Management of paediatric monomorphic post-transplant lymphoproliferative disorders with low-intensity treatment: A multicentre international experience.

BACKGROUND: Monomorphic post-transplant lymphoproliferative disorder (mPTLD) is a major cause of morbidity/mortality following solid organ transplant (SOT), with infection, mPTLD progression and organ rejection presenting equal risks. Balancing these risks is challenging, and the intensity of therapy required by individual patients is not defined. Although an increasing body of evidence supports the use of a stepwise escalation of therapy through reduction in immunosuppression (RIS) to rituximab monotherapy and low-dose chemo-immunotherapy, many centres still use B-cell non-Hodgkin lymphoma (B-NHL) protocols, especially when managing Burkitt/Burkitt-like (BL) PTLD. This study sought to define outcomes for children managed in the UK or Spanish centres using low-intensity first-line treatments. PROCEDURE: Retrospective data were anonymously collected on patients younger than 18 years of age, with post-SOT mPTLD diagnosed between 2000 and 2020. Only patients given low-intensity treatment at initial diagnosis were included. RESULTS: Fifty-six patients were identified. Age range was 0.9-18 years (median 10.7). Most (62.5%) had early-onset PTLD. Haematopathological analysis showed 75% were diffuse large B-cell like, 14.3% were BL and nine of 33 (27%) harboured a MYC-rearrangement. Stage III-IV disease was present in 78.6%. All but one had RIS, 26 received rituximab monotherapy and 24 low-dose chemo-immunotherapy, mostly R-COP. Intensified B-NHL chemotherapy was required in 10/56 (17.9%). There were a total of 13 deaths in this cohort, three related to PTLD progression. The 1-year overall survival (OS), event-free survival (EFS) and progression-free survival (PFS) were 92.8%, 78.6% and 80.2%, respectively. CONCLUSIONS: R-COP provides an effective low-dose chemotherapy option. Escalation to more intensive therapies in the minority of inadequately controlled patients is an effective strategy.

Aberrant stem cell and developmental programs in pediatric leukemia.

Hematopoiesis is a finely orchestrated process, whereby hematopoietic stem cells give rise to all mature blood cells. Crucially, they maintain the ability to self-renew and/or differentiate to replenish downstream progeny. This process starts at an embryonic stage and continues throughout the human lifespan. Blood cancers such as leukemia occur when normal hematopoiesis is disrupted, leading to uncontrolled proliferation and a block in differentiation of progenitors of a particular lineage (myeloid or lymphoid). Although normal stem cell programs are crucial for tissue homeostasis, these can be co-opted in many cancers, including leukemia. Myeloid or lymphoid leukemias often display stem cell-like properties that not only allow proliferation and survival of leukemic blasts but also enable them to escape treatments currently employed to treat patients. In addition, some leukemias, especially in children, have a fetal stem cell profile, which may reflect the developmental origins of the disease. Aberrant fetal stem cell programs necessary for leukemia maintenance are particularly attractive therapeutic targets. Understanding how hijacked stem cell programs lead to aberrant gene expression in place and time, and drive the biology of leukemia, will help us develop the best treatment strategies for patients.

Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies.

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow-stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFß stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers. SIGNIFICANCE: We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics. See related commentary by Derecka and Crispino, p. 263. This article is highlighted in the In This Issue feature, p. 247.

Pilot study to evaluate school safety zone built environment interventions.

BACKGROUND: School safety zones were created in 2017 under the City of Toronto's Vision Zero Road Safety Plan. This pilot study examined the effect of built environment interventions on driver speeds, active school transportation (AST) and dangerous driving. METHODS: Interventions were implemented at 34 schools and 45 matched controls (2017-2019). Drivers travelling over the speed limit of >30 km/hour and 85th percentile speeds were measured using pneumatic speed tubes at school frontages. Observers examined AST and dangerous driving at school arrival times. Repeated measures beta and multiple regression analyses were used to study the intervention effects. RESULTS: Most schools had posted speed limits of 40 km/hour (58%) or ≥50 km/hour (23%). A decrease in drivers travelling over the speed limit was observed at intervention schools post-intervention (from 44% to 40%; OR 0.79, 95% CI 0.66 to 0.96). Seventy-one per cent of drivers travelled >30 km/hour and the 85th percentile speed was 47 km/hour at intervention schools, with no change in either postintervention. There were no changes in speed metrics in the controls. AST increased by 5% (OR 1.22, 95% CI 0.97 to 1.54) at intervention schools. Reductions in dangerous driving were observed at all schools. CONCLUSIONS: Posted speed limits were >30 km/hour at most schools and high proportions of drivers were travelling above the speed limits. There were reductions in drivers exceeding the speed limit and in dangerous driving, and modest increased AST post intervention. Bolder interventions to slow traffic are required to effectively reduce speeding around schools, which may increase safe AST.

