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BackgroundHypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [18F]Fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [18F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors.ResultsThirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMRmax) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [18F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMRmax and HV in [18F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [18F]FMISO uptake and variable changes in TMRmax and HV.Conclusions[18F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMRmax and HV in [18F]FMISO PET imaging.

PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. EXPERIMENTAL DESIGN: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. RESULTS: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. CONCLUSIONS: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

Abstract Objectives (1) To plot the trajectory of humoral and cellular immune responses to the primary (two‐dose) COVID‐19 mRNA series and the third/booster dose in B‐cell‐depleted multiple sclerosis (MS) patients up to 2 years post‐vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID‐19 infections on SARS CoV‐2‐specific immunity. Methods Sixty ocrelizumab‐treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre‐vaccination, and then 4, 12, 24, and 48 weeks post‐primary series, and 4, 12, 24, and 48 weeks post‐booster. Binding anti‐Spike antibody responses were assessed with multiplex bead‐based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live‐virus immunofluorescence‐based microneutralization assay. Spike‐specific cellular responses were assessed with IFNγ/IL‐2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)‐3 within T‐cell receptors (Adaptive Biotechnologies). A linear mixed‐effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses. Results The primary vaccination induced an 11‐ to 208‐fold increase in binding and neutralizing antibody levels and a 3‐ to 4‐fold increase in IFNγ/IL‐2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3‐ to 5‐fold increase in binding antibodies and 4‐ to 5‐fold increase in IFNγ/IL‐2, which were maintained for up to 1 year. Infections had a variable impact on immunity. Interpretation Humoral and cellular benefits of COVID‐19 vaccination in B‐cell‐depleted MS patients were sustained for up to 2 years when booster doses were administered.

Background There is a lack of knowledge regarding siblings’ experiences of being a brother or sister of a child with a life-threatening or life-limiting condition. Siblings’ perspectives are often expressed through their parents and not by siblings themselves. Method This study has a qualitative design within hermeneutic phenomenology. Thirteen siblings (ages 3–29) of children with cancer or genetic conditions participated in semi-structured interviews. Analyses followed a thematic analysis guided by van Manen’s lifeexistentials. Results One overall theme, “What about me?”, illustrates that siblings of children with LT/LL conditions are dealing with their own challenges and needs in the situation while also struggling to receive attention from their parents. The overall theme derives from three subthemes: living with heavy strains, feeling disregarded, and having needs of one’s own. Conclusion The study revealed that siblings’ own needs compete with the needs of the ill child, resulting in the risk of siblings taking a step back rather than expressing what they might actually need themselves. These findings can inform healthcare professionals on the importance of educating and supporting parents and the surrounding community close to the sibling, for example, by helping schoolteachers understand how to meet siblings’ needs.

Background: The perspectives of children with life-threatening or life-limiting (LT/LL) conditions have predominantly been conveyed through their parents rather than heard from the children themselves. Despite an increase in studies focusing on children’s perspectives in pediatric palliative care, this research remains limited, particularly in including children who are unable to express themselves orally. Objective: This study seeks to address gaps in existing knowledge, especially the limited inclusion of children’s perspectives and the exclusion of children with communicative and cognitive disabilities. The aim of this study was to explore the lived experiences of children living with LT/LL conditions. Design: The study has a qualitative, hermeneutic phenomenological design inspired by van Manen’s phenomenology of practice. Methods: Twelve children with cancer or genetic conditions participated. Due to the children’s varying cognitive and communicative abilities, multiple data collection methods were employed to capture the children’s perspectives, including interviews, interactions, descriptions of the children’s non-verbal expressions, and an adapted photo elicitation method. Data were analyzed using thematic analysis. Results: The findings showed that the children’s attention revolved around life rather than illness. The analysis revealed the presence of three themes: wanting to engage in life, being dependent on familiar relations, and the importance of cherished items. Conclusion: Professionals across various levels within pediatric palliative care should acknowledge children’s desire to engage in life despite serious illness and facilitate participation. Practices should be implemented to support children’s agencies and expressions of what is important to them. This recognition can guide care plans and interventions at all levels of pediatric palliative care when a child is living with an LT/LL condition. The study emphasizes that children with LT/LL conditions are children first and foremost, with a fundamental need to participate in meaningful activity, just like any other child.

