Lifespan

Abstract Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

BACKGROUND: It is common practice to restore and maintain sinus rhythm in patients with atrial fibrillation and heart failure. This approach is based in part on data indicating that atrial fibrillation is a predictor of death in patients with heart failure and suggesting that the suppression of atrial fibrillation may favorably affect the outcome. However, the benefits and risks of this approach have not been adequately studied. METHODS: We conducted a multicenter, randomized trial comparing the maintenance of sinus rhythm (rhythm control) with control of the ventricular rate (rate control) in patients with a left ventricular ejection fraction of 35% or less, symptoms of congestive heart failure, and a history of atrial fibrillation. The primary outcome was the time to death from cardiovascular causes. RESULTS: A total of 1376 patients were enrolled (682 in the rhythm-control group and 694 in the rate-control group) and were followed for a mean of 37 months. Of these patients, 182 (27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 (25%) in the rate-control group (hazard ratio in the rhythm-control group, 1.06; 95% confidence interval, 0.86 to 1.30; P=0.59 by the log-rank test). Secondary outcomes were similar in the two groups, including death from any cause (32% in the rhythm-control group and 33% in the rate-control group), stroke (3% and 4%, respectively), worsening heart failure (28% and 31%), and the composite of death from cardiovascular causes, stroke, or worsening heart failure (43% and 46%). There were also no significant differences favoring either strategy in any predefined subgroup. CONCLUSIONS: In patients with atrial fibrillation and congestive heart failure, a routine strategy of rhythm control does not reduce the rate of death from cardiovascular causes, as compared with a rate-control strategy. (ClinicalTrials.gov number, NCT00597077.)

, Pseudomonas aeruginosa, and anaerobes), and lefamulin (Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae), and disk breakpoints are described for azithromycin and Neisseria gonorrhoeae. The rationale behind revised oxacillin MIC breakpoints for select staphylococci is discussed. Updates to test methods include a method for disk diffusion using positive blood culture broth and use of linezolid to predict tedizolid susceptibility. There is clarification on which drugs to suppress on bacteria isolated from the cerebrospinal fluid and clarification on the use of a caret symbol attached to the intermediate category ("I^") to indicate those antimicrobials that concentrate in the urine.

CONTEXT: Abusive head trauma (AHT) is a dangerous form of child abuse that can be difficult to diagnose in young children. OBJECTIVES: To determine how frequently AHT was previously missed by physicians in a group of abused children with head injuries and to determine factors associated with the unrecognized diagnosis. DESIGN: Retrospective chart review of cases of head trauma presenting between January 1, 1990, and December 31, 1995. SETTING: Academic children's hospital. PATIENTS: One hundred seventy-three children younger than 3 years with head injuries caused by abuse. MAIN OUTCOME MEASURES: Characteristics of head-injured children in whom diagnosis of AHT was unrecognized and the consequences of the missed diagnoses. RESULTS: Fifty-four (31.2%) of 173 abused children with head injuries had been seen by physicians after AHT and the diagnosis was not recognized. The mean time to correct diagnosis among these children was 7 days (range, 0-189 days). Abusive head trauma was more likely to be unrecognized in very young white children from intact families and in children without respiratory compromise or seizures. In 7 of the children with unrecognized AHT, misinterpretation of radiological studies contributed to the delay in diagnosis. Fifteen children (27.8%) were reinjured after the missed diagnosis. Twenty-two (40.7%) experienced medical complications related to the missed diagnosis. Four of 5 deaths in the group with unrecognized AHT might have been prevented by earlier recognition of abuse. CONCLUSION: Although diagnosing head trauma can be difficult in the absence of a history, it is important to consider inflicted head trauma in infants and young children presenting with nonspecific clinical signs.

