Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.

Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer. PAPERCLIP.

Consensus statement on networks for high-quality rural anesthesia, surgery, and obstetric care in Canada.

OBJECTIVE: To describe the essential components of well-resourced and high-functioning multidisciplinary networks that support high-quality anesthesia, surgery, and maternity care for rural Canadians, delivered as close to home as possible. COMPOSITION OF THE COMMITTEE: A volunteer Writers' Group was drawn from the Society of Obstetricians and Gynaecologists of Canada, the Society of Rural Physicians of Canada, the Royal College of Physicians and Surgeons of Canada, the Canadian Association of General Surgeons, the College of Family Physicians of Canada, and the Association of Canadian University Departments of Anesthesia. METHODS: A collaborative effort over the past several years among the professional stakeholders has culminated in this consensus statement on networked care designed to integrate and support a specialist and non-specialist, urban and rural, anesthesia, surgery, and maternity work force into high-functioning networks based on the best available evidence. REPORT: Surgical and maternity triage needs to be embedded within networks to address the tensions between sustainable regional programs and local access to care. Safety and quality must be demonstrated to be equivalent across similar patients and procedures, regardless of network site. Triage of patients across multiple sites is a quality outcome metric requiring continuous iterative scrutiny. Clinical coaching between rural and regional centres can be helpful in building and sustaining high-functioning networks. Maintenance of quality and the provision of continuing professional development in low-volume settings represent a mutual value proposition. CONCLUSION: The trusting relationships that are foundational to successful networks are built through clinical coaching, continuing professional development, and quality improvement. Currently, a collaborative effort in British Columbia is delivering a provincial program-Rural Surgical Obstetrical Networks-built on the principles and supporting evidence described in this consensus statement.

Brought about by necessity: how the pandemic accelerated a transformation of continuing professional development.

The COVID-19 pandemic has had a profound impact on medical education and accelerated an evolution in continuing professional development that was already underway. Physicians around the world have had to quickly learn a new evolving clinical entity and do so in a virtual manner. As local and international travel ceased, academic and practice deliberations on diagnosis and treatment of novel diseases which historically have occurred during in-person conferences have shifted to virtual forums enabled with technology and social media. Medical educators have the added complexity of learning to teach and assess trainees virtually as remote learning has become a necessity. National and international organisations have increased collaborative efforts to ensure the latest clinical information is disseminated promptly to front-line physicians. The shift to virtual learning has democratised clinical information, allowing for wider global participation and transforming how we approach continuing professional development.

Ontario adults' health behaviors, mental health, and overall well-being during the COVID-19 pandemic.

BACKGROUND: Public health measures such as physical distancing and work-from-home initiatives have been implemented to slow the spread of COVID-19. These measures may also be associated with unhealthy lifestyle behaviors, which could be particularly problematic for those already at highest risk for losing years of healthy life due to chronic disease (i.e., 30-59-year-olds). The purpose of this paper is two-fold: (1) to provide an overview of Ontario adults' health behaviors (i.e., physical activity, sedentary behaviors, and dietary intake), mental health, and well-being during the first few months of the COVID-19 pandemic (April-July 2020); and (2) to explore the difference between physical activity and various health behaviors (i.e., well-being, mental health, and dietary intake). METHODS: As a part of a larger, longitudinal study, participants completed an online survey that included demographic information, the Global Physical Activity Questionnaire, Starting the Conversation, the Mental Health Inventory, and the Personal Wellbeing Index-Adult. Data analyses involved computing measures of central tendency and dispersion for demographic characteristics and tools followed by descriptive statistics. Separate independent t-tests were conducted to investigate the difference between physical activity status and well-being, mental health, and dietary intake. RESULTS: A total of 2157 Ontarians completed an online survey. Descriptive statistics indicated that respondents met physical activity and sedentary behavior guidelines, reported double the amount of recommended recreational screen time, practiced moderately healthy dietary behaviors, experienced mental health problems, and scored below "normal" in some well-being domains. CONCLUSION: As the end of the COVID-19 pandemic is currently unknown, its associated restrictions and society changes may influence adults' behaviors in both the short- and longer-term. As such, our findings might provide immediate insight into the development of timely and evidence-informed health promotion and disease prevention strategies for Canadians, which could support adults' health behaviors, mental health, and well-being during the COVID-19 pandemic and other, future pandemics.

Reimagining medical education for primary care in the time of COVID-19: a world view.

