Potential for repurposing oral hypertension/diabetes drugs to decrease asthma risk in obesity.

OBJECTIVE: Risk for asthma in the overweight/obese may be mediated by adiponectin and peroxisome proliferator activated receptor pathways and may be reduced by the use of oral drugs impacting these pathways, such as angiotensin converting enzyme inhibitors (ACE-I), thiazolidinediones (TZD), and angiotensin receptor blockers (ARB). Our study objective was to determine whether ACE-I, TZD, and/or ARB use in overweight/obese adults with diabetes mellitus and/or hypertension is associated with a lower risk for incident asthma. METHODS: Using an existing cohort of American veterans, we performed a longitudinal data analysis over 15 years. Exposure was defined by the prescription pickup of ACE-I, TZD, and/or ARB for at least 4 weeks. The outcome, time until new-onset of clinician-diagnosed asthma, was studied using survival analysis. The propensity scoring method controlled for treatment selection bias. RESULTS: 2.83 million eligible veterans, including 77,278 with incident asthma, were studied. As compared to those unexposed, the use of ACE-I alone, TZD alone, or their combinations were each associated with decreased risk for incident asthma (hazard ratios of 0.88, 0.74, and 0.20, respectively; p < 0.001 for all analyses in the fully adjusted statistical models). TZD lowered the risk among racial/ethnic minority subjects more than among White participants (p < 0.001). On the other hand, ARB use alone or in combination with TZD was associated with a higher risk for incident asthma. CONCLUSIONS: Use of ACE-I and/or TZD was associated with a lower risk for incident asthma in overweight/obese patients with diabetes mellitus and/or hypertension.

Outcomes of treatment for hepatitis C virus infection by primary care providers.

BACKGROUND: The Extension for Community Healthcare Outcomes (ECHO) model was developed to improve access to care for underserved populations with complex health problems such as hepatitis C virus (HCV) infection. With the use of video-conferencing technology, the ECHO program trains primary care providers to treat complex diseases. METHODS: We conducted a prospective cohort study comparing treatment for HCV infection at the University of New Mexico (UNM) HCV clinic with treatment by primary care clinicians at 21 ECHO sites in rural areas and prisons in New Mexico. A total of 407 patients with chronic HCV infection who had received no previous treatment for the infection were enrolled. The primary end point was a sustained virologic response. RESULTS: A total of 57.5% of the patients treated at the UNM HCV clinic (84 of 146 patients) and 58.2% of those treated at ECHO sites (152 of 261 patients) had a sustained viral response (difference in rates between sites, 0.7 percentage points; 95% confidence interval, -9.2 to 10.7; P=0.89). Among patients with HCV genotype 1 infection, the rate of sustained viral response was 45.8% (38 of 83 patients) at the UNM HCV clinic and 49.7% (73 of 147 patients) at ECHO sites (P=0.57). Serious adverse events occurred in 13.7% of the patients at the UNM HCV clinic and in 6.9% of the patients at ECHO sites. CONCLUSIONS: The results of this study show that the ECHO model is an effective way to treat HCV infection in underserved communities. Implementation of this model would allow other states and nations to treat a greater number of patients infected with HCV than they are currently able to treat. (Funded by the Agency for Healthcare Research and Quality and others.).

A novel method for handling pre-existing conditions in multivariate prediction model development for COVID-19 death in the Department of Veterans Affairs.

Many mathematical models have been proposed to predict death following the Coronavirus Disease 2019 (COVID-19); all started with comorbidity subsets for this still-little understood disease. Thus, we derived a novel predicted probability of death model (PDeathDx) upon all diagnostic codes documented in the Department of Veterans Affairs. We present the conceptual underpinnings and analytic approach in estimating the independent contribution of pre-existing conditions. This is the largest study to-date following patients with COVID-19 to predict mortality. Cases were identified with at least one positive nucleic acid amplification test. Starting in 1997, we use diagnoses from the first time a patient sought care until 14 days before a positive nucleic acid amplification test. We demonstrate the clear advantage of using an unrestricted set of pre-existing conditions to model COVID-19 mortality, as models using conventional comorbidity indices often assign little weight or usually do not include some of the highest risk conditions; the same is true of conditions associated with COVID-19 severity. Our findings suggest that it is risky to pick comorbidities for analysis without a systematic review of all those experienced by the cohort. Unlike conventional approaches, our comprehensive methodology provides the flexibility that has been advocated for comorbidity indices since 1993; such an approach can be readily adapted for other diseases and outcomes. With our comorbidity risk adjustment approach outperforming conventional indices for predicting COVID-19 mortality, it shows promise for predicting outcomes for other conditions of interest.

