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Background: Establishing whether women with major depressive disorder (MDD) who develop breast cancer (BC) have poor outcomes is key to optimizing care for this population. To address this, we examined associations between MDD and BC recurrence and mortality., Methods: Using medical record data from the Veterans Affairs Healthcare System, we established a retrospective cohort of women with local or regional stage invasive BC between 2010 and 2019 and followed through 2022. We used a two-year window to identify women diagnosed with MDD prior to BC diagnosis. We used multivariable Cox-proportional hazards regression to estimate associations between MDD and BC recurrence and mortality while accounting for competing-risks and adjusting for sociodemographic, clinical, lifestyle, and tumor characteristics., Results: We identified 6,051 women with BC, of whom 1,754 (29%) had MDD. The mean age at BC diagnosis was 57 years (standard deviation = 11). In multivariable analyses, women with MDD had a 37% (hazard ratio (HR)=1.37; 95% confidence interval (CI): 1.19-1.57) higher risk of recurrence and a 30% (HR = 1.30; 95% CI: 1.02-1.64) higher risk of BC mortality. The association between MDD and recurrence was stronger among women with estrogen receptor-positive BC. In secondary analyses, there were significant interactions between MDD and multiple exposures with respect to recurrence, including current smoking, substance abuse, and non-receipt of screening mammography., Conclusions: Women with MDD had inferior BC outcomes compared to women without a history of MDD. Research is needed to investigate underlying mechanisms linking depression to BC progression and evaluate interventions to improve outcomes in this high-risk population., (Published by Oxford University Press 2024.)

Purpose: To compare longitudinal rates of health care utilization, evidence-based treatment, and mortality between rural and urban-dwelling patients with congestive heart failure (CHF)., Methods: We used electronic medical record data from the Veterans Health Administration (VHA) to identify adult patients with CHF from 2012 through 2017. We stratified our cohort using left ventricular ejection fraction percentage at diagnosis (<40% = reduced ejection fraction [HFrEF]; 40%-50% = midrange ejection fraction [HFmrEF]; >50% = preserved ejection fraction [HFpEF]). Within each ejection fraction cohort, we stratified patients into rural or urban groups. We used Poisson regression to estimate annual rates of health care utilization and CHF treatment. We used Fine and Gray regression to estimate annual hazards of CHF and non-CHF mortality., Findings: One-third of patients with HFrEF (N = 37,928/109,110), HFmrEF (N = 24,447/68,398), and HFpEF (N = 39,298/109,283) resided in a rural area. Rural compared to urban patients used VHA facilities at similar or lower annual rates for outpatient specialty care across all ejection fraction cohorts. Rural patients used VHA facilities at similar or higher rates for primary care and telemedicine-delivered specialty care. They also had lower and declining rates of VHA inpatient and urgent care use over time. There were no meaningful rural-urban differences in treatment receipt among patients with HFrEF. On multivariable analysis, the rate of CHF and non-CHF mortality was similar between rural and urban patients in each ejection fraction cohort., Conclusions: Our findings suggest the VHA may have mitigated access and health outcome disparities typically observed for rural patients with CHF., (© 2023 The Authors. The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objectives: We explored factors related to testing positive for severe acute respiratory coronavirus 2 (SARS-CoV-2) to identify populations most at risk for this airborne pathogen., Methods: Data were abstracted from the medical record database of the U.S. Department of Veterans Affairs and from public sources. Veterans testing positive were matched in a 1:4 ratio to those at a similar timepoint and local disease burden who remained negative between March 1, 2020, and December 31, 2020. Multivariable logistic regression was used to calculate odds ratios for the association of each potential risk factor with a positive test result., Results: A total of 24,843 veterans who tested positive for SARS-CoV-2 were matched with 99,324 controls. Cases and controls were similar in age, sex, ethnicity, and rurality, but cases were more likely to be Black, reside in low-income counties, and suffer from dementia. Multivariable analysis demonstrated highest risk for Black veterans, those with dementia or diabetes, and those living in nursing homes or high-poverty areas. Veterans living in counties likely to be more adherent to public health guidelines were at the lowest risk., Conclusions: Our results are similar to those from studies of other populations and add to that work by accounting for several important proxies for risk. In particular, this work has