Blood-brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses.

Intracarotid arterial hyperosmolar mannitol (ICAHM) blood-brain barrier disruption (BBBD) is effective and safe for delivery of therapeutics for central nervous system malignancies. ICAHM osmotically alters endothelial cells and tight junction integrity to achieve BBBD. However, occurrence of neuroinflammation following hemispheric BBBD by ICAHM remains unknown. Temporal proteomic changes in rat brains following ICAHM included increased damage-associated molecular patterns, cytokines, chemokines, trophic factors, and cell adhesion molecules, indicative of a sterile inflammatory response (SIR). Proteomic changes occurred within 5 min of ICAHM infusion and returned to baseline by 96 h. Transcriptomic analyses following ICAHM BBBD further supported an SIR. Immunohistochemistry revealed activated astrocytes, microglia, and macrophages. Moreover, proinflammatory proteins were elevated in serum, and proteomic and histological findings from the contralateral hemisphere demonstrated a less pronounced SIR, suggesting neuroinflammation beyond regions of ICAHM infusion. Collectively, these results demonstrate ICAHM induces a transient SIR that could potentially be harnessed for neuroimmunomodulation.

Treatment and outcome in combined scapula and rib fractures: a retrospective study.

PURPOSE: The primary aim was to describe the population characteristics of patients with combined scapula and rib fractures and outcomes associated with different treatment strategies. METHODS: All adult (≥ 18 years) patients with concurrent ipsilateral scapula and rib fractures admitted to the study hospital between 1st January 2010 and 31st June 2021 were retrospectively reviewed. RESULTS: A total of 223 patients were admitted with concurrent ipsilateral rib and scapula fractures. A total of 160 patients (72%) were treated conservatively, 63 patients (28%) operatively. Among operatively treated patients, 32 (51%) underwent rib fixation (RF) only, 24 (38%) underwent scapula fixation (SF) only, and seven patients (11%) underwent combined fixation of scapula and ribs (SRF). In general, more severely injured patients were treated with more extensive surgery. RF patients had a median hospital length of stay of 16 days, the SF patients 11 days and SRF patients 18 days. There were no significant differences in complications (pneumonia, recurrent pneumothorax and revision surgery) between groups. CONCLUSION: Injury severity resulted in different treatment modalities. As a result, different patient characteristics between treatment groups were observed, which makes direct comparison between treatment modalities impossible. All treatment modalities seem feasible; however, the additional value of both rib and scapula fixation has yet to be proven in large multicentre studies.

Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach.

BACKGROUND: Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. AIMS: To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. METHOD: This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. RESULTS: The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. CONCLUSIONS: Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Are x-waiver trainings enough? Facilitators and barriers to buprenorphine prescribing after x-waiver trainings.

BACKGROUND: In the United States, an x-waiver credential is necessary to prescribe buprenorphine medication treatment for opioid use disorder (B-MOUD). Historically, this process has required certified training, which could be a barrier to obtaining an x-waiver and subsequently prescribing. To address this barrier, the US recently removed the training requirement for some clinicians. We sought to determine if clinicians who attended x-waiver training went on to obtain an x-waiver and prescribe B-MOUD, and to examine what facilitated or impeded B-MOUD prescribing. METHODS: In September 2020, we conducted a cross-sectional, electronic survey of attendees of 15 in-person x-waiver pieces of training from June 2018 to January 2020 within the Veterans Health Administration (VHA). Of the attendees (n = 321), we surveyed current VHA clinicians who recalled taking the training. The survey assessed whether clinicians obtained the x-waiver, had prescribed B-MOUD, and barriers or facilitators that influenced B-MOUD prescribing. RESULTS: Of 251 eligible participants, 62 (24.7%) responded to the survey, including 27 (43.5%) physicians, 16 (25.8%) advanced practice clinicians, and 12 (19.4%) pharmacists. Of the 43 clinicians who could prescribe, 29 (67.4%) had obtained their x-waiver and 16 (37.2%) had reported prescribing B-MOUD. Prominent barriers to prescribing B-MOUD included a lack of supporting clinical staff and competing demands on time. The primary facilitator to prescribing was leadership support. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Nine months after x-waiver training, two-thirds of clinicians with prescribing credentials had obtained their x-waiver and one-third were prescribing B-MOUD. Removing the x-waiver training may not have the intended policy effect as other barriers to B-MOUD prescribing persist.