Effect of vaccination on the case fatality rate for COVID-19 infections 2020-2021: multivariate modelling of data from the US Department of Veterans Affairs.

OBJECTIVES: To evaluate the benefits of vaccination on the case fatality rate (CFR) for COVID-19 infections. DESIGN, SETTING AND PARTICIPANTS: The US Department of Veterans Affairs has 130 medical centres. We created multivariate models from these data-339 772 patients with COVID-19-as of 30 September 2021. OUTCOME MEASURES: The primary outcome for all models was death within 60 days of the diagnosis. Logistic regression was used to derive adjusted ORs for vaccination and infection with Delta versus earlier variants. Models were adjusted for confounding factors, including demographics, comorbidity indices and novel parameters representing prior diagnoses, vital signs/baseline laboratory tests and outpatient treatments. Patients with a Delta infection were divided into eight cohorts based on the time from vaccination to diagnosis. A common model was used to estimate the odds of death associated with vaccination for each cohort relative to that of unvaccinated patients. RESULTS: 9.1% of subjects were vaccinated. 21.5% had the Delta variant. 18 120 patients (5.33%) died within 60 days of their diagnoses. The adjusted OR for a Delta infection was 1.87±0.05, which corresponds to a relative risk (RR) of 1.78. The overall adjusted OR for prior vaccination was 0.280±0.011 corresponding to an RR of 0.291. Raw CFR rose steadily after 10-14 weeks. The OR for vaccination remained stable for 10-34 weeks. CONCLUSIONS: Our CFR model controls for the severity of confounding factors and priority of vaccination, rather than solely using the presence of comorbidities. Our results confirm that Delta was more lethal than earlier variants and that vaccination is an effective means of preventing death. After adjusting for major selection biases, we found no evidence that the benefits of vaccination on CFR declined over 34 weeks. We suggest that this model can be used to evaluate vaccines designed for emerging variants.

Expanding access to hepatitis C virus treatment--Extension for Community Healthcare Outcomes (ECHO) project: disruptive innovation in specialty care.

The Extension for Community Healthcare Outcomes (ECHO) Model was developed by the University of New Mexico Health Sciences Center as a platform to deliver complex specialty medical care to underserved populations through an innovative educational model of team-based interdisciplinary development. Using state-of-the-art telehealth technology, best practice protocols, and case-based learning, ECHO trains and supports primary care providers to develop knowledge and self-efficacy on a variety of diseases. As a result, they can deliver best practice care for complex health conditions in communities where specialty care is unavailable. ECHO was first developed for the management of hepatitis C virus (HCV), optimal management of which requires consultation with multidisciplinary experts in medical specialties, mental health, and substance abuse. Few practitioners, particularly in rural and underserved areas, have the knowledge to manage its emerging treatment options, side effects, drug toxicities, and treatment-induced depression. In addition, data were obtained from observation of ECHO weekly clinics and database of ECHO clinic participation and patient presentations by clinical provider. Evaluation of the ECHO program incorporates an annual survey integrated into the ECHO annual meeting and routine surveys of community providers about workplace learning, personal and professional experiences, systems and environmental factors associated with professional practice, self-efficacy, facilitators, and barriers to ECHO. The initial survey data show a significant improvement in provider knowledge, self-efficacy, and professional satisfaction through participation in ECHO HCV clinics. Clinicians reported a moderate to major benefit from participation. We conclude that ECHO expands access to best practice care for underserved populations, builds communities of practice to enhance professional development and satisfaction of primary care clinicians, and expands sustainable capacity for care by building local centers of excellence.

