriptive frequencies were calculated. Results The overall network scores for the Frayme network were 20.6% for density, 81.5% for centralisation and 71.7% for overall trust. The Frayme secretariat received a 3.84 out of a possible 4 for value. In addition, the youth and family advisories each received a value score of 4 and all Leadership Team organisations received a score of 2.97 or above. Conclusions The Frayme secretariat links many partners who would otherwise be disconnected and acts as a significant conduit for novel information. Frayme may have the opportunity to enhance value perceptions among broader network members by profiling individual organisations and the potential leveraging opportunities that might exist through their work. These findings increase understanding with respect to the mechanisms of network development and will be helpful to inform partnership development in the future. In addition, they contribute to the literature with respect to knowledge translation practice as well as the scaling of collaborative interventions within youth mental health.

Age-friendly cities are crucial to achieve the WHO goal of healthy aging. Such cities promote opportunities for health, participation, and security, thus enhancing quality of life as people age. Older people commonly experience psychosocial challenges such as anxiety, depression, substance abuse, loss of autonomy, grief, fear, and loneliness. Australian and Canadian cities continue to seek innovation to improve healthy urban aging and create more age-friendly environments for older adults. There is increasing evidence on the effectiveness and feasibility of mobile technology in health promotion and closing psychological treatment gaps. Older adults have been demonstrated to engage frequently with mobile devices, particularly text messaging. In this article, we conceptualize the Text4HealthyAging, an evidence-based text messaging innovation to support healthy urban aging in Canadian and Australian cities.

BackgroundDigital stories—first-person, self-made, 2- to 3-minute videos—generate awareness, impart knowledge, and promote understanding on topics such as mental illness. Digital stories are a narrative-based art form often created by individuals without formal training in filmmaking to relate personal experiences. Somewhat like digital narratives, video testimonies created within the social marketing or fundraising campaigns of government agencies and private or public corporations aim to reduce the stigma of mental illness while supporting research and services. In video testimonies, personal stories are captured on camera by professional filmmakers. Sharing critical life events greatly benefits tellers and listeners alike, supporting catharsis, healing, connectiveness, and citizenship. ObjectiveThis study explores digital stories and video testimonies featuring mental illness and recovery in their ability to elicit empathy and compassion while reducing stigma among viewers. MethodsUsing mixed methods, phase 1 will involve a search of Canadian social marketing activities and fundraising campaigns concerning mental illness and recovery. Phase 2 will involve the organization of digital storytelling workshops in which participants will create digital stories about their own experiences of mental illness and recovery. In phase 3, a pilot randomized controlled trial will be undertaken to compare marketing and fundraising campaigns with digital stories for their impact on viewers, whereas phase 4 will focus on knowledge dissemination. ResultsEthics approval for this study was received in March 2021. Data on the feasibility of the study design and the results of the controlled trial will be generated. This study will produce new knowledge on effective ways of promoting mental health awareness and decreasing stigma, with practical importance for future social marketing and fundraising campaigns. The anticipated time for completion within the 2-year study period includes 9 months for phase 1 (knowledge synthesis activities identifying social marketing and fundraising campaigns) and phase 2 (storytelling workshops), 11 months for phase 3 (feasibility assessment and data collection: randomized controlled trial), and 2 months for phase 4 (knowledge dissemination). ConclusionsThe knowledge generated will have practical implications for the public and for future social marketing and fundraising campaigns promoted by government agencies as well as nonprofit and for-profit organizations by enhancing our understanding of how individuals and societies respond to stories of mental distress and what prompts citizens to help others. Trial RegistrationClinicalTrials.gov NCT04881084; https://clinicaltrials.gov/ct2/show/NCT04881084 International Registered Report Identifier (IRRID)PRR1-10.2196/33525