This article sets out to highlight the challenges and opportunities for medical education in primary care realised during the COVID-19 pandemic and now being enacted globally. The themes were originally presented during a webinar involving educationalists from around the world and are subsequently discussed by members of the WONCA working party for education. The article recognises the importance of utilising diversity, addressing inequity and responding to the priority health needs of the community through socially accountable practice. The well-being of educators and learners is identified as priority in response to the ongoing global pandemic. Finally, we imagine a new era for medical education drawing on global connection and shared resources to create a strong community of practice.

MR imaging phenotype correlates with extent of genome-wide copy number abundance in IDH mutant gliomas.

PURPOSE: There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features. METHODS: Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis. RESULTS: There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393). CONCLUSIONS: Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.

Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness.

'Pre-leukaemic' mutations are thought to promote clonal expansion of haematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness; however, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative neoplasms and leukaemia. Here we show that a single allele of oncogenic Nras(G12D) increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all prior to leukaemia initiation. Nras(G12D) also confers long-term self-renewal potential to multipotent progenitors. To explore the mechanism by which Nras(G12D) promotes HSC proliferation and self-renewal, we assessed cell-cycle kinetics using H2B-GFP label retention and 5-bromodeoxyuridine (BrdU) incorporation. Nras(G12D) had a bimodal effect on HSCs, increasing the frequency with which some HSCs divide and reducing the frequency with which others divide. This mirrored bimodal effects on reconstituting potential, as rarely dividing Nras(G12D) HSCs outcompeted wild-type HSCs, whereas frequently dividing Nras(G12D) HSCs did not. Nras(G12D) caused these effects by promoting STAT5 signalling, inducing different transcriptional responses in different subsets of HSCs. One signal can therefore increase HSC proliferation, competitiveness and self-renewal through bimodal effects on HSC gene expression, cycling and reconstituting potential.

Improving Access to Safe Anesthetic Care in Rural and Remote Communities in Affluent Countries.

Inadequate access to anesthesia and surgical services is often considered to be a problem of low- and middle-income countries. However, affluent nations, including Canada, Australia, and the United States, also face shortages of anesthesia and surgical care in rural and remote communities. Inadequate services often disproportionately affect indigenous populations. A lack of anesthesia care providers has been identified as a major contributing factor to the shortfall of surgical and obstetrical care in rural and remote areas of these countries. This report summarizes the challenges facing the provision of anesthesia services in rural and remote regions. The current landscape of anesthesia providers and their training is described. We also explore innovative strategies and emerging technologies that could better support physician-led anesthesia care teams working in rural and remote areas. Ultimately, we believe that it is the responsibility of specialist anesthesiologists and academic health sciences centers to facilitate access to high-quality care through partnership with other stakeholders. Professional medical organizations also play an important role in ensuring the quality of care and continuing professional development. Enhanced collaboration between academic anesthesiologists and other stakeholders is required to meet the challenge issued by the World Health Organization to ensure access to essential anesthesia and surgical services for all.

Coaching and/or education intervention for parents with overweight/obesity and their children: study protocol of a single-centre randomized controlled trial.

BACKGROUND: In Canada, a majority of children and adults are insufficiently active for health gains, and about one in seven children and over 20% of adults are overweight or obese. Overweight and obesity are risk factors for many chronic diseases in both adults and children and can result in lower quality and quantity of life. Children whose parents are overweight or obese are more likely to become overweight themselves. Thus, parent/child interventions are important for reducing obesity and promoting long-term healthy weights among members of the family unit. Programs using Co-Active coaching have resulted in positive behaviour changes among adults with overweight/obesity; however, little research has explored the effects of Co-Active coaching on parents, and the consequent impact on the family unit (i.e. all parents and children in the same household). This protocol paper provides a detailed methodological account of a coaching-based program targeting parent and child dyads, in hopes of enhancing health behaviours within the family unit. METHODS: Using a randomized controlled trial design, the researchers aim to identify the impact of coaching plus education (intervention) compared to education only (control) on parents with overweight/obesity and their children (ages 2.5-10, of any weight). A total of 50 dyads are being recruited and randomly assigned using a 1:1 ratio into the control or intervention group. The control group receive 6 webinar-based education sessions focused on physical activity and nutrition. The intervention group receive the same education sessions and nine, 20-min telephone-based sessions with a certified coach. Coaching and health education sessions are conducted with the parent/guardian of the dyad. This paper provides a detailed methodological account of this program. DISCUSSION: The expected findings from this research will advance coaching literature, research, and practice on this topic by determining whether coaching and education are more effective than education alone at producing behaviour changes among a family unit. If proven effective, this approach may be applied more broadly through public health interventionists to parent and child populations in hopes of affecting change with both individuals and their families. TRIAL REGISTRATION: ISRCTN ISRCTN69091372 . Retrospectively registered 24 September 2018.

