A systematic review of the gut microbiome, metabolites, and multi-omics biomarkers across the colorectal cancer care continuum.

The gut microbiome and the microbial metabolome contribute to treatment efficacy and treatment outcomes across the cancer care spectrum. This study systematically reviewed the existing literature between 2007 to March 2022 to elucidate the role of gut microbiota-metabolite biomarkers in colorectal cancer (CRC) care and treatment-related outcomes. Using Covidence, all studies identified were screened by title and abstract, followed by a full-text review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and data extraction. We analysed 13 non-experimental and 9 experimental CRC studies and found that, usually, the α-diversity of the gut microbiome and short-chain fatty acids decreased in CRC patients, while amino acids (e.g. glutamate) increased in CRC patients. Correlations between specific gut microbial taxa and metabolites were identified, with amino acids, fatty acids, and glycerol positively associated with certain gut microbes. Interventions promoting gut microbes and microbial metabolites associated with better health outcomes (e.g. Bifidobacterium, Lactobacillus, butyric acid, and bile acid) can potentially promote treatment efficacy and improve cancer care outcomes. Gut microbial metabolism should be integrated into targeted cancer interventions for CRC patients, given the confirmed role of the gut microbiome and metabolome pathways across the CRC care continuum.

Barriers and motivators to national board certification as a certified anticoagulation care provider.

Professionals voice confusion between the distinctions of board certification and educational certificate courses, and note barriers and motivators in obtaining national anticoagulation board certification. To identify barriers vs. motivators in obtaining board certification and detail the differences in board certification and educational certificate courses, an IRB-approved electronic survey was sent to professionals completing the University of Southern Indiana (USI) Anticoagulation Therapy educational certificate course (n = 491) and existing Certified Anticoagulation Care Providers (CACP, n = 622). A total of 1049 surveys were delivered successfully, with a 26% response rate (USI = 62, CACP = 211.) Respondents identified as a nurse (n = 52, 19%), advanced practice nurse (n = 14, 5.1%), pharmacist (n = 206, 75.5%) or physician (n = 5, 1.8%). Overall, respondents indicated board certification via CACP has significant impact on patient/organizational outcomes (n = 118, 43.2%). Top motivators for board certification include personal accomplishment (n = 147, 53%) and professional growth (n = 139, 50.9%). Top barriers include lack of time to prepare (n = 102, 37.3%,) board certification exam cost (n = 95, 34.8%), and for CACP recertification, and requirement to recertify by examination (n = 74, 35.1%). Of board-certified respondents, 45.4% indicated they were not employed at an Anticoagulation Center of Excellence (ACE), 34.8% employed at an ACE and 16.8% were unsure of ACE status. Narrative comments were obtained and evaluated. Significant personal and professional barriers exist in completing, and subsequently maintaining, board certification in anticoagulation. This offers great insight for NCBAP to invoke changes to support clinicians and healthcare organizations in seeking and maintaining CACP credentialing, a component of ACE attainment.

Using the EM algorithm for Bayesian variable selection in logistic regression models with related covariates.

We develop a Bayesian variable selection method for logistic regression models that can simultaneously accommodate qualitative covariates and interaction terms under various heredity constraints. We use expectation-maximization variable selection (EMVS) with a deterministic annealing variant as the platform for our method, due to its proven flexibility and efficiency. We propose a variance adjustment of the priors for the coefficients of qualitative covariates, which controls false-positive rates, and a flexible parameterization for interaction terms, which accommodates user-specified heredity constraints. This method can handle all pairwise interaction terms as well as a subset of specific interactions. Using simulation, we show that this method selects associated covariates better than the grouped LASSO and the LASSO with heredity constraints in various exploratory research scenarios encountered in epidemiological studies. We apply our method to identify genetic and non-genetic risk factors associated with smoking experimentation in a cohort of Mexican-heritage adolescents.

Leading indicators of community-based violent events among adults with mental illness.

