Formoterol alters chemokine expression and ameliorates pain behaviors after moderate spinal cord injury in female mice.

Secondary spinal cord injury (SCI) is characterized by increased cytokines and chemokines at the site of injury that have been associated with the development of neuropathic pain. Nearly 80% of SCI patients report suffering from chronic pain, which is poorly managed with available analgesics. While treatment with the FDA-approved ß2-adrenergic receptor agonist, formoterol, improves various aspects of recovery post-SCI in vivo, its effects on cytokines, chemokines and neuropathic pain remain unknown. Female mice were subjected to moderate (60 kdyn) or severe (80 kdyn) SCI followed by daily treatment with vehicle or formoterol (0.3 mg/kg, i.p.) beginning 8h after injury. The expression of pro-inflammatory cytokines/chemokines, such as IP-10, MIP-1a, MCP-1, BCA-1 and NF-κB, was increased in the injury site of vehicle-treated mice 24h post-SCI, which was ameliorated with formoterol treatment, regardless of injury severity. Thermal hyperalgesia and mechanical allodynia, as measured by Hargreaves infrared apparatus and von Frey filaments, respectively, were assessed prior to SCI and then weekly beginning 21 days post injury (DPI). While all injured mice exhibited decreased withdrawal latency following thermal stimulation compared to baseline, formoterol treatment reduced this response ~15% by 35 DPI. Vehicle-treated mice displayed significant mechanical allodynia, as evidenced by a 55% decrease in withdrawal threshold from baseline. In contrast, mice treated with formoterol maintained a consistent withdrawal time at all times tested. These data indicate that formoterol reduces inflammation post-SCI, likely contributing to mitigation of neuropathic pain, and further supporting the therapeutic potential of this treatment strategy. Significance Statement Chronic pain is a detrimental consequence of spinal cord injury (SCI). We show that treatment with the FDA-approved drug formoterol after SCI decreases injury site pro-inflammatory chemo/cytokines and alters markers of glial cell activation and infiltration. Additionally, formoterol treatment improves locomotor function and body composition, and decreases lesion volume. Finally, formoterol treatment decreased mechanical allodynia and thermal hyperalgesia post-SCI. These data are suggestive of the mechanism of formoterol-induced recovery, and further indicate its potential as a therapeutic strategy for SCI.

Comprehensive phenotypic analysis of diverse FOXN1 variants.

BACKGROUND: Thymus hypoplasia due to stromal cell problems has been linked to mutations in several transcription factors, including Forkhead box N1 (FOXN1). FOXN1 supports T-cell development by regulating the formation and expansion of thymic epithelial cells (TECs). While autosomal recessive FOXN1 mutations result in a nude and severe combined immunodeficiency phenotype, the impact of single-allelic or compound heterozygous FOXN1 mutations is less well-defined. OBJECTIVE: With more than 400 FOXN1 mutations reported, their impact on protein function and thymopoiesis remains unclear for most variants. We developed a systematic approach to delineate the functional impact of diverse FOXN1 variants. METHODS: Selected FOXN1 variants were tested with transcriptional reporter assays and imaging studies. Thymopoiesis was assessed in mouse lines genocopying several human FOXN1 variants. Reaggregate thymus organ cultures were used to compare the thymopoietic potential of the FOXN1 variants. RESULTS: FOXN1 variants were categorized into benign, loss- or gain-of-function, and/or dominant-negatives. Dominant negative activities mapped to frameshift variants impacting the transactivation domain. A nuclear localization signal was mapped within the DNA binding domain. Thymopoiesis analyses with mouse models and reaggregate thymus organ cultures revealed distinct consequences of particular Foxn1 variants on T-cell development. CONCLUSIONS: The potential effect of a FOXN1 variant on T-cell output from the thymus may relate to its effects on transcriptional activity, nuclear localization, and/or dominant negative functions. A combination of functional assays and thymopoiesis comparisons enabled a categorization of diverse FOXN1 variants and their potential impact on T-cell output from the thymus.

How Do Standing Neutral, Supine Lateral, Standing Flexion, and Standing Extension Radiographs Compare in Detecting the Presence and Magnitude of Stable and Dynamic Spondylolisthesis?

