CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid.

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects. Using LC-MS/MS-based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer-promoting effects of LA, since the LA-rich diet fails to exacerbate colon cancer in CYP monooxygenase-deficient mice. Finally, CYP monooxygenase mediates the pro-cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota-dependent mechanisms. Overall, these results support that CYP monooxygenase-mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects.

Early embryonic lethality of mice lacking POLD2.

As a highly conserved DNA polymerase (Pol), Pol δ plays crucial roles in chromosomal DNA synthesis and various DNA repair pathways. However, the function of POLD2, the second small subunit of DNA Pol δ (p50 subunit), has not been characterized in vivo during mammalian development. Here, we report for the first time, the essential role of subunit POLD2 during early murine embryogenesis. Although Pold2 mutant mouse embryos exhibit normal morphology at E3.5 blastocyst stage, they cannot be recovered at gastrulation stages. Outgrowth assays reveal that mutant blastocysts cannot hatch from the zona pellucida, indicating impaired blastocyst function. Notably, these phenotypes can be recapitulated by small interfering RNA (siRNA)-mediated knockdown, which also exhibit slowed cellular proliferation together with skewed primitive endoderm and epiblast allocation during the second cell lineage specification. In summary, our study demonstrates that POLD2 is essential for the earliest steps of mammalian development, and the retarded proliferation and embryogenesis may also alter the following cell lineage specifications in the mouse blastocyst embryos.

A quantifiler™ trio-based HRM screening assay for the accurate prediction of single source versus mixed biological samples.

At present, the forensic DNA workflow is not capable of providing information about the contributor status (single source vs. multiple contributors) of evidentiary samples prior to end-point analysis. This exacerbates the challenges inherent to mixtures and low-template DNA samples. If additional sample information could be provided earlier in the workflow, protocols could be implemented to mitigate these challenges. An integrated Quantiplex®- high resolution melt (HRM) assay was shown to be effective in distinguishing between single source and mixture DNA samples; however, integration of the HRM assay into a more commonly used chemistry would be beneficial to the practitioner community. Thus, the assay was redesigned as an integrated Quantifiler™ Trio-HRM assay, which included the identification of a new DNA-binding dye, an increased reaction volume, and the establishment of new data analysis and standard curve metrics for all targets. This redesigned assay produced quantification values and qualitative values that were comparable to those produced when the same samples were tested using the standard Quantifiler™ Trio chemistry and settings. Further, STR profiles generated with quantification values produced from the integrated Quantifiler™ Trio-HRM assay and standard Quantifiler™ Trio chemistry were complete and fully concordant. Most importantly, the integrated Quantifiler™ Trio-HRM assay was able to accurately predict whether a sample was single source or a mixture 79.2% of the time, demonstrating the potential of this approach. With the incorporation of an expanded training set for prediction modeling, and completion of critical developmental validation studies, this assay could prove useful to the forensic DNA practitioner community.

Associations of Future Cognitive Decline with Sexual Satisfaction among Married Older Adults.

Objectives: This study sought to explore changes in longitudinal cognitive status in relation to baseline measures of intimacy and sexuality in cognitively intact, married older adults.Methods: Baseline intimacy and sexuality survey data from 155, cognitively intact, married, older adults were collected using a novel survey instrument that explored the domains of: 1) romance with one's partner, 2) sexual satisfaction, 3) beliefs about sexuality, and 4) social support and emotional intimacy. These data were analyzed in relation to change in cognitive status over a 10-year follow-up period using binary logistic regression modeling. Exploratory factor analysis was used to assess the shared variance of survey items attributable to intimacy and sexuality without specification of an a priori hypothesis regarding the association of intimacy and sexuality with future change in cognitive status.Results: Over the 10-year study period, 33.5% (n = 52) of individuals developed cognitive impairment. Participants with greater sexual satisfaction scores at baseline were statistically less likely to convert from cognitively intact to mild cognitive impairment or dementia in the future (p = .01). The domains of romance with one's partner, beliefs about sexuality, and social support/emotional intimacy were not predictive of future longitudinal changes in cognitive status.Conclusions: Sexual satisfaction is associated with longitudinal cognitive outcomes in cognitively intact, married, older adults.Clinical implications: Clinicians should routinely assess for sexual satisfaction among older adults and refer to appropriate providers, such as couples or sex therapists, when appropriate.