Abstract Background Young adult (YA) cancer survivors are a growing, yet underserved population who often face significant and long-lasting cancer-related physical (e.g., pain, fatigue) and emotional (e.g., psychological distress) symptoms. Post-treatment symptoms can persist, disrupting YA’s abilities to complete goals consistent with their developmental stage (e.g., completing their education, achieving autonomy and independence, building their careers, establishing peer and romantic relationships, building their families). While symptom management has been identified as a significant issue in YA’s transitions to survivorship, the symptom management needs of this population largely go unmet. Methods We developed an eight-session, group-based behavioral intervention that is delivered using videoconferencing to address the unique symptom management needs of YA cancer survivors. The intervention was developed in conjunction with YA survivors, leading to the novel combination of traditional behavioral symptom coping strategies, home-based physical activity, strategies from contemporary cognitive-behavioral approaches (e.g., those derived from acceptance and commitment therapy, strategies to foster self-compassion), concepts from meaning centered psychotherapy, and behavioral strategies to improve communication and health care engagement. Participants receive printed intervention materials and access to a study-specific mobile application, both of which are used throughout the program. Herein, we report on a pilot study that is in progress. Recruitment has been completed. YA cancer survivors were recruited in cohorts of n = 10 or n = 11 (n = 61) and randomized to the intervention or waitlist control arms. All participants completed a baseline assessment and four additional assessments over 1 year, with each involving a battery of self-report measures. Discussion The primary objective is to evaluate intervention feasibility and acceptability. As a secondary objective, we will examine patterns of change in intervention targets (i.e., pain, fatigue, emotional distress, symptom interference). Changes from baseline among intervention targets will be estimated for each patient and compared between arms using unadjusted statistical testing. Unadjusted and adjusted multilevel modeling will be used to estimate the effect of the intervention on changes in intervention targets. Interaction models will be used to compare the trajectory of change over time between arms. We expect that this pilot trial will inform our future approach to identify, recruit, and retain participants and provide preliminary data to support a larger, fully powered randomized controlled trial evaluating the intervention. Trial registration NCT04035447 at clinicaltrials.gov; registered July 29, 2019.

Abstract Background Hypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [18F]Fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [18F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors. Results Thirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMRmax) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [18F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMRmax and HV in [18F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [18F]FMISO uptake and variable changes in TMRmax and HV. Conclusions [18F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMRmax and HV in [18F]FMISO PET imaging.

Abstract Background To strengthen palliative care for children in the Nordic countries, an updated status of current needs, resources, clinical services, education, and research is necessary to align and consolidate future research. A Nordic research collaboration initiative for children with palliative care needs was assembled in 2023. Building on this initiative, this paper presents an overview of pediatric palliative care (PPC) in the Nordic countries’ (a) population characteristics, (b) care models and setting of care, (c) education and training, and (d) research. Methods The Nordic initiative researchers collaboratively gathered and assessed available data on the characteristics of PPC within Denmark, Finland, Greenland, Iceland, Norway, the Faroe Islands, Sweden, and Åland. Data were compiled in a matrix with population characteristics, models- and setting of care, education and training, and areas of research in a Nordic context. The findings are narratively and descriptively presented, providing an overview of Nordic PPC. Results In total, the Nordic child population comprises around six million children (0–19 years), of which about 41.200 are estimated to be living with a life-limiting and/or life-threatening condition. Healthcare services are provided through various care models, ranging from specialized care to homecare settings. Overall, there remain few opportunities for education and training with some exceptions. Also, Nordic research within PPC has been shown to be a growing field although much remains to be done. Conclusion This overview is the first outline of the current PPC in Nordic countries. Although some differences remain important to acknowledge, overall, the strengths and challenges faced within PPC in the Nordic countries are comparable and call for joint action to increase evidence, services, and education to better serve the children, families, and healthcare personnel within PPC. Despite the varying structural premises for PPC, research endeavors aiming to provide evidence in this field seem increasing, timely and relevant for the Nordic countries, as well as the international context.

