William G. McCready

Canada's New Medical School: The Northern Ontario School of Medicine: Social Accountability Through Distributed Community Engaged Learning

Like many rural regions around the world, Northern Ontario has a chronic shortage of doctors. Recognizing that medical graduates who have grown up in a rural area are more likely to practice in the rural setting, the Government of Ontario, Canada, decided in 2001 to establish a new medical school in the region with a social accountability mandate to contribute to improving the health of the people and communities of Northern Ontario. The Northern Ontario School of Medicine (NOSM) is a joint initiative of Laurentian University and Lakehead University, which are located 700 miles apart. This paper outlines the development and implementation of NOSM, Canada’s first new medical school in more than 30 years. NOSM is a rural distributed community-based medical school which actively seeks to recruit students into its MD program who come from Northern Ontario or from similar northern, rural, remote, Aboriginal, Francophone backgrounds. The holistic, cohesive curriculum for the MD program relies heavily on electronic communications to support distributed community engaged learning. In the classroom and in clinical settings, students explore cases from the perspective of physicians in Northern Ontario. Clinical education takes place in a wide range of community and health service settings, so that the students experience the diversity of communities and cultures in Northern Ontario. NOSM graduates will be skilled physicians ready and able to undertake postgraduate training anywhere, but with a special affinity for and comfort with pursuing postgraduate training and clinical practice in Northern Ontario.

Transforming health professional education through social accountability: Canada's Northern Ontario School of Medicine

Background: The Northern Ontario School of Medicine (NOSM) has a social accountability mandate to contribute to improving the health of the people and communities of Northern Ontario. NOSM recruits students from Northern Ontario or similar backgrounds and provides Distributed Community Engaged Learning in over 70 clinical and community settings located in the region, a vast underserved rural part of Canada. Methods: NOSM and the Centre for Rural and Northern Health Research (CRaNHR) used mixed methods studies to track NOSM medical learners and dietetic interns, and to assess the socioeconomic impact of NOSM. Results: Ninety-one percent of all MD students come from Northern Ontario with substantial inclusion of Aboriginal (7%) and Francophone (22%) students. Sixty-one percent of MD graduates have chosen family practice (predominantly rural) training. The socioeconomic impact of NOSM included new economic activity, more than double the Schools budget; enhanced retention and recruitment for the universities and hospital/health services; and a sense of empowerment among community participants attributable in large part to NOSM. Discussion: There are signs that NOSM is successful in graduating health professionals who have the skills and desire to practice in rural/remote communities and that NOSM is having a largely positive socioeconomic impact on Northern Ontario.

Simple Kt/V formulas based on urea mass balance theory

&NA; The ratio Kt/V (K is patient clearance, t dialysis time, V urea space) has become the standard measure of dialysis adequacy. In this article simple Kt/V equations are developed theoretically from the urea mass balance equation. Two approximations lead to the most precise equation: where R is the post to pre dialysis urea ratio, BW/V is the amount of fluid removed during dialysis (&Dgr;BW) expressed as a fraction of urea distribution space (V) at dry body weight (BW), and t is dialysis length in hours. A second equation arises with V approximated as 58% of BW. One further approximation leads to a simpler but slightly less precise Kt/V formula: These and earlier published equations were tested with two sets of data: 1) 49 sessions involving 17 patients on maintenance dialysis and 2) 540 computer simulations spanning all likely values of Kt/V (0.6‐1.6), protein catabolic rate (0.6‐1.6), interdialytic weight gain (0‐4% of BW per day) and dialysis session length (2‐4 hr). The most precise formula (upper equation above) had a maximum error of 0.031 and 0.035 Kt/V units for the clinical and simulated data, respectively, whereas the lower equation was slightly less accurate with maximum Kt/V errors of 0.079 and 0.081, respectively. The proposed Kt/V equations are considerably more accurate than previously published formulas. ASAIO Journal 1994; 40:997‐1004.

