Interrogating the Roles of Mutation-Selection Balance, Heterozygote Advantage, and Linked Selection in Maintaining Recessive Lethal Variation in Natural Populations.

For nearly a century, evolutionary biologists have observed chromosomes that cause lethality when made homozygous persisting at surprisingly high frequencies (>25%) in natural populations of many species. The evolutionary forces responsible for the maintenance of such detrimental mutations have been heavily debated-are some lethal mutations under balancing selection? We suggest that mutation-selection balance alone cannot explain lethal variation in nature and the possibility that other forces play a role. We review the potential that linked selection in particular may drive maintenance of lethal alleles through associative overdominance or linkage to beneficial mutations or by reducing effective population size. Over the past five decades, investigation into this mystery has tapered. During this time, key scientific advances have provided the ability to collect more accurate data and analyze them in new ways, making the underlying genetic bases and evolutionary forces of lethal alleles timely for study once more.

Leading During a Pandemic: A School Nurse Administrator Roundtable.

The ongoing COVID-19 pandemic has been taxing to healthcare workers, no less for those serving on the front lines in schools. From initial school closures and online learning to gradual reopening with hybrid learning models, to full in-person learning, school nurse administrators provided guidance in collaboration with public health officials, based on evolving information. Infection control was at the forefront, while government and scientists partnered to quickly develop effective vaccines. Technology provided new virtual platforms for learning, conducting meetings, and socialization, while also being widely used to deliver information, misinformation, and disinformation. Challenges have been numerous, but school nurse administrators and school nurses in general, with a commitment to the health and safety of their populations, continue to adapt to the ever-changing demands. The journal's Editorial Advisory Board interviewed five school nurse administrators, representative of diverse geographic locations, school population size, and employer models, to capture their reflections on school health leadership during the COVID-19 pandemic. History is deserving of their stories.

Customized Template for Occlusal Correction in Full Mouth Rehabilitation: A Case Report.

Reestablishing the occlusal plane involves multidisciplinary approach with extensive restorative procedure to accomplish "equilibration." Broadrick occlusal plane analyzer (BOPA) provides an easy and practical method to commensurate for curve of Spee and establishing the occlusal plane. Transferring the new occlusal plane from the diagnostic model to patients mouth needs to be precise. To achieve controlled conservative reduction, customized acrylic template was a vital tool used in this case to transfer the exact plane correction achieved by the BOPA.

Functional Brain Hyperactivations Are Linked to an Electrophysiological Measure of Slow Interhemispheric Transfer Time after Pediatric Moderate/Severe Traumatic Brain Injury.

Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker.

[Preparation and transplant in the care pathway in haematology]. / Conditionnement et greffe dans le parcours de soins en hématologie.

The stages of the preparation and subsequent allograft of haematopoietic stem cells are particularly demanding in terms of quality and safety and require the mobilisation of a multidisciplinary nursing team. Working closely with the patients, the nurse ensures hygiene measures are respected in order to minimise the risks of aplasia. She supports them in the prevention and management of the side effects linked to the treatment and surrounds them with all the relational support they need in this difficult stage of their care pathway.

Virtual Reality Assessment of Classroom - Related Attention: An Ecologically Relevant Approach to Evaluating the Effectiveness of Working Memory Training.

Computerized cognitive interventions to improve working memory also purport to improve ADHD-related inattention and off task behavior. Such interventions have been shown to improve working memory, executive functioning, and fluid reasoning on standardized neuropsychological measures. However, debate continues as to whether such programs lead to improvement on ecologically relevant outcomes, such as classroom behavior. This study sought to propose a novel, ecologically relevant approach to evaluate the effectiveness of working memory training on real-world attention performance. Participants included 15 children, aged 6-15, identified as having attention problems were assessed via the virtual classroom continuous performance task (VCCPT) before and after completing 5 weeks of Cogmed working memory training. The VCCPT is a validated measure of sustained and selective attention set within a virtual reality (VR) environment. Several key areas of attention performance were observed to improve, including omission errors, reaction time, reaction time variability, and hit variability. Results suggest that working memory training led to substantial improvements in sustained attention in a real-life scenario of classroom learning. Moreover, the use of psychometrically validated VR measurement provides incremental validity beyond that of teacher or parent report of behavior. Observing such improvements on ecologically relevant measures of attention adds to the discussion around how to evaluate the effectiveness of working memory training as it pertains to real-life improvements and serves to inform consumer awareness of such products and their claims.

Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan.

Transcriptional modulation of the process of autophagy involves the transcription factor HLH-30/TFEB. In order to systematically determine the regulatory network of HLH-30/TFEB, we performed a genome-wide RNAi screen in C. elegans and found that silencing the nuclear export protein XPO-1/XPO1 enhances autophagy by significantly enriching HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity. Lifespan extension via xpo-1 silencing requires HLH-30 and autophagy, overlapping mechanistically with several established longevity models. Selective XPO1 inhibitors recapitulated the effect on autophagy and lifespan observed by silencing xpo-1 and protected ALS-afflicted flies from neurodegeneration. XPO1 inhibition in HeLa cells enhanced TFEB nuclear localization, autophagy, and lysosome biogenesis without affecting mTOR activity, revealing a conserved regulatory mechanism for HLH-30/TFEB. Altogether, our study demonstrates that altering the nuclear export of HLH-30/TFEB can regulate autophagy and establishes the rationale of targeting XPO1 to stimulate autophagy in order to prevent neurodegeneration.

"Same-Day" administration of pegfilgrastim following myelosuppressive chemotherapy: clinical practice and provider rationale.

PURPOSE: To describe patient- and practice-related factors that physicians report affect their clinical decision to administer prophylactic pegfilgrastim to patients <24 h after completion of a myelosuppressive chemotherapy cycle (i.e., "same-day" pegfilgrastim). METHODS: Oncologists, hematologists, and hematologist-oncologists enrolled in a US national physician panel were invited to participate in a cross-sectional, web-based survey to assess physicians' reasons for prescribing "same-day" pegfilgrastim. Physicians were screened as eligible if they reported prescribing "same-day" pegfilgrastim within the previous 6 months. The survey assessed physician perspectives and physician-perceived patient/caregiver preferences. RESULTS: Of 17,478 invited physicians, 386 answered the screening questions; 151 (39.1 %) were eligible, agreed to participate, and completed the survey. Physicians estimated that overall 41.3 % of their patients treated with myelosuppressive chemotherapy received pegfilgrastim and that 31.6 % treated with pegfilgrastim received it on a "same-day" schedule. Approximately 36 % of physicians relied primarily on their clinical judgment when deciding to administer "same-day" pegfilgrastim. The clinical consideration reported most commonly by physicians as moderately or very important when deciding to administer "same-day" pegfilgrastim was previous febrile neutropenia (77.6 %). The most important patient-related consideration in the decision to administer "same-day" pegfilgrastim was patient/caregiver travel distance, and the most important practice-related consideration was the burden to the physician's practice of "next-day" administration (vs. same-day), reported by 84.7 % and 65.1 % of physicians as moderately or very important, respectively. CONCLUSIONS: While clinical judgment, patients' risk factors, and practice burden were principal influences favoring "same-day" pegfilgrastim administration, physician-perceived patient preferences and logistical barriers also have important roles in this decision.

The UCLA Study of Children with Moderate-to-Severe Traumatic Brain Injury: Event-Related Potential Measure of Interhemispheric Transfer Time.

Traumatic brain injury (TBI) frequently results in diffuse axonal injury and other white matter damage. The corpus callosum (CC) is particularly vulnerable to injury following TBI. Damage to this white matter tract has been associated with impaired neurocognitive functioning in children with TBI. Event-related potentials can identify stimulus-locked neural activity with high temporal resolution. They were used in this study to measure interhemispheric transfer time (IHTT) as an indicator of CC integrity in 44 children with moderate/severe TBI at 3-5 months post-injury, compared with 39 healthy control children. Neurocognitive performance also was examined in these groups. Nearly half of the children with TBI had IHTTs that were outside the range of the healthy control group children. This subgroup of TBI children with slow IHTT also had significantly poorer neurocognitive functioning than healthy controls-even after correction for premorbid intellectual functioning. We discuss alternative models for the relationship between IHTT and neurocognitive functioning following TBI. Slow IHTT may be a biomarker that identifies children at risk for poor cognitive functioning following moderate/severe TBI.