Abstract Background Pediatric palliative care (PPC) seeks to enhance the quality of life (QoL) for both children and their families. While most studies within PPC have focused on the ill child’s QoL, less is known about parents’ experiences of their own QoL. The aim of this study was to explore parents’ QoL when their child has a life-threatening or life-limiting condition. Methods The study has a qualitative, hermeneutic phenomenological design inspired by van Manen’s phenomenology of practice. In-depth interviews were conducted with 12 fathers and 12 mothers of children living with cancer or a genetic condition. A deeper understanding of parents’ lived experiences was obtained through an adapted photo elicitation method. Two rounds of thematic analysis were conducted, covering both the photo elicitation data, and interview data. Results The findings describe four themes related to parents’ QoL: living a normal life, giving my child a good life, having time to fulfill siblings’ needs, and feeling heard and respected in the health and social care system. Conclusions The complexity of elements shaping parents’ QoL is evident. The interconnectedness between parents, the ill child, siblings, and interactions with the health and social care system, highlights the need to understand and address diverse aspects in enhancing parents QoL.

BACKGROUND: Past research has not investigated both lower-extremity power and upper-extremity strength in the same fall injury study, particularly nonfracture fall injuries. METHODS: In the Osteoporotic Fractures in Men Study (baseline: N = 5 994; age 73.7 ± 5.9 years; 10.2% non-White), fall injuries (yes/no) were assessed prospectively with questionnaires approximately every 3 years over 9 years. Maximum leg power (Watts) from Nottingham single leg press and maximum grip strength (kg) from handheld dynamometry were assessed at baseline and standardized to kg body weight. Physical performance included gait speed (6-m usual; narrow walk) and chair stands speed. RESULTS: Of men with ≥1/4 follow-ups (N = 5 178; age 73.4 ± 5.7 years), 40.4% (N = 2 090) had ≥1 fall injury. In fully adjusted repeated-measures logistic regressions, lower power/kg and grip strength/kg had higher fall injury risk (trend across quartiles: both p < .0001), with lower quartiles at significantly increased risk versus highest Q4 except for grip strength Q3 versus Q4. Fall injury risk was 19% higher per 1 standard deviation (SD) lower power/kg (95% confidence interval [CI]: 1.12-1.26) and 16% higher per SD lower grip strength/kg (95% CI: 1.10-1.23). In models including both leg power/kg and grip strength/kg, odds ratios (ORs) were similar and independent of each other and physical performance (leg power/kg OR per SD = 1.13, 95% CI: 1.06-1.20; grip strength/kg OR per SD = 1.11, 95% CI: 1.05-1.17). CONCLUSIONS: Lower leg power/kg and grip strength/kg predicted future fall injury risk in older men independent of physical performance. Leg power potentially identifies fall injury risk better than grip strength at higher muscle function, though grip strength may be more suitable in clinical/practice settings.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

