An overview of Internal Medicine Point-of-Care Ultrasound rotations in Canada.

BACKGROUND: Point-of-care ultrasound (POCUS) is a growing part of internal medicine training programs. Dedicated POCUS rotations are emerging as a particularly effective tool in POCUS training, allowing for longitudinal learning and emphasizing both psychomotor skills and the nuances of clinical integration. In this descriptive paper, we set out to review the state of POCUS rotations in Canadian Internal Medicine training programs. RESULTS: We identify five programs currently offering a POCUS rotation. These rotations are offered over two to thirteen blocks each year, run over one to four weeks and support one to four learners. Across all programs, these rotations are set up as a consultative service that offers POCUS consultation to general internal medicine inpatients, with some extension of scope to the hospitalist service or surgical subspecialties. The funding model for the preceptors of these rotations is predominantly fee-for-service using consultation codes, in addition to concomitant clinical work to supplement income. All but one program has access to hospital-based archiving of POCUS exams. Preceptors dedicate ten to fifty hours to the rotation each week and ensure that all trainee exams are reviewed and documented in the patient's medical records in the form of a consultation note. Two of the five programs also support a POCUS fellowship. Only two out of five programs have established learner policies. All programs rely on In-Training Evaluation Reports to provide trainee feedback on their performance during the rotation. CONCLUSIONS: We describe the different elements of the POCUS rotations currently offered in Canadian Internal Medicine training programs. We share some lessons learned around the elements necessary for a sustainable rotation that meets high educational standards. We also identify areas for future growth, which include the expansion of learner policies, as well as the evolution of trainee assessment in the era of competency-based medical education. Our results will help educators that are endeavoring setting up POCUS rotations achieve success.

First year internal medicine residents' self-report point-of-care ultrasound knowledge and skills: what (Little) difference three years make.

BACKGROUND: With increasing availability of point-of-care ultrasound (POCUS) education in medical schools, it is unclear whether or not learning needs of junior medical residents have evolved over time. METHODS: We invited all postgraduate year (PGY)-1 residents at three Canadian internal medicine residency training programs in 2019 to complete a survey previously completed by 47 Canadian Internal Medicine PGY-1 s in 2016. Using a five-point Likert scale, participants rated perceived applicability of POCUS to the practice of internal medicine and self-reported skills in 15 diagnostic POCUS applications and 9 procedures. RESULTS: Of the 97 invited residents, 58 (60 %) completed the survey in 2019. Participants reported high applicability but low skills across all POCUS applications and procedures. The 2019 cohort reported higher skills in assessing pulmonary B lines than the 2016 cohort (2.3 ± SD 1.0 vs. 1.5 ± SD 0.7, adjusted p-value = 0.01). No other differences were noted. CONCLUSIONS: POCUS educational needs continue to be high in Canadian internal medicine learners. The results of this needs assessment study support ongoing inclusion of basic POCUS elements in the current internal medicine residency curriculum.

Transformation of Australian Community Pharmacies Into Good Clinical Practice Compliant Trial Pharmacies for HIV Pre-Exposure Prophylaxis.

Background: In Australia, clinical trial drugs are conventionally dispensed through clinical trial pharmacies only, while community pharmacies dispense drugs approved by Australia's regulatory body. A large HIV pre-exposure prophylaxis study aimed to deliver clinical trial drug through community pharmacies to improve convenience and mimic real world prescribing. This paper describes the process of making community trials compliant with good clinical practice and reports outcomes of delivering clinical trial drug through community pharmacies. Methods: Eight community and four clinical trial pharmacies across three Australian states were approached to participate. A good clinical practice checklist was generated and pharmacies underwent a number of changes to meet clinical trial pharmacy requirements prior to study opening. Changes were made to community pharmacies to make them compliant with good clinical trial practice including; staff training, structural changes, and implementing monitoring of study drug and prescribing practices. Study drug was ordered through standard clinical trial processes and dispensed from study pharmacies by accredited pharmacists. Throughout the trial, record logs for training, prescriber signature and delegation, temperature, participant, and drug accountability were maintained at each pharmacy. The study team monitored each log and delivered on-site training to correct protocol variations. Results: Each pharmacy that was approached agreed to participate. All community pharmacies achieved good clinical practice compliance prior to dispensing study drug. Over the course of the study, 20,152 dispensations of study drug occurred, 83% of these occurred at community pharmacies. Only 2.0% of dispensations had an error, and errors were predominantly minor. On five occasions a pharmacist who was not accredited dispensed study drug. Conclusions: Community based pharmacies can undergo training and modifications to achieve good clinical practice compliance and dispense clinical trial study drug. Community based pharmacies recorded few variations from study protocol. Community based pharmacies offer a useful alternative to clinical trial pharmacies to increase convenience for study participants and expanded use of these pharmacies should be considered for large clinical trials, including HIV prevention trials.

