Robert Wood Johnson University Hospital

BACKGROUND: Although childhood obesity may have detrimental consequences for childhood self-esteem, the prevalence and magnitude of this problem is controversial. In addition, the social and emotional effects of decreased self-esteem in obese children are unknown. METHODS: A total of 1520 children, 9 to 10 years of age, born to mothers in the National Longitudinal Survey of Youth were studied. Comprehensive demographic data including race and family income were available in 97% of the cohort. Self-esteem was measured using Self-Perception Profile for Children. The 4-year follow-up Self-Perception Profile for Children scores were available in 79% of the children. Obesity was defined as a body mass index greater than the 95th percentile for age and gender. Additional data include a self-administered questionnaire at 13 to 14 years of age concerning emotional well being, smoking, and alcohol consumption. Data were stratified by race and gender. The data were weighted to reflect a nationally representative sample of children born to mothers 17 to 28 years of age. RESULTS: Scholastic and global self-esteem scores were not significantly different among 9- to 10-year-old obese and nonobese children. However, over the 4-year period, obese Hispanic females and obese white females showed significantly decreased levels of global self-esteem compared with nonobese Hispanic females and nonobese white females, respectively. Mild decreases in self-esteem also were observed in obese boys compared with nonobese boys. As a result, by 13 to 14 years of age, significantly lower levels of self-esteem were observed in obese boys, obese Hispanic girls, and obese white girls compared with their nonobese counterparts. Decreasing levels of self-esteem in obese children were associated with significantly increased rates of sadness, loneliness, and nervousness compared with obese children whose self-esteem increased or remained unchanged. In addition, obese children with decreasing levels of self-esteem over the 4-year period were more likely to smoke and drink alcohol compared with obese children whose self-esteem increased or remained unchanged. CONCLUSIONS: Obese Hispanic and white females demonstrate significantly lower levels of self-esteem by early adolescence. In addition, obese children with decreasing levels of self-esteem demonstrate significantly higher rates of sadness, loneliness, and nervousness and are more likely to engage in high-risk behaviors such as smoking or consuming alcohol.

Placenta previa, placenta accreta, and vasa previa are important causes of bleeding in the second half of pregnancy and in labor. Risk factors for placenta previa include prior cesarean delivery, pregnancy termination, intrauterine surgery, smoking, multifetal gestation, increasing parity, and maternal age. The diagnostic modality of choice for placenta previa is transvaginal ultrasonography, and women with a complete placenta previa should be delivered by cesarean. Small studies suggest that, when the placenta to cervical os distance is greater than 2 cm, women may safely have a vaginal delivery. Regional anesthesia for cesarean delivery in women with placenta previa is safe. Delivery should take place at an institution with adequate blood banking facilities. The incidence of placenta accreta is rising, primarily because of the rise in cesarean delivery rates. This condition can be associated with massive blood loss at delivery. Prenatal diagnosis by imaging, followed by planning of peripartum management by a multidisciplinary team, may help reduce morbidity and mortality. Women known to have placenta accreta should be delivered by cesarean, and no attempt should be made to separate the placenta at the time of delivery. The majority of women with significant degrees of placenta accreta will require a hysterectomy. Although successful conservative management has been described, there are currently insufficient data to recommend this approach to management routinely. Vasa previa carries a risk of fetal exsanguination and death when the membranes rupture. The condition can be diagnosed prenatally by ultrasound examination. Good outcomes depend on prenatal diagnosis and cesarean delivery before the membranes rupture.

CONTEXT: Obesity is the most common health problem facing children. The most recent data from the National Health and Nutrition Examination Survey III suggest that 22% of children and adolescents are overweight and that 11% are obese. OBJECTIVE: To investigate prospectively the association between the home environment and socioeconomic factors and the development of obesity in children. DESIGN: Prospective cohort study. SETTING: The National Longitudinal Survey of Youth. Population. A total of 2913 normal weight children between the ages of 0 and 8 years were followed over a 6-year period. We examined the roles of race, marital status, maternal education, family income, and parental occupation, as well as standardized measures of the home environment (The Home Observation for Measurement of the Environment [HOME]-Short Form) on the development of childhood obesity. PRIMARY OUTCOME MEASURE: Incidence of obesity. Obesity was defined as a body mass index >95th percentile for age and gender at the 6-year follow-up. RESULTS: Maternal obesity was the most significant predictor of childhood obesity (OR: 3.62 [2. 65-4.96]). The HOME-Short Form cognitive scores and household income were also significant predictors of childhood obesity (OR, low HOME-cognitive: 2.64 [1.48-4.70], medium HOME-cognitive: 2.32 [1. 39-3.88]; low income: 2.91 [1.66-5.08], medium income: 2.04 [1.21-3. 44]). Children who lived with single mothers were also significantly more likely to become obese by the 6-year follow-up, as were black children, children with nonworking parents, children with nonprofessional parents, and children whose mothers did not complete high school. Neither the child's gender nor the HOME-emotional scores contributed to the development of obesity. After controlling for the child's initial weight-for-height z-score, maternal body mass index, race, marital status, occupation, education, and HOME emotional scores, only the HOME cognitive score and family income remained significant predictors of childhood obesity. CONCLUSION: Children with obese mothers, low family incomes, and lower cognitive stimulation have significantly elevated risks of developing obesity, independent of other demographic and socioeconomic factors. In contrast, increased rates of obesity in black children, children with lower family education, and nonprofessional parents may be mediated through the confounding effects of low income and lower levels of cognitive stimulation.

