IOA-244 is a Non-ATP-competitive, Highly Selective, Tolerable PI3K Delta Inhibitor That Targets Solid Tumors and Breaks Immune Tolerance.

PI3K delta (PI3Kδ) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kδ inhibition in solid tumors has recently emerged as a potential novel anticancer therapy through the modulation of T-cell responses and direct antitumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non-ATP-competitive PI3Kδ inhibitor, for the treatment of solid tumors. We confirm IOA-244's selectivity as tested against a large set of kinases, enzymes, and receptors. IOA-244 inhibits the in vitro growth of lymphoma cells and its activity correlates with the expression levels of PIK3CD, suggesting cancer cell-intrinsic effects of IOA-244. Importantly, IOA-244 inhibits regulatory T cell proliferation while having limited antiproliferative effects on conventional CD4+ T cells and no effect on CD8+ T cells. Instead, treatment of CD8 T cells with IOA-244 during activation, favors the differentiation of memory-like, long-lived CD8, known to have increased antitumor capacity. These data highlight immune-modulatory properties that can be exploited in solid tumors. In CT26 colorectal and Lewis lung carcinoma lung cancer models, IOA-244 sensitized the tumors to anti-PD-1 (programmed cell death protein 1) treatment, with similar activity in the Pan-02 pancreatic and A20 lymphoma syngeneic mouse models. IOA-244 reshaped the balance of tumor-infiltrating cells, favoring infiltration of CD8 and natural killer cells, while decreasing suppressive immune cells. IOA-244 presented no detectable safety concerns in animal studies and is currently in clinical phase Ib/II investigation in solid and hematologic tumors. Significance: IOA-244 is a first-in-class non-ATP-competitive, PI3Kδ inhibitor with direct antitumor in vitro activity correlated with PI3Kδ expression. The ability to modulate T cells, in vivo antitumor activity in various models with limited toxicity in animal studies provides the rationale for the ongoing trials in patients with solid tumors and hematologic cancers.

Usability, acceptability and clinical utility of a mobile app to screen for hearing loss in older adults in a geriatric rehabilitation hospital.

RATIONALE: Hearing loss is a common problem for older adults entering rehabilitation hospitals. AIMS AND OBJECTIVES: To pilot a hearing loss screening device to determine feasibility, usability, and impact on patient outcomes. METHODS: We screened all patients newly admitted to a geriatric day hospital for hearing loss using the SHOEBOX® QuickTest (SHOEBOX Ltd.) app as part of a quality improvement programme. We measured the time it took for each patient to complete screening and recorded any issues they had using the app. We recorded the number of patients who screened positive who did not have a previous diagnosis and changes in physician behaviours after they received their patients' results. RESULTS: Seventy-four patients with a mean age of 83.4 years used the hearing screener. All patients were able to complete the screening with a mean time to completion of 10 min and 48 s. Ninety-nine percent of patients screened positive for hearing loss. Of these positives 56% were in participants not already known to have hearing loss. Physicians often changed their behaviour after receiving results by using assistive devices during visits and referring to audiology for formal testing. CONCLUSIONS: Screening for hearing loss is feasible in a geriatric day hospital. The SHOEBOX QuickTest app is acceptable, usable, resulting in the identification of undiagnosed hearing loss and in changes to physician behaviour.

In silico identification and synthesis of a multi-drug loaded MOF for treating tuberculosis.

Conventional drug delivery systems have been applied to a myriad of active ingredients but may be difficult to tailor for a given drug. Herein, we put forth a new strategy, which designs and selects the drug delivery material by considering the properties of encapsulated drugs (even multiple drugs, simultaneously). Specifically, through an in-silico screening process of 5109 MOFs using grand canonical Monte Carlo simulations, a customized MOF (referred as BIO-MOF-100) was selected and experimentally verified to be biologically stable, and capable of loading 3 anti-Tuberculosis drugs Rifampicin+Isoniazid+Pyrazinamide at 10% + 28% + 23% wt/wt (total > 50% by weight). Notably, the customized BIO-MOF-100 delivery system cleared naturally Pyrazinamide-resistant Bacillus Calmette-Guérin, reduced growth of virulent Erdman infection in macaque macrophages 10-100-fold compared to soluble drugs in vitro and was also significantly reduced Erdman growth in mice. These data suggest that the methodology of identifying-synthesizing materials can be used to generate solutions for challenging applications such as simultaneous delivery of multiple, small hydrophilic and hydrophobic molecules in the same molecular framework.

