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BackgroundBiofeedback-based virtual reality (VR-BF) is a novel, nonpharmacologic method for teaching patients how to control their breathing, which in turn increases heart rate variability (HRV) and may reduce pain. Unlike traditional forms of biofeedback, VR-BF is delivered through a gamified virtual reality environment, increasing the accessibility of biofeedback. This is the first study to systematically integrate VR-BF use in the pediatric perioperative setting, with the ultimate goal of evaluating the efficacy of VR-BF to reduce pain, anxiety, and opioid consumption once feasibility and acceptability have been established. ObjectivesThe primary objective was to develop a clinical trial protocol for VR-BF use in the pediatric perioperative setting, including preoperative education and training, and postoperative application of VR-BF in children undergoing surgery. A secondary objective was to evaluate the patient and parent experience with VR-BF. MethodsA total of 23 patients (12-18 years of age) scheduled for surgery at Nationwide Children’s Hospital were recruited using purposive sampling. Following training, participants independently completed a daily, 10-minute VR-BF session for 7 days before surgery and during their inpatient stay. Participants could use VR-BF up to 2 weeks after hospital discharge. Patient- and session-level data of VR-BF usage and achievement of target HRV parameters were measured to identify the optimal frequency and duration of sessions before and after surgery for this population. Standardized questionnaires and semistructured interviews were conducted to obtain qualitative information about patients’ experiences with VR-BF. ResultsPatient-level data indicated that the highest odds of achieving 1 session under target HRV parameters was after 4 sessions (odds ratio [OR] 5.1 for 4 vs 3 sessions, 95% CI 1.3-20.6; OR 16.6 for 3 vs 2 sessions, 95% CI 1.2-217.0). Session-level data showed that a session duration of 9 to 10 minutes provided the greatest odds of achieving 1 session under target HRV parameters (OR 1.3 for 9 vs 8 min, 95% CI 1.1-1.7; OR 1.4 for 8 vs 7 min, 95% CI 1.1-1.8; OR 1 for 10 vs 9 min, 95% CI 0.9-1.2). Qualitative data revealed patient satisfaction with the VR-BF technology, particularly in managing perioperative stress (17/20, 85%). Few patients reported VR-BF as beneficial for pain (8/20, 40%). ConclusionsChildren and adolescents undergoing surgery successfully learned behavioral strategies with VR-BF with 10-minute sessions once daily for 5 days. To integrate VR-BF as a therapeutic intervention in a subsequent clinical trial, patients will be instructed to complete three 10-minute sessions a day for 7 days after surgery. Trial RegistrationClinicalTrials NCT04943874; https://clinicaltrials.gov/ct2/show/NCT04943874

Abstract Background Joint hypermobility is a common clinical finding amongst hereditary connective tissue disorders that is observed in pediatric rheumatological settings, and often associated with chronic pain. Joint hypermobility may also contribute to deficits in physical functioning and physical activity, but previous findings have been inconsistent. It is possible that physical activity impairment in joint hypermobility may be due to chronic aberrant movement patterns subsequent to increased joint laxity. Method As part of a larger randomized pilot trial of juvenile onset fibromyalgia (JFM), a secondary analysis was conducted to explore whether adolescents with JFM and joint hypermobility differed from non-joint hypermobility peers in terms of pain, daily functioning, and biomechanics (i.e., kinetics and kinematics) during a moderately vigorous functional task. Results From the larger sample of adolescents with JFM (N = 36), 13 adolescents (36.1%) met criteria for joint hypermobility and 23 did not have joint hypermobility. Those with joint hypermobility exhibited poorer overall functioning (Md = 20, Q 1 ,Q 3 [5.8, 7.6] vs. Md = 29, Q 1 ,Q 3 [5.1, 7.6]) but there were no differences in pain (Md = 6.9, Q 1 ,Q 3 [22, 33] , vs. Md = 6.45, Q 1 ,Q 3 [15, 29.5]). Inspection of time-series plots suggests those with joint hypermobility exhibited decreased hip flexion and frontal plane hip moment (e.g., resistance to dynamic valgus) during the landing phase (early stance) and greater hip and knee transverse plane moments during the propulsion phase (late stance) of the drop vertical jump task (DVJ). No other differences in lower extremity biomechanics were observed between study groups. Conclusions In this exploratory study, there were small but notable differences in biomechanics between patients with JFM who also had joint hypermobility versus those without joint hypermobility during a landing and jumping task (e.g., DVJ). These differences may indicate decreased joint stiffness during landing, associated with increased joint laxity and decreased joint stability, which may put them at greater risk for injury. Further study with a larger sample size is warranted to examine whether these biomechanical differences in patients with JFM and joint hypermobility affect their response to typical physical therapy or exercise recommendations.

