Toward the Identification of Distinct Phenotypes: Research Protocol for the Low Back Pain Biological, Biomechanical, and Behavioral (LB3P) Cohort Study and the BACPAC Mechanistic Research Center at the University of Pittsburgh.

As a member of the Back Pain Consortium (BACPAC), the University of Pittsburgh Mechanistic Research Center's research goal is to phenotype chronic low back pain using biological, biomechanical, and behavioral domains using a prospective, observational cohort study. Data will be collected from 1,000 participants with chronic low back pain according to BACPAC-wide harmonized and study-specific protocols. Participation lasts 12 months with one required in person baseline visit, an optional second in person visit for advanced biomechanical assessment, and electronic follow ups at months 1, 2, 3, 4, 5, 6, 9, and 12 to assess low back pain status and response to prescribed treatments. Behavioral data analysis includes a battery of patient-reported outcomes, social determinants of health, quantitative sensory testing, and physical activity. Biological data analysis includes omics generated from blood, saliva, and spine tissue. Biomechanical data analysis includes a physical examination, lumbopelvic kinematics, and intervertebral kinematics. The statistical analysis includes traditional unsupervised machine learning approaches to categorize participants into groups and determine the variables that differentiate patients. Additional analysis includes the creation of a series of decision rules based on baseline measures and treatment pathways as inputs to predict clinical outcomes. The characteristics identified will contribute to future studies to assist clinicians in designing a personalized, optimal treatment approach for each patient.

Cm-p5 Peptide Dimers Inhibit Biofilms of Candida albicans Clinical Isolates, C. parapsilosis and Fluconazole-Resistant Mutants of C. auris.

Antimicrobial peptides (AMPs) represent a promising class of therapeutic biomolecules that show antimicrobial activity against a broad range of microorganisms, including life-threatening pathogens. In contrast to classic AMPs with membrane-disrupting activities, new peptides with a specific anti-biofilm effect are gaining in importance since biofilms could be the most important way of life, especially for pathogens, as the interaction with host tissues is crucial for the full development of their virulence in the event of infection. Therefore, in a previous study, two synthetic dimeric derivatives (parallel Dimer 1 and antiparallel Dimer 2) of the AMP Cm-p5 showed specific inhibition of the formation of Candida auris biofilms. Here we show that these derivatives are also dose-dependently effective against de novo biofilms that are formed by the widespread pathogenic yeasts C. albicans and C. parapsilosis. Moreover, the activity of the peptides was demonstrated even against two fluconazole-resistant strains of C. auris.

The Mental and Physical Health of Mothers of Children with Special Health Care Needs in the United States.

OBJECTIVE: To determine the prevalence of poor mental and physical health among mothers of children with special health care needs (CSHCN) and to determine the association between maternal health and the child's number of special health care needs (SHCN) and severity of ability limitation. METHODS: We used the combined 2016-2018 National Survey of Children's Health Dataset of 102,341 children ages 0-17 including 23,280 CSHCN. We used regression models to examine the associations of a child's number of SHCN and ability limitations with maternal health. RESULTS: Twice as many mothers of CSHCN had poor mental and physical health compared to non-CSHCN (mental 10.3% vs. 4.0%, p < .001; physical 11.9% vs 5.0%, p < .001). In regression models, increased number of SHCN and severity of activity limitations were associated with significantly increased odds of poor maternal health. CONCLUSIONS FOR PRACTICE: Mothers of CSHCN have worse health compared to mothers of non-CSHCN, especially those who experience social disadvantage and those with children with complex SHCN or severe ability limitations. Interventions to improve the health of these particularly vulnerable caregivers of CSHCN are warranted.

It Takes a Village: Expanding Women's Cardiovascular Care to Include the Community as well as Cardiovascular and Primary Care Teams.

