How to Determine if a Project Is Human Subjects Research, a Quality Improvement Project, or Both.

Background: Before undertaking a research project, investigators must determine if the planned activity is human subjects research or a quality improvement project because specific regulations govern the conduct of human subjects research. Making this determination, however, can be confusing because human subjects research and quality improvement projects share similar characteristics. Methods: The definitions, questions, and examples provided in this article will help investigators decide between quality improvement projects and human subjects research or determine when to seek regulatory guidance. Results: While quality improvement and human subjects research are both rigorous processes and at times involve similar methods, the two types of studies have distinctly different overall aims. Quality improvement projects use data-driven methods to improve health delivery and quality. Such projects examine changes in human behavior and are largely experiential learning processes. Research is a systematic investigation designed to develop or contribute to generalizable knowledge. Conclusion: In most instances, the goals of human subjects research and quality improvement projects do not intersect, and quality improvement projects are generally not subject to US Department of Health and Human Services (HHS) regulatory protections. However, some projects are both quality improvement and human subjects research, and sometimes, a quality improvement project develops into a human subjects research project. Investigators must be aware of the criteria defining human subjects research to ensure that HHS regulations for the protection of human subjects are applied when necessary.

Understanding Broad Consent.

Background: The 2018 revisions to the Common Rule that were effective in January 2019 introduced a new category of informed consent: broad consent. Methods: Investigators and institutional review board (IRB) members need to understand (1) what broad consent is, (2) the role of broad consent under the revised Common Rule, (3) how and when broad consent can be used, (4) exempt research categories that relate to broad consent, and (5) the scope of limited IRB review as it relates to broad consent. Results: Under the prior regulations, researchers had two consent options: obtain study-specific informed consent or request the IRB to waive the requirement to obtain informed consent. The revision to the Common Rule introduced the third option of broad consent, but its applicability is limited. Broad consent can only be used to obtain an individual's consent for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens. The regulatory authority for broad consent is at 45 CFR §46.116(d). None of the required elements of broad consent can be omitted or altered because each element is considered essential. Broad consent shares many of the requirements for study-specific informed consent, but several elements are unique: a description of the types of secondary research that may be conducted; statements describing the private information or biospecimens that might be used in research, whether sharing of the information or biospecimens might occur, and the types of institutions or researchers that might conduct research with the information or biospecimens; information on how long the information or biospecimens may be stored, maintained, and used; a statement that subjects will or will not be informed of the details of any subsequent research; a statement that research results will or will not be disclosed to subjects; and contact information for obtaining answers to questions about the subjects' rights regarding storage and use of information or biospecimens and whom to contact regarding research-related harm. Conclusion: Broad consent provides flexibility that did not exist prior to the revision, giving researchers the option to obtain broad consent for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens. With an understanding of the regulations, an investigator can plan how best to organize his or her research plan and decide whether to obtain study-specific informed consent, to apply for a waiver of consent, or to obtain broad consent.

Teaching Medical Students to Help Patients Quit Smoking: Outcomes of a 10-School Randomized Controlled Trial.