Striving for the best: WONCA global standards for continuing professional development for family doctors.

While all physicians must continue to learn new knowledge through their careers, their post-training continuing professional development (CPD) has received less attention. Problems include lack of support for physicians, frequent deviations from best practices such as mandatory participation, focus on community need, and clear conflicts of interest amongst providers. Additionally, specialists from other disciplines catering to different patient populations often provide CPD for family doctors. The Working Party on Education of the World Organisation of Family Doctors (WONCA) sought to develop global standards in CPD for family doctors. The standards were developed through an iterative process with reference to published best practices for effective CPD. Adapted for family doctors from the World Federation for Medical Education's CPD for Medical Doctors: WFME Global Standards for Quality Improvement', the WONCA CPD Standards for Family Doctors were approved by WONCA Council in November 2016. The objectives of the standards are to: (1) Provide a resource for family doctors and/or groups of family doctors to design and structure a program of CPD to reinforce lifelong learning; (2) Optimise current CPD systems such that, through more effective program design and delivery, family doctors are advancing in patient care and their discipline; (3) Offer a set of globally recognised standards developed through a family medicine perspective to provide feedback on existing CPD programs and systems and encourage international recognition of CPD activities. The WONCA Global CPD Standards should inspire best practices in family medicine CPD, assisting family doctors in providing excellent care.

Amphiphilic and Hydrophilic Block Copolymers from Aliphatic N-Substituted 8-Membered Cyclic Carbonates: A Versatile Macromolecular Platform for Biomedical Applications.

Introduction of hydrophilic components, particularly amines and zwitterions, onto a degradable polymer platform, while maintaining precise control over the polymer composition, has been a challenge. Recognizing the importance of these hydrophilic residues in multiple aspects of the nanobiomedicine field, herein, a straightforward synthetic route to access well-defined amphiphilic and hydrophilic degradable block copolymers from diethanolamine-derived functional eight-membered N-substituted aliphatic cyclic carbonates is reported. By this route, tertiary amine, secondary amine, and zwitterion residues can be incorporated across the polymer backbone. Demonstration of pH-responsiveness of these hydrophilic residues and their utility in the development of drug-delivery vehicles, catered for the specific requirements of respective model drugs (doxorubicin and diclofenac sodium salt) are shown. As hydrophilic components in degradable polymers play crucial roles in the biological interactions, these materials offers opportunities to expand the scope and applicability of aliphatic cyclic carbonates. Our approach to these functional polycarbonates will expand the range of biocompatible and biodegradable synthetic materials available for nanobiomedicine, including drug and gene delivery, antimicrobials, and hydrophilic polymers as poly(ethylene glycol) (PEG) alternatives.

A Simple and Facile Approach to Aliphatic N-Substituted Functional Eight-Membered Cyclic Carbonates and Their Organocatalytic Polymerization.

Aliphatic N-substituted functional eight-membered cyclic carbonates were synthesized from N-substituted diethanolamines by intramolecular cyclization. On the basis of the N-substituent, three major subclasses of carbonate monomers were synthesized (N-aryl, N-alkyl and N-carbamate). Organocatalytic ring opening polymerization (ROP) of eight-membered cyclic carbonates was explored as a route to access narrowly dispersed polymers of predictable molecular weights. Polymerization kinetics was highly dependent on the substituent on the nitrogen atom and the catalyst used for the reaction. The use of triazabicyclodecene (TBD), instead of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), as the catalyst for the N-alkyl substituted monomers significantly enhanced the rate of polymerizations. Computational studies were performed to rationalize the observed trends for TBD catalyzed polymerizations. With the optimal organocatalyst all monomers could be polymerized generating well-defined polymers within a timespan of ≤2 h with relatively high monomer conversion (≥80%) and low molar-mass dispersity (D(M) ≤ 1.3). Both the glass transition temperatures (T(g)) and onset of degradation temperatures (T(onset)) of these polymers were found to be N-substituent dependent and were in the range of about -45 to 35 °C and 230 to 333 °C, respectively. The copolymerization of the eight membered monomers with 6-membered cyclic comonomers including commercially available l-lactide and trimethylene carbonate produced novel copolymers. The combination of inexpensive starting materials, ease of ring-closure and subsequent polymerization makes this an attractive route to functional polycarbontes.

Injectable biodegradable hydrogels from vitamin D-functionalized polycarbonates for the delivery of avastin with enhanced therapeutic efficiency against metastatic colorectal cancer.