Complex inhibitory effects of nitric oxide on autophagy.

Autophagy, a major degradation process for long-lived and aggregate-prone proteins, affects various human processes, such as development, immunity, cancer, and neurodegeneration. Several autophagy regulators have been identified in recent years. Here we show that nitric oxide (NO), a potent cellular messenger, inhibits autophagosome synthesis via a number of mechanisms. NO impairs autophagy by inhibiting the activity of S-nitrosylation substrates, JNK1 and IKKß. Inhibition of JNK1 by NO reduces Bcl-2 phosphorylation and increases the Bcl-2-Beclin 1 interaction, thereby disrupting hVps34/Beclin 1 complex formation. Additionally, NO inhibits IKKß and reduces AMPK phosphorylation, leading to mTORC1 activation via TSC2. Overexpression of nNOS, iNOS, or eNOS impairs autophagosome formation primarily via the JNK1-Bcl-2 pathway. Conversely, NOS inhibition enhances the clearance of autophagic substrates and reduces neurodegeneration in models of Huntington's disease. Our data suggest that nitrosative stress-mediated protein aggregation in neurodegenerative diseases may be, in part, due to autophagy inhibition.

Nontyphoidal Salmonella enterica Nonsusceptible to Both Levofloxacin and Ceftriaxone in Nebraska, United States 2014-2015.

Nontyphoidal Salmonella enterica is a common cause of illness in humans ranging from gastroenteritis to invasive disease. National surveillance programs continually monitor trends in antimicrobial resistance patterns and mechanisms of resistance to identify emerging public health threats. Our study shows the emergence of nonsusceptibility to both levofloxacin and ceftriaxone, a concerning phenotype that threatens first-line antibiotic therapy, in Salmonella isolates recovered between 2014 and 2015. From 2010 to 2013 the rate of resistance increased from 0.0% (0/1181) to 1.5% (9/593) in 2014 and 2015. The isolates with this phenotype were found to be from multiple serotypes, including Typhimurium, Newport, and Enteritidis. Resistance to ceftriaxone was attributed to the presence of either an AmpC or extended-spectrum ß-lactamase, and resistance to fluoroquinolones was attributable to the presence of mutations in the quinolone resistance-determining region or the presence of plasmid-mediated quinolone resistance genes. As this resistance pattern was seen in a variety of Salmonella serotypes harboring varied resistance mechanisms, it indicates a worrying trend in the spread of isolates resistant to both first-line treatment options.

Forgotten, silent, and overruled: Hearing the voice of the nursing home patient.

As the population ages, more Americans are moving into nursing homes/long-term care facilities. Per Accreditation Council for Graduate Medical Education 2017 guidelines, family medicine residents are required to gain experience and competence working in long-term care facilities; however, this unique environment poses several challenges for residents to hear the wishes of their patients over the demands of the patient's medical care team and family members. Also, many patients in long-term care facilities have sensory impairments (e.g., poor eyesight, deafness) and/or cognitive deficits (e.g., dementia). One solution for hearing the patient's voice over the demands of medical professionals and family members is to train physicians on how to overcome communication barriers with their patients. This article will discuss solution-focused approaches to reducing the barriers of sensory and cognitive impairments through the use of adaptive communication behaviors and adaptive equipment. Ways to improve communication between physicians, nursing-home staff, and patients' family in order to improve the care patients receive in long-term care facilities will also be addressed. These recommendations are designed to assist with reducing physician frustration, increasing each patient's input in medical decision-making, and improving communication across the patient care team.

Cochlear implantation for single-sided deafness and tinnitus suppression.