In vivo CRISPR screening for novel noncoding RNA functional targets in glioblastoma models.

CRISPR (clustered regularly interspaced short palindromic repeat)-based genetic screens offer unbiased and powerful tools for systematic and specific evaluation of phenotypes associated with specific target genes. CRISPR screens have been utilized heavily in vitro to identify functional coding and noncoding genes in a large number of cell types, including glioblastoma (GB), though no prior study has described the evaluation of CRISPR screening in GB in vivo. Here, we describe a protocol for targeting and transcriptionally repressing GB-specific long noncoding RNAs (lncRNAs) by CRISPR interference (CRISPRi) system in vivo, with tumor growth in the mouse cerebral cortex. Given the target-specific parameters of each individual screen, we list general steps involved in transducing guide RNA libraries into GB tumor lines, maintaining sufficient coverage, as well as cortically injecting and subsequently isolating transduced screen tumor cell populations for analysis. Finally, in order to demonstrate the use of this technique to discern an essential lncRNA, HOTAIR, from a nonessential lncRNA, we injected a 1:1 (HOTAIR:control nonessential lncRNA knockdown) mixture of fluorescently tagged U87 GB cells into the cortex of eight mice, evaluating selective depletion of HOTAIR-tagged cells at 2 weeks of growth. Fluorescently tagged populations were analyzed via flow cytometry for hiBFP (control knockdown) and green fluorescent protein (HOTAIR knockdown), revealing 17% (p = 0.007) decrease in fluorescence associated with HOTAIR knockdown relative to control. The described in vivo CRISPR screening methodology thus appears to be an effective option for identifying noncoding (and coding) genes affecting GB growth within the mouse cortex.

Skin pigmentation and its control: From ultraviolet radiation to stem cells.

In the light of substantial discoveries in epithelial and hair pigmentation pathophysiology, this review summarizes the current understanding of skin pigmentation mechanisms. Melanocytes are pigment-producing cells, and their key regulating transcription factor is the melanocyte-specific microphthalmia-associated transcription factor (m-MITF). Ultraviolet (UV) radiation is a unique modulator of skin pigmentation influencing tanning pathways. The delayed tanning pathway occurs as UVB produces keratinocyte DNA damage, causing p53-mediated expression of the pro-opiomelanocortin (POMC) gene that is processed to release α-melanocyte-stimulating hormone (α-MSH). α-MSH stimulates the melanocortin 1 receptor (MC1R) on melanocytes, leading to m-MITF expression and melanogenesis. POMC cleavage also releases ß-endorphin, which creates a neuroendocrine pathway that promotes UV-seeking behaviours. Mutations along the tanning pathway can affect pigmentation and increase the risk of skin malignancies. MC1R variants have received considerable attention, yet the allele is highly polymorphic with varied phenotypes. Vitiligo presents with depigmented skin lesions due to autoimmune destruction of melanocytes. UVB phototherapy stimulates melanocyte stem cells in the hair bulge to undergo differentiation and upwards migration resulting in perifollicular repigmentation of vitiliginous lesions, which is under sophisticated signalling control. Melanocyte stem cells, normally quiescent, undergo cyclic activation/differentiation and downward migration with the hair cycle, providing pigment to hair follicles. Physiological hair greying results from progressive loss of melanocyte stem cells and can be accelerated by acute stress-induced, sympathetic driven hyperproliferation of the melanocyte stem cells. Ultimately, by reviewing the pathways governing epithelial and follicular pigmentation, numerous areas of future research and potential points of intervention are highlighted.

Barriers to and Facilitators of Multimodal Chronic Pain Care for Veterans: A National Qualitative Study.