BACKGROUND: The public health, public safety and clinical implications of violent events among adults with mental illness are significant; however, the causes and consequences of violence and victimization among adults with mental illness are complex and not well understood, which limits the effectiveness of clinical interventions and risk management strategies. This study examined interrelationships between violence, victimization, psychiatric symptoms, substance use, homelessness and in-patient treatment over time. METHOD: Available data were integrated from four longitudinal studies of adults with mental illness. Assessments took place at baseline, and at 1, 3, 6, 9, 12, 15, 18, 24, 30 and 36 months, depending on the parent studies' protocol. Data were analysed with the autoregressive cross-lag model. RESULTS: Violence and victimization were leading indicators of each other and affective symptoms were a leading indicator of both. Drug and alcohol use were leading indicators of violence and victimization, respectively. All psychiatric symptom clusters - affective, positive, negative, disorganized cognitive processing - increased the likelihood of experiencing at least one subsequent symptom cluster. Sensitivity analyses identified few group-based differences in the magnitude of effects in this heterogeneous sample. CONCLUSIONS: Violent events demonstrated unique and shared indicators and consequences over time. Findings indicate mechanisms for reducing violent events, including trauma-informed therapy, targeting internalizing and externalizing affective symptoms with cognitive-behavioral and psychopharmacological interventions, and integrating substance use and psychiatric care. Finally, mental illness and violence and victimization research should move beyond demonstrating concomitant relationships and instead focus on lagged effects with improved spatio-temporal contiguity.

An in vitro model of the tumor-lymphatic microenvironment with simultaneous transendothelial and luminal flows reveals mechanisms of flow enhanced invasion.

The most common cancers, including breast and skin, disseminate initially through the lymphatic system, yet the mechanisms by which tumor cells home towards, enter and interact with the lymphatic endothelium remain poorly understood. Transmural and luminal flows are important biophysical cues of the lymphatic microenvironment that can affect adhesion molecules, growth factors and chemokine expression as well as matrix remodeling, among others. Although microfluidic models are suitable for in vitro reconstruction of highly complex biological systems, the difficult assembly and operation of these systems often only allows a limited throughput. Here we present and characterize a novel flow chamber which recapitulates the lymphatic capillary microenvironment by coupling a standard Boyden chamber setup with a micro-channel and a controlled fluidic environment. The inclusion of luminal and transmural flow renders the model more biologically relevant, combining standard 3D culture techniques with advanced control of mechanical forces that are naturally present within the lymphatic microenvironment. The system can be monitored in real-time, allowing continuous quantification of different parameters of interest, such as cell intravasation and detachment from the endothelium, under varied biomechanical conditions. Moreover, the easy setup permits a medium-high throughput, thereby enabling downstream quantitative analyses. Using this model, we examined the kinetics of tumor cell (MDA-MB-231) invasion and transmigration dynamics across lymphatic endothelium under varying flow conditions. We found that luminal flow indirectly upregulates tumor cell transmigration rate via its effect on lymphatic endothelial cells. Moreover, we showed that the addition of transmural flow further increases intravasation, suggesting that distinct flow-mediated mechanisms regulate tumor cell invasion.

Response to an exercise intervention after endometrial cancer: differences between obese and non-obese survivors.

OBJECTIVE: The objective of this paper is to describe baseline differences between obese and non-obese endometrial cancer survivor in anthropometrics, exercise behavior, fitness, heart rate and blood pressure, and quality of life, and to analyze whether the effect of a home-based exercise intervention on these outcomes differed for obese and non-obese participants. METHODS: One hundred post-treatment Stage I-IIIa endometrial cancer survivors participated in a single arm 6month study in which they received a home-based exercise intervention. Cardiorespiratory fitness, anthropometrics, and exercise behavior were measured every two months, and quality of life (QOL) and psychological distress were measured at baseline and 6months. RESULTS: Adjusting for potential confounders, at baseline obese survivors had poorer cardiorespiratory fitness (p=.002), higher systolic blood pressure (p=.018), and lower physical functioning (p<.001) and ratings of general health (p=.002), and more pain (p=.037) and somatization (.002). Significant improvements were seen in exercise behavior, resting heart rate, systolic blood pressure, and multiple QOL domains over the course of the intervention. Obese survivors had less improvement in exercise behavior and cardiorespiratory fitness than non-obese survivors, but there were no differences with regard to improvements in QOL and stress. CONCLUSIONS: Home based exercise interventions are beneficial to endometrial cancer survivors, including those whose BMI is in the obese range. While obese survivors have lower levels of physical activity and fitness, they experienced similar activity, fitness, quality of life and mental health benefits. Exercise should be encouraged in endometrial cancer survivors, including those who are obese.