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components.

A variety of Good Manufacturing Practice (GMP) compliant processes have been reported for production of non-replicating adenovirus vectors, but important challenges remain. Most clinical development of adenovirus vectors now uses simian adenoviruses or rare human serotypes, whereas reported manufacturing processes mainly use serotypes such as AdHu5 which are of questionable relevance for clinical vaccine development. Many clinically relevant vaccine transgenes interfere with adenovirus replication, whereas most reported process development uses selected antigens or even model transgenes such as fluorescent proteins which cause little such interference. Processes are typically developed for a single adenovirus serotype - transgene combination, requiring extensive further optimization for each new vaccine. There is a need for rapid production platforms for small GMP batches of non-replicating adenovirus vectors for early-phase vaccine trials, particularly in preparation for response to emerging pathogen outbreaks. Such platforms must be robust to variation in the transgene, and ideally also capable of producing adenoviruses of more than one serotype. It is also highly desirable for such processes to be readily implemented in new facilities using commercially available single-use materials, avoiding the need for development of bespoke tools or cleaning validation, and for them to be readily scalable for later-stage studies. Here we report the development of such a process, using single-use stirred-tank bioreactors, a transgene-repressing HEK293 cell - promoter combination, and fully single-use filtration and ion exchange components. We demonstrate applicability of the process to candidate vaccines against rabies, malaria and Rift Valley fever, each based on a different adenovirus serotype. We compare performance of a range of commercially available ion exchange media, including what we believe to be the first published use of a novel media for adenovirus purification (NatriFlo® HD-Q, Merck). We demonstrate the need for minimal process individualization for each vaccine, and that the product fulfils regulatory quality expectations. Cell-specific yields are at the upper end of those previously reported in the literature, and volumetric yields are in the range 1 × 1013 - 5 × 1013 purified virus particles per litre of culture, such that a 2-4 L process is comfortably adequate to produce vaccine for early-phase trials. The process is readily transferable to any GMP facility with the capability for mammalian cell culture and aseptic filling of sterile products.

Point of care ultrasound training for internal medicine: a Canadian multi-centre learner needs assessment study.

BACKGROUND: Significant gaps currently exist in the Canadian internal medicine point-of-care ultrasound (POCUS) curriculum. From a learner's perspective, it remains unknown what key POCUS skills should be prioritized. This needs assessment study seeks to establish educational priorities for POCUS for internal medicine residents at five Canadian residency training programs. METHODS: All internal medicine trainees [postgraduate year (PGY) 1-5] from five internal medicine residency training programs in Canada (n = 598) were invited to complete an online survey on 15 diagnostic POCUS applications, 9 bedside procedures, and 18 POCUS knowledge items. For POCUS applications and procedures, participants were asked how applicable they are to patient care in internal medicine and the participants' reported skills in those domains. Self-reported knowledge and skills were rated on a 5-point Likert scale, where 1 = very poor and 5 = very good. Applicability was rated, where 1 = not at all applicable and 5 = very applicable. RESULTS: A total of 253 of 598 residents (42%) participated in our study. Data from one centre (n = 15) was removed because of low response rate (15%) and significant baseline differences between those trainees and the remaining participants. Of the remaining analyzable data from four training programs (n = 238), participants reported highest applicability to internal medicine for the following applications and procedures: identifying ascites/free fluid [mean applicability score of 4.9 ± standard deviation (SD) 0.4]; gross left ventricular function (mean 4.8 ± SD 0.5) and pericardial effusion (mean 4.7 ± SD 0.5); thoracentesis (mean score 4.9 ± SD 0.3), central line insertion (mean 4.9 ± SD 0.3), and paracentesis (mean 4.9 ± SD 0.3), respectively. Overall reported knowledge/skills was low, with skill gaps being the highest for identifying deep vein thrombosis (mean gap 2.7 ± SD 1.1), right ventricular strain (mean 2.7 ± SD 1.1), and gross left ventricular function (mean 2.7 ± SD 1.0). CONCLUSIONS: Many POCUS applications and procedures were felt to be applicable to the practice of internal medicine. Significant skill gaps exist in the four Canadian training programs included in the study. POCUS curriculum development efforts should target training based on these perceived skill gaps.

