The venous system of E14.5 mouse embryos-reference data and examples for diagnosing malformations in embryos with gene deletions.

Approximately one-third of randomly produced knockout mouse lines produce homozygous offspring, which fail to survive the perinatal period. The majority of these die around or after embryonic day (E)14.5, presumably from cardiovascular insufficiency. For diagnosing structural abnormalities underlying death and diseases and for researching gene function, the phenotype of these individuals has to be analysed. This makes the creation of reference data, which define normal anatomy and normal variations the highest priority. While such data do exist for the heart and arteries, they are still missing for the venous system. Here we provide high-quality descriptive and metric information on the normal anatomy of the venous system of E14.5 embryos. Using high-resolution digital volume data and 3D models from 206 genetically normal embryos, bred on the C57BL/6N background, we present precise descriptive and metric information of the venous system as it presents itself in each of the six developmental stages of E14.5. The resulting data shed new light on the maturation and remodelling of the venous system at transition of embryo to foetal life and provide a reference that can be used for detecting venous abnormalities in mutants. To explore this capacity, we analysed the venous phenotype of embryos from 7 knockout lines (Atp11a, Morc2a, 1700067K01Rik, B9d2, Oaz1, Celf4 and Coro1c). Careful comparisons enabled the diagnosis of not only simple malformations, such as dual inferior vena cava, but also complex and subtle abnormalities, which would have escaped diagnosis in the absence of detailed, stage-specific referenced data.

A staging system for correct phenotype interpretation of mouse embryos harvested on embryonic day 14 (E14.5).

We present a simple and quick system for accurately scoring the developmental progress of mouse embryos harvested on embryonic day 14 (E14.5). Based solely on the external appearance of the maturing forelimb, we provide a convenient way to distinguish six developmental sub-stages. Using a variety of objective morphometric data obtained from the commonly used C57BL/6N mouse strain, we show that these stages correlate precisely with the growth of the entire embryo and its organs. Applying the new staging system to phenotype analyses of E14.5 embryos of 58 embryonic lethal null mutant lines from the DMDD research programme (https://dmdd.org.uk) and its pilot, we show that homozygous mutant embryos are frequently delayed in development. To demonstrate the importance of our staging system for correct phenotype interpretation, we describe stage-specific changes of the palate, heart and gut, and provide examples in which correct diagnosis of malformations relies on correct staging.

Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy.

HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the ß-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue. Allelic imbalance has been shown to occur in a broad range of genes. Therefore, we aimed to examine whether the MYH7-alleles are intrinsically expressed imbalanced or whether the allelic imbalance is solely associated with the disease. We compared the expression of MYH7-alleles in non-HCM donors and in HCM-patients with different MYH7-missense mutations. In the HCM-patients, we identified imbalanced as well as equal expression of both alleles. Also at the protein level, allelic imbalance was determined. Most interestingly, we also discovered allelic imbalance and balance in non-HCM donors. Our findings therefore strongly indicate that apart from mutation-specific mechanisms, also non-HCM associated allelic-mRNA expression regulation may account for the allelic imbalance of the MYH7 gene in HCM-patients. Since the relative amount of mutant mRNA and protein or the extent of allelic imbalance has been associated with the severity of HCM, individual analysis of the MYH7-allelic expression may provide valuable information for the prognosis of each patient.

The longitudinal relationship between quality of life and survival in advanced stage cancer.

OBJECTIVES: Quality of Life (QoL) at baseline is frequently found to be a prognostic factor in cancer studies. However, little is known about the relationship of the trajectory of QoL and survival in patients with advanced cancer. This study evaluates the effects of both level and change of QoL on survival to explore the potential of utilizing longitudinal information of QoL for prognosis. METHODS: A series of joint models were used in a sample (N = 512) of patients diagnosed with advanced cancer (sample consisted of nine different cancer sites) with assessments of QoL across six time points and with survival information recorded up to 28 months after diagnosis. We used FACT-G as the QoL measure, and we evaluated the effects of change in QoL controlling for the time-dependent effects of chemotherapy and radiation. RESULTS: The median survival for patients was 14.2 months, and 10% of the sample had survived beyond 28 months after the diagnosis of advanced cancer. The effect of change of QoL on survival was significant (hazard ratio = 0.98; p < 0.001) controlling for time-dependent treatment effects. Also, the slope of the trajectory in QoL was found to be a significant predictor of survival (hazard ratio = 0.18; p < 0.001). CONCLUSION: These preliminary findings suggest that the patient's longitudinal experience in QoL may be a significant prognostic factor of survival, a novel finding with potentially important implications in medical decision making. Longitudinal information on QoL can be used for updating the patient's prognosis of survival.