Enhancing Clinical Visibility of Hearing Loss in Cognitive Decline.

BACKGROUND: Hearing loss is the largest potentially modifiable risk factor for dementia and is highly prevalent among older adults, yet it goes largely unreported, unidentified, and untreated, at great cost to health and quality of life. Hearing screening is a proven cost-effective solution to overcome delays in its identification and management yet is not typically recommended by physicians for older adults. OBJECTIVE: To demonstrate the feasibility and value of hearing screening for older adults at risk for dementia in order to enhance physicians' awareness of hearing loss and improve access to timely hearing care. METHODS: Patients referred to two academic medical clinics for memory disorders were offered hearing screening as part of clinic protocol. Patients with hearing loss were recruited to the study if they consented to a post-appointment telephone interview and chart review. Memory Clinic physicians were surveyed about the usefulness of the screening information and referral of patients with hearing loss to audiology. RESULTS: Hearing loss was reliably detected in Memory Clinic patients with both in-office and online screening tools. Physicians reported that screening enhanced their awareness of hearing loss and increased the referral rate to audiology. CONCLUSION: Hearing screening in Memory Clinic patients is a useful component of clinic protocol that facilitates timely access to management and addresses an important risk factor for dementia.

Granular Cell Tumor in a 13-Year-Old Girl.

Granular cell tumors are rare benign soft-tissue lesions that most commonly occur in the head and neck. They usually present in adulthood and are rarely seen in children. Here we present a 13-year-old girl who experienced symptoms of hoarseness of voice for most of her childhood and was unsuccessfully treated for asthma, acid reflux, allergies, and bronchitis before direct visualization revealed what was initially thought to be a vocal cord cyst. Surgical excision and pathology revealed the unexpected diagnosis of a vocal cord granular cell tumor. The patient has had resolution of dysphonia and is undergoing voice therapy.

Validation of SHOEBOX QuickTest Hearing Loss Screening Tool in Individuals With Cognitive Impairment.

Objectives: The aim of this study was to validate a novel iPad-based rapid hearing loss screening tool (SHOEBOX QuickTest) in individuals with cognitive impairment. Design: Cross-sectional validation study. Setting: Bruyère Research Institute, Ottawa, Canada. Subjects and Methods: Twenty-five individuals with mild cognitive impairment (MCI) and mild dementia from the Bruyère Memory Program were included in this study. The study consisted of two components: (1) SHOEBOX QuickTest hearing screener and (2) a conventional hearing test (pure tone audiometry). Measurements: Hearing was assessed at 1,000, 2,000, and 4,000 Hz separately for each ear. The agreement between hearing ability groupings (good vs. reduced) from conventional hearing test and SHOEBOX QuickTest was determined. Specifically, accuracy, sensitivity, specificity, as well as alignment between conventional thresholds and hearing threshold ranges. Results: An overall accuracy of 84% was observed for SHOEBOX QuickTest, and a sensitivity and specificity of 100 and 66.7%, respectively. 72% ([95% CI], 60.0-84.1%) of conventional audiometry thresholds were within the pre-established 10 dB SHOEBOX QuickTest. Conclusion: SHOEBOX QuickTest is a valid hearing loss screening tool for individuals with cognitive impairment. Implementing this iPad-based screening tool in memory clinics could not only aid in the timely diagnosis of hearing loss, but also assist physicians in providing a better assessment of cognitive impairment by ruling out hearing loss as a confounding variable.

iHear: Canadian medical student based hearing assessment program for grade school children using a tablet audiometer.

