What's the CATCH? A Participatory Learning Model for Case Review Rounds to Support a Culture of Safety and Quality Improvement in Pediatric Hospital Medicine.

OBJECTIVE: To evaluate the effectiveness of a new model, Case Analysis and Translation to Care in Hospital (CATCH), for the review of pediatric inpatient cases when an adverse event or "close call" had occurred. STUDY DESIGN: The curricular intervention consisted of an introductory podcast/workshop, mentorship of presenters, and monthly CATCH rounds over 16 months. The study was conducted with 22 pediatricians at a single tertiary care center. Intervention assessment occurred using participant surveys at multiple intervals: pre/post the intervention, presenter experience (post), physicians involved and mentors experience (post), and after each CATCH session. Paired t-tests and thematic analysis were used to analyze data. Time required to support the CATCH process was used to assess feasibility. RESULTS: Our overall experience and data revealed a strong preference for the CATCH model, high levels of engagement and satisfaction with CATCH sessions, and positive presenter as well as physicians-involved and mentor experiences. Participants reported that the CATCH model is feasible, engages physicians, promotes a safe learning environment, facilitates awareness of tools for case analysis, and provides opportunities to create "CATCH of the Day" recommendations to support translation of learning to clinical practice. CONCLUSIONS: The CATCH model has significant potential to strengthen clinical case rounds in pediatric hospital medicine. Future research is needed to assess the effectiveness of the model at additional sites and across medical specialities.

Integrative Oncology in Young Women With Breast Cancer.

Small studies have demonstrated the benefit of integrative oncology (IO) therapies in patients with breast cancer; however, referral patterns and timing of therapies are unknown. This study describes the referral pattern and utilization of IO services by young women with breast cancer. A retrospective review identified female patients, 40 years or younger, with a breast cancer diagnosis between 2014 and 2019, and a documented IO consultation. Patient demographics, cancer characteristics, treatments, reasons for seeking and timing of IO consultation, and IO treatment modalities were analyzed. The IO program treated 64 young women with a median age of 38.6 years. Clinical staging was primarily IA (27%), IIA (34%), or IIB (27%), and 64% of patients were clinically node negative with no evidence of metastasis. Women utilized the IO program for recurrence risk reduction and for treatment-related adverse effects (TRAEs), most commonly vasomotor complaints (44%). Therapies utilized were acupuncture (36%), healing touch (28%), oncology massage (30%), and other (75%; music therapy, therapeutic art, spiritual care, meditation, t'ai chi, yoga, and nutrition), which were commonly initiated during treatment (69%). Our data suggest that young women utilize IO services to reduce their future cancer risk and TRAEs, but they are often referred after standard cancer care treatments have begun. Future studies could examine the optimal timing for IO intervention.

Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.

Cetuximab in Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Ovarian Cancer Without KRAS, NRAS, or BRAF Mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

BACKGROUND: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. OBJECTIVE: With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. PATIENTS AND METHODS: Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. CONCLUSIONS: Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. CLINICAL TRIAL REGISTRATION: NCT02693535 (26 February, 2016).

Municipal Solid Waste Disposal Operational Performance in Wa Municipality, Ghana.