OBJECTIVE: Chronic pain is more common among veterans than among the general population. Expert guidelines recommend multimodal chronic pain care. However, there is substantial variation in the availability and utilization of treatment modalities in the Veterans Health Administration. We explored health care providers' and administrators' perspectives on the barriers to and facilitators of multimodal chronic pain care in the Veterans Health Administration to understand variation in the use of multimodal pain treatment modalities. METHODS: We conducted semi-structured qualitative interviews with health care providers and administrators at a national sample of Veterans Health Administration facilities that were classified as either early or late adopters of multimodal chronic pain care according to their utilization of nine pain-related treatments. Interviews were conducted by telephone, recorded, and transcribed verbatim. Transcripts were coded and analyzed through the use of team-based inductive and deductive content analysis. RESULTS: We interviewed 49 participants from 25 facilities from April through September of 2017. We identified three themes. First, the Veterans Health Administration's integrated health care system is both an asset and a challenge for multimodal chronic pain care. Second, participants discussed a temporal shift from managing chronic pain with opioids to multimodal treatment. Third, primary care teams face competing pressures from expert guidelines, facility leadership, and patients. Early- and late-adopting sites differed in perceived resource availability. CONCLUSIONS: Health care providers often perceive inadequate support and resources to provide multimodal chronic pain management. Efforts to improve chronic pain management should address both organizational and patient-level challenges, including primary care provider panel sizes, accessibility of training for primary care teams, leadership support for multimodal pain care, and availability of multidisciplinary pain management resources.

Molecular Pathways Modulating Sensory Hair Cell Regeneration in Adult Mammalian Cochleae: Progress and Perspectives.

Noise-induced, drug-related, and age-related disabling hearing loss is a major public health problem and affect approximately 466 million people worldwide. In non-mammalian vertebrates, the death of sensory hair cells (HCs) induces the proliferation and transdifferentiation of adjacent supporting cells into new HCs; however, this capacity is lost in juvenile and adult mammalian cochleae leading to permanent hearing loss. At present, cochlear implants and hearing devices are the only available treatments and can help patients to a certain extent; however, no biological approach or FDA-approved drug is effective to treat disabling hearing loss and restore hearing. Recently, regeneration of mammalian cochlear HCs by modulating molecular pathways or transcription factors has offered some promising results, although the immaturity of the regenerated HCs remains the biggest concern. Furthermore, most of the research done is in neonates and not in adults. This review focuses on critically summarizing the studies done in adult mammalian cochleae and discusses various strategies to elucidate novel transcription factors for better therapeutics.

MR-guided pulsed focused ultrasound improves mesenchymal stromal cell homing to the myocardium.

Image-guided pulsed focused ultrasound (pFUS) is a non-invasive technique that can increase tropism of intravenously (IV)-infused mesenchymal stromal cells (MSC) to sonicated tissues. MSC have shown promise for cardiac regenerative medicine strategies but can be hampered by inefficient homing to the myocardium. This study sonicated the left ventricles (LV) in rats with magnetic resonance imaging (MRI)-guided pFUS and examined both proteomic responses and subsequent MSC tropism to treated myocardium. T2-weighted MRI was used for pFUS targeting of the entire LV. pFUS increased numerous pro- and anti-inflammatory cytokines, chemokines, and trophic factors and cell adhesion molecules in the myocardial microenvironment for up to 48 hours post-sonication. Cardiac troponin I and N-terminal pro-B-type natriuretic peptide were elevated in the serum and myocardium. Immunohistochemistry revealed transient hypoxia and immune cell infiltration in pFUS-targeted regions. Myocardial tropism of IV-infused human MSC following pFUS increased twofold-threefold compared with controls. Proteomic and histological changes in myocardium following pFUS suggested a reversible inflammatory and hypoxic response leading to increased tropism of MSC. MR-guided pFUS could represent a non-invasive modality to improve MSC therapies for cardiac regenerative medicine approaches.

Association Between Opioid Dose Reduction Against Patients' Wishes and Change in Pain Severity.