PURPOSE: To evaluate the progress and challenges of a hearing screening program as well as review the incidence of pediatric hearing loss in grade school children participating in this program. METHODS: Medical students from the University of Ottawa established iHear, a grade school hearing assessment program that uses novel tablet audiometry. Over 3 years, children in grades 1 and 2 were assessed and those found to have abnormal results on iHear assessment were then referred to audiology for formal testing, and to otolaryngology if needed. RESULTS: From 2014 to 2017, 753 children aged 5-9 years old were assessed for hearing loss. Mean age of participants was 6.7 years, 51.9% of whom were female. Of the children assessed, 86 (11.4%) had abnormal results and 6 (0.8%) had inconsistent results, necessitating 92 referrals for assessment by a professional audiologist. Of the 65 participants who completed secondary audiologic assessment, 54 (83.1%) were normal and 11 (16.9%) had a definitive hearing loss or abnormal tympanometry. A total of 32 children were lost to follow-up. A total of 118 medical students were involved in the iHear program. CONCLUSIONS: Hearing loss in grade school populations continues to go undetected across Canada. Programs such as iHear demonstrate that gaps in the provision of hearing assessment can be filled effectively by medical students equipped with tablet audiometry. Medical student exposure to audiology and otolaryngology increased through the iHear program.

Cerebrospinal Fluid Leaks From the Lateral Ventricle: A Case Series.

OBJECTIVES: Describe the diagnosis and management of lateral skull base (LSB) cerebrospinal fluid (CSF) leaks originating from the lateral ventricle. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral academic center. PATIENTS: Patients with CSF leaks with direct communication to the lateral ventricle on preoperative imaging. INTERVENTION: Surgical repair via the middle cranial fossa (MCF) approach. MAIN OUTCOME MEASURES: CSF leak patient characteristics (age, sex, body mass index [BMI]) and postoperative course (complications and CSF leak resolution) were collected. RESULTS: Three patients had CSF leaks from the lateral ventricle and all patients demonstrated encephalomalacia of the temporal lobe on preoperative imaging. Encephalomalacia resulted from trauma in one case (age 5) and neurodegeneration in two cases (age 77 and 84). BMI ranged from 16.3 to 26.6 mg/kg2 and follow-up ranged from 4 to 21 months. Two patients presented with preoperative meningitis and all patients had resolution of CSF leaks after MCF repair. With the exception of the higher rate of meningitis, patient presentations did not differ from other spontaneous CSF leaks through middle fossa defects. There were no minor or major postoperative complications. CONCLUSIONS: CSF leaks from the lateral ventricle represent a rare subset of LSB CSF leaks and can occur in non-obese patients secondary to temporal lobe encephalomalacia. The MCF approach allows for repair of the dura and skull base in this cohort of patients with high-flow CSF leaks and loss of brain parenchyma.

Pedicled Cervical Lymphoadipose Tissue for Volume Reconstruction after Superficial Parotidectomy.

Volume restoration is often required after parotidectomy due to the resultant facial contour deformity. Common procedures include local pedicled flaps, such as the sternocleidomastoid muscle flap, fat grafting, and even autologous free flaps, for more extensive defects. Local pedicled flaps have the advantage of a single surgical site, which spares the patient the added morbidity of a separate fat graft donor site, while simultaneously reducing the operative time. We report two cases of a novel reconstructive option using pedicled level I and II cervical lymphoadipose tissue for volume restoration after superficial parotidectomy. This reconstruction would be useful for patients with benign parotid lesions and inferior parotid defects. In addition, with maintained blood supply to this tissue, it would likely provide sustained bulk over time.

The transcriptional signature associated with human motile cilia.

Cilia are complex microtubule-based organelles essential to a range of processes associated with embryogenesis and tissue homeostasis. Mutations in components of these organelles or those involved in their assembly may result in a diverse set of diseases collectively known as ciliopathies. Accordingly, many cilia-associated proteins have been described, while those distinguishing cilia subtypes are poorly defined. Here we set out to define genes associated with motile cilia in humans based on their transcriptional signature. To define the signature, we performed network deconvolution of transcriptomics data derived from tissues possessing motile ciliated cell populations. For each tissue, genes coexpressed with the motile cilia-associated transcriptional factor, FOXJ1, were identified. The consensus across tissues provided a transcriptional signature of 248 genes. To validate these, we examined the literature, databases (CilDB, CentrosomeDB, CiliaCarta and SysCilia), single cell RNA-Seq data, and the localisation of mRNA and proteins in motile ciliated cells. In the case of six poorly characterised signature genes, we performed new localisation experiments on ARMC3, EFCAB6, FAM183A, MYCBPAP, RIBC2 and VWA3A. In summary, we report a set of motile cilia-associated genes that helps shape our understanding of these complex cellular organelles.