OBJECTIVE: To quantify the potential effectiveness of cochlear implantation for tinnitus suppression in patients with single-sided deafness using the Tinnitus Handicap Inventory. METHODS: The study included 12 patients with unilateral tinnitus who were undergoing cochlear implantation for single-sided deafness. The Tinnitus Handicap Inventory was administered at the patient's cochlear implant candidacy evaluation appointment prior to implantation and every cochlear implant follow-up appointment, except activation, following implantation. Patient demographics and speech recognition scores were also retrospectively recorded using the electronic medical record. RESULTS: A significant reduction was found when comparing Tinnitus Handicap Inventory score preoperatively (61.2±27.5) to the Tinnitus Handicap Inventory score after three months of cochlear implant use (24.6±28.2, p=0.004) and the Tinnitus Handicap Inventory score beyond 6months of CI use (13.3±18.9, p=0.008). Further, 45% of patients reported total tinnitus suppression. Mean CNC word recognition score improved from 2.9% (SD 9.4) pre-operatively to 40.8% (SD 31.7) by 6months post-activation, which was significantly improved from pre-operative scores (p=0.008). CONCLUSION: The present data is in agreement with previously published studies that have shown an improvement in tinnitus following cochlear implantation for the large majority of patients with single-sided deafness.

A framework for assessing outcomes from newborn screening: on the road to measuring its promise.

UNLABELLED: Newborn screening (NBS) is intended to identify congenital conditions prior to the onset of symptoms in order to provide early intervention that leads to improved outcomes. NBS is a public health success, providing reduction in mortality and improved developmental outcomes for screened conditions. However, it is less clear to what extent newborn screening achieves the long-term goals relating to improved health, growth, development and function. We propose a framework for assessing outcomes for the health and well-being of children identified through NBS programs. The framework proposed here, and this manuscript, were approved for publication by the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). This framework can be applied to each screened condition within the Recommended Uniform Screening Panel (RUSP), recognizing that the data elements and measures will vary by condition. As an example, we applied the framework to sickle cell disease and phenylketonuria (PKU), two diverse conditions with different outcome measures and potential sources of data. Widespread and consistent application of this framework across state NBS and child health systems is envisioned as useful to standardize approaches to assessment of outcomes and for continuous improvement of the NBS and child health systems. SIGNIFICANCE: Successful interventions for newborn screening conditions have been a driving force for public health newborn screening for over fifty years. Organizing interventions and outcome measures into a standard framework to systematically assess outcomes has not yet come into practice. This paper presents a customizable outcomes framework for organizing measures for newborn screening condition-specific health outcomes, and an approach to identifying sources and challenges to populating those measures.

Strengthening partnerships between Black Churches and HIV service providers in the United States.

Across the United States, Black Churches play a significant role among the Black community and are increasingly being used to deliver Human Immunodeficiency Virus (HIV) prevention services. This study sought to investigate HIV service providers' strategies for strengthening partnerships with churches to deliver HIV prevention services. Using a community-based participatory research approach, an HIV coalition and an academic institution formed a partnership to address the study aim. Individual interviews (n = 16) were conducted with providers from medical institutions and HIV social support agencies. A thematic analysis focusing on recommendations for addressing the challenges and benefits of partnership with churches for HIV services was conducted. Participants' interest in and intention to work with churches, as well as their comfort level discussing sexual health-related topics with religious congregations, was high. Four themes emerged to highlight the different perspectives of service providers' recommendations for addressing challenges and strengthening partnerships with churches to deliver HIV services including: (1) carefully selecting churches and HIV services to provide, (2) gaining "buy-in" and support of church leadership, (3) taking advantage of conflict with church doctrine, and (4) choosing appropriate delivery strategies. Study findings demonstrate that although challenges exist, heath service providers in this region of the United States may be interested in addressing HIV among faith communities. Study findings also provide concrete solutions to previously documented barriers to HIV prevention in Black Churches. Such information will benefit researchers and practitioners seeking to expand effective HIV prevention efforts with Black Churches in communities who bear a disproportionate burden of HIV infections.

