The Relationship Between Transfusion in Cardiac Surgery Patients and Adverse Outcomes.

OBJECTIVES: To understand if red blood cell (RBC) transfusions are independently associated with a risk of mortality, prolonged intubation, or infectious, cardiac, or renal morbid outcomes. DESIGN: A retrospective review. SETTING: A single-institution university hospital. PARTICIPANTS: A total of 2,458 patients undergoing coronary bypass artery graft and/or valvular surgery from July 2014 through January 2018. INTERVENTIONS: No interventions were done. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of an adverse event or prolonged intubation. Infectious, cardiac, and renal composite outcomes were also defined. These composites, along with mortality, were analyzed individually and then combined to form the "any adverse events" composite. Preoperative demographic and intraoperative parameters were analyzed as univariate risk factors for adverse outcomes. Logistic regression was used to screen variables, with a p value criterion of p < 0.05 for entry into the model selection procedure. A backward selection algorithm was used with variable entry and retention criteria of p < 0.05 to select the final multivariate model. Multivariate logistic regression models were used to determine whether there was an association between the volume of RBC transfusion and the defined adverse event after adjusting for covariates. A p value < 0.01 was considered statistically significant in the final model of each aim to adjust for multiple comparisons. The final logistic models for each of the following outcomes indicate an increased risk of that outcome per each additional unit of RBC transfused. For prolonged intubation, the odds ratio (OR) was 1.493 (p < 0.0001), OR = 1.358 (p < 0.0001) for infectious composite outcomes, OR = 1.247 (p < 0.0001) for adverse renal outcomes, and OR = 1.467 (p < 0.0001) for any adverse event. CONCLUSIONS: The authors demonstrated a strong independent association between RBC transfusion volume and adverse outcomes after cardiac surgery. Efforts should be undertaken, such as preoperative anemia management and control of coagulopathy, in order to minimize the need for RBC transfusion.

CMC Regulatory Considerations for Antibody-Drug Conjugates.

Antibody-drug conjugates unite the specificity and long circulation time of an antibody with the toxicity of a chemical cytostatic or otherwise active drug using appropriate chemical linkers to reduce systemic toxicity and increase therapeutic index. This combination of a large biological molecule and a small molecule creates an increase in complexity. Multiple production processes are required to produce the native antibody, the drug and the linker, followed by conjugation of afore mentioned entities to form the final antibody-drug conjugate. The connected processes further increase the number of points of control, resulting in necessity of additional specifications and intensified analytical characterization. By combining scientific understanding of the production processes with risk-based approaches, quality can be demonstrated at those points where control is required and redundant comparability studies, specifications or product characterization are avoided. Over the product development lifecycle, this will allow process qualification to focus on those areas critical to quality and prevent redundant studies. The structure of the module 3 common technical document for an ADC needs to reflect each of the production processes and the combined overall approach to quality. Historically, regulatory authorities have provided varied expectations on its structure. This paper provides an overview of essential information to be included and shows that multiple approaches work as long as adequate cross-referencing is included.

Asymmetrical aortic root aneurism in patient with Filamin A mutation.

We report the case of a 28 years old woman with periventricular nodular heterotopia, due to Filamin A mutation. She had an asymmetrical aneurysm of the aortic root, involving, above all, noncoronary Valsalva sinus. She was asymptomatic and she had moderate aortic regurgitation. Reimplantation of the aortic valve with replacement of the aortic root was successfully accomplished. Filamin A is a protein that is encoded by the FLNA gene, which shows X-linked dominant inheritance. This protein is involved in neuronal migration, angiogenesis, cytoskeleton regulation, and cell signaling. Therefore, mutations of FLNA gene might result in brain, blood vessels, heart, and connective tissue disorders. A miscellany of cardiovascular abnormalities could be present in this subset of patients; cardiac symptoms may precede neurological manifestations. Aorta seems to be frequently affected. Consequently, in presence of FLNA gene mutations, cardiovascular evaluation should include vascular magnetic resonance imaging or computed tomography scan.