Introduction The primary aim of the National Institute of Health Research-funded global health research group, Warwick-India-Canada (WIC), is to reduce the burden of psychotic disorders in India. India has a large pool of undetected and untreated patients with psychosis and a treatment gap exceeding 75%. Evidence-based packages of care have been piloted, but delivery of treatments still remains a challenge. Even when patients access treatment, there is minimal to no continuity of care. The overarching ambition of WIC programme is to improve patient outcomes through (1) developing culturally tailored clinical interventions, (2) early identification and timely treatment of individuals with mental illness and (3) improving access to care by exploiting the potential of digital technologies.Methods and analysis This multicentre, multicomponent research programme, comprising five work packages and two cross-cutting themes, is being conducted at two sites in India: Schizophrenia Research Foundation, Chennai (South India) and All India Institute of Medical Sciences, New Delhi (North India). WIC will (1) develop and evaluate evidence-informed interventions for early and first-episode psychosis; (2) determine pathways of care for early psychosis; (3) investigate the efficacy and cost-effectiveness of community care models, including digital and mobile technologies; (4) develop strategies to reduce the burden of mental illnesses among youth; (5) assess the economic burden of psychosis on patients and their carers; and (6) determine the feasibility of an early intervention in psychosis programme in India.Ethics and dissemination This study was approved by the University of Warwick’s Biomedical and Scientific Research Ethics Committee (reference: REGO-2018-2208), Coventry, UK and research ethics committees of all participating organisations. Research findings will be disseminated through peer-reviewed scientific publications, presentations at learnt societies and visual media.

Abstract Background Systemic bevacizumab is a novel targeted anti-angiogenic therapy for high-output cardiac failure (HOCF) in hereditary hemorrhagic telangiectasia (HHT) but published data is limited. This survey-based study measured physician-reported safety, effectiveness and current treatment practices for systemic bevacizumab in HHT-HOCF. Methods A 27-item survey was sent to center directors of 31 international HHT Centers of Excellence. Results Response rate was 74% with centers reporting 150 total patients receiving systemic bevacizumab for HHT-HOCF. Approximately two-thirds of centers had treated ≥5 patients. All centers utilize a 5 mg/kg dose for induction treatment and most administer 6 doses (range, 4–6) every 2 weeks, although maintenance regimens varied considerably. Center directors reported bevacizumab to be effective, with 55% reporting significant improvement in cardiac index and HOCF symptoms in most patients treated with bevacizumab, although normalization of cardiac parameters was uncommon. Adverse events were uncommon with three-quarters of centers reporting adverse event rates

Abstract Background Many Canadian adolescents and young adults with mental health problems face delayed detection, long waiting lists, poorly accessible services, care of inconsistent quality and abrupt or absent inter-service transitions. To address these issues, ACCESS Open Minds, a multi-stakeholder network, is implementing and systematically evaluating a transformation of mental health services for youth aged 11 to 25 at 14 sites across Canada. The transformation plan has five key foci: early identification, rapid access, appropriate care, the elimination of age-based transitions between services, and the engagement of youth and families. Methods The ACCESS Open Minds Research Protocol has multiple components including a minimum evaluation protocol and a stepped-wedge cluster randomized trial, that are detailed in this paper. Additional components include qualitative methods and cost-effectiveness analyses. The services transformation is being evaluated at all sites via a minimum evaluation protocol. Six sites are participating in the stepped-wedge trial whereby the intervention (a service transformation along the key foci) was rolled out in three waves, each commencing six months apart. Two sites, one high-population and one low-population, were randomly assigned to each of the three waves, i.e., randomization was stratified by population size. Our primary hypotheses pertain to increased referral numbers, and reduced wait times to initial assessment and to the commencement of appropriate care. Secondary hypotheses pertain to simplified pathways to care; improved clinical, functional and subjective outcomes; and increased satisfaction among youth and families. Quantitative measures addressing these hypotheses are being used to determine the effectiveness of the intervention. Discussion Data from our overall research strategy will help test the effectiveness of the ACCESS Open Minds transformation, refine it further, and inform its scale-up. The process by which our research strategy was developed has implications for the practice of research itself in that it highlights the need to actively engage all stakeholder groups and address unique considerations in designing evaluations of complex healthcare interventions in multiple, diverse contexts. Our approach will generate both concrete evidence and nuanced insights, including about the challenges of conducting research in real-world settings. More such innovative approaches are needed to advance youth mental health services research. Trial registration number Clinicaltrials.gov, ISRCTN23349893 (Retrospectively registered: 16/02/2017).