BACKGROUND: Early in medical education, physicians must develop competencies needed for tobacco dependence treatment. OBJECTIVE: To assess the effect of a multi-modal tobacco dependence treatment curriculum on medical students' counseling skills. DESIGN: A group-randomized controlled trial (2010-2014) included ten U.S. medical schools that were randomized to receive either multi-modal tobacco treatment education (MME) or traditional tobacco treatment education (TE). SETTING/PARTICIPANTS: Students from the classes of 2012 and 2014 at ten medical schools participated. Students from the class of 2012 (N = 1345) completed objective structured clinical examinations (OSCEs), and 50 % (N = 660) were randomly selected for pre-intervention evaluation. A total of 72.9 % of eligible students (N = 1096) from the class of 2014 completed an OSCE and 69.7 % (N = 1047) completed pre and post surveys. INTERVENTIONS: The MME included a Web-based course, a role-play classroom demonstration, and a clerkship booster session. Clerkship preceptors in MME schools participated in an academic detailing module and were encouraged to be role models for third-year students. MEASUREMENTS: The primary outcome was student tobacco treatment skills using the 5As measured by an objective structured clinical examination (OSCE) scored on a 33-item behavior checklist. Secondary outcomes were student self-reported skills for performing 5As and pharmacotherapy counseling. RESULTS: Although the difference was not statistically significant, MME students completed more tobacco counseling behaviors on the OSCE checklist (mean 8.7 [SE 0.6] vs. mean 8.0 [SE 0.6], p = 0.52) than TE students. Several of the individual Assist and Arrange items were significantly more likely to have been completed by MME students, including suggesting behavioral strategies (11.8 % vs. 4.5 %, p < 0.001) and providing information regarding quitline (21.0 % vs. 3.8 %, p < 0.001). MME students reported higher self-efficacy for Assist, Arrange, and Pharmacotherapy counseling items (ps ≤0.05). LIMITATIONS: Inclusion of only ten schools limits generalizability. CONCLUSIONS: Subsequent interventions should incorporate lessons learned from this first randomized controlled trial of a multi-modal longitudinal tobacco treatment curriculum in multiple U.S. medical schools. NIH Trial Registry Number: NCT01905618.

Can L-Cysteine and Vitamin D Rescue Vitamin D and Vitamin D Binding Protein Levels in Blood Plasma of African American Type 2 Diabetic Patients?

AIMS: Vitamin D (VD) deficiency has become a worldwide epidemic, particularly affecting African Americans (AA). VD deficiency has been implicated in the excessive rate of complications associated with diabetes in AA. Blood levels of VD binding protein (VDBP) and glutathione (GSH) are lower in AA compared with those in Caucasians. This study tested the hypothesis that lower GSH levels are linked to VDBP and VD deficiency in AA-type 2 diabetic (AA-T2D) patients. Blood was analyzed from T2D and nondiabetic subjects (N). Experiments examining GSH deficiency and l-cysteine (LC) supplementation were performed using THP-1 monocytes. RESULTS: Plasma levels of LC, GSH, VDBP, and VD were significantly lower in AA-T2D compared with age-matched AA-N or Caucasian-T2D. Lower levels of LC and GSH showed a significant positive correlation with lower VDBP and VD levels in AA-T2D. GSH deficiency investigated using an antisense approach depleted VDBP/vitamin D receptor (VDR); LC supplementation caused significant upregulation of GSH and of VDBP/VDR, while supplementation with VD+LC caused a significantly greater GSH and VDBP/VDR upregulation compared with that of VD alone in monocytes. INNOVATION AND CONCLUSION: The reported observations suggest that VD deficiency may be linked to GSH and LC status and lead to a novel hypothesis that supplementation with LC in combination with VD will be effective in increasing VD levels and reducing health disparities in AA.

Epidemiology of acute pancreatitis in hospitalized children in the United States from 2000-2009.

BACKGROUND: Single-center studies suggest an increasing incidence of acute pancreatitis (AP) in children. Our specific aims were to (i) estimate the recent secular trends, (ii) assess the disease burden, and (iii) define the demographics and comorbid conditions of AP in hospitalized children within the United States. METHODS: We used the Healthcare Cost and Utilization Project Kids' Inpatient Database, Agency for Healthcare Research and Quality for the years 2000 to 2009. Extracted data were weighted to generate national-level estimates. We used the Cochrane-Armitage test to analyze trends; cohort-matching to evaluate the association of AP and in-hospital mortality, length of stay, and charges; and multivariable logistic regression to test the association of AP and demographics and comorbid conditions. RESULTS: We identified 55,012 cases of AP in hospitalized children (1-20 years of age). The incidence of AP increased from 23.1 to 34.9 (cases per 10,000 hospitalizations per year; P<0.001) and for all-diagnoses 38.7 to 61.1 (P<0.001). There was an increasing trend in the incidence of both primary and all-diagnoses of AP (P<0.001). In-hospital mortality decreased (13.1 to 7.6 per 1,000 cases, P<0.001), median length of stay decreased (5 to 4 days, P<0.001), and median charges increased ($14,956 to $22,663, P<0.001). Children with AP compared to those without the disease had lower in-hospital mortality (adjusted odds ratio, aOR 0.86, 95% CI, 0.78-0.95), longer lengths of stay (aOR 2.42, 95% CI, 2.40-2.46), and higher charges (aOR 1.62, 95% CI, 1.59-1.65). AP was more likely to occur in children older than 5 years of age (aORs 2.81 to 5.25 for each 5-year age interval). Hepatobiliary disease was the comorbid condition with the greatest association with AP. CONCLUSIONS: These results demonstrate a rising incidence of AP in hospitalized children. Despite improvements in mortality and length of stay, hospitalized children with AP have significant morbidity.