N, N' N"-triethylenethiophosphoramide (thiotepa) and cyclophosphamide (CP) are alkylating agents used for a variety of malignant and non-malignant disorders. Both drugs are metabolized by cytochrome P450 enzymes to form active metabolites. To support pharmacokinetic studies of thiotepa and CP in children, we sought to develop assays to determine parent drug and metabolite concentration in small volume plasma samples. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for assay development. CP metabolite 4-hydroxycyclophosphamide (4OHCP) was converted to the more stable semicarbazone derivative (4OHCP-SCZ) for quantitation. Samples (10 μL) were extracted by solid-phase extraction and injected onto the LC-MS/MS system equipped with a pentafluorophenyl reverse phase column (2.1 × 50 mm, 2.7 μm). Electrospray ionization in positive mode was used for detection. Multiple reaction monitoring of the precursor-to-product ion transitions m/z 190→147 for thiotepa, 174→131 for tepa, 261→233 for CP, and 334→221 for 4OHCP-SCZ was selected for quantification. The ion transitions m/z 202→155 for thiotepa-d12, 186→139 for tepa-d12, 267→237 for CP-d4, and 340→114 for 4OHCP-d4-SCZ were selected for the internal standard (IS) corresponding to each analyte. The less abundant IS ions from 37Cl were used for CP-d4 and 4OHCP-d4-SCZ to overcome the cross-talk interference from the analytes. Under optimized conditions, retention times were 0.67 min for tepa and its IS, 2.50 min for thiotepa and its IS, 2.52 min for 4OHCP-SCZ and its IS, and 2.86 min for CP and its IS. Total run time was 5 min per sample. The calibration ranges were 2.5-2,000ng/mL for thiotepa and tepa, 20-10,000ng/mL for CP and 20-5,000 ng/mL for 4OHCP; Dilution integrity for samples above the calibration range was validated with 10-fold dilution for thiotepa/tepa and 20-fold dilution for CP/4OHCP. Recoveries ranged from 86.3-93.4% for thiotepa, 86.3-89.0% for tepa, 90.2-107% for CP, and 99.3-115% for 4OHCP-SCZ. The IS normalized matrix effect was within (100±7) % for all 4 analytes. Plasma samples at room temperature were stable for at least 60 hours for thiotepa, 6 days for tepa, and 24 hours for CP and 4OHCP-SCZ. Plasma samples for thiotepa/tepa were stable after 4 freeze-thaw cycles, and for CP/4OHCP-SCZ were stable after 3 freeze-thaw cycles. The assays were validated and applied to clinical studies requiring small sample volumes.

KIT is a type 3 receptor tyrosine kinase that plays a crucial role in cellular growth and proliferation. Mutations in KIT can dysregulate its active-inactive equilibrium. Activating mutations drive cancer growth, while deactivating mutations result in the loss of skin and hair pigmentation in a disease known as piebaldism. Here, we propose a method based on molecular dynamics and free energy calculations to predict the functional effect of KIT mutations. Our calculations may have important clinical implications by defining the functional significance of previously uncharacterized KIT mutations and guiding targeted therapy.

The article discusses the Norwegian judicial framework for the work by boards of limited liability companies with sustainability. Sustainability regulation is no longer a result of more or less targeted political initiatives, it largely presents as a coherent system of rules and it has in many ways indisputably been integrated into the field of company law in Norway. The starting point for the analysis is that the boards of Norwegian limited liability companies and public limited liability companies are expected to create value for their owners, but they are also expected to do this in a sustainable manner. Therefore, we firstly give a description of the ‘company interestʼ and its central elements. The article seeks among other things to demonstrate the trade-off between profit seeking and the boardʼs right and duty to integrate sustainability in the management of the company. The boardʼs work on sustainability in limited liability companies and public limited liability companies must be carried out within the framework stipulated by company law and other legislation, the companyʼs articles of association, and the companyʼs other governing bodies. Neither the Limited Liability Companies Act nor the Public Limited Liability Companies Act includes any specific statutory regulation of sustainability. A starting point is, therefore, that the company law framework for the boardʼs work on sustainability is constituted by the general rules in the Companies Acts on the boardʼs right and duty to manage the company in accordance with the company interest. Norwegian company law is stakeholder-oriented and takes into account both shareholder interests and stakeholder interests. Company interest includes the interests of shareholders, employees, counterparties, creditors and society as a whole. As pointed out in the article, these interests include what can be described as ‘sustainability considerationsʼ. The boards of limited liability companies and public limited liability companies must exercise their management of the company within the statutory framework. This framework also includes mandatory legislation other than the Companies Acts, for example the legislation dealing with sustainability matters. For public limited companies listed on the stock exchange, the Norwegian Code of Practice for Corporate Governance includes a specific expectation that the board must integrate sustainability into its governance of the companyʼs business activities. Another important question is to what extent the board can attach importance to sustainability considerations. It is a prerequisite for companies to be able to consider environmental and social considerations that they are financially sustainable. However, it is conceivable that the profit motive can come into conflict with social and environmental considerations. The article discusses the balance between the profit motive and social and environmental considerations. One question deals with the boardʼs ability to attach weight to sustainability in the light of the companyʼs advertising and reputation values (‘goodwillʼ). The article discusses also the relationship between sustainability and the companyʼs ability to make gifts.