implications for the value of infection control measures at the population level in helping to stem widespread outbreaks of this type., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Introduction: Early identification of patients with coronavirus disease 2019 (COVID-19) who are at risk for hospitalization may help to mitigate disease burden by allowing healthcare systems to conduct sufficient resource and logistical planning in the event of case surges. We sought to develop and validate a clinical risk score that uses readily accessible information at testing to predict individualized 30-day hospitalization risk following COVID-19 diagnosis., Methods: We assembled a retrospective cohort of U.S. Veterans Health Administration patients (age ≥ 18 years) diagnosed with COVID-19 between March 1, 2020, and December 31, 2020. We screened patient characteristics using Least Absolute Shrinkage and Selection Operator logistic regression and constructed the risk score using characteristics identified as most predictive for hospitalization. Patients diagnosed before November 1, 2020, comprised the development cohort, while those diagnosed on or after November 1, 2020, comprised the validation cohort. We assessed risk score discrimination by calculating the area under the receiver operating characteristic (AUROC) curve and calibration using the Hosmer-Lemeshow (HL) goodness-of-fit test. This study was approved by the Veteran's Institutional Review Board of Northern New England at the White River Junction Veterans Affairs Medical Center (Reference no.:1473972-1)., Results: The development and validation cohorts comprised 11,473 and 12,970 patients, of whom 4,465 (38.9%) and 3,669 (28.3%) were hospitalized, respectively. The independent predictors for hospitalization included in the risk score were increasing age, male sex, non-white race, Hispanic ethnicity, homelessness, nursing home/long-term care residence, unemployed or retired status, fever, fatigue, diarrhea, nausea, cough, diabetes, chronic kidney disease, hypertension, and chronic obstructive pulmonary disease. Model discrimination and calibration was good for the development (AUROC = 0.80; HL P-value = .05) and validation (AUROC = 0.80; HL P-value = .31) cohorts., Conclusions: The prediction tool developed in this study demonstrated that it could identify patients with COVID-19 who are at risk for hospitalization. This could potentially inform clinicians and policymakers of patients who may benefit most from early treatment interventions and help healthcare systems anticipate capacity surges., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The COVID-19 pandemic rattled Canada's long-term care (LTC) sector by exacerbating the ingrained systemic and structural issues, resulting in tragic consequences for the residents, family members and LTC staff. At the core of LTC's challenges is chronic under-staffing, leading to lower quality of care for residents and higher degrees of moral distress among staff. A rejuvenation of the LTC sector to support its workforce is overdue. A group of diverse and renowned researchers from across Canada set out to implement innovative evidence-informed solutions in various LTC homes. Their findings call for immediate action from policy makers and LTC decision makers., (Copyright © 2022 Longwoods Publishing.)

Objective: To evaluate societal outcomes including unemployment and homelessness among US veterans with schizophrenia with a history of relapse., Methods: A retrospective cohort study was conducted using US Veterans Health Administration (VHA) data from January 1, 2013, to September 30, 2019. Veterans with ≥ 2 diagnoses of schizophrenia, schizotypal disorder, and/or schizoaffective disorders ( ICD-9-CM 295.xx, ICD-10-CM F20.x, F21, or F25.x) during the study period on different days were identified. The index date was the earliest observed diagnosis. Two cohorts were created and propensity score matched: (1) the relapse cohort of veterans with ≥ 1 prior relapse, defined as hospitalization or emergency department visit associated with a schizophrenia diagnosis during the 12-month preindex period, and (2) the nonrelapse cohort of veterans with no evidence of relapse during the preindex period. The frequencies of unemployment, divorce, homelessness, incarceration, and premature death were compared between matched cohorts using standardized mean difference (SMD ≥ 0.1 indicating imbalance)., Results: Each cohort included 16,862 veterans (92.0% male, 57.0% White, median age of 58-59 years). In the relapse cohort, 67.4% and 42.0% of veterans had a history of substance use disorder and non-schizophrenia mental health disorder, respectively, compared to 43.5% and 23.8% in the matched nonrelapse cohort (both SMD > 0.1). The relapse cohort had a higher frequency of unemployment (75.4% vs 71.4%), divorce (35.6% vs 33.7%), homelessness (38.9% vs 23.7%), incarceration (0.6% vs 0.4%), and premature death (23.3% vs 16.9%) compared to the nonrelapse cohort (all SMD > 