Objective: To identify preoperative factors predicting early admission (within 30 days) of adult kidney transplant recipients to the intensive care unit (ICU). Patients and Methods: This is a single-center retrospective study of consecutive kidney transplant recipients between January 1, 2007, and December 31, 2016. Children (aged

The purpose of this research paper is to offer/propose a framework/model of specific imaginative practices, classroom engagement ideas, and implementation pathways that can be adapted across various grade levels within the K-12 (preferably language and literacy) classrooms to utilize the inherent diversity (of lived experiences) amongst the learners as a resources for fostering equity, diversity, and inclusion (EDI) in the classroom while simultaneously generating ‘new’ knowledge for learning and sense-making. Essentially, the framework proposed will afford expressive outlets into the curriculum via imaginative practices that are designed to allow opportunities for critical literacy learning by bringing common experiences and issues to the fore (utilizing dialogic comprehension-as-sensemaking pedagogy) and thus perpetuating diversity consciousness. The paper also includes a mock-up (i.e. present an example for each step in the framework when possible) of the proposed model in the hope that it will provide an impetus to teacher scholars and educators interested in adapting/including the framework into their classroom.

In this opinion article, we highlight that the cultural policy of language in India has resulted in an impasse in regard to determining and deciding upon a national language policy. We then summarize how English use across India has been elevated to the status of a lingua franca (amidst the language policy impasse), making it an indispensable part of the system and the economy. In that context, this opinion article presents the various tenets of the language policy issue with recommendations for educators in India on how to utilize best practices from literacy, culture, and language education (LCLE) literature to improve and maintain the quality of education whilst operating within the confines of the language policy impasse.

Abstract Currently described hyperkalemia (HK) animal models are typically acute and cause significant distress and mortality to the animals, warranting new approaches for studying chronic HK in a more appropriate clinical setting. Using the spontaneously hypertensive rat (SHR) model as a more relevant disease template, as well as surgical (unilateral nephrectomy), dietary (3% potassium [K+] supplementation), and pharmacological (amiloride) interventions, we were able to stably induce HK on a chronic basis for up to 12 weeks to serum K+ elevations between 8 and 9 mmol/L, with minimal clinical stress to the animals. Short‐term proof‐of‐concept and long‐term chronic studies in hyperkalemic SHRs showed concomitant increases in serum aldosterone, consistent with the previously reported relationship between serum K+ and aldosterone. Treatment with the K+ binder patiromer demonstrated that the disease model was responsive to pharmacological intervention, with significant abrogation in serum K+, as well as serum aldosterone to levels near baseline, and this was consistent in both short‐term and long‐term 12‐week chronic studies. Our results demonstrate the feasibility of establishing a chronic HK disease state, and this novel HK animal model may be suitable for further evaluating the effects of long‐term, K+‐lowering therapies on effects such as renal fibrosis and end‐organ damage.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHT-associated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, epistaxis severity score, red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. 238 HHT patients received bevacizumab for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% CI, 2.9-3.5 g/dL) [mean hemoglobin 8.6 (8.5, 8.8) g/dL versus 11.8 (11.5, 12.1) g/dL, p