Abstract Background Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by joint and skin laxity, and often accompanied by chronic pain, dysautonomia, increased distress and, functional limitations. The journey to accurate diagnosis is often prolonged due to unclear etiology of symptoms. This manuscript is a narrative review of the literature on illness uncertainty (IU) in hEDS, highlighting the unique facets of IU in this population, as compared to the broader chronic pain population (given symptom overlap between these two disease groups), that warrant additional investigation. Additionally, we considered the unique challenges associated with IU in the context of the developmental nuances of pediatric populations. Specifically, we aimed to (1) map the extant literature of the IU experience in chronic pain conditions broadly including the pediatric and adult research to identify key concepts related to IU and incorporate potential developmental considerations in IU; (2) delineate and describe the IU experience specifically in patients with hEDS, with the goal of identifying gaps in the literature based on aspects of presentation in hEDS that do and do not differ from the broader chronic pain population; and (3) elucidate the potential areas of adverse impact of IU in both general chronic pain populations, and those with hEDS specifically, to provide actionable areas for future research and clinical care of individuals with hEDS. Results of this review indicate that IU has been well-studied in chronic pain generally, but inadequately evaluated in hEDS specifically. Specific features of hEDS (complexity of the disorder, involvement of multiple bodily systems, contribution of organic pathology) may uniquely contribute to IU in this population. This review suggests that ambiguities surrounding the diagnosis of hEDS, symptom course, and treatment recommendations, along with misdiagnosis, perceived dismissal of symptoms, or attribution of symptoms to mental health concerns might increase risk for IU and related distress in patients. Conclusion Findings from the present review suggest that distinct features of hEDS yield a set of driving factors for IU that may be somewhat different than those faced by patients with chronic pain or other medical conditions. The development of a validated measure of IU to appropriately assess this construct in patients with hEDS is a research priority. In the clinical setting, providers should be attentive to the potentially aversive diagnostic and treatment experiences reported by patients and attempt to provide clear explanations based on the extant knowledge of hEDS, and implement best-practice recommendations for multidisciplinary treatment.

We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.

Nearshore sandbars are common features along sandy coasts. However, identifying sandbars within a beach profile traditionally requires a large historical dataset or subjective input from an observer. Several existing methodologies rely on reference profiles, which is problematic for new study sites with limited data sets and for nourished beaches that have drastic fluctuations in the cross-shore. This novel technique is suitable for beaches where a reference profile does not exist, as it identifies morphological sandbar features by a quantitative automated process. The technique identifies sandbars with a minimum steepness of 2% grade and a minimum height of 0.2 m. The morphological boundaries of sandbars were previously not well-defined, especially the seaward limit of the sandbar, contributing to difficulty in comparing surveys and sandbar morphologies. This technique standardizes the definitions of the bar limits mathematically via standard MATLAB functions, thus removing subjectivity and allowing results to be replicated. Bar identification is focused on the beach profile below the mean high water line, not cross on-shore positions, making the technique appropriate for nourished shorelines as well as those with large seasonal fluctuations. The automated technique was tested on 840 profiles collected near a recently completed beach nourishment project in Long Branch, NJ, USA. Results indicate success in identifying prominent sandbars within the test data set.

BackgroundFunctional abdominal pain disorders (FAPD) are the most common chronic pain conditions of childhood and are made worse by co-occurring anxiety. Our research team found that the Aim to Decrease Pain and Anxiety Treatment (ADAPT), a six-session coping skills program using cognitive behavioral therapy strategies, was effective in improving pain-related symptoms and anxiety symptoms compared to standard care. In follow-up, this current randomized clinical trial (RCT) aims to test potential neural mechanisms underlying the effect of ADAPT. Specifically, this two-arm RCT will explore changes in amygdalar functional connectivity (primary outcome) following the ADAPT protocol during the water loading symptom provocation task (WL-SPT). Secondary (e.g., changes in regional cerebral blood flow via pulsed arterial spin labeling MRI) and exploratory (e.g., the association between the changes in functional connectivity and clinical symptoms) outcomes will also be investigated.MethodsWe will include patients ages 11 to 16 years presenting to outpatient pediatric gastroenterology care at a midwestern children's hospital with a diagnosis of FAPD plus evidence of clinical anxiety based on a validated screening tool (the Generalized Anxiety Disorder-7 [GAD-7] measure). Eligible participants will undergo baseline neuroimaging involving the WL-SPT, and assessment of self-reported pain, anxiety, and additional symptoms, prior to being randomized to a six-week remotely delivered ADAPT program plus standard medical care or standard medical care alone (waitlist). Thereafter, subjects will complete a post assessment neuroimaging visit similar in nature to their first visit.ConclusionsThis small scale RCT aims to increase understanding of potential neural mechanisms of response to ADAPT.Trial registrationClinicalTrials.gov registration: NCT03518216.