BACKGROUND: A previous analysis in this trial showed that among patients with severe, symptomatic aortic stenosis who were at low surgical risk, the rate of the composite end point of death, stroke, or rehospitalization at 1 year was significantly lower with transcatheter aortic-valve replacement (TAVR) than with surgical aortic-valve replacement. Longer-term outcomes are unknown. METHODS: We randomly assigned patients with severe, symptomatic aortic stenosis and low surgical risk to undergo either TAVR or surgery. The first primary end point was a composite of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure. The second primary end point was a hierarchical composite that included death, disabling stroke, nondisabling stroke, and the number of rehospitalization days, analyzed with the use of a win ratio analysis. Clinical, echocardiographic, and health-status outcomes were assessed through 5 years. RESULTS: A total of 1000 patients underwent randomization: 503 patients were assigned to undergo TAVR, and 497 to undergo surgery. A component of the first primary end point occurred in 111 of 496 patients in the TAVR group and in 117 of 454 patients in the surgery group (Kaplan-Meier estimates, 22.8% in the TAVR group and 27.2% in the surgery group; difference, -4.3 percentage points; 95% confidence interval [CI], -9.9 to 1.3; P = 0.07). The win ratio for the second primary end point was 1.17 (95% CI, 0.90 to 1.51; P = 0.25). The Kaplan-Meier estimates for the components of the first primary end point were as follows: death, 10.0% in the TAVR group and 8.2% in the surgery group; stroke, 5.8% and 6.4%, respectively; and rehospitalization, 13.7% and 17.4%. The hemodynamic performance of the valve, assessed according to the mean (±SD) valve gradient, was 12.8±6.5 mm Hg in the TAVR group and 11.7±5.6 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group. CONCLUSIONS: Among low-risk patients with severe, symptomatic aortic stenosis who underwent TAVR or surgery, there was no significant between-group difference in the two primary composite outcomes. (Funded by Edwards Lifesciences; PARTNER 3 ClinicalTrials.gov number, NCT02675114.).

-methyladenosine; MEFs, mouse embryo fibroblasts; Mer, mutated estrogen receptor domains; METTL3, methyltransferase like 3; METTL14, methyltransferase like 14; mRFP, monomeric red fluorescent protein; MTORC1, mechanistic target of rapamycin kinase complex 1; NMVCs, neonatal mouse ventricular cardiomyocytes; PCNA, proliferating cell nuclear antigen; PE, phosphatidylethanolamine; PI, propidium iodide; PTMs, post-translational modifications; PVDF, polyvinylidenedifluoride; RIP, RNA-immunoprecipitation; siRNA, small interfering RNA; SQSTM1, sequestosome 1; TFEB, transcription factor EB; TUBA: tublin alpha; WTAP, WT1 associated protein; YTHDF, YTH N6-methyladenosine RNA binding protein.