Staff happiness and work satisfaction in a tertiary psychiatric centre.

BACKGROUND: Mental health professionals are at a high risk of burnout. Positive psychology outcomes of staff in acute in-patient psychiatric wards are poorly researched and unclear. AIMS: To quantify the satisfaction with life and work-life satisfaction of mental health staff at a large university-affiliated tertiary psychiatric centre. METHODS: We utilized the Satisfaction with Life Scale (SWLS) and the Work-Life Satisfaction Questionnaire (WLSQ). RESULTS: Two hundred and nine out of 450 staff members (46%) participated; mean age 48.2 + 9.9 years; 63% were male. On average the participants had been practising their speciality for 21.1 + 9.8 years (range: 2-48). The mean total SWLS scores differed significantly between professions (P < 0.05). The highest levels of happiness were reported by psychologists and social workers, followed by the administrative staff, the psychiatrists and finally the nursing staff. Staff scored the highest for work as a 'calling' followed by work as a 'career' and the lowest rating for work as a 'job'. The mean total WLSQ score differed between professions, (P < 0.01). The highest levels of work as a calling were reported by psychiatrists (mean 2.87 of possible 5.0), followed by psychologists and social workers, nursing staff and finally administrative staff. CONCLUSIONS: Satisfaction with life and work orientation do not correlate among mental health professionals. Although highly motivated and perceiving psychiatry as a 'calling' psychiatrists score low on levels of satisfaction with life. Improving staff happiness may contribute to increase in moral and counter burnout.

Remission amongst elderly schizophrenia patients.

Remission in elderly patients has been little studied. The present analysis utilized a European database to focus on the elderly. Using five different instruments examining remission, we report that aging did not adversely affect remission in the elderly. Management of elderly schizophrenia patients should thus be targeted towards remission.

Using Ascertainment for Targeted Resequencing to Increase Power to Identify Causal Variants.

Researchers continue to use genome-wide association studies (GWAS) to find the genetic markers associated with disease. Recent studies have added to the typical two-stage analysis a third stage that uses targeted resequencing on a randomly selected subset of the cases to detect the causal single-nucleotide polymorphism (SNP). We propose a design for targeted resequencing that increases the power to detect the causal variant. The design features an ascertainment scheme wherein only those cases with the presence of a risk allele are selected for targeted resequencing. We simulated a disease with a single causal SNP to evaluate our method versus a targeted resequencing design using randomly selected individuals. The simulation studies showed that ascertaining individuals for the targeted resequencing can substantially increase the power to detect a causal SNP, without increasing the false-positive rate.

Design, fabrication, and characterization of a composite scaffold for bone tissue engineering.

Poly(lactide-co-glycolide) (PLGA) scaffolds have been successfully used in bone tissue engineering, with or without hydroxyapatite (HA) and with a macroporosity given either by simple PLGA sphere packaging and/or by leaching out NaCl. The objective of this work was the optimization of the design parameters for bone tissue engineering scaffolds made by sintering microspheres of PLGA, HA nanocrystals for matrix reinforcement and osteoconduction, and salt crystals for macroporosity and control of matrix pore size. Microsphere fabrication by a single-emulsion and solvent evaporation technique was first optimized to obtain a high yield of PLGA microspheres with a diameter between 80 and 300 microm. The influence of the sintering process and matrix composition on the scaffold structure was then evaluated morphologically and mechanically. Three scaffold types were tested for biocompatibility by culturing with human fibroblasts for up to 14 days. The most important parameters to obtain microspheres with the selected diameter range were the viscosity ratio of the dispersed phase to the continuous phase and the relative volume fraction of the 2 phases. The Young's modulus and the ultimate strength of the sintered matrices ranged between 168-265 MPa and 6-17 MPa, respectively, within the range for trabecular bone. Biocompatibility was demonstrated by fibroblast adhesion, proliferation, and spreading throughout the matrix. This work builds upon previous work of the PLGA/HA sintering technique to give design criteria for fabricating a bone tissue engineered matrix with optimized morphological, functional, and biological properties to fit the requirements of bone replacements.