Cancer patient age and family caregiver bereavement outcomes.

PURPOSE: This study drew on life course theory to argue that the strains of cancer caregiving and bereavement are modified by the age of the patient. We expected that caregivers of middle-aged patients would be more distressed than caregivers of older patients. METHODS: This panel study conducted 199 interviews with family caregivers of advanced cancer patients; first following diagnosis and again shortly after the patient's death. RESULTS: Among caregivers of middle-aged patients (40-59), grief mediated the relationship between baseline caregiving and bereavement depressed mood, with grief increasing risk of depression in bereavement. Among caregivers of young-old patients (60-79), grief had a suppressor effect on the relationship between caregiving and bereavement depressed mood, showing greater distress during caregiving than at bereavement. CONCLUSIONS: Caregiving for middle-aged cancer patients may increase the risk for severe grief and depression, whereas caregivers of young-old cancer patients appeared to experience relief at bereavement. After bereavement, continued observation may be warranted for caregivers of a middle-aged patient; grief, added to the ongoing demands of their lives (which may include those left behind by a middle-aged patient), may put such caregivers at risk for greater psychological and emotional distress.

Preferences for aggressive care in underserved populations with advanced-stage lung cancer: looking beyond race and resuscitation.

PURPOSE: This paper examines the relationship between race, religiousness, spiritual well-being, antitumor treatment and preference for aggressive care among Black and White patients with advanced stage lung cancer receiving ambulatory cancer care in an urban setting. METHODS: A cross-sectional exploration of patients enrolled in a Cleveland-based longitudinal study after initial diagnosis of advanced lung cancer were interviewed in Cleveland regarding religiousness, spiritual well-being, preferences for cardiopulmonary resuscitation (CPR), goals of aggressive care, and willingness to tolerate adverse health states. Receipt of antitumor treatment was identified from medical records. RESULTS: We analyzed data from 67 Black and 129 White patients (N=196). Regression analysis for CPR showed that race was not associated with preference for CPR (OR=1.12, CI 0.44-2.85). The odds of choosing CPR were three times higher among patients receiving antitumor treatment (OR=3.26, CI 1.12-9.44). Greater willingness to endure adverse health states was associated with higher spiritual well-being scores (b=0.12, CI 0.01-0.25). Choosing goals to extend life versus relieve pain was higher among persons with higher spiritual well-being as well (RRR=1.08, CI 1.01-1.16), yet the relationship with religiousness was negative (RRR=0.46, CI 0.22-0.98). CONCLUSIONS: After controlling for multiple factors, race was associated only with CPR, but not with other measures of preference for aggressive care. In addition, receipt of active antitumor treatment was positively associated with preference for CPR and spiritual well-being was important to setting end-of-life care goals and perspectives. Future directions for tailoring end-of-life care decision-making initiatives should move beyond race and discussions of CPR alone and focus on a full spectrum of patient beliefs and preferences at the end of life.

Sleepiness in elderly veterans.

PURPOSE: This observational study seeks to describe the distribution of sleepiness among elderly male veterans and to explain the relationship between sleepiness and age, function, mobility, and depression in this population. METHODS: Veterans who were age 60 or older and had two or more functional limitations based on their activities of daily living or instrumental activities of daily living were recruited in outpatient clinics. They were recruited as part of a longitudinal study and completed questionnaires reported here at the 18-month data collection time point. RESULTS: Veterans report higher sleepiness than normal controls. Self-reported sleepiness scores are similar to those of patients who have been diagnosed with sleep disturbances. CONCLUSIONS: Interventions to identify and support aging veterans with perceived sleepiness should be developed and carefully evaluated.

An Exploration of the relative influence of patient's age and cancer recurrence status on symptom distress, anxiety, and depression over time.

Past research suggests that psychosocial responses to advanced or recurrent cancer vary by age. This study compares the relative influences of patients' age and recurrence status on indicators of symptom distress, anxiety, and depression following a diagnosis of advanced cancer. A prospective study of advanced cancer support provided patient outcome data reported at baseline, 3-, and 6-month intervals. Cohorts were defined by age group and recurrence status and latent growth curves fit to anxiety, depression, and symptom distress outcomes. Middle-age recurrent patients reported the highest symptom distress, depression, and anxiety across time points. Older recurrent patients fared worse at baseline than older nonrecurrent patients, but outcome scores converged across time points. Recurrent cancer presents a distinct challenge that, for middle-age patients, persists across time. It may be beneficial to develop targeted educational and support resources for middle-age patients with recurrent disease.