Nutrition status has an important effect on quality of life and sense of well-being in cancer patients. Malnutrition and weight loss are often contributors to the cause of death in cancer patients.1 Cancer cachexia is a syndrome characterized by progressive, involuntary weight loss. Clinical features include host tissue wasting, anorexia, skeletal muscle atrophy, anergy, fatigue, anemia, and hypoalbuminemia. Causes of cancer cachexia include anorexia, mechanical factors affecting the gastrointestinal tract related to tumor, side effects of surgery, chemotherapy and/or radiation therapy, alterations in intermediary and energy metabolism, and changes in the host cytokine and hormonal milieu. The cancer cachexia syndrome (CCS), which is observed in approximately 50% of cancer patients, involves heterogeneous physiologic and metabolic derangements resulting in potentially life-threatening malnutrition.2 Although often seen in patients with advanced malignancies, CCS may be present in the early stages of tumor growth. Weight loss in cancer patients is of prognostic significance. For any given tumor type, survival is shorter in patients who experience pretreatment weight loss.3-5 Furthermore, CCS is a problematic cause of symptom distress in cancer patients.6,7 Early recognition and intervention to prevent worsening of CCS may afford the best opportunity to prevent its debilitating consequences. Pharmacologic interventions play only a limited role in overcoming the anorexia and metabolic derangements seen in CCS. Research has focused on the use of nutrition support therapy (NST), bypassing oral intake to circumvent CCS related anorexia. Numerous studies, as summarized by Bozetti, have looked at the effect of nutrition support therapy on nutrition parameters in surgical cancer patients.8 Other papers have also examined the use of NST in non-surgical cancer patients.9,10 Parenteral nutrition (PN) consistently causes weight gain, increases body fat, and improves nitrogen balance. The effect of PN on lean body mass is minimal. The effects of enteral nutrition (EN) on body composition are less consistent; EN usually causes weight gain and improves nitrogen balance. Neither EN nor PN, when administered for 7-49 days, have demonstrably beneficial effects on serum proteins. NST has less of an effect on nutrition indices in cancer patients than in non-cancer patients, probably due to the changes that occur in the metabolism of macronutrient substrates in the presence of cancer.8,11 Enthusiasm for the use of NST in cancer patients has historically been tempered by concern that provision of nutrients may stimulate tumor growth and metastasis, as observed in animal studies and cell culture.12 There are few relevant clinical studies.13-17 Most recently, a study of PN in malnourished gastric cancer patients indicated no significant difference in tumor cell proliferation with administration of PN preoperatively.18 Absent any overt effects, it is reasonable to ignore this theoretical consideration when contemplating the use of NST in patients. The purpose of this paper is to examine the literature and develop guidelines only for NST in adult cancer patients (during anticancer treatment and in hematopoietic cell transplantation). Nutrition and cancer prevention or alternative medicine approaches using nutritional supplements in the treatment of cancer is beyond the scope of this paper. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) is an organization comprised of healthcare professionals representing the disciplines of medicine, nursing, pharmacy, dietetics, and nutrition science. The mission of A.S.P.E.N. is to improve patient care by advancing the science and practice of NST. A.S.P.E.N. vigorously works to support quality patient care, education, and research in the fields of nutrition and metabolic support in all healthcare settings. These clinical guidelines were developed under the guidance of the A.S.P.E.N. Board of Directors. Promotion of safe and effective patient care by nutrition support practitioners is a critical role of the A.S.P.E.N. organization. The A.S.P.E.N. Board of Directors has been publishing clinical guidelines since 1986.19-21 Starting in 2007, A.S.P.E.N. has been revising these clinical guidelines on an ongoing basis, reviewing about 20% of the chapters each year in order to keep them as current as possible. These A.S.P.E.N. Clinical Guidelines are based upon general conclusions of health professionals who, in developing such guidelines, have balanced potential benefits to be derived from a particular mode of medical therapy against certain risks inherent with such therapy. However, the professional judgment of the attending health professional is the primary component of quality medical care. Because guidelines cannot account for every variation in circumstances, the practitioners must always exercise professional judgment in their application. These Clinical Guidelines are intended to supplement, but not replace, professional training and judgment. These clinical guidelines were created in accordance with Institute of Medicine recommendations as "systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances."22 These clinical guidelines are for use by healthcare professionals who provide nutrition support services and offer clinical advice for managing adult and pediatric (including adolescent) patients in inpatient and outpatient (ambulatory, home, and specialized care) settings. The utility of the clinical guidelines is attested to by the frequent citation of this document in peer-reviewed publications and their frequent use by A.S.P.E.N. members and other healthcare professionals in clinical practice, academia, research, and industry. They guide professional clinical activities, they are helpful as educational tools, and they influence institutional practices and resource allocation.23 These clinical guidelines are formatted to promote the ability of the end user of the document to understand the strength of the literature used to grade each recommendation. Each guideline recommendation is presented as a clinically applicable statement of care and should help the reader make the best patient care decision. The best available literature was obtained and carefully reviewed. Chapter author(s) completed a thorough literature review using MEDLINE®, the Cochrane Central Registry of Controlled Trials, the Cochrane Database of Systematic Reviews, and other appropriate reference sources. This paper includes older as well as current research related to the use of NST in individuals with cancer. Dates prior to 1990 were not excluded from the analyses, as there are no obvious trends over time to suggest that more modern practice has had an impact on outcome. These results of the literature search and review formed the basis of an evidence-based approach to the clinical guidelines. Chapter editors work with the authors to ensure compliance with the author's directives regarding content and format. Then the initial draft is reviewed internally to ensure consistency with the other A.S.P.E.N. Guidelines and Standards, and externally reviewed (by experts in the field within our organization and/or outside of our organization) for appropriateness of content. The final draft is reviewed and approved by the A.S.P.E.N. Board of Directors. The system used to categorize the level of evidence for each study or article used in the rationale of the guideline statement and to grade the guideline recommendation is outlined in Table 1.24 The grade of a guideline is based on the levels of evidence of the studies used to support the guideline. A randomized controlled trial (RCT), especially one that is double blind in design, is considered to be the strongest level of evidence to support decisions regarding a therapeutic intervention in clinical medicine.25 A systematic review (SR) is a specialized type of literature review that analyzes the results of several RCTs. A high-quality SR usually begins with a clinical question and a protocol that addresses the methodology to answer this question. These methods usually state how the literature is identified and assessed for quality, what data are extracted, how they are analyzed, and whether there were any deviations from the protocol during the course of the study. In most instances, meta-analysis (MA), a mathematical tool to combine data from several sources, is used to analyze the data. However, not all SRs use MA. SR is considered among the most important level of evidence in the field of Evidence-Based Medicine. A level of I, the highest level, will be given to large RCTs where results are clear and the risk of alpha and beta error is low (well-powered). A level of II will be given to RCTs that include a relatively low number of patients or are at moderate-to-high risk for alpha and beta error (under-powered). A level of III is given to cohort studies with contemporaneous controls, while cohort studies with historic controls will receive a level of IV. Case series, uncontrolled studies, and articles based on expert opinion alone will receive a level of V. Table 2 provides the entire set of guidelines recommendations for NST during adult anticancer treatment and in hematopoietic cell transplantation. 1. Patients with cancer are nutritionally-at-risk and should undergo nutrition screening to identify those who require formal nutrition assessment with development of a nutrition care plan. (Grade: D) Rationale: There is clear evidence that nutrition screening with appropriate screening tools will identify cancer patients who are malnourished.26-32 Among the developed screening tools are the patient generated subjective global assessment (PGSGA),27,28 the subjective global assessment (SGA),26,27,30,31 and the nutrition risk index (NRI).30 They all have validated specificity and sensitivity in cancer patients, have been the subjects of prospective clinical trials, and share an emphasis on clinical data. Given the effectiveness of the instruments in detecting malnutrition in cancer patients, it makes sense to utilize these instruments to identify malnutrition and risk of malnutrition. Although there is limited evidence available specifically examining the efficacy of nutrition screening in improving clinical outcomes in cancer patients, the detrimental effects of weight loss on outcomes has been demonstrated.3,33,34 In addition, the benefits of nutrition counseling in cancer patients have been reported.35-38 It seems logical that a formal nutrition screening should be performed in every cancer patient to identify individuals at-risk who require a formal nutrition assessment in an attempt to minimize weight changes and identify individuals who may benefit from further nutrition intervention. Clinical trials are needed to assess the impact of nutrition screening on outcomes in cancer patients. See Table A1. 2. Nutrition support therapy should not be used routinely in patients undergoing major cancer operations. (Grade: A) Rationale: Many studies have investigated the use of NST in patients undergoing major cancer operations, such as resections in the thoracic and abdominal cavities. The use of PN in surgical patients has been studied in prospective, randomized, controlled trials in comparison to standard oral diet (SOD) and EN. Likewise, EN has been examined in relation to SOD. The majority of PN vs SOD41-51 studies find no differences in morbidity41 or mortality,41,48 or even increased morbidity46,47,50 or mortality,42 with the use of PN. Those studies that did indicate benefits from PN tended to include heterogeneous populations43,45 that consisted of both malnourished and well nourished patients. Unfortu nately, some studies reporting benefits also had faulty study designs.44 These studies suggest that PN may be beneficial when used perioperatively in severely malnourished patients; however, PN is not beneficial when used routinely in all patients. Comparisons of PN to EN52-63 also indicate few differences in morbidity53-56,58 or mortality52-54,56 between the modalities. However, EN is favored to preserve gut integrity56,60,64 and immune markers55,57,61,63 and to simplify glycemic management.56,59 Similarly, the majority of studies comparing EN to SOD65-69 indicate no benefit of EN over SOD with respect to morbidity65,66,68,69 and mortality.65,66,68,69 The evidence does not indicate improved outcomes with routine use of NST in all patients undergoing major cancer operations. See Table A2. 