Productively infected cells are generally thought to arise from HIV infection of activated CD4+ T cells, and these infected activated cells are thought to be a recurring source of latently infected cells when a portion of the population transitions to a resting state. We discovered and report here that productively and latently infected cells can instead originate from direct infection of resting CD4+ T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting CD4+ T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting CD4+ T cells in which expression of pTEFb enabled productive infection, and we documented persistence of HIV-producing resting T cells during antiretroviral therapy (ART). Thus, we provide evidence of a mechanism by which direct infection of resting T cells in lymphoid tissues to generate productively and latently infected cells creates a mechanism by which the productively infected cells can replenish both populations and maintain two sources of virus from which HIV infection can rebound, even if ART is instituted at the earliest stage of detectable infection.

Accurate characterization of the HIV reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.

There is a great need for nonpharmacologic pain management strategies, given the catastrophic effects of the opioid epidemic and the role of opioid prescription in precipitating addiction [1], particularly in children and adolescents at risk of chronic pain and opioid use after surgery [2–4]. Biofeedback-based virtual reality (VR-BF) is an innovative approach to managing pain that compliments and may even increase accessibility [5] and acceptability [6] of existing mind-body therapies for pain management, like biofeedback (BF). BF teaches patients behavioral modification techniques that impact involuntary processes [7,8]. For example, slow breathing increases heart rate variability (HRV) [9] to reduce pain through the downregulation of the sympathetic nervous system [10,11]. However, barriers to widespread use, such as the need for trained personnel and high costs of direct intervention, have hindered its widespread clinical use and access to this therapy [5,12]. VR-BF has not yet been integrated into perioperative care, and as such, no defined treatment protocols for preoperative training and postoperative application of VR-BF exist, particularly in children. The dataset presented in this article may help fill the unmet, critical need for accessible, effective, alternative therapeutic options for reducing postoperative pain and opioid exposure in children.This investigation aimed to establish measurable outcomes impacting a perioperative treatment protocol of VR-BF, a novel VR-based therapy that teaches patients relaxation techniques and monitors the sensitivity of heart rate variability (HRV) to different frequencies and durations of VR-BF sessions. Achievement of target physiological parameters, including HRV, was measured in children and adolescents undergoing surgery anticipated to cause moderate to severe pain (e.g., orthopedic, chest) requiring postoperative pain management by the Acute Pain Services at Nationwide Children's Hospital (NCH).This dataset included 23 surgical patients evaluated quantitatively and qualitatively to refine a treatment protocol for the feasibility and acceptability of (a) preoperative education and training in relaxation, and (b) postoperative application of a VR-BF intervention for pain management [13]. Qualitative data was collected using an investigator-derived questionnaire to obtain feedback and understand the patient and family experience using VR-BF. Descriptive statistics (mean±SD or median with interquartile range [IQR] for continuous variables; frequencies and percentages for categorical variables) and exploratory spline regression analyses were generated to define measurable outcomes for a future pilot, randomized clinical trial protocol.

Accurate characterization of the HIV reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.

ABSTRACT Cholera has been a human scourge since the early 1800s and remains a global public health challenge, caused by the toxigenic strains of the bacterium Vibrio cholerae. In its aquatic reservoirs, V. cholerae has been shown to live in association with various arthropod hosts, including the chironomids, a diverse insect family commonly found in wet and semiwet habitats. The association between V. cholerae and chironomids may shield the bacterium from environmental stressors and amplify its dissemination. However, the interaction dynamics between V. cholerae and chironomids remain largely unknown. In this study, we developed freshwater microcosms with chironomid larvae to test the effects of cell density and strain on V. cholerae-chironomid interactions. Our results show that chironomid larvae can be exposed to V. cholerae up to a high inoculation dose (109 cells/mL) without observable detrimental effects. Meanwhile, interstrain variability in host invasion, including prevalence, bacterial load, and effects on host survival, was highly cell density-dependent. Microbiome analysis of the chironomid samples by 16S rRNA gene amplicon sequencing revealed a general effect of V. cholerae exposure on microbiome species evenness. Taken together, our results provide novel insights into V. cholerae invasion dynamics of the chironomid larvae with respect to various doses and strains. The findings suggest that aquatic cell density is a crucial driver of V. cholerae invasion success in chironomid larvae and pave the way for future work examining the effects of a broader dose range and environmental variables (e.g., temperature) on V. cholerae-chironomid interactions. IMPORTANCE Vibrio cholerae is the causative agent of cholera, a significant diarrheal disease affecting millions of people worldwide. Increasing evidence suggests that the environmental facets of the V. cholerae life cycle involve symbiotic associations with aquatic arthropods, which may facilitate its environmental persistence and dissemination. However, the dynamics of interactions between V. cholerae and aquatic arthropods remain unexplored. This study capitalized on using freshwater microcosms with chironomid larvae to investigate the effects of bacterial cell density and strain on V. cholerae-chironomid interactions. Our results suggest that aquatic cell density is the primary determinant of V. cholerae invasion success in chironomid larvae, while interstrain variability in invasion outcomes can be observed under specific cell density conditions. We also determined that V. cholerae exposure generally reduces species evenness of the chironomid-associated microbiome. Collectively, these findings provide novel insights into V. cholerae-arthropod interactions using a newly developed experimental host system.