PURPOSE OF REVIEW: Our aim is to highlight some of the current issues that prevent women from getting sex-specific and gender-specific cardiovascular care and provide recommendations for new approaches and delivery models to improve cardiovascular care for all women. RECENT FINDINGS: Cardiovascular disease remains the number one cause of death for women in the US. Many women remain unaware of cardiovascular risk factors and many healthcare providers who care for women are also poorly informed and feel ill prepared to assess women for cardiovascular risk. Women's Heart Centers have tried to bridge the gaps in women's care between primary care and cardiology. Many of the impediments to care in the current models are lack of comprehensive care and socioeconomic societal limitations. New models of care and delivery are essential to change cardiovascular outcomes for all women, especially women at high risk.

Understanding help-seeking in rural counties: A serial mediation analysis.

OBJECTIVE: Rural areas in the Southern United States are characterized by certain cultural values that may delay or prevent mental health service utilization. The present study examined a four-stage chain of serial mediation where higher levels of general self-reliance would be related to greater levels of public stigma, which would in turn be related to higher levels of self-stigma, followed by greater self-reliance about managing mental health problems, and finally, more negative attitudes toward seeking help from psychologists. METHOD: Community members who lived in rural counties in the Southern United States (N = 783) completed measures of these constructs online. RESULTS: Mediation analyses supported a direct association between general self-reliance and attitudes toward help-seeking that was explained in serial by higher levels of public stigma, self-stigma, and mental health self-reliance. CONCLUSIONS: Clinical implications for rural practitioners are suggested including instilling policy changes, increasing provider visibility, and addressing barriers in therapy.

Predictors of posttraumatic stress symptom severity and meaning made in treatment-seeking veterans.

OBJECTIVE: Combat-exposed veterans risk encountering events that disrupt beliefs. To facilitate reduced discrepancy between prior beliefs and current trauma appraisals, veterans may engage in a process of meaning-making. Meaning-making can lead to positive outcomes, such as integrating the traumatic event into one's life narrative or adapting global meaning (meaning made) or elicit distress. Given these potentially different outcomes, this study examined potential correlates of posttraumatic stress symptom (PTSS) severity and meaning made, including relationship attachment dimensions of anxiety and avoidance, and difficulties with emotion regulation, while controlling for combat exposure. METHOD: Veterans receiving mental health services at a Veterans Affairs (VA) Medical Center and a VA community-based outpatient clinic (N = 130) completed measures through a paper-and-pencil survey. Almost all participants (92%) were male, with a mean age of 55.92 years. RESULTS: In terms of meaning made, lower levels of attachment anxiety and emotional clarity (an aspect of emotion regulation) predicted higher meaning made. In terms of PTSS severity, higher attachment avoidance, attachment anxiety, and difficulties engaging in goal-directed behavior (an aspect of emotion regulation) significantly predicted higher PTSS severity. CONCLUSION: Aspects of both attachment style and emotion regulation difficulties affect meaning made and PTSS severity. These constructs may be especially relevant for clinicians working with veterans to help PTSS and support meaning made postcombat.

Aging Immune System in Acute Ischemic Stroke: A Transcriptomic Analysis.

[Figure: see text].

Treelet transform analysis to identify clusters of systemic inflammatory variance in a population with moderate-to-severe traumatic brain injury.