Early-life single-episode sevoflurane exposure impairs social behavior and cognition later in life.

BACKGROUND: Single-episode anesthetic exposure is the most prevalent surgery-related incidence among young children in the United States. Although numerous studies have used animals to model the effects of neonatal anesthetics on behavioral changes later on in life, our understanding of the functional consequences to the developing brain in a comprehensive and clinically relevant manner is unclear. METHODS: The volatile anesthetic, sevoflurane (sevo) was administered to C57BL6 postnatal day 7 (P7) mice in a 40% oxygen and 60% nitrogen gas mixture. In order to examine the effects of sevo alone on the developing brain in a clinically relevant manner, mice were exposed to an average of 2.38 ± 0.11% sevo for 2 h. No sevo (control) mice were treated in an identical manner without sevo exposure. Mice were examined for cognition and neuropsychiatric-like behavioral changes at 1-5 months of age. RESULTS: Using the active place avoidance (APA) test and the novel object recognition (NOR) test, we demonstrated that P7 sevo-treated mice showed a deficit in learning and memory both during periadolescence and adulthood. We then employed a battery of neuropsychiatric-like behavioral tests to examine social interaction, communication, and repetitive behavior. Interestingly, compared to the no-sevo-treated group, sevo-treated mice showed significant reductions in the time interacting with a novel mouse (push-crawl and following), time and interaction in a chamber with a novel mouse, and time sniffing a novel social odor. CONCLUSIONS: Our study established that single-episode, 2-h sevo treatment during early life impairs cognition later on in life. With this approach, we also observed neuropsychiatric-like behavior changes such as social interaction deficits in the sevo-treated mice. This study elucidated the effects of a clinically relevant single-episode sevo application, given during the neonatal period, on neurodevelopmental behavioral changes later on in life.

Analysis of the polyphenols content in medicinal plants based on the reduction of Cu(II)/bicinchoninic complexes.

A spectrophotometric method is proposed for the determination of the polyphenols content in aqueous extracts of plants. The method is based on the reduction of Cu(II) to Cu(I) by polyphenols, in the presence of bicinchoninic acid in a buffered medium (ammonium acetate, pH 7.0) with the formation of Cu(I)/BCA complexes. A calibration curve of absorbance (at 558 nm) vs tannic acid concentration is linear (r = 0.995; n = 7) with tannic acid from 0.1 to 0.7 micromol L(-1). The limit of detection and relative standard deviation were 40 nmol L(-1) (99% confidence level) and 3.8% (0.4 micromol L(-1) tannic acid, n = 7), respectively. For the aqueous extracts of Hamamelis virginiana L., Maytenus ilicifolia Mart. ex Reissek, Hydrocotyle bonariensis Lam, Annona muricata L., Myrciaria cauliflora (Mart.) O. Berg., Caesearia sylvestris Sw., Schinus terebinthifolia (Raddi), and Stryphnodendron adstringens (Mart.) Coville, the total polyphenol contents, expressed as tannic acid, were 3.5, 1.3, 2.0, 3.1, 15.4, 3.1, 9.1, and 6.9%, respectively.

Health-related quality of life of children and adolescents with type 1 or type 2 diabetes mellitus: SEARCH for Diabetes in Youth Study.

