Augusta University

Although clinician‐supported computer‐assisted cognitive‐behaviour therapy (CCBT) is well established as an effective treatment for depression and anxiety, less is known about the specific interventions used during coaching sessions that contribute to outcomes. The current study used artificial intelligence (AI) to identify specific components of clinician‐supported CCBT and correlated those scores with therapy outcomes. Data from a randomized clinical trial comparing clinician‐supported CCBT with treatment as usual in a primary care setting were utilized. Participants ( n = 95) engaged in CCBT with coaching sessions. The primary outcome was the Patient Health Questionnaire (PHQ‐9), with Generalized Anxiety Disorder (GAD‐7), Satisfaction with Life Scale (SWLS) and Automatic Thoughts Questionnaire (ATQ) ratings as secondary outcomes, which were assessed at 12 weeks (post), 3‐ and 6‐month follow‐up. The Lyssn system utilized AI technology to code CBT techniques and common general psychotherapeutic techniques. After controlling for initial ratings, 13 Lyssn‐variables were observed to be significantly associated with reducing anxiety on the GAD‐7 after 12 weeks of treatment. Among the most effective CBT interventions for anxiety included the use of guided discovery, understanding, interpersonal effectiveness and agenda setting. The most beneficial intervention was the proportion of open questions across all variables. Lyssn did not identify any CBT‐specific interventions significantly associated with PHQ‐9, SWLS or ATQ. Therapist use of CBT‐specific techniques was significantly associated with reduction of anxiety symptoms after 12 weeks, but such gains were not observed at follow up. Therapist use of open questions was observed to be the most impactful technique contributing to treatment outcomes.

Objectives To examine how long COVID is associated with financial hardship (food insecurity, inability to pay bills, or threat of losing service) across income and education levels, and to assess the role of employment loss or reduced work hours in this hardship. Data Source and Study Setting We used nationally representative data on 271,076 adults from the 2022 Behavioral Risk Factor Surveillance System (BRFSS). Study Design We used multivariable binomial logistic regression models to estimate the average marginal effect of long COVID on financial hardships across multiple income and education groups. Principal Findings In general, we found a significant positive association between long COVID and the three measures of financial hardships across income and education groups (1–11 percentage points increase, 95% CI 0.00–0.02 and 0.07–0.14, respectively). Mediation analysis showed that lost or reduced hours of employment accounted for a significant portion (6%–20%) of the changes in financial distress. Conclusions Long COVID has affected the economic wellbeing of people from all socioeconomic statuses, although at a higher rate for lower income groups. Policy attention is needed to address its economic impacts across income and education levels.

Extracellular histones are released in two major forms: free histones and nucleosomes (DNA‐bound histones). However, little distinction has been made between these two forms of circulating extracellular histones. Our study detected increased circulating nucleosomes in acute lung injury patients. Further, our group identified nucleosomes as the leading form of extracellular histones compared to free histones in the plasma of COVID‐19 patients, underscoring the necessity to reassess the forms of circulating histones and nucleosome contributions to immunopathology. Functionally, nucleosomes activated macrophages and induced inflammation in different organs. Mechanistically, we observed nucleosomes activating the NF‐κB signaling, while inhibition of NF‐κB by sulfasalazine attenuated nucleosome‐induced macrophage activation. Taken together, our study indicates that extracellular histones are predominantly released as nucleosomes, playing a critical role in the inflammation of the lungs and other organs.