Colorectal cancer screening adherence is higher with fecal immunochemical tests than guaiac-based fecal occult blood tests: a randomized, controlled trial.

OBJECTIVES: Determine whether colorectal cancer screening adherence is greater with fecal immunochemical tests (FIT) or guaiac-based fecal occult blood tests (gFOBT). METHODS: We used electronic health records to identify 3869 New Mexico Veterans Affairs Health Care System primary care patients due for screening in 2008 for whom fecal blood testing was appropriate. We invited randomly selected patients by mail to participate in a study comparing FIT and gFOBT. We randomly allocated 404 subjects to receive FIT (n=202) or gFOBT (n=202) by mail. We determined the proportion of subjects completing testing within 90days of agreeing to participate in the study. We also used multivariate logistic regression to evaluate screening completion, adjusting for age, gender, race/ethnicity, clinic site, previous gFOBT testing, and co-morbidity. RESULTS: Screening adherence was higher with FIT than gFOBT (61.4% vs. 50.5%, P=0.03). The adjusted odds ratio for completing FIT vs. gFOBT was 1.56, 95% CI 1.04, 2.32. CONCLUSION: In a clinic setting of patients who were due for colorectal cancer screening, adherence was significantly higher with FIT than gFOBT.

Hepatotoxicity associated with metformin therapy in treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease.

OBJECTIVE: To report a case of idiosyncratic hepatotoxicity associated with metformin in the treatment of type 2 diabetes with nonalcoholic fatty liver disease (NAFLD). CASE SUMMARY: A 61-year-old obese man presented with jaundice, nausea, fatigue, and an unintentional weight loss 2 weeks following initiation of metformin. Laboratory findings revealed aminotransferase values 10-15 times the upper limit of normal. Potential causative agents, including metformin, simvastatin, and Niaspan (extended-release niacin), were discontinued. Two months later, the patient's signs and symptoms had resolved and aminotransferase values returned to normal. An objective causality assessment revealed that the adverse reaction was probably associated with metformin. DISCUSSION: Since numerous medications and disease states can cause abnormalities in liver enzymes, it is important for providers to be able to distinguish the cause(s) and take appropriate actions. This can take a great deal of time and effort in patients with multiple medications and comorbidities. In this patient's case, viral hepatitis, worsening NAFLD, and the concomitant drugs were highly suspected. As hydroxymethylglutaryl coenzyme A reductase inhibitors offer substantial cardiovascular benefits and as metformin is a first-line agent in helping to lower blood glucose concentrations and to normalize the metabolic profile in type 2 diabetes, reintroduction of metformin and simvastatin would likely be beneficial. CONCLUSIONS: This is a case report of metformin-induced hepatotoxicity. As the prevalence of type 2 diabetes and subsequent metabolic effects increases in the US, metformin use will likewise increase. As potential for increased idiosyncratic hepatotoxicity associated with metformin use is likely to occur, clinicians should be vigilant.

Sources of variation in estimates of lean body mass by creatinine kinetics and by methods based on body water or body mass index in patients on continuous peritoneal dialysis.

OBJECTIVE: We identified factors that account for differences between lean body mass computed from creatinine kinetics (LBM(cr)) and from either body water (LBM(V)) or body mass index (LBM(BMI)) in patients on continuous peritoneal dialysis (CPD). DESIGN: We compared the LBM(cr) and LBM(V) or LBM(BMI) in hypothetical subjects and actual CPD patients. PATIENTS: We studied 439 CPD patients in Albuquerque, Pittsburgh, and Toronto, with 925 clearance studies. INTERVENTION: Creatinine production was estimated using formulas derived in CPD patients. Body water (V) was estimated from anthropometric formulas. We calculated LBM(BMI) from a formula that estimates body composition based on body mass index. In hypothetical subjects, LBM values were calculated by varying the determinants of body composition (gender, diabetic status, age, weight, and height) one at a time, while the other determinants were kept constant. In actual CPD patients, multiple linear regression and logistic regression were used to identify factors associated with differences in the estimates of LBM (LBM(cr)LBM(V). The differences in determinants of body composition between groups with high versus low LBM(cr) were similar in hypothetical and actual CPD patients. Multivariate analysis in actual CPD patients identified serum creatinine, height, age, gender, weight, and body mass index as predictors of the differences LBM(V)-LBM(cr) and LBM(BMI)-LBM(cr). CONCLUSIONS: Overhydration is not the sole factor accounting for the differences between LBM(cr) and either LBM(V) or LBM(BMI) in CPD patients. These differences also stem from the coefficients assigned to major determinants of body composition by the formulas estimating LBM.

