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Background: During World War II (WWII), the Manhattan Engineering District established a secret laboratory in the mountains of northern New Mexico. The mission was to design, construct and test the first atomic weapon, nicknamed 'The Gadget' that was detonated at the TRINITY site in Alamogordo, NM. After WWII, nuclear weapons research continued, and the laboratory became the Los Alamos National Laboratory (LANL)., Materials and Methods: The mortality experience of 26,328 workers first employed between 1943 and 1980 at LANL was determined through 2017. Included were 6157 contract workers employed by the ZIA Company. Organ dose estimates for each worker considered all sources of exposure, notably photons, neutrons, tritium, 238 Pu and 239 Pu. Vital status determination included searches within the National Death Index, Social Security Administration and New Mexico State Mortality Files. Standardized Mortality Ratios (SMR) and Cox regression models were used in the analyses., Results: Most workers (55%) were hired before 1960, 38% had a college degree, 25% were female, 81% white, 13% Hispanic and 60% had died. Vital status was complete, with only 0.1% lost to follow-up. The mean dose to the lung for the 17,053 workers monitored for radiation was 28.6 weighted-mGy (maximum 16.8 weighted-Gy) assuming a Dose Weighting Factor of 20 for alpha particle dose to lung. The Excess Relative Risk (ERR) at 100 weighted-mGy was 0.01 (95%CI -0.02, 0.03; n  = 839) for lung cancer. The ERR at 100 mGy was -0.43 (95%CI -1.11, 0.24; n  = 160) for leukemia other than chronic lymphocytic leukemia (CLL), -0.06 (95%CI -0.16, 0.04; n  = 3043) for ischemic heart disease (IHD), and 0.29 (95%CI 0.02, 0.55; n  = 106) for esophageal cancer. Among the 6499 workers with measurable intakes of plutonium, an increase in bone cancer (SMR 2.44; 95%CI 0.98, 5.03; n  = 7) was related to dose. The SMR for berylliosis was significantly high, based on 4 deaths. SMRs for Hispanic workers were significantly high for cancers of the stomach and liver, cirrhosis of the liver, nonmalignant kidney disease and diabetes, but the excesses were not related to radiation dose., Conclusions: There was little evidence that radiation increased the risk of lung cancer or leukemia. Esophageal cancer was associated with radiation, and plutonium intakes were linked to an increase of bone cancer. IHD was not associated with radiation dose. More precise evaluations will await the pooled analysis of workers with similar exposures such as at Rocky Flats, Savannah River and Hanford.

Purpose: To present the methodology used to determine vital status and obtain cause of death (COD) within the Million Person Study of Low-Dose Health Effects (MPS). Data sources and vital status tracing techniques used to obtain vital status and COD for six (n = 424,238 subjects) of the ∼20+ cohorts under study are described., Methods and Materials: A multistage approach using multiple sources of vital status information was used to determine vital status (or 'trace') study participants from as early as 1940 to the present. Mortality records from state departments of vital statistics and the Social Security Administration Death Master File (SSA-DMF) were matched to study participants by Social Security Number (SSN), full name, date of birth (DOB), and/or sex using deterministic and probabilistic algorithms. The National Death Index (NDI) and SSA Service for Epidemiological Researchers (SSA-SER) were used to obtain COD (after 1978) and verification of alive status, respectively. Online public records and ancestry services, death certificates, and specialized mortality sources were also utilized., Results: For the MPS cohorts traced to date (nuclear power plant workers, industrial radiographers, atomic veterans, and workers at Rocketdyne/Atomics International, Mound nuclear facility, and Mallinckrodt Chemical Works), vital status was confirmed for over 90% of all study subjects in all but one cohort (88%). The ascertainment of COD was over 96% for all cohorts., Conclusions: A hallmark of a high-quality epidemiologic cohort mortality study is a low percentage of subjects with unknown vital status and a low percentage of deaths without a COD. The sources and methods used for vital status tracing and COD determination for the MPS have been successful and should be useful for other investigators tracing large, historic study populations. Some of the approaches would be applicable for use in all cohort studies using regional-specific mortality data or modifications to the approach.

Objective: Fetal surgery for myelomeningocele has become an established treatment that offers less risk of requiring a ventricular shunt and improved functional outcomes for patients. An increasing body of literature has suggested that social determinants of health have a profound influence on health outcomes. The authors sought to determine the socioeconomic and racial and ethnic backgrounds of patients who were treated with fetal surgery versus those who underwent postnatal repair., Methods: Demographic data, the method of myelomeningocele repair, insurance status, and zip code data for patients entered into the National Spina Bifida Patient Registry (NSBPR) from Children's Wisconsin were collected. The zip code was used to determine the Distressed Communities Index (DCI) score, a composite socioeconomic ranking with scores ranging from 0 (no distress) to 100 (severe distress). The zip code was also used to determine the median household income for each patient based on the US Census Bureau 2013-2017 American Community Survey 5-year estimates., Results: A total of 205 patients were identified with zip code and insurance data. There were 23 patients in the fetal surgery group and 182 patients in the postnatal surgery group. All patients were born between 2000 and 2019. Patients in the fetal surgery group were more likely to have commercial insurance (100% vs 52.2%, p < 0.001). Fetal surgery patients were also more likely to be non-Hispanic White (95.7% vs 68.7%, p = 0.058), just missing the level of statistical significance. Patients who underwent fetal surgery tended to reside in zip codes with a higher median household income (mean $66,507 vs $59,133, p = 0.122) and less-distressed communities (mean DCI score 31.3 vs 38.5, p = 0.289); however, these differences did not reach statistical significance., Conclusions: Patients treated with fetal surgery were more likely to have commercial insurance and have a non-Hispanic White racial and ethnic background. The preliminary data suggest that socioeconomic and racial and ethnic disparities may exist regarding access to fetal surgery, and investigation of a larger population of spina bifida patients is warranted.