Humanized vascular endothelial growth factor (VEGF) antibody (bevacizumab; Avastin) is a highly effective monoclonal antibody against metastatic colorectal cancer and several other advanced late stage cancers. However, limited aqueous solubility and short circulation half-life of the antibody result in long infusion time (30-90 min) and frequent injections. Such direful medical procedures often cause considerable patient inconvenience and prolonged pharmacy preparation. Subcutaneous delivery of Avastin using injectable hydrogels can continuously provide Avastin to treat the malignancy and mitigate antibody degradation. In this study, ABA triblock copolymers of vitamin D-functionalized polycarbonate and poly(ethylene glycol), that is, VDm-PEG-VDm were synthesized and employed to form physically cross-linked injectable hydrogels for encapsulation and subcutaneous delivery of Avastin in a sustained fashion. Antitumor studies were performed using two different HCT116 xenograft mouse models: a subcutaneous and an intraperitoneal metastatic tumor models. The therapeutic efficacy of Avastin-loaded hydrogel injected subcutaneously (s.c.) was compared to an Avastin solution injected via either intravenous (i.v.) or intraperitoneal (i.p.) route. In the subcutaneous tumor model, the Avastin-loaded hydrogel resulted in greater tumor suppression as compared to i.v. and i.p. administration of Avastin solution. The biodistribution pattern of the hydrogel delivery system was also different from the other formulations as there was significantly higher accumulation in the tumor tissue and lesser accumulation within the liver and kidneys as compared to Avastin delivered through i.v. and i.p. administration. Furthermore, in vivo studies carried out on mice with peritoneal metastasis demonstrated that Avastin-loaded hydrogel and weekly administration of Avastin solution resulted in higher survival (87 and 77% over 62 days, respectively) when compared to the control, blank hydrogel and bolus Avastin solution (i.v.; 50-60%). The antimetastatic activity of Avastin delivered using a one-time injection of the hydrogel was as effective as that of 4× weekly injections (i.v.) of Avastin. The reduced injection frequency provided by the subcutaneous formulation may enhance patient convenience and compliance for metastatic cancer therapy.

d(1) Oxosulfido-Mo(V) Compounds: First Isolation and Unambiguous Characterization of an Extended Series.

Reaction of Tp(iPr)Mo(VI)OS(OAr) with cobaltocene in toluene results in the precipitation of brown, microcrystalline oxosulfido-Mo(V) compounds, [CoCp2][Tp(iPr)Mo(V)OS(OAr)] (Cp(-) = η(5)-C5H5(-), Tp(iPr)(-) = hydrotris(3-isopropylpyrazol-1-yl)borate, OAr(-) = phenolate or 2-(s)Bu, 2-(t)Bu, 3-(t)Bu, 4-(s)Bu, 4-Ph, 3,5-(s)Bu2, 2-CO2Me, 2-CO2Et or 2-CO2Ph derivative thereof). The compounds are air- and water-sensitive and display ν(Mo═O) and ν(Mo[Formula: see text]S) IR absorption bands at ca. 890 and 435 cm(-1), respectively, 20-40 cm(-1) lower in energy than the corresponding bands in Tp(iPr)MoOS(OAr). They are electrochemically active and exhibit three reversible cyclovoltammetric waves (E(Mo(VI)/Mo(V)) = -0.40 to -0.66 V, E([CoCp2](+)/CoCp2) = -0.94 V and E(CoCp2/[CoCp2](-)) = -1.88 V vs SCE). Structural characterization of [CoCp2][Tp(iPr)MoOS(OC6H4CO2Et-2)]·2CH2Cl2 revealed a distorted octahedral Mo(V) anion with Mo═O and Mo[Formula: see text]S distances of 1.761(5) and 2.215(2) Å, respectively, longer than corresponding distances in related Tp(iPr)MoOS(OAr) compounds. The observation of strong S(1s) → (S(3p) + Mo(4d)) S K-preedge transitions indicative of a d(1) sulfido-Mo(V) moiety and the presence of short Mo═O (ca. 1.72 Å) and Mo[Formula: see text]S (ca. 2.25 Å) backscattering contributions in the Mo K-edge EXAFS further support the oxosulfido-Mo(V) formulation. The compounds are EPR-active, exhibiting highly anisotropic (Δg 0.124-0.150), rhombic, frozen-glass spectra with g1 close to the value observed for the free electron (ge = 2.0023). Spectroscopic studies are consistent with the presence of a highly covalent Mo[Formula: see text]S π* singly occupied molecular orbital. The compounds are highly reactive, with reactions localized at the terminal sulfido ligand. For example, the compounds react with cyanide and PPh3 to produce thiocyanate and SPPh3, respectively, and various (depending on solvent) oxo-Mo(V) species. Reactions with copper reagents also generally lead to desulfurization and the formation of oxo-Mo(V) or -Mo(IV) complexes.