BACKGROUND: The generation and management of solid waste pose potential adverse impacts on human health and the environment. OBJECTIVE: The present study examines the operational performance of municipal solid waste (MSW) disposal in the Wa Municipality, Ghana. METHODS: The study applied both qualitative and quantitative research methods and modelled the Wa Municipality's MSW disposal system using the municipal solid waste decision support tool (MSW DST). Acid gases (sulphur oxides and nitrogen oxides) and total particulate matter that have a direct impact on human health were set as the objective functions for modelling five MSW disposal scenarios. The modelled scenarios were: 1) landfill disposal only; 2) composting and landfill disposal; 3) composting, incineration, refuse derived fuels (RDF) and landfill disposal; 4) separation, composting, incineration, RDF and landfill disposal; and 5) separation, transfer, material recovery, composting, incineration, RDF and landfill disposal. The pollutants chosen as indicators for substance flow analysis included lead, cadmium, arsenic, mercury, copper, chromium, and zinc. RESULTS: Scenarios 4 and 5 produced the least engineering cost of 1 150 000 US $/year for the entire MSW disposal system, whereas scenario 2 produced the highest cost of 1 340 000 US $/year. Scenario 5 produced the least average health impacts of -5.812E-04 lbs/year, while scenario 2 generated the highest engineering cost and produced the highest average health impact of 9.358E-05 lbs/year. Scenarios 5 and 4, which included waste-to-energy conversion in the systems, produced the lowest average health impacts (-5.812E-04 lbs/year and -5.611E-04 lbs/year, respectively). CONCLUSIONS: The adoption of an integrated solid waste management concept, including waste-to-energy technologies, will not only help to lessen MSW disposal hazards, but also to produce alternative sources of energy for Ghana and other developing countries. COMPETING INTERESTS: The authors declare no competing financial interests.

What patient assessment skills are required by pharmacists prescribing systemic anti-cancer therapy? A consensus study.

BACKGROUND: In the UK, pharmacist independent prescribers can prescribe for any condition within their clinical competence including systemic anti-cancer therapy. Competency frameworks have been developed but contain little detail on the patient assessment skills pharmacist independent prescribers require to prescribe systemic anti-cancer therapy with concern in the literature over current training on these skills. AIM: To gain consensus on the patient assessment skills required by pharmacist independent prescribers prescribing systemic anti-cancer therapy for genitourinary cancer (prostate and renal) and lung cancer across National Health Service Scotland. METHOD: Two phases were performed to generate patient assessment skill consensus. Initially, the Nominal Group Technique was performed within a local cancer network by discussion and participant ranking within genitourinary and lung cancer multi-disciplinary teams. Where consensus was achieved, patient assessment skills were carried forward to try to achieve national (National Health Service Scotland) consensus using a two-round Delphi questionnaire. RESULTS: Of the 27 patient assessment skills, consensus was gained for 21 and 23 patient assessment skills in the genitourinary and lung Nominal Group Technique groups, respectively. Within the genitourinary and lung national groups, 13/21 and 18/23 patient assessment skills were agreed as required for a pharmacist independent prescriber to prescribe systemic anti-cancer therapy in genitourinary and lung cancer, respectively. Eight common patient assessment skills were identified as core skills. Reasons for not reaching consensus included pharmacist independent prescriber competence, knowledge, skills and the roles and responsibilities of pharmacist independent prescribers within the multi-disciplinary team. CONCLUSION: We identified the core and specific patient assessment skills required to prescribe systemic anti-cancer therapy within two tumour groups. Further work is necessary to develop patient assessment skill competency frameworks, training and assessment methods and to redefine the roles of pharmacist independent prescribers within the multi-disciplinary team.

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.

PURPOSE: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. PATIENTS AND METHODS: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. RESULTS: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. CONCLUSION: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. CLINICAL TRIAL: (NCT01305941).

Determination of glucose exchange rates and permeability of erythrocyte membrane in preeclampsia and subsequent oxidative stress-related protein damage using dynamic-19F-NMR.

The cause of the pregnancy condition preeclampsia (PE) is thought to be endothelial dysfunction caused by oxidative stress. As abnormal glucose tolerance has also been associated with PE, we use a fluorinated-mimic of this metabolite to establish whether any oxidative damage to lipids and proteins in the erythrocyte membrane has increased cell membrane permeability. Data were acquired using 19F Dynamic-NMR (DNMR) to measure exchange of 3-fluoro-3-deoxyglucose (3-FDG) across the membrane of erythrocytes from 10 pregnant women (5 healthy control women, and 5 from women suffering from PE). Magnetisation transfer was measured using the 1D selective inversion and 2D EXSY pulse sequences, over a range of time delays. Integrated intensities from these experiments were used in matrix diagonalisation to estimate the values of the rate constants of exchange and membrane permeability. No significant differences were observed for the rate of exchange of 3-FDG and membrane permeability between healthy pregnant women and those suffering from PE, leading us to conclude that no oxidative damage had occurred at this carrier-protein site in the membrane.