This paper introduces an experimental approach to study the distribution of power losses in an oil jet-lubricated planetary gear set, with the aim of increasing the efficiency of these gearboxes. A thermal model is developed to estimate power losses associated with temperature distribution. This model is applied to analyze experimental data collected from a dedicated test setup. Different configurations are studied to progressively validate the thermal network. In this paper, only a configuration composed of a rotating ring gear and a fixed planet carrier is studied. This configuration enables the validation of a thermal network developed from a basic configuration where power loss sources are not numerous. The study reveals that, for this configuration, load-independent power losses are primarily attributed to hydrodynamic losses in the bearings, while the gear windage effects are of second order. The power losses are then compared to those generated by the same planetary gear set but using a rotating planet carrier. The comparison shows that the configuration composed of the rotating ring gear and fixed planet carrier produces less power loss than the other configuration.

We examine the process of developing web-based case studies, a novel form of professional learning for principals, specifically related to inclusive school leadership. Based on the input from 39 principals, 5 case studies were developed with branching scenarios that provided multiple options for decision-making. These "choose your own adventure" case studies were used in a special education for school administrators course with 109 participants in Ontario, Canada. We consider the authenticity of the cases, the importance of incorporating multiple perspectives, and issues related to function, form, and choice. We incorporate five lessons for developing web-based case studies.

Objective: We evaluated the impact of a telemedicine bridge clinic on treatment outcomes and cost for patients with opioid use disorder. Telemedicine bridge clinics deliver low-barrier rapid assessment of patients with opioid use disorder via audio-only and audiovisual telemedicine to facilitate induction on medication therapy and connection to ongoing care. Methods: A pre-post analysis of UPMC Health Plan member claims was performed to evaluate the impact of this intervention on the trajectory of care for patients with continuous coverage before and after bridge clinic visit(s). Results: Analysis included 150 UPMC Health Plan members evaluated at the bridge clinic between April 2020 and October 2021. At least one buprenorphine prescription was filled within 30 days by 91% of patients; median proportion of days covered by buprenorphine was 73.3%, 54.4%, and 50.6% at 30, 90, and 180 days after an initial visit compared to median of no buprenorphine claims 30 days prior among the same patients. Patients had an 18% decline in unplanned care utilization 30 days after initial Bridge Clinic visit, with a 62% reduction in unplanned care cost per member per month (PMPM), 38% reduction in medical cost PMPM, and 10% reduction in total PMPM (medical + pharmacy cost) at 180 days. Primary care, outpatient behavioral health, and laboratory costs increased while emergency department, urgent care, and inpatient costs declined. Conclusion: Utilization of a telemedicine bridge clinic was associated with buprenorphine initiation, linkage to ongoing care with retention including medication treatment, reduced unplanned care cost, and overall savings.

