Alcaligenes faecalis corrects aberrant matrix metalloproteinase expression to promote reepithelialization of diabetic wounds.

Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here, we focused on Alcaligenes faecalis, a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes reepithelialization of diabetic keratinocytes, a process that is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

The microbiota and T cells non-genetically modulate inherited phenotypes transgenerationally.

The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations.

Reactive and control processes in the development of internalizing and externalizing problems across early childhood to adolescence.

Reactive and control processes - e.g., negative emotionality and immediacy preference - may predict distinct psychopathology trajectories. However, externalizing and internalizing problems change in behavioral manifestation across development and across contexts, thus necessitating the use of different measures and informants across ages. This is the first study that created developmental scales for both internalizing and externalizing problems by putting scores from different informants and measures onto the same scale to examine temperament facets as risk factors. Multidimensional linking allowed us to examine trajectories of internalizing and externalizing problems from ages 2 to 15 years (N = 1,364) using near-annual ratings by mothers, fathers, teachers, other caregivers, and self report. We examined reactive and control processes in early childhood as predictors of the trajectories and as predictors of general versus specific psychopathology in adolescence. Negative emotionality at age 4 predicted general psychopathology and unique externalizing problems at age 15. Wait times on an immediacy preference task at age 4 were negatively associated with age 15 general psychopathology, and positively associated with unique internalizing problems. Findings demonstrate the value of developmental scaling for examining development of psychopathology across a lengthy developmental span and the importance of considering reactive and control processes in development of psychopathology.

Explaining Brain-Behavior Relations: Inhibitory Control as an Intermediate Phenotype Between the N2 ERP and the Externalizing Spectrum in Childhood.

Identifying neural and cognitive mechanisms in externalizing problems in childhood is important for earlier and more targeted intervention. Meta-analytic findings have shown that smaller N2 event-related potential (ERP) amplitudes, thought to reflect inhibitory control, are associated with externalizing problems in children. However, it is unclear how (i.e., through which cognitive processes) N2 amplitudes relate to externalizing problems. We examined whether inhibitory control may be a cognitive process that links N2 amplitudes and externalizing problems in early childhood. Children (N = 147, 74 girls) were assessed at four time points, spanning 3-7 years of age. Children's externalizing behavior was assessed via questionnaires completed by mothers, fathers, and teachers/secondary caregivers. Children's inhibitory control was assessed using eleven performance-based tasks and two questionnaires. Developmental scaling linked differing measures of inhibitory control and externalizing behavior across ages onto the same scale. Children's N2 amplitudes were extracted from electroencephalography data collected during a go/no-go task. Smaller N2 amplitudes were associated with externalizing problems and poorer inhibitory control. A concurrent analysis of indirect effects revealed that poorer inhibitory control partially explained the association between smaller N2 amplitudes and externalizing problems, even when controlling for the child's age, sex, and socioeconomic status. This is among the first studies to link N2 amplitudes, inhibitory control, and externalizing problems during early childhood. Findings suggest that smaller N2 amplitudes may be an early neural indicator of inhibitory control deficits and externalizing psychopathology. Moreover, inhibitory control may be an important target for early intervention in the development of externalizing psychopathology.

A Developmentally Informed Systematic Review and Meta-Analysis of the Strength of General Psychopathology in Childhood and Adolescence.

Considerable support exists for higher-order dimensional conceptualizations of psychopathology in adults. A growing body of work has focused on understanding the structure of general and specific psychopathology in children and adolescents. No prior meta-analysis has examined whether the strength of the general psychopathology factor (p factor)-measured by explained common variance (ECV)-changes from childhood to adolescence. The primary objective of this multilevel meta-analysis was to determine whether general psychopathology strength changes across development (i.e. across ages) in childhood and adolescence. Several databases were searched in November 2021; 65 studies, with 110 effect sizes (ECV), nested within shared data sources, were identified. Included empirical studies used a factor analytic modeling approach that estimated latent factors for child/adolescent internalizing, externalizing, and optionally thought-disordered psychopathology, and a general factor. Studies spanned ages 2-17 years. Across ages, general psychopathology explained over half (~ 56%) of the reliable variance in symptoms of psychopathology. Age-moderation analyses revealed that general factor strength remained stable across ages, suggesting that general psychopathology strength does not significantly change across childhood to adolescence. Even if the structure of psychopathology changes with development, the prominence of general psychopathology across development has important implications for future research and intervention.

Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.

BACKGROUND: The cytokine TSLP promotes type 2 immune responses and can induce adipose loss by stimulating lipid loss from the skin through sebum secretion by sebaceous glands, which enhances the skin barrier. However, the mechanism by which TSLP upregulates sebaceous gland function is unknown. OBJECTIVES: This study investigated the mechanism by which TSLP stimulates sebum secretion and adipose loss. METHODS: RNA-sequencing analysis was performed on sebaceous glands isolated by laser capture microdissection and single-cell RNA-sequencing analysis was performed on sorted skin T cells. Sebocyte function was analyzed by histological analysis and sebum secretion in vivo and by measuring lipogenesis and proliferation in vitro. RESULTS: This study found that TSLP sequentially stimulated the expression of lipogenesis genes followed by cell death genes in sebaceous glands to induce holocrine secretion of sebum. TSLP did not affect sebaceous gland activity directly. Rather, single-cell RNA-sequencing revealed that TSLP recruited distinct T-cell clusters that produce IL-4 and IL-13, which were necessary for TSLP-induced adipose loss and sebum secretion. Moreover, IL-13 was sufficient to cause sebum secretion and adipose loss in vivo and to induce lipogenesis and proliferation of a human sebocyte cell line in vitro. CONCLUSIONS: This study proposes that TSLP stimulates T cells to deliver IL-4 and IL-13 to sebaceous glands, which enhances sebaceous gland function, turnover, and subsequent adipose loss.

Multiomic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity.

Leishmania braziliensis is a parasitic infection that can result in inflammation and skin injury with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 patients infected with L. braziliensis. We found that overall bacterial burden and microbiome configurations dominated with Staphylococcus spp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Quantification of host and bacterial transcripts on human lesions revealed that high lesional S. aureus transcript abundance was associated with delayed healing and increased expression of IL-1ß. This cytokine was critical for modulating disease outcomes in L. braziliensis-infected mice colonized with S. aureus, given that its neutralization reduced pathology and inflammation. These results highlight how the human microbiome can shape disease outcomes in cutaneous leishmaniasis and suggest pathways toward host-directed therapies to mitigate the inflammatory consequences.

Wound microbiota-mediated correction of matrix metalloproteinase expression promotes re-epithelialization of diabetic wounds.

Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here we focused on Alcaligenes faecalis , a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes re-epithelialization of diabetic keratinocytes, a process which is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

The P3 ERP in Relation to General Versus Specific Psychopathology in Early Childhood.

There is considerable covariation between externalizing and internalizing problems across the lifespan. Partitioning general and specific psychopathology is crucial to identify (a) processes that confer specific risk for externalizing versus internalizing problems and (b) transdiagnostic processes that confer risk for the covariation between externalizing and internalizing problems. The oddball P3 event-related potential (ERP) component, thought to reflect attentional orienting, has been widely examined in relation to psychopathology. However, prior studies have not examined the P3-or other aspects of neural functioning-in relation to general versus specific psychopathology in children. The present study examined whether children's (N = 124, ages 3-7 years) P3 amplitudes were associated with general versus specific psychopathology. Children's electroencephalography data were recorded during an oddball task. Parents rated their children's externalizing and internalizing problems. Using bifactor models to partition variance in parents' ratings of children's psychopathology symptoms, we examined children's P3 amplitudes in relation to three latent factors: (1) the general factor of psychopathology-the covariation of externalizing and internalizing psychopathology, (2) unique externalizing problems-the variance in externalizing problems after controlling for the general factor, and (3) unique internalizing problems. Results indicated that smaller P3 amplitudes were associated with unique externalizing problems at ages 3-5, and with general psychopathology at ages 6-7. Findings suggest that smaller P3 amplitudes may be associated with externalizing problems from a very young age. Moreover, there may be a developmental shift in the functional significance of the P3 in relation to general and specific psychopathology in childhood.