Investigating a Relationship between the Mutagenicity of Arylboronic Acids and (11)B NMR Chemical Shifts.

The mutagenicity of arylboronic acids has recently become an important area of research because of their potential to be genotoxic impurities in active pharmaceutical ingredients. There is no known mechanism, so currently all structure-activity relationships have been derived using Ames test data. We present preliminary data supporting a hypothesis that the mutagenicity of arylboronic acids is related to the (11)B NMR chemical shift. This could indicate that the mutagenic activity of the arylboronic acids is related to the reactivity of the boron center.

An iron(ii) spin-crossover metallacycle from a back-to-back bis-[dipyrazolylpyridine].

The syntheses of 4-mercapto-2,6-di(pyrazol-1-yl)pyridine (bppSH) and bis[2,6-di(pyrazol-1-yl)pyrid-4-yl]disulfide (bppSSbpp) are reported. In contrast to previously published "back-to-back" bis-[2,6-di(pyrazol-1-yl)pyridine] derivatives, which form coordination polymers with transition ions that are usually insoluble, bppSSbpp yields soluble oligomeric complexes with iron(ii) and zinc(ii). Mass spectrometry and DOSY data show that [{Fe(µ-bppSSbpp)}n](2n+) and [{Zn(µ-bppSSbpp)}n](2n+) form tetranuclear metallacycles in nitromethane solution (n = 4), although (1)H NMR and conductivity measurements imply the iron compound may undergo more fragmentation than its zinc congener. Both [{Fe(bppSH)2](2+) and [{Fe(µ-bppSSbpp)}n](2n+) exhibit thermal spin-crossover in CD3NO2 solution, with midpoint temperatures near 245 K. The similarity of these equilibria implies there is little cooperativity between the iron centres in the metallacyclic structures.

Stabilization of a Bimolecular Triplex by 3'-S-Phosphorothiolate Modifications: An NMR and UV Thermal Melting Investigation.

Triplexes formed from oligonucleic acids are key to a number of biological processes. They have attracted attention as molecular biology tools and as a result of their relevance in novel therapeutic strategies. The recognition properties of single-stranded nucleic acids are also relevant in third-strand binding. Thus, there has been considerable activity in generating such moieties, referred to as triplex forming oligonucleotides (TFOs). Triplexes, composed of Watson-Crick (W-C) base-paired DNA duplexes and a Hoogsteen base-paired RNA strand, are reported to be more thermodynamically stable than those in which the third strand is DNA. Consequently, synthetic efforts have been focused on developing TFOs with RNA-like structural properties. Here, the structural and stability studies of such a TFO, composed of deoxynucleic acids, but with 3'-S-phosphorothiolate (3'-SP) linkages at two sites is described. The modification results in an increase in triplex melting temperature as determined by UV absorption measurements. (1) H NMR analysis and structure generation for the (hairpin) duplex component and the native and modified triplexes revealed that the double helix is not significantly altered by the major groove binding of either TFO. However, the triplex involving the 3'-SP modifications is more compact. The 3'-SP modification was previously shown to stabilise G-quadruplex and i-motif structures and therefore is now proposed as a generic solution to stabilising multi-stranded DNA structures.

Stereocontrolled protein surface recognition using chiral oligoamide proteomimetic foldamers.