Factors Influencing Black Churches' Readiness to Address HIV.

This study employed a community-based participatory research approach to understand factors that influence church readiness to engage in HIV prevention and treatment activities. A convenience sample of twenty-six Black faith leaders participated in four focus groups. Data analysis was done through qualitative content analysis. Three themes emerged. First, the pastor's blessing and authority as the church's decision-maker determines readiness to engage in HIV prevention. Second, the church's purview of sexual health as part of a holistic ministry facilitates faith leader's readiness. Lastly, securing financial and human resources makes it feasible for faith leaders to implement activities. Findings suggest HIV-related stigma alone does not explain readiness to address HIV. Participants also discussed activities their churches are equipped to handle, including HIV testing events and health fairs.

Clinical evaluation of an image-guided cochlear implant programming strategy.

The cochlear implant (CI) has been labeled the most successful neural prosthesis. Despite this success, a significant number of CI recipients experience poor speech understanding, and, even among the best performers, restoration to normal auditory fidelity is rare. While significant research efforts have been devoted to improving stimulation strategies, few developments have led to significant hearing improvement over the past two decades. We have recently introduced image processing techniques that open a new direction for advancement in this field by making it possible, for the first time, to determine the position of implanted CI electrodes relative to the nerves they stimulate using computed tomography images. In this article, we present results of an image-guided, patient-customized approach to stimulation that utilizes the electrode position information our image processing techniques provide. This approach allows us to identify electrodes that cause overlapping stimulation patterns and to deactivate them from a patient's map. This individualized mapping strategy yields significant improvement in speech understanding in both quiet and noise as well as improved spectral resolution in the 68 adult CI recipients studied to date. Our results indicate that image guidance can improve hearing outcomes for many existing CI recipients without requiring additional surgery or the use of 'experimental' stimulation strategies, hardware or software.

Development and validation of the pediatric AzBio sentence lists.

OBJECTIVES: The goal of this study was to create and validate a new set of sentence lists that could be used to evaluate the speech-perception abilities of listeners with hearing loss in cases where adult materials are inappropriate due to difficulty level or content. The authors aimed to generate a large number of sentence lists with an equivalent level of difficulty for the evaluation of performance over time and across conditions. DESIGN: The original Pediatric AzBio sentence corpus included 450 sentences recorded from one female talker. All sentences included in the corpus were successfully repeated by kindergarten and first-grade students with normal hearing. The mean intelligibility of each sentence was estimated by processing each sentence through a cochlear implant simulation and calculating the mean percent correct score achieved by 15 normal-hearing listeners. After sorting sentences by mean percent correct scores, 320 sentences were assigned to 16 lists of equivalent difficulty. List equivalency was then validated by presenting all sentence lists, in a novel random order, to adults and children with hearing loss. A final-validation stage examined single-list comparisons from adult and pediatric listeners tested in research or clinical settings. RESULTS: The results of the simulation study allowed for the creation of 16 lists of 20 sentences. The average intelligibility of each list ranged from 78.4 to 78.7%. List equivalency was then validated, when the results of 16 adult cochlear implant users and 9 pediatric hearing aid and cochlear implant users revealed no significant differences across lists. The binomial distribution model was used to account for the inherent variability observed in the lists. This model was also used to generate 95% confidence intervals for one and two list comparisons. A retrospective analysis of 361 instances from 78 adult cochlear implant users and 48 instances from 36 pediatric cochlear implant users revealed that the 95% confidence intervals derived from the model captured 94% of all responses (385 of 409). CONCLUSIONS: The cochlear implant simulation was shown to be an effective method for estimating the intelligibility of individual sentences for use in the evaluation of cochlear implant users. Furthermore, the method used for constructing equivalent sentence lists and estimating the inherent variability of the materials has also been validated. Thus, the AzBio Pediatric Sentence Lists are equivalent and appropriate for the assessment of speech-understanding abilities of children with hearing loss as well as adults for whom performance on AzBio sentences is near the floor.

