Self-Directed Home and Community-Based Services Improve Outcomes for Family Caregivers: A Systematic Review.

BACKGROUND AND OBJECTIVES: Self-direction is an approach that allows older adults and people with disabilities to determine the home and community-based services they receive, including the ability to hire caregivers of their choice. Self-direction has been shown to improve outcomes for the service recipients. The promotion of choice and control in self-direction may also affect family caregivers. We conducted a systematic review examining the impact of self-direction on a broad range of caregiver outcomes. RESEARCH DESIGN AND METHODS: We conducted a systematic review guided by PRISMA guidelines. Literature search was conducted in 8 databases. We appraised risk of bias using the Joanna Briggs Institute critical appraisal checklists and assessed certainty of evidence using the GRADE framework. RESULTS: Sixteen studies meeting inclusion criteria were included. We found, with moderate certainty, that self-direction is associated with improved caregivers' personal and social wellbeing. Caregivers also reported reduced unmet needs and increased access to care for the care recipients under self-direction. Self-direction did not appear to reduce caregiving hours. With less certainty, self-direction was also positively associated with increased respite care use, perception of choice, and intention to continue caregiving by caregivers. DISCUSSION AND IMPLICATIONS: Beyond delivering person-centered services that improve recipient outcomes, self-direction may also improve the outcomes of family caregivers.

Inhibition of mTORC2 promotes natriuresis in Dahl salt-sensitive rats via the decrease of NCC and ENaC activity.

We have previously observed that prolonged administration of rapamycin, an inhibitor targeting the mammalian target of rapamycin 1 (mTORC1), partially reduced hypertension and alleviated kidney inflammation in Dahl salt-sensitive (SS) rats. In contrast, treatment with PP242, an inhibitor affecting both mTORC1/mTORC2, not only completely prevented hypertension but also provided substantial protection against kidney injury. Notably, PP242 exhibited potent natriuretic effects that were not evident with rapamycin. The primary objective of this study was to pinpoint the specific tubular sites responsible for the natriuretic effect of PP242 in SS rats subjected to either 0.4% NaCl (NS) or 4.0% NaCl (HS) diet. Acute effects of PP242 on natriuretic, diuretic, and kaliuretic responses were determined in unanesthetized SS rats utilizing benzamil, furosemide, or hydrochlorothiazide (inhibitors of ENaC, NKCC2, or NCC, respectively) either administered alone or in combination. The findings indicate that the natriuretic effects of PP242 in SS rats stem predominantly from the inhibition of NCC and a reduction of ENaC open probability. Molecular analysis revealed that mTORC2 regulates NCC activity through protein phosphorylation and ENaC activity through proteolytic cleavage in vivo. Evidence also indicated that PP242 also prevents the loss of K+ associated with the inhibition of NCC. These findings suggest that PP242 may represent an improved therapeutic approach for antihypertensive intervention, potentially controlling blood pressure and mitigating kidney injury in salt-sensitive human subjects.

Evaluation of 90-day repeated dose oral toxicity of an aloe vera inner leaf gel beverage.

Despite its popularity along with many proposed therapeutic applications, the safety profile of Aloe vera gel beverages remains unsettled. The putative toxicology concern has focused on the hydroxyanthraquinone derivatives (HADs) found in the latex portion of the Aloe leaf. Despite harvesting and processing designed to eliminate or significantly reduce these compounds, certain HADs, such as aloin, may be present and have been associated with carcinogenicity in non-decolorized whole leaf extract containing approximately 6400 ppm aloin A and 71 ppm aloin-emodin. Sprague Dawley rats had free access to drinking water or a commercially and widely available Aloe vera gel beverage (Forever Living Products) prepared from the inner leaves of Aloe barbadensis Miller containing 3.43 ppm total aloin for 90 days. Under the conditions of the study and based on the toxicological endpoints evaluated, there were no adverse test substance-related findings, including altered thyroid hormones. No histologic differences or histopathological changes were detected in the multiple tissues and organs examined. The Ki-67 proliferation assay demonstrated no increased cell proliferation in the liver, lungs, kidneys, or urinary bladder, which might have been attributed to the dietary administration of the Aloe vera gel beverage via drinking water for 90 days. These data lend increasing confidence regarding the safety of appropriately processed Aloe vera gel beverages, such as the beverage tested in this study.