Primary post-transplant lymphoproliferative disorder of the central nervous system: characteristics, management and outcome in 25 paediatric patients.

Primary central nervous system (CNS) post-transplant lymphoproliferative disorder (PTLD) in childhood is rare. Twenty-five patients were retrieved from nine European Intergroup for Childhood Non-Hodgkin's Lymphoma and/or international Berlin-Frankfurt-Münster Study Group members. Types of allografts included kidney (n = 11), liver (n = 4), heart (n = 5), bowel (n = 1) and haematopoietic stem cells (n = 4). Eighteen were male, 16 ≥ 10 years old, 21 had monomorphic disease and 24 solid intracranial tumour masses. Four-year event-free and overall survival rates were 50% ± 10% and 74% ± 9% respectively. This report represents the largest paediatric series of CNS PTLD reported to date, showing favourable survival odds following systemic and intrathecal chemotherapy and rituximab administration.

The Origin of B-cells: Human Fetal B Cell Development and Implications for the Pathogenesis of Childhood Acute Lymphoblastic Leukemia.

Human B-lymphopoiesis is a dynamic life-long process that starts in utero by around six post-conception weeks. A detailed understanding of human fetal B-lymphopoiesis and how it changes in postnatal life is vital for building a complete picture of normal B-lymphoid development through ontogeny, and its relevance in disease. B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common cancers in children, with many of the leukemia-initiating events originating in utero. It is likely that the biology of B-ALL, including leukemia initiation, maintenance and progression depends on the developmental stage and type of B-lymphoid cell in which it originates. This is particularly important for early life leukemias, where specific characteristics of fetal B-cells might be key to determining how the disease behaves, including response to treatment. These cellular, molecular and/or epigenetic features are likely to change with age in a cell intrinsic and/or microenvironment directed manner. Most of our understanding of fetal B-lymphopoiesis has been based on murine data, but many recent studies have focussed on characterizing human fetal B-cell development, including functional and molecular assays at a single cell level. In this mini-review we will give a short overview of the recent advances in the understanding of human fetal B-lymphopoiesis, including its relevance to infant/childhood leukemia, and highlight future questions in the field.

Supracondylar Humerus Fractures in Older Children: Success of Closed Reduction and Percutaneous Pinning.

BACKGROUND: The incidence of supracondylar humerus (SCH) fracture declines and fracture types change as children grow. Optimal treatment method is unclear in older children. The aim of the study was to determine if fracture type and configuration of distal humerus fractures changes as patients approach skeletal maturity, and to assess the success of closed reduction and percutaneous pin (CRPP) in extra-articular SCH fractures in this transitional age group. METHODS: Inclusion criteria for this retrospective review were (1) distal humerus fractures with extension types 2 and 3, flexion type, T-type; (2) surgically managed, and (3) modified Sauvegrain score ≥1. Reviewed parameters included fracture type and configuration, grade of skeletal maturity, fixation technique, and loss of reduction. Primary analysis was to determine the distribution of fracture type and configuration with age or grade of skeletal maturity. Secondary analysis was used to determine the factors affecting treatment success of CRPP in extra-articular fractures. RESULTS: A total of 142 patients were included (58 males and 84 females). Fracture types revealed significant changes with increased age (P=0.031) and skeletal maturity grade (P<0.005). Skeletal maturity was a better predictor of changing fracture type than chronological age. T-type fractures were only seen in patients with modified Sauvegrain score ≥6 and flexion-type fractures were only seen in patients with modified Sauvegrain score ≤4. Loss of reduction rate after CRPP was 5%. The success of CRPP was not affected by age, sex, modified Sauvegrain score, fracture type, direction of displacement, coronal fracture pattern, number of pins or medial pin use. Fracture obliquity in the sagittal plane (P=0.05), suboptimal pin spread (P<0.01), and lack of bicolumnar fixation (P<0.01) were found as statistically significant factors associated with failed CRPP. CONCLUSION: The distribution of fracture type changed with increased age and skeletal maturity. CRPP of extra-articular fractures in older children is a reliable option regardless of the stage of skeletal maturity. Determinants of a good outcome include optimal pinning technique with adequate pin spread at the fracture site and bicolumnar fixation. LEVEL OF EVIDENCE: Level IV-retrospective case series.