Optimal Hemodialysis—The Role of Quantification

Mathematical modeling of urea dynamics is the most common method currently used to measure and deliver the optimal dose of hemodialysis for each patient. The modeling concept was popularized by Gotch, Sargent, and coworkers (1, 2) in 1974 and became known as urea kinetic modeling (UKM). Since then, hundreds of papers have been published by a myriad of workers, but two landmarks stand out: the U.S. National Cooperative Dialysis Study (NCDS) published in 1983 (3, 4) and Gotch and Sargents proposal in 1985 (5) of KtIV as a measure of the quantity of dialysis delivered to each patient. Roughly a decade has passed since the final report of the NCDS and the formulation of KtIV, yet quantification of patient therapy is not universally practiced among dialysis centers. Whether and how to use UKM remain controversial. In 1994, we find ourselves at a promising crossroads in the field of dialysis quantification. Emerging technology for automated urea sensing and a shift from blood-based to dialysate-based measurements offer a realistic expectation of improved accuracy and less complexity. This article will review the application and limitations of classical UKM, and will include simplified methods for measuring KtIV and the patients protein catabolic rate from blood concentrations. It will then focus on methods based on measurement of urea in spent dialysate and explore current developments in urea sensing that offer the prospect of automated UKM.

Risk of Invasive Haemophilus influenzae Type b (Hib) Disease in Adults with Secondary Immunodeficiency in the Post-Hib Vaccine Era

ABSTRACT Prior to the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines, invasive Hib disease affected almost exclusively children. According to some recent studies, in the postvaccine era, adults, the elderly, and immunocompromised persons can be affected more often than children. As the production of type-specific anti-capsular polysaccharide antibodies is the major defense mechanism against Hib, individuals with defects in humoral immune responses have high susceptibility to infections caused by Hib. We hypothesized that nonvaccinated adults with chronic conditions causing immunosuppression may lack protective antibody to Hib. We assessed serum anti-Hib IgG levels and bactericidal activity in 59 patients with chronic renal failure, 30 patients with type 2 diabetes mellitus, 28 patients with chronic obstructive pulmonary disease (COPD), and 20 patients with multiple myeloma compared to 32 healthy controls of similar age. Considering antibody at >0.15 μg/ml as the protective correlate in unvaccinated individuals, we detected subprotective Hib antibody levels in 29% of chronic renal failure, 20% of diabetes, 14% of COPD, and 55% of myeloma patients compared to 3% of healthy controls. Additionally, 70% of myeloma and 58% of chronic renal failure patients did not have detectable serum bactericidal activity against Hib. Among individuals with severe diseases causing secondary immunodeficiency, patients with multiple myeloma and chronic renal failure are at an increased risk of invasive Hib disease. Considering that Hib continues to circulate in the population, this study provides a rationale for the immunization of some adult patients with secondary immunodeficiency with the pediatric Hib vaccine to achieve protective immunity.

Simple equations for protein catabolic rate determination from pre dialysis and post dialysis blood urea nitrogen.

&NA; Several simple equations exist for Kt/V determination from pre dialysis (Cpre) and post dialysis (Cpost) blood urea. However, comparable equations have not been available for calculation of protein catabolic rate (PCR), an essential parameter for assessing patient status. Three simple formulas for PCR determination were developed from the urea mass balance equation for an anuric patient in protein steady state receiving thrice weekly dialysis. The simplest formula, PCR = 0.0076[Kt/V][Cpre + Cpost] + 0.17 relates PCR (in g protein/kg/day) to Kt/V and pre and post dialysis blood urea nitrogen measurements (in mg urea nitrogen/dl) for the midweek session. When tested for 540 simulated patients spanning a range of Kt/V (0.6‐1.6); PCR (0.6‐1.6 g/kg/day); dialysis duration t (2‐4 hrs) and interdialytic weight gain expressed as a percentage of dry body weight gained daily (0‐4%), this equation yielded a maximum error of less than ±5%, within the accuracy generally required for clinical needs. A more accurate formula, where Clm is the logarithmic mean of Cpre and Cpost, gave maximum errors in PCR estimation for the same 540 simulated patients of less than ±0.6%. Both formulas require a precise value of Kt/V. The equation below incorporates a very accurate simple Kt/V equation recently published by the authors, allowing PCR to be expressed in terms of Cpre, the ratio of Cpost to Cpre (R), the ratio of session ultrafiltration volume (&Dgr;BW) to urea distribution volume (V), and dialysis time (t, in min). This equation was accurate to within a maximum error of ±1% for the simulated patient group. These equations allow simple and accurate patient PCR determination, and should be used in conjunction with a simple formula for accurate Kt/V determination to guide end‐stage renal failure patient therapy. ASAIO Journal 1995;41:889‐895.