Alterations in brain network connectivity and subjective experience induced by psychedelics: a scoping review.

Intense interest surrounds current research on psychedelics, particularly regarding their potential in treating mental health disorders. Various studies suggest a link between the subjective effects produced by psychedelics and their therapeutic efficacy. Neuroimaging evidence indicates an association of changes in brain functional connectivity with the subjective effects of psychedelics. We conducted a review focusing on psychedelics and brain functional connectivity. The review focused on four psychedelic drugs: ayahuasca, psilocybin and LSD, and the entactogen MDMA. We conducted searches in databases of MEDLINE, Embase, APA PsycInfo and Scopus from inception to Jun 2023 by keywords related to functional connectivity and psychedelics. Using the PRISMA framework, we selected 24 articles from an initial pool of 492 for analysis. This scoping review and analysis investigated the effects of psychedelics on subjective experiences and brain functional connectivity in healthy individuals. The studies quantified subjective effects through psychometric scales, revealing significant experiences of altered consciousness, mood elevation, and mystical experiences induced by psychedelics. Neuroimaging results indicated alterations in the functional connectivity of psychedelics, with consistent findings across substances of decreased connectivity within the default mode network and increased sensory and thalamocortical connectivity. Correlations between these neurophysiological changes and subjective experiences were noted, suggesting a brain network basis of the psychedelics' neuropsychological impact. While the result of the review provides a potential neural mechanism of the subjective effects of psychedelics, direct clinical evidence is needed to advance their clinical outcomes. Our research serves as a foundation for further exploration of the therapeutic potential of psychedelics.

Genome organization around nuclear speckles drives mRNA splicing efficiency.

The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies1,2. One example is the nuclear speckle, which is defined by high concentrations of protein and noncoding RNA regulators of pre-mRNA splicing3. What functional role, if any, speckles might play in the process of mRNA splicing is unclear4,5. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs and higher co-transcriptional splicing levels than genes that are located farther from nuclear speckles. Gene organization around nuclear speckles is dynamic between cell types, and changes in speckle proximity lead to differences in splicing efficiency. Finally, directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Together, our results integrate the long-standing observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a crucial role for dynamic three-dimensional spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing.

Genetically dissecting the electron transport chain of a soil bacterium reveals a generalizable mechanism for biological phenazine-1-carboxylic acid oxidation.

The capacity for bacterial extracellular electron transfer via secreted metabolites is widespread in natural, clinical, and industrial environments. Recently, we discovered the biological oxidation of phenazine-1-carboxylic acid (PCA), the first example of biological regeneration of a naturally produced extracellular electron shuttle. However, it remained unclear how PCA oxidation was catalyzed. Here, we report the mechanism, which we uncovered by genetically perturbing the branched electron transport chain (ETC) of the soil isolate Citrobacter portucalensis MBL. Biological PCA oxidation is coupled to anaerobic respiration with nitrate, fumarate, dimethyl sulfoxide, or trimethylamine-N-oxide as terminal electron acceptors. Genetically inactivating the catalytic subunits for all redundant complexes for a given terminal electron acceptor abolishes PCA oxidation. In the absence of quinones, PCA can still donate electrons to certain terminal reductases, albeit much less efficiently. In C. portucalensis MBL, PCA oxidation is largely driven by flux through the ETC, which suggests a generalizable mechanism that may be employed by any anaerobically respiring bacterium with an accessible cytoplasmic membrane. This model is supported by analogous genetic experiments during nitrate respiration by Pseudomonas aeruginosa.

Systematic review of contemporary interventions for improving discharge support and transitions of care from the patient experience perspective.

