Advantages of large medical record database for outcomes research: Insights into post‐menopausal hormone therapy

Approximately 25 years ago, our team initiated studies to determine whether outcome results from a large medical record database would yield valid results. We utilized the data in the United Kingdom (UK) General Practice Research Database (GPRD) to replicate the randomized controlled trial (RCT) study result and compared them to confirm the database results. The initial studies compared favorably, but some subsequent studies did not. This prompted development of a new strategy to determine and correct for unrecognized confounding in the database. This strategy divided outcome rates prior to initiation of therapy in the database study (which should include both identified and unidentified confounders) into the outcome rates during the treatment interval. When they differed from Cox‐adjusted results, it reflected unrecognized confounding. We called this strategy Prior Event Rate Ratio (PERR)–adjusted outcome.One of our previously published observational studies replicated the Women’s Health Initiative (WHI) RCT study of hormone therapy in post‐menopausal women. Our study results replicated the WHI RCT results except it did not exhibit an increase in heart attack in contrast to the RCT. Furthermore, we could not evaluate death reliably since our analytic approach to overcome unrecognized confounding does not work for this outcome. In Volume 1, Issue 1 of the Learning Health Systems open access journal, we published a new study (titled “A new method to address unmeasured confounding of mortality in observational studies”) that reported a novel death method, based on our prior methodology, that could analyze unrecognized confounding of the death outcome. This new methodology, termed Post Treatment Event Rate Ratio (PTERR), permitted a reliable examination of mortality in post‐menopausal women undergoing hormone therapy. These results are reported in this manuscript. The study used the data from our previous observational study. It demonstrates that estrogen therapy markedly reduced death in post‐menopausal women.This work also illuminates principles of database construction and correspondingly demonstrates the use of novel methodologies for obtaining valid results, which can be applied to enable learning from such databases. Work to advance such methodologies is essential to advancing the scientific integrity Core Value underpinning learning health systems (LHSs). Indeed, in the absence of such efforts to develop and refine methodologies for learning trustworthy lessons from real‐world data, we risk inadvertently creating mis‐learning systems.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150513/1/lrh210193.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150513/2/lrh210193_am.pd

Use of primary care electronic medical record database in drug efficacy research on cardiovascular outcomes: comparison of database and randomised controlled trial findings

Objectives To determine whether observational studies that use an electronic medical record database can provide valid results of therapeutic effectiveness and to develop new methods to enhance validity

Effect of pH on metabolism of the glutamine carbon skeleton by renal cortical mitochondria

1. 1. To determine the effect of altered acid-base homeostasis on the intramitochondrial metabolism of the glutamine carbon skeleton 14CO2 production from [U-14C]glutamine by isolated rat renal cortical mitochondria was measured.2. 2. Mitochondria from rats with chronic metabolic acidosis either showed no change or diminished 14CO2 production in comparison with pair fed controls.3. 3. By contrast, when the pH of the medium incubating mitochondria from normal rats was manipulated (pH 7.0, 7.4, 7.7), 14CO2 production was clearly altered, but the direction and magnitude of the change depended on the glutamine concentration used (0.5 or 10.0 mM).4. 4. Mitochondria produced significant quantities of 14CO2 when [1,4 14C]succinate was used as substrate, indicating that 14CO2 production from glutamine does not originate solely from the decarboxylation of [alpha] KG.5. 5. Thus chronic acidosis and pH, per se, affect intramitochondrial glutamine carbon skeleton metabolism in different fashions, but the specific mechanism cannot be elucidated using 14CO2 production from [U-14C]glutamine.6. 6. Additional studies directly quantitating the metabolic products of glutamine have confirmed these findings and more precisely defined the sites of metabolic alteration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23380/1/0000325.pd

Vocational teachers and workplace learning: integrative, complementary and implicit accounts of boundary crossing

Where young people’s upper-secondary education spans work and institutional domains, questions arise about learning across both spheres and its guidance. Theoretical accounts of ‘boundary crossing’ have explored how vocational teachers can integrate learning across domains by drawing on extended concepts and theoretical knowledge to solve workplace problems; whilst empirical accounts have validated the role of vocational educators by describing the workplace and schools as equally valid, complementary spheres. Different understandings, described here as ‘integrative’, ‘complementary’ and ‘implicit’, appear to reflect different national patterns of vocational education. The paper reports a qualitative study conducted around two case studies, located in Germany and England, of the way vocational teachers’ understandings of facilitating learning across domains are constructed. Vocational teachers working in Germany’s ‘dual training’ claimed to provide advanced knowledge that they compared to practical work skills, reflecting ‘implicit’ or ‘complementary’ approaches to learning across domains. Teachers in England, where workplace learning elements are more unevenly developed and lack institutional foundations, nevertheless described colleges and workplaces as distinctive, little-connected spheres. These differences suggest that teachers’ approaches are less shaped by the potential or necessity for ‘integrative’ approaches than by the way different systems enable or constrain their conceptualisation of ‘possible futures’.N/