Ian Boggero,1,2 Cecelia Valrie,3,4 Krystal Morgan,5 Nao Hagiwara,3 Susmita Kashikar-Zuck,2,6 Christopher King2,6 1Department of Oral Health Science, Division of Orofacial Pain, University of Kentucky College of Dentistry, Lexington, KY, USA; 2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 3Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA; 4Institute for Inclusion, Inquiry, and Innovation, Virginia Commonwealth University, Richmond, VA, USA; 5Division of Transplant, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 6Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USACorrespondence: Ian Boggero, 740 S Limestone, Lexington, KY, 40536, USA, Tel +859-562-3291, Email ian.boggero@uky.eduContext: General fatigue, sleep-related fatigue, and cognitive fatigue are prevalent and disruptive in adults with chronic musculoskeletal (MSK) pain, but little is known about these fatigue subtypes in pediatric musculoskeletal pain.Objective: To compare fatigue and its subtypes between adolescents with chronic MSK pain and pain-free controls and to test if fatigue subtypes were associated with concurrent pain and its impact (pain intensity, number of pain sites, pain interference, and functional disability) or experimental pain (intensity and tolerance) in adolescents with chronic MSK pain. Finally, we sought to explore adolescents’ qualitative characterizations of their fatigue.Methods: Adolescents with chronic MSK pain (12– 17 y.o., n = 26) and pain-free controls (n = 26) completed validated self-report measures of fatigue, pain, and functional disability, underwent an experimental pain tolerance task (cold water immersion of the hand), and provided qualitative descriptions of their fatigue (pain group only).Results: Adolescents with chronic MSK pain reported significantly greater general, sleep-related, and cognitive fatigue than pain-free controls (all p’s < 0.001). In adolescents with chronic MSK pain, fatigue subtypes were associated with clinical pain and pain impact (r’s = 0.43– 0.84) but not experimental pain measures (p’s > 0.05). Adolescents with chronic MSK pain qualitatively described the negative implications of the different fatigue subtypes, particularly when perceived as long-lasting.Conclusion: This preliminary study suggests that fatigue subtypes are prevalent and impactful in pediatric patients with chronic MSK pain. When planning multi-disciplinary treatment for pediatric MSK pain, providers should recognize fatigue as another disabling symptom.Keywords: disability, fatigue, pediatric, musculoskeletal pain, widespread bodily pain

Introduction Current clinical applications of virtual reality (VR) provide patients with transient pain relief during acutely painful events by redirecting attention. Biofeedback (BF) is a mind–body therapy that effectively produces sustained pain reduction, but there are obstacles to its routine use. Combined, BF-based VR (VR-BF) may increase accessibility while enhancing the benefits of BF. VR-BF has yet to be employed in perioperative care, and as such, no defined treatment protocol for VR-BF exists. The primary aim of this study is to assess the feasibility of the perioperative use of VR-BF in children and adolescents. The secondary aims are to assess the acceptability of VR-BF and to collect pilot efficacy data.Methods and analysis This is a single-centre, randomised controlled pilot clinical trial. A total of 70 patients (12–18 years) scheduled for surgery anticipated to cause moderate to severe pain with ≥1 night of hospital admission will be randomised to one of two study arms (VR-BF or control). Participants randomised to VR-BF (n=35) will use the ForeVR VR platform to engage their breathing in gamified VR applications. Participants randomised to control (n=35) will interact with a pain reflection app, Manage My Pain. The primary outcome is feasibility of VR-BF use in adolescents undergoing surgery as assessed through recruitment, enrolment, retention and adherence to the protocol. Secondary outcomes are acceptability of VR-BF and pilot efficacy measures, including pain, anxiety and opioid consumption.Ethics and dissemination The protocol was approved by the Nationwide Children’s Hospital Institutional Review Board (IRB #STUDY00002080). Patient recruitment begins in March 2023. Written informed consent is obtained for all participants. All information acquired will be disseminated via scientific meetings and published in peer-reviewed journals. Data will be available per request and results will be posted on ClinicalTrials.gov.Trial registration number ClinicalTrials.gov Registry (NCT04943874).