AIM: To synthesize the impact of improvement interventions related to care coordination, discharge support and care transitions on patient experience measures. METHOD: Systematic review. Searches were completed in six scientific databases, five specialty journals, and through snowballing. Eligibility included studies published in English (2015-2023) focused on improving care coordination, discharge support, or transitional care assessed by standardized patient experience measures as a primary outcome. Two independent reviewers made eligibility decisions and performed quality appraisals. RESULTS: Of 1240 papers initially screened, 16 were included. Seven studies focused on care coordination activities, including three randomized controlled trials [RCTs]. These studies used enhanced supports such as improvement coaching or tailoring for vulnerable populations within Patient-Centered Medical Homes or other primary care sites. Intervention effectiveness was mixed or neutral relative to standard or models of care or simpler supports (e.g., improvement tool). Eight studies, including three RCTs, focused on enhanced discharge support, including patient education (e.g., teach back) and telephone follow-up; mixed or neutral results on the patient experience were also found and with more substantive risks of bias. One pragmatic trial on a transitional care intervention, using a navigator support, found significant changes only for the subset of uninsured patients and in one patient experience outcome, and had challenges with implementation fidelity. CONCLUSION: Enhanced supports for improving care coordination, discharge education, and post-discharge follow-up had mixed or neutral effectiveness for improving the patient experience with care, compared to standard care or simpler improvement approaches. There is a need to advance the body of evidence on how to improve the patient experience with discharge support and transitional approaches.

Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation.

Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis for terminal EEC diversity remains obscure. By forcing activity of the transcription factor (TF) NEUROG3 in 2D cultures of human intestinal stem cells, we replicated physiologic EEC differentiation and examined transcriptional and cis-regulatory dynamics that culminate in discrete cell types. Abundant EEC precursors expressed stage-specific genes and TFs. Before expressing pre-terminal NEUROD1, post-mitotic precursors oscillated between transcriptionally distinct ASCL1+ and HES6hi cell states. Loss of either factor accelerated EEC differentiation substantially and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and non-EC cell features. These TFs mainly bind cis-elements that are accessible in undifferentiated stem cells, and they tailor subsequent expression of TF combinations that underlie discrete EEC identities. Thus, early TF oscillations retard EEC maturation to enable accurate diversity within a medically important cell lineage.

Association Between Anatomic and Clinical Indicators of Injury Severity After Moderate-Severe Traumatic Brain Injury: A Pilot Study Using Multiparametric Magnetic Resonance Imaging.

This study sought to identify whether an anatomical indicator of injury severity as measured by multiparametric magnetic resonance imaging (MRI) including magnetic resonance elastography (MRE), is predictive of a clinical measure of injury severity after moderate-severe traumatic brain injury (TBI). Nine individuals who were admitted to acute inpatient rehabilitation after moderate-to-severe TBI completed a comprehensive MRI protocol prior to discharge from rehabilitation, which included conventional MRI with diffusion tensor imaging (DTI). Of those, five of nine also underwent brain MRE to measure the brain parenchyma stiffness. Clinical severity of injury was measured by the length of post-traumatic amnesia (PTA). MRI-assessed non-hemorrhage contusion score and hemorrhage score, DTI-measured white matter fractional anisotropy, and MRE-measured lesion stiffness were all assessed. A higher hemorrhagic score was significantly associated with a longer length of PTA (p = 0.026). Participants with a longer PTA tended to have a higher non-hemorrhage contusion score and softer contusion lesions than the contralateral control side, although the small sample size did not allow for assessment of a significant association. To our knowledge, this is the first report applying MRI/MRE imaging protocol to quantitate altered brain anatomy after moderate-severe TBI and its association with PTA, a known clinical predictor of post-acute outcome. Future larger studies could lead to the development of prediction models that integrate clinical data with anatomical (MRI), structural (DTI), and mechanical (MRE) changes caused by TBI, to inform prognosis and care planning.

Trajectories of Perceived Gratitude and Change Following Relationship Interventions: A Randomized Controlled Trial With Lower-Income, Help-Seeking Couples.