Urea kinetic modeling with a prototype urea sensor in the spent dialysate stream.

The authors have previously demonstrated the feasibility and accuracy of urea kinetic modeling (UKM) based on monitoring urea concentration in the spent dialysate stream (SDS) throughout the hemodialysis (HD) session. They describe here a prototype urea sensor for this purpose and initial experience with HD patients. The sensor is based on ammonium ion and reference electrodes housed in a cell through which the entire SDS passes. The two electrode tips are bathed in urease solution on one side of a dialysis membrane; the SDS flows along the adjacent side. Urea diffusing across the membrane from the SDS is converted by the urease into ammonium ion, which is measured by the electrode pair. For evaluation, the prototype flowthrough urea sensor was installed in the SDS of a Cobe Centry 3 HD machine for 36 HD sessions. Independent measurement demonstrated a linear relationship between mv output of the sensor and logarithm of SDS urea concentration. The use of SDS urea concentration time profiles obtained with this sensor to obtain accurate values of patient protein catabolic rate (PCR) and KT/V is illustrated. Incorporation of urea sensors such as this prototype into HD machines, will permit complete automation of UKM in the near future.

Antibody against Haemophilus influenzae protein D in patients with chronic conditions causing secondary immunodeficiency

Prevalence of non-typeable Haemophilus influenzae (NTHi) in the etiology of invasive infections in immunocompromised individuals is increasing. Serum IgG antibody levels to H. influenzae protein D (PD) were significantly lower in adults suffering from chronic conditions causing secondary immunodeficiency (COPD, cancer, chronic renal failure, and diabetes) compared to age-matched healthy controls. A lack of naturally acquired antibody against this highly conserved antigen may contribute to an increased susceptibility to invasive NTHi disease. As COPD patients frequently infected with NTHi during disease exacerbations were unable to develop antibody response to PD, such defect could potentially contribute to the pathogenesis. Considering that pediatric PD-containing vaccines show protective effect against NTHi-caused otitis media, our data suggest the possibility of improving the defense against NTHi in COPD patients using immunization against PD. Although more research on the role of anti-PD antibody in protection against invasive NTHi disease is warranted, development of adult formulations of PD-based vaccines may be advantageous for prevention of severe infections in immunocompromised individuals.

Activation of Innate Immune Responses by Haemophilus influenzae Lipooligosaccharide

ABSTRACT A Gram-negative pathogen Haemophilus influenzae has a truncated endotoxin known as lipooligosaccharide (LOS). Recent studies on H. influenzae LOS highlighted its structural and compositional implications for bacterial virulence; however, the role of LOS in the activation of innate and adaptive immunity is poorly understood. THP-1 monocytes were stimulated with either lipopolysaccharide (LPS) from Escherichia coli or LOS compounds derived from H. influenzae Eagan, Rd, and Rd lic1 lpsA strains. Cell surface expression of key antigen-presenting, costimulatory, and adhesion molecules, as well as gene expression of some cytokines and pattern recognition receptors, were studied. Eagan and Rd LOS had a lower capacity to induce the expression of ICAM-1, CD40, CD58, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) compared to LPS. In contrast, antigen-presenting (HLA-ABC or HLA-DR) and costimulatory (CD86) molecules and NOD2 were similarly upregulated in response to LOS and LPS. LOS from a mutant Rd strain (Rd lic1 lpsA) consistently induced higher expression of innate immune molecules than the wild-type LOS, suggesting the importance of phosphorylcholine and/or oligosaccharide extension in cellular responses to LOS. An LOS compound with a strong ability to upregulate antigen-presenting and costimulatory molecules combined with a low proinflammatory activity may be considered a vaccine candidate to immunize against H. influenzae.

Immune Response to Haemophilus influenzae Type b Vaccination in Patients with Chronic Renal Failure

ABSTRACT Adult chronic renal failure patients undergoing hemodialysis are at an increased risk of invasive Haemophilus influenzae type b (Hib) disease due to the lack of functionally active anti-Hib antibodies. The pediatric Hib polysaccharide-protein conjugate vaccine is highly immunogenic in these patients and can provide protection against invasive Hib infection for at least 1 year.