Objective: To describe protocol adaptations to the Fibromyalgia Integrative Training for Teens (FIT Teens) randomized controlled trial in response to the COVID-19 pandemic. The overarching aims of the FIT Teens multi-site 3-arm comparative effectiveness trial are to assess whether a specialized neuromuscular exercise training intervention combined with cognitive-behavioral therapy (CBT) is superior to CBT alone or graded aerobic exercise alone. Design/methods: The trial was originally designed as an in-person, group-based treatment with assessments at baseline, mid- and post-treatment, and four follow-up time points. The original study design and methodology was maintained with specific modifications to screening, consenting, assessments, and group-based treatments to be delivered in remote (telehealth) format in response to COVID-19 restrictions. Results: Study enrollment was paused in March 2020 for five months to revise operations manuals, pilot remote treatment sessions for accuracy and fidelity, complete programming of REDCap assent/consent and assessment materials, train study staff for new procedures and obtain regulatory approvals. The trial was relaunched and has been successfully implemented in remote format since July 2020. Trial metrics thus far demonstrate a consistent rate of enrollment, strong attendance at remote treatment sessions, high retention rates and high treatment fidelity after protocol adaptations were implemented. Conclusions: Preliminary findings indicate that FIT Teens protocol adaptations from in-person to remote are feasible and allowed for sustained enrollment, retention, and treatment fidelity comparable to the in-person format. Methodologic and statistical considerations resulting from the adaptations are discussed as well as implications for interpretation of results upon completion of the trial.

Abstract We describe the development and analysis of a new teletherapy modality that, through a novel approach to targeted radiation delivery, has the potential to provide greater conformality than conventional photon-based treatments. The proposed system uses an X-ray lens to reflect photons from a conventional X-ray tube toward a focal spot. The resulting dose distributions have a highly localized peak dose, with lower doses in the converging radiation cone. Physical principles governing the design of this system are presented, along with a series of measurements analyzing various characteristics of the converging beam. The beam was designed to be nearly monoenergetic (~ 59 keV), with an energy bandwidth of approximately 10 keV allowing for treatment energies lower than conventional therapies. The focal spot was measured to be approximately 2.5 cm long and 4 mm wide. Mounting the proposed X-ray delivery system on a robotic arm would allow sub-millimeter accuracy in focal spot positioning, resulting in highly conformal dose distribution via the optimal placement of individual focal spots within the target volume. Aspects of this novel radiation beam are discussed considering their possible clinical application as a treatment approach that takes maximum advantage of the unique properties afforded by converging X-ray beam therapy.

Abstract Background Juvenile-onset Fibromyalgia (JFM) is a chronic pain condition characterized by widespread musculoskeletal pain, fatigue, sleep difficulties, mood concerns, and other associated symptoms. Although diagnosed in childhood, JFM often persists into adulthood can result in continued physical, social, and psychological impairment. The purpose of this qualitative study was to identify themes of risk and resilience for long-term outcomes among young adults diagnosed with JFM in childhood. Methods The sample included 13 young adults (ages 26–34) who had been diagnosed with JFM in adolescence. Focus groups were used to elicit qualitative information about living with JFM and perceived challenges and buffering factors impacting their adjustment. Results The majority of participants (80%, N = 12) continued to meet criteria for fibromyalgia (FM). An iterative, thematic analysis revealed themes of resilience (e.g., greater acceptance, re-setting expectations, active coping, addressing mental health) and risk (e.g., lack of information, stigma, isolation, negative healthcare experiences). Conclusion Results suggest the need for longer follow-up of youth with JFM as they transition to adulthood with multidisciplinary care and more attention to education about JFM and associated symptoms such as fatigue, as well as ongoing support for coping and mental health needs. A holistic approach to care during the transition years could be beneficial to minimize impact of JFM on long-term functioning.

Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes into osteoclasts. It is often used in combination with dexamethasone (Dex), a glucocorticoid that promotes the resolution of inflammation, to treat malignant diseases, such as multiple myeloma. This treatment can result in bone pathologies, namely medication related osteonecrosis of the jaw, with a poor understanding of the molecular mechanism on monocyte differentiation. IFN-β is a pro-resolving cytokine well-known as an osteoclast differentiation inhibitor. Here, we explored whether Zol and/or Dex regulate macrophage osteoclastic differentiation via IFN-β. RAW 264.7 and peritoneal macrophages were treated with Zol and/or Dex for 4–24 h, and IFN-β secretion was examined by ELISA, while the IFN stimulated gene (ISG) 15 expression was evaluated by Western blotting. RANKL-induced osteoclastogenesis of RAW 264.7 cells was determined by TRAP staining following treatment with Zol+Dex or IFN-β and anti-IFN-β antibodies. We found only the combination of Zol and Dex increased IFN-β secretion by RAW 264.7 macrophages at 4 h and, correspondingly, ISG15 expression in these cells at 24 h. Moreover, Zol+Dex blocked osteoclast differentiation to a similar extent as recombinant IFN-β. Neutralizing anti-IFN-β antibodies reversed the effect of Zol+Dex on ISG15 expression and partially recovered osteoclastic differentiation induced by each drug alone or in combination. Finally, we found Zol+Dex also induced IFN-β expression in peritoneal resolution phase macrophages, suggesting these drugs might be used to enhance the resolution of acute inflammation. Altogether, our findings suggest Zol+Dex block the differentiation of osteoclasts through the expression of IFN-β. Revealing the molecular pathway behind this regulation may lead to the development of IFN-β-based therapy to inhibit osteoclastogenesis in multiple myeloma patients.

Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. However, the lack of well-defined features within vaccine-elicited antibody responses that correlate with protection represents a major roadblock to improving on current generation vaccines. We vaccinated mice (BALB/cJ and C57BL/6J) with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated vaccine-elicited humoral immunity and identified immunological factors associated with protection after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice. In contrast, all C57BL/6J mice were infected similar to controls. Protection was mediated by antibodies and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer CSP-specific germinal center experienced B cells and class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that the development of protective antibody responses in BALB/cJ mice in response to vaccination with PyCSP was associated with increased germinal center activity and somatic mutation compared to C57BL/6J mice, highlighting the key role B cell maturation may have in the development of vaccine-elicited protective antibodies against CSP.

Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with bromodomain (BD) and extraterminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single-cell RNA-Seq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bD-selective BET, or selective BET isoform targeting in CD4+ T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA, but lesser induction of fully elongated and tat-rev RNA compared with T cell activation–positive controls. IAPi+BETi resulted in HIV protein induction in bulk cultures of CD4+ T cells using an ultrasensitive p24 assay, but did not result in enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. This study defines HIV transcriptional elongation and splicing as important barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their BDs in HIV latency, and provides a rationale for exploration of IAPi+BETi in animal models of HIV latency.

This article outlines a pilot study conducted with persisting and non-persisting students in a mid-sized public university in the West. Based on those findings, a retention initiative was developed. The study and initiative both utilize the ASCA [American School Counselor Association] framework, making a case that this model has application in institutions of higher education as well as public schools. The significance of collaborations between school counseling programs and college advising centers is also portrayed.

Transcatheter mitral valve repair using the MitraClip (Abbott Vascular, Santa Clara, CA) is a reasonable option for the treatment of patients with severe symptomatic degenerative mitral regurgitation (MR) who are at prohibitive surgical risk. The occurrence of recurrent severe MR after initial successful MitraClip repair is uncommon. Data are sparse on the management of recurrent severe MR after initial successful repair using the MitraClip. We describe a successful case of redo MitraClip repair for late recurrent severe MR secondary to progressive degenerative mitral valve disease after a successful initial MitraClip procedure and review the literature. Résumé: La réparation transcathéter de la valve mitrale au moyen d’un dispositif MitraClip (Abbott Vascular, Santa Clara, CA) constitue une bonne option pour le traitement de l’insuffisance mitrale (IM) dégénérative symptomatique grave lorsque la chirurgie représente un risque prohibitif pour le patient. Il est rare qu’une IM grave récurrente survienne après l’implantation réussie d’un dispositif MitraClip. On dispose de très peu de données sur la prise en charge de l’IM grave récurrente après une première réparation au moyen d’un dispositif MitraClip. Nous présentons le cas d’une seconde réparation au moyen d’un dispositif MitraClip pour remédier à une IM grave récurrente tardive secondaire à une atteinte dégénérative évolutive de la valve mitrale survenue après une première intervention efficace au moyen d’un dispositif MitraClip, et nous passons en revue les publications portant sur cette question.

This case demonstrates the feasibility and procedural success of a novel supra-annular transcatheter mitral valve, the AltaValve via transapical approach in a patient with severe symptomatic mitral regurgitation who was a prohibitive surgical risk candidate. (Level of Difficulty: Advanced.)