The current study was designed to advance basic and applied research on perceived gratitude from one's partner in established couple relationships. From a three-arm randomized controlled trial involving 615 lower-income, help-seeking couples (N = 1,224 individuals), study analyses examined (a) the trajectory of perceived gratitude from one's partner among couples assigned to the wait-list condition (i.e., absent of any intervention), and (b) changes in perceived gratitude for individuals assigned to either the OurRelationship (OR) or ePREP relationship intervention condition. With respect to the first aim, levels of perceived gratitude among wait-listed couples demonstrated no significant mean increase over the 6-month period; this rate of change was significantly different from rates of change observed in other relationship constructs (e.g., satisfaction, communication, support) during the wait-list period. Being married, female, and having more children were all associated with lower initial levels of perceived gratitude. For the second aim, individuals assigned to either the OR or ePREP treatment condition demonstrated significant improvements in levels of perceived partner gratitude compared to wait-listed couples. The magnitude of program effect sizes for gratitude (d = 0.33), however, was 3%-48% smaller compared to the magnitude of program effects of other relationship constructs (0.34 < d < 0.64). Results indicated that perceived gratitude is a distinct component of couple relationships, generally lower in more established relationships, and can be improved by participating in OR or ePREP relationship interventions. Implications for research and practice related to gratitude in couple relationships are discussed.

Depth- and curvature-based quantitative susceptibility mapping analyses of cortical iron in Alzheimer's disease.

In addition to amyloid beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been associated with elevated iron in deep gray matter nuclei using quantitative susceptibility mapping (QSM). However, only a few studies have examined cortical iron, using more macroscopic approaches that cannot assess layer-specific differences. Here, we conducted column-based QSM analyses to assess whether AD-related increases in cortical iron vary in relation to layer-specific differences in the type and density of neurons. We obtained global and regional measures of positive (iron) and negative (myelin, protein aggregation) susceptibility from 22 adults with AD and 22 demographically matched healthy controls. Depth-wise analyses indicated that global susceptibility increased from the pial surface to the gray/white matter boundary, with a larger slope for positive susceptibility in the left hemisphere for adults with AD than controls. Curvature-based analyses indicated larger global susceptibility for adults with AD versus controls; the right hemisphere versus left; and gyri versus sulci. Region-of-interest analyses identified similar depth- and curvature-specific group differences, especially for temporo-parietal regions. Finding that iron accumulates in a topographically heterogenous manner across the cortical mantle may help explain the profound cognitive deterioration that differentiates AD from the slowing of general motor processes in healthy aging.

Improving estimates of the illicit cigarette trade through collaboration: lessons from two studies of Malaysia.

This paper critically analyses contrasting estimates of Malaysia's illicit cigarette trade in 2011, 2015 and 2019 by Bui et al and Koya et al who previously produced independent estimates at about the same time using tax gap analysis. Collaboration between the two authors' teams emerged due to the discrepancies in their results, generating this paper to explore the methodological issues identified and hence produce revised estimates of the rate of illicit. Key issues identified were: Bui et al's assessment of legally imported cigarettes impacting all years; their exclusion of ad valorem duty affecting the 2011 and 2015 estimates; Koya et al overlooked the value of cigarettes for export market in their ad valorem calculation and used the sales value of imported tobacco/tobacco products, not just cigarettes, both of which impact estimates for 2011 and 2015. Recalculations using Koya et al's consumption data reveal that in 2019, illicit cigarettes accounted for about 70% of the market, which is higher than Bui et al's estimate (38%) but slightly lower than Koya et al's (72%). For 2011 and 2015 where ad valorem applied, the corrected estimates show a share of the illicit cigarette market of approximately 41.1% and 52.7%, respectively, differing from Bui et al's 0% in 2011 and 29.6% in 2015, and Koya et al's 51% in 2011 and 55% in 2015. This paper provides essential lessons for addressing methodological issues between authors' teams and updated estimates of Malaysia's illicit cigarette trade, verifying that Malaysia faces a substantial illicit cigarette trade problem.

Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation.