Development and validation of prediction rules to target care intensification in veteran patients with diabetes.

BACKGROUND: Diabetes affects 30.3 million people in the USA. Among these people, a major risk factor for microvascular complications is having a glycated haemoglobin (HbA1c) value of ≥75 mmol/mol; therefore, it would be helpful to identify patients who will obtain future HbA1c values of <75 mmol/mol. OBJECTIVES: To develop and validate two prediction rules among patients with diabetes having a baseline HbA1c value of ≥75 mmol/mol: (1) HbA1c measurement ever <75 mmol/mol and (2) final HbA1c measurement of <75 mmol/mol. METHODS: Retrospective cohort study using a registry extracting data from the Department of Veterans Affairs's (VA's) electronic health records system. Baseline was 1 Jul 2013-30 June 2014; patients were followed up until 31 July 2016. RESULTS: Our population consisted of 145 659 patients. Across models, predictors were age, sex, minority status, baseline HbA1c value, time, HbA1c≥75 mmol/mol, receiving insulin treatment and consecutive number of HbA1c values of 75 mmol/mol. The overall likelihood of a patient ever having an HbA1c<75 mmol/mol was 73.65%; with the rule, predicted probabilities were 38.94%, 50.75% and 78.88%. The overall likelihood of patients having a final HbA1c measurement of <75 mmol/mol was 55.35%; the rule provided predicted probabilities of 29.93%, 50.17% and 68.58%. CONCLUSIONS: Within each rule, there were similar observed and predicted tertile probabilities; maintaining HbA1c values of <75 mmol/mol resulted in probability shifts in the majority of patients. We recommend psychosocial screening for 15% of patients for whom there is less than one-third chance of maintaining HbA1c<75 mmol/mol. We plan to conduct additional research to see whether this approach helps.

Female Veterans With Diagnoses of Both Chronic Pelvic Pain and Overactive Bladder; How Do They Compare to Women Diagnosed With Interstitial Cystitis?

OBJECTIVE: The objective of this study was to compare women with a known diagnosis of interstitial cystitis (IC) to a population that might be at risk for the diagnosis of IC, women with diagnoses of both chronic pelvic pain (CPP) and overactive bladder (OAB). METHODS: We conducted a retrospective study of data from the Veterans Affairs Corporate Data Warehouse. The cohort included all female veterans who had established care with a primary care provider from 1997 to present. International Classification of Diseases, Ninth Revision codes were used to identify women with a diagnosis of IC, CPP, and OAB. Demographic data and comorbidities were compared between groups. RESULTS: A total of 596,815 women were identified. Two thousand three hundred one women (0.4%) were diagnosed with IC; 4459 women (0.7%) were diagnosed with CPP and OAB. At baseline, women with OAB and CPP were more likely to identify as minority (P < 0.001). Anxiety (57.3% vs 49.5%), depression (39.0% vs 46.0%), and posttraumatic stress disorder (29.7 vs 26.4%) were all more common in the CPP and OAB group than in the IC group. In the multivariable model, women with CPP and OAB were more likely to identify as a minority, use tobacco, and carry a diagnosis of anxiety. CONCLUSIONS: There were more patients diagnosed with CPP and OAB compared with patients diagnosed with IC in this population of female veterans. Given the high rate of comorbid anxiety and depression in both groups, further study is warranted to determine whether these women are misdiagnosed.

Dialysis-associated hyperglycemia: manifestations and treatment.