Clearance of apoptotic neutrophils by macrophages is important for the resolution of inflammation. Here, the authors show that interferon-β produced by resolution phase macrophages promotes neutrophil apoptosis and efferocytosis and induces macrophage reprogramming to a pro-resolving phenotype, thereby identifying IFN-β as a multi-pronged pro-resolution cytokine.

Abstract Background To develop and test the feasibility and initial effectiveness of the Treatment and Education Approach for Childhood-onset Lupus (TEACH) protocol, a 6-session cognitive behavioral therapy (CBT) intervention for adolescents and young adults (AYA) with childhood-onset systemic lupus erythematosus (cSLE). Methods Females with cSLE (n = 14; ages 13–19 years, M = 16.21 years) presenting to a pediatric rheumatology clinic subsequently completed the protocol, which was iteratively modified based on participant/interventionist feedback. Upon intervention completion, participants provided qualitative data on feasibility, acceptability, potential modifications, and perceived effectiveness of the program via a semi-structured interview, which was analyzed for shared themes. Participants also completed measures of fatigue, psychological distress, and pain intensity before and after the intervention. Nonparametric statistics were conducted to examine changes in outcome measures following the intervention. Results During the study, several protocol modifications were employed to better address the unique needs of individuals with cSLE (e.g., separate content for adolescents versus young adults). Results suggest that TEACH is feasible, acceptable, and potentially effective in the management of cSLE symptoms. Following the intervention, there was a statistically significant reduction in fatigue (Z = − 2.81, p

Greater than 90% of HIV-1 proviruses are thought to be defective and incapable of viral replication. While replication competent proviruses are of primary concern with respect to disease progression or transmission, studies have shown that even defective proviruses are not silent and can produce viral proteins, which may contribute to inflammation and immune responses. Viral protein expression also has implications for immune-based HIV-1 clearance strategies, which rely on antigen recognition. Thus, sensitive assays aimed at quantifying both replication-competent proviruses and defective, yet translationally competent proviruses are needed to understand the contribution of viral protein to HIV-1 pathogenesis and determine the effectiveness of HIV-1 cure interventions. Previously, we reported a modified HIV-1 gag p24 digital enzyme-linked immunosorbent assay with single molecule array (Simoa) detection of cell-associated viral protein. Here we report a novel p24 protein enrichment method coupled with the digital immunoassay to further extend the sensitivity and specificity of viral protein detection. Immunocapture of HIV gag p24 followed by elution in a Simoa-compatible format resulted in higher protein recovery and lower background from various biological matrices and sample volumes. Quantification of as little as 1 fg of p24 protein from cell lysates from cells isolated from peripheral blood or tissues from ART-suppressed HIV participants, as well as simian–human immunodeficiency virus–infected non-human primates (NHPs), with high recovery and reproducibility is demonstrated here. The application of these enhanced methods to patient-derived samples has potential to further the study of the persistent HIV state and examine in vitro response to therapies, as well as ex vivo study of translationally competent cells from a variety of donors.

During the resolution of acute inflammation, macrophages undergo reprogramming from pro-inflammatory, to anti-inflammatory/reparative, and eventually to pro-resolving macrophages. Galectin-1 (Gal-1) is a bona fide pro-resolving lectin while interferon β (IFN-β) was recently shown to facilitate macrophage reprogramming and resolution of inflammation. In this study, we found Gal-1null mice exhibit a hyperinflammatory phenotype during the resolution of zymosan A-induced peritonitis but not during the early inflammatory response. This phenotype was characterized by reduced macrophage numbers, increased secretion of pro-inflammatory cytokines, such as interleukin-12 (IL-12), and reduced secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10). In addition, we found a delayed expression of the pro-resolving enzyme 12/15-lipoxygenase in macrophages and heightened levels of the inflammatory protease proteinase-3 (PR3) in peritoneal fluids from Gal-1null mice. Moreover, we observed sex-dependent differences in the inflammatory profile of Gal-1null mice. Notably, we found that IFN-β levels were reduced in resolution-phase exudates from Gal-1null mice. Administration of IFN-β in vivo or ex vivo treatment was able to rescue, at least in part, the hyperinflammatory profile of Gal-1null mice. In particular, IFN-β recovered a subset of F4/80+GR-1+ macrophages, restored IL-12 and IL-10 secretion from macrophages to WT values and diminished abnormal peritoneal PR3 levels in Gal-1null mice. In conclusion, our results revealed a new Gal-1-IFN-β axis that facilitates the resolution of inflammation and might restrain uncontrolled inflammatory disorders.