Childhood abuse and initial presentation for HIV care: an opportunity for early intervention.

An alarmingly high prevalence of childhood sexual and physical abuse has been observed in HIV-infected men and women, with rates several times higher than observed in the general population. Childhood abuse history has been associated with worse antiretroviral adherence and negative health behaviours in HIV-infected patients. This study evaluates the relationship between childhood abuse and the timing of presentation for HIV care. Participants in a multi-center prospective cohort study, who established initial HIV care after January 1996 and had a CD4 count available within six months of initial presentation, were included in this analysis. Bivariate contingency tables and multivariate logistic regression were used to evaluate the association of childhood abuse with early presentation for HIV care (initial CD4 count > or =200/mm3). Among the 186 subjects included in this analysis, 33% had childhood abuse histories and 58% had an initial CD4 count > or =200/mm3. Participants with a history of childhood abuse were more likely to present early for HIV care (AOR=2.12; p=0.03), perhaps because survivors of abuse tend to have higher utilization of health services. Because HIV-infected patients with childhood abuse histories have worse antiretroviral medication adherence and are more likely to engage in high-risk sexual and injection drug use behaviours, early presentation affords clinicians the opportunity for timely institution of interventions that may improve patient outcomes and prevent secondary HIV infections.

Improving health outcomes among individuals with HIV, mental illness, and substance use disorders in the Southeast.

Providing behavioral treatment for mental health and substance use disorders among HIV-infected individuals is critical because these disorders have been associated with negative outcomes such as poorer medication adherence. This study examines the effectiveness of an integrated treatment model for HIV-infected individuals who have both substance use and mental disorders. Study participants (n = 141) were recruited through routine mental health and substance abuse screening at tertiary Infectious Disease clinics in North Carolina. The study participants received integrated mental health and substance abuse treatment for one year and were interviewed at three-month intervals. Using linear regression analyses, we detected statistically significant decreases in participants' psychiatric symptomatology, illicit substance use, alcohol use, and inpatient hospital days. Participants also reported fewer emergency room visits and were more likely to be receiving antiretroviral medications and adequate psychotropic medication regimens at follow-up. No changes in sexual risk, physical health, or medical adherence were detected after treatment participation. This integrated treatment model offers an option for treating HIV-infected individuals with mental health and substance use disorders that can be adapted for use in a variety of psychiatric and medical treatment settings.

Comorbid posttraumatic stress disorder is associated with suicidality in male veterans with schizophrenia or schizoaffective disorder.

The purpose of this study was to determine if patients with schizophrenia or schizoaffective disorders and comorbid posttraumatic stress disorder (PTSD) are at higher risk for suicidality than patients without comorbid PTSD. Participants were 165 male veterans with primary diagnoses of schizophrenia or schizoaffective disorder. Those with comorbid PTSD reported higher rates of suicidal ideation and suicidal behaviors compared to those without comorbid PTSD. These findings suggest that patients with comorbid PTSD are at higher risk for suicidality. Enhanced screening and targeted interventions may be warranted to address comorbid PTSD and increased suicide risk in this population.

EphA4 constitutes a population-specific guidance cue for motor neurons.

Motor neurons in the ventral neural tube project axons specifically to their target muscles in the periphery. Although many of the transcription factors that specify motor neuron cell fates have been characterized, less is understood about the mechanisms that guide motor axons to their correct targets. We show that ectopic expression of EphA4 receptor tyrosine kinase alters the trajectories of a specific population of motor axons in the avian hindlimb. Most motor neurons in the medial portion of the lateral motor column (LMC) extend their axons aberrantly in the dorsal nerve trunk at the level of the crural plexus, in the presence of ectopic EphA4. This misrouting of motor axons is not accompanied by alterations in motor neuron identity, settling patterns in the neural tube, or the fasciculation of spinal nerves. However, ectopic EphA4 axons do make errors in pathway selection during sorting in the plexus at the base of the hindlimb. These results suggest that EphA4 in motor neurons acts as a population-specific guidance cue to control the dorsal trajectory of their axons in the hindlimb.