PURPOSE: Dialysis-associated hyperglycemia (DAH), is associated with a distinct fluid and electrolyte pathophysiology. The purpose of this report was to review the pathophysiology and provide treatment guidelines for DAH. METHODS: Review of published reports on DAH. Synthesis of guidelines based on these reports. RESULTS: The following fluid and solute abnormalities have been identified in DAH: (a) hypoglycemia: this is a frequent complication of insulin treatment and its prevention requires special attention. (b) Elevated serum tonicity. The degree of hypertonicity in DAH is lower than in similar levels of hyperglycemia in patients with preserved renal function. Typically, correction of hyperglycemia with insulin corrects the hypertonicity of DAH. (c) Extracellular volume abnormalities ranging from pulmonary edema associated with osmotic fluid shift from the intracellular into the extracellular compartment as a consequence of gain in extracellular solute (glucose) to hypovolemia from osmotic diuresis in patients with residual renal function or from fluid losses through extrarenal routes. Correction of DAH by insulin infusion reverses the osmotic fluid transfer between the intracellular and extracellular compartments and corrects the pulmonary edema, but can worsen the manifestations of hypovolemia, which require saline infusion. (d) A variety of acid-base disorders including ketoacidosis correctable with insulin infusion and no other interventions. (e) Hyperkalemia, which is frequent in DAH and is more severe when ketoacidosis is also present. Insulin infusion corrects the hyperkalemia. Extreme hyperkalemia at presentation or hypokalemia developing during insulin infusion require additional measures. CONCLUSIONS: In DAH, insulin infusion is the primary management strategy and corrects the fluid and electrolyte abnormalities. Patients treated for DAH should be monitored for the development of hypoglycemia or fluid and electrolyte abnormalities that may require additional treatments.

Blood glucose monitoring is associated with better glycemic control in type 2 diabetes: a database study.

BACKGROUND: The value of self-monitoring blood glucose (SMBG) in type 2 diabetes is controversial. OBJECTIVE: To determine SMBG testing rates are positively associated with glycemic control in veterans on oral hypoglycemic agents (OHA). DESIGN: Observational database study. SUBJECTS: Southwestern Healthcare Network veterans taking OHA in 2002 and followed through the end of 2004. MEASUREMENTS: OHA and glucose test strip (GTS) prescriptions were derived from pharmacy files. Subjects were categorized into five groups according to their end-of-study treatment status: group 1 (no medication changes), group 2 (increased doses of initial OHA), group 3 (started new OHA), group 4 (both OHA interventions), and group 5 (initiated insulin). We then used multiple linear regression analyses to examine the relationship between the SMBG testing rate and hemoglobin A1c (HbA1c) within each group. RESULTS: We evaluated 5,862 patients with a mean follow-up duration of 798 +/- 94 days. Overall, 44.2% received GTS. Ultimately, 47% of subjects ended up in group 1, 21% in group 2, 9% in group 3, 8% in group 4, and 16% in group 5. A univariate analysis showed no association between the SMBG testing rate and HbA1c. However, after stratifying by group and adjusting for initial OHA dose, we found that more frequent testing was associated with a significantly lower HbA1c in groups 1, 4, and 5. The effect ranged from -0.22% to -0.94% for every ten GTS/week. CONCLUSIONS: Higher SMBG testing rates were associated with lower HbA1c, but only when stratifying the analyses to control for treatment intensification.

Hospitalizations in patients treated sequentially by chronic hemodialysis and continuous peritoneal dialysis.