Background: The use of telemedicine for continuity of care during disruptions in health care delivery and routine primary care is now well known. Insufficient scientific evidence from assessing telemedicine persists, with widespread use of nonvalidated questionnaires resulting in the inability to pool data on the quality of telemedicine encounters from numerous small-sample studies. This study examines the comprehensiveness of the recently developed Telemedicine Assessment Toolkit (TAT), among articles published after the toolkit was created. Methods: We conducted a PubMed search for articles that used questionnaires to assess telemedicine encounters, published between November 1, 2021, and July 31, 2023. We extracted individual questions from nonvalidated questionnaires and analyzed them to determine their similarity with TAT items. We used a statistical proportion test to see if rates of inclusion were similar across the initial TAT questionnaires and the follow-up set. We calculated p-values for proportions. Results: The database search had an initial yield of 277 articles in which there were 21 articles each with its nonvalidated questionnaire and 348 individual questions. Test of proportions revealed no statistical difference between initial and follow-up articles tested, adjusted for multiple tests. Further analysis found that 85.6% (298 of 348) of the questions used in the follow-up articles match items in the TAT. Conclusion: These results provide insight into the comprehensiveness and potential suitability of the TAT as a toolkit for telemedicine assessment. Future work to standardize TAT involving expert, cognitive testing, and weighting toward a single score would improve telemedicine encounter assessment.

This study's objective was to investigate the extent to which two different levels of low‐intensity vibration training (0.6 g or 1.0 g ) affected musculoskeletal structure and function after a volumetric muscle loss (VML) injury in male C57BL/6J mice. All mice received a unilateral VML injury to the posterior plantar flexors. Mice were randomized into a control group (no vibration; VML‐noTX), or one of two experimental groups. The two experimental groups received vibration training for 15‐min/day, 5‐days/week for 8 weeks at either 0.6 g (VML‐0.6 g ) or 1.0 g (VML‐1.0 g ) beginning 3‐days after induction of VML. Muscles were analyzed for contractile and metabolic adaptations. Tibial bone mechanical properties and geometric structure were assessed by a three‐point bending test and microcomputed tomography (µCT). Body mass‐normalized peak isometric‐torque was 18% less in VML‐0.6 g mice compared with VML‐noTx mice ( p = 0.030). There were no statistically significant differences of vibration intervention on contractile power or muscle oxygen consumption ( p ≥ 0.191). Bone ultimate load, but not stiffness, was ~16% greater in tibias of VML‐1.0 g mice compared with those from VML‐noTx mice ( p = 0.048). Cortical bone volume was ~12% greater in tibias of both vibration groups compared with VML‐noTx mice ( p = 0.003). Importantly, cross‐section moment of inertia, the primary determinant of bone ultimate load, was 44% larger in tibias of VML‐0.6 g mice compared with VML‐noTx mice ( p = 0.006). These changes indicate that following VML, bones are more responsive to the selected vibration training parameters than muscle. Vibration training represents a possible adjuvant intervention to address bone deficits following VML.

BACKGROUND Ang-II (angiotensin II) impairs the function of the antihypertensive enzyme ACE2 (angiotensin-converting enzyme 2) by promoting its internalization, ubiquitination, and degradation, thus contributing to hypertension. However, few ACE2 ubiquitination partners have been identified, and their role in hypertension remains unknown. METHODS Proteomics and bioinformatic analyses were used to identify ACE2 ubiquitination partners in the brain, heart, and kidney of hypertensive C57BL6/J mice of both sexes. The interaction between UBR1 (ubiquitin protein ligase E3 component N-recognin) and ACE2 was validated in cells. Central and peripheral UBR1 knockdown was then performed in male mice to investigate its role in the maintenance of hypertension. RESULTS Proteomics analysis of the hypothalamus identified UBR1 as a potential E3 (ubiquitin protein ligase) ligase promoting ACE2 ubiquitination. Enhanced UBR1 expression, associated with ACE2 reduction, was confirmed in various tissues from hypertensive male mice and human samples. Treatment of endothelial and smooth muscle cells with testosterone, but not 17β-estradiol, confirmed a sex-specific regulation of UBR1. In vivo silencing of UBR1 using chronic administration of small interference RNA resulted in the restoration of ACE2 levels in hypertensive male mice. A transient decrease in blood pressure after intracerebroventricular, but not systemic, infusion was also observed. Interestingly, UBR1 knockdown increased brain activation of Nedd4-2 (neural precursor cell expressed developmentally downregulated protein 4), an E3 ligase promoting ACE2 ubiquitination, and reduced expression of serum and glucocorticoid-regulated kinase 1, the kinase that inactivates Nedd4-2. CONCLUSIONS These data demonstrate that UBR1 is a novel E3 ubiquitin ligase targeting ACE2 in hypertension. UBR1 and Nedd4-2 appear to work synergistically to ubiquitinate ACE2. Targeting these ubiquitin ligases may represent a novel strategy to restore ACE2 compensatory activity in hypertension.