Improving colon cancer screening in community clinics.

BACKGROUND: The authors evaluated the effectiveness and cost effectiveness of 2 interventions designed to promote colorectal cancer (CRC) screening in safety-net settings. METHODS: A 3-arm, quasi-experimental evaluation was conducted among 8 clinics in Louisiana. Screening efforts included: 1) enhanced usual care, 2) literacy-informed education of patients, and 3) education plus nurse support. Overall, 961 average-risk patients ages 50 to 85 years were eligible for routine CRC screening and were recruited. Outcomes included CRC screening completion and incremental cost effectiveness using literacy-informed education of patients and education plus nurse support versus enhanced usual care. RESULTS: The baseline screening rate was <3%. After the interventions, the screening rate was 38.6% with enhanced usual care, 57.1% with education, and 60.6% with education that included additional nurse support. After adjusting for age, race, sex, and literacy, patients who received education alone were not more likely to complete screening than those who received enhanced usual care; and those who received additional nurse support were 1.60-fold more likely to complete screening than those who received enhanced usual care (95% confidence interval, 1.06-2.42; P = .024). The incremental cost per additional individual screened was $1337 for education plus nurse support over enhanced usual care. CONCLUSIONS: Fecal occult blood test rates were increased beyond enhanced usual care by providing brief education and nurse support but not by providing education alone. More cost-effective alternatives to nurse support need to be investigated.

In African American type 2 diabetic patients, is vitamin D deficiency associated with lower blood levels of hydrogen sulfide and cyclic adenosine monophosphate, and elevated oxidative stress?

African Americans (AA) have a higher incidence of cardiovascular disease and vitamin D (VD) deficiency compared with Caucasians. Hydrogen sulfide (H(2)S) is an important signaling molecule. This study examined the hypothesis that blood levels of H(2)S are lower in AA type 2 diabetic patients (T2D). Fasting blood was obtained from T2D and healthy controls. Results showed a significant decrease in plasma levels of cyclic adenosine monophosphate (cAMP) and H(2)S in AA T2D but not in Caucasian T2D when compared with those of respective age- and race-matched healthy controls. Plasma VD levels were significantly lower in AA T2D compared with Caucasian T2D. Cell culture studies demonstrate that 1,25(OH)(2)-VD supplementation significantly increased expression of cystathionine-γ-lyase (CSE), H(2)S formation, and cAMP secretion, but decreased reactive oxygen species in high glucose-treated U937 monocytes. This suggests that VD supplementation upregulates CSE and H(2)S formation and decreases oxidative stress, and that VD deficiency may contribute to the malfunctioning of H(2)S signaling and thus a higher incidence of vascular inflammation in AA. These results lead to the hypothesis that VD supplementation can replenish blood concentrations of H(2)S and cAMP and lower oxidative stress and cardiovascular disease in AA T2D.

The effect of sleep apnea and insomnia on blood levels of leptin, insulin resistance, IP-10, and hydrogen sulfide in type 2 diabetic patients.