0.1)., Conclusions: Schizophrenia relapse is associated with increased adverse societal outcomes in the VHA population., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Background: The burden associated with schizophrenia is substantial. Impacts on the individual, healthcare system, and society may be particularly striking within the veteran population due to the presence of physical and mental health comorbidities. Disease burden is also influenced by a complex interplay between social determinants of health and health disparities. The objective of the current study was to compare non-healthcare societal outcomes between veterans with and without schizophrenia in the United States Veterans Health Administration (VHA)., Methods: A retrospective cohort study was conducted using the VHA database (01/2013-09/2019; study period). Veterans with schizophrenia (≥2 diagnoses of ICD-9295.xx, ICD-10 F20.x, F21, and/or F25.x during the study period) were identified; the index date was the earliest observed schizophrenia diagnosis. Veterans with schizophrenia were propensity score-matched to those without schizophrenia using baseline characteristics. A 12-month baseline and variable follow-up period were applied. The frequency of unemployment, divorce, incarceration, premature death, and homelessness were compared between the matched cohorts using standardized mean difference (SMD). Risk of unemployment and homelessness were estimated using logistic regression models., Results: A total of 102,207 veterans remained in each cohort after matching (91% male; 61% White [per AMA]; median age, 59 years). Among veterans with schizophrenia, 42% had a substance use disorder and 30% had mental health-related comorbidities, compared with 25 and 15%, respectively, of veterans without schizophrenia. Veterans with schizophrenia were more likely to experience unemployment (69% vs. 41%; SMD: 0.81), divorce (35% vs. 28%; SMD: 0.67), homelessness (28% vs. 7%; SMD: 0.57), incarceration (0.4% vs. 0.1%; SMD: 0.47), and premature death (14% vs. 12%; SMD < 0.1) than veterans without schizophrenia. After further adjustments, the risk of unemployment and of homelessness were 5.4 and 4.5 times higher among veterans with versus without schizophrenia. Other predictors of unemployment included Black [per AMA] race and history of substance use disorder; for homelessness, younger age (18-34 years) and history of mental health-related comorbidities were additional predictors., Conclusion: A greater likelihood of adverse societal outcomes was observed among veterans with versus without schizophrenia. Given their elevated risk for unemployment and homelessness, veterans with schizophrenia should be a focus of targeted, multifactorial interventions to reduce disease burden., (© 2022. The Author(s).)

Background: This study examined MDD treatment regimens received during the first observed and treated major depressive episode (MDE) among US veterans., Methods: This retrospective study, conducted using the Veterans Health Administration (VHA) database, supplemented with Medicare Part A/B/D data, included adults with ≥1 MDD diagnosis (index date) between 10/1/2015-2/28/2017 and ≥1 line of therapy (LOT) within the first observed complete MDE. Patient baseline (6-month pre-index) characteristics and up to six LOTs received during the first observed and treated MDE were assessed., Results: Of 40,240 veterans with MDD identified (mean age: 50.9 years, 83.9% male, 63.4% White, 88.6% non-Hispanic), hypertension (27.5%), hyperlipidemia (20.8%), and post-traumatic stress disorder (17.5%) were the most common baseline comorbidities. During the first observed and treated MDE, patients received a mean of 1.6 ± 1.0 LOTs, with 14.6% of patients receiving ≥3 LOTs. SSRI-monotherapy was the most commonly observed regimen in the first six LOTs, followed by SNRI-monotherapy in LOT 1 and antidepressants augmented by anticonvulsants in the remaining five LOTs. The antidepressant class of the previous LOT was commonly used in the subsequent LOT. SSRI-SSRI-SSRI was the most common LOT1-to-LOT3 sequencing pattern among patients receiving ≥3 LOTs., Limitations: The study findings are limited to data in the VHA database and may not be generalizable to the non-veteran US population., Conclusions: During the first observed and treated MDE, SSRI-monotherapy was the most common therapy in the first six LOTs. Cycling within SSRI class was the leading sequencing pattern of the first three LOTs among veterans who received ≥3 LOTs., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: We explored longitudinal trends in sociodemographic characteristics, reported symptoms, laboratory findings, pharmacological and non-pharmacological treatment, comorbidities, and 30-day in-hospital mortality among hospitalized patients with coronavirus disease 2019 (COVID-19)., Methods: This retrospective cohort study included patients diagnosed with COVID-19 in the United States Veterans Health Administration between 03/01/20 and 08/31/20 and