Systematic use of phenotype evidence in clinical genetic testing reduces the frequency of variants of uncertain significance.

Guidelines for variant interpretation include criteria for incorporating phenotype evidence, but this evidence is inconsistently applied. Systematic approaches to using phenotype evidence are needed. We developed a method for curating disease phenotypes as highly or moderately predictive of variant pathogenicity based on the frequency of their association with disease-causing variants. To evaluate this method's accuracy, we retrospectively reviewed variants with clinical classifications that had evolved from uncertain to definitive in genes associated with curated predictive phenotypes. To demonstrate the clinical validity and utility of this approach, we compared variant classifications determined with and without predictive phenotype evidence. The curation method was accurate for 93%-98% of eligible variants. Among variants interpreted using highly predictive phenotype evidence, the percentage classified as pathogenic or likely pathogenic was 80%, compared with 46%-54% had the evidence not been used. Positive results among individuals harboring variants with highly predictive phenotype-guided interpretations would have been missed in 25%-37% of diagnostic tests and 39%-50% of carrier screens had other approaches to phenotype evidence been used. In summary, predictive phenotype evidence associated with specific curated genes can be systematically incorporated into variant interpretation to reduce uncertainty and increase the clinical utility of genetic testing.

Using a Culturally Tailored Narrative to Increase Cervical Cancer Detection Among Spanish-Speaking Mexican-American Women.

The objective of this study was to determine the feasibility and effectiveness of translating films, and whether the use of narrative is an effective vehicle for producing changes in knowledge, attitudes, and behaviors regarding cervical cancer compared with a nonnarrative film. A randomized controlled telephone trial surveyed the effectiveness of two films our team produced among a sample of 300 monolingual Spanish-speaking women, ages 25 to 45, who were of Mexican origin. Participants were recruited using random digit dialing (RDD) procedures from 2013 to 2014 in Los Angeles County and were randomly selected to view either a narrative or nonnarrative film. Data were collected by phone at baseline, 2 weeks, and 6 months after viewing. On average, participants arrived in the USA 25 years ago. The majority reported having less than high school education and limited English proficiency. Compared with their nonnarrative counterparts, women who received the cervical cancer-related information in the narrative film showed a significantly greater increase in new knowledge (p = 0.01) and in supportive attitudes about Pap tests expense (p = 0.05). Importantly, at 6 months, although not statistically significant, women who viewed the narrative film were also more likely to have had or scheduled a Pap test (62% vs 42%). Narratives are a useful and underutilized tool to communicate information about cancer prevention. These findings have important implications for the delivery of health education among Spanish-speaking, low-literacy immigrant women, and for the reduction of cancer-related disparities.

Neighborhoods and Perceived Norms: Understanding the Impact of Neighborhoods on Perceived Norms and Cancer Screening.

This study examines the importance of urban ethnic neighborhoods as the context of everyday life, where normative influences on health are formed, modified, and maintained. Built on communication infrastructure theory, this study investigates the role of women's connections to their neighborhood storytelling network-consisting of residents, local/ethnic media, and community organizations-in shaping their descriptive normative perceptions regarding cervical cancer screening. Specifically, we explore the communication mechanisms that underlie Latinas' exposure and attention to media information about Pap tests, their discussions with health-care professionals about Pap tests, their perceptions about how normative Pap tests are among "women like them", and their compliance with cervical cancer screening guidelines. Our findings suggest that neighborhood storytelling resources hold promise for health communication research to understand not only the uptake of Pap tests but also health disparities in other domains that affect diverse populations and communities.

Understanding Cervical Cancer Screening among Latinas through the Lens of Structure, Culture, Psychology and Communication.

This study explored how structural and cultural forces work together with psychological and communication factors in influencing Pap test compliance among Latinas in Los Angeles County, a group who face health disparities related to cervical cancer screening, incidence and mortality. By adopting a multilevel approach to obtain a grounded understanding of this issue, this work revealed that structural barriers, fatalism, religious service attendance, perceived susceptibility, perceived costs, and cues to action from health care providers are all associated with Pap test compliance. Financial barriers also influence compliance, with underinsurance having a stronger negative impact compared to no insurance at all. These findings provide insights into how communication efforts can be strategically designed to address both individual- and system-level barriers to promote health-seeking behaviors among Latinas, and potentially among other population groups experiencing health disparities due to similar reasons.

Comparing the Relative Efficacy of Narrative vs Nonnarrative Health Messages in Reducing Health Disparities Using a Randomized Trial.