BACKGROUND: Since many successful dieters regain the weight they lose, programs that teach maintenance skills are needed. We developed a maintenance program based on self-regulation theory and tested the efficacy of delivering the program face to face or over the Internet. METHODS: We randomly assigned 314 participants who had lost a mean of 19.3 kg of body weight in the previous 2 years to one of three groups: a control group, which received quarterly newsletters (105 participants), a group that received face-to-face intervention (105), and a group that received Internet-based intervention (104). The content of the programs in the two intervention groups was the same, emphasizing daily self-weighing and self-regulation, as was the frequency of contact with the groups. The primary outcome was weight gain over a period of 18 months. RESULTS: The mean (+/-SD) weight gain was 2.5+/-6.7 kg in the face-to-face group, 4.7+/-8.6 kg in the Internet group, and 4.9+/-6.5 kg in the control group, with a significant difference between the face-to-face group and the control group (2.4 kg; 95% confidence interval [CI], 0.002 to 10.8; P=0.05). The proportion of participants who regained 2.3 kg or more over the 18-month period was significantly higher in the control group (72.4%) than in the face-to-face group (45.7%; absolute difference, 27%; 95% CI, 14 to 39; P<0.001) or the Internet group (54.8%; absolute difference, 18%; 95% CI, 5 to 30; P=0.008). Daily self-weighing increased in both intervention groups and was associated with a decreased risk of regaining 2.3 kg or more (P<0.001). CONCLUSIONS: As compared with receiving quarterly newsletters, a self-regulation program based on daily weighing improved maintenance of weight loss, particularly when delivered face to face. (ClinicalTrials.gov number, NCT00067145 [ClinicalTrials.gov].)

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

Enterococci have the potential for resistance to virtually all clinically useful antibiotics. Their emergence as important nosocomial pathogens has coincided with increased expression of antimicrobial resistance by members of the genus. The mechanisms underlying antibiotic resistance in enterococci may be intrinsic to the species or acquired through mutation of intrinsic genes or horizontal exchange of genetic material encoding resistance determinants. This paper reviews the antibiotic resistance mechanisms in Enterococcus faecium and Enterococcus faecalis and discusses treatment options.

This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA). Angina pectoris affects approximately 112 million people globally. Up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease, more common in women than in men, and a large proportion have INOCA as a cause of their symptoms. INOCA patients present with a wide spectrum of symptoms and signs that are often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment. INOCA can result from heterogeneous mechanism including coronary vasospasm and microvascular dysfunction and is not a benign condition. Compared to asymptomatic individuals, INOCA is associated with increased incidence of cardiovascular events, repeated hospital admissions, as well as impaired quality of life and associated increased health care costs. This consensus document provides a definition of INOCA and guidance to the community on the diagnostic approach and management of INOCA based on existing evidence from research and best available clinical practice; noting gaps in knowledge and potential areas for further investigation.

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

TP53 is the most commonly mutated gene in human cancer with over 100,000 literature citations in PubMed. This is a heavily studied pathway in cancer biology and oncology with a history that dates back to 1979 when p53 was discovered. The p53 pathway is a complex cellular stress response network with multiple diverse inputs and downstream outputs relevant to its role as a tumor suppressor pathway. While inroads have been made in understanding the biology and signaling in the p53 pathway, the p53 family, transcriptional readouts, and effects of an array of mutants, the pathway remains challenging in the realm of clinical translation. While the role of mutant p53 as a prognostic factor is recognized, the therapeutic modulation of its wild-type or mutant activities remain a work-in-progress. This review covers current knowledge about the biology, signaling mechanisms in the p53 pathway and summarizes advances in therapeutic development.

Abstract A rift that has opened up between basic research (bench) and clinical research and patients (bed) who need their new treatments, diagnostics and prevention, and this rift is widening and getting deeper. The crisis involving the “translation” of basic scientific findings in a laboratory setting into human applications and potential treatments or biomarkers for a disease is widely recognized both in academia and industry. Despite the attempts that have been made both in academic and industry settings to mitigate this problem, the high attrition rates of drug development and the problem with reproducibility and translatability of preclinical findings to human applications remain a fact and the return on the investment has been limited in terms of clinical impact. Here I provide an overview of the challenges facing the drug development, and translational discordance with specific focus on a number of “culprits” in translational research including poor hypothesis, irreproducible data, ambiguous preclinical models, statistical errors, the influence of organizational structures, lack of incentives in the academic setting, governmental funding mechanisms, the clinical relevance of basic research, insufficient transparency, and lack of data sharing in research. I further provide some suggestions and new strategies that include some new aspects on open innovation models, entrepreneurship, transparency, and decision making to overcome each of the many problems during the drug discovery and development process and to more dynamically adjust for innovation challenges with broader scientific feedback.

BACKGROUND: Concern regarding change in the onset of sexual maturation of US girls has increased the need for current information on age at menarche from a national sample. Previous reports have been sparse and interpretation has been limited because of the racial composition and ages of the samples. OBJECTIVE: The objectives of this study were to estimate the distribution of age at menarche for all US girls and for non-Hispanic white, black, and Mexican American girls in the Third National Health and Nutrition Examination Survey and to test for racial differences. DESIGN: Menstrual status data were collected from 2510 girls aged 8.0 to 20.0 years. The Third National Health and Nutrition Examination Survey followed a complex, stratified, multistage probability cluster design. SUDAAN was used to calculate proportions of girls reaching menarche at an age. Ages at menarche were estimated by probit analysis at the ages at which 10%, 25%, 50%, 75%, and 90% of the girls attained menarche. RESULTS: Less than 10% of US girls start to menstruate before 11 years, and 90% of all US girls are menstruating by 13.75 years of age, with a median age of 12.43 years. This age at menarche is not significantly different (0.34 years earlier) than that reported for US girls in 1973. Age at menarche for non-Hispanic black girls was significantly earlier than that of white girls at 10%, 25%, and 50% of those who had attained menarche, whereas Mexican American girls were only significantly earlier than the white girls at 25%. CONCLUSION: Overall, US girls are not gaining reproductive potential earlier than in the past. The age at menarche of non-Hispanic black girls is significantly earlier than that of non-Hispanic white and Mexican American girls.

Abstract COVID-19 pandemic is a global calamity posing an unprecedented opportunity to study resilience. We developed a brief resilience survey probing self-reliance, emotion-regulation, interpersonal-relationship patterns and neighborhood-environment, and applied it online during the acute COVID-19 outbreak (April 6–15, 2020), on a crowdsourcing research website ( www.covid19resilience.org ) advertised through social media. We evaluated level of stress (worries) regarding COVID-19: (1) contracting, (2) dying from, (3) currently having, (4) family member contracting, (5) unknowingly infecting others with (6) experiencing significant financial burden following. Anxiety (GAD7) and depression (PHQ2) were measured. Totally, 3042 participants ( n = 1964 females, age range 18–79, mean age = 39) completed the resilience and COVID-19-related stress survey and 1350 of them (mean age = 41, SD = 13; n = 997 females) completed GAD7 and PHQ2. Participants significantly endorsed more distress about family contracting COVID-19 (48.5%) and unknowingly infecting others (36%), than getting COVID-19 themselves (19.9%), p &lt; 0.0005 covarying for demographics and proxy COVID-19 exposures like getting tested and knowing infected individuals. Patterns of COVID-19 related worries, rates of anxiety (GAD7 &gt; 10, 22.2%) and depression (PHQ2 &gt; 2, 16.1%) did not differ between healthcare providers and non-healthcare providers. Higher resilience scores were associated with lower COVID-19 related worries (main effect F 1,3054 = 134.9; p &lt; 0.00001, covarying for confounders). Increase in 1 SD on resilience score was associated with reduced rate of anxiety (65%) and depression (69%), across healthcare and non-healthcare professionals. Findings provide empirical evidence on mental health associated with COVID-19 outbreak in a large convenience sample, setting a stage for longitudinal studies evaluating mental health trajectories following COVID-19 pandemic.

Human cortical thickness and surface area are genetically independent, emerge through different neurobiological events during development, and are sensitive to different clinical conditions. However, the relationship between changes in the two over time is unknown. Additionally, longitudinal studies have almost invariably been restricted to older adults, precluding the delineation of adult life span trajectories of change in cortical structure. In this longitudinal study, we investigated changes in cortical thickness, surface area, and volume after an average interval of 3.6 years in 207 well screened healthy adults aged 23-87 years. We hypothesized that the relationships among metrics are dynamic across the life span, that the primary contributor to cortical volume reductions in aging is cortical thinning, and that magnitude of change varies with age and region. Changes over time were seen in cortical area (mean annual percentage change [APC], -0.19), thickness (APC, -0.35), and volume (APC, -0.51) in most regions. Volume changes were primarily explained by changes in thickness rather than area. A negative relationship between change in thickness and surface area was found across several regions, where more thinning was associated with less decrease in area, and vice versa. Accelerating changes with increasing age was seen in temporal and occipital cortices. In contrast, decelerating changes were seen in prefrontal and anterior cingulate cortices. In conclusion, a dynamic relationship between cortical thickness and surface area changes exists throughout the adult life span. The mixture of accelerating and decelerating changes further demonstrates the importance of studying these metrics across the entire adult life span.