Background People with severe or profound intellectual disability and visual impairment tend to have serious problems in orientation and mobility and need assistance for their indoor traveling. The use of technology solutions may be critically important to help them curb those problems and achieve a level of independence. Objective This study aimed to assess a new technology system to help people with severe to profound intellectual disability and blindness find room destinations during indoor traveling. Methods A total of 7 adults were included in the study. The technology system entailed a barcode reader, a series of barcodes marking the room entrances, a smartphone, and a special app that controlled the presentation of different messages (instructions) for the participants. The messages varied depending on whether the participants were (1) in an area between room entrances, (2) in correspondence with a room entrance to bypass, or (3) in correspondence with a room entrance representing the destination to enter. The intervention with the technology system was implemented according to a nonconcurrent multiple baseline design across participants. Sessions included 7 traveling trials, in each of which the participants were to reach and enter a specific room (1 of the 7 or 9 available) to deliver an object they had carried (transported) during their traveling. Results The participants’ mean frequency of traveling trials completed correctly was between zero and 2 per session during the baseline (without the system). Their mean frequency increased to between about 6 and nearly 7 per session during the intervention (with the system). Conclusions The findings suggest that the new technology system might be a useful support tool for people with severe to profound intellectual disability and blindness.

Multiple studies have highlighted the crucial role of mitochondrial bioenergetics in understanding the progression of cardiorenal diseases, revealing new potential treatment targets related to mitochondrial metabolism. There are well-established sexual dimorphisms in cardiac and renal physiology, with premenopausal females being generally protected from pathology compared with males. The mechanisms of this protection remain to be fully elucidated, however, they clearly depend, at least in part, on sex hormones. Sex hormones contribute to regulating mitochondrial function, and vice versa, highlighting the existence of a bidirectional relationship pivotal for cellular energy metabolism; however, there are still large gaps in knowledge when the sex differences in mitochondrial bioenergetics in health and disease are concerned. This manuscript provides an overview of the new evidence that has been accumulated regarding the role of sex hormones in renal and cardiac mitochondria-dependent cellular energetics, metabolism, and signaling, mainly focusing on the data obtained within the last 3–5 years. We briefly discuss mitochondrial function and different types of sex hormones for the reader and then focus on novel research underscoring the emerging mitochondrial pathways regulated by sex hormones, which might be of interest for the development of novel therapeutic strategies for cardiorenal conditions.

Background The 2014 AAP Bronchiolitis Guidelines deimplemented or recommended against the routine therapeutic use of albuterol, hypertonic saline, and epinephrine for infants and children presenting in the outpatient setting. Our objective was to perform an umbrella review of all meta‐analyses that included outpatient subanalyses or network meta‐analyses with medication treatment comparisons to study the clinical benefits of these deimplemented medications in the outpatient (i.e., primary care, urgent care, and emergency department) setting. Methods Searches were performed in the databases PubMed and Scopus and the Web search engine Google Scholar on the following three topics: albuterol and bronchiolitis, epinephrine and bronchiolitis, and hypertonic saline and bronchiolitis. Article types were limited to systematic reviews and meta‐analyses with outpatient subanalyses, with English language and age restrictions. The search strategy was based on the Population, Intervention, Comparator, Outcomes, Studies (PICOS) framework. The studies were uploaded to Rayyan, a Web‐based platform for managing articles of systematic reviews. Citation tracking and manual review of references were performed for the included studies. The meta‐analyses and network meta‐analyses were reviewed for outpatient subanalyses focused on clinical responses and risk of hospital admission. Results A total of 6 meta‐analyses for albuterol, 4 meta‐analyses for epinephrine, and 11 meta‐analyses for hypertonic saline were included. Our review identified evidence from predominantly low and moderate evidence meta‐analyses (assessed using GRADE and AMSTAR 2) indicating that all three deimplemented medications exhibit one or more therapeutic effects and benefits for infants with the bronchiolitis syndrome in the outpatient setting. Effect sizes ranged from medium to near medium. These clinical benefits include decreased hospital admissions and lower clinical severity scores. Conclusions Given the heterogeneity of patients under the umbrella term “acute bronchiolitis” and the potential for some patients to respond clinically to albuterol, hypertonic saline, and epinephrine, current evidence supports conducting therapeutic trials in infants with acute bronchiolitis in outpatient settings. However, further well‐designed and adequately powered randomized controlled trials and high‐quality meta‐analyses are still needed.