OBJECTIVE: To examine the associations between demographic and diabetes management variables and the health-related quality of life (HRQOL) of youths with type 1 or type 2 diabetes mellitus (DM). DESIGN: Cross-sectional study. SETTINGS: Selected populations in Ohio, Washington, South Carolina, Colorado, Hawaii, and California; health service beneficiaries in 3 American Indian populations; and participants in the Pima Indian Study in Arizona. PARTICIPANTS: Two thousand four hundred forty-five participants aged 8 to 22 years in the SEARCH for Diabetes in Youth Study. MAIN OUTCOME MEASURE: Pediatric Quality of Life Inventory scores. RESULTS: Among youths with type 2 DM, HRQOL was lower compared with those with type 1. Among those with type 1 DM, worse HRQOL was associated with a primary insurance source of Medicaid or another government-funded insurance, use of insulin injections vs an insulin pump, a hemoglobin A(1c) value of at least 9%, and more comorbidities and diabetes complications. There was a significant age x sex interaction, such that, in older groups, HRQOL was lower for girls but higher for boys. For youths with type 2 DM, injecting insulin at least 3 times a day compared with using an oral or no diabetes medication was associated with better HRQOL, and having 2 or more emergency department visits in the past 6 months was associated with worse HRQOL. CONCLUSIONS: Youths with types 1 and 2 DM reported HRQOL differences by type of treatment and complications. The significant age x sex interaction suggests that interventions to improve HRQOL should consider gender differences in diabetes adjustment and management in different age groups.

Weight loss strategies associated with BMI in overweight adults with type 2 diabetes at entry into the Look AHEAD (Action for Health in Diabetes) trial.

OBJECTIVE: Intentional weight loss is recommended for those with type 2 diabetes, but the strategies patients attempt and their effectiveness for weight management are unknown. In this investigation we describe intentional weight loss strategies used and those related to BMI in a diverse sample of overweight participants with type 2 diabetes at enrollment in the Look AHEAD (Action for Health in Diabetes) clinical trial. RESEARCH DESIGN AND METHODS: This was a cross-sectional study of baseline weight loss strategies, including self-weighing frequency, eating patterns, and weight control practices, reported in 3,063 women and 2,082 men aged 45-74 years with BMI > or =25 kg/m(2). RESULTS: Less than half (41.4%) of participants self-weighed > or =1/week. Participants ate breakfast 6.0 +/- 1.8 days/week, ate 5.0 +/- 3.1 meals/snacks per day, and ate 1.9 +/- 2.7 fast food meals/week. The three most common weight control practices (increasing fruits and vegetables, cutting out sweets, and eating less high-carbohydrate foods) were reported by approximately 60% of participants for > or =20 weeks over the previous year. Adjusted models showed that self-weighing less than once per week (B = 0.83), more fast food meals consumed per week (B = 0.14), and fewer breakfast meals consumed per week (B = -0.19) were associated (P < 0.05) with a higher BMI (R(2) = 0.24). CONCLUSIONS: Regular self-weighing and breakfast consumption, along with infrequent consumption of fast food, were related to lower BMI in the Look AHEAD study population.

The stereochemical course of bromoetherification of enynes.

Enynes undergo stereoselective syn intramolecular bromoetherification; the stereochemical course of the reaction was elucidated by X-ray crystallographic studies and by stereospecific synthesis of authentic bromoallenes.

Multigram synthesis of a water-soluble porphyrazine and derived seco-porphyrazine labeling agents.

Porphyrazine III has been synthesized on a large scale (18.4 g), with minimal chromatographic purification by employing a novel one-pot, 3-step sequence. Two dinitrile precursors I and II, the latter of which consisted of a mixture of geometric isomers, were transformed, via the corresponding pyrroline diimines, into a mixture of III and the octa-Ar1-porphyrazine. Isolated macrocycle III was subsequently transformed into IV, a water-soluble seco-porphyrazine suitable for the labeling of biological vectors.

Genetic screening for iron overload: No evidence of discrimination at 1 year.