BACKGROUND: Clinical guidelines recommend standing radiographs as the most appropriate imaging for detecting degenerative spondylolisthesis, although reliable evidence about the standing position is absent. To our knowledge, no studies have compared different radiographic views and pairings to detect the presence and magnitude of stable and dynamic spondylolisthesis. QUESTIONS/PURPOSES: (1) What is the percentage of new patients presenting with back or leg pain with stable (3 mm or greater listhesis on standing radiographs) and dynamic (3 mm or greater listhesis difference on standing-supine radiographs) spondylolisthesis? (2) What is the difference in the magnitude of spondylolisthesis between standing and supine radiographs? (3) What is the difference in the magnitude of dynamic translation among flexion-extension, standing-supine, and flexion-supine radiographic pairs? METHODS: This cross-sectional, diagnostic study was performed at an urban, academic institution between September 2010 and July 2016; 579 patients 40 years or older received a standard radiographic three-view series (standing AP, standing lateral, and supine lateral radiographs) at a new patient visit. Of those individuals, 89% (518 of 579) did not have any of the following: history of spinal surgery, evidence of vertebral fracture, scoliosis greater than 30°, or poor image quality. In the absence of a reliable diagnosis of dynamic spondylolisthesis using this three-view series, patients may have had flexion and extension radiographs, and approximately 6% (31 of 518) had flexion and extension radiographs. A total of 53% (272 of 518) of patients were female, and the patients had a mean age of 60 ± 11 years. Listhesis distance (in mm) was measured by two raters as displacement of the posterior surface of the superior vertebral body in relation to the posterior surface of the inferior vertebral body from L1 to S1; interrater and intrarater reliability, assessed with intraclass correlation coefficients, was 0.91 and 0.86 to 0.95, respectively. The percentage of patients with and the magnitude of stable spondylolisthesis was estimated on and compared between standing neutral and supine lateral radiographs. The ability of common pairs of radiographs (flexion-extension, standing-supine, and flexion-supine) to detect dynamic spondylolisthesis was assessed. No single radiographic view or pair was considered the gold standard because stable or dynamic listhesis on any radiographic view is often considered positive in clinical practice. RESULTS: Among 518 patients, the percentage of patients with spondylolisthesis was 40% (95% CI 36% to 44%) on standing radiographs alone, and the percentage of patients with dynamic spondylolisthesis was 11% (95% CI 8% to 13%) on the standing-supine pair. Standing radiographs detected greater listhesis than supine radiographs did (6.5 ± 3.9 mm versus 4.9 ± 3.8 mm, difference 1.7 mm [95% CI 1.2 to 2.1 mm]; p < 0.001). Among 31 patients, no single radiographic pairing identified all patients with dynamic spondylolisthesis. The listhesis difference detected between flexion-extension was no different from the listhesis difference detected between standing-supine (1.8 ± 1.7 mm versus 2.0 ± 2.2 mm, difference 0.2 mm [95% CI -0.5 to 1.0 mm]; p = 0.53) and flexion-supine (1.8 ± 1.7 mm versus 2.5 ± 2.2 mm, difference 0.7 mm [95% CI 0.0 to 1.5]; p = 0.06). CONCLUSION: This study supports current clinical guidelines that lateral radiographs should be obtained with patients in the standing position, because all cases of stable spondylolisthesis of 3 mm or greater were detected on standing radiographs alone. Each radiographic pair did not detect different magnitudes of listhesis, and no single pair detected all cases of dynamic spondylolisthesis. Clinical concern for dynamic spondylolisthesis may justify standing neutral, supine lateral, standing flexion, and standing extension views. Future studies could identify and evaluate a set of radiographic views that provides the greatest capacity to diagnose stable and dynamic spondylolisthesis. LEVEL OF EVIDENCE: Level III, diagnostic study.

Acetabular fracture pattern is altered by pre-injury sacroiliac joint autofusion.