The microbiota and immune system non-genetically affect offspring phenotypes transgenerationally.

The host-microbiota relationship has evolved to shape mammalian processes, including immunity, metabolism, and development 1-3 . Host phenotypes change in direct response to microbial exposures by the individual. Here we show that the microbiota induces phenotypic change not only in the individual but also in their succeeding generations of progeny. We found that germ-free mice exhibit a robust sebum secretion defect and transcriptional changes in various organs, persisting across multiple generations despite microbial colonization and breeding with conventional mice. Host-microbe interactions could be involved in this process, since T cell-deficient mice, which display defective sebum secretion 4 , also transgenerationally transmit their phenotype to progeny. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that epigenetic information in the gametes is required for phenotypic transmission. Accordingly, small non-coding RNAs that can regulate embryonic gene expression 5 were strikingly and similarly altered in gametes of germ-free and T cell-deficient mice. Thus, we have uncovered a novel mechanism whereby the microbiota and immune system induce phenotypic changes in successive generations of offspring. This epigenetic form of inheritance could be advantageous for host adaptation to environmental perturbation, where phenotypic diversity can be introduced more rapidly than by genetic mutation.

The skin microbiome enhances disease through IL-1b and delays healing in cutaneous leishmaniasis patients.

Leishmania braziliensis infection results in inflammation and skin injury, with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 L. braziliensis -infected patients. We found that overall bacterial burden and microbiome configurations dominated with Staphylococcus spp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Dual RNA-seq of human lesions revealed that high lesional S. aureus transcript abundance was associated with delayed healing and increased expression of IL-1ß. This cytokine was critical for modulating disease outcome in L. braziliensis -infected mice colonized with S. aureus , as its neutralization reduced pathology and inflammation. These results implicate the microbiome in cutaneous leishmaniasis disease outcomes in humans and suggest host-directed therapies to mitigate the inflammatory consequences.

Associations Between COVID-19 Vaccine Hesitancy and Socio-Spatial Factors in NYC Transit Workers 50 Years and Older.

This analysis investigates how age, race/ethnicity, and geographic location contributed to vaccine hesitancy in a sample of 645 New York City (NYC) Transport Workers Union (TWU), Local 100 members surveyed in August 2020. Union members ages 50+ were 46% less likely to be vaccine hesitant than their younger counterparts (OR 0.64; 95% CI 0.42, 0.97). Non-Whites (OR 3.95; 95% 2.44, 6.39) and those who did not report their race (OR 3.10; 95% CI 1.87, 5.12) were significantly more likely to be vaccine hesitant than Whites. Those who were not concerned about contracting COVID-19 in the community had 1.83 greater odds (95% CI 1.12, 2.98) of being vaccine hesitant than those who were concerned. Older respondents tended to reside in Queens while vaccine hesitant and non-White respondents were clustered in Brooklyn. General trends observed in COVID-19 vaccine hesitancy persist in a population of high risk, non-healthcare essential workers.

A case series of desmoplakin cardiomyopathy: a mimic of viral myocarditis.