Background: Multi-cancer early detection (MCED) next-generation-sequencing blood tests represent a potential paradigm shift in screening., Methods: We estimated the impact of screening in the US and UK. We used country-specific parameters for uptake, and test-specific sensitivity and false-positive rates for current screening: breast, colorectal, cervical and lung (US only) cancers. For the MCED test, we used cancer-specific sensitivities by stage. Outcomes included the true-positive:false-positive (TP:FP) ratio; and the cost of diagnostic investigations among screen positives, per cancer detected (Diag cost ). Outcomes were estimated for recommended screening only, and then when giving the MCED test to anyone without cancer detected by current screening plus similarly aged adults ineligible for recommended screening., Results: In the US, current screening detects an estimated 189,498 breast, cervical, colorectal and lung cancers. An MCED test with 25-100% uptake detects an additional 105,526-422,105 cancers (multiple types). The estimated TP:FP (Diag cost ) was 1.43 ($89,042) with current screening but only 1:1.8 ($7060) using an MCED test. For the UK the corresponding estimates were 1:18 (£10,452) for current screening, and 1:1.6 (£2175) using an MCED test., Conclusions: Adding an MCED blood test to recommended screening can potentially be an efficient strategy. Ongoing randomised studies are required for full efficacy and cost-effectiveness evaluations., (© 2021. The Author(s).)

Background: Establishing energy requirements in infants and young children is important in developing age-appropriate diet recommendations but most published guidelines for energy requirements have 1 or more limitations related to the data underlying the calculations., Objective: To develop a comprehensive set of daily energy requirements for infants and young children aged 0-24 mo meeting the ideals of worldwide applicability to all healthy children based on the use of the doubly labeled water (DLW) technique to measure total energy expenditure (TEE), the use of recent, international growth charts, and calculation of values across a wide range of body weight., Methods: Daily estimated energy requirements (EERs) were calculated in 1-mo increments from 0 to 24 mo for boys, girls, and combined, using as inputs the following: 1 ) TEE measured using the DLW technique, 2 ) energy deposition estimates from the Institute of Medicine, and 3 ) body weight values from the 25th to 75th percentiles from the 2006 WHO growth charts. EERs were combined for age groups 0 to <6, 6-8, 9-11, and 12-24 mo by averaging EERs from individual months. The EER calculations were supported by a systematic literature review and a meta-regression of existing studies., Results: Energy requirements naturally increase with age and are slightly higher in boys than in girls. The EERs derived in this study are similar to those in other recent international efforts., Conclusions: This updated set of EERs for infants and young children expand and improve upon the methodology used to establish previous published guidelines. These estimates have multiple potential uses including planning age-appropriate menus for the complementary feeding period, the development of foods that are more precisely targeted to the needs of infants and children at particular ages, and establishing macronutrient requirements within specific age groups based on a percentage of energy, such as dietary fat., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Obesity is highly prevalent and associated with several adverse outcomes including health-related quality-of-life (HRQoL), work productivity, and activity impairment. The objective of this study is to examine group differences in HRQoL and labor-related health outcomes among participants in the OPTIWIN program, which compared the effectiveness of two intensive behavioral weight loss interventions. Participants ( n = 273) were randomized to OPTIFAST ® (OP) or food-based (FB) dietary interventions for 52 weeks. HRQoL and labor-related health outcomes were measured at baseline, week 26, and week 52, using two questionnaires. At baseline, there were no differences between groups on the Impact of Weight on Quality-of-Life Questionnaire (IWQOL-Lite). At week 26, the OP group had statistically significant differences towards better HRQoL for Physical Function, Self-Esteem, and the total score compared with the FB group. At week 52, the OP group showed better HRQoL in the total score ( p = 0.0012) and in all but one domain. Moreover, the adjusted change-from-baseline normalized total score at week 52 was -5.9 points ( p = 0.0001). Finally, the mean IWQOL-Lite normalized score showed that HRQoL improves by 0.4442 units ( p < 0.0001) per kg lost, and that greater weight reduction was positively associated with better HRQoL. No statistically significant group differences were found with the Work Productivity and Activity Impairment (General Health) (WPAI-GH) Questionnaire. HRQoL improves with highly intensive, well-structured weight loss interventions. Greater weight loss lead to larger improvements. The lack of negative effect on productivity and activity suggests that these interventions may be compatible with an active work lifestyle.

Studies of bullying among youth usually focus on those who are bullied. Understanding the factors that affect youth who exhibit bullying behaviors is equally important. Such knowledge can heighten effectiveness of prevention and interventions at the individual, family, school, and community levels. We performed a secondary data analysis using data from the 2009 to 2010 World Health Organization's (WHO's) Health Behavior in School-Aged Children cross-sectional survey ( n  = 12,642), the most recent WHO data collected in the USA. Using latent class analysis, we clustered sample participants into categories of children who do not bully, bully with a low cyberbullying element, bully with a moderate cyberbullying element, and bully with a high cyberbullying element. We used multinomial logistic regression to explore the relationships between youth's perception of certain family characteristics (e.g., parental emotional support and socio-demographic characteristics) and the odds ratios of falling into one of the four latent classes generated. Establishing if a relationship exists between youth's perception of parental support factors and their bullying behavior can enhance understanding of variables that might modify adolescents' bullying. Findings of this study point to the importance of parental emotional support as a factor that can affect adolescent cyberbullying behavior. This evidence is useful for parents, education and healthcare professionals, and others involved in young people's lives., (© Springer Nature Switzerland AG 2020.)