It is not established whether hospitalizations are more frequent or longer in patients on peritoneal dialysis (PD) or chronic in-center hemodialysis (HD). Comorbidity is a major factor affecting the comparison of hospitalizations. To account for comorbidity, we compared hospitalizations between the PD and HD periods in 16 patients, 8 of whom were treated by PD first (group A), and 8, by HD first (group B). In group A, causes of renal failure were diabetes (n = 3), primary renal disease (n = 2), systemic disease (n = 2), and hereditary nephropathy (n = 1). Age at onset of PD was 53 +/- 11 years; duration of PD, 31 +/- 17 months; and duration of HD, 40 +/- 33 months. This group had 52 hospitalizations in the PD period and 80 hospitalizations in the HD period. Hospitalization rate (n/ patient-year) was 2.5 +/- 2.0 during PD and 3.0 +/- 3.0 during HD (nonsignificant), and duration of hospitalization (days/patient-year) was 19.6 +/- 15.5 during PD and 21.9 +/- 17.7 during HD (nonsignificant). The three most common causes of hospitalization were peritonitis (27%), other infections (21%), and cardiovascular disease (14%) in the PD period, and HD access problems (35%), infections (16%), and cardiovascular disease (12%) in the HD period. In group B, causes of renal failure were diabetes (n = 4), primary renal disease (n = 3), and hypertension (n = 1). Age at onset of HD was 56 +/- 10 years; duration of HD, 41 +/- 19 months; and duration of PD, 60 +/- 24 months. This group had 82 hospitalizations in the HD period and 76 hospitalizations in the PD period. Hospitalization rate was 3.0 +/- 2.4 during HD and 1.9 +/- 2.8 during PD (nonsignificant), and duration of hospitalization was 17.3 +/- 25.1 during HD and 12.7 +/- 21.3 during PD (nonsignificant). The three most common causes of hospitalization were HD access problems (40%), cardiovascular disease (19%), and infections (12%) in the HD period, and other infections (36%), cardiovascular disease (19%), and peritonitis (21%) in the PD period. In patients changing dialysis modalities, rate and duration of hospitalizations did not vary between HD and PD. The causes of hospitalization were similar in the HD and PD periods regardless of which modality was applied first.

Body fluid abnormalities in severe hyperglycemia in patients on chronic dialysis: review of published reports.

Reports of dialysis-associated hyperglycemia (DH) were compared to reports of diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) in patients with preserved renal function. Average serum values in DH (491 observations), DKA (1036 observations), and NKH (403 observations) were as follows, respectively: glucose, 772, 649, and 961 mg/dl; sodium, 127, 134, and 149, mmol/l; and tonicity, 298, 304, and 355 mOsm/kg. Assuming that euglycemic (serum glucose, 90 mg/dl) values were the same (sodium, 140 mmol/l; tonicity, 285 mOsm/kg) for all three states, the hyperglycemic rise in the average serum tonicity value per 100-mg/dl rise in serum glucose concentration was 1.9 mOsm/kg in DH, 3.5 mOsm/kg in DKA, and 8.1 mOsm/kg in NKH. Neurological manifestations in DH patients were caused by coexisting conditions (ketoacidosis, sepsis, and neurological disease) in most instances, and by severe hypertonicity (>320 mOsm/kg), with clearing after insulin administration, in a few instances. In 148 episodes of DH corrected with insulin only, the mean increase in serum sodium per 100-mg/dl decrease in serum glucose (Delta[Na]/Delta[Glu]) was -1.61 mmol/l. In agreement with theoretical predictions, Delta[Na]/Delta[Glu] was numerically smaller in patients with edema than in those with euvolemia. The average hyperglycemic increase in extracellular volume, calculated from changes in serum sodium concentration during correction of DH using insulin alone, was 0.013 l/l per 100-mg/dl increase in serum glucose concentration. A small number of DH patients presented with pulmonary edema rectified by insulin alone. DH causes modest hypertonicity, with few patients having neurological manifestations caused usually by other coexisting conditions. In contrast to DKA or NKH, which usually presents with hypovolemia, DH causes hypervolemia manifested occasionally by pulmonary edema. Insulin is adequate treatment for DH.

Pathophysiology and management of fluid and electrolyte disturbances in patients on chronic dialysis with severe hyperglycemia.