Invasive fungal sinusitis is an uncommon but life-threatening infection. Opportunistic molds, especially Aspergillus and Mucorales species, are the main causes of invasive fungal sinusitis. This entity primarily affects patients who are immunocompromised (e.g., hematologic malignancies, transplant recipients on immunosuppressive medications), or who have uncontrolled diabetes. The mortality is approximately 50%, but varies widely (20–80%). For patients with malignancy as their risk factor, invasive fungal sinusitis can have profound effects on malignancy-related survival by delaying chemotherapy. Limited available interventions, suboptimal early diagnosis, and slow development of new antifungal agents have led to incremental improvements in outcomes. Early use of imaging, rapid institution of appropriate treatment, and a coordinated effort among specialists including infectious disease physicians and otolaryngologists are essential for improved survival. This chapter reviews the risk factors, clinical features, approach to diagnosis, and treatment of invasive fungal sinusitis.

Background: Being able to choose elements of an exercise session, known as autonomy support, improves motor performance and psychological responses. Virtual reality (VR) programs provide many options for embedding autonomy support in exercise sessions. The purpose of this study was to investigate the effects of autonomy support in a VR setting on physiological and psychological responses to self-regulated rowing exercise. Methods: Using a repeated-measures crossover design, healthy untrained men and women (N = 20, age = 23.0 ± 7.4) completed exercise sessions on a rowing ergometer coupled with a head-mounted immersive VR application. In the Choice condition, participants chose the virtual environment, and in the Control condition, the environment was assigned to the participant. Participants were instructed to complete 1500 m as quickly as possible in both conditions, while ratings of perceived exertion, affective valence, and heart rate were recorded throughout the trials. Finishing time and remembered pleasure were assessed at the end of each session. Repeated-measures analyses with an alpha level of 0.05 were used for all variables as appropriate, with Bonferroni adjustments applied for any post hoc tests. Results: There was a main effect of condition on affective valence which was higher in Choice (2.07 ± 1.67) than Control (1.64 ± 2.12, P = 0.03, η2 = 0.22). No other differences were detected between conditions for finishing time or the remaining variables. Conclusion: During self-regulated exercise accompanied by an immersive VR application, being able to choose the virtual environment oneself leads to a more positive affective state without compromising exercise effort, physiological strain, or performance.

Trigeminal neuropathic pain (TNP), migraine, and cluster headache (CH) profoundly impact the quality of life and present significant clinical challenges due to their complex neurobiological underpinnings. This review delves into the pivotal role of the hypothalamus in the pathophysiology of these facial pain syndromes, highlighting its distinctive functions and potential as a primary target for research, diagnosis, and therapy. While the involvement of the hypothalamus in migraine and CH has been increasingly supported by imaging and clinical studies, the precise mechanisms of its role remain under active investigation. The role of the hypothalamus in TNP, in contrast, is less explored and represents a critical gap in our understanding. The hypothalamus’s involvement varies significantly across these conditions, orchestrating a unique interplay of neural circuits and neurotransmitter systems that underlie the distinct characteristics of each pain type. We have explored advanced neuromodulation techniques, such as deep brain stimulation (DBS) and optogenetics, which show promise in targeting hypothalamic dysfunction to alleviate pain symptoms. Furthermore, we discuss the neuroplastic changes within the hypothalamus that contribute to the chronicity of these pains and the implications of these findings for developing targeted therapies. By offering a comprehensive examination of the hypothalamus’s roles, this paper aims to bridge existing knowledge gaps and propel forward the understanding and management of facial neuralgias, underscoring the hypothalamus’s critical position in future neurological research.