PURPOSE: This study measured the extent of insurance and employment problems associated with population screening for hereditary hemochromatosis and iron overload. METHODS: 101,168 primary care patients from the US and Canada were screened for iron phenotypes and HFE genotypes associated with hemochromatosis. Those identified to be at risk (2253) were offered a clinical examination, which 1677 (74%) accepted, and the 1154 of these who responded to an initial questionnaire about psychosocial issues were surveyed 1 year later about whether they had experienced problems with insurance or employment that they attributed to hereditary hemochromatosis and iron overload. RESULTS: 832 (72.1%) of the 1154 participants surveyed after 1 year responded to the second survey. Three (0.4%) had verified problems with insurance or employment that they believed were related to hereditary hemochromatosis and iron overload. Two had problems with life insurance, and one with long-term care insurance. All 3 had elevated iron levels but not a relevant HFE genotype. One of the life insurance problems was resolved; the second one was not serious. The participant who was denied long-term care insurance had other health conditions unrelated to hereditary hemochromatosis and iron overload that could have contributed to the denial. No problems were verified for health insurance or employment, or from any of the comparison group participants (controls and those with inconclusive screening results). CONCLUSIONS: The risk of insurance or employment problems 1 year after phenotype and genotype screening for hereditary hemochromatosis and iron overload is very low.

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study.

Elevated mean corpuscular volume (MCV) is common in persons with hemochromatosis associated with HFE C282Y homozygosity. We evaluated data from the subset of non-Hispanic white participants in the Hemochromatosis and Iron Overload Screening Study to determine if elevated MCV in C282Y homozygotes is related to this genotype or to serum iron measures. Regression analysis was used to model MCV and Hb from transferrin saturation (TfSat), serum ferritin (SF), mean corpuscular hemoglobin concentration, red blood cell count, age, HFE genotype, Field Center, and presence of liver-related abnormalities in C282Y homozygotes and control subjects without HFE mutations (wt/wt genotype). Mean MCV was higher in C282Y homozygotes than in HFE wt/wt controls (94.4 vs. 89.7 fL in women; 95.3 vs. 91.2 fL in men; P < 0.0001 for both). These differences were largely associated with increased mean TfSat and SF in C282Y homozygotes. Adjusted mean MCV was 92.0 fL (95% confidence interval, 91.1, 92.9) in female C282Y homozygotes and 90.9 fL (90.3, 91.5) in controls. Among women with SF in the reference range 20-200 microg/L, adjusted mean MCV was 92.9 fL, (91.7, 94.2) in C282Y homozygotes, 1.8 fL higher than in controls (P = 0.013). The adjusted mean MCV of male C282Y homozygotes and controls was similar (P = 0.30). Adjusted mean Hb was 0.2 g/dL higher in women with C282Y/C282Y than in controls. Greater mean MCV in C282Y homozygosity reflects increased mean TfSat and mean SF in men and women; an additional effect of genotype on MCV and Hb was detected in women.

Impact of hemochromatosis screening in patients with indeterminate results: the hemochromatosis and iron overload screening study.

PURPOSE: Assess the quality of life impact of receiving indeterminate test results for hemochromatosis, a disorder involving HFE genetic mutations and/or elevated serum transferrin saturation and ferritin. METHODS: The study sample was from the Hemochromatosis and Iron Overload Screening Study, a large observational study of hemochromatosis among primary care patients in the US and Canada using HFE genotype and serum transferrin saturation and ferritin screening. Study subjects included 2,304 patients found with hemochromatosis risk of uncertain clinical significance. Assessed was SF-36 general health and emotional well-being before screening and six weeks after participants received their test results. Health worries were assessed after screening. RESULTS: Of the study subjects, 1,268 participants (51.5%) completed both assessments. Compared to normal controls, those with HFE mutations or elevated serum transferrin saturation and ferritin levels of uncertain significance were more likely to report diminished general health and mental well-being, and more health worries. These effects were associated with participants' belief of having tested positive for hemochromatosis or iron overload. CONCLUSION: Notification of indeterminate results from screening may be associated with mild negative effects on well-being, and might be a potential participant risk in screening programs for disorders with uncertain genotype-phenotype.

Prevalence and correlates of depressed mood among youth with diabetes: the SEARCH for Diabetes in Youth study.