The mechanisms of fluid and solute abnormalities that should be considered in any patient with severe hyperglycemia include changes in the total amount of extracellular solute, osmotic diuresis, intake of water driven by thirst, and influences from associated conditions. The absence of osmotic diuresis distinguishes dialysis-associated hyperglycemia (DH) from hyperglycemia with preserved renal function (HPRF). Mainly because of this absence, comparable degrees of hyperglycemia tend to produce less hypertonicity and less severe intracellular volume contraction in DH than in HPRF, while extracellular volume is expanded in DH but contracted in HPRF. Ketoacidosis can develop in both DH and HPRF. Among DH patients, hyperkalemia appears to be more frequent when ketoacidosis is present than when nonketotic hyperglycemia is present. Among HPRF patients, the frequency of hyperkalemia appears to be similar whether ketoacidosis or nonketotic hyperglycemia is present. Usually patients with severe DH have no symptoms or may exhibit a thirst. Infrequent clinical manifestations of DH include coma and seizures from hypertonicity or ketoacidosis and pulmonary edema from extracellular expansion. Insulin infusion is usually the only treatment required to correct the biochemical abnormalities and reverse the clinical manifestations of DH. Monitoring of the clinical manifestations and biochemical parameters during treatment of DH with insulin is needed to determine whether additional measures, such as administration of saline, free water, or potassium salts, as well as emergency hemodialysis (HD) are needed. Emergency HD carries the risk of excessively rapid decline in tonicity; its benefits in the treatment of DH have not been established.

Twenty-first Century ethics of medical research involving human subjects: achievements and challenges.

The field of ethics in medical research has seen important developments in the last three decades, but it also faces great challenges in the new century. The purposes of this report are to examine the current status of ethics of medical research involving human subjects and the nature of the ethical challenges facing this research, to identify the weakness of the current system of safeguards for ethical research, and to stress the importance of the ethical character of the researcher, which is the safeguard that has the greatest potential for protecting the research subjects. Researchers appreciate the risks of human medical research that create ethical dilemmas and the need for an ethical compromise in order to proceed with the research. The main elements of the compromise, formulated primarily from experiences in the Second World War, include: (1) the dominant position of the ethical principle of autonomy; (2) the demand for a signed informed consent; (3) the likelihood of improving health with the research protocol, which must be approved by a duly appointed supervising committee; and (4) an acceptable risk/benefit ratio. The main weakness of this set of safeguards is the difficulty with obtaining a truly informed consent. The new challenges to ethical medical research stem from certain types of research, such as genetic and stem cell research, and from the increasing involvement of the industry in planning and funding the research studies. Developing medical researchers with an ethical character and knowledge about ethics in medicine may be the most effective safeguard in protecting participants of medical research experiments.

A 10-yr Analysis of Chronic Pelvic Pain and Chronic Opioid Therapy in the Women Veteran Population.

Introduction: Chronic pelvic pain (CPP) affects an estimated 30% of women Veterans. Previous research shows high rates of narcotic abuse in the women Veteran population. Narcotics are not recommended for the treatment of CPP. Understanding how CPP impacts narcotic prescribing in the women Veteran population is critical to addressing the public health crisis of opioid abuse. Our objective was to compare chronic opioid therapy (COT) prescribed 5 yr prior to and following CPP diagnosis and to identify predictors of COT as well as adverse events associated with COT. We choose to look at 10 yr of data because we thought this time period would provide unique insight into the longitudinal associations of CPP and COT and was available in the database. Materials and Methods: Women with non-cancer CPP were included for analyses from the Veteran's Affairs Corporate Database Warehouse. COT was defined as 90 d of opiates/calendar year for each of the 5 yr proceeding and following the diagnosis of CPP. Patient characteristics and potential variables influencing COT were collected. We compared baseline demographics between the women who received COT to the women who did not receive COT to find additional demographic predictors of COT in association with CPP. Multivariable analysis identified predictors of COT in this population of women with CPP. We utilized an interrupted time series analysis to understand the impact of the diagnosis of CPP on COT. Results: A total of 49,601 women met inclusion criteria with an average age of 40.1 ± 11.5 yr; 37.3% self-characterized as being a racial minority and 24% had a history of military sexual trauma. Chronic use increased significantly (p < 0.001) in the 5 yr preceding the diagnosis of CPP from 6.3% (n = 3124) of women at time -5 to 13.6% (n = 6746) at time 0. In the first year following the diagnosis of CPP, 16.8% (n = 8,333) of women with CPP met the criteria for COT (p < 0.001) and 15% (n = 7440) of women with CPP remained in the COT group for the remaining 5 yr following the diagnosis. On average women in the COT group had 250-292 d of opioids/year. When comparing women who received chronic narcotics following the diagnosis of CPP versus those who did not receive chronic narcotics, women who received COT were older, more likely to smoke and more frequently diagnosed with other pain conditions such as back pain, headaches, and fibromyalgia. (All p < 0.001). In the multivariable model, predictors of COT following CPP diagnosis included prior COT (OR = 10.0 (95% CI 9.4, 10.6), a positive history of military sexual trauma, smoking, and other chronic pain conditions. Conclusions: The distinct pattern of prescribing shown in this cohort may mean COT is prescribed for CPP and this prescribing pattern contributes to the adverse events associated with COT. As COT is not recommended for CPP, physicians need more education on the therapies available to help CPP patients.