The purpose of this analysis was to develop and validate computable phenotypes for heart failure (HF) with preserved ejection fraction (HFpEF) using claims-type measures using the Rochester Epidemiology Project. This retrospective study utilized an existing cohort of Olmsted County, Minnesota residents aged ≥ 20 years diagnosed with HF between 2007 and 2015. The gold standard definition of HFpEF included meeting the validated Framingham criteria for HF and having an LVEF ≥ 50%. Computable phenotypes of claims-type data elements (including ICD-9/ICD-10 diagnostic codes and lab test codes) both individually and in combinations were assessed via sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with respect to the gold standard. In the Framingham-validated cohort, 2,035 patients had HF; 1,172 (58%) had HFpEF. One in-patient or two out-patient diagnosis codes of ICD-9 428.3X or ICD-10 I50.3X had 46% sensitivity, 88% specificity, 84% PPV, and 54% NPV. The addition of a BNP/NT-proBNP test code reduced sensitivity to 35% while increasing specificity to 91% (PPV = 84%, NPV = 51%). Broadening the diagnostic codes to ICD-9 428.0, 428.3X, and 428.9/ICD-10 I50.3X and I50.9 increased sensitivity at the expense of decreasing specificity (diagnostic code-only model: 87% sensitivity, 8% specificity, 56% PPV, 30% NPV; diagnostic code and BNP lab code model: 61% sensitivity, 43% specificity, 60% PPV, 45% NPV). In an analysis conducted to mimic real-world use of the computable phenotypes, any one in-patient or out-patient code of ICD-9 428/ICD-10 150 among the broader population (N = 3,755) resulted in lower PPV values compared with the Framingham cohort. However, one in-patient or two out-patient instances of ICD-9 428.0, 428.9, or 428.3X/ICD-10 150.3X or 150.9 brought the PPV values from the two cohorts closer together. While some misclassification remains, the computable phenotypes defined here may be used in claims databases to identify HFpEF patients and to gain a greater understanding of the characteristics of patients with HFpEF., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Objectives: Therapeutic hypothermia is an effective neuroprotective intervention for infants with moderate or severe hypoxic-ischemic encephalopathy (HIE). With the introduction of new medical therapy comes a learning curve with regards to its proper implementation and understanding of eligibility guidelines. We hypothesized that variation in patient selection and lack of adherence to established protocols contributed to the utilization drift away from the original eligibility guidelines., Methods: A retrospective cohort study was conducted including infants who received therapeutic hypothermia in the neonatal intensive care unit (NICU) for HIE to determine utilization drift. We then used QI methodology to address gaps in medical documentation that may lead to the conclusion that therapeutic hypothermia was inappropriately applied., Results: We identified 54% of infants who received therapeutic hypothermia who did not meet the clinical, physiologic, and neurologic examination criteria for this intervention based on provider admission and discharge documentation within the electronic medical record (EMR). Review of the charts identified incomplete documentation in 71% of cases and led to the following interventions: 1) implementation of EMR smartphrases; 2) engagement of key stakeholders and education of faculty, residents, and neonatal nurse practitioners; and 3) performance measurement and sharing of data. We were able to improve both adherence to the therapeutic hypothermia guidelines and achieve 100% documentation of the modified Sarnat score., Conclusions: Incomplete documentation can lead to the assumption that therapeutic hypothermia was inappropriately applied when reviewing a patient's EMR. However, in actual clinical practice physicians follow the clinical guidelines but are not documenting their medical decision making completely. QI methodology addresses this gap in documentation, which will help determine the true utilization drift of therapeutic hypothermia in future studies., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: For every weight loss treatment, there are usually groups of people who lose less than expected. This study sought to determine if response rates to a total diet replacement (TDR) differed from those of a calorie-restricted, food-based (FB) diet., Methods: Data from OPTIWIN, a 12-month multicenter trial in adults with a BMI of 30-55 kg/m 2 , with 26-week weight-loss and weight-maintenance phases, were utilized. Participants ( n = 330) were randomized to the OPTIFAST programme (OP) or to a reduced-energy FB diet. Treatment non-responders were defined as those who lost <3% of initial weight at months 6 or 12., Results: There were 103 (76%) responders in the OP compared with 78 (57%) in the FB group at 12 months. The odds of treatment response at 12 months among participants who were non-responders at 3 months was not significantly different between the OP and FB groups ( p = 0.64). Race, type 2 diabetes status and previous weight loss attempts were significantly associated with responder status. OP responders had higher meal plan adherence and non-caloric fluid intake compared with FB responders., Conclusion: Early treatment response is more likely and better sustained with TDR compared with an FB diet. Individual and treatment level factors appear to influence early treatment response to behavioural interventions for weight reduction., Competing Interests: JDA and JL are consultants for Nestlé Healthcare Nutrition; JDA, KHL, AER and LM receive grant funding from Nestlé Health Science; and SP is an employee of Nestlé Health Science. All remaining authors have no relevant disclosures. Nestlé Healthcare Nutrition owns the OPTIFAST programme., (© 2020 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: Protein deficits have been associated with longer intensive care unit (ICU) stays and increased mortality. Current view suggests if protein goals are met, meeting full energy targets may be less important and prevent deleterious effects of overfeeding. We proposed a very-high protein (VHP) enteral nutrition (EN) formula could provide adequate protein, without overfeeding energy, in the first week of critical illness., Methods: This was a retrospective study of medical/surgical ICU patients receiving EN exclusively for ≥5 days during the first week of ICU admission. Twenty participants received standard EN; 20 participants received the VHP-EN formula (1 kcal/mL, 37% protein). Protein and energy prescribed/received, gastrointestinal tolerance, and feeding interruptions were examined., Results: Forty ICU patients [average Acute Physiology and Chronic Health Evaluation II score of 20.1] were included. Protein prescribed and received was significantly higher in the VHP group vs the standard EN group (135.5 g/d ± 22.9 vs 111.4 g/d ± 25; P = .003 and 112.2 g/d ± 27.8 vs 81.7 g/d ± 16.7, respectively; P = .002). Energy prescribed and received was similar between groups (1696 kcal/d ± 402 vs 1893 kcal/d ± 341, respectively; P = .101 and 1520 kcal/d ± 346 vs 1506 ± 380 kcal/d; P = .901). There were no differences in EN tolerance (P = .065) or feeding interruptions (P = .336)., Conclusions: Use of a VHP formula in ICU patients resulted in higher protein intakes without overfeeding energy or use of modular protein in the first 5 days of exclusive EN., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Background: To meet protein needs in critical illness (CI), guidelines suggest ≥1.2-2.5 g protein/kg/d; however, most intensive care unit (ICU) patients receive ≤0.7 g/kg/d. Higher protein enteral nutrition (EN) formulas may be part of the solution to provide prescribed protein. Our objective was to demonstrate that an EN formula with 37% protein can deliver ≥80% of prescribed protein, without overfeeding calories within the first 5 days of feeding and to describe ICU clinicians' experience., Methods: This quality improvement (QI) project included patients requiring exclusive EN for up to 5 days from 6 Canadian ICUs. Rationale for choosing formula, patient's BMI (kg/m 2 ), nutrition targets, daily protein and energy delivered, feeding interruptions, and general tolerance were recorded., Results: Forty-four of 49 patients received the formula ≥2 days. Average protein prescribed was 137.5 g/d (82.5-200) or 1.9 g/kg/d (1.5-2.5). Average protein delivered was 116.9 g/d (33.5-180) or 1.6 g/kg/d (0.4-2.4). Seventy-five percent to 83% of patients received ≥80% prescribed protein on days 2-5. Average energy prescribed was 1638.6 kcal/d (990-2500) or 17.8 kcal/kg (11-26). Average energy delivered was 1523.9 kcal/d (693.0-2557.5) or 17.3 kcal/kg/d (1.35-64.7). The formula was well tolerated with no gastrointestinal symptoms reported in 38 (86%) patients. The most common reasons to prescribe the formula were obesity and use of fat-based medications., Conclusions: We demonstrated in a QI study that a high-protein EN formula was tolerated in a small, heterogeneous group of ICU patients and effective in meeting protein targets without overfeeding., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Background: Inadequate calorie and protein intake during critical illness is associated with poor clinical outcomes. Unfortunately, most critically ill patients do not consume adequate levels of these nutrients. An enteral formula with appropriate macronutrient composition may assist patients in meeting nutritional goals., Design: This study was a single center, prospective, observational study of 29 adults in the medical intensive care unit who required enteral nutrition for at least 3 days. Subjects received a calorically dense, enzymatically hydrolyzed 100% whey peptide-based enteral formula for up to 5 days to assess the ability to achieve 50% of caloric goals within the first 3 days (primary outcome), the daily percentage of protein goals attained and gastrointestinal tolerance (secondary outcomes)., Result: A total of 29 subjects consented and began the study. Four subjects dropped out before first day and 25 subjects were included in analyses. Subjects were aged 55.5 ± 16.9 years with mean body mass index (BMI) of 27.9 ± 7.5 kg/m 2 . Most (92%) subjects were on a mechanical ventilator and experienced organ failure. At least 50% of caloric and protein goals were achieved in 78.9% and 73.7% of the subjects, respectively, during the first 3 days. Overall, 75.0 ± 26.3% and 69.3 ± 26.7% of calorie and protein goals were achieved using the study formula., Conclusions: Subjects fed enterally with a calorically dense, enzymatically hydrolyzed 100% whey peptide-based enteral formula exceeded 50% of caloric and protein goals in most critically ill subjects included in this study. Use of study formula did not lead to severe gastrointestinal intolerance., Competing Interests: Declaration of conflicting interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SY, KR and MBH are employees and receive salary from Nestlé Health Science. The institutions of KA, KRJ, and SSC received payments from Nestlé Health Science for the work of this trial., (© The Author(s) 2020.)