Background: Clinical features and imaging presentation of myocarditis can overlap with other inflammatory or arrhythmogenic cardiomyopathies. Desmoplakin (DSP) is an important structural cardiac protein. Mutations in the DSP gene are associated with a variant of arrhythmogenic right ventricular cardiomyopathy (ARVC). Interestingly, this distinct genetic cardiomyopathy can also present with a myocardial inflammation and fibrosis pattern that may mimic other forms of myocarditis including viral myocarditis, which can raise a clinical challenge. We report two cases of DSP cardiomyopathy, which were initially thought to represent coronavirus disease of 2019 (COVID-19) myocarditis. Case summary: First patient is a 21-your-old woman with no past medical history but family history of presumed 'viral myocarditis' and ventricular tachycardia in her brother. She presented with acute chest pain and elevated cardiac enzymes. She tested positive for COVID-19 and given the suspicion for possible COVID-19 related acute myocarditis, cardiac magnetic resonance imaging obtained and revealed regional wall motion abnormalities, several areas of subepicardial and pericardial late gadolinium enhancement (LGE). Ambulatory cardiac monitoring showed runs of non-sustained ventricular tachycardia and considering her family history of arrhythmogenic myocarditis, genetic testing was performed that was positive for a likely pathogenic heterozygous mutation of DSP gene. She declined the recommended implantable cardioverter defibrillator (ICD).Second patient is a 34-year-old physician with no significant past medical history who works at a COVID-19 unit and presented with syncope and was found to have ventricular tachycardia. Echocardiogram revealed severely dilated left ventricle and globally depressed systolic function with left ventricular ejection fraction of 20%. Coronary computed tomography angiography showed no evidence of coronary atherosclerosis. Cardiac magnetic resonance imaging revealed several areas of mid myocardial and pericardial LGE. Subcutaneous ICD was implanted and an endomyocardial biopsy had evidence of lymphocytic myocarditis and adipose tissue infiltration of the myocardium. Genetic testing revealed pathogenic heterozygous DSP mutation. He underwent epicardial ablation for the episodes of ventricular tachycardia despite medical therapy. He was able to return to work and has not had any further episodes of arrhythmia. Conclusion: Mutations in the DSP gene are associated with left dominant arrhythmogenic cardiomyopathy, which is a variant of ARVC. Beside left ventricular systolic dysfunction and ventricular tachyarrhythmias, carriers of these mutations may present with episodes of chest pain associated with elevated cardiac enzymes and cardiac imaging findings indistinguishable from other forms of acute myocarditis including viral myocarditis. Currently, there are no guidelines for diagnosis and treatment of this entity.

Studying children's growth in self-regulation using changing measures to account for heterotypic continuity: A Bayesian approach to developmental scaling.

Self-regulation is thought to show heterotypic continuity-its individual differences endure but its behavioral manifestations change across development. Thus, different measures across time may be necessary to account for heterotypic continuity of self-regulation. This longitudinal study examined children's (N = 108) self-regulation development using 17 measures, including 15 performance-based measures, two questionnaires, and three raters across seven time points. It is the first to use different measures of self-regulation over time to account for heterotypic continuity while using developmental scaling to link the measures onto the same scale for more accurate growth estimates. Assessed facets included inhibitory control, delayed gratification, sustained attention, and executive functions. Some measures differed across ages to retain construct validity and account for heterotypic continuity. A Bayesian longitudinal mixed model for developmental scaling was developed to link the differing measures onto the same scale. This allowed charting children's self-regulation growth across ages 3-7 years and relating it to both predictors and outcomes. Rapid growth occurred from ages 3-6. As a validation of the developmental scaling approach, greater self-regulation was associated with better school readiness (math and reading skills) and fewer externalizing problems. Our multi-wave, multi-facet, multi-method, multi-measure, multi-rater, developmental scaling approach is the most comprehensive to date for assessing the development of self-regulation. This approach demonstrates that developmental scaling may enable studying development of self-regulation across the lifespan.

Objective Measurement of Hyperactivity Using Mobile Sensing and Machine Learning: Pilot Study.