followed until 09/30/20. We focused our analysis on patients that were subsequently hospitalized, and categorized them into groups based on the month of hospitalization. We summarized our findings through descriptive statistics. We used Cuzick's Trend Test to examine any differences in the distribution of our study variables across the six months., Results: During our study period, we identified 43,267 patients with COVID-19. A total of 8,240 patients were hospitalized, and 13.1% (N = 1,081) died within 30 days of admission. Hospitalizations increased over time, but the proportion of patients that died consistently declined from 24.8% (N = 221/890) in March to 8.0% (N = 111/1,396) in August. Patients hospitalized in March compared to August were younger on average, mostly black, urban-dwelling, febrile and dyspneic. They also had a higher frequency of baseline comorbidities, including hypertension and diabetes, and were more likely to present with abnormal laboratory findings including low lymphocyte counts and elevated creatinine. Lastly, there was a decline from March to August in receipt of mechanical ventilation (31.4% to 13.1%) and hydroxychloroquine (55.3% to <1.0%), while treatment with dexamethasone (3.7% to 52.4%) and remdesivir (1.1% to 38.9%) increased., Conclusion: Among hospitalized patients with COVID-19, we observed a trend towards decreased disease severity and mortality over time., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the effect of a preexisting posttraumatic stress disorder (PTSD) diagnosis on suicide and non-suicide mortalities among men with newly diagnosed prostate cancer, and examine potential mediating factors for the relationship between PTSD and suicide., Methods: We used patient-level data from Veterans Health Administration electronic medical records to identify men (age ≥40 years) diagnosed with prostate cancer between 2004 and 2014. We used Fine and Gray regression model to estimate the risk for competing mortality outcomes (suicide, non-suicide, and alive). We used structural equation models to evaluate the mediating factors., Results: Our cohort comprised 214,649 men with prostate cancer, of whom 12,208 (5.7%) had a preexisting PTSD diagnosis. Patients with PTSD compared to those without utilized more healthcare services and had lower risk cancer at diagnosis. Additionally, they experienced more suicide deaths (N = 26, 0.21% vs. N = 269, 0.13%) and fewer non-suicide deaths (N = 1399, 11.5% vs. N = 45,625, 22.5%). On multivariable analysis, PTSD was an independent suicide risk factor (HR = 2.35; 95% CI: 1.16, 4.78). Depression, substance use disorder, and any definitive prostate cancer treatment were partial mediators. However, PTSD was associated with lower non-suicide mortality risk (HR = 0.86; 95% CI: 0.77, 0.96)., Conclusion: Patients with PTSD experienced greater suicide risk even after adjusting for important mediators. They may have experienced lower non-suicide mortality risk due to favorable physical health resulting from greater healthcare service use and early diagnosis of lower risk cancer. Our findings highlight the importance of considering psychiatric illnesses when treating patients with prostate cancer and the need for interventions to ameliorate suicide risk., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: Most evaluations of quality improvement and patient safety (QI/PS) training programs provide inadequate data on their impact on alumni careers and QI/PS involvement. To address this gap, the authors investigated continued participation in and barriers to QI/PS work, employment, and satisfaction with training among alumni of the Department of Veterans Affairs (VA) Chief Resident in Quality and Safety (CRQS) program., Method: A cross-sectional, web-based survey was administered in January 2018 to all 238 CRQS program alumni (program years 2009-2017, 54 program sites)., Results: A total of 145 alumni (61%) completed the survey, of whom 40% were employed at the VA. Participants reported various professional roles including academic appointments, QI/PS-specific positions, and hospital leadership positions. Most respondents reported involvement in QI/PS activities within the past year, including conducting QI or PS projects and teaching QI or PS. Alumni dedicated a median 15% of their work time to QI/PS. Almost all alumni reported experiencing barriers to QI/PS involvement, most frequently lack of time given clinical responsibilities. Most were satisfied with the training, and almost all reported CRQS participation helped their professional career advancement., Conclusions: The continued involvement in QI/PS reported by alumni suggests training programs such as the CRQS program may be successful in building a workforce of leaders equipped to conduct and teach QI/PS. Dedicated time for QI/PS efforts is an important barrier. Future research should address possible career options and assess the larger, overall effect training physicians in QI/PS has on health systems and patient care.