TALPID3 in Joubert syndrome and related ciliopathy disorders.

TALPID3 (KIAA0586) is a centrosomal protein which has specific functions during centriole maturation during the formation of the centrosomal-dependent organelle, the cilia, as well as less well understood roles in the cytoskeleton and during cell polarisation. Cilia are an essential component of signal transduction during embryonic development and the loss of TALPID3 function in humans can cause both severe lethal and mild cilia-related developmental disorders known as 'ciliopathies' the most common being Joubert syndrome. TALPID3 related ciliopathies affect the development of multiple organ systems including the brain, skeleton, eyes, lungs and liver. The consequences of TALPID3 dysfunction outside of the cilia and the implications for human diseases are less well understood.

East meets West: Shadow coaching to support online reflective practice.

OBJECTIVES: A structured, reflection-based electronic portfolio program (ePortfolio), with novel faculty development initiative, involving 'shadow coaches', was shared with the newly formed Ottawa-Shanghai Joint School of Medicine (OSJSM). OSJSM is a partnership between Shanghai Jiao Tong University and the University of Ottawa. As the world's first Sino-Canadian Joint Medical School, OSJSM introduced North American undergraduate medical curriculum to China. 'Shadow coaching' involved trans-Pacific pairing of coaches, supplemented by local faculty development. FRAMEWORK: (a) Pre-implementation: The well-established online ePortfolio platform at the University of Ottawa was mirrored at OSJSM. University of Ottawa ePortfolio coaches were recruited to serve as shadow coaches to their OSJSM counterparts. Shadow coaches provided mentoring and resources while maintaining awareness of cross-cultural issues. Faculty development consisted of face-to-face faculty development in Shanghai, several online synchronous sessions, and familiarization of University of Ottawa coaches with the Chinese medical education system. (b) Description/Components: This intervention, introduced in 2016-2017, involved five University of Ottawa shadow coaches paired with five OSJSM ePortfolio coaches. Student reflection encourages open frank discussion which is a new paradigm for Chinese students and faculty. Shadow coaches were encouraged to challenge new OSJSM coaches to widely explore physician roles and competencies. RESULTS: Initial results indicate that the experience served to effectively develop OSJSM coaches' skills as evidenced by shadow coaches' review of anonymized OSJSM student reflective writing. CONCLUSIONS: Our project describes a novel tool using shadow coaching for faculty development for a cross-cultural partnership. Similar approaches can be utilized for culturally-sensitive long-distance faculty development.

The use of electronic consultations is associated with lower specialist referral rates: a cross-sectional study using population-based health administrative data.

Background: The referral-consultation process can be difficult to navigate. Electronic consultations (eConsults) can help streamline referrals by facilitating inter-provider communication. Objective: We evaluated the potential effect of eConsult on specialist referral rates in Ontario among family physicians providing comprehensive care. Methods: We conducted a retrospective 1:3 matched cohort study examining total referrals and referrals to all available medical specialties from primary care providers between 1 April 2014 and 31 March 2015. We used multivariable random effects Poisson regression analysis to compare referral rates between eConsult and non-eConsult users while adjusting for relevant patient and provider characteristics. Referral rates were expressed per physician, per 100 patients and per 100 patient encounters. Results: There were 113197 referrals across all medical specialties made by 119 eConsult physicians and 352 matched controls. Referral rates per physician were significantly lower in the eConsult group for all specialty groupings [unadjusted rate ratio (RR) = 0.87, 95% confidence interval (CI) = 0.80-0.95; adjusted RR = 0.92, 95% CI = 0.85-1.00]. Referral rates per patient were lower among eConsult physicians (unadjusted RR = 0.91, 95% CI = 0.84-0.98) but this difference was not statistically significant after adjustment (adjusted RR = 0.96, 95% CI = 0.90-1.02). No statistically significant difference was observed when referrals were expressed per 100 patient encounters. Conclusion: This is the first Canadian study to examine the potential effect of eConsult on overall referrals at a population level. Our findings demonstrate that using eConsult service is associated with fewer referrals from primary to specialist care, with considerable potential for cost savings to our single-payer system.