Enteroendocrine cells (EECs), which secrete serotonin (enterochromaffin cells, EC) or a dominant peptide hormone, serve vital physiologic functions. As with any adult human lineage, the basis for terminal cell diversity remains obscure. We replicated human EEC differentiation in vitro , mapped transcriptional and chromatin dynamics that culminate in discrete cell types, and studied abundant EEC precursors expressing selected transcription factors (TFs) and gene programs. Before expressing the pre-terminal factor NEUROD1, non-replicating precursors oscillated between epigenetically similar but transcriptionally distinct ASCL1 + and HES6 hi cell states. Loss of either factor substantially accelerated EEC differentiation and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and hormone-producing cell features. Expressed late in EEC differentiation, the latter TFs mainly bind cis -elements that are accessible in undifferentiated stem cells and tailor the subsequent expression of TF combinations that specify EEC types. Thus, TF oscillations retard EEC maturation to enable accurate EEC diversification.

Effectiveness of Behavioral and Pharmacologic Interventions for Depressive Symptoms After Spinal Cord Injury: Findings From a Systematic Review.

OBJECTIVE: To summarize and evaluate evidence regarding the efficacy of interventions for depressive symptoms in adults living with spinal cord injury (SCI) and comorbid major depressive disorder or significant depressive symptoms to inform the development of clinical practice guidelines. DATA SOURCES: Articles published since 2013 and available in Medline, The Cochrane Library, Embase, Scopus, CINAHL, or PsycINFO. Databases were searched in June 2022 and updated November 2023. STUDY SELECTION: Inclusion criteria: age 18 years or older, traumatic SCI, and clinically significant depression (Population), mental health interventions including behavioral, pharmacologic, and complementary and alternative medicine (Intervention), inclusion of a control group (Comparator), with a primary outcome of depression symptom reduction (Outcome). Criteria were applied by multiple reviewers and disagreements were reconciled via unanimous decision among the entire research team. Eight articles of 2780 screened met the selection criteria. DATA EXTRACTION: Data were extracted independently by multiple reviewers. Two reviewers independently assigned a quality score using the guidelines described by Hawker and associates and independently evaluated the risk of bias of each article using version 2 of the Cochrane risk-of-bias tool. DATA SYNTHESIS: All studies assessed depressive symptoms during participant recruitment, screening, and/or at a baseline assessment stage. Pharmacotherapy with venlafaxine XR and several behavioral interventions appear promising, including an online mindfulness course and eye movement desensitization and reprocessing therapy. Remote interventions may be effective in reaching individuals who are unable to travel to in-person therapy sessions. CONCLUSIONS: This systematic review provides valuable information for clinicians who treat individuals with SCI and comorbid major depressive disorder or significant depressive symptoms. It highlights the importance of considering a variety of interventions and individualizing treatment to meet individuals' needs and preferences. Future research should aim to identify effective interventions for treating depressive symptoms in individuals with SCI and optimal delivery methods for these interventions.

scATAnno: Automated Cell Type Annotation for single-cell ATAC Sequencing Data.

Recent advances in single-cell epigenomic techniques have created a growing demand for scATAC-seq analysis. One key analysis task is to determine cell type identity based on the epigenetic data. We introduce scATAnno, a python package designed to automatically annotate scATAC-seq data using large-scale scATAC-seq reference atlases. This workflow generates the reference atlases from publicly available datasets enabling accurate cell type annotation by integrating query data with reference atlases, without the use of scRNA-seq data. To enhance annotation accuracy, we have incorporated KNN-based and weighted distance-based uncertainty scores to effectively detect cell populations within the query data that are distinct from all cell types in the reference data. We compare and benchmark scATAnno against 7 other published approaches for cell annotation and show superior performance in multiple data sets and metrics. We showcase the utility of scATAnno across multiple datasets, including peripheral blood mononuclear cell (PBMC), Triple Negative Breast Cancer (TNBC), and basal cell carcinoma (BCC), and demonstrate that scATAnno accurately annotates cell types across conditions. Overall, scATAnno is a useful tool for scATAC-seq reference building and cell type annotation in scATAC-seq data and can aid in the interpretation of new scATAC-seq datasets in complex biological systems.

Skin-deep Resilience and Early Adolescence: Neighborhood Disadvantage, Executive Functioning, and Pubertal Development in Minority Youth.