3. Perioperative nutrition support therapy may be beneficial in moderately or severely malnourished patients if administered for 7-14 days preoperatively, but the potential benefits of nutrition support must be weighed against the potential risks of the nutrition support therapy itself and of delaying the operation. (Grade: A) Rationale: Studies specifically assessing the use of perioperative NST in moderately or severely malnourished cancer patients, as assessed by the SGA, the PGSGA, or the NRI,41,42,45,46,49,51,52,57 indicate a benefit in morbidity8,45,46,51,52,57 and mortality.8,51,57 These studies began administration of NST 7-14 days preoperatively.46,49,51 See Table A3. 4. Nutrition support therapy should not be used routinely as an adjunct to chemotherapy. (Grade: B) Rationale: Malnutrition can occur in cancer patients starting or receiving chemotherapy as a result of the tumor-induced abnormalities or due to treatment-induced toxicity. Several studies have examined the use of NST during chemotherapy to prevent the development of malnutrition or to mitigate its consequences.64,70-82 When used in this fashion, NST does not reduce chemotherapy-related toxicity70-75,77,78,80,81 and does not improve tumor response70-75,77,78,80,81 or patient survival.70,71,75 All studies were limited by small sample size. Because of an associated increase in the risk of infection with the use of PN in this setting, routine adjunctive use in well-nourished patients receiving chemotherapy is actually deleterious. See Table A4. 5. Nutrition support therapy should not be used routinely in patients undergoing head and neck, abdominal, or pelvic irradiation. (Grade: B) Rationale: Few clinical trials investigating the routine use of NST as an adjunct to radiation therapy in cancer patients have been reported.83-86 One study of upper GI cancer patients indicated less weight loss and fewer treatment interruptions in patients who received EN prior to radiation therapy (XRT).83 Two studies in head and neck cancer patients failed to demonstrate reduced weight loss84; furthermore, worse survival85 was observed in patients who received PN and/or EN before XRT. The role for routine EN, PN, or oral supplement use during head and neck, abdominal, or pelvic irradiation is not clear. The use of NST should be reserved for those patients who are unable to eat as a result of tumor or treatment related side-effects who are becoming progressively malnourished. See Table A5. 6. Nutrition support therapy is appropriate in patients receiving active anticancer treatment who are malnourished and who are anticipated to be unable to ingest and/or absorb adequate nutrients for a prolonged period of time. (Grade: B) Rationale: NST is appropriate in patients receiving active anticancer treatment who are malnourished and who will be unable to absorb adequate nutrients for a prolonged period of time to minimize risk of poor outcomes associated with malnutrition. Seven to fourteen days seems an appropriate definition of "prolonged period of time"; this time period is referred to in many studies, although there are no well designed studies that specifically address this issue. Although no survival benefit with NST intervention has been reported, multiple studies have reported improvements in weight81,83 and nitrogen balance.81,82 The strength of this guideline is tempered by the fact that the best and largest RCT is limited to a head and neck population receiving radiation.85 See Table A6. 7. The palliative use of nutrition support therapy in terminally ill cancer patients is rarely indicated. (Grade: B) Rationale: The palliative use of NST in cancer patients is rarely appropriate, although this issue remains controversial and is emotionally charged. The decision to initiate NST in patients with advanced cancer must include consideration of the patient's and family's wishes, potential risks and benefits, and the patient's estimated survival. The primary objective for initiating NST in advanced cancer patients is to conserve or restore the best possible quality of life and to control any nutrition related symptoms that cause distress.88 There are limited data on the use of PN in palliative care.8,89-96 Although the adverse events caused by PN may actually worsen quality of life and overall palliative care of some patients, home PN may lengthen survival89,92 and improve quality of life in carefully selected patients.90,91,94 Examples of patients who have demonstrated a favorable response to PN include patients with a good performance status, such as Karnofsky score >50, those with inoperable bowel obstruction, those with minimal symptoms from disease involving major organs such as brain, liver, and lungs, and those with indolent disease progression.88,97 If patients are to benefit from this complex, intrusive, and expensive therapy they (1) must be physically and emotionally capable of participating in their own care; (2) should have an estimated life expectancy of >40-60 days; (3) require strong social and financial support at home, including a dedicated in-home lay care provider; and (4) must have failed trials of less invasive medical therapies such as appetite stimulants and enteral feedings.98 Those patients with a life expectancy of <40 days may be palliated with home intravenous fluid therapy, although this is also controversial.88,90,97,99 See Table A7. 8. ω-3 Fatty acid supplementation may help stabilize weight in cancer patients on oral diets experiencing progressive, unintentional weight loss. (Grade: B) Rationale: ω-3 Fatty acids favor production of prostaglandins in the 3-series (PGE3) and leukotrienes in the 5-series (which are associated with improved immunocompetence and reduced inflammatory responses) and reduce levels of the PGE2 and leukotrienes in the 4-series (immunosuppressive and proinflammatory) in comparison with ω-6 fatty acids.100,101ω -3 Fatty acids have been supplemented enterally in pill form102-106 and in liquid nutritional In to the effects of ω-3 fatty acids on and a they also to be effective in in Early studies of ω-3 fatty acids were performed in cancer more studies have looked at other cancer Enteral ω-3 fatty acids to stabilize or the of weight in cancer patients, although this to occur with or no increase in lean body A of 2 of acid This may be administered as available ω-3 liquid nutritional supplements or as ω-3 fatty acid supplements in most Because these supplements are not by health the of this intervention should be See Table Patients should not use therapeutic diets to cancer. (Grade: enteral of and fatty acids may be beneficial in malnourished patients undergoing major cancer operations. (Grade: A) Rationale: of specific for effects beyond their nutrition role may be referred to as nutritional nutrients especially have been the of and fatty Clinical trials nutritional interventions in perioperative cancer patients using an enteral a of substrates including and ω-3 fatty have reported improved immune and clinical the of these studies the ability to the best for of immune EN. The on Enteral recommendations regarding the use of these in surgical It was that individuals undergoing gastrointestinal or major head and neck in there is malnutrition benefit from days studies have examined supplementation with The data on the use of or are limited at this time to make recommendations on the use of these However, based on the studies of use of and ω-3 fatty acids with clinical EN supplemented with these nutrients may be beneficial in malnourished patients undergoing major cancer operations. See Table cell to an of therapies and outcomes are by disease type related of vs cell prior therapy, and nutrition involves chemotherapy with or irradiation to tumor in patients with with of with In the patient's own immune system is to prevent are among the most therapies used in may be used to a with of host tract or are always the for these The of the to the development of during the period of that may as as a result of and effects of patients experience a prolonged period of minimal oral This may well beyond the of cell to the effects of therapy on gastric and 1. All patients undergoing hematopoietic cell with are at nutrition risk and should undergo nutrition screening to identify those who require formal nutrition assessment with development of a nutrition care plan. (Grade: D) Rationale: patients are to developing malnutrition of their the and other in and has been reported in malnourished patients receiving in nutrition status with as many of 50% of patients not to weight at Although evidence the clinical impact of nutrition in patients is appropriate screening of patients should minimize risk of the detrimental effects of weight loss in patients with cancer including those undergoing Clinical trials are needed to assess the impact of nutrition screening on outcomes in cancer patients. See Table 2. Nutrition support therapy is appropriate in patients undergoing hematopoietic cell who are malnourished and who are anticipated to be unable to ingest and/or absorb adequate nutrients for a prolonged period of time for prolonged period of When nutrition is it should be as as have cell (Grade: B) Rationale: NST is appropriate in patients undergoing who are malnourished and who will be unable to absorb adequate nutrients for a prolonged period of time to minimize risk of poor outcomes associated with malnutrition. Seven to days seems an appropriate definition prolonged period of time"; this time period is referred to in many studies, although there are no well designed studies that specifically address this issue. the effect of PN and EN in patients is of patient and treatment The risks and benefits of using PN in have been assessed comparing PN vs or vs PN vs intravenous Studies of PN vs SOD or EN demonstrate increased more more and time to but less weight and less loss of body with PN. There to be no differences in or of of PN to indicate of oral intake with but no difference in A study of and reported a effect of PN on to those who received in patients who received but not There was no difference in between however, the patients had of which with PN. These results have not been The effects of PN composition on has been results indicate no benefit to use of There may be a in the of with the use of PN of from to a of from If PN is used in it should be cell when adequate EN or oral intake is See Table 3. Enteral nutrition should be used in patients with a gastrointestinal tract in oral intake is to nutrition (Grade: Rationale: of EN has been Studies have small of patients receiving enteral or oral intake to PN alone or in of EN or PN, which makes of clinical outcomes In less and less as have been reported in patients receiving The effect on time to is not EN may also be associated with a risk of The of safe enteral are to the risk of and/or abdominal gastric and However, safe enteral has been reported in patients during the and have and gastrointestinal have EN is safe as a from PN to oral diet or when NST is indicated for such as See Table 4. Pharmacologic of may benefit patients undergoing hematopoietic cell (Grade: is not available by the and but as a by a in the on the of in Rationale: The of both and supplementation in have been Studies assessing the impact of enterally administered indicate no in or administered is associated with improved nitrogen shorter of and One study of PN vs PN a in oral intake indicated that patients who received had a shorter with no impact on or overall The results indicated a of in patients receiving These results were not seen with supplemented A Cochrane review that in PN may not be associated with reduced of but a benefit of fewer remains by a of available intravenous research is needed to appropriate and See Table 5. Patients should receive counseling regarding which may risks and safe during the period of (Grade: Rationale: Although the effect of or diets on risk of infection is patients should associated with an increased Several studies have examined the role of diet and risk in with other interventions such as and It is to make between these the were not One study a reduced of infection in patients who received a however, a study indicated no A by that of of Cancer low There were in the cell and used to of low A more small RCT that diet to the guidelines indicated no benefit of the diet in pediatric patients receiving This was also seen in a study of and diets in patients undergoing therapy for there is a for more systematic research on this this is it seems to to provide on during the period of while to the of in these patients. See Table 6. Nutrition support therapy is appropriate for patients undergoing hematopoietic cell who develop to disease by poor oral intake and/or significant (Grade: Rationale: data are available on the impact of NST on the of PN does not to the of in individuals undergoing In PN has been associated with an increased of of to with increased intake in patients or oral nutrition can Although there are no data on the impact of NST on the of it seems logical that NST should be used to nutrition status during prolonged nutrition resulting from See Table