PURPOSE: Acetabular fracture shape is determined by the direction of force applied. We perceive an anecdotally observed connection between pre-existing autofused sacroiliac joints (aSIJ) and high anterior column (HAC) injuries. The purpose of this study was to compare variations in acetabular fracture patterns sustained in patients with and without pre-injury sacroiliac (SI) joint autofusion. METHODS: All adult patients receiving unilateral acetabular fixation (level 1 academic trauma; 2008-2018) were reviewed. Injury radiographs and CT scans were reviewed for fracture patterns and pre-existing aSIJ. Fracture types were subgrouped presence of HAC injury (includes anterior column (AC), anterior column posterior hemitransverse (ACPHT), or associated both column (ABC)). ANALYSIS: Logistic regression determined the association between aSIJ and HAC. RESULTS: A total of 371 patients received unilateral acetabular fixation (2008-2018); 61 (16%) demonstrated CT evidence of idiopathic aSIJ. These patients were older (64.1 vs. 47.4, p < 0.01), more likely to be male (95% vs. 71%, p < 0.01), less likely to be smokers (19.0% vs. 44.8%, p < 0.01), and were injured from lower energy mechanisms (21.3% vs. 8.4%, p = 0.01). The most common patterns with autofusion were ACPHT (n = 13, 21%) and ABC (n = 25, 41%). Autofusion was associated with greater odds of patterns involving a high anterior column injury (ABC, ACPHT, or isolated anterior column; OR = 4.97, p < 0.01). After adjusting for age, mechanism, and body mass index, the connection between autofusion and high anterior column injuries remained significant (OR = 2.60, p = 0.01). CONCLUSIONS: SI joint autofusion appears to change mode of failure in acetabular injuries; a more rigid posterior ring may precipitate a high anterior column injury. LEVEL OF EVIDENCE: Prognostic level III.

Traditional Versus Digital Media-Based Hand Therapy After Distal Radius Fracture.

PURPOSE: Distal radius fractures (DRFs) are common injuries with a rising incidence. A substantial portion of the cost of care is attributable to therapy services. Our purpose was to evaluate the effectiveness of a self-directed hand therapy program guided by digital media compared with that of traditional therapy. METHODS: We conducted a randomized controlled trial in patients aged 18 years or older who underwent open reduction and internal fixation of a DRF with volar plating. Subjects were randomized to traditional hand therapy using a 12-week protocol or an identical protocol presented in digital videos and performed at home. Disabilities of the Arm, Shoulder, and Hand (QuickDASH) scores were collected as the primary outcome at 2 weeks (baseline), 6 weeks, and 12 weeks or greater. Pain visual analog scale (VAS) scores, Veterans RAND 12-Item Health Survey (VR-12) scores, wrist and forearm range of motion, wrist circumference, and grip strength were recorded as secondary outcomes. RESULTS: Fifty-one patients were enrolled. Forty-nine patients were included in the analysis-21 in the digital media group and 28 in the traditional group. Both groups demonstrated significant improvements in QuickDASH scores between baseline and 12-week or greater time points. The QuickDASH scores in the digital media group were slightly more improved than those in the traditional group at the 6-week and 12-week or greater time points; however, these differences were not statistically significant. Pain VAS and VR-12 scores were comparable between group differences at each time point. CONCLUSIONS: Our digital media program was at least as effective as traditional therapy for patients undergoing volar plating of DRF. These results may help inform the design of future trials investigating the effectiveness of digital media-based hand therapy programs. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Humeral shaft fractures: a cost-effectiveness analysis of operative versus nonoperative management.

BACKGROUND: Humeral shaft fractures can be managed operatively or nonoperatively with functional bracing in the absence of neurovascular injury, open fracture, or polytrauma. A consensus on optimal management has not been reached, nor has the cost-effectiveness perspective been investigated. METHODS: A decision tree was constructed describing the management of humeral shaft fractures with open reduction-internal fixation (ORIF), intramedullary nailing (IMN), and functional bracing in a non-elderly population. Probabilities were defined using weighted averages determined from systematic review of the literature. Cost-effectiveness was evaluated with incremental cost-effectiveness ratios, measured in cost per quality-adjusted life-year (QALY). Willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY were evaluated. RESULTS: Eighty-six studies were included. Using bracing as the referent in the health care model, we observed that bracing was the preferred strategy at both incremental cost-effectiveness ratio thresholds. ORIF and IMN had higher overall effectiveness (0.917 QALYs and 0.913 QALYs, respectively) compared with bracing (0.877 QALYs). The cost-effectiveness of bracing was driven by a substantially lower overall cost. In the societal model-accounting for both health care and societal costs-the cost difference narrowed between bracing, ORIF, and IMN. Bracing remained the preferred strategy at the $50,000/QALY threshold; ORIF was preferred at the $100,000/QALY threshold. ORIF and IMN were comparable strategies across a range of probability values in sensitivity analyses. CONCLUSIONS: Functional bracing, with its low cost and satisfactory clinical outcomes, is often the most cost-effective strategy for humeral shaft fracture management. ORIF becomes preferable at the higher willingness-to-pay threshold when societal burden is considered. QALY values for ORIF and IMN were comparable.