Background: Clinicians are key drivers for improving health care quality and safety. However, some may lack experience in quality improvement and patient safety (QI/PS) methodologies, including root cause analysis (RCA)., Objective: The Department of Veterans Affairs (VA) sought to develop a simulation approach to teach clinicians from the VA's Chief Resident in Quality and Safety program about RCA. We report the use of experiential learning to teach RCA, and clinicians' preparedness to conduct and teach RCA post-training. We provide curriculum details and materials to be adapted for widespread use., Methods: The course was designed to meet the learning objectives through simulation. We developed course materials, including presentations, a role-playing case, and an elaborate RCA case. Learning objectives included (1) basic structure of RCA, (2) process flow diagramming, (3) collecting information for RCA, (4) cause and effect diagramming, and (5) identifying actions and outcomes. We administered a voluntary, web-based survey in November 2016 to participants (N = 114) post-training to assess their competency with RCA., Results: A total of 93 individuals completed the survey of the 114 invited to participate, culminating an 82% response rate. Nearly all respondents (99%, N = 92) reported feeling at least moderately to extremely prepared to conduct and teach RCA post-training. Most respondents reported feeling very to extremely prepared to conduct and teach RCA (77%, N = 72)., Conclusions: Experiential learning involving simulations may be effective to improve clinicians' competency in QI/PS practices, including RCA. Further research is warranted to understand how the training affects clinicians' capacity to participate in real RCA teams post-training, as well as applicability to other disciplines and interdisciplinary teams., Competing Interests: Declaration of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Objective: In this study, we aim to compare shared decision-making (SDM) knowledge and attitudes between US-based physician assistants (PAs), nurse practitioners (NPs) and physicians across surgical and family medicine specialties., Setting: We administered a cross-sectional, web-based survey between 20 September 2017 and 1 November 2017., Participants: 272 US-based NPs, PA and physicians completed the survey. 250 physicians were sent a generic email invitation to participate, of whom 100 completed the survey. 3300 NPs and PAs were invited, among whom 172 completed the survey. Individuals who met the following exclusion criteria were excluded from participation: (1) lack of English proficiency; (2) area of practice other than family medicine or surgery; (3) licensure other than physician, PA or NP; (4) practicing in a country other than the US., Results: We found few substantial differences in SDM knowledge and attitudes across clinician types, revealing positive attitudes across the sample paired with low to moderate knowledge. Family medicine professionals (PAs) were most knowledgeable on several items. Very few respondents (3%; 95% CI 1.5% to 6.2%) favoured a paternalistic approach to decision-making., Conclusions: Recent policy-level promotion of SDM may have influenced positive clinician attitudes towards SDM. Positive attitudes despite limited knowledge warrant SDM training across occupations and specialties, while encouraging all clinicians to promote SDM. Given positive attitudes and similar knowledge across clinician types, we recommend that SDM is not confined to the patient-physician dyad but instead advocated among other health professionals., Competing Interests: Competing interests: M-AD was involved in developing the Option Grid patient decision aids, which are licensed to EBSCO Health. She receives consulting income from EBSCO Health and may receive royalties in the future. M-AD is also a consultant for ACCESS Community Health Network and delivers shared decision making training to ACCESS clinicians. GE has edited and published books that provide royalties on sales by the publishers: the books include Shared Decision Making (Oxford University Press) and Groups (Radcliffe Press). He has in the past provided consultancy for (1) Emmi Solutions LLC who develop patient decision support tools; (2) National Quality Forum on the certification of decision support tools; (3) Washington State Health Department on the certification of decision support tools; (4) SciMentum LLC, Amsterdam (workshops for shared decision making). GE is Director of &think LLC which owns the registered trademark for Option GridsTM patient decision aids. He provides consultancy in the domain of shared decision making and patient decision aids to: (1) Access Community Health Network, Chicago (Federally Qualified Medical Centers) and to (2) EBSCO Health Option GridsTM patient decision aids. GE initiated the Option Grid Collaborative, tools that are hosted on a website managed by Dartmouth College, on http://optiongrid.org/). Existing Option Grids hosted at this website are freely available until such time as the tools have expired. He owns copyright in measures of shared decision making and care integration, namely CollaboRATE, IntegRATE and Observer OPTION. These measures are freely available for use., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Vast efforts are directed toward curing or prolonging the life of patients with cancer. However, less attention is given to mental health aspects of cancer care, and there is elevated incidence of death by suicide in this population. Evaluating Root Cause Analyses (RCAs) of cancer-related suicides may further our understanding of system-level factors