OBJECTIVES: We compared the relative efficacy of a fictional narrative film to a more traditional nonnarrative film in conveying the same health information. METHODS: We used a random digit dial procedure to survey the cervical cancer-related knowledge, attitudes, and behavior of non-Hispanic White, Mexican American, and African American women, aged 25 to 45 years, living in Los Angeles, California, from 2011 to 2012. Participants (n = 704) were randomly assigned to view either a narrative or nonnarrative film containing the same information about how cervical cancer could be prevented or detected, and they were re-contacted 2 weeks and 6 months later. RESULTS: At 2 weeks, both films produced a significant increase in cervical cancer-related knowledge and attitudes, but these effects were significantly higher for the narrative film. At 6 months, viewers of both films retained greater than baseline knowledge and more positive attitudes toward Papanicolaou (Pap) tests, but women who saw the narrative were significantly more likely to have had or scheduled a Pap test. The narrative was particularly effective for Mexican American women, eliminating cervical cancer screening disparities found at baseline. CONCLUSIONS: Narratives might prove to be a useful tool for reducing health disparities.

Telling stories, saving lives: creating narrative health messages.

Increasingly, health communication practitioners are exploring the use of narrative storytelling to convey health information. For this study, a narrative film was produced to provide information about the human papillomavirus (HPV) and cervical cancer prevention. The storyline centered on Lupita, a young woman recently diagnosed with HPV who informs her family about HPV and the availability of the HPV vaccine for her younger sister. The objective was to examine the roles of identification with characters and narrative involvement (made up of three dimensions: involvement, perceived relevance, and immersion) on perceived response efficacy, perceived severity, and perceived susceptibility to HPV and behavior (discussing the HPV vaccine with a health care provider). A random sample of 450 European American, Mexican American, and African American women between the ages of 25 and 45 years, living in the Los Angeles area, was surveyed by phone before, 2 weeks after, and 6 months after viewing the film. The more relevant women found the narrative to their own lives at 2 weeks, the higher they perceived the severity of the virus and the perceived response efficacy of the vaccine to be. Also at 2 weeks, identifying with characters was positively associated with perceived susceptibility to HPV but negatively associated with perceived severity. At 6 months, identification with specific characters was significantly associated with perceived threat and behavior. These findings suggest that different aspects of narrative health messages should be manipulated depending on the specific beliefs and behaviors being targeted. Implications for narrative message design are discussed.

The association between cardiovascular health and cognition in adults with Down syndrome.

INTRODUCTION: Evidence in the general population suggests that predictors of cardiovascular health such as moderate to vigorous physical activity (MVPA), cardiorespiratory fitness, and systolic blood pressure are associated with cognitive function. Studies supporting these associations in adults with Down syndrome (DS) are limited. The purpose of this study was to examine the associations between systolic blood pressure, cardiorespiratory fitness, and MVPA on cognition in adults with DS. METHODS: This is a cross-sectional analysis using baseline data from a trial in adults with DS. Participants attended a laboratory visit where resting blood pressure, cardiorespiratory fitness (VO2 Peak), and cognitive function (CANTAB® DS Battery) were obtained. The cognitive battery included tests measuring multitasking, episodic memory, and reaction time. Physical activity (accelerometer) was collected over the week following the laboratory visit. Pearson correlations and linear regressions were used to measure the impact of systolic blood pressure, cardiorespiratory fitness, and MVPA on cognitive outcomes. RESULTS: Complete data was available for 72 adults with DS (26.8 ± 9.3 years of age, 57% female). At baseline, VO2 Peak (21.1 ± 4.2 ml/kg/min) and MVPA were low (14.4 ± 14.4 min/day), and systolic blood pressure was 118.3 ± 13.3 mmHg. VO2 Peak was correlated with simple movement time (rho = - 0.28, p = 0.03) but was not significant using a linear regression controlling for age and sex. Systolic blood pressure was significantly associated with episodic memory (first attempt memory score: ß = - 0.11, p = 0.002; total errors: ß = 0.58, p = 0.001) and reaction time (five-choice movement time: ß = 4.11, p = 0.03; simple movement time: ß = 6.14, p = 0.005) using age- and sex-adjusted linear regressions. No associations were observed between MVPA and multitasking, episodic memory, or reaction time. CONCLUSION: Predictors of cardiovascular health, including cardiorespiratory fitness and systolic blood pressure, were associated with some aspects of cognition in adults with DS. While future research should examine the role of improved cardiovascular health on delaying decreases in cognitive function and dementia in adults with DS, we recommend that health care providers convey the importance of exercise and cardiovascular health to their patients with DS. TRIAL REGISTRATION: NCT04048759, registered on August 7, 2019.