BACKGROUND: Inflammatory cascades following traumatic brain injury (TBI) can have both beneficial and detrimental effects on recovery. Single biomarker studies do not adequately reflect the major arms of immunity and their relationships to long-term outcomes. Thus, we applied treelet transform (TT) analysis to identify clusters of interrelated inflammatory markers reflecting major components of systemic immune function for which substantial variation exists among individuals with moderate-to-severe TBI. METHODS: Serial blood samples from 221 adults with moderate-to-severe TBI were collected over 1-6 months post-injury (n = 607 samples). Samples were assayed for 33 inflammatory markers using Millipore multiplex technology. TT was applied to standardized mean biomarker values generated to identify latent patterns of correlated markers. Treelet clusters (TC) were characterized by biomarkers related to adaptive immunity (TC1), innate immunity (TC2), soluble molecules (TC3), allergy immunity (TC4), and chemokines (TC5). For each TC, a score was generated as the linear combination of standardized biomarker concentrations and cluster load for each individual in the cohort. Ordinal logistic or linear regression was used to test associations between TC scores and 6- and 12-month Glasgow Outcome Scale (GOS), Disability Rating Scale (DRS), and covariates. RESULTS: When adjusting for clinical covariates, TC5 was significantly associated with 6-month GOS (odds ratio, OR = 1.44; p-value, p = 0.025) and 6-month DRS scores (OR = 1.46; p = 0.013). TC5 relationships were attenuated when including all TC scores in the model (GOS: OR = 1.29, p = 0.163; DRS: OR = 1.33, p = 0.100). When adjusting for all TC scores and covariates, only TC3 was associated with 6- and 12-month GOS (OR = 1.32, p = 0.041; OR = 1.39, p = 0.002) and also 6- and 12-month DRS (OR = 1.38, p = 0.016; OR = 1.58, p = 0.0002). When applying TT to inflammation markers significantly associated with 6-month GOS, multivariate modeling confirmed that TC3 remained significantly associated with GOS. Biomarker cluster membership remained consistent between the GOS-specific dendrogram and overall dendrogram. CONCLUSIONS: TT effectively characterized chronic, systemic immunity among a cohort of individuals with moderate-to-severe TBI. We posit that chronic chemokine levels are effector molecules propagating cellular immune dysfunction, while chronic soluble receptors are inflammatory damage readouts perpetuated, in part, by persistent dysfunctional cellular immunity to impact neuro-recovery.

Perturbation of cortical activity elicits regional and age-dependent effects on unconstrained reaching behavior: a pilot study.

Contributions from premotor and supplementary motor areas to reaching behavior in aging humans are not well understood. The objective of these experiments was to examine effects of perturbations to specific cortical areas on the control of unconstrained reaches against gravity by younger and older adults. Double-pulse transcranial magnetic stimulation (TMS) was applied to scalp locations targeting primary motor cortex (M1), dorsal premotor area (PMA), supplementary motor area (SMA), or dorsolateral prefrontal cortex (DLPFC). Stimulation was intended to perturb ongoing activity in the targeted cortical region before or after a visual cue to initiate moderately paced reaches to one of three vertical target locations. Regional effects were observed in movement amplitude both early and late in the reach. Perturbation of PMA increased reach distance before the time of peak velocity to a greater extent than all other regions. Reaches showed greater deviation from a straight-line path around the time of peak velocity and greater overall curvature with perturbation of PMA and M1 relative to SMA and DLPFC. The perturbation increased positional variability of the reach path at the time of peak velocity and the time elapsing after peak velocity. Although perturbations had stronger effects on reaches by younger subjects, this group exhibited less reach path variability at the time of peak velocity and required less time to adjust the movement trajectory thereafter. These findings support the role of PMA in visually guided reaching and suggest an age-related change in sensorimotor processing, possibly due to a loss of cortical inhibitory control.

Effect of the Assistive Technology Professional on the Provision of Mobility Assistive Equipment.

OBJECTIVE: The purpose of this study was to examine factors associated with variability in satisfaction with functional mobility (as measured by the Functional Mobility Assessment [FMA]) in users of mobility devices. Our primary hypothesis was that device type and Assistive Technology Professional (ATP) involvement will be the most significant predictors of FMA score. Our secondary hypothesis was that ATP involvement is associated with use of more custom-fitted manual wheelchairs and group 3 and 4 power wheelchairs. DESIGN: Retrospective cohort study. SETTING: Data were collected from equipment suppliers who collaborate with clinicians to administer the FMA and associated Uniform Data Set within various settings (ie, rehabilitation clinic, school, supplier place of business). PARTICIPANTS: A data set of 4743 cases was included in the analysis (N=4743). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FMA questionnaire collected at baseline, client age, gender, primary diagnosis, years since disability onset, device type, device age, living situation, ATP involvement, and geographic area. RESULTS: Ordinal logistic regression modeling showed that geographic area, device type, ATP involvement, primary diagnosis, gender, age, device age, and years since onset of disability significantly predicted the variance in FMA scores at P<.05. Device type was the most significant predictor of variance in FMA score. Involvement of an ATP had a significant effect on the type of device that participants used (χ220=1739.18, P<.001; odds ratio, 0.589; 95% confidence interval, 0.49-0.708). If an ATP was involved, there were significantly higher proportions (all P<.05) of individuals using custom-fitted manual wheelchair and high-end groups 3 and 4 power wheelchairs prescribed compared with when no ATP was involved or when involvement was uncertain. CONCLUSIONS: The relationship between ATP involvement and functional outcome supports the concept that ATP certification recognizes demonstrated competence in analyzing the needs of consumers with disabilities and selection of appropriate mobility assistive equipment with improved functional outcomes.