The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse.

Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.

Preparing anesthesiology faculty for competency-based medical education.

PURPOSE: Competency-based medical education (CBME) is quickly becoming the dominant organizing principle for medical residency programs. As CBME requires changes in the way medical education is delivered, faculty will need to acquire new skills in teaching and assessment in order to navigate the transition. In this paper, we examine the evidence supporting best practices in faculty development, propose strategies for faculty development for CBME-based residency programs, and discuss the results of faculty development initiatives at the pioneering anesthesia CBME residency program at the University of Ottawa. SOURCE: Review of the current literature and information from the University of Ottawa anesthesia residency program. PRINCIPAL FINDINGS: Faculty development is critical to the success of CBME programs. Attention must be paid to the competence of faculty to teach and assess all of the CanMEDS roles. At the University of Ottawa, some faculty development initiatives were very successful, while others were hindered by factors both internal and external to the residency program. Many faculty development activities had low attendance rates. CONCLUSIONS: Faculty development must be considered in the rollout of any new educational initiative. Experts suggest that faculty development for CBME should incorporate educational activities using multiple teaching and delivery methods, and should be offered longitudinally through the planning, development, and implementation phases of curriculum change. Additionally, these educational activities must continue until all faculty have demonstrated an acceptable level of competence. Faculty buy-in is paramount to the successful delivery of any faculty development program that is not mandatory in nature.

Cognitive Aids for Role Definition (CARD) to improve interprofessional team crisis resource management: An exploratory study.

This study aimed to assess the perceived value of the Cognitive Aids for Role Definition (CARD) protocol for simulated intraoperative cardiac arrests. Sixteen interprofessional operating room teams completed three consecutive simulated intraoperative cardiac arrest scenarios: current standard, no CARD; CARD, no CARD teaching; and CARD, didactic teaching. Each team participated in a focus group interview immediately following the third scenario; data were transcribed verbatim and qualitatively analysed. After 6 months, participants formed eight new teams randomised to two groups (CARD or no CARD) and completed a retention intraoperative cardiac arrest simulation scenario. All simulation sessions were video recorded and expert raters assessed team performance. Qualitative analysis of the 16 focus group interviews revealed 3 thematic dimensions: role definition in crisis management; logistical issues; and the "real life" applicability of CARD. Members of the interprofessional team perceived CARD very positively. Exploratory quantitative analysis found no significant differences in team performance with or without CARD (p > 0.05). In conclusion, qualitative data suggest that the CARD protocol clarifies roles and team coordination during interprofessional crisis management and has the potential to improve the team performance. The concept of a self-organising team with defined roles is promising for patient safety.

Curriculum reform for residency training: competence, change, and opportunities for leadership.

PURPOSE: Certain pressures stemming from within the medical community and from society in general, such as the need for increased accountability in resident training and restricted resident duty hours, have prompted a re-examination of methods for training physicians. Leaders in medical education in North America and around the world champion competency-based medical education (CBME) as a solution. The Department of Anesthesiology at the University of Ottawa launched Canada's first CBME program for anesthesiology residents on July 1, 2015. In this paper, we discuss the opportunities and challenges associated with CBME and delineate the elements of the new CBME program at the University of Ottawa. SOURCE: Review of the current literature. PRINCIPAL FINDINGS: Competency-based medical education addresses some of the challenges associated with physician training, such as ensuring that specialists are competent in all key areas and reducing training costs. In principle, competency-based medical education can better meet the needs of patients, providers, and other stakeholders in the healthcare system, but its success will depend on support from all involved. As CBME is implemented, anesthesiologists have the opportunity to become leaders in innovation and medical education. The University of Ottawa has implemented a CBME program with a twofold purpose, namely, to focus learning opportunities on the development of the specific competencies required of practicing anesthesiologists and to test the effectiveness of a reduction in the length of training. CONCLUSION: Canadian anesthesia residency programs will soon transition to CBME in order to promote better transparency, accountability, fairness, fiscal responsibility, and patient safety. Competency-based medical education offers significant potential advantages for healthcare stakeholders.

TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23).

Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects.