Specific and shared mechanisms associated with treatment for chronic neck pain: study protocol for the SS-MECH trial.

BACKGROUND: Treatment mechanisms involve the steps or processes through which an intervention unfolds and produces change in an outcome variable. Treatment mechanisms can be specific to the intervention provided (i.e. pain modulation) or shared with other treatments (i.e. reduced fear of movement). Whether specific and shared treatment mechanisms are different across interventions and whether they lead to the outcomes seen in trials is largely unknown. The management of individuals with chronic neck pain routinely include manual therapy (MT) and resistance exercise (RE), as both approaches are included in clinical practice guidelines and both yield similar outcomes. OBJECTIVES: Our study plans to answer two research questions: 1) what are the specific mechanisms associated with MT versus interventions (and are these different), and 2) what are the shared mechanisms associated with these interventions, and do specific or shared mechanisms mediate clinical outcomes? METHODS: This study will involve a 2-group parallel (1:1) single-blinded randomized trial to compare the specific and potential shared treatment mechanisms between these two approaches. We will enroll individuals with a history of chronic neck pain and evaluate whether specific or shared mechanisms mediate clinical outcomes. RESULTS: We hypothesize that MT and RE approaches will both exhibit different specific treatment mechanisms, and that both approaches will exhibit shared treatment mechanisms, which will notably influence outcomes at both discharge and 6-months. CONCLUSIONS: This study is important because it will help identify what specific or shared treatment mechanisms are associated with different interventions and, how different treatment mechanisms influence clinical outcomes.

Pilot Study: Short Term Impact of Radiation Therapy on Bone Mineral Density and Bone Metabolism.

Despite the risk of complications, high dose radiation therapy is increasingly utilized in the management of selected bone malignancies. In this study, we investigate the impact of moderate to high dose radiation (over 50 Gy) on bone metabolism and structure. Between 2015 and 2018, patients with a primary malignant bone tumor of the sacrum that were either treated with high dose definitive radiation only or a combination of moderate to high dose radiation and surgery were prospectively enrolled at a single institution. Quantitative CTs were performed before and after radiation to determine changes in volumetric bone mineral density (BMD) of the irradiated and non-irradiated spine. Bone histomorphometry was performed on biopsies of the irradiated sacrum and the non-irradiated iliac crest of surgical patients using a quadruple tetracycline labeling protocol. In total, 9 patients were enrolled. Two patients received radiation only (median dose 78.3 Gy) and 7 patients received a combination of preoperative radiation (median dose 50.4 Gy), followed by surgery. Volumetric BMD of the non-irradiated lumbar spine did not change significantly after radiation, while the BMD of the irradiated sacrum did (pre-radiation median: 108.0 mg/cm3 (IQR 91.8-167.1); post-radiation median: 75.3 mg/cm3 (IQR 57.1-110.2); p = 0.010). The cancellous bone of the non-irradiated iliac crest had a stable bone formation rate, while the irradiated sacrum showed a significant decrease in bone formation rate [pre-radiation median: 0.005 mm3/mm2/year (IQR 0.003-0.009), post-radiation median: 0.001 mm3/mm2/year (IQR 0.001-0.001); p = 0.043]. Similar effects were seen in the cancellous and endocortical envelopes. This pilot study shows a decrease of volumetric BMD and bone formation rate after high-dose radiation therapy. Further studies with larger cohorts and other endpoints are needed to get more insight into the effect of radiation on bone. Level of evidence: IV.

The Mindful Reappraisal of Pain Scale (MRPS): Validation of a New Measure of Psychological Mechanisms of Mindfulness-Based Analgesia.