Optimizing Graft Extraction From the Femoral Condyle for Fresh Osteochondral Allograft Transplantation in Treating Osteochondritis Dissecans of the Capitellum: Best Fit Based on Radius of Curvature.

BACKGROUND: Osteochondritis dissecans (OCD) of the capitellum is a common cause of pain and dysfunction in adolescents that engage in repetitive elbow loading. For large, unstable lesions fresh osteochondral allograft transplantation (FOCAT) from the femoral condyle has been described as an effective treatment. Current practice involves significant guesswork in obtaining an appropriately sized graft, with anatomic variations resulting in poor graft fit. No studies currently exist that analyze and identify the best distal femur FOCAT graft site to repair OCD lesions of the capitellum based on the radius of curvature (ROC) and simulated matching. METHODS: Computed tomography scans of the elbow were used to estimate the subchondral bone ROC of capitella in adolescents aged 11 to 21 years. The capitellar location used corresponds to the most commonly reported site of OCD lesions in the elbow. Computed tomography scans of the lower extremity were used to estimate the subchondral bone ROC of 4 potential donor femoral condyle grafts. ROC from distinct regions at the posterior section of both the medial and lateral femoral condyles were measured: 2 areas representing 10 mm grafts from the center (MC1 and LC1), and 2 areas estimating 10 mm grafts posterior and adjacent to the physeal scar (MC2 and LC2). Intraobserver and interobserver reliability measurements were preformed to corroborate precision and validate the method. RESULTS: The mean ROC of healthy subchondral bone at the region of the capitellum were OCD lesions most commonly occur was 9.79±1.39 mm. The mean ROC of MC1 was 18.61±2.26 mm. The average ROC of the MC2 was 15.23±1.43 mm. The average ROC of LC1 was 16.47±1.34 mm. The average ROC of LC2 was 18.19±3.09 mm. After 15,000 simulated condyle-to-capitellar site matchings based on these measurements, a good fit graft was achieved at a frequency of 15%. DISCUSSION: No site measured from the femoral condyle demonstrated a subchondral ROC that exactly matched the subchondral ROC of the capitellum at the center location where OCD lesions most commonly occur; of the locations measured, a 10 mm section from MC2 demonstrated the closest match. On the basis of this analysis, extracting a graft from MC2 has the potential to further optimize FOCAT fit to the capitellum. LEVEL OF EVIDENCE: Level III.

Acoustic characteristics of American English liquids /ɹ/, /l/, /ɹl/ produced by Korean L2 adults.

This study examined the acoustic characteristics of American English liquids /ɹ/, /l/, and /ɹl/ produced by 14 adult learners of English (L2) and 13 native speakers of English. Several temporal and spectral measures were examined, including a novel measure to describe the relative timing of the maximum constriction during liquid production. The results indicated that L2 speakers rely more on duration contrasts to distinguish the three liquids than spectral contrasts. Reduced spectral differences among the liquids in L2 speakers are discussed concerning the influence of the native language of L2 speakers.

Relation of second formant trajectories to tongue kinematics.

In this study, the relationship between the acoustic and articulatory kinematic domains of speech was examined among nine neurologically healthy female speakers using two derived relationships between tongue kinematics and F2 measurements: (1) second formant frequency (F2) extent to lingual displacement and (2) F2 slope to lingual speed. Additionally, the relationships between these paired parameters were examined within conversational, more clear, and less clear speaking modes. In general, the findings of the study support a strong correlation for both sets of paired parameters. In addition, the data showed significant changes in articulatory behaviors across speaking modes including the magnitude of tongue motion, but not in the speed-related measures.

Use of a Large Tenaculum Clamp as a Reduction Technique for Treatment of Distal Radius Fractures.

Distal radius fractures are common upper extremity injuries requiring surgical treatment. In the context of management with a volar locking plate (VLP), a number of described techniques assist with restoration of individual anatomical parameters such as radial length, volar tilt, and articular congruity. We present a surgical technique that utilizes a large tenaculum bone clamp to provide an efficacious reduction in several planes. With anteroposterior compression, the clamp enables volar translation of the distal fracture fragment. This compression also decreases the interval between the distal portion of the VLP and the fracture fragments. With a rotational force, the clamp can restore volar tilt of the articular surface. By positioning the tines of the clamp across the fracture in the coronal plane, a clamping force can correct medial or lateral translation of the distal fracture fragment. Proper reduction substantially minimizes complications such as abrasion or rupture of the flexor tendons along the VLP.