Exploring the potential moderating role of self-compassion on the relationships between event centrality and post-assault psychological outcomes.

OBJECTIVE: The present study examined whether post-assault internal processes (i.e., present control, event centrality, and compassionate and uncompassionate self-responding) were associated with distress and resilience among women who have experienced adult sexual assault. The authors also tested whether compassionate and uncompassionate self-responses would moderate the relationships between event centrality and outcomes. METHOD: A convenience sample of women who had experienced sexual assault during adulthood (N = 253) completed an anonymous online survey. RESULTS: Regression analyses showed that lower present control, higher event centrality, and higher uncompassionate responses to the self were associated with posttraumatic stress disorder. Additionally, higher present control and higher compassionate responses to the self were associated with resilience. Moderation analyses were not significant. CONCLUSIONS: Endorsing greater levels of uncompassionate responses was associated with greater distress while engaging in greater compassionate responses was associated with greater resilience, even when accounting for levels of present control and event centrality.

Relationships among non-interpersonal and interpersonal trauma types, posttraumatic stress, and posttraumatic growth.

METHODS: Adults seeking behavioral health or medical treatment (N = 158) were recruited from a community healthcare agency and a residential support program in the southeastern United States. RESULTS: Individuals who reported interpersonal trauma had significantly higher total PTS severity and symptom clusters. No significant difference was found in perceived PTG based on trauma type. No significant curvilinear relationship between PTS and perceived PTG was found. A significant negative linear relationship was observed between PTS and perceived PTG for non-interpersonal trauma, but not interpersonal trauma. CONCLUSION: Trauma type may influence the PTS and perceived PTG relationship and, while associated with PTS, seems less important to reporting of perceived PTG.

A qualitative analysis of meaning-making and mental health among OIF/OEF veterans.

OBJECTIVE: After combat, veterans may experience mental health symptomology and attempt to make meaning from their experiences. The present study qualitatively examined the mental health effects of deployment and meaning-making among Operation Iraqi Freedom (OIF) or Operation Enduring Freedom (OEF) veterans. METHOD: OIF/OEF veterans who were exposed to combat (N = 14) participated in semi-structured interviews to assess how their perspectives had changed post-deployment. Most participants (86%) were male, with a mean age of 30. RESULTS: Veterans described issues post-combat that caused psychological distress or promoted distancing from others. Veterans also discussed factors that could promote or hinder meaning-making, including perceptions of growth, changed global beliefs, and disillusionment. Finally, veterans described psychological reactions to death, which could be related to moral injury. CONCLUSION: Mental health concerns, meaning-making, and consideration of mortality appear to characterize veterans' experiences post-deployment. These constructs may be important for clinicians to consider when working with OIF/OEF veterans.

Erosive pustular dermatosis of the scalp.

Erosive pustular dermatosis of the scalp (EPDS) is a rare inflammatory condition commonly associated with antecedent iatrogenic insult. EPDS may be diagnostically challenging owing to a lack of pathognomonic histologic findings and cutaneous manifestations that overlap with alternative dermatologic conditions. Therefore, EPDS may be more common than previously recognized. We present a 60-year-old woman with a four-year history of non-healing scalp erosions, progressive skin atrophy, and scarring alopecia despite intravenous antibiotics and intraoperative debridement who improved with systemic glucocorticoids. Our report emphasizes the importance of early recognition of EPDS when delayed wound healing and erosive disease occur in the setting of iatrogenic injury to the scalp. Timely treatment with systemic anti-inflammatory agents is paramount to prevent cicatricial alopecia and mitigate further scalp insult in EPDS.