Active school transportation and the built environment across Canadian cities: Findings from the child active transportation safety and the environment (CHASE) study.

Walking and bicycling to school (active school transportation, AST) has been in decline for decades in North America and globally with the rise of automobility. This cross-sectional study estimated associations between the built environment and AST in seven Canadian communities. We observed the travel behaviours of almost 118,000 students at 552 schools. Using beta regression, we modeled the proportion of children using AST, considering built environment and social environment factors around schools. Across all schools, the average proportion of children using AST was 54.3% (SD 18.9%), with variability among cities from a low of 39.5% (SD 22.1%) in Laval, Quebec to 69.7% (SD 18.1%) in Montreal, Quebec. Overall, several modifiable road design features were associated with AST, including the presence of school crossing guards, cycling infrastructure, Walk Score® and traffic signal density. There was variability in the directionality and statistical significance of associations with design variables across cities, suggesting that the local context and directed local interventions are important to support AST. Natural experiment studies are necessary to examine local approaches related to the built environment to increase AST and ensure appropriate new policy and program interventions are developed.

Effect of reducing the posted speed limit to 30 km per hour on pedestrian motor vehicle collisions in Toronto, Canada - a quasi experimental, pre-post study.

BACKGROUND: Pedestrian related deaths have recently been on the rise in Canada. The effect of changing posted speeds on the frequency and severity of pedestrian motor vehicle collisions (PMVC) is not well studied using controlled quasi-experimental designs. The objective of this study was to examine the effect of lowering speed limits from 40 km/h to 30 km/h on PMVC on local roads in Toronto, Canada. METHODS: A 30 km/h speed limit on local roads in Toronto was implemented between January 2015 and December 2016. Streets that remained at a 40 km/h speed limit throughout the study period were selected as comparators. A quasi-experimental, pre-post study with a comparator group was used to evaluate the effect of the intervention on PMVC rates before and after the speed limit change using repeated measures Poisson regression. PMVC data were obtained from police reports for a minimum of two years pre- and post-intervention (2013 to 2018). RESULTS: Speed limit reductions from 40 km/h to 30 km/h were associated with a 28% decrease in the PMVC incidence rate in the City of Toronto (IRR = 0.72, 95% CI: 0.58-0.89). A non-significant 7% decrease in PMVC incidence rates were observed on comparator streets that remained at 40 km/h speed limits (IRR = 0.93, 95% CI: 0.70-1.25). Speed limit reduction also influenced injury severity, with a significant 67% decrease in major and fatal injuries in the post intervention period on streets with speed limit reductions (IRR = 0.33, 95% CI: 0.13-0.85) compared with a 31% not statistically significant decrease in major and fatal injuries on comparator streets (IRR = 0.69, 95% CI: 0.37-1.31). The interaction term for group and pre-post comparisons was not statistically significant (p = 0.14) indicating that there was no evidence to suggest a pre-post difference in IRRs between the intervention and comparator streets. CONCLUSIONS: Declines in the rate of PMVC were observed on roads with posted speed limit reductions from 40 km/h to 30 km/h, although this effect was not statistically greater than reductions on comparator streets.

Investigating the relationship between vancomycin-resistant Enterococcus control practices and the incidence of health care-associated Clostridioides difficile infections in Ontario.

We evaluated the impact of discontinuing vancomycin-resistant Enterococcus (VRE) screening and use of contact precautions on the incidence of health care-associated Clostridioides difficile infection (HA-CDI) in acute teaching hospitals in Ontario, Canada. Among hospitals that stopped VRE screening and contact precaution measures, there was a significant change in HA-CDI rates after the discontinuation of practices (incidence rate ratios, 1.11; 95% confidence interval, 1.01-1.22). No change in rate was observed among hospitals that continued VRE control practices. Screening and use of contact precautions for VRE may provide hospitals additional advantages for broadened HA-CDI control and prevention.