Effects of Deep-Brain Stimulation on Speech: Perceptual and Acoustic Data.

PURPOSE: This study examined speech changes induced by deep-brain stimulation (DBS) in speakers with Parkinson's disease (PD) using a set of auditory-perceptual and acoustic measures. METHOD: Speech recordings from nine speakers with PD and DBS were compared between DBS-On and DBS-Off conditions using auditory-perceptual and acoustic analyses. Auditory-perceptual ratings included voice quality, articulation precision, prosody, speech intelligibility, and listening effort obtained from 44 listeners. Acoustic measures were made for voicing proportion, second formant frequency slope, vowel dispersion, articulation rate, and range of fundamental frequency and intensity. RESULTS: No significant changes were found between DBS-On and DBS-Off for the five perceptual ratings. Four of six acoustic measures revealed significant differences between the two conditions. While articulation rate and acoustic vowel dispersion increased, voicing proportion and intensity range decreased from the DBS-Off to DBS-On condition. However, a visual examination of the data indicated that the statistical significance was mostly driven by a small number of participants, while the majority did not show a consistent pattern of such changes. CONCLUSIONS: Our data, in general, indicate no-to-minimal changes in speech production ensued from DBS stimulation. The findings are discussed with a focus on large interspeaker variability in PD in terms of their speech characteristics and the potential effects of DBS on speech.

Does Native Language Matter in Perceptual Ratings of Dysarthria?

PURPOSE: Despite the general agreement that dysarthria characteristics are largely language-independent, few efforts have attempted a systematic comparison across languages. To examine the role of native languages in the perception of speech characteristics of dysarthria secondary to Parkinson's disease (PD), auditory-perceptual ratings of dysarthria, and confidence level of the judgments were compared between two listener groups: language-matched and language-crossed. METHOD: A total of 60 listeners (35 native speakers of Korean and 25 native speakers of American English) estimated speech abnormality for 20 speech dimensions using a visual analog scale method for both language-matched and language-crossed speech stimuli. Speech stimuli were passage readings of the respective languages obtained from individuals with and without PD. RESULTS: For speech dimension ratings, eight of 20 speech dimensions revealed significant differences in response to PD speech between the two listener groups, for most of which, language-crossed listeners' estimation was lower (i.e., more impaired) than language-matched listeners. For confidence-level ratings, language-matched listeners were less confident in the ratings of speakers with PD compared to the language-crossed listeners. CONCLUSIONS: The data support both language-universal and language-specific aspects in perceiving dysarthria characteristics, such that native language plays a role, especially when rating articulatory- and rhythmic-related characteristics. The findings are discussed with respect to the role of linguistic information, such as phonetic inventories and prosodic structures, in perceiving dysarthria characteristics.

5-HT1F receptor agonism induces mitochondrial biogenesis and increases cellular function in brain microvascular endothelial cells.

Introduction: Vascular and mitochondrial dysfunction are well-established consequences of multiple central nervous system (CNS) disorders, including neurodegenerative diseases and traumatic injuries. We previously reported that 5-hydroxytryptamine 1F receptor (5-HT1FR) agonism induces mitochondrial biogenesis (MB) in multiple organ systems, including the CNS. Methods: Lasmiditan is a selective 5-HT1FR agonist that is FDA-approved for the treatment of migraines. We have recently shown that lasmiditan treatment induces MB, promotes vascular recovery and improves locomotor function in a mouse model of spinal cord injury (SCI). To investigate the mechanism of this effect, primary cerebral microvascular endothelial cells from C57bl/6 mice (mBMEC) were used. Results: Lasmiditan treatment increased the maximal oxygen consumption rate, mitochondrial proteins and mitochondrial density in mBMEC, indicative of MB induction. Lasmiditan also enhanced endothelial cell migration and tube formation, key components of angiogenesis. Trans-endothelial electrical resistance (TEER) and tight junction protein expression, including claudin-5, were also increased with lasmiditan, suggesting improved barrier function. Finally, lasmiditan treatment decreased phosphorylated VE-Cadherin and induced activation of the Akt-FoxO1 pathway, which decreases FoxO1-mediated inhibition of claudin-5 transcription. Discussion: These data demonstrate that lasmiditan induces MB and enhances endothelial cell function, likely via the VE-Cadherin-Akt-FoxO1-claudin-5 signaling axis. Given the importance of mitochondrial and vascular dysfunction in neuropathologies, 5-HT1FR agonism may have broad therapeutic potential to address multiple facets of disease progression by promoting MB and vascular recovery.