The well-being of healthcare providers and the influence of healthcare provider mental health and wellness on patient safety have garnered national interest and attention, though the concept of burnout among healthcare professionals is not new.1,2 Healthcare, as an industry, places numerous pressures on healthcare providers, including the challenges of clinical work, time constraints, competing demands, lack of control over work processes and scheduling, and conflicting roles and relationships with leadership.2 Burnout syndrome is increasingly recognized among healthcare professionals, with the Agency for Healthcare Research and Quality estimating that burnout may affect 10–70% of nurses and 30–50% of physicians, nurse practitioners, and physician assistants.2 Pharmacists’ job satisfaction may vary according to practice setting, with community pharmacists likely experiencing lower job satisfaction and, consequently, higher rates of burnout, compared with pharmacists practicing in other settings.3,4 Results of the 2016 Pharmacist Salary Survey, which examined the views of 3,085 pharmacists practicing in a variety of settings across the United States, revealed that 72.5% of pharmacists are satisfied with their jobs, with 63.4% of respondents reporting increased job stress over the previous year.5

CONTEXT: Although studies have documented cognitive impairment in children who were born small for gestational age (SGA), other studies have not demonstrated differences in IQ or other cognitive scores. The need exists for long-term studies of such children to assess functional outcomes not measurable with standardized testing. OBJECTIVE: To determine the long-term functional outcome of SGA infants. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 14,189 full-term infants born in the United Kingdom on April 5 through 11, 1970, were studied as part of the 1970 British Birth Cohort; 1064 were SGA (birth weight less than the fifth percentile for age at term). Follow-up at 5, 10, 16, and 26 years was 93%, 80%, 72%, and 53%, respectively. MAIN OUTCOME MEASURES: School performance and achievement, assessed at 5, 10, and 16 years; and years of education, occupational status, income, marital status, life satisfaction, disability, and height, assessed at 26 years, comparing persons born SGA with those who were not. RESULTS: At 5, 10, and 16 years of age, those born SGA demonstrated small but significant deficits in academic achievement. In addition, teachers were less likely to rate those born SGA in the top 15th percentile of the class at 16 years (13% vs 20%; P<.01) and more likely to recommend special education (4.9% vs 2.3%; P<.01) compared with those born at normal birth weight (NBW). At age 26 years, adults who were SGA did not demonstrate any differences in years of education, employment, hours of work per week, marital status, or satisfaction with life. However, adults who were SGA were less likely to have professional or managerial jobs (8.7% vs 16.4%; P<.01) and reported significantly lower levels of weekly income (mean [SD], 185 [91] vs 206 [102] pound sterling; P<.01) than adults who were NBW. Adults who were SGA also reported significant height deficits compared with those who were NBW (mean [SD] z score, -0.55 [0.98] vs 0.08 [1.02]; P<.001). Similar results were also obtained after adjusting for social class, sex, region of birth, and the presence of fetal or neonatal distress. CONCLUSIONS: In this cohort, adults who were born SGA had significant differences in academic achievement and professional attainment compared with adults who were NBW. However, there were no long-term social or emotional consequences of being SGA: these adults were as likely to be employed, married, and satisfied with life.