Insulin-producing intestinal K cells protect nonobese diabetic mice from autoimmune diabetes.

BACKGROUND & AIMS: Type 1 diabetes is caused by an aberrant response against pancreatic ß cells. Intestinal K cells are glucose-responsive endocrine cells that might be engineered to secrete insulin. We generated diabetes-prone non-obese diabetic (NOD) mice that express insulin, via a transgene, in K cells. We assessed the effects on immunogenicity and diabetes development. METHODS: Diabetes incidence and glucose homeostasis were assessed in NOD mice that expressed mouse preproinsulin II from a transgene in K cells and nontransgenic NOD mice (controls); pancreas and duodenum tissues were collected and analyzed by histology. We evaluated T cell responses to insulin, levels of circulating autoantibodies against insulin, and the percentage of circulating antigen-specific T cells. Inflammation of mesenteric and pancreatic lymph node cells was also evaluated. RESULTS: The transgenic mice tended to have lower blood levels of glucose than control mice, associated with increased plasma levels of immunoreactive insulin and proinsulin. Fewer transgenic mice developed diabetes than controls. In analyses of pancreas and intestine tissues from the transgenic mice, insulin-producing K cells were not affected by the immune response and the mice had reduced destruction of endogenous ß cells. Fewer transgenic mice were positive for insulin autoantibodies compared with controls. Cells isolated from mesenteric lymph nodes of the transgenic mice had significantly lower rates of proliferation and T cells from transgenic mice tended to secrete lower levels of inflammatory cytokines than from controls. At 15 weeks, transgenic mice had fewer peripheral CD8(+) T cells specific for NRP-V7 than control mice. CONCLUSIONS: NOD mice with intestinal K cells engineered to express insulin have reduced blood levels of glucose, are less likely to develop diabetes, and have reduced immunity against pancreatic ß cells compared with control NOD mice. This approach might be developed to treat patients with type 1 diabetes.

Work limitations, workplace concerns, and job satisfaction of persons with chronic disease.

INTRODUCTION: This study investigates the workplace experiences of people with chronic diseases, including their work limitations, emotional health, concerns about discrimination, and support from colleagues and employer. This study identifies the factors that contribute to work adjustment (job tenure and job satisfaction). METHODS: A purposive sample of 136 persons aged 18 to 60 with chronic diseases who had been employed in the past 6 months completed a survey about their workplace experience. The questionnaire included several standardized instruments: the Perceived Health and Self-efficacy in Managing Chronic Disease Scale, Work Limitations Questionnaire, Overall Job Satisfaction Scale, and the Depression Anxiety Stress Scale-21. The researchers also designed original items to measure concerns about discriminatory practices, workplace support, and self-stigma. RESULTS: Persons with chronic diseases were fairly satisfied with their jobs and had extended stays in those jobs. They reported a minor productivity loss and physical limitations. Most participants let co-workers, employers, and supervisors know they had chronic disease, but they were concerned about the support those people provide. Participants were more likely to be highly satisfied with their jobs if they had high self-efficacy in managing their disease, perceived more workplace support, and had less work limitations (especially output demands). Job tenure is associated age, education, and monthly income, but not clinical indicators. CONCLUSIONS: Persons with chronic disease who were able to maintain good work adjustment tended to be "fit" with few work limitations and little emotional distress. The key factors affecting work adjustment were efficacy in managing their disease, workplace support, and output demands.