Callosal Function in Pediatric Traumatic Brain Injury Linked to Disrupted White Matter Integrity.

Traumatic brain injury (TBI) often results in traumatic axonal injury and white matter (WM) damage, particularly to the corpus callosum (CC). Damage to the CC can lead to impaired performance on neurocognitive tasks, but there is a high degree of heterogeneity in impairment following TBI. Here we examined the relation between CC microstructure and function in pediatric TBI. We used high angular resolution diffusion-weighted imaging (DWI) to evaluate the structural integrity of the CC in humans following brain injury in a sample of 32 children (23 males and 9 females) with moderate-to-severe TBI (msTBI) at 1-5 months postinjury, compared with well matched healthy control children. We assessed CC function through interhemispheric transfer time (IHTT) as measured using event-related potentials (ERPs), and related this to DWI measures of WM integrity. Finally, the relation between DWI and IHTT results was supported by additional results of neurocognitive performance assessed using a single composite performance scale. Half of the msTBI participants (16 participants) had significantly slower IHTTs than the control group. This slow IHTT group demonstrated lower CC integrity (lower fractional anisotropy and higher mean diffusivity) and poorer neurocognitive functioning than both the control group and the msTBI group with normal IHTTs. Lower fractional anisotropy-a common sign of impaired WM-and slower IHTTs also predicted poor neurocognitive function. This study reveals that there is a subset of pediatric msTBI patients during the post-acute phase of injury who have markedly impaired CC functioning and structural integrity that is associated with poor neurocognitive functioning. SIGNIFICANCE STATEMENT: Traumatic brain injury (TBI) is the primary cause of death and disability in children and adolescents. There is considerable heterogeneity in postinjury outcome, which is only partially explained by injury severity. Imaging biomarkers may help explain some of this variance, as diffusion weighted imaging is sensitive to the white matter disruption that is common after injury. The corpus callosum (CC) is one of the most commonly reported areas of disruption. In this multimodal study, we discovered a divergence within our pediatric moderate-to-severe TBI sample 1-5 months postinjury. A subset of the TBI sample showed significant impairment in CC function, which is supported by additional results showing deficits in CC structural integrity. This subset also had poorer neurocognitive functioning. Our research sheds light on postinjury heterogeneity.

From depolarization-dependent contractions in gastrointestinal smooth muscle to aortic pulse-synchronized contractions.

For decades, it was believed that the diameter of gastrointestinal smooth muscle cells is sufficiently narrow, and that the diffusion of calcium across the plasma membrane is sufficient, to support contractile activity. Thus, depolarization-triggered release of intracellular calcium was not believed to be operative in gastrointestinal smooth muscle. However, after the incubation of muscle segments in solutions devoid of calcium and containing the calcium chelator ethylene glycol tetraacetic acid, an alternative electrical event occurred that was distinct from normal slow waves and spikes. Subsequently, it was demonstrated in gastrointestinal smooth muscle segments that membrane depolarization associated with this alternative electrical event triggered rhythmic contractions by release of intracellular calcium. Although this concept of depolarization-triggered calcium release was iconoclastic, it has now been demonstrated in multiple gastrointestinal smooth muscle preparations. On the basis of these observations, we investigated whether a rhythmic electrical and mechanical event would occur in aortic smooth muscle under the same calcium-free conditions. The incubation of aortic segments in a solution with no added calcium plus ethylene glycol tetraacetic acid induced a fast electrical event without corresponding tension changes. On the basis of the frequency of these fast electrical events, we pursued, contrary to what has been established dogma for more than three centuries, the question of whether the smooth muscle wall of the aorta undergoes rhythmic activation during the cardiac cycle. As with depolarization-triggered contractile activity in gastrointestinal smooth muscle, it was "well known" that rhythmic activation of the aorta does not occur in synchrony with the heartbeat. In a series of experiments, however, it was demonstrated that rhythmic contractions occur in the aortic wall in synchrony with the heartbeat and share a common pacemaker with the heart. We conclude that important observations in the vascular system became derivative from those in the gastrointestinal system. The challenging of scientific dogma potentially leads to the expansion of our fundamental knowledge base.

Executive function changes before memory in preclinical Alzheimer's pathology: a prospective, cross-sectional, case control study.