BACKGROUND AND PURPOSE: Early treatment is a critical determinant of successful intervention in acute stroke. The study was designed to find current patterns of stroke care by determining delays in time from onset of signs or symptoms to arrival at the emergency department and to initial evaluation by physicians and by identifying factors associated with these delays. METHODS: Data were prospectively collected by nurses and physicians from patients, patients' family members, and medical records from 10 hospitals of the Robert Wood Johnson Health System in New Jersey. RESULTS: A total of 553 patients who presented with signs or symptoms of acute stroke were studied. Thirty-two percent of patients arrived at the emergency department within 1.5 hours of stroke onset. Forty-six percent of patients arrived within 3 hours and 61% within 6 hours. Delays in arrival time were significantly associated with sex, race, transportation mode, and history of cardiovascular disease. Patients arriving by ambulance were more likely to present earlier (odds ratio [OR] 3.7 for arrival within 3 hours; OR 4.5 for arrival within 6 hours). Patients arriving by ambulance (OR 2.3 within 15 minutes; OR 1.7 within 30 minutes) and those requiring admission to intensive care units (OR 4.5 within 15 minutes and OR 5.2 within 30 minutes) were examined sooner by physicians. CONCLUSIONS: Despite national efforts to promote prompt stroke evaluation and treatment, significant delays still exist. The lack of improvement throughout the past decade underscores the need for implementation of effective public health programs designed to minimize the time to evaluation and treatment of stroke.

MicroRNAs are predicted to regulate approximately 30% of all human genes by targeting sequences in their 3' UTR. Polymorphisms in 3' UTR of several genes have been reported to affect gene expression, but the mechanism is not fully understood. Here, we demonstrate that 829C-->T, a naturally occurring SNP, near the miR-24 binding site in the 3' UTR of human dihydrofolate reductase (DHFR) affects DHFR expression by interfering with miR-24 function, resulting in DHFR overexpression and methotrexate resistance. miR-24 has a conserved binding site in DHFR 3' UTR. DHFR with WT and 3' UTR containing the 829C-->T mutation were expressed in DG44 cells that lack DHFR. Overexpression of miR-24 in cells with WT DHFR resulted in down-regulation of DHFR protein, whereas no effect on DHFR protein expression was observed in the mutant 3' UTR-expressing cells. Inhibition of endogenous miR-24 with a specific inhibitor led to up-regulation of DHFR in WT and not in mutant cells. Cells with the mutant 3' UTR had a 2-fold increase in DHFR mRNA half-life, expressed higher DHFR mRNA and DHFR protein, and were 4-fold more resistant to methotrexate as compared with WT cells. SNP-829C-->T, therefore, leads to a decrease in microRNA binding leading to overexpression of its target and results in resistance to methotrexate. We demonstrate that a naturally occurring miRSNP (a SNP located at or near a microRNA binding site in 3' UTR of the target gene or in a microRNA) is associated with enzyme overproduction and drug resistance.