BACKGROUND: There is inadequate evidence of long-term benefit from opioid medications for chronic pain and substantial evidence of potential harms. For patients, dose reduction may be beneficial when implemented voluntarily and supported by a multidisciplinary team but experts have advised against involuntary opioid reduction. OBJECTIVES: To assess the prevalence of self-reported involuntary opioid reduction and to examine whether involuntary opioid reduction is associated with changes in pain severity. DESIGN: Prospective observational cohort study. PARTICIPANTS: Primary care patients treated with long-term opioid therapy in the Veterans Health Administration (N = 290). MAIN MEASURES: The primary exposure was self-reported past year involuntary opioid reduction. The primary outcome was the three-item PEG scale, which measures past-week average pain intensity and interference with enjoyment of life and general activity. KEY RESULTS: Past year opioid reduction or discontinuation was reported by 63% (184/290). Similar numbers reported involuntary (88/290) and voluntary (96/290) opioid reduction. At baseline, there were no significant differences in pain severity between the groups (mean PEG, 7.08 vs. 6.73 vs. 7.07 for past year involuntary opioid reduction, past year voluntary opioid reduction, and no past year opioid reduction, respectively; P = 0.32). For the primary outcome of change in pain severity from baseline to 18 months, there were no significant differences between groups (mean PEG change, - 0.05 vs. - 0.44 vs. - 0.23 for past year involuntary opioid reduction, past year voluntary opioid reduction, and no past year opioid reduction, respectively; P = 0.28). CONCLUSIONS: Self-reported past year involuntary opioid reduction was common among a national sample of veterans treated with long-term opioid therapy. Opioid dose reduction, whether involuntary or voluntary, was not associated with change in pain severity. Future studies should examine involuntary opioid reduction in different populations and trends over time and explore further patient- and provider-level factors that may impact patient experience and outcomes during opioid reduction.

Implementation and Policy Recommendations from the VHA State-of-the-Art Conference on Strategies to Improve Opioid Safety.

Evidence-based treatment of opioid use disorder, the prevention of opioid overdose and other opioid-related harms, and safe and effective pain management are priorities for the Veterans Health Administration (VHA). The VHA Office of Health Services Research and Development hosted a State-of-the-Art Conference on "Effective Management of Pain and Addiction: Strategies to Improve Opioid Safety" on September 10-11, 2019. This conference convened a multidisciplinary group to discuss and achieve consensus on a research agenda and on implementation and policy recommendations to improve opioid safety for Veterans. Participants were organized into three workgroups: (1) managing opioid use disorder; (2) Long-term opioid therapy and opioid tapering; (3) managing co-occurring pain and substance use disorder. Here we summarize the implementation and policy recommendations of each workgroup and highlight important cross-cutting issues related to telehealth, care coordination, and stepped care model implementation.

Stakeholder Engagement in Pragmatic Clinical Trials: Emphasizing Relationships to Improve Pain Management Delivery and Outcomes.

BACKGROUND: The NIH-DOD-VA Pain Management Collaboratory (PMC) supports 11 pragmatic clinical trials (PCTs) on nonpharmacological approaches to management of pain and co-occurring conditions in U.S. military and veteran health organizations. The Stakeholder Engagement Work Group is supported by a separately funded Coordinating Center and was formed with the goal of developing respectful and productive partnerships that will maximize the ability to generate trustworthy, internally valid findings directly relevant to veterans and military service members with pain, front-line primary care clinicians and health care teams, and health system leaders. The Stakeholder Engagement Work Group provides a forum to promote success of the PCTs in which principal investigators and/or their designees discuss various stakeholder engagement strategies, address challenges, and share experiences. Herein, we communicate features of meaningful stakeholder engagement in the design and implementation of pain management pragmatic trials, across the PMC. DESIGN: Our collective experiences suggest that an optimal stakeholder-engaged research project involves understanding the following: i) Who are research stakeholders in PMC trials? ii) How do investigators ensure that stakeholders represent the interests of a study's target treatment population, including individuals from underrepresented groups?, and iii) How can sustained stakeholder relationships help overcome implementation challenges over the course of a PCT? SUMMARY: Our experiences outline the role of stakeholders in pain research and may inform future pragmatic trial researchers regarding methods to engage stakeholders effectively.

Whole Health Options and Pain Education (wHOPE): A Pragmatic Trial Comparing Whole Health Team vs Primary Care Group Education to Promote Nonpharmacological Strategies to Improve Pain, Functioning, and Quality of Life in Veterans-Rationale, Methods, and Implementation.