Heart Centers for Women: Historical Perspective on Formation and Future Strategies to Reduce Cardiovascular Disease.

Heart Centers for Women (HCW) developed as a response to the need for improved outcomes for women with cardiovascular disease (CVD). From 1984 until 2012, more women died of CVD every single year in comparison with men. Initially, there was limited awareness and sex-specific research regarding mortality or outcomes in women. HCW played an active role in addressing these disparities, provided focused care for women, and contributed to improvements in these gaps. In 2014 and 2015, death from CVD in women had declined below the level of death from CVD in comparison with men. Even though awareness of CVD in women has increased among the public and healthcare providers and both sex- and gender-specific research is currently required in all research trials, not all women have benefitted equally in mortality reduction. New strategies for HCW need to be developed to address these disparities and expand the current HCW model. The HCW care team needs to direct academic curricula on sex- and gender-specific research and care; expand to include other healthcare professionals and other subspecialties; provide new care models; address diversity; and include more male providers.

Exploring the mediating role of self-blame and coping in the relationships between self-compassion and distress in females following the sexual assault.

OBJECTIVE: The present study investigated the associations between self-compassion, self-blame, disengagement coping, and posttraumatic stress disorder (PTSD) and depression symptom severity among females who had experienced sexual assault. We also examined whether the relationships between self-compassion and both PTSD and depression severity were mediated by self-blame and coping. METHOD: A volunteer sample of female adults (N = 207) completed surveys online or on paper. RESULTS: Mediational analyses showed that higher self-compassion was associated with lower behavioral self-blame, characterological self-blame (CSB), and disengagement coping which, in turn, were associated with less PTSD. Higher self-compassion was associated with less depression severity directly and indirectly via CSB. CONCLUSIONS: These findings suggest that self-compassion may be relevant for understanding postassault mental health, partially through its associations with self-blame and coping. Clinicians working with sexual assault survivors may choose to augment treatment-as-usual with interventions designed to increase self-compassion.

Replicative DNA polymerase δ but not ε proofreads errors in Cis and in Trans.

It is now well established that in yeast, and likely most eukaryotic organisms, initial DNA replication of the leading strand is by DNA polymerase ε and of the lagging strand by DNA polymerase δ. However, the role of Pol δ in replication of the leading strand is uncertain. In this work, we use a reporter system in Saccharomyces cerevisiae to measure mutation rates at specific base pairs in order to determine the effect of heterozygous or homozygous proofreading-defective mutants of either Pol ε or Pol δ in diploid strains. We find that wild-type Pol ε molecules cannot proofread errors created by proofreading-defective Pol ε molecules, whereas Pol δ can not only proofread errors created by proofreading-defective Pol δ molecules, but can also proofread errors created by Pol ε-defective molecules. These results suggest that any interruption in DNA synthesis on the leading strand is likely to result in completion by Pol δ and also explain the higher mutation rates observed in Pol δ-proofreading mutants compared to Pol ε-proofreading defective mutants. For strains reverting via AT→GC, TA→GC, CG→AT, and GC→AT mutations, we find in addition a strong effect of gene orientation on mutation rate in proofreading-defective strains and demonstrate that much of this orientation dependence is due to differential efficiencies of mispair elongation. We also find that a 3'-terminal 8 oxoG, unlike a 3'-terminal G, is efficiently extended opposite an A and is not subject to proofreading. Proofreading mutations have been shown to result in tumor formation in both mice and humans; the results presented here can help explain the properties exhibited by those proofreading mutants.

A heuristic model for working memory deficit in schizophrenia.