Strenge restriksjoner under koronapandemien transformerte barnehagers hverdagsliv, noe som medførte endringer i handlings- og samhandlingsmønstre. Artikkelen presenterer deler av et forskningsprosjekt om konsekvensene av pandemien for barnehagesektoren gjennomført i 2020/2022. Studien hadde et mixed-method-design og inkluderte blant annet nærstudier i ni barnehager, informativ vlogg, hvor barnehagelærerne formidlet sine refleksjoner, fokussamtaler med barnehagelærerne, intervju med foreldre og samtaler med barna. Barnesamtalene ble gjennomført av barnehagelærerne i de deltakende barnehagene. Barnehagelærerne fungerte som medforskere i denne delen av studien. På grunn av restriksjonene ble nærstudiene gjennomført med digitale strategier. Vårt fokus her er på barnas opplevelser. Tre typer restriksjoner fremsto som betydningsfulle for barnas handlingsrom: territoriale restriksjoner (hvor barna kunne oppholde seg), materielle restriksjoner (tilgang til leketøy og materiell) og relasjonelle restriksjoner (hvem barna kunne være sammen med). For barna handlet det om å balansere kollektivt ansvar for fellesskapet opp mot individuelle rettigheter og ønsker. Barna i vår studie viste høy grad av lojalitet og tilpasset seg stadige endringer. Det kan muligens tilskrives den unisone formidlingen av alvoret i situasjonen og ansattes vilje og evne til å kommunisere med barna om årsakene til endrede rutiner og organiseringsmåter. Vi stiller spørsmål om hvilke valg og muligheter for innflytelse barna hadde i tilpassingen til den nye «normaliteten». English abstract “That’s the Way it Has to Be Now.” Children’s Agency in Kindergartens During the COVID-19 Pandemic Strict restrictions during the COVID-19 pandemic changed daily life in kindergartens and led to changes in agency and interaction. The article presents parts of a research project concerning the consequences of the pandemic for the kindergarten sector conducted in 2020/2022. The study had a mixed-method design and included close studies in nine kindergartens and an informative vlog, where the kindergarten teachers communicated their reflections, focus conversations with the kindergarten teachers, interviews with parents, and conversations with children. The teachers in the participating kindergartens conducted the conversations with the children and served as co-researchers in this part of the study. Due to the restrictions, the studies were conducted using digital strategies. Our focus is on the children’s experiences. Three types of restrictions seemed to be significant for the children’s agency: territorial restrictions (where the children could stay), material restrictions (access to toys and materials), and relational restrictions (who the children could be with). For the children, it was a question about balancing collective responsibility for the community with individual rights and desires. The children in our study showed a high degree of loyalty and adapted to constant changes. This can possibly be attributed to the unanimous communication of the seriousness of the situation and the staff’s willingness and ability to communicate with the children about the reasons for changed routines and organizational methods. We ask what choices and opportunities for influence the children had in adapting to the new “normal.”

The offshore Northern shrimp (Pandalus borealis) bottom trawl fishery in eastern Canada currently uses 22 and 28 mm bar spacing Nordmøre grids to limit bycatch from using small mesh codends. However, a recent rebound of juvenile redfish (Sebastes spp.), that can pass through the grids, has greatly increased bycatch. To address this concern, this study investigated the effectiveness of 17 and 15 mm bar spacing Nordmøre grids in a twin-trawl (paired) configuration against the traditional 22 mm bar spacing grid. Size selectivity analyses showed that the 17 and 15 mm grids resulted in no significant reduction in shrimp catch across all length classes. The 17 mm grid significantly reduced redfish bycatch for all length classes and the 15 mm grid significantly reduced redfish bycatch for individuals larger than 95 mm total length. Less redfish entered the codend with the experimental grids, however, the overlap in width between redfish and Northern shrimp limits the overall sorting efficiency of the grids, leaving some redfish still vulnerable to capture.

Abstract Background Measuring outcomes facilitates evaluation of palliative services for children, adolescents, and young adults (CAYAs) with life-limiting and/or life-threatening (LL/LT) conditions. Implementation of patient-reported, proxy-reported, or patient-centered outcome measures (hereafter PROMs) is recommended to ensure palliative services. The purpose of this scoping review was to provide an overview of PROMs relevant for CAYAs living with LL/LT conditions eligible for pediatric palliative care (PPC). Methods Arksey and O’Malley’s 6-stage scoping review framework was used to guide the review. The identified citations had to report on PROMs in any context including CAYAs with LL/LT conditions up to 25 years of age. A systematic search of Medline, EMBASE, CINAHL, APA PsycInfo, Health and Psychosocial Instruments, and AMED took place in January 2021 and was updated in June 2022. Citations were screened independently by pairs of researchers. The scoping review protocol was registered, and peer-review published. Results Of 3690 identified citations, 98 reports were included, of which the majority were from Western countries and about PROMs in CAYAs living with cancer or organ failure. A total of 80 PROMs were identified, assessing a range of phenomena, where quality of life and symptoms (especially pain) during the stage of ongoing care were the most frequent. There were only a few reports about outcome measures at time of diagnosis or in end-of-life care. CAYAs self-reported on the PROMs or collaborated with their parents in about half of the reports, while the remaining had proxies answering on behalf of the CAYAs. In the identified reports, PROMs were used to characterize a sample through cross-sectional or longitudinal research, and less often to assess effects of interventions. Conclusion The identified PROMs in the CAYA population eligible for PPC is characterized by studies in high-income countries during ongoing care, primarily in patients with cancer or organ failure. More research is needed in patients living with other LL/LT conditions, and during different stages of the disease course, especially at time of diagnosis, during transition to adulthood, and in end-of-life care. This scoping review of PROMs relevant for young patients eligible for PPC may inform future research about patient-/proxy-reported or patient-centered outcome measures in PPC. Trial registration Review registration: ( https://osf.io/yfch2/ ) and published protocol (Holmen et al. Syst Rev. 10:237, 2021).