Summary: Background: The Lancet Commission on Global Surgery established the Three Delays framework, categorising delays in accessing timely surgical care into delays in seeking care (First Delay), reaching care (Second Delay), and receiving care (Third Delay). Globally, knowledge gaps regarding delays for fracture care, and the lack of large prospective studies informed the rationale for our international observational study. We investigated delays in hospital admission as a surrogate for accessing timely fracture care and explored factors associated with delayed hospital admission. Methods: In this prospective observational substudy of the ongoing International Orthopaedic Multicenter Study in Fracture Care (INORMUS), we enrolled patients with fracture across 49 hospitals in 18 low-income and middle-income countries, categorised into the regions of China, Africa, India, south and east Asia, and Latin America. Eligible patients were aged 18 years or older and had been admitted to a hospital within 3 months of sustaining an orthopaedic trauma. We collected demographic injury data and time to hospital admission. Our primary outcome was the number of patients with open and closed fractures who were delayed in their admission to a treating hospital. Delays for patients with open fractures were defined as being more than 2 h from the time of injury (in accordance with the Lancet Commission on Global Surgery) and for those with closed fractures as being a delay of more than 24 h. Secondary outcomes were reasons for delay for all patients with either open or closed fractures who were delayed for more than 24 h. We did logistic regression analyses to identify risk factors of delays of more than 2 h in patients with open fractures and delays of more than 24 h in patients with closed fractures. Logistic regressions were adjusted for region, age, employment, urban living, health insurance, interfacility referral, method of transportation, number of fractures, mechanism of injury, and fracture location. We further calculated adjusted relative risk (RR) from adjusted odds ratios, adjusted for the same variables. This study was registered with ClinicalTrials.gov, NCT02150980, and is ongoing. Findings: Between April 3, 2014, and May 10, 2019, we enrolled 31 255 patients with fractures, with a median age of 45 years (IQR 31–62), of whom 19 937 (63·8%) were men, and 14 524 (46·5%) had lower limb fractures, making them the most common fractures. Of 5256 patients with open fractures, 3778 (71·9%) were not admitted to hospital within 2 h. Of 25 999 patients with closed fractures, 7141 (27·5%) were delayed by more than 24 h. Of all regions, Latin America had the greatest proportions of patients with delays (173 [88·7%] of 195 patients with open fractures; 426 [44·7%] of 952 with closed fractures). Among patients delayed by more than 24 h, the most common reason for delays were interfacility referrals (3755 [47·7%] of 7875) and Third Delays (cumulatively interfacility referral and delay in emergency department: 3974 [50·5%]), while Second Delays (delays in reaching care) were the least common (423 [5·4%]). Compared with other methods of transportation (eg, walking, rickshaw), ambulances led to delay in transporting patients with open fractures to a treating hospital (adjusted RR 0·66, 99% CI 0·46–0·93). Compared with patients with closed lower limb fractures, patients with closed spine (adjusted RR 2·47, 99% CI 2·17–2·81) and pelvic (1·35, 1·10–1·66) fractures were most likely to have delays of more than 24 h before admission to hospital. Interpretation: In low-income and middle-income countries, timely hospital admission remains largely inaccessible, especially among patients with open fractures. Reducing hospital-based delays in receiving care, and, in particular, improving interfacility referral systems are the most substantial tools for reducing delays in admissions to hospital. Funding: National Health and Medical Research Council of Australia, Canadian Institutes of Health Research, McMaster Surgical Associates, and Hamilton Health Sciences.

Background: Hypereosinophilia (HE) is defined by the presence of >1.5 × 109/L eosinophils in the peripheral blood. Paraneoplastic HE has been reported in a number of solid and hematologic malignancies including ovarian cancer. We present a case with paraneoplastic HE in the setting of underlying endometrioid ovarian carcinoma. Case presentation: An 88-year-old woman presented with cough, dyspnea and 20-pound unintentional weight loss of one month duration. Evaluation revealed peripheral hypereosinophilia (HE) with absolute eosinophil count of 15.38 × 109/L (53.8%) and an elevated exhaled nitric oxide at 172 parts per billion (normal

Pneumocystis pneumonia affects immunocompromised hosts. The typical imaging finding is bilateral diffuse ground glass opacities. Here we presented a case of Pneumocystis causing biopsy-confirmed cavitary lung lesions in a patient with a predominant B cell defect with common variable immune deficiency.

Background: While chemotherapeutic agents result in an improvement in both disease-free and overall survival in cancer patients, treatment can result in short and long-term complications. One well-known complication is neuropathy which can result from a number of chemotherapeutic agents. However, chemotherapy-induced phrenic neuropathy is an exceedingly rare phenomenon with few cases reported in the literature. Case: A 34-year-old male with metastatic testicular cancer presented with progressive dyspnea on exertion after initiation of chemotherapy with bleomycin, cisplatin, and etoposide. Multiple diagnostic studies were performed including pulmonary function testing, chest computed tomography, fluoroscopic sniff evaluation, in addition to phrenic nerve electromyography. Based on results of these tests, the diagnosis of chemotherapy-induced phrenic neuropathy was made. Conclusion: Chemotherapy-induced phrenic neuropathy, although rare, should be considered as a cause of dyspnea in cancer patients following initiation of chemotherapy.