Clinical assessment of spectral modulation detection for adult cochlear implant recipients: a non-language based measure of performance outcomes.

OBJECTIVE: Spectral modulation detection (SMD) provides a psychoacoustic estimate of spectral resolution. The SMD threshold for an implanted ear is highly correlated with speech understanding and is thus a non-linguistic, psychoacoustic index of speech understanding. This measure, however, is time and equipment intensive and thus not practical for clinical use. Thus the purpose of the current study was to investigate the efficacy of a quick SMD task with the following three study aims: (1) to investigate the correlation between the long psychoacoustic, and quick SMD tasks, (2) to determine the test/retest variability of the quick SMD task, and (3) to evaluate the relationship between the quick SMD task and speech understanding. DESIGN: This study included a within-subjects, repeated-measures design. STUDY SAMPLE: Seventy-six adult cochlear implant recipients participated. RESULTS: The results were as follows: (1) there was a significant correlation between the long psychoacoustic, and quick SMD tasks, (2) the test-retest variability of the quick SMD task was highly significant and, (3) there was a significant positive correlation between the quick SMD task and monosyllabic word recognition. CONCLUSIONS: The results of this study represent the direct clinical translation of a research-proven task of SMD into a quick, clinically feasible format.

Impedance testing on cochlear implants after electroconvulsive therapy.

OBJECTIVE: Cochlear implants (CI) are neural prostheses that restore hearing to individuals with profound sensorineural hearing loss. The surgically implanted component consists of an electrode array, which is threaded into the cochlea, and an electronic processor, which is buried under the skin behind the ear. The Food and Drug Administration and CI manufacturers contend that electroconvulsive therapy (ECT) is contraindicated in CI recipients owing to risk of damage to the implant and/or the patient. We hypothesized that ECT does no electrical damage to CIs. METHODS: Ten functional CIs were implanted in 5 fresh cadaveric human heads. Each head then received a consecutive series of 12 unilateral ECT sessions applying maximum full pulse-width energy settings. Electroconvulsive therapy was delivered contralaterally to 5 CIs and ipsilaterally to 5 CIs. Electrical integrity testing (impedance testing) of the electrode array was performed before and after CI insertion, and after the first, third, fifth, seventh, ninth, and 12th ECT sessions. Electroconvulsive therapy was performed by a staff psychiatrist experienced with the technique. Explanted CIs were sent back to the manufacturer for further integrity testing. RESULTS: No electrical damage was identified during impedance testing. Overall, there were statistically significant decreases in impedances (consistent with no electrical damage) when comparing pre-ECT impedance values to those after 12 sessions. There was no statistically significant difference (P > 0.05) in impedance values comparing ipsilateral to contralateral ECT. Manufacturer testing revealed no other electrical damage to the CIs. CONCLUSION: Electroconvulsive therapy does not seem to cause any detectable electrical injury to CIs.

Screening for distress, the sixth vital sign: examining self-referral in people with cancer over a one-year period.

PURPOSE: Although research has indicated a diagnosis of cancer is most often distressing for patients and their families, few studies have examined which patients access resources to manage distress or how distress levels affect resource utilization. This study explored psychosocial and supportive care resource utilization in a large cancer population at a Canadian tertiary cancer centre over a 12-month period in a usual care setting. METHODS: Patients who were new to the Tom Baker Cancer Centre completed the Distress Thermometer, the Pain and Fatigue Thermometers, the Psychological Screen for Cancer (Part C) that measures anxiety and depression, self-report questions on resources accessed and a demographic form at baseline, 3, 6 and 12 months. No feedback or specific triage to services was provided in order to observe usual care practices. RESULTS: A total of 714 patients provided baseline data with 505 retained at 12 months. Twenty-four percent indicated they accessed at least one service (e.g. individual counselling, nutritionist or resource social worker) over the 12 months. Patients who were older, less educated and with lower income were less likely to access services. People who reported higher symptom burden were more likely to access services at each time point. CONCLUSIONS: Overall levels of access of psychosocial services were relatively low in this population and varied by socio-demographic variables and symptom burden. Routine monitoring of psychosocial, practical and physical concerns is a potential strategy for targeting individuals who may require additional information or support in accessing available services to manage their concerns.

Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis.

Persistence of unrepaired DNA damage in oocytes is detrimental and may cause genetic aberrations, miscarriage, and infertility. RPA, an ssDNA-binding complex, is essential for various DNA-related processes. Here we report that RPA plays a novel role in DNA damage repair during postnatal oocyte development after meiotic recombination. To investigate the role of RPA during oogenesis, we inactivated RPA1 (replication protein A1), the largest subunit of the heterotrimeric RPA complex, specifically in oocytes using two germline-specific Cre drivers (Ddx4-Cre and Zp3-Cre). We find that depletion of RPA1 leads to the disassembly of the RPA complex, as evidenced by the absence of RPA2 and RPA3 in RPA1-deficient oocytes. Strikingly, severe DNA damage occurs in RPA1-deficient GV-stage oocytes. Loss of RPA in oocytes triggered the canonical DNA damage response mechanisms and pathways, such as activation of ATM, ATR, DNA-PK, and p53. In addition, the RPA deficiency causes chromosome misalignment at metaphase I and metaphase II stages of oocytes, which is consistent with altered transcript levels of genes involved in cytoskeleton organization in RPA1-deficient oocytes. Absence of the RPA complex in oocytes severely impairs folliculogenesis and leads to a significant reduction in oocyte number and female infertility. Our results demonstrate that RPA plays an unexpected role in DNA damage repair during mammalian folliculogenesis.

A brief look at diagnosing neurocognitive disorders in a VA primary care setting: Understanding the practices of our physician partners and the future of integration.

OBJECTIVE: The population aged 65 and over is growing rapidly and with it are increased demands for integrative care and management of cognitive health issues. Such care models often do not include neuropsychologists or other psychology specialties. METHODS: In this study, 72 medical charts of VA patients diagnosed with neurocognitive disorders were reviewed using best practice guidelines for diagnosing and managing neurocognitive disorders, adapted from Downs et al. (2006). RESULTS: Results indicated that physicians typically used clinical judgment through review of medications, blood work within the past year, and a history of symptoms to make diagnostic conclusions. Cognitive assessment and consideration of other reversible causes of cognitive decline (e.g., depression) were less commonly considered. CONCLUSIONS: The results are discussed in terms of potential implications for neuropsychologists and the integration of neuropsychology and primary care.

Genetic counseling following the detection of hemoglobinopathy trait on the newborn screen is well received, improves knowledge, and relieves anxiety.

PURPOSE: The primary purpose of newborn screening for hemoglobinopathies is the presymptomatic diagnosis and early treatment of sickle cell disease. Hemoglobinopathy traits detected on the newborn screening provide an opportunity for genetic counseling of families regarding the trait and information that may impact reproductive decisions of the parents. We describe the results of a study to determine the impact of newborn screening and genetic counseling on the lives of families in which an abnormal hemoglobin trait had been identified. METHODS: From June 2003 to December 2009, families of children with trait attending a clinic visit and receiving professional genetic counseling were asked to participate in a semistructured follow-up survey regarding their experience and the impact of genetic counseling on their families. RESULTS: Of the 300 patients seen in clinic during the specified time period, 209 consented to be recontacted and 114 have completed the survey. Eighty-five percent of responders reported knowing that the newborn screen had been performed, but only 55% understood the purpose of newborn screening. When asked about the effect of finding out that trait was present in their baby, 19% reported feeling guilty or upset, whereas 4% believed that their partner blamed them for the child's results. That genetic counseling was found to be beneficial was indicated by the fact that 99% reported that their questions were answered, 82% reported feeling less anxious, and 78% discussed the trait with their partner after the appointment. CONCLUSIONS: Genetic counseling after newborn screening relieves anxiety, provides knowledge, facilitates dialog within families and between partners about hemoglobinopathy trait, and was seen as a positive experience for the majority of responders.