Monocyte-derived macrophages are readily differentiating cells that adapt their gene expression profile to environmental cues and functional needs. During the resolution of inflammation, monocytes initially differentiate to reparative phagocytic macrophages and later to pro-resolving non-phagocytic macrophages that produce high levels of IFNβ to boost resolutive events. Here, we performed in-depth analysis of phagocytic and non-phagocytic myeloid cells to reveal their distinct features. Unexpectedly, our analysis revealed that the non-phagocytic compartment of resolution phase myeloid cells is composed of Ly6CmedF4/80− and Ly6ChiF4/80lo monocytic cells in addition to the previously described Ly6C−F4/80+ satiated macrophages. In addition, we found that both Ly6C+ monocytic cells differentiate to Ly6C−F4/80+macrophages, and their migration to the peritoneum is CCR2 dependent. Notably, satiated macrophages expressed high levels of IFNβ, whereas non-phagocytic monocytes of either phenotype did not. A transcriptomic comparison of phagocytic and non-phagocytic resolution phase F4/80+ macrophages showed that both subtypes express similar gene signatures that make them distinct from other myeloid cells. Moreover, we confirmed that these macrophages express closer transcriptomes to monocytes than to resident peritoneal macrophages (RPM) and resemble resolutive Ly6Clo macrophages and monocyte-derived macrophages more than their precursors, inflammatory Ly6Chi monocytes, recovered following liver injury and healing, and thioglycolate-induced peritonitis, respectively. A direct comparison of these subsets indicated that the non-phagocytic transcriptome is dominated by satiated macrophages and downregulate gene clusters associated with excessive tissue repair and fibrosis, ROS and NO synthesis, glycolysis, and blood vessel morphogenesis. On the other hand, non-phagocytic macrophages enhance the expression of genes associated with migration, oxidative phosphorylation, and mitochondrial fission as well as anti-viral responses when compared to phagocytic macrophages. Notably, conversion from phagocytic to satiated macrophages is associated with a reduction in the expression of extracellular matrix constituents that were demonstrated to be associated with idiopathic pulmonary fibrosis (IPF). Thus, macrophage satiation during the resolution of inflammation seems to bring about a transcriptomic transition that resists tissue fibrosis and oxidative damage while promoting the restoration of tissue homeostasis to complete the resolution of inflammation.

The purpose of this study was to explore the perspective of renal dietitians regarding plant-based diets for chronic kidney disease (CKD) management and evaluate the acceptability of a hypothetical plant-based dietary prescription aiming for the consumption of 30 unique plant foods per week. This study used an exploratory mixed methods design. Forty-six renal dietitians participated in either an online survey (n = 35) or an in-depth interview (n = 11). Dietitians perceived that plant-based diets could address multiple clinical concerns relevant to CKD. Forty percent of survey respondents reported the hypothetical dietary prescription was realistic for people with CKD, 34.3% were unsure, and 25.7% perceived it as unrealistic. Strengths of the hypothetical prescription included shifting the focus to whole foods and using practical resources like recipes. Limited staffing, time, and follow-up opportunities with patients, as well as differing nutrition philosophies were the most commonly reported challenges to implementation; while a supportive multidisciplinary team was identified as an important enabler. To increase patient acceptance of plant-based dietary approaches, education about plant food benefits was recommended, as was implementing small, incremental dietary changes. Successful implementation of plant-based diets is perceived to require frequent patient contact and ongoing education and support by a dietitian. Buy-in from the multidisciplinary team was also considered imperative.

Abstract. Psychological therapies, such as cognitive behavioral therapy, are widely used multifaceted approaches that have been shown to improve pain-related functioning. A small but growing number of studies have used brain imaging to support the use of psychological therapies for pain. Although these studies have led to an increased understanding of how therapies may engage neural systems, there are multiple technical and conceptual challenges to consider. Based on the current literature, several components of effective psychological therapies for pain may be supported by changes in neural circuitry, which are most consistently represented by diminished activation and/or reduced hyperconnectivity in brain regions related to pain processing, emotion, and cognitive control. Findings may vary based on methodological approaches used and may also differ depending on targets of treatment. To provide a nuanced understanding of the current literature, specific targets and components of effective treatments for which a neural basis has been investigated are reviewed. These treatment components include catastrophic thinking about pain, increasing self-efficacy, mindfulness, anxiety symptom reduction, and exposure-based approaches. In general, such strategies have the potential to normalize regional hyperactivations and reduce hyperconnectivity in brain regions associated with nociceptive processing, cognition, and emotion, although additional research is needed. By determining if there are indeed distinct brain mechanisms engaged by different components of psychological therapy and evidence for specific changes in neural function after these interventions, future therapies may be more optimally tailored for individuals afflicted with chronic pain.