BACKGROUND: The life of schizophrenia patients is severely affected by deficits in working memory. In various brain regions, the reciprocal interactions between excitatory glutamatergic neurons and inhibitory GABAergic neurons are crucial. Other neurotransmitters, in particular dopamine, serotonin, acetylcholine, and norepinephrine, modulate the local balance between glutamate and GABA and therefore regulate the function of brain regions. Persistent alterations in the balances between the neurotransmitters can result in working memory deficits. METHODS: Here we present a heuristic computational model that accounts for interactions among neurotransmitters across various brain regions. The model is based on the concept of a neurochemical interaction matrix at the biochemical level and combines this matrix with a mobile model representing physiological dynamic balances among neurotransmitter systems associated with working memory. RESULTS: The comparison of clinical and simulation results demonstrates that the model output is qualitatively very consistent with the available data. In addition, the model captured how perturbations migrated through different neurotransmitters and brain regions. Results showed that chronic administration of ketamine can cause a variety of imbalances, and application of an antagonist of the D2 receptor in PFC can also induce imbalances but in a very different manner. CONCLUSIONS: The heuristic computational model permits a variety of assessments of genetic, biochemical, and pharmacological perturbations and serves as an intuitive tool for explaining clinical and biological observations. GENERAL SIGNIFICANCE: The heuristic model is more intuitive than biophysically detailed models. It can serve as an important tool for interdisciplinary communication and even for psychiatric education of patients and relatives. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.

Increased Mindfulness Skills as Predictors of Reduced Trauma-Related Guilt in Treatment-Seeking Veterans.

The present study examined the predictive role of increased self-reported mindfulness skills on reduced trauma-related guilt in a sample of veterans over the course of residential treatment for posttraumatic stress disorder (PTSD; N = 128). The residential treatment consisted of seven weeks of intensive cognitive processing therapy (CPT) for PTSD, as well as additional psychoeducational groups, including seven sessions on mindfulness skills. Increased mindfulness skills describing, acting with awareness, and accepting without judgment were significantly associated with reductions in trauma-related guilt over the course of treatment. Increases in the ability to act with awareness and accept without judgment were significantly associated with reductions in global guilt, R2 = .26, guilt distress, R2 = .23, guilt cognitions, R2 = .23, and lack of justification, R2 = .11. An increase in the ability to accept without judgment was the only self-reported mindfulness skill that was associated with reductions in hindsight bias, ß = -.34 and wrongdoing, ß = -.44. Increases in self-reported mindfulness skills explained 15.1 to 24.1% of the variance in reductions in trauma-related guilt, suggesting that mindfulness skills may play a key role in reducing the experience of trauma-related guilt during psychotherapy. Our results provide preliminary support for the use of mindfulness groups as an adjunct to traditional evidence-based treatments aimed at reducing trauma-related guilt, though this claim needs to be tested further using experimental designs.

Functional genomics of candidate genes derived from genome-wide association studies for five common neurological diseases.

AIM: Recent genome-wide association studies (GWAS) are identifying novel candidate genes for several neurological diseases (NDs). However, a global functional analysis of those genes derived from GWAS for NDs is missing. We explored the genomic and functional features of novel candidate genes for five common NDs: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke and migraine. MATERIALS AND METHODS: A functional enrichment analysis was performed for GWAS-derived genes, for categories such as Kyoto Encyclopedia of Genes and Genomes pathways, gene expression, InterPro domains, transcription factor binding sites, gene ontology (GO) terms and microRNA (miRNA) targets. An analysis of protein-protein interactions was carried out. RESULTS: Six hundred and forty-two unique single nucleotide polymorphisms (SNPs) were identified for the five NDs and 2.3% of them were non-synonymous SNPs. There were no common SNPs for all five NDs and eight genes were associated with more than one ND. The enrichment analysis showed significant values for several GO categories, such as cell-cell adhesion and location in neurites and for expression in prefrontal cortex. An analysis of protein-protein interactions showed the evidence of a large component. Fifty-one of these GWAS-derived genes are known to be potentially druggable and twelve are known to harbor mutations for neuropsychiatric disorders. CONCLUSIONS: Our results suggest that there is little overlap between the genes identified in GWAS for the five common NDs. Identification of functional categories in the GWAS-derived candidate genes for common NDs could lead to a better understanding of their functional consequences and could be useful for the future discovery of additional genetic risk factors for those diseases.