EphA4/ephrin-A5 interactions in muscle precursor cell migration in the avian forelimb.

Limb muscles derive from muscle precursor cells that lie initially in the lateral portion of the somitic dermomyotome and subsequently migrate to their target limb regions, where muscle-specific gene transcription is initiated. Although several molecules that control the generation and delamination of muscle precursor cells have been identified, little is known about the mechanisms that guide muscle precursor cell migration in the limb. We have examined the distribution of members of the Eph family during muscle precursor cell development. The EphA4 receptor tyrosine kinase and its ligand, ephrin-A5, are expressed by muscle precursor cells and forelimb mesoderm in unique spatiotemporal patterns during the period when muscle precursors delaminate from the dermomyotome and migrate into the limb. To test the function of EphA4/ephrin-A5 interactions in muscle precursor migration, we used targeted in ovo electroporation to express ephrin-A5 ectopically specifically in the presumptive limb mesoderm. In the presence of ectopic ephrin-A5, Pax7-positive muscle precursor cells are significantly reduced in number in the proximal limb, compared with controls, and congregate abnormally near the lateral dermomyotome. In stripe assays, isolated muscle precursor cells avoid substrate-bound ephrin-A5 and this avoidance is abolished by addition of soluble ephrin-A5. These data suggest that ephrin-A5 normally restricts migrating, EphA4-positive muscle precursor cells to their appropriate territories in the forelimb, disallowing entry into abnormal embryonic regions.

Effects of involuntary outpatient commitment and depot antipsychotics on treatment adherence in persons with severe mental illness.

This study examines potential improvement in treatment adherence during a study of involuntary outpatient commitment among individuals with severe mental illnesses. Involuntarily hospitalized subjects, awaiting discharge under outpatient commitment, were randomly assigned to be released or continue under outpatient commitment after hospital discharge. A nonrandomized group with a recent history of serious violence was also studied under outpatient commitment. Randomized control and outpatient commitment groups did not differ significantly in group comparisons of treatment adherence. However, analyses of all subjects, including nonrandomized violent subjects, showed that those who underwent sustained periods of outpatient commitment (6 months or more) were significantly more likely to remain adherent with medication and other treatment, compared with those who underwent only brief outpatient commitment or none. Administration of depot antipsychotics also significantly improved treatment adherence independently of the effect of sustained outpatient commitment. Sustained periods of outpatient commitment may significantly improve adherence with community-based mental health treatment for persons with severe mental illness and thus may help improve other clinical outcomes affected by adherence.

Lymphatic function, lymphangiogenesis, and cancer metastasis.

The lymphatic system serves as the primary route for the metastasis of many cancers and the extent of lymph node involvement is the most important indicator of tumor aggressiveness. Despite the apparent importance of the lymphatic vessels for tumor dissemination, it has remained unclear whether activation of lymphatic endothelial cells may affect tumor progression and metastasis and the molecular mechanisms of lymphangiogenesis are just beginning to be elucidated. This overview describes the unique structural and functional characteristics of the lymphatic vessels that render them particularly suitable for invasion by tumor cells and for their efficient transport to lymph nodes. Recent evidence indicates occurrence of tumor lymphangiogenesis and its correlation with metastasis. Molecular regulation of tumor lymphangiogenesis, its significance for tumor metastasis, and implications for cancer therapy are discussed.

Mandated community treatment: beyond outpatient commitment.

Outpatient commitment, although often viewed as merely an extension of inpatient commitment, is only one of a growing array of legal tools used to mandate treatment adherence. The authors describe various forms of mandated community treatment. People with severe and chronic mental disorders often depend on goods and services provided by the social welfare system. Benefits disbursed by representative payees and the provision of subsidized housing have both been used as leverage to ensure treatment adherence. Many discharged patients are arrested for criminal offenses. Favorable disposition of their cases by a mental health court may be tied to participation in treatment. Under outpatient commitment statutes, judges can order committed patients to comply with prescribed treatment. Patients may attempt to maximize their control over treatment in the event of later deterioration by executing an advance directive. The ideological posturing that currently characterizes the field must be replaced by an evidence-based approach.