BACKGROUND: Early treatment of Alzheimer's disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer's disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology. METHODS AND FINDINGS: We recruited adults with probable Alzheimer's disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer's disease. We separated the asymptomatic group into those with (n = 34; preclinical Alzheimer's disease) and without (n = 36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-ε genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR = 0.13, 95% CI = 0.04-0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study. CONCLUSIONS: Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer's disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach.

The Warrington Recognition Memory Test for words as a measure of response bias: total score and response time cutoffs developed on "real world" credible and noncredible subjects.

Several studies have examined the usefulness of the Warrington Recognition Memory Test-Words as a measure to detect suspect effort, although samples have generally been small and/or comprised of simulators rather than "real world" credible and noncredible patients. The current study examined the Warrington Recognition Memory Test-Words total score and response time of "real world" noncredible patients (as determined by motive to feign, failure on > or =2 independent measures of response bias, low cognitive scores inconsistent with normal ADLs; n = 190) versus credible patients (as determined by no motive to feign, failure of < or =1 measure of response bias; n = 124) derived from an archival database of individuals from the Harbor-UCLA Medical Center, Department of Psychiatry, Outpatient Neuropsychology Service, and the private practice of the second author. Noncredible patients obtained significantly lower total scores and longer times to complete the task. A total correct cutoff of < or =42 was found to have excellent specificity (91.9%) and sensitivity (88.9%), whereas a time cutoff of > or =207'' was associated with 65.5% sensitivity at 90.7% specificity, and when the time cut-score was used in combination with the total score cutoff, an additional 5% of the noncredible participants were captured, raising overall sensitivity to 93.7% (at 87.1% specificity). Thus, the Warrington Recognition Memory Test-Words, although not originally created for the purposes of measuring suspect effort, appears to be an excellent measure for detecting response bias on neuropsychological testing.

Examination of various WMS-III logical memory scores in the assessment of response bias.

The assessment of response validity during neuropsychological evaluation is an integral part of the testing process. Research has increasingly focused on the use of "embedded" effort measures (derived from standard neuropsychological tasks) because they do not require additional administration time and are less likely to be identified as effort indicators by test takers because of their primary focus as measures of cognitive function. The current study examined the clinical utility of various WMS-III Logical Memory scores in detecting response bias, as well as the Rarely Missed Index, an embedded effort indicator derived from the WMS-III Logical Memory Delayed Recognition subtest. The Rarely Missed Index cut-off only identified 24.1% of 63 non-credible participants (at >/=90% specificity in 125 credible patients), and cut-offs for other Logical Memory variables were in fact found to be more sensitive to non-credible performance. A new indicator, consisting of the weighted combination of the two most sensitive Logical Memory subtest scores (Logical Memory II raw score and Logical Memory Delayed Recognition raw score), was associated with 53% to 60% sensitivity, and thus may be an effective adjunct when utilized in conjunction with other validated effort indicators and collateral information in identifying non-credible performance.

Metabolic levels in the corpus callosum and their structural and behavioral correlates after moderate to severe pediatric TBI.

Diffuse axonal injury (DAI) secondary to traumatic brain injury (TBI) contributes to long-term functional morbidity. The corpus callosum (CC) is particularly vulnerable to this type of injury. Magnetic resonance spectroscopy (MRS) was used to characterize the metabolic status of two CC regions of interest (ROIs) (anterior and posterior), and their structural (diffusion tensor imaging; DTI) and neurobehavioral (neurocognitive functioning, bimanual coordination, and interhemispheric transfer time [IHTT]) correlates. Two groups of moderate/severe TBI patients (ages 12-18 years) were studied: post-acute (5 months post-injury; n = 10), and chronic (14.7 months post-injury; n = 8), in addition to 10 age-matched healthy controls. Creatine (energy metabolism) did not differ between groups across both ROIs and time points. In the TBI group, choline (membrane degeneration/inflammation) was elevated for both ROIs at the post-acute but not chronic period. N-acetyl aspartate (NAA) (neuronal/axonal integrity) was reduced initially for both ROIs, with partial normalization at the chronic time point. Posterior, not anterior, NAA was positively correlated with DTI fractional anisotropy (FA) (r = 0.88), and most domains of neurocognition (r range 0.22-0.65), and negatively correlated with IHTT (r = -0.89). Inverse corerlations were noted between creatine and posterior FA (r = -0.76), neurocognition (r range -0.22 to -0.71), and IHTT (r = 0.76). Multimodal studies at distinct time points in specific brain structures are necessary to delineate the course of the degenerative and reparative processes following TBI, which allows for preliminary hypotheses about the nature and course of the neural mechanisms of subsequent functional morbidity. This will help guide the future development of targeted therapeutic agents.