that may contribute to suicide in patients with cancer and highlight strategies to mitigate this risk., Methods: We searched the Veterans Health Administration National Center for Patient Safety RCA database for cancer-related suicides between 2002 and 2017 to evaluate the context of the suicides and identify root causes and suggested actions. These variables were coded by consensus and evaluated using descriptive statistics., Results: We identified 64 RCA reports involving cancer-related suicide; 100% were males of older age. Many suicides occurred during treatment with palliative intent (44%, N = 28). Depression (59%, N = 38), medical comorbidities (59%, N = 38), and pain (47%, N = 30) were common suicide risk factors identified. Most suicides occurred within 7 days of a medical visit (67%, N = 43), especially within the first 24 hours (41%, N = 26). Root causes included a need to improve recognition of triggers for assessment and interdisciplinary communication., Conclusion: This analysis uncovers opportunities to mitigate risk of death by suicide among patients with cancer. Suggested actions include use of comprehensive cancer centers and development of a distress checklist using information from the National Comprehensive Cancer Network Guidelines. Further studies should assess additional factors that may increase the risk of other adverse mental health outcomes in this population., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: Oncology providers are leaders in patient safety. Despite their efforts, oncology-related medical errors still occur, sometimes resulting in patient injury or death. The Veterans Health Administration (VHA) National Center of Patient Safety used data obtained from root cause analysis (RCA) to determine how and why these adverse events occurred in the VHA, and how to prevent future reoccurrence. This study details the types of oncology adverse events reported in VHA hospitals and their root causes and suggests actions for prevention and improvement., Methods: We searched the National Center for Patient Safety adverse event reporting database for RCA related to oncology care from October 1, 2013, to September 8, 2017, to identify event types, root causes, severity of outcomes, care processes, and suggested actions. Two independent reviewers coded these variables, and inter-rater agreement was calculated by κ statistic. Variables were evaluated using descriptive statistics., Results: We identified 48 RCA reports that specifically involved an oncology provider. Event types included care delays (39.5% [n = 19]), issues with chemotherapy (25% [n = 12]) and radiation (12.5% [n = 6]), other (12.5% [n = 6]), and suicide (10.5% [n = 5]). Of the 48 events, 27.1% (n = 13) resulted in death, 4.2% (n = 2) in severe harm, 18.8% (n = 9) in temporary harm, 20.8% (n = 10) in minimal harm, and 2.1% (n = 1) in no harm. The majority of root causes identified a need to improve care processes and policies, interdisciplinary communication, and care coordination., Conclusion: This analysis highlights an opportunity to implement system-wide changes to prevent similar events from reoccurring. These actions include comprehensive cancer clinics, usability testing of medical equipment, and standardization of processes and policies. Additional studies are necessary to assess oncologic adverse events across specialties.

The initial events in glucose metabolism by all cells are the transport and phosphorylation of glucose. To quantify the relative contributions of these two processes to overall glucose utilization, we have developed an experimental approach for their in situ measurement as parallel processes. The method is based on the use of intracellular [2-3H]glucose as a substrate for both the transporter and hexokinase, and involves simultaneous measurement of [2-3H]glucose efflux and of 3H2O released by phosphorylation. The Xenopus oocyte expression system was used to test the method, since in these cells transport and phosphorylation activities can be regulated by expression of mRNA or injection of foreign protein. Oocytes microinjected with [2-3H]glucose showed no release of injected glucose, but did have saturable phosphorylation kinetics, with a Km of 40 microM and a Vmax of 0.1 nmol/min/oocyte. Co-injection of yeast hexokinase increased glucose phosphorylation by five-fold. Expression of human glucose transporter (GLUT1) mRNA resulted in a 25-30-fold increase in the rate of saturable efflux of microinjected glucose compared to control oocytes. The kinetics of transport and phosphorylation of [2-3H]glucose were analyzed by a multiple curve-fitting program that provided estimates of kinetic coefficients for both processes from a single time course. The analysis showed that expression of GLUT1 shifted the rate-limiting step in glucose utilization from transport to phosphorylation. A similar shift occurred at a three-fold lower extracellular concentration of 2-deoxyglucose. In a pancreatic beta cell line both transport and phosphorylation showed high Km values, with phosphorylation as the limiting step. The in situ measurement of glucose transport and phosphorylation as parallel processes should be useful in defining the relative contributions of each step to overall glucose metabolism in other cell and tissue models.

This article presents a new approach for a more thorough study of the coronary arteries at postmortem examination involving whole-heart fixation followed by decalcification prior to examination and sampling. This allows preservation of the integrity of the entire specimen and avoids artifacts and other shortcomings usually associated with the other procedures.