Conversation and compliance: role of interpersonal discussion and social norms in public communication campaigns.

This study explores the role of interpersonal discussion and social norms in a public health campaign, the BBC Condom Normalization Campaign, designed to promote conversation and change the public perception of condom use in India. Drawing upon the integrative model of behavioral prediction, attitudes, self-efficacy, subjective norms, and descriptive norms were predicted to relate to behavioral intentions to use condoms. It is important to note that the valence of discussion was hypothesized to relate to each of these more proximal predictors. The authors used structural equation modeling to test the model on 3 separate samples of Indian men between the ages of 15 and 49 years: (a) high-risk men who had sex with nonspouses; (b) low-risk, sexually inactive, unmarried men; and (c) low-risk, monogamous, married men. Results were similar for low- and high-risk audiences, with valence of discussion about condoms predicting condom-related attitudes, self-efficacy, and subjective and descriptive social norms with respect to condom use, which, in turn, predicted behavioral intent to use condoms. These findings underscore the need to take not only the frequency but also the valence of interpersonal discussion into account when assessing the effect of health campaigns. Implications for theory and design of future public communication campaigns are explored.

Pan-cancer analysis of co-occurring mutations in RAD52 and the BRCA1-BRCA2-PALB2 axis in human cancers.

In human cells homologous recombination (HR) is critical for repair of DNA double strand breaks (DSBs) and rescue of stalled or collapsed replication forks. HR is facilitated by RAD51 which is loaded onto DNA by either BRCA2-BRCA1-PALB2 or RAD52. In human culture cells, double-knockdowns of RAD52 and genes in the BRCA1-BRCA2-PALB2 axis are lethal. Mutations in BRCA2, BRCA1 or PALB2 significantly impairs error free HR as RAD51 loading relies on RAD52 which is not as proficient as BRCA2-BRCA1-PALB2. RAD52 also facilitates Single Strand Annealing (SSA) that produces intra-chromosomal deletions. Some RAD52 mutations that affect the SSA function or decrease RAD52 association with DNA can suppress certain BRCA2 associated phenotypes in breast cancers. In this report we did a pan-cancer analysis using data reported on the Catalogue of Somatic Mutations in Cancers (COSMIC) to identify double mutants between RAD52 and BRCA1, BRCA2 or PALB2 that occur in cancer cells. We find that co-occurring mutations are likely in certain cancer tissues but not others. However, all mutations occur in a heterozygous state. Further, using computational and machine learning tools we identified only a handful of pathogenic or driver mutations predicted to significantly affect the function of the proteins. This supports previous findings that co-inactivation of RAD52 with any members of the BRCA2-BRCA1-PALB2 axis is lethal. Molecular modeling also revealed that pathogenic RAD52 mutations co-occurring with mutations in BRCA2-BRCA1-PALB2 axis are either expected to attenuate its SSA function or its interaction with DNA. This study extends previous breast cancer findings to other cancer types and shows that co-occurring mutations likely destabilize HR by similar mechanisms as in breast cancers.

Brain-derived neurotrophic factor regulates hedonic feeding by acting on the mesolimbic dopamine system.

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, play prominent roles in food intake regulation through central mechanisms. However, the neural circuits underlying their anorexigenic effects remain largely unknown. We showed previously that selective BDNF depletion in the ventromedial hypothalamus (VMH) of mice resulted in hyperphagic behavior and obesity. Here, we sought to ascertain whether its regulatory effects involved the mesolimbic dopamine system, which mediates motivated and reward-seeking behaviors including consumption of palatable food. We found that expression of BDNF and TrkB mRNA in the ventral tegmental area (VTA) of wild-type mice was influenced by consumption of palatable, high-fat food (HFF). Moreover, amperometric recordings in brain slices of mice depleted of central BDNF uncovered marked deficits in evoked release of dopamine in the nucleus accumbens (NAc) shell and dorsal striatum but normal secretion in the NAc core. Mutant mice also exhibited dramatic increases in HFF consumption, which were exacerbated when access to HFF was restricted. However, mutants displayed enhanced responses to D(1) receptor agonist administration, which normalized their intake of HFF in a 4 h food intake test. Finally, in contrast to deletion of Bdnf in the VMH of mice, which resulted in increased intake of standard chow, BDNF depletion in the VTA elicited excessive intake of HFF but not of standard chow and increased body weights under HFF conditions. Our findings indicate that the effects of BDNF on eating behavior are neural substrate-dependent and that BDNF influences hedonic feeding via positive modulation of the mesolimbic dopamine system.