Mitigating Racial Inequity by Addressing Racism in the Criminal Justice System: A Behavior Analytic Approach.

Racial inequity in the U.S. criminal justice system is a long-standing problem that has recently garnered international attention. This article frames the problem of racial inequity in a behavior analytic context and offers potential solutions based on existent research and behavior analytic principles. We draw a parallel between the analysis of racist behavior enabled by the definitions provided by Kendi in How to Be an Antiracist and the analysis of verbal behavior made possible by the terminology posited by Skinner in Verbal Behavior in order to highlight the pertinence of applying a behavior analytic approach to the problem of racial inequity upheld by racist behavior. Immediately actionable steps to address racism in the criminal justice system and beyond are offered on a cultural, organizational, and individual level.

Production can enhance semantic encoding: Evidence from forced-choice recognition with homophone versus synonym lures.

The production effect-better memory for words read aloud rather than silently-has been attributed to responses at test being guided by memory for the act of production. In Experiment 1, we evaluated this distinctiveness account by comparing production effects in forced-choice recognition when lures were either homophones of the targets (toad or towed?) or unrelated words (toad or seam?). If the production effect at test was driven solely by memory for the productive act (e.g., articulation, auditory processing), then the effect should be reduced with homophone lures. Contrary to that prediction, the production effect did not differ credibly between homophone-lure and unrelated-lure groups. Experiment 1 led us to hypothesize that production may also boost semantic encoding, and that participants use memory of semantic encoding to guide their forced-choice responses. Consistent with these hypotheses, using synonym lures to interfere with semantic-based decisions (poison or venom?) reduced the production effect relative to using unrelated lures (poison or ethics?) in Experiment 2. Our findings suggest that enhanced conceptual encoding may be another useful product of production.

Comorbid obsessive-compulsive disorder in individuals with eating disorders: An epidemiological meta-analysis.

The present study aimed to provide a precise, meta-analytic estimate of the prevalence of obsessive-compulsive disorder (OCD) amongst those with a current primary eating disorder (ED) diagnosis, and to isolate its predictors. An online search of PubMed and PsycINFO was conducted with a Boolean search phrase incorporating keywords related to OCD, EDs, comorbidity, prevalence, and epidemiology, complemented by references coded from related review articles and contact with experts in the field. Articles were included if they (a) reported an observational study examining current ED diagnoses, (b) used a semi-structured or structured diagnostic interview for OCD and ED diagnosis, (c) applied DSM or ICD criteria, (d) included adolescent or adult samples (age > 12), (e) included patient or community samples, and (f) reported lifetime or current OCD comorbidity. From the 846 articles identified, 35 lifetime and 42 current estimates were calculated. OCD prevalence was extracted from each study for each ED diagnostic category, along with eleven additional potential moderators. Analyses revealed an aggregate lifetime OCD prevalence of 13.9% CI95% [10.4 to 18.1] and current OCD prevalence of 8.7% CI95% [5.8 to 11.8] across EDs. Moderator analyses revealed the prevalence of and risk for OCD in EDs to be greatest in anorexia nervosa binge-eating purging type (ANBP). Further, OCD is most prevalent amongst patient samples than samples recruited from the community.

Artefacts in Volume Data Generated with High Resolution Episcopic Microscopy (HREM).

High resolution episcopic microscopy (HREM) produces digital volume data by physically sectioning histologically processed specimens, while capturing images of the subsequently exposed block faces. Our study aims to systematically define the spectrum of typical artefacts inherent to HREM data and to research their effect on the interpretation of the phenotype of wildtype and mutant mouse embryos. A total of 607 (198 wildtypes, 409 mutants) HREM data sets of mouse embryos harvested at embryonic day (E) 14.5 were systematically and comprehensively examined. The specimens had been processed according to essentially identical protocols. Each data set comprised 2000 to 4000 single digital images. Voxel dimensions were 3 × 3 × 3 µm3. Using 3D volume models and virtual resections, we identified a number of characteristic artefacts and grouped them according to their most likely causality. Furthermore, we highlight those that affect the interpretation of embryo data and provide examples for artefacts mimicking tissue defects and structural pathologies. Our results aid in optimizing specimen preparation and data generation, are vital for the correct interpretation of HREM data and allow distinguishing tissue defects and pathologies from harmless artificial alterations. In particular, they enable correct diagnosis of pathologies in mouse embryos serving as models for deciphering the mechanisms of developmental disorders.

Relationship quality and burden among caregivers for late-stage cancer patients.