One and the Same? Nocturnal Enuresis and Overactive Bladder in the Female Veteran Population: Evaluation of a Large National Database.

OBJECTIVES: The aims of this study were to describe relationships between women given a diagnosis of nocturnal enuresis (NE) and controls without any urinary complaints and to compare women with NE with those with overactive bladder (OAB). We hypothesized that NE has unique associations with demographics and medical and psychosocial diagnoses. METHODS: This is a secondary analysis of a database that included all female veterans who established care with a primary care provider from 1997 to 2015. International Classification of Diseases, Ninth Revision, codes identified women with a diagnosis of NE or OAB. Patient characteristics, medical diagnoses, and psychosocial factors previously described as relating to NE and/or OAB were compared between the 2 distinct comparative groups, with significance set at P < 0.05. Stepwise logistic regression was used to assess all significant findings. RESULTS: A total of 596,815 women were identified; controls totaled 570,049, the group with OAB totaled 26,446 (4.4%), and the group with NE totaled 301 (0.05%).Multivariable analysis compared the group with NE with controls; all measured psychosocial characteristics remained significantly associated with an NE diagnosis (all Ps < 0.05), as well as obstructive sleep apnea history, stroke, self-identification as "minority," smoking, hypertension, and a body mass index higher than those of the general control population (all Ps < 0.05).When the populations with NE and OAB were compared, a diagnosis of posttraumatic stress disorder, an overdose history, depression, military sexual trauma, increasing body mass index, and younger age remained significantly associated with NE (all Ps < 0.05). CONCLUSIONS: The association of NE with psychosocial characteristics and psychiatric illnesses persisted irrespective of the comparison population. Practitioners should investigate the diagnosis of NE in those female veterans with psychosocial issues.

Fluid balance concepts in medicine: Principles and practice.

The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water (TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment (mainly sodium salts) and in the intracellular compartment (mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume (EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.

Principles of quantitative water and electrolyte replacement of losses from osmotic diuresis.

Osmotic diuresis results from urine loss of large amounts of solutes distributed either in total body water or in the extracellular compartment. Replacement solutions should reflect the volume and monovalent cation (sodium and potassium) content of the fluid lost. Whereas the volume of the solutions used to replace losses that occurred prior to the diagnosis of osmotic diuresis is guided by the clinical picture, the composition of these solutions is predicated on serum sodium concentration and urinary sodium and potassium concentrations at presentation. Water loss is relatively greater than the loss of sodium plus potassium leading to hypernatremia which is seen routinely when the solute responsible for osmotic diuresis (e.g., urea) is distributed in body water. Solutes distributed in the extracellular compartment (e.g., glucose or mannitol) cause, in addition to osmotic diuresis, fluid transfer from the intracellular into the extracellular compartment with concomitant dilution of serum sodium. Serum sodium concentration corrected to euglycemia should be substituted for actual serum sodium concentration when calculating the composition of the replacement solutions in hyperglycemic patients. While the patient is monitored during treatment, the calculation of the volume and composition of the replacement solutions for losses of water, sodium and potassium from ongoing osmotic diuresis should be based directly on measurements of urine volume and urine sodium and potassium concentrations and not by means of any predictive formulas. Monitoring of clinical status, serum sodium, potassium, glucose, other relevant laboratory values, urine volume, and urine sodium and potassium concentrations during treatment of severe osmotic diuresis is of critical importance.