Skin-deep resilience, in which youth overcome adversity and achieve success in psychological and academic domains but at a cost to their physiological well-being, has been documented in late adolescence and adulthood. However, its potential to emerge at earlier developmental stages is unknown. To address this gap, secondary data analyses were executed using waves 1 and 2 of the Adolescent Brain Cognitive Development study (n = 7712; ages 9-10 years at baseline [mean: 9.92; SD = 0.63]; 47.1% female; 66.1% White, 13.4% Black, and 20.6% Hispanic). The results indicated high levels of executive functioning were associated with improved psychological and behavioral outcomes at one-year follow-up. However, for racial and ethnic minority (i.e., Black or Hispanic) youth from disadvantaged neighborhoods, high levels of executive functioning were also associated with accelerated pubertal development. No significant interaction was observed among White youth. The findings suggest the skin-deep resilience pattern may be evident in early adolescence.

α-Carboxysome Size Is Controlled by the Disordered Scaffold Protein CsoS2.

Carboxysomes are protein microcompartments that function in the bacterial CO2 concentrating mechanism (CCM) to facilitate CO2 assimilation. To do so, carboxysomes assemble from thousands of constituent proteins into an icosahedral shell, which encapsulates the enzymes Rubisco and carbonic anhydrase to form structures typically > 100 nm and > 300 megadaltons. Although many of the protein interactions driving the assembly process have been determined, it remains unknown how size and composition are precisely controlled. Here, we show that the size of α-carboxysomes is controlled by the disordered scaffolding protein CsoS2. CsoS2 contains two classes of related peptide repeats that bind to the shell in a distinct fashion, and our data indicate that size is controlled by the relative number of these interactions. We propose an energetic and structural model wherein the two repeat classes bind at the junction of shell hexamers but differ in their preferences for the shell contact angles, and thus the local curvature. In total, this model suggests that a set of specific and repeated interactions between CsoS2 and shell proteins collectively achieve the large size and monodispersity of α-carboxysomes.

Investigation of air dispersal during a rhinovirus outbreak in a pediatric intensive care unit.

BACKGROUND: While airborne transmission of rhinovirus is recognized in indoor settings, its role in hospital transmission remains unclear. METHODS: We investigated an outbreak of rhinovirus in a pediatric intensive care unit (PICU) to assess air dispersal. We collected clinical, environmental, and air samples, and staff's surgical masks for viral load and phylogenetic analysis. Hand hygiene compliance and the number of air changes per hour in the PICU were measured. A case-control analysis was performed to identify nosocomial rhinovirus risk factors. RESULTS: Between March 31, 2023, and April 2, 2023, three patients acquired rhinovirus in a cubicle (air changes per hour: 14) of 12-bed PICU. A portable air-cleaning unit was placed promptly. Air samples (72,000 L in 6 hours) from the cohort area, and outer surfaces of staff's masks (n = 8), were rhinovirus RNA-negative. Hand hygiene compliance showed no significant differences (31/34, 91.2% vs 33/37, 89.2%, P = 1) before and during outbreak. Only 1 environmental sample (3.8%) was positive (1.86 × 103 copies/mL). Case-control and next-generation sequencing analysis implicated an infected staff member as the source. CONCLUSIONS: Our findings suggest that air dispersal of rhinovirus was not documented in the well-ventilated PICU during the outbreak. Further research is needed to better understand the dynamics of rhinovirus transmission in health care settings.

Histone Modifications and Their Contributions to Hypertension.

Essential hypertension, a multifaceted disorder, is a worldwide health problem. A complex network of genetic, epigenetic, physiological, and environmental components regulates blood pressure (BP), and any dysregulation of this network may result in hypertension. Growing evidence suggests a role for epigenetic factors in BP regulation. Any alterations in the expression or functions of these epigenetic regulators may dysregulate various determinants of BP, thereby promoting the development of hypertension. Histone posttranslational modifications are critical epigenetic regulators that have been implicated in hypertension. Several studies have demonstrated a clear association between the increased expression of some histone-modifying enzymes, especially HDACs (histone deacetylases), and hypertension. In addition, treatment with HDAC inhibitors lowers BP in hypertensive animal models, providing an excellent opportunity to design new drugs to treat hypertension. In this review, we discuss the potential contribution of different histone modifications to the regulation of BP.