OBJECTIVE: This study explores how caregiver relationship quality with family, patient, and patient's health care provider (HCP) is associated with subjective caregiver burden during the early treatment phase for late-stage cancer. METHOD: Burden and relationship quality were assessed in telephone interviews with family caregivers (FCGs) of advanced cancer patients. The five subscales of the Caregiver Reaction Assessment measured burden, while relationships were measured with the Family Relationship Index, the Family Inventory of Needs subscale of met needs, and a scale assessing family discord in cancer communication. RESULTS: Multiple linear regression analyses in SPSS (v16) of 420 FCGs showed that higher quality relationship with family was associated with lower burden in FCG abandonment, health, scheduling (p < 0.001) and finances (p < 0.01). Higher quality relationship with patients' HCPs was associated with lower burden in FCG abandonment (p < 0.05), health, and finances (p < 0.001). More discordant communication in patient relationship was associated with lower financial burden (p < 0.05). Relationship quality was not associated with caregiver self-esteem. CONCLUSIONS: Findings demonstrate that caregiver relationship quality with family and with HCP are important factors in understanding caregiver burden during the early treatment phase of late-stage cancer care.

The Col4a2em1(IMPC)Wtsi mouse line: lessons from the Deciphering the Mechanisms of Developmental Disorders program.

The Deciphering the Mechanisms of Developmental Disorders (DMDD) program uses a systematic and standardised approach to characterise the phenotype of embryos stemming from mouse lines, which produce embryonically lethal offspring. Our study aims to provide detailed phenotype descriptions of homozygous Col4a2em1(IMPC)Wtsi mutants produced in DMDD and harvested at embryonic day 14.5. This shall provide new information on the role Col4a2 plays in organogenesis and demonstrate the capacity of the DMDD database for identifying models for researching inherited disorders. The DMDD Col4a2em1(IMPC)Wtsi mutants survived organogenesis and thus revealed the full spectrum of organs and tissues, the development of which depends on Col4a2 encoded proteins. They showed defects in the brain, cranial nerves, visual system, lungs, endocrine glands, skeleton, subepithelial tissues and mild to severe cardiovascular malformations. Together, this makes the DMDD Col4a2em1(IMPC)Wtsi line a useful model for identifying the spectrum of defects and for researching the mechanisms underlying autosomal dominant porencephaly 2 (OMIM # 614483), a rare human disease. Thus we demonstrate the general capacity of the DMDD approach and webpage as a valuable source for identifying mouse models for rare diseases.

Patient age, well-being, perspectives, and care practices in the early treatment phase for late-stage cancer.

BACKGROUND: Among advanced-stage cancer patients, age is an important determinant of decision making about medical care. We examined age-related differences in patient well-being, care perspectives, and preferences, and the relationship between these patient characteristics and subsequent care practices including care communication, pain management, and acute care utilization during the early treatment phase of late-stage cancer. METHODS: Patient demographics, well-being, and care perspectives were assessed during patient and physician baseline interviews. Care practices were measured using outpatient and inpatient records for the 30-day period after baseline assessment. Multivariate regression models were used to examine the patterns of association of age and other patient characteristics with care practices. RESULTS: A total of 174 middle-aged and 149 older patients with recently diagnosed late-stage cancer were included. Older patients had more comorbidities but lower levels of depression, anxiety, and symptom distress. Older patients preferred pain relief/comfort as a treatment goal, but received fewer prescriptions for opioids. Whereas provider-initiated communication with patients/families was positively associated with severity of illness, patient/family-initiated communication was associated with patient psychosocial attributes and care perspectives. Satisfaction with care was inversely associated with reports of pain. Symptom distress was positively associated with subsequent opioid prescriptions and hospitalizations. CONCLUSIONS: Our results help to explain the role of patients' psychosocial attributes, care perspectives, and preferences in subsequent care practices during the early treatment phase for late-stage cancer. Age-related differences in patient well-being and care perspectives suggest a role for age-sensitive interventions in the treatment of advanced cancer patients.

The Cancer Communication Assessment Tool for Patients and Families (CCAT-PF): a new measure.

OBJECTIVES: Caregivers and cancer patients frequently have conflicting and unmet communication needs. The Cancer Communication Assessment Tool for Patients and Families (CCAT-PF) is a new instrument that assesses congruence in patient-family caregiver communication for both research and clinical purposes. METHODS: The scale was developed using a sample of 190 lung cancer patient-caregiver pairs. Standard psychometric procedures were used to develop and test the scale including qualitative item pool development, item reduction and ascertainment of scale properties. RESULTS: The multiple correlation of the 18-item CCAT-PF scale with the longer 30-item scale was 0.94. All but three items had less than 20% variance accounted for when each item was regressed on the remaining 17, indicating that responses to an individual item were not readily predicted by the remaining items. Test re-test reliability was 0.35 and Cronbach's alpha was 0.49 as the CCAT-PF scale represents the sum of mostly independent items. Higher CCAT-PF scores were significantly correlated with greater patient depression, greater patient perceived family conflict, lower patient-caregiver assessment and well-being and less expressiveness and family cohesion. For both patients and caregivers, physical, functional and emotional well-being were not associated with CCAT-PF scores. CONCLUSION: The CCAT-PF is a brief but reliable and valid tool. Although administering both family and patient versions is optimal, administering it to a patient or family caregiver only also produces reliable information.