INTRODUCTION: Sleep deficits associated with sleep apnea and insomnia increase the risk of vascular inflammation and insulin resistance. This study examined the hypothesis that inflammation markers are higher in those diabetic patients who experience sleep deficits compared with those without any history of a sleep disorder. METHODS: Fasting blood was obtained after written informed consent, and sleep disorder histories were obtained from type 2 diabetic patients (n=81) attending clinics of the Louisiana State University Health Sciences Center. RESULTS: There was a significant correlation between body weight and leptin, and leptin in turn was significantly correlated with 10-kDa interferon-γ-induced protein (IP-10) levels and insulin resistance in type 2 diabetic patients. Fasting blood levels of leptin, IP-10, and insulin resistance were significantly elevated in patients with sleep deficits compared with diabetics with normal sleep patterns. There were no differences in glycosylated hemoglobin (HbA1c) or fasting glucose in patients with sleep deficits compared with those with normal sleep patterns. Sleep deficits increase circulating levels of leptin, IP-10, and insulin resistance compared to levels seen in patients with diabetes who reported no difficulty with sleep. Patients with sleep apnea had significantly lower hydrogen sulfide (H(2)S) levels compared with patients with normal sleep patterns or patients with insomnia. Low levels of circulating H(2)S could contribute to higher vascular inflammation in patients with sleep apnea. CONCLUSIONS: These results suggest that sleep apnea is associated with a decrease in circulating H(2)S and sleep disorders increase the risk of inflammation and insulin resistance, which can contribute to the increased risk of vascular disease in subjects with type 2 diabetes.

Effect of chromium dinicocysteinate supplementation on circulating levels of insulin, TNF-α, oxidative stress, and insulin resistance in type 2 diabetic subjects: randomized, double-blind, placebo-controlled study.

SCOPE: Chromium and cysteine supplementation have been shown to improve glucose metabolism in animal studies. This study examined the hypothesis that chromium dinicocysteinate (CDNC), a complex of chromium and l-cysteine, is beneficial in lowering oxidative stress, vascular inflammation, and glycemia in type 2 diabetic subjects. METHODS AND RESULTS: Type 2 diabetic subjects enrolled in this study were given placebo for 1 month for stabilization and then randomized into one of three groups: placebo (P), chromium picolinate (CP), or CDNC, after which they received daily oral supplementation for 3 months. Of the 100 patients enrolled in the study, 74 patients completed it. There were 25 patients in the P supplemented group, 25 in the CP supplemented and 24 in the CDNC supplemented group who completed the study. Blood markers of glycemia, vascular inflammation, HOMA insulin resistance, and oxidative stress were determined at randomization and after 3 months of supplementation with P, CP, or CDNC. There was a significant decrease at 3 months in insulin resistance (p = 0.02) and in the levels of protein oxidation (p = 0.02) and TNF-α (p = 0.01) in the CDNC supplemented cohort compared to baseline. However, there was no statistically significant change in these markers in the CP supplemented group compared to baseline. Insulin levels significantly decreased (p = 0.01) for subjects receiving CDNC but not CP. There was no significant impact of supplementation on HbA(1c) or glucose levels in either of the groups. CONCLUSION: CDNC supplementation lowers insulin resistance by reducing blood levels of TNF-α, insulin, and oxidative stress in type 2 diabetic subjects. Therefore, CDNC supplementation has potential as an adjunct therapy for individuals with type 2 diabetes.

Arriving at correct conclusions: the importance of association, causality, and clinical significance.

Declaring that a causal and not solely a correlative relation exists between a risk factor and a disease creates significant implications for patients and physicians. No matter the forum, when investigators or clinicians make such a claim, it is essential to explain how this determination was made so that appropriate recommendations are made in all areas of our professional practice. When we review the medical literature it is similarly crucial to understand this distinction between causality and association. The Bradford Hill criteria of strength of association, consistency, temporality, biological gradient, biological plausibility, coherence, experimental evidence, and analogy can be used to help establish causality. It is also important to understand the distinction between clinical and statistical significance to complete our appraisal of the implications of a clinical study. Statistically significant results, although not the result of chance, may be clinically insignificant. Statistically insignificant results, conversely, may not exclude the possibility of a clinically important relation. This article reviews the concepts of causality and association and clinical versus statistical significance and provides examples from the literature.

HIV, rods, and the muscles--a discussion about HIV-associated nemaline rod myopathy.