Changes in post-transplant serum testosterone levels in men undergoing lung transplantation: a pilot study using the TriNetX Research Network.

Hypogonadism is understudied in men requiring solid organ transplants, particularly among lung transplant recipients. Improvement in serum testosterone levels has been reported in kidney and liver transplantation. Using the TriNetX Research Network, we performed a retrospective cohort study to evaluate the incidence of peri-transplant hypogonadism and the natural course of serum testosterone following successful lung transplantation. Men aged ≥ 18 with a lung transplant and total testosterone drawn within one year pre- and post-transplant were included. Men with receipt of testosterone therapy were excluded. A low testosterone (<300 ng/dL) and normal testosterone (≥300 ng/dL) cohort was created before employing descriptive and analytic statistics to investigate the incidence of peri-transplant hypogonadism and the change in serum testosterone levels following lung transplantation. In our entire cohort, lung transplantation was not associated with a significant increase in post-transplant serum testosterone (329.86 ± 162.56 ng/dL pre-transplant and 355.13 ± 216.11 ng/dL post-transplant, p = 0.483). The number of men with low testosterone decreased by 9.8% following lung transplantation but was not significant, p = 0.404. In this pilot study, no significant change in the number of hypogonadal men nor serum testosterone levels was observed among men undergoing lung transplantation.

Isolation and monoculture of functional primary astrocytes from the adult mouse spinal cord.

Astrocytes are a widely heterogenic cell population that play major roles in central nervous system (CNS) homeostasis and neurotransmission, as well as in various neuropathologies, including spinal cord injury (SCI), traumatic brain injury, and neurodegenerative diseases, such as amyotrophic lateral sclerosis. Spinal cord astrocytes have distinct differences from those in the brain and accurate modeling of disease states is necessary for understanding disease progression and developing therapeutic interventions. Several limitations to modeling spinal cord astrocytes in vitro exist, including lack of commercially available adult-derived cells, lack of purchasable astrocytes with different genotypes, as well as time-consuming and costly in-house primary cell isolations that often result in low yield due to small tissue volume. To address these issues, we developed an efficient adult mouse spinal cord astrocyte isolation method that utilizes enzymatic digestion, debris filtration, and multiple ACSA-2 magnetic microbead purification cycles to achieve an astrocyte monoculture purity of ≅93-98%, based on all markers assessed. Importantly, the isolated cells contain active mitochondria and express key astrocyte markers including ACSA-1, ACSA-2, EAAT2, and GFAP. Furthermore, this isolation method can be applied to the spinal cord of male and female mice, mice subjected to SCI, and genetically modified mice. We present a primary adult mouse spinal cord astrocyte isolation protocol focused on purity, viability, and length of isolation that can be applied to a multitude of models and aid in targeted research on spinal-cord related CNS processes and pathologies.

Pre-treatment bone mineral density and the benefit of pharmacologic treatment on fracture risk and BMD change: analysis from the FNIH-ASBMR SABRE project.

Some osteoporosis drug trials have suggested that treatment is more effective in those with low BMD measured by DXA. This study used data from a large set of randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subjects) of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. Participants were stratified into FN BMD T-score subgroups (≤-2.5, > -2.5). We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes and logistic regression for the radiographic vertebral fracture outcome. We also performed analyses based on BMD quintiles. Overall, 42% had a FN BMD T-score ≤ -2.5. Treatment with anti-osteoporosis drugs led to significant reductions in fractures in both T-score ≤ -2.5 and > -2.5 subgroups. Compared to those with FN BMD T-score > -2.5, the risk reduction for each fracture outcome was greater in those with T-score ≤ -2.5, but only the all-fracture outcome reached statistical significance (interaction P = .001). Results were similar when limited to bisphosphonate trials. In the quintile analysis, there was significant anti-fracture efficacy across all quintiles for vertebral fractures and with greater effects on fracture risk reduction for non-vertebral, all, and all clinical fractures in the lower BMD quintiles (all interaction P ≤ .03). In summary, anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD. Significant fracture risk reduction with treatment for 4 of the 5 fracture endpoints was seen in participants with T-scores above -2.5, though effects tended to be larger and more significant in those with baseline T-scores <-2.5.

