Defining Trajectories of Linguistic, Cognitive-Communicative, and Quality of Life Outcomes in Aphasia: Longitudinal Observational Study Protocol.

Objective: To describe the trajectories of linguistic, cognitive-communicative, and health-related quality of life (HRQOL) outcomes after stroke in persons with aphasia. Design: Longitudinal observational study from inpatient rehabilitation to 18 months after stroke. Setting: Four US mid-west inpatient rehabilitation facilities (IRFs). Participants: We plan to recruit 400 adult (older than 21 years) English speakers who meet the following inclusion criteria: (1) Diagnosis of aphasia after a left-hemisphere infarct confirmed by CT scan or magnetic resonance imaging (MRI); (2) first admission for inpatient rehabilitation due to a neurologic event; and (3) sufficient cognitive capacity to provide informed consent and participate in testing. Exclusion criteria include any neurologic condition other than stroke that could affect language, cognition or speech, such as Parkinson's disease, Alzheimer's disease, traumatic brain injury, or the presence of right-hemisphere lesions. Interventions: Not applicable. Main Outcome Measures: Subjects are administered a test battery of linguistic, cognitive-communicative, and HRQOL measures. Linguistic measures include the Western Aphasia Battery-Revised and the Apraxia of Speech Rating Scale. Cognitive-communicative measures include the Communication Participation Item Bank, Connor's Continuous Performance Test-3, the Communication Confidence Rating Scale for Aphasia, the Communication Effectiveness Index, the Neurological Quality of Life measurement system (Neuro-QoL) Communication short form, and the Neuro-QoL Cognitive Function short form. HRQOL measures include the 39-item Stroke & Aphasia Quality of Life Scale, Neuro-QoL Fatigue, Sleep Disturbance, Depression, Ability to Participate in Social Roles & Activities, and Satisfaction with Social Roles & Activities tests, and the Patient-Reported Outcome Measurement and Information System 10-item Global Health short form. The test battery is administered initially during inpatient rehabilitation, and at 3-, 6-, 12-, and 18-months post-IRF discharge. Biomarker samples are collected via saliva samples at admission and a subgroup of participants also undergo resting state fMRI scans. Results: Not applicable. Conclusions: This longitudinal observational study will develop trajectory models for recovery of clinically relevant linguistic, cognitive-communicative, and quality of life outcomes over 18 months after inpatient rehabilitation. Models will identify individual differences in the patterns of recovery based on variations in personal, genetic, imaging, and therapy characteristics. The resulting models will provide an unparalleled representation of recovery from aphasia resulting from stroke. This improved understanding of recovery will enable clinicians to better tailor and plan rehabilitation therapies to individual patient's needs.

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer.

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime , we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily 'active' mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

Near real-time patient experience feedback with data relay to providers: a systematic review of its effectiveness.

Near Real-Time Feedback (NRTF) on the patient's experience with care, coupled with data relay to providers, can inform quality-of-care improvements, including at the point of care. The objective is to systematically review contemporary literature on the impact of the use of NRTF and data relay to providers on standardized patient experience measures. Six scientific databases and five specialty journals were searched supplemented by snowballing search strategies, according to the registered study protocol. Eligibility included studies in English (2015-2023) assessing the impact of NRTF and data relay on standardized patient-reported experience measures as a primary outcome. Eligibility and quality appraisals were performed by two independent reviewers. An expert former patient (Patient and Family Advisory Council and communication sciences background) helped interpret the results. Eight papers met review eligibility criteria, including three randomized controlled trials (RCTs) and one non-randomized study. Three of these studies involved in-person NRTF prior to data relay (patient-level data for immediate corrective action or aggregated and peer-compared) and led to significantly better results in all or some of the experience measures. In turn, a kiosk-based NRTF achieved no better experience results. The remaining studies were pre-post designs with mixed or neutral results and greater risks of bias. In-person NRTF on the patient experience followed by rapid data relay to their providers, either patient-level or provider-level as peer-compared, can improve the patient experience of care. Reviewed kiosk-based or self-reported approaches combined with data relay were not effective. Further research should determine which approach (e.g. who conducts the in-person NRTF) will provide better, more efficient improvements and under which circumstances.

Facilitators and barriers to employment for people with physical disabilities: A cross-sectional study.

BACKGROUND: There is increasing evidence that employment, or the lack thereof, affects an individual's health. Consequently, employment provides people with physical disabilities (PWPD) with financial independence, enhances their well-being and self-worth, and facilitates a sense of purpose. People with physical disabilities often retain job skills and motivation to return to work after acquiring a disability. Their vocational rehabilitation and job accommodation needs likely differ from people with disabilities resulting from developmental, sensory, cognitive, and mental health conditions. To better target the needs of PWPD and improve vocational rehabilitation services, it is crucial to identify the modifiable factors that influence their employment outcomes. OBJECTIVE: This research aimed to examine systematically the client-, employer-, and context-related facilitators and barriers to employment experienced by PWPD. METHODS: We recruited to this cross-sectional study, PWPD from the Midwestern United States who returned to work after injury or illness. An online survey collected data on demographic characteristics and educational history; disability and functional status; supports, facilitators and barriers to employment; and job information and accommodations. RESULTS: 347 working-age PWPD completed the survey; at the time of survey completion, 270 were working and 77 were not. People with physical disabilities who reported social support and encouragement at work were more likely to be working than respondents who did not. Negative attitudes of supervisors and colleagues, inaccessible work environments, and inflexible work schedules were barriers to employment. Important reasons for working included financial needs, a sense of purpose, and self-worth. CONCLUSIONS: Results provide insights into the importance of social supports in the work environment. Novel approaches are needed to develop supportive relationships with supervisors and coworkers.

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 well-being. 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.

The Underlying Neurobiological Mechanisms of Psychosis: Focus on Neurotransmission Dysregulation, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction.

Psychosis, defined as a set of symptoms that results in a distorted sense of reality, is observed in several psychiatric disorders in addition to schizophrenia. This paper reviews the literature relevant to the underlying neurobiology of psychosis. The dopamine hypothesis has been a major influence in the study of the neurochemistry of psychosis and in development of antipsychotic drugs. However, it became clear early on that other factors must be involved in the dysfunction involved in psychosis. In the current review, it is reported how several of these factors, namely dysregulation of neurotransmitters [dopamine, serotonin, glutamate, and γ-aminobutyric acid (GABA)], neuroinflammation, glia (microglia, astrocytes, and oligodendrocytes), the hypothalamic-pituitary-adrenal axis, the gut microbiome, oxidative stress, and mitochondrial dysfunction contribute to psychosis and interact with one another. Research on psychosis has increased knowledge of the complexity of psychotic disorders. Potential new pharmacotherapies, including combinations of drugs (with pre- and probiotics in some cases) affecting several of the factors mentioned above, have been suggested. Similarly, several putative biomarkers, particularly those related to the immune system, have been proposed. Future research on both pharmacotherapy and biomarkers will require better-designed studies conducted on an all stages of psychotic disorders and must consider confounders such as sex differences and comorbidity.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.