Evaluating the replicability of social science experiments in Nature and Science between 2010 and 2015.

Being able to replicate scientific findings is crucial for scientific progress1-15. We replicate 21 systematically selected experimental studies in the social sciences published in Nature and Science between 2010 and 201516-36. The replications follow analysis plans reviewed by the original authors and pre-registered prior to the replications. The replications are high powered, with sample sizes on average about five times higher than in the original studies. We find a significant effect in the same direction as the original study for 13 (62%) studies, and the effect size of the replications is on average about 50% of the original effect size. Replicability varies between 12 (57%) and 14 (67%) studies for complementary replicability indicators. Consistent with these results, the estimated true-positive rate is 67% in a Bayesian analysis. The relative effect size of true positives is estimated to be 71%, suggesting that both false positives and inflated effect sizes of true positives contribute to imperfect reproducibility. Furthermore, we find that peer beliefs of replicability are strongly related to replicability, suggesting that the research community could predict which results would replicate and that failures to replicate were not the result of chance alone.

Caregiver objective burden and assessments of patient-centered, family-focused care for frail elderly veterans.

PURPOSE: There is a growing consensus that quality of care for frail elders should include family and be evaluated in terms of patient-centered, family-focused care (PCFFC). Family caregivers are in a unique and sometimes sole position to evaluate such care. In the context of caring for physically frail elders, this study examined the extent to which objective burden was associated with caregiver perceptions of PCFFC and the extent to which it mediated the influence of other variables on perceptions of PCFFC. DESIGN AND METHODS: In a study of frail elderly veterans receiving care in U.S. Department of Veterans Affairs ambulatory primary care clinics, informal caregivers assessed quality of care with 13 questions. Factor analysis of these items revealed an eight-item scale that specifically assessed PCFFC (alpha =.90). Regression analysis identified variables associated with caregiver (N = 210) assessments of PCFFC and the potential mediating effect of objective burden. RESULTS: Caregiver assessments of PCFFC were positively associated with care recipient instrumental activity of daily living limitations (p =.04) and perspectives on the quality of their own patient care (p <.001). Greater objective burden was negatively associated with caregiver assessments of PCFFC (p <.001) and mediated (i.e., reduced) the relationship between care recipient perceptions of the quality of their own patient care and caregiver assessments of PCFFC (DeltaR(2) =.06). IMPLICATIONS: These findings support recommendations for conducting caregiver assessments as part of routine care and highlight the importance of measuring objective burden and expectations for PCFFC in assisting physically frail elders. Primary care providers will require additional training in order to effectively implement and translate such caregiver assessments into clinical practice improvement.

The structure and function of frail male veterans' informal networks.

OBJECTIVE: This research focuses on the role of informal networks in providing emotional support, instrumental aid, and assistance with chronic disease management for frail male veterans. METHODS: Telephone interviews were conducted with nursing home eligible veterans living in the community. Name-generating questions were used to illicit network members. RESULTS: Data on 198 frail male veterans indicate that they have about three people they rely on for emotional support, instrumental aid, health appraisal, and health monitoring. Networks are composed primarily of family, and adult sons are mentioned almost as often as adult daughters. DISCUSSION: Findings illustrate not only the role women play as providers of the majority of informal care to veterans but also the substantial role adult sons have in providing support to their fathers. Many veterans are at risk of institutionalization by having no one to provide instrumental support and health monitoring.

Cancer in the elderly.

As the population expands, over the period from 2000 to 2050, the number and percentage of Americans over age 65 is expected to double. This population expansion will be accompanied by a marked increase in patients requiring care for disorders with high prevalence in the elderly. Since cancer incidence increases exponentially with advancing age, it is expected that there will be a surge in older cancer patients that will challenge both healthcare institutions and healthcare professionals. In anticipation of this challenge, researchers at the Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio are conducting a series of investigations focused on the intersection of aging and cancer. Studies will be addressed in the high priority research areas of 1) Treatment Efficacy and Tolerance, 2) Effects of Comorbidities, 3) Psychosocial Issues, and 4) Biology of Aging Cancer.