It is important to know whether our treatments for osteoporosis are effective at reducing the risk of fracture no matter what the BMD before starting treatment. This study used data from many clinical trials to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We found that anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD, though effects tended to be larger and more significant in those with lower BMD scores.

Influence of age on the efficacy of pharmacologic treatments on fracture risk reduction and increases in BMD: RCT results from the FNIH-ASBMR-SABRE project.

There is a common belief that antiosteoporosis medications are less effective in older adults. This study used data from randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments and their effects on BMD differ in people ≥70 compared to those <70 yr. We used individual patient data from 23 RCTs of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. We assessed the following fractures: radiographic vertebral, non-vertebral, hip, all clinical, and all fractures. We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes, logistic regression for the radiographic vertebral fracture outcome, and linear regression to estimate treatment effect on 24-mo change in hip and spine BMD in each age subgroup. The analysis included 123 164 (99% female) participants; 43% being ≥70 yr. Treatment with anti-osteoporosis drugs significantly and similarly reduced fractures in both subgroups (eg, odds ratio [OR] = 0.47 and 0.51 for vertebral fractures in those below and above 70 yr, interaction P = .19; hazard ratio [HR] for all fractures: 0.72 vs 0.70, interaction P = .20). Results were similar when limited to bisphosphonate trials with the exception of hip fracture risk reduction which was somewhat greater in those <70 (HR = 0.44) vs ≥70 (HR = 0.79) yr (interaction P = .02). Allocation to anti-osteoporotic drugs resulted in significantly greater increases in hip and spine BMD at 24 mo in those ≥70 compared to those <70 yr. In summary, anti-osteoporotic medications similarly reduced the risk of fractures regardless of age, and the few small differences in fracture risk reduction by age were of uncertain clinical significance.

Medications used for osteoporosis maybe are less effective in older adults. This study used data from clinical trials to determine whether these medications work equally well in reducing the risk of fractures in people ≥70 compared to those <70 yr. The analysis included 123 164 participants with data from 23 trials. Treatment with anti-osteoporosis drugs significantly reduced fractures in both groups in a similar way. The BMD increased more in the older group.

The relationship between treatment-related changes in total hip bone mineral density measured after 12, 18 and 24 months and fracture risk reduction in osteoporosis clinical trials: the FNIH-ASBMR-SABRE Project.

There is a strong association between total hip bone mineral density (THBMD) changes after 24 months of treatment and reduced fracture risk. We examined whether changes in THBMD after 12- and 18 months of treatment are also associated with fracture risk reduction. We used individual patient data (n = 122 235 participants) from 22 randomised, placebo-controlled, double-blind trials of osteoporosis medications. We calculated the difference in mean percent change in THBMD (active-placebo) at 12, 18, and 24 months using data available for each trial. We determined the treatment-related fracture reductions for the entire follow-up period, using logistic regression for radiologic vertebral fractures and Cox regression for hip, non-vertebral, "all" (combination of non-vertebral, clinical vertebral, and radiologic vertebral) fractures, and all clinical fractures (combination of non-vertebral and clinical vertebral). We performed meta-regression to estimate the study-level association (r2 and 95% confidence interval) between treatment-related differences in THBMD changes for each BMD measurement interval and fracture risk reduction. The meta-regression revealed that for vertebral fractures, the r2 (95% confidence interval) was 0.59 (0.19, 0.75), 0.69 (0.32, 0.82), and 0.73 (0.33, 0.84) for 12, 18 and 24 months, respectively. Similar patterns were observed for hip: r2 = 0.27 (0.00, 0.54), 0.39 (0.02, 0.63), and 0.41 (0.02, 0.65); non-vertebral: r2 = 0.27 (0.01, 0.52), 0.49 (0.10, 0.69), and 0.53 (0.11, 0.72); all fractures: r2 = 0.44 (0.10, 0.64), 0.63 (0.24, 0.77), and 0.66 (0.25, 0.80); and all clinical fractures: r2 = 0.46 (0.11, 0.65), 0.64 (0.26, 0.78), and 0.71 (0.32, 0.83), for 12-, 18- and 24-month changes in THBMD, respectively. These findings demonstrate that treatment-related THBMD changes at 12, 18 and 24 months are associated with fracture risk reductions across trials. We conclude that BMD measurement intervals as short as 12 months could be used to assess fracture efficacy, but the association is stronger with longer BMD measurement intervals.