Cerebral small vessel disease: genetic risk assessment for prevention and treatment.

Cerebrovascular disease is a major burden to individuals and their communities worldwide. Stroke is one of the leading causes of death and disability, and the prevention and treatment of stroke can be improved with a better understanding of its causation. Cerebral small vessel disease (SVD) is a subset of cerebrovascular disease, and has an equally large impact on an individual's quality of life. Although many risk factors are involved, we propose that genetics has a significant role in the pathogenesis of SVD through a complex interplay of environmental and multigenetic factors. Advances in molecular technology have enabled the human genome to be investigated both at a population and, more recently, an individual level. A better understanding of the molecular basis of SVD will enable the development of therapies to help in its prevention and treatment. This review assesses the molecular genetics underlying cerebral SVD.

Treatment of obesity and diabetes in mice by transplant of gut cells engineered to produce leptin.

Leptin injections evoke weight loss by causing a reduction in food consumption and an increase in energy expenditure. Also, the administration of leptin lowers blood glucose levels in some rodent models of diabetes and in humans with lipodystrophy. We explored the therapeutic potential of delivering leptin to obese, diabetic ob/ob mice and to mice fed on a high-fat diet (HFD), by transplanting gut-derived cells engineered to produce leptin, under the regulation of an inducing agent, mifepristone. These cells expressed and released leptin in a mifepristone dose-dependent and time-dependent manner. The engineered cells were either transplanted into the mice under the kidney capsule or were encapsulated in alginate and injected into the intraperitoneal cavity, while mifepristone was delivered by implanting 14-day release pellets. In ob/ob mice, leptin delivery by this method caused a significant reduction in food intake and profound weight loss, which was controllable by adjusting the dose of mifepristone. These transplants also achieved rapid and persistent amelioration of diabetes. However, mice fed on a HFD were resistant to the leptin therapy. These results indicate that gut cells can be modified to express leptin in an inducible manner and that the transplantation of these cells has a therapeutic effect in leptin-deficient mice, but not in mice fed on a HFD.

Cyclosporin monitoring in Australasia: survey of laboratory practices in 2000.

Therapeutic drug monitoring of cyclosporin has been established as part of the routine clinical management of patients following organ transplantation for some 20 years. The current practices of laboratories in Australia and New Zealand have been surveyed for the year 2000 to update previous similar surveys in the light of considerable changes in CsA formulation (now exclusively Neoral throughout Australasia), assay methods, and blood sampling strategies. The results, representing 93% of CsA laboratories in Australasia (n = 44), found that there was still a plethora of approaches adopted within each organ type for monitoring the established trough (C0) CsA concentration. There was a considerable uptake of 2-hour post-dose sampling (C2) monitoring practices, as demonstrated by assay requests to the responding laboratories, particularly in renal and liver transplantation (46% of centers). Most of these laboratories were also assaying C0 and/or to a much lesser extent, so-called limited sampling strategy AUC (lssAUC) samples at this time. The mFPIA (on TDx and AxSYM analyzers) were still strongly represented (54%) (relatively consistent with international data from the UKQAS proficiency testing scheme at this time) despite on-going concerns expressed in the literature about these methods. However, the Cedia assays had made considerable impact so soon after their introduction with 22% of the laboratories using Cedia or Cedia Plus (Microgenics or Roche Diagnostics; Sydney, Australia) methods. There were a wide variety of dilution protocols adopted in many centers for measuring samples above calibration ranges (such as C2 samples), and hence there was scope for improvement to fully validated techniques. Few centers (16%) made any attempt at interpretation of their results, many seeing their role as purely "measuring" (i.e., an analytical role), not "monitoring" (i.e., including assay and result interpretation). Despite many detailed attempts at providing international or national guidelines for CsA monitoring, etc., there is still considerable scope for improving the quality of the laboratory services offered in this complex as well as expensive area. Several respondents volunteered their support for further Australasian CsA monitoring consensus guidelines.