Leptin regulation of the mesoaccumbens dopamine pathway.

Leptin is an adipose-derived hormone that acts on hypothalamic leptin receptors to regulate energy balance. Leptin receptors are also expressed in extrahypothalamic sites including the ventral tegmental area (VTA), critical to brain reward circuitry. We report that leptin targets DA and GABA neurons of the VTA, inducing phosphorylation of signal-transducer-and-activator-of-transcription-3 (STAT3). Retrograde tracing combined with pSTAT3 immunohistochemistry show leptin-responsive VTA neurons projecting to nucleus accumbens (NAc). Assessing leptin function in the VTA, we showed that ob/ob mice had diminished locomotor response to amphetamine and lacked locomotor sensitization to repeated amphetamine injections, both defects reversed by leptin infusion. Electrically stimulated DA release from NAc shell terminals was markedly reduced in ob/ob slice preparations, and NAc DA levels and TH expression were lower. These data define a role for leptin in mesoaccumbens DA signaling and indicate that the mesoaccumbens DA pathway, critical to integrating motivated behavior, responds to this adipose-derived signal.

Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats.

The association between dietary obesity and mesolimbic systems that regulate hedonic aspects of feeding is currently unresolved. In the present study, we examined differences in baseline and stimulated central dopamine levels in obesity-prone (OP) and obesity-resistant (OR) rats. OP rats were hyperphagic and showed a 20% weight gain over OR rats at wk 15 of age, when fed a standard chow diet. This phenotype was associated with a 50% reduction in basal extracellular dopamine, as measured by a microdialysis probe in the nucleus accumbens, a projection site of the mesolimbic dopamine system that has been implicated in food reward. Similar defects were also observed in younger animals (4 wk old). In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.

Veterinary Neurologic Rehabilitation: The Rationale for a Comprehensive Approach.

The increase in client willingness to pursue surgical procedures, the heightened perceived value of veterinary patients, and the desire to provide comprehensive medical care have driven the recent demand of using an integrative treatment approach in veterinary rehabilitation. Physical therapy following neurologic injury has been the standard of care in human medicine for decades, whereas similar rehabilitation techniques have only recently been adapted and utilized in veterinary medicine. Spinal cord injury is the most common neurologic disease currently addressed by veterinary rehabilitation specialists and will be the primary focus of this review; however, research in other neurologic conditions will also be discussed. Of particular interest, to clients and veterinarians are techniques and modalities used to promote functional recovery after neurologic injury, which can mean the difference between life and death for many veterinary patients. The trend in human neurologic rehabilitation, often regardless of etiology, is a multimodal approach to therapy. Evidence supports faster and improved recoveries in people after neurologic injury using a combination of rehabilitation techniques. Although the primary neurological disorders researched tend to be spinal cord injury, peripheral neuropathies, allodynia, multiple sclerosis, and strokes-many correlations can be made to common veterinary neurological disorders. Such comprehensive protocols entail gait training activities in combination with neuromuscular electrical stimulation and directed exercises. Additionally, pain-relieving and functional benefits are bolstered when acupuncture is used in addition to rehabilitation. Studies, both laboratory and clinical, support the use of acupuncture in the management of neurologic conditions in small animals, specifically in cases of intervertebral disc disease, other myelopathies, and neuropathic pain conditions. Acupuncture's ability to promote analgesia, stimulate trophic factors, and decrease inflammation, including neuroinflammation, make it an alluring adjunct therapy after neurologic injury. Although there is limited research in veterinary medicine on physical techniques that expedite recovery after neurologic injury, there are sparse publications on clinical veterinary research suggesting the benefits of acupuncture, rehabilitation, and LASER in dogs with intervertebral disk disease. Accordingly, due to the relative lack of evidence-based studies in veterinary neurologic rehabilitation, much of the data available is human or laboratory-animal based, however, evidence supports the utilization of an early, comprehensive treatment protocol for optimal neurologic recovery. The rationale for why an integrative approach is critical will be detailed in this review; in addition, literature on specific physical rehabilitation techniques that have evidence of improved recoveries after neurologic injury, will be addressed.

Acupuncture for Small Animal Neurologic Disorders.