This case reports a 21-year-old, homosexual African-American male who presented to our facility with a two-week history of progressive proximal muscle weakness. Quadriceps muscle biopsy showed a diagnosis of Nemaline Rod Myopathy, the presenting disease of his HIV infection. A review of the literature shows 13 prior case reports of similar disease process, often as the presenting symptom of the HIV disease. Anecdotal reports of effective treatment regimens include steroids and intravenous immune globulin; our patient had a profound response to high-dose steroids. This case report discusses this rare presentation of HIV in hopes to increase awareness amongst clinicians as the incidence and prevalence of HIV increases.

Serum markers for severe Clostridium difficile infection in immunosuppressed hospitalized patients.

Clostridium difficile infection (CDI) has emerged as the leading cause of nosocomial diarrhea in the developed world. The prompt recognition of severe CDI is essential in providing early aggressive therapy. Though previous studies have identified leukocytosis, azotemia, and hypoalbuminemia as markers to differentiate severe from non-severe CDI in the general patient population, there is little data in immunosuppressed patients. We conducted a retrospective chart review of immunosuppressed patients with CDI to identify serum markers associated with severe CDI. Twenty-nine immunosuppressed patients with CDI (nine with severe disease) were identified. Those with severe disease were older and had evidence of renal dysfunction. The white blood cell count, platelet, and albumin levels were the same in the severe and non-severe immunosuppressed CDI patients. Therefore, recognized serum markers of severe CDI are not universally useful in immunosuppressed patients. Moreover, the clinician must be aware that immunosuppressed patients can develop severe CDI while remaining leukopenic.

Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation?

Hydrogen sulfide (H(2)S) is emerging as a physiological neuromodulator as well as a smooth muscle relaxant. We submit the first evidence that blood H(2)S levels are significantly lower in fasting blood obtained from type 2 diabetes patients compared with age-matched healthy subjects, and in streptozotocin-treated diabetic rats compared with control Sprague-Dawley rats. We further observed that supplementation with H(2)S or an endogenous precursor of H(2)S (l-cysteine) in culture medium prevents IL-8 and MCP-1 secretion in high-glucose-treated human U937 monocytes. These first observations led to the hypothesis that lower blood H(2)S levels may contribute to the vascular inflammation seen in diabetes.

Laboratory markers as predictors of mortality in patients with Clostridium difficile infection.

Previous studies have identified laboratory markers for severe Clostridium difficile infection (CDI). The most consistent of these markers is the presence of marked leukocytosis. We examined the validity of these markers as predictors of mortality in patients with CDI. We excluded patients with preexisting hematologic conditions that would be expected to impair their ability to demonstrate leukocytosis. On univariate analysis, marked leukocytosis (P = 0.02), thrombocytopenia (P = 0.008), and increased blood urea nitrogen (P < 0.001) and creatinine (P = 0.001) levels were found to be significantly associated with mortality in patients with CDI. However, on logistic regression analysis, only renal impairment was found to be an independent predictor (odds ratio, 5.07). Importantly, in our study, leukocytosis was not an independent predictor after adjustment for other variables, which may be due to our selection criteria when adjusting for confounding variables. We are therefore of the opinion that in immunocompromised hosts who are leukopenic at the time of CDI diagnosis, other laboratory markers should be identified to serve as indicators for severe disease.

Langerhans cell histiocytosis, a case of Letterer Siwe disease.

An 8-month-old male infant presented with a progressively worsening generalized rash of 5-6 months duration, fever, poor feeding, and abdominal distension. An initial laboratory workup revealed anemia, thrombocytopenia, and hepatosplenomegaly. The patient was started on i.v. antibiotics, and a working diagnosis of Langerhans cell histiocytosis was reached that was later confirmed with a skin biopsy. Subsequently, the patient received first-round chemotherapy with vinblastine and prednisone, on which he appeared to improve clinically; however, he soon relapsed. He then received combination salvage therapy with cladribine (2CdA) and cytarabine (Ara-C) for three cycles. The patient responded well to this regimen with resolution of his condition. The patient was then referred for a bone marrow transplant.

Preprinted order sets as a safety intervention in pediatric sedation.