OBJECTIVES: To describe the occurrence of delirium in a cohort of older medical intensive care unit (ICU) patients and its short-term duration in the hospital and to determine the association between preexisting dementia and the occurrence of delirium. DESIGN: Prospective cohort study. SETTING: Fourteen-bed medical ICU of an 800-bed university teaching hospital. PARTICIPANTS: One hundred eighteen consecutive patients aged 65 and older admitted to the ICU. MEASUREMENTS: Baseline characteristics were obtained through surrogate interviews and medical chart review. Dementia was determined using two validated surrogate-rated instruments. Delirium was assessed daily in the ICU using the Confusion Assessment Method (CAM) for the ICU (CAM-ICU). After discharge from the ICU, patients were followed for up to 7 days using the CAM. RESULTS: Delirium was present in 37 of 118 (31%) patients on admission. Only 45 patients had a normal mental status on admission, of whom 14 (31%) became delirious during their hospital stay. In the post-ICU period, delirium occurred in 40% of patients. Almost half of patients with delirium in the ICU had persistent delirium in the post-ICU period. Overall, 83 of 118 (70%) had delirium during hospitalization. Stupor or coma occurred in 44% of the patients overall, and 89% of survivors of stupor/coma progressed to delirium. Patients with dementia were 40% more likely to be delirious (relative risk = 1.4, 95% confidence interval = 1.1-1.7), even after controlling for comorbidity, baseline functional status, severity of illness, and invasive procedures. CONCLUSION: Delirium is a frequent complication in older ICU patients and often persists beyond their ICU stay. Delirium in older ICU persons is a dynamic and complex process. Dementia is an important predisposing risk factor for the development of delirium in this population during and after the ICU stay.

The protracted development of structural and functional brain connectivity within distributed association networks coincides with improvements in higher-order cognitive processes such as executive function. However, it remains unclear how white-matter architecture develops during youth to directly support coordinated neural activity. Here, we characterize the development of structure–function coupling using diffusion-weighted imaging and n -back functional MRI data in a sample of 727 individuals (ages 8 to 23 y). We found that spatial variability in structure–function coupling aligned with cortical hierarchies of functional specialization and evolutionary expansion. Furthermore, hierarchy-dependent age effects on structure–function coupling localized to transmodal cortex in both cross-sectional data and a subset of participants with longitudinal data ( n = 294). Moreover, structure–function coupling in rostrolateral prefrontal cortex was associated with executive performance and partially mediated age-related improvements in executive function. Together, these findings delineate a critical dimension of adolescent brain development, whereby the coupling between structural and functional connectivity remodels to support functional specialization and cognition.

OBJECTIVE: To provide clinically meaningful, normative reference data that describe the timing of sexual maturity indicators among a national sample of US children and to determine the degree of racial/ethnic differences in these estimates for each maturity indicator. METHODS: Tanner staging assessment of sexual maturity indicators was recorded from 4263 non-Hispanic white, black, and Mexican American girls and boys aged 8.00 to 19.00 years as part of the Third National Health and Nutrition Examination Survey (NHANES III) conducted between 1988 and 1994. NHANES III followed a complex, stratified, multistage probability cluster design. SUDAAN was used to calculate the mean age and standard error for each maturity stage and the proportion of entry into a maturity stage and to incorporate the sampling weight and design effects of the NHANES III complex sampling design. Probit analysis and median age at entry into a maturity stage and its fiducial limits were calculated using SAS 8.2. RESULTS: Reference data for age at entry for maturity stages are presented in tabular and graphical format. Non-Hispanic black girls had an earlier sexual development for pubic hair and breast development either by median age at entry for a stage or for the mean age for a stage than Mexican American or non-Hispanic white girls. There were few to no significant differences between the Mexican American and non-Hispanic white girls. Non-Hispanic black boys also had earlier median and mean ages for sexual maturity stages than the non-Hispanic white and Mexican American boys. CONCLUSION: Non-Hispanic black girls and boys mature early, but US children completed their sexual development at approximately the same ages. The present reference data for the timing of sexual maturation are recommended for the interpretation of assessments of sexual maturity in US children.