Cyclist-motor vehicle collisions before and after implementation of cycle tracks in Toronto, Canada.

BACKGROUND: Cycling, as a mode of active transportation, has numerous health and societal benefits, but carries risks of injury when performed on-road with vehicles. Cycle tracks are dedicated lanes with a physical separation or barrier between bicycles and motor vehicles. Studies on the effectiveness of cycle tracks in urban areas in North America, as well as the area-wide effects of cycle tracks are limited. AIMS: Study objectives were to examine the effect of cycle track implementation on cyclist-motor vehicle collisions (CMVC) occurring: (1) on streets treated with new cycle tracks; (2) on streets surrounding new cycle tracks in Toronto, Canada. METHODS: Intervention and outcome data were obtained from the City of Toronto. All police-reported CMVC from 2000 to 2016 were mapped. Analyses were restricted to 2 years pre- and 2 years post-track implementation. Rates were calculated for CMVC on streets with cycle tracks (objective 1) and in five defined areas surrounding cycle tracks (objective 2). Zero-Inflated Poisson regression was used to compare changes to CMVC rates before and after cycle track implementation for both objectives. All models controlled for season of collision and cycle track. RESULTS: The majority of CMVC on cycle tracks occurred at intersections (75%). The crude CMVC rate increased two-fold after cycle track implementation (IRR = 2.06, 95% CI: 1.51-2.81); however, after accounting for the increase in cycling volumes post-implementation, there was a 38% reduction in the CMVC rate per cyclist-month (IRR = 0.62, 95% CI: 0.44-0.89). On streets between 151 m - 550 m from cycle tracks, there was a significant 35% reduction in CMVC rates per km-month following track implementation (IRR = 0.65, 95% CI: 0.54-0.76). CONCLUSIONS: Cycle track implementation was associated with increased safety for cyclists on cycle tracks, after adjusting for cycling volume. In addition, there was a significant reduction in CMVC on streets surrounding cycle tracks between 151 m - 550 m distance from the tracks (a 'safety halo' effect), suggesting an area-wide safety effect of cycle track implementation.

Telepsychiatry in an Alaska Native Residential Substance Abuse Treatment Program.

Introduction: Alaska Native communities experience high rates of alcohol and substance abuse and face challenges accessing quality, culturally appropriate treatment. Telepsychiatry could help bridge this gap, but no publications have examined its impacts for alcohol and substance abuse treatment directed at Alaska Native communities. This study explores one telepsychiatry clinic's impact on a residential substance abuse treatment serving the Alaska Native community in Anchorage, Alaska. Methods: Using a matched case - control design, 103 cases receiving telepsychiatry services between 2007 and 2012 were matched with 103 controls who did not. Outcome measures included length of stay, discharge plans, emergency room visits, and hospital admissions; clinical history, including previous suicide attempts, history of violence, and trauma history; social stressors such as current legal issues, unemployment, and homelessness; mental health, medical, and substance abuse diagnoses; and number of telepsychiatry appointments and nature of telepsychiatry services rendered. Results: Both groups exhibited high rates of mental and medical illness, socioeconomic challenges, and substance abuse. However, the telepsychiatry group demonstrated a significantly higher rate of post-traumatic stress disorder, history of violence, ongoing legal issues, and children in outside custody. It also remained engaged in treatment longer, had fewer discharges against medical advice, and was more likely to complete treatment. Discussion/Conclusions: Our study highlights this telepsychiatry clinic's real-world difference serving the complex substance abuse treatment needs of Alaska Native individuals. It also reinforces telepsychiatry's promise in serving other communities facing a high burden of addiction and mental illness yet facing barriers to high-quality, culturally competent services.

Effects of large-scale oceanic phenomena on non-cholera vibriosis incidence in the United States: implications for climate change.