The purpose of this study is to describe lipid-lowering therapy (LLT) prescriptions and low-density lipoprotein cholesterol (LDL-C) monitoring in patients with diabetes mellitus (DM) with or without concomitant cardiovascular disease (CVD). Olmsted County, Minnesota residents with a first-ever diagnosis of DM or CVD (ischemic stroke/transient ischemic attack, myocardial infarction, unstable angina pectoris, or revascularization procedure) between 2005 and 2012 were classified as having DM only, CVD only, or CVD + DM. All LLT prescriptions and LDL-C measurements were obtained for 2 years after diagnosis. A total of 4,186, 2,368, and 724 patients had DM, CVD, and CVD + DM, respectively. Rates of LDL-C measurement were 1.31, 1.66, and 1.88 per person-year and 14%, 32%, and 42% of LDL-C measurements were <70 mg/dl in those with DM, CVD, and CVD + DM. Within 3 months after diagnosis, 47%, 71%, and 78% of patients with DM, CVD, and CVD + DM were prescribed LLT. Most prescriptions were for moderate-intensity statins. Under one-fifth of patients with CVD and CVD + DM were prescribed high-intensity statins. Predictors of high-intensity statin prescriptions included male sex, having CVD or CVD + DM, increasing LDL-C, and LDL-C measured more recently (2012 to 2014 vs before 2012). In conclusion, a large proportion of patients at high CVD risk are not adequately treated with LLT. Despite often being considered a risk equivalent, patients with DM have substantially lower rates of LLT prescriptions and lesser controlled LDL-C than those with CVD or CVD + DM., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Much of the discourse surrounding children's advocacy in the United States relies on a rights-based approach. We argue that this approach has limitations that impede progress in advancing children's well-being., Purpose: The purpose of this article is to explain alternatives to a rights-based approach in advocating for children, such as developmental, economic, capabilities, and mutualism frameworks., Methods: Our analysis is based on the independent work of two separate university-based groups studying children's rights; the authors were each members of one of the groups and subsequently integrated their findings for this article., Discussion: US policies for children, especially in the domains of health and education, depict an unevenness that results in many children failing to receive certain critical services and benefits. Relying on a rights-based approach to correct these disparities and inequities is contentious and has yet to sufficiently change state and federal policies or improve children's health outcomes. Other approaches are needed to advance children's well-being., Conclusion: Nurses individually and collectively need to be mindful of the pitfalls of a rights-based approach and use other frameworks in advocating for children and youth., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study describes subsequent cardiovascular events and deaths by low-density lipoprotein cholesterol (LDL-C) level in patients with atherosclerotic cardiovascular disease (ASCVD) receiving moderate- to high-intensity statins. Olmsted County, Minnesota residents with index ASCVD (myocardial infarction, unstable angina, coronary revascularization, ischemic stroke or transient ischemic attack) occurring between 2005 and 2012 were identified, and those with a prescription for a moderate- or high-intensity statin and an LDL-C measurement in the 90 days after index were included. Cox regression models were used to examine associations between LDL-C, modeled as a time-dependent variable, and a composite outcome of subsequent cardiovascular events or all-cause death. Among 1,854 patients with ASCVD (mean [SD] age 66.0 [13.3] years, 63.6% male), a total of 1,241 events were observed from index ASCVD through follow-up (median of 5.9 years). The rate (95% confidence interval) per 100 person-years was 11.26 (10.64 to 11.91). Starting follow-up 90 days after index ASCVD event, the rates per 100 person-years were 10.51 (9.57 to 11.52), 9.57 (8.66 to 10.55), and 11.40 (9.96 to 12.98) for LDL-C <70, 70-<100 and ≥100 mg/dl, respectively. After adjustment for age, sex, and previous diagnoses of ASCVD, diabetes, hypertension, heart failure, and chronic kidney disease, the hazard ratio for cardiovascular event and/or death was significantly higher for patients with LDL-C ≥100 mg/dl than those with LDL-C <70 mg/dl (1.31 [1.08 to 1.59]). In conclusion, in patients with ASCVD, subsequent cardiovascular events occur at a high rate and the rates are highest in patients with LDL-C ≥100 mg/dl suggesting unmet treatment needs even in patients receiving moderate- to high-intensity statins., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Human milk oligosaccharides are important components of breast milk. We evaluated feeding tolerance of the human milk oligosaccharide 2'-fucosyllactose (2'FL) in a 100% whey, partially hydrolyzed infant formula with the probiotic Bifidobacterium animalis ssp lactis strain Bb12 ( B lactis ; Test) as compared with the same formula without 2'FL (Control) in a randomized controlled trial of healthy infants enrolled at 2 weeks of age (±5 days). After 6 weeks of feeding the assigned formula, the primary outcome of tolerance was assessed using the Infant Gastrointestinal Symptom Questionnaire. Stooling, vomiting, spit-up, crying, and fussing were compared between groups. Seventy-nine infants were enrolled and 63 completed the study per protocol (30 Test, 33 Control). Infant Gastrointestinal Symptom Questionnaire scores were similar between groups (Test 20.9 ± 4.8, Control 20.7 ± 4.3, P = .82). Partially hydrolyzed infant formula with 2'FL and B lactis is tolerated well, as confirmed by a validated multi-symptom index., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HMS, LMC, BK, and RC are employees of Nestlé Nutrition, the sponsor of this study. JS, SSC, and HR are paid consultants for Nestlé Nutrition.