The appropriate treatment and control of infectious gastroenteritis depend on the ability to rapidly detect the wide range of etiologic agents associated with the disease. Clinical laboratories currently utilize an array of different methodologies to test for bacterial, parasitic, and viral causes of gastroenteritis, a strategy that suffers from poor sensitivity, potentially long turnaround times, and complicated ordering practices and workflows. Additionally, there are limited or no testing methods routinely available for most diarrheagenic Escherichia coli strains, astroviruses, and sapoviruses. This study assessed the performance of the FilmArray Gastrointestinal (GI) Panel for the simultaneous detection of 22 different enteric pathogens directly from stool specimens: Campylobacter spp., Clostridium difficile (toxin A/B), Plesiomonas shigelloides, Salmonella spp., Vibrio spp., Vibrio cholerae, Yersinia enterocolitica, enteroaggregative E. coli, enteropathogenic E. coli, enterotoxigenic E. coli, Shiga-like toxin-producing E. coli (stx1 and stx2) (including specific detection of E. coli O157), Shigella spp./enteroinvasive E. coli, Cryptosporidium spp., Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia, adenovirus F 40/41, astrovirus, norovirus GI/GII, rotavirus A, and sapovirus. Prospectively collected stool specimens (n = 1,556) were evaluated using the BioFire FilmArray GI Panel and tested with conventional stool culture and molecular methods for comparison. The FilmArray GI Panel sensitivity was 100% for 12/22 targets and ≥94.5% for an additional 7/22 targets. For the remaining three targets, sensitivity could not be calculated due to the low prevalences in this study. The FilmArray GI Panel specificity was ≥97.1% for all panel targets. The FilmArray GI Panel provides a comprehensive, rapid, and streamlined alternative to conventional methods for the etiologic diagnosis of infectious gastroenteritis in the laboratory setting. The potential advantages include improved performance parameters, a more extensive menu of pathogens, and a turnaround time of as short as 1 h.

With the growing popularity of intensive longitudinal research, the modeling techniques and software options for such data are also expanding rapidly. Here we use dynamic multilevel modeling, as it is incorporated in the new dynamic structural equation modeling (DSEM) toolbox in Mplus, to analyze the affective data from the COGITO study. These data consist of two samples of over 100 individuals each who were measured for about 100 days. We use composite scores of positive and negative affect and apply a multilevel vector autoregressive model to allow for individual differences in means, autoregressions, and cross-lagged effects. Then we extend the model to include random residual variances and covariance, and finally we investigate whether prior depression affects later depression scores through the random effects of the daily diary measures. We end with discussing several urgent-but mostly unresolved-issues in the area of dynamic multilevel modeling.

INTRODUCTION: In 2015, the US Alzheimer's Disease Centers (ADC) implemented Version 3 of the Uniform Data Set (UDS). This paper describes the history of Version 3 development and the UDS data that are freely available to researchers. METHODS: UDS Version 3 was developed after years of coordination between the National Institute on Aging-appointed Clinical Task Force (CTF), clinicians from ∼30 ADCs, and the National Alzheimer's Coordinating Center (NACC). The CTF recognized the need for updates to align with the state of the science in dementia research, while being flexible to the diverse needs and diseases studied at the ADCs. Version 3 also developed a nonproprietary neuropsychological battery. RESULTS: This paper focuses on the substantial Version 3 changes to the UDS forms related to clinical diagnosis and characterization of clinical symptoms to match updated consensus-based diagnostic criteria. Between March 2015 and March 2018, 4820 participants were enrolled using UDS Version 3. Longitudinal data were available for 25,337 of the 37,568 total participants using all UDS versions. DISCUSSION: The results from utilization of the UDS highlight the possibility for numerous research institutions to successfully collaborate, produce, and use standardized data collection instruments for over a decade.