Convergent synthesis of thiodiazole dioxides from simple ketones and amines through an unusual nitrogen-migration mechanism.

We report the modular preparation of dihydro-1,2,5-thiodiazole dioxide heterocycles starting from methyl ketones and primary amines. This one-pot, three-component coupling employs 2,3-dimethylimidazole-1-sulfonyl azide triflate as a coupling reagent and oxidant. The transformation is scalable and various ketones and amines can be used, yielding thiodiazole dioxide products in up to 89% yield. In addition, 15N- and 13C-labeling studies suggest a mechanism involving a 1,2-nitrogen migration. Together with the mechanistic studies, DFT calculations provide insight into the reaction pathway and set the stage for further exploration of the mechanistic nuances of reactions that use sulfamoyl azides. In combination with the demonstrated modularity of the approach reported herein, the derivatization of the thiodiazole dioxide products highlights the potential of this methodology to rapidly access diverse chemical structures.

Lessons learned from regional training of paediatric nephrology fellows in Africa.

BACKGROUND: Access to care for children with kidney disease is limited in less well-resourced regions of the world and paediatric nephrology (PN) workforce development with good practical skills is critical. METHODS: Retrospective review of a PN training program and trainee feedback from 1999 to 2021, based at Red Cross War Memorial Children's Hospital (RCWMCH), University of Cape Town. RESULTS: A regionally appropriate 1-2-year training program enrolled 38 fellows with an initial 100% return rate to their country of origin. Program funding included fellowships from the International Pediatric Nephrology Association (IPNA), International Society of Nephrology (ISN), International Society of Peritoneal Dialysis (ISPD), and the African Paediatric Fellowship Program (APFP). Fellows were trained on both in- and out-patient management of infants and children with kidney disorders. "Hands-on skills" training included examination, diagnosis and management skills, practical insertion of peritoneal dialysis catheters for management of acute kidney injury and kidney biopsies. Of 16 trainees who completed > 1 year of training, 14 (88%) successfully completed subspecialty exams and 9 (56%) completed a master's degree with a research component. PN fellows reported that their training was appropriate and enabled them to make a difference in their respective communities. CONCLUSIONS: This training program has successfully equipped African physicians with the requisite knowledge and skills to provide PN services in resource-constrained areas for children with kidney disease. The provision of funding from multiple organizations committed to paediatric kidney disease has contributed to the success of the program, along with the fellows' commitment to build PN healthcare capacity in Africa. A higher resolution version of the Graphical abstract is available as Supplementary information.

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia.

A common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q [del(6q)] as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3, FOXO1 expression suppressed growth of TCF3::PBX1 and ETV6::RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4, and chemokine, CXCR4. CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID50 < 50 nM).

hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia.

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.

Knowledge gaps in the management of refractory reflux-like symptoms: Healthcare provider survey.

BACKGROUND: Refractory reflux-like symptoms have a substantial impact on patients and healthcare providers. The aim of the survey was to qualitatively assess the needs and attitudes of practicing clinicians around the management of refractory reflux symptoms and refractory gastroesophageal reflux disease (rGERD). METHODS: An International Working Group for the Classification of Oesophagitis (IWGCO) steering committee invited clinicians to complete an online survey including 17 questions. KEY RESULTS: Of the 113 clinicians who completed the survey, 70% were GIs, 20% were primary care physicians, and 10% were other specialties. Functional heartburn was considered the most common reason for an incomplete response to proton pump inhibitor (PPI) therapy (82%), followed by stress/anxiety (69%). More GIs identified esophageal hypersensitivity as a cause, while more non-GIs identified esophageal dysmotility and non-reflux-related esophageal conditions. As the first step, most clinicians would order investigations (70-88%). Overall, 72% would add supplemental therapy for patients with partial response, but only 58% for those with non-response. Antacid/alginate was the most common choice overall, while non-GIs were more likely to add a prokinetic than were GIs (47.8 vs. 24.1%). Approximately 40% of clinicians would switch PPIs in patients with partial response, but only 29% would do so in non-responders. Preferences for long-term therapy were highly variable. The most common initial investigation was upper endoscopy. Choice of esophageal manometry and pH monitoring was more variable, with no clear preference for whether pH monitoring should be conducted on, or off, PPI therapy. CONCLUSIONS AND INFERENCES: The survey identified a number of challenges for clinicians, especially non-GI physicians, treating patients with refractory reflux-like symptoms or rGERD on a daily basis.