Objective: Our study identified risk factors for the development of clinically identifiable catheter-associated thrombosis (CT)., Study Design: We performed a retrospective cohort study of neonates in whom a central catheter was present. A total of 1,475 catheters were identified in 766 patients during a 36-month study period. The odds ratio (OR) of thrombi formation in catheterized neonates was modeled using simple (single predictor) and multiple (multiple predictors) logistic regressions as well as simple and multiple Cox's proportional hazard models., Result: The incidence of CT was 1.17 per 100 neonates. Unadjusted factors including age at insertion, history of surgery before or during line placement, cholestasis, femoral location, and line size significantly increased the OR or hazards ratio (HR) of developing thrombi formation. In multiple logistic and Cox's regression analyses, three factors continued to be significantly associated with OR or HR of thrombi formation: line size, femoral location, and cholestasis., Conclusion: We conclude that clinically identifiable CT is rare in the neonatal population. Furthermore, catheter-specific characteristics are predictive for CT and require further investigation., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Pediatric feeding disorders (PFDs) lack a universally accepted definition. Feeding disorders require comprehensive assessment and treatment of 4 closely related, complementary domains (medical, psychosocial, and feeding skill-based systems and associated nutritional complications). Previous diagnostic paradigms have, however, typically defined feeding disorders using the lens of a single professional discipline and fail to characterize associated functional limitations that are critical to plan appropriate interventions and improve quality of life. Using the framework of the World Health Organization International Classification of Functioning, Disability, and Health, a unifying diagnostic term is proposed: "Pediatric Feeding Disorder" (PFD), defined as impaired oral intake that is not age-appropriate, and is associated with medical, nutritional, feeding skill, and/or psychosocial dysfunction. By incorporating associated functional limitations, the proposed diagnostic criteria for PFD should enable practitioners and researchers to better characterize the needs of heterogeneous patient populations, facilitate inclusion of all relevant disciplines in treatment planning, and promote the use of common, precise, terminology necessary to advance clinical practice, research, and health-care policy.

Objective: The aim of this study was to test the effectiveness of the OPTIFAST program (OP), a total meal replacement dietary intervention, compared with a food-based (FB) dietary plan for weight loss., Methods: Participants with BMI 30 to 55 kg/m 2 , age 18 to 70 years old, were randomized to OP or FB dietary and lifestyle interventions for 26 weeks, followed by a weight-maintenance phase. Outcomes were percent change in body weight (%WL) from baseline to weeks 26 and 52, associated changes in body composition (using dual energy x-ray absorptiometry), and adverse events. Primary analysis used repeated-measures multivariable linear mixed models to compare outcomes between groups in a modified intention-to-treat fashion (mITT)., Results: A total of 273 participants (83% of randomized; 135 OP, 138 FB) made up the mITT population. Mean age was 47.1 ± 11.2 years; 82% were female and 71% non-Hispanic white. Baseline BMI was 38.8 ± 5.9 kg/m 2 . At 26 weeks, OP %WL was 12.4% ± 0.6% versus 6.0% ± 0.6% in FB (P < 0.001). At 52 weeks, OP %WL was 10.5% ± 0.6% versus 5.5% ± 0.6% in FB (P < 0.001). Fat mass loss was greater for OP; lean mass loss was proportional to total weight loss. There was no difference in serious adverse event rates between groups., Conclusions: Compared with an FB approach, OP was more effective with greater sustained weight loss., (© 2018 The Obesity Society.)