Bimanual motor coordination in agenesis of the corpus callosum.

The nature and extent of deficiencies in bimanual motor coordination in individuals with agenesis of the corpus callosum (ACC) was studied using the computerized Bimanual Coordination Test (cBCT). Compared with previous bimanual tasks, the cBCT is more specifically reliant on interhemispheric interactions of lateralized motor control, allows more precise measurement, and permits examination of performance over a wider range of bimanual challenges. The cBCT performance of 13 high-functioning individuals with complete ACC was compared to 21 age- and IQ-matched controls. The groups did not differ in unimanual response speed. On trials involving angled paths that require bimanual coordination, the ACC group performed significantly slower and less accurately across all angles. The largest group differences in speed occurred on trials where the hands must respond symmetrically, while mirror-image (vs. parallel) responding produced the greatest deficits in accuracy. These data confirm previous findings of deficits in bimanual coordination in callosal absence, but using significantly improved measurement technology. Deficits in bimanual coordination in ACC are present across different demands for interhand interactions in the speed and direction of movement.

The role of proopiomelanocortin (POMC) in sequentially dependent self-injurious behavior.

Self-injuring behavior (SIB) is a life-threatening behavior exhibited by many species, including humans, and has no known cause and no agreed upon treatment. The role of the stress axis in the maintenance of this mysterious behavior was examined in subjects with life-long SIB. Over a 6-year period, 40 hr of direct observations of behavior and the environment were recorded on palmtop computers while 36 residential subjects (28 target and 8 control subjects) conducted their daily activities. Blood samples were collected in morning and evening for all subjects and within minutes after a self-injuring act in 28 target subjects who exhibited SIB to determine levels of ACTH and B-endorphin (BE). Self-injuring events in the patient group were significantly sequentially dependent (i.e., the only predictor of a self-injuring act was an antecedent self-injuring act). Higher morning levels of BE relative to ACTH predicted [r(df=27) = .57, p < .001] the sequentially dependent pattern of SIB. This effect was validated in a subgroup retested several months later [r(df=22) = .60, p < .001]. A subgroup of seven subjects exhibiting sequentially dependent patterns were administered an opiate blocker (naltrexone) in a double-blind, crossover design with an additional 14 hr/week of observation for 7 weeks. Naltrexone challenge interrupted the sequential pattern (improved behavior) in subjects with elevated BE immediately following SIB (r = .85, p < .01). The pattern of results supported the conclusion that the stress axis played a significant role in the maintenance of complex episodes of self-injury.

Age-associated predictors of medication adherence in HIV-positive adults: health beliefs, self-efficacy, and neurocognitive status.

OBJECTIVE: Although most agree that poor adherence to antiretrovirals is a common problem, relatively few factors have been shown to consistently predict treatment failure. In this study, a theoretical framework encompassing demographic characteristics, health beliefs/attitudes, treatment self-efficacy, and neurocognitive status was examined in relationship to highly active antiretroviral therapy adherence. DESIGN: Prospective, cross-sectional observational design. MAIN OUTCOME MEASURES: Neuropsychological test performance, health beliefs and attitudes, and medication adherence tracked over a 1-month period using electronic monitoring technology (Medication Event Monitoring System caps). RESULTS: The rate of poor adherence was twice as high among younger participants than with older participants (68% and 33%, respectively). Results of binary logistic regression revealed that low self-efficacy and lack of perceived treatment utility predicted poor adherence among younger individuals, whereas decreased levels of neurocognitive functioning remained the sole predictor of poor adherence among older participants. CONCLUSION: These data support components of the health beliefs model in predicting medication adherence among younger HIV-positive individuals. However, risk of adherence failure in those ages 50 years and older appears most related to neurocognitive status.