OBJECTIVE: The objective of this study was to determine if depressed mood among youth with diabetes was associated with type and duration of diabetes, mean glycosylated hemoglobin (HbA1c) level, and the frequency of diabetic ketoacidosis (DKA) and hypoglycemic episodes, hospitalizations, and emergency department (ED) visits. METHODS: A total of 2672 youth (aged 10-21 years) who had diabetes for a mean duration of 5 years completed a SEARCH study visit, in which their HbA1c was measured and information about their demographic characteristics, diabetes type and duration, and episodes of DKA, hypoglycemia, hospitalizations, and ED visits over the previous 6 months was collected. Their level of depressed mood was measured using the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Among these youth, 14% had mildly (CES-D 16-23) and 8.6% had moderately or severely (CES-D > or =24) depressed mood. Females had a higher mean CES-D score than males. After adjusting for demographic factors, and duration of diabetes, we found the prevalence of depressed mood to be higher among males with type 2 diabetes than those with type 1 diabetes and to be higher among females with comorbidities than those without comorbidities. Higher mean HbA1c and frequency of ED visits were associated with depressed mood. The prevalence of depressed mood among youth with diabetes was similar to that of published estimates of depressed mood among youth without diabetes. CONCLUSIONS: Physicians and other health care professionals should consider screening youth with diabetes for depressed mood in clinical settings, particularly youth with poor glycemic control, those with a history of frequent ED visits, males with type 2 diabetes, and females with comorbidities.

Predictors of belief that genetic test information about hemochromatosis should be shared with family members.

We queried 101,951 white, Hispanic, black, Asian, American Indian (i.e., American Indian or Alaska Native in the United States and North American Indian, Metis, or Inuit in Canada) and Pacific Islander (including Native Hawaiian) adults who agreed to be genotypically and phenotypically screened for hemochromatosis as part of the Hemochromatosis and Iron Overload Screening (HEIRS) study about their views on sharing genetic test information with family members. Multiple logistic regression (adjusting for study site, age group, race/ethnicity, preferred language, gender, education group, income group, SF-36 General Health and Mental Health subscales, perceived benefits and limitations of genetic testing, and belief that genetic testing is a good idea) evaluated independent predictors of responding "Strongly Agree" or "Agree" versus "Disagree" or "Strongly Disagree" to the statement "Information about a person's genetic risk should be shared with family members". Agreement that genetic risk information should be shared with family members was high (93% in the overall sample of 78,952 who answered this question), but differed among racial/ethnic groups. Hispanics were significantly less likely to agree that genetic test information should be shared with family members (i.e., 88% versus 92% or more among all other ethnicities). The relationship of perceived limitations and benefits of testing, gender, and age group to the belief that information should be shared differed among racial/ethnic groups, with Spanish-preferring Hispanics being the most different from other subgroups.

Testing the accelerator hypothesis: body size, beta-cell function, and age at onset of type 1 (autoimmune) diabetes.

OBJECTIVE: The "accelerator hypothesis" predicts that fatness is associated with an earlier age at onset of type 1 diabetes. We tested the hypothesis using data from the SEARCH for Diabetes in Youth study. RESEARCH DESIGN AND METHODS: Subjects were 449 youth aged <20 years at diagnosis who had positive results for diabetes antibodies measured 3-12 months after diagnosis (mean 7.6 months). The relationships between age at diagnosis and fatness were examined using BMI as measured at the SEARCH visit and reported birth weight, both expressed as SD scores (SDSs). RESULTS: Univariately, BMI SDS was not related to age at diagnosis. In multiple linear regression, adjusted for potential confounders, a significant interaction was found between BMI SDS and fasting C-peptide (FCP) on onset age (P < 0.0001). This interaction remained unchanged after additionally controlling for number and titers of diabetes antibodies. An inverse association between BMI and age at diagnosis was present only among subjects with FCP levels below the median (<0.5 ng/ml) (regression coefficient -7.9, P = 0.003). A decrease of 1 SDS in birth weight (639 g) was also associated with an approximately 5-month earlier age at diagnosis (P = 0.008), independent of sex, race/ethnicity, current BMI, FCP, and number of diabetes antibodies. CONCLUSIONS: Increasing BMI is associated with younger age at diagnosis of type 1 diabetes only among those U.S. youth with reduced beta-cell function. The intrauterine environment may also be an important determinant of age at onset of type 1 diabetes.