Objective: To use a quantitative approach to evaluate the literature for quantity, quality, and consistency of studies of maternal and infant characteristics in association with breastfeeding initiation and continuation, and to conduct a meta-analysis to produce summary relative risks (RRs) for selected factors., Study Design: A systematic review using PubMed and CINAHL through March 2016 was conducted to identify relevant observational studies in developed nations, reporting a measure of risk for 1 or more of 6 quantitatively derived, high impact factors in relation to either breastfeeding initiation or continuation. One author abstracted data using a predesigned database, which was reviewed by a second independent author; data evaluation and interpretation included all co-authors. These factors were summarized using standard meta-analysis techniques., Results: Six high impact factors were identified (smoking [39 papers], mode of delivery [47 papers], parity [31 papers], dyad separation [17 papers], maternal education [62 papers], and maternal breastfeeding education [32 papers]). Summary RR from random-effects models for breastfeeding initiation were highest for high vs low maternal education (RR 2.28 [95% CI 1.92-2.70]), dyad connection vs not (RR 2.01 [95% CI 1.38-2.92]), and maternal nonsmoking vs smoking (RR = 1.76 [95% CI 1.59-1.95]); results were similar for breastfeeding continuation., Conclusions: Despite methodological heterogeneity across studies, relatively consistent results were observed for these perinatally identifiable factors associated with breastfeeding initiation and continuation, which may be informative in developing targeted interventions to provide education and support for successful breastfeeding in more families., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Online educational materials are largely disseminated through videos, and yet there is little understanding of how these videos engage students and fuel academic success. We hypothesized that components of the electroencephalogram (EEG), previously shown to reflect video engagement, would be predictive of academic performance in the context of educational videos. Two groups of subjects watched educational videos in either an intentional learning paradigm, in which they were aware of an upcoming test, or in an incidental learning paradigm, in which they were unaware that they would be tested. "Neural engagement" was quantified by the inter-subject correlation (ISC) of the EEG that was evoked by the videos. In both groups, students with higher neural engagement retained more information. Neural engagement also discriminated between attentive and inattentive video viewing. These results suggest that this EEG metric is a marker of the stimulus-related attentional mechanisms necessary to retain information. In the future, EEG may be used as a tool to design and assess online educational content., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: For infants who are partially or exclusively fed infant formula, many options exist with compositional differences between formulas making choices difficult for caregivers and healthcare professionals. The protein in routine infant formulas differs by the source, fraction of cow's milk protein used, and degree of hydrolysis. All commercially available regulated infant formulas support growth and development, but different stool patterns have been observed based on formula composition. A pooled analysis of seven clinical trials was conducted to examine growth, stool consistency, and stool frequency of infants fed an intact cow's milk-based formula (CMF) or a partially hydrolyzed whey formula (PHF-W) from a single manufacturer. Method s. Individual subject data from seven infant formula growth studies (3 CMF, 4 PHF-W) were pooled and analyzed. All studies included healthy, full-term, formula-fed infants enrolled at 14 days of age with outcomes assessed over 4 months. Gains in weight and length to 4 months were analyzed using linear regression accounting for clustering within study. Outcomes of caregiver-reported stool consistency and frequency were analyzed using a longitudinal multinomial model., Results: Data from 511 infants were included (197 CMF, 314 PHF-W). There were no differences in weight gain between groups. There was no difference in length gain in girls fed PHF-W while boys fed PHF-W had a significant difference of +0.016 cm/month compared to boys fed CMF. Infants fed PHF-W had a significantly higher probability of soft and lower probability of hard stools as compared to infants fed CMF at each time point (p<0.001). Stool frequency was similar between groups., Conclusions: Infants fed CMF and PHF-W exhibit appropriate growth with comparable gains in weight and length through 4 months. More soft and fewer hard stools are observed in infants fed PHF-W compared to CMF. This difference could help to inform decision-making when choosing an infant formula.

Objective: The Patient-Centered Outcomes Research Institute (PCORI) uses a unique approach to Merit Review that includes patients and stakeholders as reviewers with scientists, and includes unique review criteria (patient-centeredness and active engagement of end users in the research). This study assessed the extent to which different reviewer types influence review scores and funding outcomes, the emphasis placed on technical merit compared to other criteria by a multistakeholder panel, and the impact of the in-person discussion on agreement among different reviewer types., Methods: Cross-sectional analysis of administrative data from PCORI online and in-person Merit Review (N = 1312 applications from the five funding cycles from November 2013 to August 2015). Linear and logistic regression models were used to analyze the data., Results: For all reviewer types, final review scores were associated with at least one review criterion score from each of the three reviewer types. The strongest predictor of final overall scores for all reviewer types was scientists' prediscussion ratings of technical merit. All reviewers' prediscussion ratings of the potential to improve health care and outcomes, and scientists' ratings of technical merit and patient-centeredness, were associated with funding success. For each reviewer type, overall impact scores from the online scoring were changed on at least half of the applications at the in-person panel discussion. Score agreement across reviewer types was greater after panel discussion., Conclusions: Scientist, patient, and stakeholder views all contribute to PCORI Merit Review of applications for research funding. Technical merit is critical to funding success but patient and stakeholder ratings of other criteria also influence application disposition., (Copyright © 2018 ISPOR --The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Standard enteral nutrition (EN) formulas can  worsen hyperglycemia in diabetic patients. We hypothesized that altering the proportion of macronutrients in a formula; increasing protein while decreasing carbohydrate concentrations would improve glycemic response. The objective of this study was to demonstrate that an EN formula containing a very high concentration of protein (in the form of whey peptides) and low concentration of carbohydrate provide better control of postprandial blood glucose relative to a very high-protein/higher-carbohydrate formula., Subjects and Methods: This was a randomized crossover clinical trial of 12 ambulatory adult subjects with type 2 diabetes. The primary outcome was glycemic response following a bolus of isocaloric amounts of two EN formulas; the secondary outcome was insulin response. Subjects were randomized to the experimental or the control formula, on two separate days, 5-7 days apart., Results: Mean blood glucose concentrations at 10-180 min post-infusion and mean area under the curve for glucose over 240 min post-infusion were significantly lower with the experimental formula than with the control formula (71.99 ± 595.18 and 452.62 ± 351.38, respectively; p = 0.025). There were no significant differences in the mean insulin concentrations over time, insulinogenic indices, and first-phase insulin measurements., Conclusions: An EN formula containing high-protein and low-carbohydrate loads can significantly improve glucose control in subjects with type 2 diabetes in ambulatory settings as evidenced by observed improved glucose control without significant difference in insulin response.