Non-essential amino acids are often overlooked in biomedical research; however, they are crucial components of organismal metabolism. One such metabolite that is integral to physiological function is serine. Serine acts as a pivotal link connecting glycolysis with one-carbon and lipid metabolism, as well as with pyruvate and glutathione syntheses. Interestingly, increasing evidence suggests that serine metabolism may impact the aging process, and supplementation with serine may confer benefits in safeguarding against aging and age-related disorders. This review synthesizes recent insights into the regulation of serine metabolism during aging and its potential to promote healthy lifespan and mitigate a spectrum of age-related diseases.

TIMP-1 (tissue inhibitor of metalloproteinases-1) is a physiologic inhibitor of the matrix metalloproteinases (MMPs), but little is known about the role of TIMP-1 in regulating the pathogenesis of influenza A virus (IAV) infection. Here, we performed both in vivo and in vitro experiments to investigate the regulation and function of TIMP-1 during IAV infection. Specifically, plasma levels of TIMP-1 are significantly increased in human subjects and wild-type (WT) mice infected with 2009 H1N1 IAV compared with levels in uninfected controls. Also, TIMP-1 is strikingly upregulated in PDGFRα positive (PDGFRα ⁺ ) cells in IAV-infected murine lungs as demonstrated using conditional KO (cKO) mice with a specific deletion of Timp-1 in PDGFRα ⁺ cells. Our in vitro data indicated that TIMP-1 is induced by TGF-β during lipofibroblast (lipoFBs)-to-myofibroblast (myoFB) transdifferentiation. Timp-1 deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. IAV-infected Timp-1 deficient mice showed increased macrophages, and B and T cell counts in bronchoalveolar lavage (BAL) on day 7 post-infection (p.i.), but reduced BAL neutrophil counts. Increased Cxcl12 levels were detected in both BAL cells and lungs from Timp-1 deficient mice on day 3 p.i. Taken together, our data strongly link TIMP-1 to IAV pathogenesis. We identified that PDGFRα-lineage cells are the main cellular source of elevated TIMP-1 during IAV infection. Loss of Timp-1 attenuates IAV-induced mortality and promotes T and B cell recruitment. Thus, TIMP-1 may be a novel therapeutic target for IAV infection.

Adoptive cell therapy (ACT) using retrovirally transduced T cells represents a promising strategy for enhancing antitumor responses. When used with TriVax, a peptide vaccination strategy, this approach synergistically expands antigen-specific cell populations. STAT5 plays a vital role as a transcription factor in regulating T cell proliferation and their differentiation into effector and memory T cells. We aimed to explore the combination therapy using CD8 T cells engineered to express constitutively active STAT5 (CA-STAT5) with vaccines. CD8 T cells were transduced with a retrovirus (RV) encoding the mouse gp100 T cell receptor (TCR). In certain treatment groups, cells were also co-transduced with RV encoding CA-STAT5. We assessed transduction efficiency and functional activity through flow cytometry and various functional assays. B16F10 tumor-bearing mice were treated with ACT using RV-transduced CD8 T cells and subsequently vaccinated with TriVax. We demonstrate that TriVax selectively enhanced the expansion of ACT cell populations bearing gp100-specific TCRs. T cells engineered to express CA-STAT5 showed not only increased expansion and polyfunctionality but also reduced PD-1 expression, leading to decreased cellular exhaustion. In a B16F10 melanoma mouse model, our approach yielded a potent antitumor effect, with CA-STAT5 further amplifying this response. We found that CA-STAT5 improved antitumor activities, in part, by attenuating the PD-1/PD-L1 inhibitory pathway. These findings indicate that TCR-transduced CD8 T cells can undergo antigen-dependent expansion when exposed to TriVax. Additionally, the expression of CA-STAT5 enhances T cell proliferation and persistence, partly by promoting resistance to PD-1/PD-L1-mediated inhibition in antitumor T cells.