BACKGROUND: The Whole Health model of the U.S. Department of Veterans Affairs (VA) emphasizes holistic self-care and multimodal approaches to improve pain, functioning, and quality of life. wHOPE (Whole Health Options and Pain Education) seeks to be the first multisite pragmatic trial to establish evidence for the VA Whole Health model for chronic pain care. DESIGN: wHOPE is a pragmatic randomized controlled trial comparing a Whole Health Team (WHT) approach to Primary Care Group Education (PC-GE); both will be compared to Usual VA Primary Care (UPC). The WHT consists of a medical provider, a complementary and integrative health (CIH) provider, and a Whole Health coach, who collaborate with VA patients to create a Personalized Health Plan emphasizing CIH approaches to chronic pain management. The active comparator, PC-GE, is adapted group cognitive behavioral therapy for chronic pain. The first aim is to test whether the WHT approach is superior to PC-GE and whether both are superior to UPC in decreasing pain interference in functioning in 750 veterans with moderate to severe chronic pain (primary outcome). Secondary outcomes include changes in pain severity, quality of life, mental health symptoms, and use of nonpharmacological and pharmacological therapies for pain. Outcomes will be collected from the VA electronic health record and patient-reported data over 12 months of follow-up. Aim 2 consists of an implementation-focused process evaluation and budget impact analysis. SUMMARY: This trial is part of the Pain Management Collaboratory, which seeks to create national-level infrastructure to support evidence-based nonpharmacological pain management approaches for veterans and military service personnel.

Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation.

MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL+ neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68+ macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.

In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study.

BACKGROUND: Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics' delivery, has been advocated as an adjuvant treatment for neurodegenerative diseases and malignancies. Sterile neuroinflammation has been recently described following pFUS+MB BBBO. In this study, we used PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO), to assess for neuroinflammatory changes following single and multiple pFUS+MB sessions. METHODS: Three groups of Sprague-Dawley female rats received MRI-guided pFUS+MB (Optison™; 5-8 × 107 MB/rat) treatments to the left frontal cortex and right hippocampus. Group A rats were sonicated once. Group B rats were sonicated twice and group C rats were sonicated six times on weekly basis. Passive cavitation detection feedback (PCD) controlled the peak negative pressure during sonication. We performed T1-weighted scans immediately after sonication to assess efficiency of BBBO and T2*-weighted scans to evaluate for hypointense voxels. [18F]DPA-714 PET/CT scans were acquired after the BBB had closed, 24 h after sonication in group A and within an average of 10 days from the last sonication in groups B and C. Ratios of T1 enhancement, T2* values, and [18F]DPA-714 percent injected dose/cc (%ID/cc) values in the targeted areas to the contralateral brain were calculated. Histological assessment for microglial activation/astrocytosis was performed. RESULTS: In all groups, [18F]DPA-714 binding was increased at the sonicated compared to non-sonicated brain (%ID/cc ratios > 1). Immunohistopathology showed increased staining for microglial and astrocytic markers in the sonicated frontal cortex compared to contralateral brain and to a lesser extent in the sonicated hippocampus. Using MRI, we documented BBB disruption immediately after sonication with resolution of BBBO 24 h later. We found more T2* hypointense voxels with increasing number of sonications. In a longitudinal group of animals imaged after two and after six sonications, there was no cumulative increase of neuroinflammation on PET. CONCLUSION: Using [18F]DPA-714 PET, we documented in vivo neuroinflammatory changes in association with pFUS+MB. Our protocol (utilizing PCD feedback to minimize damage) resulted in neuroinflammation visualized 24 h post one sonication. Our findings were supported by immunohistochemistry showing microglial activation and astrocytosis. Experimental sonication parameters intended for BBB disruption should be evaluated for neuroinflammatory sequelae prior to implementation in clinical trials.

Challenges with Implementing the Centers for Disease Control and Prevention Opioid Guideline: A Consensus Panel Report.