Abstract Background Vasoactive medications are essential in septic shock, but are not fully incorporated into current mortality prediction risk scores. We sought to develop a novel mortality prediction model for septic shock incorporating quantitative vasoactive medication usage. Methods Quantitative vasopressor use was calculated in a cohort of 5352 septic shock patients and compared using norepinephrine equivalents (NEE), cumulative vasopressor index and the vasoactive inotrope score models. Having best discrimination prediction, log10NEE was selected for further development of a novel prediction model for 28-day and 1-year mortality via backward stepwise logistic regression. This model termed ‘MAVIC’ (Mechanical ventilation, Acute Physiology And Chronic Health Evaluation-III, Vasopressors, Inotropes, Charlson comorbidity index) was then compared to Acute Physiology And Chronic Health Evaluation-III (APACHE-III) and Sequential Organ Failure Assessment (SOFA) scores in an independent validation cohort for its accuracy in predicting 28-day and 1-year mortality. Measurements and main results The MAVIC model was superior to the APACHE-III and SOFA scores in its ability to predict 28-day mortality (area under receiver operating characteristic curve [AUROC] 0.73 vs. 0.66 and 0.60) and 1-year mortality (AUROC 0.74 vs. 0.66 and 0.60), respectively. Conclusions The incorporation of quantitative vasopressor usage into a novel ‘MAVIC’ model results in superior 28-day and 1-year mortality risk prediction in a large cohort of patients with septic shock.

Abstract Background It is essential to understand the mechanisms responsible for hepatocellular carcinoma (HCC) progression and chemoresistance in order to identify prognostic biomarkers as well as potential therapeutic avenues. Recent findings have shown that SLIT3 appears to function as a novel tumor suppressor gene in various types of cancers, yet its clinical correlation and role in HCC has not been understood clearly. Methods We determined the transcript levels of Slit3 in tumor and adjacent normal tissues within two cohorts (N = 40 and 25) of HCC patients, and correlated the gene expression with the clinicopathological data. Subsequently, the functional effects and underlying molecular mechanisms of Slit3 overexpression and/or repression were studied using cell-line and mouse models. Results Our results demonstrated a repression in Slit3 expression in nearly 50% of the HCC patients, while the overall expression of Slit3 inversely correlated with the size of the tumor in both cohorts of patients. Stable down-regulation of Slit3 in HCC cell-lines induced cell proliferation in vitro and tumor growth in vivo, while stable Slit3 overexpression repressed these effects. Molecular investigations showed that the stable Slit3 repression-induced cell proliferation was associated with a higher expression of β-catenin and a repressed GSK3β activity. Moreover, Slit3-repression induced chemoresistance to sorafenib, oxaliplatin and 5-FU through impairment of β-catenin degradation and induction of cyclin D3 and survivin levels. The effects induced by stable Slit3-repression were diminished by transient repression of β-catenin by siRNA approach. Conclusion This study suggests that Slit3 acts as a tumor suppressor in HCC by repressing the tumor growth and thus tumor progression. Low Slit3 level indicates a poor response of HCC cells to chemotherapy. Restoration or overexpression of Slit3 is a potential therapeutic approach to repress the tumor growth and enhance the efficacy of chemotherapeutic agents.

Bronchial Thermoplasty is a procedure that involves the delivery of radiofrequency energy during bronchoscopy to airways in order to selectively ablate airway smooth muscles. Bronchial Thermoplasty was approved by the FDA in 2010 and remains the only device based non-pharmacological treatment approach for severe asthma. We appraise the trials leading to the approval of Bronchial Thermoplasty in light of the FDA approval process. Current international guidelines regarding use of Bronchial Thermoplasty and emering pharmacological options for severe asthma are reviewed.