The Carbon Cost of Travel to a Medical Conference: Modelling the Annual Meeting of the Canadian Association of Gastroenterology.

Objectives: We estimated and compared the travel related carbon emissions of the annual meeting of the Canadian Association of Gastroenterology between the two most common geographical locations of the meeting. Methods: We modelled the car, train and flight travel journey of each registrant to two annual meetings. One was held in Toronto, close to where the majority of Gastroenterogists live, the other in Banff in the west of the country. We used validated carbon emission outputs per kilometer of travel. Results: The average per capita distance travelled to the Toronto meeting was 2845 km, resulting in 0.540 tonnes (t) of CO2equivalent (CO2e) emitted per person. When the meeting was held in Banff emissions were 41% higher than those in Toronto with an average distance travelled of 3949 km and 0.760t of CO2e emitted per person. Almost all of the travel related carbon emissions for both meetings were generated by flying. Conclusions: Even when held close to the largest population centre, there is a large environmental impact from travel to annual meetings. Importantly, choice of meeting location has a very big impact on difference in carbon emissions. Societies need to consider the site of meetings and reduce the number of in-person attendees if they wish to reduce their carbon footprint. Hybrid models participants should be considered. Our analysis also suggests, other medical societies who wish to model their annual meetings can use a simplified model, using flying distance only, to estimate travel-related emissions.

Merging Strategy, Improvisation, and Conversation to Solve Problems in Target Synthesis.

Total synthesis has long been depicted as the quest to conquer the structures created by nature, requiring an unflinching, single-minded devotion to the task. The goal is achieved by chemists with grit, strength of will, and a competitive spirit. While there is some truth to this viewpoint, it does not fully capture the rich experiences gained in this research realm. In our lab, strategic planning, improvisation, and conversation have worked in concert to enable progress. This Account summarizes our efforts to synthesize four different bioactive targets: merrilactone A, rocaglamide, phomactin A, and tetrapetalone A. Certain missteps were integral to success in these synthetic projects. As such, we include the hiccups, and their roles in the evolution of the strategies, along with the results that aligned with our expectations.Two of these projects (merrilactone A and rocaglamide) culminated in the total synthesis of the targets. The challenges presented by merrilactone A spawned a new design strategy for pentannulation using Nazarov cyclization chemistry. This work demonstrated that Lewis acid catalysis is often a viable electrocyclization strategy in activated, polarized pentadienyl cation intermediates. We sought to apply the same logic to the rocaglamide target, but precursors we prepared did not behave according to plan. This situation pushed us to adapt our approach to match the innate reactivity of the substrate, resulting in an on-the-spot improvisation that was not only integral to the success of the project but also expanded our understanding of pentadienyl cation chemistry. In the other two projects (phomactin A and tetrapetalone A), we did not complete a total synthesis but did build the polycyclic core of the target. Even though the hetero [4 + 2] cycloaddition plan for assembling the macrocyclic oxadecalin ring system of phomactin A failed, the original experimental design still enabled us to solve the problem. Through a wholly unanticipated series of events, our focus on the oxadecalin ring system primed us for the discovery of a sequential iodoaldol/oxa-Michael sequence, using the original [4 + 2] building blocks. Then, the bridging ring present in phomactin A demanded we implement this sequence in a transannular fashion. Finally, our successful synthesis of the tetrapetalone core was enabled by consultations with others in the community. Each bond formation seemed to require different expertise, and in three separate instances (C-N cross-coupling, diastereoselective ring-closing metathesis, and oxidative dearomatization) synthetic challenges were overcome through conversation and collaboration.In our experience, the amount of creative power we summon during a target synthesis project correlates directly with the magnitude of the structural challenges we face. When reactivity surprises us, we analyze the problem anew, consult with colleagues, and improvise with the tools at hand. The inevitable misbehavior of a complex system is a strong motivating force, and one that has helped to shape our research program for nearly two decades.