BACKGROUND: A national crisis of opioid-related morbidity, mortality, and misuse has led to initiatives to address the appropriate role of opioids to treat pain. Deployment of a guideline from the Centers for Disease Control and Prevention to reduce the risks of opioid therapy has raised substantial clinical and public policy challenges. The agency anticipated implementation challenges and committed to reevaluating the guideline for intended and unintended effects on clinician and patient outcomes. OBSERVATIONS: A multidisciplinary expert panel met to review the influence of the core recommendations of the guideline on pain management practices, principally regarding the estimated 5 to 8 million Americans with chronic pain currently on opioids. The panel identified implementation challenges, including application of dosage ceilings and prescription duration guidance, failure to appreciate the importance of patient involvement in decisions to taper or discontinue opioids, barriers to diagnosis and treatment of opioid use disorder, and impeded access to recommended comprehensive, multimodal pain care. Furthermore, policy-making and regulatory bodies may misapply guideline recommendations without flexibility and, sometimes, without full awareness of what the guideline contains. CONCLUSIONS AND RELEVANCE: The panel largely supported the guideline, endorsing its focal points of safety and comprehensive assessment and monitoring. To mitigate clinical and policy challenges identified with implementing the guideline, the panel discussed areas where viewpoints diverged and arrived at consensus proposals. The target audience includes the leaders and institutions that create policy and influence guideline implementation to include regulatory agencies, legislators, public and private payers, and health care systems.

Mesenchymal stromal cell potency to treat acute kidney injury increased by ultrasound-activated interferon-γ/interleukin-10 axis.

Mesenchymal stromal cell (MSC) therapies combined with renal pulsed focused ultrasound (pFUS) pretreatment increase MSC homing and improve cisplatin-induced acute kidney injury (AKI) better than MSC alone. However, mechanisms underlying improved outcomes remain unknown. We hypothesize pFUS up-regulates renal interferon-γ (IFNγ) and stimulates MSC to produce interleukin-10 (IL-10) after migrating to kidneys. To demonstrate initially, MSC cultured with IFNγ up-regulated IL-10. More MSC-derived IL-10 was detected in kidneys when IFNγ-stimulated MSC were infused and they improved AKI better than unstimulated MSC. Next, IFNγ-knockout mice with AKI received pFUS+MSC, but MSC-derived IL-10 expression and AKI were similar to using MSC alone. AKI in wild-type mice receiving pFUS and IL-10-deficient MSC was also unimproved compared to administering IL-10-deficient MSC alone. Indoleamine 2,3-dioxygenase (IDO), an anti-inflammatory enzyme up-regulated in MSC by IFNγ, was up-regulated during AKI, but was not further elevated in MSC from pFUS-treated kidneys, suggesting that IDO is not involved in improved AKI healing by pFUS+MSC. These data suggest IFNγ is up-regulated by pFUS and after i.v.-infused MSC home to pFUS-treated kidneys, IFNγ stimulates additional IL-10 production by MSC to improve AKI. Analogous mechanisms of ultrasound-treated tissue microenvironments stimulating therapeutic MSC may exist in other pathologies where adjuvant ultrasound techniques are successful.

Association Between Facility-Level Utilization of Non-pharmacologic Chronic Pain Treatment and Subsequent Initiation of Long-Term Opioid Therapy.