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.

Objective: To better understand the strategies family caregivers of children with medical complexity (CMC) utilize to deal with the stress and challenges associated with caregiving. Methods: We conducted a cross-sectional qualitative study among family caregivers of CMC receiving medical care at a children’s hospital in Western Pennsylvania. Participants completed in-depth, semi-structured interviews focused on how CMC family caregivers approach and manage caregiving-related challenges and stress. Using constant comparative methodology, we inductively analyzed deidentified transcripts for emergent themes. Results: We interviewed 19 participants (89.4% female) with a mean age of 43 years (range 32–54 years). The mean age of the participants’ children was 10.8 years (range 1–20 years). Twelve participants’ children identified as white and four identified as Black. Three central themes regarding CMC caregivers’ stress-coping strategies emerged: (1) maintaining a positive mindset, (2) developing and relying on interpersonal support networks, and (3) making time for self-preservation. All three themes were universally reported (n = 19/19) by our participants. The most common subthemes for each theme, respectively, focused on staying hopeful and celebrating moments of joy; cultivating supportive relationships with family, friends, and fellow CMC family caregivers; and finding pleasure in “little things” (e.g., everyday activities and hobbies). Conclusion: Family caregivers of CMC utilize a multi-faceted approach to cope with the stress and challenges routinely encountered in caring for CMC. This study’s findings could be used to inform future clinical efforts and research directions aiming to improve clinicians’ ability to support CMC caregivers’ well-being.

The transition from wakefulness to sleep occurs when the core body temperature decreases. The latter is facilitated by an increase in the cutaneous blood flow, which dissipates internal heat into the micro-environment surrounding the sleeper’s body. The rise in cutaneous blood flow near sleep onset causes the distal (hands and feet) and proximal (abdomen) temperatures to increase by about 1 °C and 0.5 °C, respectively. Characterizing the dynamics of skin temperature changes throughout sleep phases and understanding its relationship with sleep quality requires a means to unobtrusively and longitudinally estimate the skin temperature. Leveraging the data from a temperature sensor strip (TSS) with five individual temperature sensors embedded near the surface of a smart bed’s mattress, we have developed an algorithm to estimate the distal skin temperature with a minute-long temporal resolution. The data from 18 participants who recorded TSS and ground-truth temperature data from sleep during 14 nights at home and 2 nights in a lab were used to develop an algorithm that uses a two-stage regression model (gradient boosted tree followed by a random forest) to estimate the distal skin temperature. A five-fold cross-validation procedure was applied to train and validate the model such that the data from a participant could only be either in the training or validation set but not in both. The algorithm verification was performed with the in-lab data. The algorithm presented in this research can estimate the distal skin temperature at a minute-level resolution, with accuracy characterized by the mean limits of agreement [−0.79 to +0.79 °C] and mean coefficient of determination R2=0.87. This method may enable the unobtrusive, longitudinal and ecologically valid collection of distal skin temperature values during sleep. Therelatively small sample size motivates the need for further validation efforts.

This study explores the correlation between learning about basic form factors and learning automotive exterior design (AED) for the first time. To help beginner AED students learn smoothly, we developed modular courses and proposed to teach basic form generation. Six modular assignments were developed for the courses on Form Theory and Transportation Design, and 22 and 20 students, respectively, completed all the assignments of each course. All students were guided to become familiar with the five form factors: proportion, contour, volume, surface, and detail. According to the student self-assessments and responses for the Form Theory course, students gained a statistically equivalent learning experience of form factors from the four assignments; however, they gained significantly different levels of understanding and confidence. There was also a significant difference in understanding form factors during AED clay modeling. Further, students considered that the last two assignments in the Form Theory course had a significantly stronger relationship with learning AED than the first two assignments did. These findings are conducive to ensuring improvements in the modular courses to help future students begin learning AED.