Modern research on traditional Chinese veterinary medicine (TCVM), including herbal medicine and acupuncture, has made evident the role of the nervous system as a cornerstone in many of the mechanisms of action of TCVM. Laboratory models and clinical research available are supportive for the use of TCVM in the management of neurologic conditions in small animals, specifically in cases of intervertebral disk disease, other myelopathies, and painful conditions. This article is meant to help guide the use of TCVM for neurologic disorders in small animals, based on available information and recommendations from experienced TCVM practitioners.

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats.

There is considerable evidence of interactions between adenosine A2A receptors and dopamine D2 receptors in striatal areas, and antagonists of the A2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 microg or 5.0 microg in 0.5 microl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.

Each Medium Tells a Different Story: The Effect of Message Channel on Narrative Persuasion.

Limited attention has been given to the medium of story presentation in this process of narrative persuasion. The present study (N = 243) fills this gap by directly comparing narrative involvement across print and audiovisual versions of the same cervical cancer-related story. The mediation analysis revealed that exposure to an audiovisual narrative was associated with higher levels of cognitive and emotional involvement, than exposure to the exact same narrative in its printed form. Yet, the higher levels of transportation in the audiovisual condition came at a price of enhancing psychological reactance, eliminating the relative advantage of the film narrative.

Individual, Cultural and Structural Predictors of Vaccine Safety Confidence and Influenza Vaccination Among Hispanic Female Subgroups.

Rates of influenza vaccination among US Hispanics are lower than for non-Hispanic whites, yet little is known about factors affecting vaccination in this population. Additionally, although Hispanics are a diverse population with culturally distinct subgroups, they are often treated as a homogenous population. This study (1) examines how confidence in vaccine safety and influenza vaccine use vary by Hispanic subgroup and (2) identifies individual, cultural and structural correlates of these outcomes. This study analyzed survey data from 1565 Hispanic women who were recruited at clinic- and community-based sites in Los Angeles. Education, healthcare coverage, acculturation, fatalism, and religiosity were predictors of influenza vaccination behavior and predictors varied by subgroup. These findings provide guidance for how influenza vaccine promotion efforts can be developed for Hispanic subgroups. Confidence in the safety of a vaccine is a major predictor of flu vaccination and an important modifiable target for intervention.

Information scanning and vaccine safety concerns among African American, Mexican American, and non-Hispanic White women.

OBJECTIVE: A significant number of parents delay or refuse vaccinating their children. Incidental exposure to vaccine information (i.e., scanned information) may be an important contributor to anti-vaccine sentiment. This study examines the association between scanned information, trust in health information sources and vaccine safety concerns among African American, Mexican American, and non-Hispanic White women. METHODS: Women (N=761) in Los Angeles County were sampled via random digit dial and surveyed regarding use of and trust in health information resources and vaccine safety concerns. RESULTS: Analyses indicate that the sources of information associated with vaccine safety concerns varied by ethnicity. Each ethnic group exhibited different patterns of association between trust in health information resources and vaccine safety concerns. CONCLUSIONS: Information scanning is associated with beliefs about vaccine safety, which may lead parents to refuse or delay vaccinating their children. These relationships vary by ethnicity. PRACTICE IMPLICATIONS: These findings help inform practitioners and policy makers about communication factors that influence vaccine safety concerns. Knowing these sources of information will equip practitioners to better identify women who may have been exposed to anti-vaccine messages and counter these beliefs with effective, vaccine-promoting messages via the most relevant information sources.

A pilot test of the acceptability and efficacy of narrative and non-narrative health education materials in a low health literacy population.

Although entertainment-education narratives are increasingly being used to communicate health information to a diversity of populations, there is limited evidence examining the use of narrative health education videos in low compared with adequate health literacy populations. There are also very few studies directly comparing narrative materials to more traditional, non-narrative materials. Because individuals with low health literacy are less likely than those with adequate health literacy to benefit from health communication interventions, it is especially important to develop an evidence base supporting the use of narrative health education materials in low literacy populations. This study extends knowledge on the use of narrative health education materials in populations with low health literacy by conducting a randomized trial comparing the acceptability and efficacy (knowledge gain) of two fact-equivalent films, one in a narrative and one in a non-narrative format, on individuals with adequate and low health literacy. This study finds that while both films were well-accepted and produced knowledge gains, the narrative film was more effective in this regard. This effect occurred regardless of health literacy level, indicating that narrative health communication materials are appropriate for individuals with low health literacy and do not exacerbate existing health disparities. These findings add to a small but growing body of evidence testing narrative health education materials in individuals with low health literacy, and provide new evidence supporting narrative, entertainment-education style video as a health communication tool to help reduce health literacy-related health disparities.