BACKGROUND: Expert guidelines recommend non-pharmacologic treatments and non-opioid medications for chronic pain and recommend against initiating long-term opioid therapy (LTOT). OBJECTIVE: We examined whether veterans with incident chronic pain receiving care at facilities with greater utilization of non-pharmacologic treatments and non-opioid medications are less likely to initiate LTOT. DESIGN: Retrospective cohort study PARTICIPANTS: Veterans receiving primary care from a Veterans Health Administration facility with incident chronic pain between 1/1/2010 and 12/31/2015 based on either of 2 criteria: (1) persistent moderate-to-severe patient-reported pain and (2) diagnoses "likely to represent" chronic pain. MAIN MEASURES: The independent variable was facility-level utilization of pain-related treatment modalities (non-pharmacologic, non-opioid medications, LTOT) in the prior calendar year. The dependent variable was patient-level initiation of LTOT (≥ 90 days within 365 days) in the subsequent year, adjusting for patient characteristics. KEY RESULTS: Among 1,094,569 veterans with incident chronic pain from 2010 to 2015, there was wide facility-level variation in utilization of 10 pain-related treatment modalities, including initiation of LTOT (median, 16%; range, 5-32%). Veterans receiving care at facilities with greater utilization of non-pharmacologic treatments were less likely to initiate LTOT in the year following incident chronic pain. Conversely, veterans receiving care at facilities with greater non-opioid and opioid medication utilization were more likely to initiate LTOT; this association was strongest for past year facility-level LTOT initiation (adjusted rate ratio, 2.10; 95% confidence interval, 2.06-2.15, top vs. bottom quartile of facility-level LTOT initiation in prior calendar year). CONCLUSIONS: Facility-level utilization patterns of non-pharmacologic, non-opioid, and opioid treatments for chronic pain are associated with subsequent patient-level initiation of LTOT among veterans with incident chronic pain. Further studies should seek to understand facility-level variation in chronic pain care and to identify facility-level utilization patterns that are associated with improved patient outcomes.

Pain Management for Primary Care Providers: A Narrative Review of High-Impact Studies, 2014-2016.

Objective: This manuscript reviews high-impact, peer-reviewed studies published from January 2014 to March 2016 that are relevant to pain management in primary care. Given the recent release of the US Centers for Disease Control and Prevention's "Guideline for Prescribing Opioids for Chronic Pain" emphasizing the primacy of nonopioid treatment, we focused our review on nonopioid pain management. Design: Narrative review of peer-reviewed literature. Methods: We searched three article summary services and queried expert contacts for high-impact, English-language studies related to the management of pain in adults in primary care. All authors reviewed 142 study titles to arrive at group consensus on article content domains. Within article domains, individual authors selected studies approved by the larger group according to their impact on primary care clinical practice, policy, and research, as well as quality of the study methods. Through iterative discussion, 12 articles were selected for detailed review, discussion, and presentation in this narrative review. Results: We present key articles addressing each of six domains of pain management: pharmacotherapy for acute pain; interventional treatments; medical cannabis; complementary and integrative medicine; care management in chronic pain; and prevention. Within each section, we conclude with implications for pain management in primary care. Conclusions: There is growing evidence for multiple nonopioid treatment modalities available to clinicians for the management of pain in primary care. The dissemination and implementation of these studies, including innovative care management interventions, warrant additional study and support from clinicians, educators, and policy-makers.

"Those Conversations in My Experience Don't Go Well": A Qualitative Study of Primary Care Provider Experiences Tapering Long-term Opioid Medications.

Objective: Given the risks of long-term opioid therapy, patients may benefit from tapering these medications. There is little evidence to guide providers' approach to this process. We explored primary care providers' experiences discussing and implementing opioid tapering with patients on long-term opioid therapy. Design: Qualitative study using six semistructured, in-person focus groups. Subject: Primary care providers (N = 40). Setting: Six academically affiliated primary care clinics in university, urban safety net, and Veterans Health Administration medical centers in Colorado. Methods: Focus groups were audio-recorded, transcribed, and analyzed using a mixed inductive-deductive approach in ATLAS.ti. Emergent themes were identified through an iterative, multidisciplinary team-based process. Results: We identified 1) strategies for identifying candidates for opioid tapering, 2) barriers to opioid tapering, and 3) facilitators of opioid tapering. Strategies for identifying candidates for opioid tapering included evidence of high-risk behavior, serious adverse events, opioid-related side effects, and patient preference. Barriers included the providers' emotional burden, inadequate resources, and a lack of trust between patient and provider. Facilitators of opioid tapering included empathizing with the patient's experience, preparing patients for opioid tapering, individualizing implementation of opioid tapering, and supportive guidelines and policies. Conclusions: While discussing and implementing opioid tapering present significant challenges, primary care providers described key facilitators. These findings suggest a need to develop and test the effectiveness of resources to support patient-centered opioid tapering and locally developed policies to support and standardize providers' approaches to opioid prescribing.