Mallinckrodt Chemical Works was the earliest uranium processing facility in the Manhattan Project, beginning in 1942. Even then, concern existed about possible health effects resulting from exposure to radiation and pitchblende dust. This concern was well founded as the facility processed Belgian Congo pitchblende ore that was up to 60% pure uranium with high U content and up to 100 mg of radium per ton. Workers were exposed to external gamma radiation plus internal radiation from inhalation and ingestion of pitchblende dust (uranium, radium, and silica). Multiple sources of exposure were available for organ dose reconstruction to a degree unique for an epidemiologic study. Personal film badge measures available from 1945 captured external exposures. Additional external exposure included 15,518 occupational medical x-rays and 210 radiation exposure records from other facilities outside of Mallinckrodt employment. Organ dose calculations considered organ-specific coefficients that account for photon energy and job-specific orientation of workers to the radiation source during processing. Intakes of uranium and radium were based on 39,451 uranium urine bioassays and 2,341 breath radon measurements, and International Commission on Radiological Protection (ICRP) Publication 68 biokinetic models were used to estimate organ-specific radiation absorbed dose. Estimates of exposure to airborne radon and its short-lived progeny were based on radon measurements in work areas where radium-containing materials were handled or stored, together with estimated exposure times in these areas based on job titles. Dose estimates for radon and its short-lived progeny were based on models and methods recently recommended in ICRP Publication 137. This comprehensive dosimetric approach follows methods outlined by the National Council on Radiation Protection Scientific Committee 6-9 for the Million Worker Study. Annual doses were calculated for six organs: lung, brain, heart, kidney, colon and red bone marrow. Evaluation and adjustment for individual cumulative measures of pitchblende dust inhalation were made for lung and kidney diseases.

The purpose of this paper is to present an overview of ongoing work on the Million Worker Study (MWS), highlighting some of the key methods and progress so far as exemplified by the study of workers at the Mallinckrodt Chemical Works (MCW). The MWS began nearly 25 y ago and continues in a stepwise fashion, evaluating one study cohort at a time. It includes workers from U.S. Department of Energy (DOE) Manhattan Project facilities, U.S. Nuclear Regulatory Commission (NRC) regulated nuclear power plants, industrial radiographers, U.S. Department of Defense (DoD) nuclear weapons test participants, and physicians and technologists working with medical radiation. The purpose is to fill the major gap in radiation protection and science: What is the risk when exposure is received gradually over time rather than briefly as for the atomic bomb survivors? Studies published or planned in 2018 include leukemia (and dosimetry) among atomic veterans, leukemia among nuclear power plant workers, mortality among workers at the MCW, and a comprehensive National Council on Radiation Protection and Measurements (NCRP) Report on dosimetry for the MWS. MCW has a singular place in history: the 40 tons (T) of uranium oxide produced at MCW were used by Enrico Fermi on 2 December 1942 to produce the first manmade sustained and controlled nuclear reaction, and the atomic age was born. Seventy-six years later, the authors followed the over 2,500 MCW workers for mortality and reconstructed dose from six sources of exposure: external gamma rays from the radioactive elements in pitchblende; medical x rays from occupationally required chest examinations; intakes of pitchblende (uranium, radium, and silica) measured by urine samples; radon breath analyses and dust surveys overseen by Robley Evans and Merril Eisenbud; occupational exposures received before and after employment at MCW; and cumulative radon concentrations and lung dose from the decay of radium in the work environment. The unique exposure reconstructions allow for multiple evaluations, including estimates of silica dust. The study results are relevant today. For example, NASA is interested that radium, deposited in the brain, releases high-LET alpha particles - the only human analogue, though limited, for high energy, high-Z particles (galactic cosmic rays) traveling through space that might affect astronauts on Mars missions. Don't discount the past; it's the prologue to the future!

There have been numerous reviews related to the cerebral circulation. Most of these reviews are similar in many ways. In the present review, we thought it important to provide an overview of function with specific attention to details of cerebral arterial control related to brain homeostasis, maintenance of neuronal energy demands, and a unique perspective related to the role of astrocytes. A coming review in this series will discuss cerebral vascular development and unique properties of the neonatal circulation and developing brain, thus, many aspects of development are missing here. Similarly, a review of the response of the brain and cerebral circulation to heat stress has recently appeared in this series (8). By trying to make this review unique, some obvious topics were not discussed in lieu of others, which are from recent and provocative research such as endothelium-derived hyperpolarizing factor, circadian regulation of proteins effecting cerebral blood flow, and unique properties of the neurovascular unit. © 2018 American Physiological Society. Compr Physiol 8:801-821, 2018., (Copyright © 2018 American Physiological Society. All rights reserved.)

Neural development is generally marked by an increase in the efficiency and diversity of neural processes. In a large sample ( n = 114) of human children and adults with ages ranging from 5 to 44 yr, we investigated the neural responses to naturalistic video stimuli. Videos from both real-life classroom settings and Hollywood feature films were used to probe different aspects of attention and engagement. For all stimuli, older ages were marked by more variable neural responses. Variability was assessed by the intersubject correlation of evoked electroencephalographic responses. Young males also had less-variable responses than young females. These results were replicated in an independent cohort ( n = 303). When interpreted in the context of neural maturation, we conclude that neural function becomes more variable with maturity, at least during the passive viewing of real-world stimuli., Competing Interests: Authors report no conflict of interest.

It is said that we lose track of time - that "time flies" - when we are engrossed in a story. How does engagement with the story cause this distorted perception of time, and what are its neural correlates? People commit both time and attentional resources to an engaging stimulus. For narrative videos, attentional engagement can be represented as the level of similarity between the electroencephalographic responses of different viewers. Here we show that this measure of neural engagement predicted the duration of time that viewers were willing to commit to narrative videos. Contrary to popular wisdom, engagement did not distort the average perception of time duration. Rather, more similar brain responses resulted in a more uniform perception of time across viewers. These findings suggest that by capturing the attention of an audience, narrative videos bring both neural processing and the subjective perception of time into synchrony.