COVID-19 represented a challenge for health care worldwide and led to new tasks and a rethinking of resource use. It was necessary to establish capacity within hospitals and to reassign critical resources between hospitals. This study aimed to explore pediatric nurses’ experiences of redeployment, new tasks, and use of specialized competencies during the first wave of COVID-19. An exploratory design, involving qualitative individual interviews with 12 pediatric nurses was used. The analysis resulted in 3 main themes. Firstly, a feeling of social responsibility focused on how pediatric nurses felt committed to use their competencies during the crisis, whether they remained on the pediatric ward or were redeployed. Secondly, fewer children to counterbalance the shortage of pediatric nurses showed how redeployment was offset by fewer pediatric patients. Thirdly, adapting pediatric nursing competencies to new tasks described how the nurses adapted their skills to new tasks either in pediatric or adult wards. The results revealed that pediatric nurses had a social and ethical commitment to society in a crisis. They agreed to be redeployed and take on new tasks but were still concerned about the health and well-being of the children and their families, which led to a sense of ambivalence. They questioned whether their skills were being used appropriately in redeployment to adult wards. Fewer pediatric patients mitigated the workload of the remaining nurses. There is a risk of neglecting the needs of hospitalized children and their families during a pandemic. There was concern that “voluntary coercion” was a counterproductive strategy for reassignment.

IntroductionInsomnia causes serious adverse health effects and is estimated to affect 10–30% of the worldwide population. This study leverages personalized fine-tuned machine learning algorithms to detect insomnia risk based on questionnaire and longitudinal objective sleep data collected by a smart bed platform.MethodsUsers of the Sleep Number smart bed were invited to participate in an IRB approved study which required them to respond to four questionnaires (which included the Insomnia Severity Index; ISI) administered 6 weeks apart from each other in the period from November 2021 to March 2022. For 1,489 participants who completed at least 3 questionnaires, objective data (which includes sleep/wake and cardio-respiratory metrics) collected by the platform were queried for analysis. An incremental, passive-aggressive machine learning model was used to detect insomnia risk which was defined by the ISI exceeding a given threshold. Three ISI thresholds (8, 10, and 15) were considered. The incremental model is advantageous because it allows personalized fine-tuning by adding individual training data to a generic model.ResultsThe generic model, without personalizing, resulted in an area under the receiving-operating curve (AUC) of about 0.5 for each ISI threshold. The personalized fine-tuning with the data of just five sleep sessions from the individual for whom the model is being personalized resulted in AUCs exceeding 0.8 for all ISI thresholds. Interestingly, no further AUC enhancements resulted by adding personalized data exceeding ten sessions.DiscussionThese are encouraging results motivating further investigation into the application of personalized fine tuning machine learning to detect insomnia risk based on longitudinal sleep data and the extension of this paradigm to sleep medicine.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.

Abstract Objective This study aimed to evaluate safety (infusion‐related reactions [IRRs]) and patient satisfaction (patient‐reported outcomes [PROs]) for at‐home ocrelizumab administration for patients with multiple sclerosis (MS). Methods This open‐label study included adult patients with an MS diagnosis who had completed a ≥ 600‐mg ocrelizumab dose, had a patient‐determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600‐mg ocrelizumab home‐based infusion over 2 h, followed by 24‐h and 2‐week post‐infusion follow‐up calls. IRRs and adverse events (AEs) were documented during infusions and follow‐up calls. PROs were completed before and 2 weeks post infusion. Results Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)—similar to other shorter ocrelizumab infusion studies—and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at‐home infusion process and confidence in the care provided. Patients also reported a significant preference for at‐home infusion compared with prior infusion center experiences. Interpretation IRRs and AEs occurred at acceptable rates during in‐home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home‐based ocrelizumab infusion over a shorter infusion period.