Background There is a large unmet need for alternative, non‐invasive, and accurate diagnosis of small intestinal bacterial overgrowth (SIBO). The smart capsule bacterial detection system (SCBDS) device contains a targeted sampling technology and an onboard SCBDS assay to detect metabolically active bacteria in the small intestine. Here, we evaluated the agreement of SCBDS assay with duodenal aspiration/culture ex vivo in a multicenter clinical study. Methods Duodenal aspiration was performed in subjects with gastrointestinal symptoms suggestive of SIBO. Aspirated fluid was sent to local and central microbiology labs to evaluate the agreement for detecting bacteria with SCBDS assay compared to the total bacterial count (TBC) reference standard. The performance of SCBDS assay was evaluated using a receiver operator curve, sensitivities, and specificities. Key Results Aspirates from 66 patients were collected and analyzed for TBC and SCDBS assay. The overall agreement between the two assays was 82%–92% across 3 clinical sites. The SCBDS assay had a sensitivity of 67%–100% and a specificity of 90%–97% using either ≥ 10³ or 10⁵ CFU mL⁻¹ cutoff. Additionally, there was a good correlation (r = 0.82) for the TBC culture between the local and central labs. Conclusions and Inferences The SCBDS assay showed a high level of agreement with TBC and improved performance compared to other non‐invasive tests. These results demonstrate the potential utility of SCBDS device to aid SIBO diagnosis as a simple and non‐invasive tool that merits further clinical validation.

Anorectal neuropathy causes anorectal dysfunction, yet it is poorly recognized. This stems from both a lack of understanding of the extrinsic and intrinsic innervation of the anorectum and tools for evaluation of neuronal function. Our objective was to provide an improved understanding of the neuronal networks of the anorectum and discuss its functional significance. We performed a comprehensive and up-to-date review of the published literature on anorectal neuroanatomy to generate our findings. Anorectal nerve innervation appears to be much more complex than hitherto known with an extensive overlap, intercommunications and variations The innervations arise from five sources as evidenced by immunohistochemical markers: sympathetic innervation arises from the superior hypogastric plexus, hypogastric plexus and splanchnic nerves (T1-L2), the parasympathetic from pelvic splanchnic nerves (S1-S4), the mixed autonomic from inferior hypogastric plexus, the somatic from pudendal nerves, and the intercommunicating nerves. Further, they are fine, closely packed nerves susceptible to damage from obstetric or spinal cord injury, or pelvic surgery that may not manifest with bowel problems immediately but later in life. This illustrated review provides a new understanding of the afferent and efferent pathways between the rectum, spinal cord and brain, and a framework for clinical implications of anorectal neuropathy, such as anal sphincter or rectal sensory or rectal accommodation dysfunction, causing bowel problems. Insights into the functional neuroanatomy provide an improved mechanistic understanding of anorectal symptoms and could facilitate the development of neurophysiological tests such as translumbosacral anorectal magnetic stimulation and neuromodulation treatments such as sacral neuromodulation and translumbosacral neuromodulation treatment.

Background and Objectives: Black/African American medical professionals and students engage in patient-centered communication in ways that are not yet described in medical education literature. The purpose of this paper is to explore the ways in which Black/African American attending physicians, residents, and medical students enact patient-centered communication while interacting with their Black/African American patients. Methods: Forty-one Black/African American attending physicians, residents, and medical students were recruited through a snowball sample of the authors’ personal and professional networks. Participants engaged in semistructured interviews about their experiences of being Black in a predominantly White profession. Data were transcribed and analyzed using thematic analysis. Results: Black/African American attending physicians, residents, and medical students used patient-centered communication when engaging with Black/African American patients. Rather than relying on physician-focused styles of communication, participants situated their communication within their shared cultural backgrounds and approached their patients as they would approach family members. Participants reported that by centering the patient, they could communicate in a way that reflects shared norms and understandings. Conclusions: This study suggests that Black/African American attending physicians, residents, and medical students approach communication from a personal and familial space in an effort to disrupt conventional modes of provider-patient communication that do not center the patient or consider the patient’s cultural background.