Our brains integrate information across sensory modalities to generate perceptual experiences and form memories. However, it is difficult to determine the conditions under which multisensory stimulation will benefit or hinder the retrieval of everyday experiences. We hypothesized that the determining factor is the reliability of information processing during stimulus presentation, which can be measured through intersubject correlation of stimulus-evoked activity. We therefore presented biographical auditory narratives and visual animations to 72 human subjects visually, auditorily, or combined, while neural activity was recorded using electroencephalography. Memory for the narrated information, contained in the auditory stream, was tested 3 weeks later. While the visual stimulus alone led to no meaningful retrieval, this related stimulus improved memory when it was combined with the story, even when it was temporally incongruent with the audio. Further, individuals with better subsequent memory elicited neural responses during encoding that were more correlated with their peers. Surprisingly, portions of this predictive synchronized activity were present regardless of the sensory modality of the stimulus. These data suggest that the strength of sensory and supramodal activity is predictive of memory performance after 3 weeks, and that neural synchrony may explain the mnemonic benefit of the functionally uninformative visual context observed for these real-world stimuli.

The possible relationship between dietary cholesterol and cardiac outcomes has been scrutinized for decades. However, recent reviews of the literature have suggested that dietary cholesterol is not a nutrient of concern. Thus, we conducted a meta-analysis of egg intake (a significant contributor to dietary cholesterol) and risk of coronary heart disease (CHD) and stroke. A comprehensive literature search was conducted through August 2015 to identify prospective cohort studies that reported risk estimates for egg consumption in association with CHD or stroke. Random-effects meta-analysis was used to generate summary relative risk estimates (SRREs) for high vs low intake and stratified intake dose-response analyses. Heterogeneity was examined in subgroups where sensitivity and meta regression analyses were conducted based on increasing egg intake. A 12% decreased risk (SRRE = 0.88, 95% confidence interval [CI], 0.81-0.97) of stroke was observed in the meta-analysis of 7 studies of egg intake (high vs low; generally 1/d vs <2/wk), with little heterogeneity (p-H = 0.37, I 2 = 7.50). A nonstatistically significant SRRE of 0.97 (95% CI, 0.88-1.07, p-H = 0.67, I 2 = 0.00) was observed in the meta-analysis of 7 studies of egg consumption and CHD. No clear dose-response trends were apparent in the stratified intake meta-analyses or the meta regression analyses. Based on the results of this meta-analysis, consumption of up to one egg daily may contribute to a decreased risk of total stroke, and daily egg intake does not appear to be associated with risk of CHD. Key Teaching Points: • The role of egg consumption in the risk of stroke and coronary heart disease has come under scrutiny over many years. • A comprehensive meta-analysis of prospective cohort studies that reported risk estimates for egg consumption in association with CHD or stroke was performed on the peer-reviewed epidemiologic literature through August 2015. • Overall, summary associations indicate that intake of up to 1 egg daily may be associated with reduced risk of total stroke. • Overall, summary associations show no clear association between egg intake and increased or decreased risk of CHD. • Eggs are a relatively low-cost and nutrient-dense whole food that provides a valuable source of protein, essential fatty acids, antioxidants, choline, vitamins, and minerals.

Objective: The purpose of this clinical trial was to compare the glucose usage of two oral nutritional supplement (ONS) products and to assess whether a diabetes-specific formulation provides improved glucose stabilization and management compared with a standard formula., Research Design and Methods: A total of 12 subjects with type 2 diabetes (7 males and 5 females) completed a randomized, cross-over design trial. Each subject consumed isocaloric amounts of either the standard ONS or the diabetes-specific formula ONS on different dates, 1 week apart. Glucose and insulin measures were recorded at baseline, and 10, 20, 30, 60, 90, 120, 150, 180, 210 and 240 min after the beverage was consumed and then used to calculate area under the curve (AUC) for each subject., Results: The mean glucose AUC was lower in the diabetes-specific ONS group than in the standard group (p<0.0001), but there was not a significant difference observed for mean insulin AUC (p=0.068). A sensitivity analysis of the mean insulin AUC measures was performed by removing a potential outlier from the analysis, and this resulted in a significant difference between the groups (p=0.012). First-phase insulin measures and an insulinogenic index calculated for the beverages showed no significant differences., Conclusions: On the basis of the results of this trial of 12 subjects, the diabetes-specific ONS appears to provide better glucose maintenance in persons with type 2 diabetes when compared to the standard formula ONS., Trial Registration Number: NCT02612675.

Background: Sleep has been suggested to influence breast cancer risk; however, the evidence is mixed. Black women have a higher prevalence of both short (<6 h) and long (≥9 h) sleep duration and are more likely to develop more aggressive, hormone receptor-negative breast cancer. No study has examined the relationship between sleep and breast cancer in blacks. We focused on race-specific associations among the blacks., Methods: In the Southern Community Cohort Study (SCCS), a prospective study of which two-thirds of the population were black, we prospectively investigated self-reported sleep duration in relation to overall breast cancer risk by estrogen (ER) and progesterone receptor (PR) status in all women and in black women alone., Results: Sleep duration was not associated with risk of total or hormone receptor-positive breast cancer. However, we found an inverse relationship between sleep duration and risk of ER- and PR- breast cancer among all women and in black women alone. Compared to the reference group (8 h), black women who reported shorter sleep duration had an increased risk of ER- PR- breast cancer (odds ratios; ORs (95% confidence intervals; CIs): 2.13 (1.15, 3.93), 1.66 (0.92, 3.02), and 2.22 (1.19, 4.12) for <6, 6, and 7 h, respectively, (p for trend, 0.04)., Conclusions: Short sleep duration may be a risk factor for hormone receptor-negative breast cancer among black women., (Published by Elsevier B.V.)

This study examines the practice environment for nurse practitioners (NPs) in New Mexico and assesses whether the future supply of NPs will be adequate to meet the health care needs of a varied population in a sparsely populated state with a relatively low average standard of living, yet one that offers a broad scope of practice authority for its NPs. The study's models forecast decreasing numbers of New Mexico NPs between the ages of 40 and 60 in the state's metropolitan counties. These decreases are not offset by gains in other age brackets. Thus, over time, the state's metro areas may not maintain their 2013 NP-to-insured and NP-to-senior population ratios. In contrast, the study's models forecast improving ratios in nonmetropolitan counties. The future need for NPs in New Mexico and similarly situated states may therefore be greatest in fast-growing urban areas, where the number of newly insured individuals with primary care needs is likely to be high.

Unlabelled: Antibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop., Importance: The levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies., (Copyright © 2015 Zolla-Pazner et al.)