Relationship of renal ammonia production and potassium homeostasis

The renal production of ammonia is classically perceived as a regulatory system which responds to perturbations in the acid-base status of the organism [1–4]. A growing body of evidence suggests that ammonia production is also intimately related to potassium homeostasis, and that these two parameters may form the components of a feedback system with an important regulatory function [5–7]. It has been proposed that potassium homeostasis regulates renal ammonia production, which in turn influences both urinary potassium and hydrogen ion excretion [5–7]. The first section of this review will focus on the clinical and physiologic observations supporting an ammonia production-potassium relationship, and the second portion will consider the data currently available concerned with the biochemical mechanisms whereby potassium modulates renal ammoniagenesis

Mechanism by which enhanced ammonia production reduces urinary potassium excretion

Mechanism by which enhanced ammonia production reduces urinary potassium excretion. To determine the mechanism whereby an increase in ammonia production decreases urinary potassium excretion, we perfused isolated rat kidneys at a pH of either 7.0 or 7.4. After 45min of perfusion at either pH, glutamine or ammonium chloride was added to the perfusate to result in concentrations of 5 and 0.8mM, respectively and observations were continued for 50min. Control kidneys were perfused at both pH's without further additions to the perfusate. At pH 7.0, glutamine increased ammonia production and increased urinary ammonium excretion strikingly; whereas the addition of ammonium chloride did not change ammonia production but increased urinary ammonium excretion to a comparable degree. Both maneuvers resulted in a reciprocal fall in urinary potassium excretion in comparison with control perfusions. The decrease in potassium excretion could not be accounted for by differences in perfusate or urinary acid-base parameters, or by changes in urinary sodium, water, or chloride excretion. At pH 7.4, glutamine also significantly increased ammonia production and perfusate ammonia concentration. In contrast to the studies at pH 7.0 in which the urine pH was acid (5.9), the urine remained alkaline (pH 7.2), and both urinary ammonium excretion and urinary potassium excretion were unaltered. Thus, potassium sparing is not a nonspecific effect of glutamine, its metabolism to ammonia, or perfusate ammonia concentration but is directly related to an increase in urinary ammonium excretion.Mécanisme par lequel une augmentation de la production d'ammoniaque réduit l'excrétion urinaire de potassium. Afin de déterminer le mécanisme par lequel une augmentation de la production d'ammoniaque diminue l'excrétion urinaire de potassium, des reins de rats isolés ont été perfuses soit à pH 7,0, soit à pH 7,4. Après 45min de perfusion à l'un ou l'autre pH, de la glutamine ou du chlorure d'ammonium ont été ajoutés au perfusat afin d'obtenir des concentrations respectivement de 5.0 et 0,8mM, puis la préparation a encore été étudiée pendant 50min. Des reins témoins ont été perfuses aux deux pH sans autres additions au perfusat. A pH 7,0 la glutamine augmente la production d'ammoniaque et augmente considérablement l'excrétion d'ammoniaque alors que l'addition de chorure d'ammonium ne modifie pas la production d'ammoniaque mais augmente de façon comparable l'excrétion urinaire. Les deux manoeuvres ont pour conséquence une diminution de l'excrétion urinaire de potassium par comparaison avec les perfusions contrôles. La diminution de l'excrétion de potassium ne peut pas être expliquée par des différences d'état acido-basique du perfusat ou de l'urine ou par des modifications de l'excrétion urinaire de sodium, d'eau ou de chlore. A pH 7,4 la glutamine augmente aussi la production d'ammoniaque et la concentration d'ammoniaque dans le perfusat. Cependant, à la différence des études à pH 7,0 au cours desquelles le pH de l'urine était acide (5,9), l'urine est restée alcaline (pH 7,2) et l'excrétion urinaire d'ammoniaque de même que l'excrétion de potassium n'ont pas été modifiées. Ainsi l'économie de potassium n'est pas un effet non spécifique de la glutamine, de son métabolisme en ammoniaque ou de la concentration en ammoniaque du perfusat, mais est directement liéeà l'augmentation de l'excrétion urinaire de potassium