In this study, we looked at how changes in hip bone density over time relate to the risk of fractures in people taking osteoporosis medications. We analysed data from over 122 000 participants across 22 different clinical trials. We found that the increase in bone density measured after 12, 18, and 24 months of treatment was linked to the risk of fractures. Specifically, greater improvements in bone density were associated with fewer fractures in the spine, hips, and other bones. Using statistical methods, we calculated the strength of this association. We discovered that the later we measured bone mineral density in people taking the medication, the stronger the link between improved bone density and reduced fracture risk became. Our findings suggest that bone density measurements after 12 months of treatment could help predict how well a medication will prevent fractures. However, the best predictions came from bone density changes measured over longer periods.

Virtually delivered Mindfulness-Oriented Recovery Enhancement (MORE) reduces daily pain intensity in patients with lumbosacral radiculopathy: a randomized controlled trial.

Introduction: Lumbosacral radiculopathy (LR), also known as sciatica, is a common type of radiating neurologic pain involving burning, tingling, and numbness in the lower extremities. It has an estimated lifetime prevalence as high as 43%. Objectives: The objective of this randomized controlled trial was to evaluate the impact of virtually delivered Mindfulness-Oriented Recovery Enhancement (MORE) on patients with LR during the COVID-19 pandemic. Methods: Potentially eligible patients were identified using electronic health record queries and phone screenings. Participants were then randomized to MORE or treatment-as-usual (TAU) for 8 weeks, with pain intensity assessed daily. At baseline and follow-up visits, participants completed questionnaires assessing the primary outcome, disability, as well as quality of life, depression, mindful reinterpretation of pain, and trait mindfulness. Results: In our study, patients undergoing virtual delivery of MORE had greater improvements in daily pain intensity (P = 0.002) but not in disability (P = 0.09), depression (P = 0.26), or quality of life (P = 0.99 and P = 0.89, SF-12 physical and mental component scores, respectively), relative to TAU patients. In addition, patients in MORE experienced significantly greater increases in mindful reinterpretation of pain (P = 0.029) and trait mindfulness (P = 0.035). Conclusion: Among patients with lumbar radiculopathy, MORE significantly reduced daily pain intensity but did not decrease disability or depression symptoms. Given the long duration of symptoms in our sample, we hypothesize the discrepancy between changes in daily pain intensity and disability is due to fear avoidance behaviors common in patients with chronic pain. As the first trial of a mindfulness intervention in patients with LR, these findings should inform future integrative approaches to LR treatment, particularly when considering the increasing use of virtual interventions throughout the COVID-19 pandemic.

A refined protocol for the isolation and monoculture of primary mouse renal peritubular endothelial cells.

During an episode of acute kidney injury (AKI), a sudden and rapid decline in renal function is often accompanied by a persistent reduction in mitochondrial function, microvasculature dysfunction/rarefaction, and tubular epithelial injury/necrosis. Additionally, patients who have experienced an AKI are at an elevated risk of developing other progressive renal, cardiovascular, and cardiorenal related diseases. While restoration of the microvasculature is imperative for oxygen and nutrient delivery/transport during proper renal repair processes, the mechanism(s) by which neovascularization and/or inhibition of microvascular dysfunction improves renal recovery remain understudied. Interestingly, pharmacological stimulation of mitochondrial biogenesis (MB) post-AKI has been shown to restore mitochondrial and renal function in mice. Thus, targeting MB pathways in microvasculature endothelial cell (MV-EC) may provide a novel strategy to improve renal vascular function and repair processes post-AKI. However, limitations to studying such mechanisms include a lack of commercially available primary renal peritubular MV-ECs, the variability in both purity and outgrowth of primary renal MV-EC in monoculture, the tendency of primary renal MV-ECs to undergo phenotypic loss in primary monoculture, and a limited quantity of published protocols to obtain primary renal peritubular MV-ECs. Thus, we focused on refining the isolation and phenotypic retention of mouse renal peritubular endothelial cells (MRPEC) for future physiological and pharmacological based studies. Here, we present a refined isolation method that augments the purity, outgrowth, and phenotypic retention of primary MRPEC monocultures by utilizing a collagenase type I enzymatic digestion, CD326+ (EPCAM) magnetic microbead epithelial cell depletion, and two CD146+ (MCAM) magnetic microbead purification cycles to achieve a monoculture MRPEC purity of ≅ 91-99% by all markers evaluated.