OBJECTIVE: To evaluate outcomes and predictors of neonatal survival in pregnancies complicated by vasa previa and to compare outcomes in prenatally diagnosed cases of vasa previa with those not diagnosed prenatally. METHODS: We performed a multicenter study of 155 pregnancies complicated by vasa previa. Cases were obtained from the Vasa Previa Foundation and 6 large hospitals. Comparisons were made between groups based on prenatal diagnosis status and neonatal survival. RESULTS: The overall perinatal mortality was 36% (55 of 155). In 61 cases (39%), vasa previa was diagnosed prenatally; 59 of 61 (97%) infants from these pregnancies survived compared with 41 of 94 (44%) in cases not diagnosed prenatally (P <.001). Median 1- and 5-minute Apgar scores in cases diagnosed prenatally were 8 and 9, respectively, compared with 1 and 4 among survivors in cases not diagnosed prenatally (P <.001). More than half (24 of 41) of surviving neonates born to women without prenatal diagnosis required blood transfusions compared with 2 of 59 diagnosed prenatally (P <.001). Multivariable logistic regression analysis showed that the only significant predictors of neonatal survival were prenatal diagnosis (P <.001) and gestational age at delivery (P =.01). CONCLUSIONS: Good outcomes with vasa previa depend primarily on prenatal diagnosis and cesarean delivery at 35 weeks of gestation or earlier should rupture of membranes, labor, or significant bleeding occur.

The strength, resorption rate, and biocompatibility of collagenous biomaterials are profoundly influenced by the method and extent of crosslinking. We compared the effects of two physical crosslinking methods, ultraviolet irradiation (UV) (254 nm) and dehydrothermal (DHT) treatment, on the mechanical properties and molecular integrity of collagen fibers extruded from an acidic dispersion of type I bovine dermal collagen. Collagen fibers exposed to UV irradiation for 15 min had ultimate tensile strength (54 MPa) and modulus (184 MPa) values greater than or equivalent to values for fibers crosslinked with DHT treatment for 3 or 5 days. UV irradiation is a rapid and easily controlled means of increasing the mechanical strength of collagen fibers. Characterization of collagen extracted from the crosslinked samples by dilute acetic acid and limited pepsin digestion indicate that both UV and DHT treatments cause fragmentation of at least a portion of the collagen molecules. Partial loss of the native collagen structure may influence attachment migration, and proliferation of cells on collagen fiberbased ligament analogs. These issues are currently being addressed in our laboratory.

Background: Remarkable progress has been made during the last decade in defining the molecular mechanisms that underlie septic shock. This rapidly expanding field is leading to new therapeutic opportunities in the management of severe sepsis. Aim: To provide the clinician with a timely summary of the molecular biology of sepsis and to better understand recent advances in sepsis research. Data Selection: Medline search of relevant publications in basic mechanisms of sepsis/severe sepsis/septic shock, and selected literature review of other manuscripts about the signalosome, inflammasome, apoptosis, or mechanisms of shock. Data Synthesis and Findings: The identification of the toll-like receptors and the associated concept of innate immunity based upon pathogen- or damage-associated molecular pattern molecules allowed significant advances in our understanding of the pathophysiology of sepsis. The essential elements of the inflammasome and signal transduction networks responsible for activation of the host response have now been characterized. Apoptosis, mitochondrial dysfunction, sepsis-related immunosuppression, late mediators of systemic inflammation, control mechanisms for coagulation, and reprogramming of immune response genes all have critical roles in the development of sepsis. Conclusions: Many of these basic discoveries have direct implications for the clinical management of sepsis. The translation of these “bench-to-bedside” findings into new therapeutic strategies is already underway. This brief review provides the clinician with a primer into the basic mechanisms responsible for the molecular biology of sepsis, severe sepsis, and septic shock.

Although it has been widely appreciated for many years among physicians and microbiologists that blood cultures are among the most important laboratory tests performed in the diagnosis of serious infections (35), it has become equally apparent in more recent years that contaminated blood cultures are common (25, 42), enormously costly (3, 29), and frequently confusing for clinicians (1, 12, 14, 26). Clinical studies of bloodstream infections over 3 decades have provided guidelines for differentiating true pathogens from contaminants or organisms of unknown significance (14, 18, 41, 42); however, a true “gold standard” for differentiating pathogens from contaminants does not exist (4, 25). Moreover, the most common blood culture contaminants, coagulase-negative staphylococci (CoNS), which were almost always such several decades ago (18, 41), now are pathogens more frequently (19, 25, 26, 42), and judging the clinical significance of this group of microorganisms in blood has proven to be especially problematic (1, 11, 22, 24, 26, 42; S. J. Peacock, I. C. Bowler, and D. W. Crook., Letter, Lancet 346:191-192, 1995). This review focuses on how pathogen-contaminant decisions are made, the phenomenon of increasing contamination of blood cultures, potential methods for addressing high contamination rates, and practical laboratory approaches to the workup of likely contaminants.

The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood. Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months. Histological response, inflammatory gene expression, and cellular infiltration in psoriasis plaques were evaluated. There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes. The observed decreases in IL-8, IFN-gamma-inducible protein-10 (CXCL10), and MIP-3alpha (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively. DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein. Decreases in T cell-inflammatory gene expression (IFN-gamma, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation. Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes. This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques.

Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Although the mechanisms by which perturbation of microtubule function leads to selective death of cancer cells remain unclear, several new microtubule-targeting compounds are undergoing clinical testing. In part, these efforts focus on overcoming some of the problems associated with taxane-based therapies, including formulation and administration difficulties and susceptibility to resistance conferred by P-glycoprotein. Epothilones have emerged from these efforts as a promising new class of anticancer drugs. Preclinical studies indicate that epothilones bind to and stabilize microtubules in a manner similar but not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor models. Clinical phase I and early phase II data are available for BMS-247550, BMS-310705, EPO906, and KOS-862. The results suggest that these compounds have a broad range of antitumor activity at doses and schedules associated with tolerable side effects.