Non-cholera Vibrio (NCV) species are important causes of disease. These pathogens are thermophilic and climate change could increase the risk of NCV infection. The El Niño Southern Oscillation (ENSO) is a 'natural experiment' that may presage ocean warming effects on disease incidence. In order to evaluate possible climatic contributions to observed increases in NCV infection, we obtained NCV case counts for the United States from publicly available surveillance data. Trends and impacts of large-scale oceanic phenomena, including ENSO, were evaluated using negative binomial and distributed non-linear lag models (DNLM). Associations between latitude and changing risk were evaluated with meta-regression. Trend models demonstrated expected seasonality (P < 0.001) and a 7% (6.1%-8.1%) annual increase in incidence from 1999 to 2014. DNLM demonstrated increased vibriosis risk following ENSO conditions over the subsequent 12 months (relative risk 1.940, 95% confidence interval (CI) 1.298-2.901). The 'relative-relative risk' (RRR) of annual disease incidence increased with latitude (RRR per 10° increase 1.066, 95% CI 1.027-1.107). We conclude that NCV risk in the United States is impacted by ocean warming, which is likely to intensify with climate change, increasing NCV risk in vulnerable populations.

Sustained inflations during delivery suite stabilisation in prematurely-born infants - A randomised trial.

BACKGROUND: Sustained inflations at initial stabilisation in the delivery suite may reduce the need for intubation and result in a shorter duration of initial ventilation, but have not been compared to routine UK practice. AIMS: To compare the early efficacy of sustained inflation during stabilisation after delivery to UK practice. STUDY DESIGN: A randomised trial was performed of a fifteen second sustained inflation compared to five inflations lasting 2 to 3 s, each intervention could be repeated once if no chest rise was apparent. Respiratory function monitoring was undertaken. SUBJECTS: Infants born prior to 34 weeks of gestation. OUTCOME MEASURES: The minute volume and maximum end-tidal carbon dioxide level in the first minute after the interventions, the time to the first spontaneous breath after the beginning of stabilisation and the duration of ventilation in the first 48 h. RESULTS: There were no significant differences in the minute volume or maximum end tidal carbon dioxide level between the groups. Infants in the sustained inflation group made a respiratory effort sooner (median 3.5 (range 0.2-59) versus median 12.8 (range 0.4-119) s, p = 0.001). The sustained inflation group were ventilated for a shorter duration in the first 48 h (median 17 (range 0-48) versus median 32.5 (range 0-48) h, p = 0.025). CONCLUSIONS: A sustained inflation of 15 s compared to five two to three second inflations during initial stabilisation was associated with a shorter duration of mechanical ventilation in the first 48 h after birth.

Disease Monitoring and Health Campaign Evaluation Using Google Search Activities for HIV and AIDS, Stroke, Colorectal Cancer, and Marijuana Use in Canada: A Retrospective Observational Study.

BACKGROUND: Infodemiology can offer practical and feasible health research applications through the practice of studying information available on the Web. Google Trends provides publicly accessible information regarding search behaviors in a population, which may be studied and used for health campaign evaluation and disease monitoring. Additional studies examining the use and effectiveness of Google Trends for these purposes remain warranted. OBJECTIVE: The objective of our study was to explore the use of infodemiology in the context of health campaign evaluation and chronic disease monitoring. It was hypothesized that following a launch of a campaign, there would be an increase in information seeking behavior on the Web. Second, increasing and decreasing disease patterns in a population would be associated with search activity patterns. This study examined 4 different diseases: human immunodeficiency virus (HIV) infection, stroke, colorectal cancer, and marijuana use. METHODS: Using Google Trends, relative search volume data were collected throughout the period of February 2004 to January 2015. Campaign information and disease statistics were obtained from governmental publications. Search activity trends were graphed and assessed with disease trends and the campaign interval. Pearson product correlation statistics and joinpoint methodology analyses were used to determine significance. RESULTS: Disease patterns and online activity across all 4 diseases were significantly correlated: HIV infection (r=.36, P<.001), stroke (r=.40, P<.001), colorectal cancer (r= -.41, P<.001), and substance use (r=.64, P<.001). Visual inspection and the joinpoint analysis showed significant correlations for the campaigns on colorectal cancer and marijuana use in stimulating search activity. No significant correlations were observed for the campaigns on stroke and HIV regarding search activity. CONCLUSIONS: The use of infoveillance shows promise as an alternative and inexpensive solution to disease surveillance and health campaign evaluation. Further research is needed to understand Google Trends as a valid and reliable tool for health research.

Rizatriptan for acute migraine headaches in adults.

This is the protocol for a review and there is no abstract. The objectives are as follows: The objective of the review will be to determine the efficacy and tolerability of rizatriptan compared to placebo and other active interventions in the treatment of acute migraine headaches in adults.