BACKGROUND: Although hyperactivity is a core symptom of attention-deficit/hyperactivity disorder (ADHD), there are no objective measures that are widely used in clinical settings. OBJECTIVE: We describe the development of a smartwatch app to measure hyperactivity in school-age children. The LemurDx prototype is a software system for smartwatches that uses wearable sensor technology and machine learning to measure hyperactivity. The goal is to differentiate children with ADHD combined presentation (a combination of inattentive and hyperactive/impulsive presentations) or predominantly hyperactive/impulsive presentation from children with typical levels of activity. METHODS: In this pilot study, we recruited 30 children, aged 6 to 11 years, to wear a smartwatch with the LemurDx app for 2 days. Parents also provided activity labels for 30-minute intervals to help train the algorithm. Half of the participants had ADHD combined presentation or predominantly hyperactive/impulsive presentation (n=15), and half were in the healthy control group (n=15). RESULTS: The results indicated high usability scores and an overall diagnostic accuracy of 0.89 (sensitivity=0.93; specificity=0.86) when the motion sensor output was paired with the activity labels. CONCLUSIONS: State-of-the-art sensors and machine learning may provide a promising avenue for the objective measurement of hyperactivity.

Development and Validation of the Parenting Skill Use Diary (PSUD) in a Nationally Representative Sample.

Objective: We describe the development and psychometric properties of an instrument designed to assess the use of effective parenting skills reported with a daily diary. The Parenting Skill Use Diary (PSUD) was developed iteratively relying on a "common elements" approach to quantify the use of evidence-based parenting techniques for responding to child misbehaviors and positive behaviors.Method: The PSUD was administered online daily for seven days to parents/guardians of children aged 5-12. The nationally representative sample (N = 1,570) was selected to match the US population of such parents/guardians on key demographic variables.Results: The instrument demonstrated the ability to capture significant between person variability in the appropriate use of parent management skills. A weekly summary score discriminated between parents/guardians whose children screened positive versus negative for Conduct Disorder (AUC = .72) and Oppositional Defiant Disorder (AUC = .70).Conclusions: The results supported the reliability of validity of the diary as a research tool for examining mean differences.

Sharing the 'weight' of obesity management in primary care: integration of registered dietitian nutritionists to provide intensive behavioural therapy for obesity for Medicare patients.

BACKGROUND: Clinical provision of intensive behavioral therapy for obesity (IBTO) has been a reimbursable treatment for obesity since 2012. However, gaps remain in the literature regarding its impact on patient outcomes. OBJECTIVES: The primary objective of this study was to examine the integration of registered dietitian nutritionist provided IBTO into a primary care setting and evaluate clinic outcomes for Medicare Part B beneficiaries. A secondary objective was to examine intensity of IBTO (quantity of IBTO visits) versus clinical outcomes and influence of socioeconomic factors. METHODS: A case-control retrospective chart review was conducted at a rural, Academic Family Medicine Clinic in Eastern North Carolina for patients seen between 1 January 2016 and 1 January 2019. In order to be included in the treatment group, patients had to be female, white or black race, have Medicare insurance and a body mass index ≥ 30 kg/m2. RESULTS: Mixed model analysis showed statistically significant improvements in clinical outcomes from IBTO treatment. Weight decreased by nearly 3 pounds, while body mass index was half a point lower. A1C was 0.1 units lower for IBTO patients, and they took prescription medication and average of 6 days less than the control group. Minorities and older respondents experienced smaller, all else constant, and annual fixed effects suggest that differentials widen over time. CONCLUSIONS: Registered dietitian nutritionist (RDN) provision of IBTO has demonstrated benefit in improving clinical outcomes including weight, A1C, and reduced medication duration (use) as demonstrated by the IBTO treatment group versus control. IBTO intensity was not predictive of success, and its impact was reduced with older and African American patients. IBTO is beneficial and can be delivered within the primary care setting by a RDN.

Workforce Turnover in Community Behavioral Health Agencies in the USA: A Systematic Review with Recommendations.

Rates of behavioral health workforce turnover are chronically high, with detrimental effects on the agency and remaining staff, as well as hypothesized negative impacts on client care and outcomes. Turnover also creates challenges for studies investigating the effectiveness and/or implementation of behavioral health interventions. Research examining factors that precede and predict behavioral health staff turnover has become increasingly important, as have studies that include recommendations for preventing and reducing turnover. The current paper systematically reviews the body of research on factors associated with behavioral health staff turnover, synthesizes recommendations made for combating turnover, and identifies gaps in this important area of research.