BACKGROUND: There is little systematically derived evidence-based guidance to inform plasma transfusion decisions. To address this issue, the AABB commissioned the development of clinical practice guidelines to help direct appropriate transfusion of plasma. STUDY DESIGN AND METHODS: A systematic review (SR) and meta-analysis of randomized and observational studies was performed to quantify known benefits and harms of plasma transfusion in common clinical scenarios (see accompanying article). A multidisciplinary guidelines panel then used the SR and the GRADE methodology to develop evidence-based plasma transfusion guidelines as well as identify areas for future investigation. RESULTS: Based on evidence ranging primarily from moderate to very low in quality, the panel developed the following guidelines: 1) The panel suggested that plasma be transfused to patients requiring massive transfusion. However, 2) the panel could not recommend for or against transfusion of plasma at a plasma : red blood cell ratio of 1:3 or more during massive transfusion, 3) nor could the panel recommend for or against transfusion of plasma to patients undergoing surgery in the absence of massive transfusion. 4) The panel suggested that plasma be transfused in patients with warfarin therapy-related intracranial hemorrhage, 5) but could not recommend for or against transfusion of plasma to reverse warfarin anticoagulation in patients without intracranial hemorrhage. 6) The panel suggested against plasma transfusion for other selected groups of patients. CONCLUSION: We have systematically developed evidence-based guidance to inform plasma transfusion decisions in common clinical scenarios. Data from additional randomized studies will be required to establish more comprehensive and definitive guidelines for plasma transfusion.

BACKGROUND AND PURPOSE: Statin therapy decreases the risk of ischemic stroke. An increased risk of intracerebral hemorrhage (ICH) has been observed in some studies. To investigate this issue, we performed a meta-analysis of randomized controlled trials using statins that reported ICH. METHODS: We performed a literature search of Medline, Web of Science, and The Cochrane Library through January 25, 2012, and identified additional randomized controlled trials by reviewing reference lists of retrieved studies and prior meta-analyses. All randomized controlled trials of statin therapy that reported ICH or hemorrhagic stroke were included. The primary outcome variable was ICH. Thirty-one randomized controlled trials were included. All analyses used random effects models and heterogeneity was not observed in any of the analyses. RESULTS: A total of 91,588 subjects were included in the active group and 91,215 in the control group. There was no significant difference in incidence of ICH observed in the active treatment group versus control (OR, 1.08; 95% CI, 0.88-1.32; P=0.47). ICH risk was not related to the degree of low-density lipoprotein reduction or achieved low-density lipoprotein cholesterol. Total stroke (OR, 0.84; 95% CI, 0.78-0.91; P<0.0001) and all-cause mortality (OR, 0.92; CI, 0.87-0.96; P=0.0007) were significantly reduced in the active therapy group. There was no evidence of publication bias. CONCLUSIONS: Active statin therapy was not associated with significant increase in ICH in this meta-analysis of 31 randomized controlled trials of statin therapy. A significant reduction in all stroke and all-cause mortality was observed with statin therapy.

BACKGROUND: A profound difference between cancer and normal tissues is the preferential utilization of glycolysis by cancer cells. To translate this paradigm in the clinic, we completed a phase I study of 2-deoxyglucose (2DG), and assessed 2DG uptake with fluorodeoxyglucose (FDG) positron emission tomography (PET) and the autophagy substrate p62 as a marker of 2DG resistance. METHODS: Patients received 2DG orally on days 1-14 of a 21-day cycle in cohorts of three in a dose-escalating manner. Correlative assessments included PET scans at baseline and day 2 and p62 protein in peripheral blood mononuclear cells as a potential marker of 2DG resistance. RESULTS: The dose of 45 mg/kg was defined as the recommended phase II dose, secondary to dose-limiting toxicity of grade 3 asymptomatic QTc prolongation at a dose of 60 mg/kg. PK evaluation of 2DG revealed linear pharmacokinetics with C(max) 45 microg/ml (277 microM), 73.7 microg/ml (449 microM), and 122 microg/ml (744 microM) in dose levels 30, 45, and 60 mg/kg, respectively. Five of eight patients assessed with FDG-PET scanning demonstrated decreased FDG uptake by day 2 of therapy, suggesting competition of 2DG with FDG. Five of six patients assessed for p62 had a decrease in p62 at 24 hr. CONCLUSIONS: These data support the safety of 2DG, defined 2DG PK, demonstrated the effect of 2DG on FDG-PET imaging, and demonstrated the feasibility of assessment of p62 as an autophagic resistance marker. These data support future studies of 2DG alone or in combination with approaches to abrogate autophagy.

In a double-blind randomized crossover trial, oxycodone or placebo was given in divided night-time doses to 11 patients with idiopathic restless legs syndrome (RLS) for 2 weeks prior to appropriate polysomnographic studies. Under double-blinded conditions, patients were asked to do daily ratings of their leg sensations, motor restlessness and daytime alertness on a 1-4 scale for the 2 weeks prior to the polysomnographic studies and for the nights of the polysomnographic studies as well. Leg sensations (p < 0.009), motor restlessness (p < 0.006) and daytime alertness (p < 0.03) were significantly improved on oxycodone as compared to baseline or placebo. Patients were studied polysomnographically under double-blinded conditions for 2 nights in each phase of the protocol. On an average dose of 15.9 mg oxycodone (equivalent to approximately three 5-mg tablets of commercial preparation), there was a statistically significant reduction in the number of periodic limb movements in sleep [(PLMS)/hour sleep (p < 0.004)] and in the number of arousals/hour sleep (p < 0.009) on drugs as compared to baseline or placebo. A statistically significant improvement was also noted in sleep efficiency (p < 0.006) and 10 of the 11 patients preferred oxycodone over placebo. We conclude that oxycodone is an effective treatment for RLS and PLMS.