Investigation of the Diels-Alder cycloadditions of 2(H)-1,4-oxazin-2-ones.

[Reaction: see text]. A variety of 5-chloro-2(H)-1,4-oxazin-2-ones bearing a range of substituents at their 3- and 6-positions undergo Diels-Alder cycloaddition as a 2-azadiene component with electron-rich, electron-deficient, and electron-neutral dienophiles. These reactions proceed with moderate regio- and stereoselectivity to afford relatively stable and readily isolable bridged bicyclic lactone cycloadducts. Chemical manipulation of these cycloadducts affords highly substituted and functionally rich piperidines. The regio- and stereochemical preferences of the cycloadditions of 5-chloro-2(H)-1,4-oxazin-2-ones are investigated computationally using density functional theory (B3LYP/6-31G).

Concerns in a primary care population about genetic discrimination by insurers.

PURPOSE: Fear of genetic discrimination might deter participation in research or therapy. This is a major impetus for laws limiting insurers' use of genetic information, yet there is little information about the extent of this fear in the general population and how it varies by social factors. METHODS: This study measures concern about insurance problems relating to genetic testing, as part of primary-care screening for hereditary hemochromatosis (iron overload). Data come from a multiethnic, primary care-based survey of 86,859 adults in five field centers in the United States (AL, CA, DC, HI, OR), and one in Canada (Ontario). Logistic regression was used to model the probability of agreeing to the question "Genetic testing is not a good idea because you might have trouble getting or keeping your insurance." RESULTS: Overall, 40.0% of participants agreed. Adjusting for other characteristics, African Americans and Asians were much less likely (OR = 0.52 and 0.39), and Hispanics were more likely (OR = 1.124), than Caucasians to express concern about insurance discrimination. Participants under 65 years old, US residents, and those without a high school diploma were substantially more likely to be concerned (ORs ranging from 1.4-1.6), as were participants with lower mental health scores. Education showed a nonlinear relationship, with significantly higher concern among both those with less than a high school education and those with a college degree, compared to high school graduates. CONCLUSIONS: Concern about genetic discrimination varies substantially by race and other demographic factors and by nationality. One possible explanation for lower concern about Canadians and by people over 64 is that both groups are covered by social insurance for health care (Medicare). However, US residents in states with some legal protections against genetic discrimination had more, not less, concern than either Canadians or US residents in states with no legal protections.

Rates and predictors of rehospitalization among formerly hospitalized adolescents.

OBJECTIVE: The authors examined rates and predictors of rehospitalization among 180 adolescents followed up for up to 10.3 years after discharge from an inpatient psychiatric unit. METHODS: In this prospective, naturalistic study, demographic variables, including gender, race, and age, and psychiatric variables, including diagnoses, prehospitalization suicide attempts, and previous hospitalizations, were examined as potential predictors of rehospitalization. Information about rehospitalizations was repeatedly assessed and verified with treatment records. RESULTS: During the follow-up period, 79 adolescents (44 percent) had one or more rehospitalizations. By six months after discharge, 19 percent of the adolescents had been rehospitalized. The mean time to first rehospitalization was estimated to be 5.7 years. Univariate analyses revealed significant differences between adolescents who were rehospitalized and those who were not in terms of age, presence of an affective disorder, and presence of a comorbid psychiatric disorder. In the multivariate predictor model, age and the presence of an affective disorder were the only significant predictors of rehospitalization. CONCLUSIONS: Clinicians should examine risk of rehospitalization before discharge, especially for younger patients and those with depression. Future research must focus on methods of intervention for this high-risk group.