The development of foldamers capable of selective molecular recognition of solvent exposed protein surfaces represents an outstanding challenge in supramolecular chemical biology. Here we introduce an oligoamide foldamer with well-defined conformation that bears all the hallmarks of an information rich oligomer. Specifically, the foldamer recognizes its target protein hDM2 leading to inhibition of its protein-protein interaction with p53 in a manner that depends upon the composition, spatial projection and stereochemistry of functional groups appended to the scaffold. Most significantly, selective inhibition of p53/hDM2 can be achieved against four other targets and the selectivity for p53/hDM2 inhibition versus Mcl-1/NOXA-B inhibition is critically dependent upon the stereochemistry of the helix mimetic.

Metallo-cryptophanes decorated with bis-N-heterocyclic carbene ligands: self-assembly and guest uptake into a nonporous crystalline lattice.

Pd3L2 metallo-cryptophane cages with cyclotriveratrylene-type L ligands can be stabilized by use of a bis-N-heterocyclic carbene as an auxiliary cis-protecting ligand, while use of more common protecting chelating ligands such as ethylenediamine saw a Pd3L2 to Pd6L8 rearrangement occur in solution. The crystalline Pd3L2 complexes act as sponges, taking up 1,2-dichorobenzene or iodine in a single-crystal-to-single-crystal fashion despite not exhibiting conventional porosity.

Optimal reaction coordinate as a biomarker for the dynamics of recovery from kidney transplant.

The evolution of disease or the progress of recovery of a patient is a complex process, which depends on many factors. A quantitative description of this process in real-time by a single, clinically measurable parameter (biomarker) would be helpful for early, informed and targeted treatment. Organ transplantation is an eminent case in which the evolution of the post-operative clinical condition is highly dependent on the individual case. The quality of management and monitoring of patients after kidney transplant often determines the long-term outcome of the graft. Using NMR spectra of blood samples, taken at different time points from just before to a week after surgery, we have shown that a biomarker can be found that quantitatively monitors the evolution of a clinical condition. We demonstrate that this is possible if the dynamics of the process is considered explicitly: the biomarker is defined and determined as an optimal reaction coordinate that provides a quantitatively accurate description of the stochastic recovery dynamics. The method, originally developed for the analysis of protein folding dynamics, is rigorous, robust and general, i.e., it can be applied in principle to analyze any type of biological dynamics. Such predictive biomarkers will promote improvement of long-term graft survival after renal transplantation, and have potentially unlimited applications as diagnostic tools.

Solvent-dependent self-assembly behaviour and speciation control of Pd6L8 metallo-supramolecular cages.

The C3-symmetric chiral propylated host-type ligands (±)-tris(isonicotinoyl)-tris(propyl)-cyclotricatechylene (L1) and (±)-tris(4-pyridyl-4-benzoxy)-tris(propyl)-cyclotricatechylene (L2) self-assemble with Pd(II) into [Pd6L8](12+) metallo-cages that resemble a stella octangula. The self-assembly of the [Pd6(L1)8](12+) cage is solvent-dependent; broad NMR resonances and a disordered crystal structure indicate no chiral self-sorting of the ligand enantiomers in DMSO solution, but sharp NMR resonances occur in MeCN or MeNO2. The [Pd6(L1)8](12+) cage is observed to be less favourable in the presence of additional ligand, than is its counterpart, where L=(±)-tris(isonicotinoyl)cyclotriguaiacylene (L1 a). The stoichiometry of reactant mixtures and chemical triggers can be used to control formation of mixtures of homoleptic or heteroleptic [Pd6L8](12+) metallo-cages where L=L1 and L1 a.

Encapsulation of sodium alkyl sulfates by the cyclotriveratrylene-based, [Pd(6)L(8)](12+) stella octangula cage.

We have previously described a cyclotriveratrylene (CTV)-based complex, [Pd6L8](12+), that forms a highly symmetric stella octangula cage. Here we report on the ability of this system to host sodium salts of three alkyl sulfates; octyl (SOS), dodecyl (SDS) and tetradecyl (STS). (1)H NMR chemical shift and diffusion coefficient measurements reveal that two molecules of alkyl sulfate reside in the cage, though rapid exchange between cage and bulk solvent is apparent. Host : guest association constants have been determined and support for the internalisation of the sulfates is available from 2D ROESY and NOESY data.