OBJECTIVES: Implement preprinted packets for pediatric procedural sedations to increase documentation compliance and decrease medication ordering errors. STUDY DESIGN: Retrospective chart review of pediatric inpatients undergoing procedural sedation before and after implementation of a preprinted packet including an order set, consent form, and sedation monitoring form. Patient charts before and after the intervention were reviewed for completeness of medical documentation, correct medication dosages, and adverse events. Chi2 or Fisher exact test was used to determine preintervention vs postintervention differences. RESULTS: Forty-two charts preintervention and 42 postintervention were reviewed. Documentation compliance increased on consent forms (P < .001), procedure notes (P = .113), and sedation monitoring forms (P = .003), while dating and timing of order forms decreased. Ordering of resuscitation equipment (P = .12), documentation of American Society of Anesthesiologists' (ASA) physical status classification (P < .001) and allergies (P < .001), and postsedation orders (P < .001) also increased. Medications ordered using unit/kg increased 43% (P < .05). Medication ordering errors for sedation agents decreased 64% (P < .001). Ordering of appropriate reversal agents increased 73% (P = .02). CONCLUSIONS: Implementing preprinted physician orders, consent forms, and prepared packets increased documentation compliance and ordering of reversal agents and resuscitation equipment. Medication dosage ordering errors decreased.

Harbingers for Clostridium difficile-associated diarrhea.

PURPOSE: : Recent research has recognized surrogate markers for Clostridium difficile-associated diarrhea (CDAD). Among the most consistently identified markers are the leukocyte count, platelet count, and albumin level. Previous investigators failed to exclude patients with hematologic disorders that may have confounded their results. Therefore, the exclusion of this subset from our study lends it a unique perspective. METHODS: : We undertook a retrospective review of inpatients at our institution that were diagnosed with nosocomial diarrhea and subsequently had a stool sample sent for C. difficile toxins A and B. Patients with major hematologic disorders were excluded. RESULTS: : A total of 77 C. difficile-positive patients and 91 C. difficile-negative patients were studied. Patients with CDAD had a significantly higher leukocyte and platelet count but a lower albumin level compared with patients without CDAD. CONCLUSION: : Our results support the conclusion of preceding studies that leukocytosis, thrombocytosis, and hypoalbuminemia are reliable clinical predictors for CDAD even after careful exclusion of confounding factors.

Improving patient understanding of prescription drug label instructions.

BACKGROUND: Patient misunderstanding of instructions on prescription drug labels is common and a likely cause of medication error and less effective treatment. OBJECTIVE: To test whether the use of more explicit language to describe dose and frequency of use for prescribed drugs could improve comprehension, especially among patients with limited literacy. DESIGN: Cross-sectional study using in-person, structured interviews. PATIENTS: Three hundred and fifty-nine adults waiting for an appointment in two hospital-based primary care clinics and one federally qualified health center in Shreveport, Louisiana; Chicago, Illinois; and New York, New York, respectively. MEASUREMENT: Correct understanding of each of ten label instructions as determined by a blinded panel review of patients' verbatim responses. RESULTS: Patient understanding of prescription label instructions ranged from 53% for the least understood to 89% for the most commonly understood label. Patients were significantly more likely to understand instructions with explicit times periods (i.e., morning) or precise times of day compared to instructions stating times per day (i.e., twice) or hourly intervals (89%, 77%, 61%, and 53%, respectively, p < 0.001). In multivariate analyses, dosage instructions with specific times or time periods were significantly more likely to be understood compared to instructions stating times per day (time periods--adjusted relative risk ratio (ARR) 0.42, 95% Confidence Interval (CI) 0.34-0.52; specific times--ARR 0.60, 95% CI 0.49-0.74). Low and marginal literacy remained statistically significant independent predictors of misinterpreting instructions (low--ARR 2.70, 95% CI 1.81-4.03; marginal--ARR 1.66, 95% CI 1.18-2.32). CONCLUSIONS: Use of precise wording on prescription drug label instructions can improve patient comprehension. However, patients with limited literacy were more likely to misinterpret instructions despite use of more explicit language.