Patient Engagement and Multidisciplinary Involvement Has an Impact on Clinical Guideline Development and Decisions: A Comparison of Two Irritable Bowel Syndrome Guidelines Using the Same Data.

BACKGROUND AND AIM: The value of a multidisciplinary group and patient engagement in guideline groups is uncertain. We compared the recommendations of two guidelines that used the same data during the same time frame but with different participants to obtain a "real world" perspective on influence of the composition of guideline groups. METHODS: The Canadian Association of Gastroenterology (CAG) and the American College of Gastroenterology (ACG) recently updated their clinical practice guidelines for the management of Irritable Bowel Syndrome (IBS). Both the CAG and ACG used the same methodology and methodologist and were presented with the same data for interpretation. The ACG group consisted of predominantly academic gastroenterologists, while the CAG group also included general practitioners, a psychiatrist, a psychologist and a patient representative. The CAG group were also asked what components of the group were valuable. RESULTS: There were 14 statements with the same or similar recommendations. There were 10 statements in the CAG guideline not addressed by the ACG guideline and five recommendations where the opposite was the case. There was one statement that the two groups both addressed, but each group came to different conclusions. CAG members were in 100% agreement that involving a patient and having a multidisciplinary team was valuable and may have played a role in these differing interpretations of the same data in an IBS guideline. CONCLUSIONS: There has been little uptake of patient involvement and multidisciplinary teams in guideline groups. However, this study provides a unique example of added benefit through broader group representation.

The use of a self-check-in kiosk for early patient identification and queuing in the emergency department.

OBJECTIVE: Delays in triage processes in the emergency department (ED) can compromise patient safety. The aim of this study was to provide proof-of-concept that a self-check-in kiosk could decrease the time needed to identify ambulatory patients arriving in the ED. We compared the use of a novel automated self-check-in kiosk to identify patients on ED arrival to routine nurse-initiated patient identification. METHODS: We performed a prospective trail with random weekly allocation to intervention or control processes during a 10-week study period. During intervention weeks, patients used a self-check-in kiosk to self-identify on arrival. This electronically alerted triage nurses to patient arrival times and primary complaint before triage. During control weeks, kiosks were unavailable and patients were identified using routine nurse-initiated triage. The primary outcome was time-to-first-identification, defined as the interval between ED arrival and identification in the hospital system. RESULTS: Median (interquartile range) time-to-first-identification was 1.4 minutes (1.0-2.08) for intervention patients and 9 minutes (5-18) for control patients. Regression analysis revealed that the adjusted time-to-first-identification was 13.6 minutes (95% confidence interval 12.8-14.5) faster for the intervention group. CONCLUSION: A self-check-in kiosk significantly reduced the time-to-first-identification for ambulatory patients arriving in the ED.

OBJECTIF: Les délais d'attente inhérents au processus de triage des malades au service des urgences (SU) peuvent mettre en péril leur sécurité. L'étude visait donc à valider le principe selon lequel l'utilisation d'un guichet d'auto-inscription diminuerait le temps nécessaire pour signaler l'arrivée des malades ambulatoires au SU. A été comparé le processus d'utilisation d'un guichet d'auto-inscription d'un nouveau type pour signaler l'arrivée des malades au SU avec le processus habituel d'inscription des malades par le personnel infirmier. MÉTHODE: L'étude consistait en un essai prospectif, à répartition aléatoire et hebdomadaire, d'inscription, réalisé selon le processus expérimental ou le processus témoin, sur une période de 10 semaines. Durant les semaines d'expérimentation, les malades se dirigeaient vers le guichet d'auto-inscription à leur arrivée; un signal électronique informait le personnel infirmier affecté au triage de l'heure d'arrivée des malades et des motifs de consultation avant le triage lui-même. Durant les semaines témoins, les guichets étaient fermés et les malades étaient inscrits selon le processus habituel de triage effectué par le personnel infirmier. Le principal critère d'évaluation était le temps écoulé avant le signal d'arrivée, défini comme l'intervalle entre l'arrivée des malades au SU et leur inscription dans le système de l'hôpital. RÉSULTATS: Le temps médian (écart interquartile) écoulé avant le signal d'arrivée était de 1,4 minute (1,0­2,08) durant les semaines d'expérimentation contre 9 minutes (5 ­18) durant les semaines témoins. D'après les résultats de l'analyse de régression, le temps rajusté écoulé avant le signal d'arrivée était de 13,6 minutes (IC à 95% : 12,8­14,5) plus court dans le groupe d'expérimentation que dans le groupe témoin. CONCLUSION: L'utilisation d'un guichet d'auto-inscription a permis de réduire considérablement le temps écoulé avant le signal d'arrivée des malades ambulatoires au SU.

SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain.

In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein, SH2B3, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of SH2B3 occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and SH2B3 abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (p = 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.

Uganda at Glance of 5.7 Magnitude Earthquake: Lessons for Earthquake Risk Reduction.

INTRODUCTION: Uganda remains seismically vulnerable to earthquakes, which constitute one of the most deadly naturally triggered disasters in the world. This is not surprising given the country's location in the East African Rift Valley System. METHOD: This paper draws mainly on the authors' live event experience and some media reports to narratively outline the nature of a sizable earthquake, which measured a magnitude of 5.7 on the Richter scale that struck Uganda and other countries within the Lake Victoria Basin region on 10th September 2016 in the afternoon. RESULTS: Rakai - a district in central region was the worst affected in Uganda. It witnessed the death of four people; 20 people were admitted to the hospital with injuries; a total of 590 people were affected; and serious structural damages mainly in buildings were reported, leaving many either razed to the ground or left with cracks. DISCUSSIONS: Although this earthquake was less devastating in terms of injuries and fatalities compared to two previous earthquakes in Uganda, based on the Modified Mercalli Intensity Scale it was still considered to be severe. Therefore, this paper identified some proactive lessons as far as earthquake risk reduction in Uganda is concerned, which among others include: encouraging earthquake-resistant buildings; the safety of essential infrastructure; earthquake early warning systems supported by free global technologies; and the safety of rescue workers along with prioritizing the psychosocial needs of rescue teams. With all this in mind, the September 2016 earthquake should serve as a timely reminder that there is a real need for the proactive ex-ante earthquake preparedness rather than risking an expensive post-ante approach to responding to any future devastating earthquakes in Uganda.

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of cases of childhood precursor B-cell acute lymphoblastic leukemia. These abnormalities are too complex to engineer faithfully in animal models and are unrepresented in leukemia cell lines. As a resource for future functional and preclinical studies, we have created xenografts from the leukemic blasts of patients with intrachromosomal amplification of chromosome 21 and characterized them by in-vivo and ex-vivo luminescent imaging, flow immunophenotyping, and histological and ultrastructural analyses of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia-initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumor suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-cell acute lymphoblastic leukemia. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-cell acute lymphoblastic leukemia and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions.

Anthropological contributions to historical ecology: 50 questions, infinite prospects.

This paper presents the results of a consensus-driven process identifying 50 priority research questions for historical ecology obtained through crowdsourcing, literature reviews, and in-person workshopping. A deliberative approach was designed to maximize discussion and debate with defined outcomes. Two in-person workshops (in Sweden and Canada) over the course of two years and online discussions were peer facilitated to define specific key questions for historical ecology from anthropological and archaeological perspectives. The aim of this research is to showcase the variety of questions that reflect the broad scope for historical-ecological research trajectories across scientific disciplines. Historical ecology encompasses research concerned with decadal, centennial, and millennial human-environmental interactions, and the consequences that those relationships have in the formation of contemporary landscapes. Six interrelated themes arose from our consensus-building workshop model: (1) climate and environmental change and variability; (2) multi-scalar, multi-disciplinary; (3) biodiversity and community ecology; (4) resource and environmental management and governance; (5) methods and applications; and (6) communication and policy. The 50 questions represented by these themes highlight meaningful trends in historical ecology that distill the field down to three explicit findings. First, historical ecology is fundamentally an applied research program. Second, this program seeks to understand long-term human-environment interactions with a focus on avoiding, mitigating, and reversing adverse ecological effects. Third, historical ecology is part of convergent trends toward transdisciplinary research science, which erodes scientific boundaries between the cultural and natural.

CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response.

Relapsed acute lymphoblastic leukemia is the most common cause of cancer-related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are particularly frequent in relapsed childhood acute lymphoblastic leukemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but has no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid-induced apoptosis, sensitivity to other acute lymphoblastic leukemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signaling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signaling in acute lymphoblastic leukemia but do not alter response to MEK inhibitors.

The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts.

Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.Cg- ITALIC! Prkdc (ITALIC! scid) ITALIC! Il2rg (ITALIC! tm1Wjl)/SzJ mice. CNS engraftment was seen in 23 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood-cerebrospinal fluid barrier situated close to the dural sinuses, the site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed no evidence for chemokine receptor-mediated selective trafficking. The high frequency of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a generic property of leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. Clonal tracking techniques confirmed the polyclonal nature of CNS-infiltrating cells, with multiple clones engrafting in both the CNS and periphery. Overall, these findings suggest that subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.

Availability of ambulance patient care reports in the emergency department.

Clinical handovers of patient care among healthcare professionals is vulnerable to the loss of important clinical information. A verbal report is typically provided by paramedics and documented by emergency department (ED) triage nurses. Paramedics subsequently complete a patient care report which is submitted electronically. This emergency medical system (EMS) patient care report often contains details of paramedic assessment and management that is not all captured in the nursing triage note. EMS patient care reports are often unavailable for review by emergency physicians and nurses. Two processes occur in the distribution of EMS patient care reports. The first is an external process to the ED that is influenced by the prehospital emergency medical system and results in the report being faxed to the ED. The second process is internal to the ED that requires clerical staff to distribute the fax report to accompany patient charts. A baseline audit measured the percentage of EMS patient care reports that were available to emergency physicians at the time of initial patient assessments and showed a wide variation in the availability of EMS reports. Also measured were the time intervals from patient transfer from EMS to ED stretcher until the EMS report was received by fax (external process measure) and the time from receiving the EMS fax report until distribution to patient chart (internal process measure). These baseline measures showed a wide variation in the time it takes to receive the EMS reports by fax and to distribute reports. Improvement strategies consisted of: 1. Educating ED clerical staff about the importance of EMS reports 2. Implementing a new process to minimize ED clerical staff handling of EMS reports for nonactive ED patients 3. Elimination of the automatic retrieval of old hospital charts and their distribution for ED patients 4. Introduction of an electronic dashboard for patients arriving by ambulance to facilitate more efficient distribution of EMS reports. Implementation of change strategies did not result in a significant improvement in the percentage of EMS reports available to emergency physicians at the time of initial patient assessment. However, tracking both external and internal processes that influence EMS report availability showed the internal process time from fax report receipt to distribution significantly improved. This improvement reflected the change strategies that were all directed at improving the internal process. EMS patient care reports are more efficiently processed and distributed in the ED due to change strategies implemented that targeted the ED's internal process of EMS report distribution. The external process responsible for transmitting EMS reports to the ED is the limiting factor that prevents consistent timely access of EMS reports by emergency physicians and will require dedicated improvement strategies.

Canadian Association of Gastroenterology policy on the application for, and implementation of, clinical practice guidelines.

An important mandate of the Canadian Association of Gastroenterology (CAG), as documented in the Association's governance policies, is to optimize the care of patients with digestive disorders. Clinical practice guidelines are one means of achieving this goal. The benefits of timely, high-quality and evidenced-based recommendations include: Enhancing the professional development of clinical members through education and dissemination of synthesized clinical research; Improving patient care provided by members by providing focus on quality and evidence; Creating legislative environments that favour effective clinical practice; Enhancing the clinical care provided to patients with digestive disease by nongastroenterologists; and Identifying areas that require further information or research to improve clinical care. The present document provides the foundation required to ensure that clinical practice guidelines produced by the CAG are necessary, appropriate, credible and applicable. These recommendations should be adhered to as closely as possible to obtain CAG endorsement.