Development and evaluation of global child health educational modules.

OBJECTIVES: To determine if a standardized global child health (GCH) modular course for pediatric residents leads to satisfaction, learning, and behavior change. METHODS: Four 1-hour interactive GCH modules were developed addressing priority GCH topics. "Site champions" from 4 Canadian institutions delivered modules to pediatric residents from their respective programs during academic half-days. A pre-post, mixed methods evaluation incorporated satisfaction surveys, multiple-choice knowledge tests, and focus group discussions involving residents and satisfaction surveys from program directors. RESULTS: A total of 125 trainees participated in ≥1 module. Satisfaction levels were high. Focus group participants reported high satisfaction with the concepts taught and the dynamic, participatory approach used, which incorporated multimedia resources. Mean scores on knowledge tests increased significantly postintervention for 3 of the 4 modules (P < .001), and residents cited increases in their practical knowledge, global health awareness, and motivation to learn about global health. Program directors unanimously agreed that the modules were relevant, interesting, and could be integrated within existing formal training time. CONCLUSIONS: A relatively short, participatory, foundational GCH modular curriculum facilitated knowledge acquisition and attitude change. It could be scaled up and serve as a model for other standardized North American curricula.

Thermal stabilisation of RNA·RNA duplexes and G-quadruplexes by phosphorothiolate linkages.

The effect of 3'-S-phosphorothiolate linkages on the stability of RNA·RNA duplexes and G-quadruplex structures has been studied. 3'-Thio-2'-deoxyuridine was incorporated into RNA duplexes and thermal melting studies revealed that the resulting 3'-S-phosphorothiolate linkages increased the stability of the duplex to thermal denaturation. Additionally, and contrary to expectation, a similar effect on duplex stability was observed when the same thionucleoside was incorporated into the RNA strand of a RNA·DNA duplex. A suitably protected derivative of 3'-thio-2'-deoxyguanosine was prepared using an oxidation-reduction strategy and this residue also increased the thermal stability the [d(TGGGGT)](4) G-quadruplex when positioned centrally. The results are discussed in terms of the influence that the sulfur atom has on the conformation of the furanose ring and imply that the previously noted high thermal stability of parallel RNA quadruplexes is not derived from H-bonding interactions of the 2'-hydroxyl group, but can be attributed to conformational effects.

Metabolic profiling of follicular fluid and plasma from natural cycle in vitro fertilization patients--a pilot study.

OBJECTIVE: To investigate changes in follicular fluid (FF) and plasma composition during the follicular and periovulatory phases of the menstrual cycle in patients undergoing assisted conception, using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy-based metabolite profiling. DESIGN: A pilot prospective laboratory study. SETTING: Assisted conception clinic in a university hospital. PATIENT(S): Ten women undergoing natural-cycle (NC) in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with either male factor subfertility or unexplained subfertility. INTERVENTION(S): FF and plasma were collected during the midfollicular phase or at the LH-surge and at the time of oocyte collection. MAIN OUTCOME MEASURE(S): (1)H-NMR spectroscopy was performed on the fluids and the metabolic profiles compared across the phases with the use of principal components analysis (PCA). RESULT(S): LH-surge FF resembled periovulatory FF more than midfollicular FF, with higher levels of lactate and pyruvate and lower glucose. Periovulatory plasma contained higher levels of glucose and acetate and lower glycoprotein, trimethylamine, and glycine compared with midfollicular and LH-surge plasma. CONCLUSION(S): NMR-based metabolite profiling of FF and plasma has potential for identifying changes across menstrual stages, studying the impact of exogenous hCG administration, and in the pursuit of biomarkers to predict fertility treatment outcome.