Objectives: Mindfulness is theorized to decrease the affective amplification of chronic pain by facilitating a shift from emotionally-laden, catastrophic pain appraisals of nociceptive input to reappraising chronic pain as an innocuous sensory signal that does not signify harm. Understanding of these hypothetical psychological mechanisms of mindfulness-based analgesia has been limited by a lack of direct measures. We conducted a series of psychometric and experimental studies to develop and validate the Mindful Reappraisal of Pain Sensations Scale (MPRS). Methods: After item generation, we conducted exploratory and confirmatory factor analyses of the MRPS in samples of opioid-treated chronic pain patients both before (n=450; n=90) and after (n=222) participating in Mindfulness-Oriented Recovery Enhancement (MORE). We then examined the convergent and divergent validity of the MRPS. Finally, in data from a randomized clinical trial (n=250), the MRPS was tested as a mediator of the effects of MORE on reducing chronic pain severity. Results: Exploratory and confirmatory factor analyses demonstrated the single-factor structure of the MRPS. The MRPS also evidenced convergent and divergent validity. Mindfulness training through MORE significantly increased MRPS scores relative to supportive psychotherapy (F4,425.03 = 16.15, p < .001). Changes in MRPS scores statistically mediated the effect of MORE on reducing chronic pain severity through 9-month follow-up. Conclusions: Taken together, these studies demonstrate that the MRPS is a psychometrically sound and valid measure of novel analgesic mechanisms of mindfulness including attentional disengagement from affective pain appraisals and interoceptive exposure to pain sensations.

Effect of Spatial and Spectral Scaling on Joint Characterization of the Spectral Mixture Residual: Comparative Analysis of AVIRIS and WorldView-3 SWIR for Geologic Mapping in Anza-Borrego Desert State Park.

A geologic map is both a visual depiction of the lithologies and structures occurring at the Earth's surface and a representation of a conceptual model for the geologic history in a region. The work needed to capture such multifaced information in an accurate geologic map is time consuming. Remote sensing can complement traditional primary field observations, geochemistry, chronometry, and subsurface geophysical data in providing useful information to assist with the geologic mapping process. Two novel sources of remote sensing data are particularly relevant for geologic mapping applications: decameter-resolution imaging spectroscopy (spectroscopic imaging) and meter-resolution multispectral shortwave infrared (SWIR) imaging. Decameter spectroscopic imagery can capture important mineral absorptions but is frequently unable to spatially resolve important geologic features. Meter-resolution multispectral SWIR images are better able to resolve fine spatial features but offer reduced spectral information. Such disparate but complementary datasets can be challenging to integrate into the geologic mapping process. Here, we conduct a comparative analysis of spatial and spectral scaling for two such datasets: one Airborne Visible/Infrared Imaging Spectrometer-Classic (AVIRIS-classic) flightline, and one WorldView-3 (WV3) scene, for a geologically complex landscape in Anza-Borrego Desert State Park, California. To do so, we use a two-stage framework that synthesizes recent advances in the spectral mixture residual and joint characterization. The mixture residual uses the wavelength-explicit misfit of a linear spectral mixture model to capture low variance spectral signals. Joint characterization utilizes nonlinear dimensionality reduction (manifold learning) to visualize spectral feature space topology and identify clusters of statistically similar spectra. For this study area, the spectral mixture residual clearly reveals greater spectral dimensionality in AVIRIS than WorldView (99% of variance in 39 versus 5 residual dimensions). Additionally, joint characterization shows more complex spectral feature space topology for AVIRIS than WorldView, revealing information useful to the geologic mapping process in the form of mineralogical variability both within and among mapped geologic units. These results illustrate the potential of recent and planned imaging spectroscopy missions to complement high-resolution multispectral imagery-along with field and lab observations-in planning, collecting, and interpreting the results from geologic field work.

Cost-Effectiveness Analysis Evaluating Delivery Strategies for Pain Coping Skills Training in Women With Breast Cancer.

Pain coping skills training (PCST) is efficacious in patients with cancer, but clinical access is limited. To inform implementation, as a secondary outcome, we estimated the cost-effectiveness of 8 dosing strategies of PCST evaluated in a sequential multiple assignment randomized trial among women with breast cancer and pain (N = 327). Women were randomized to initial doses and re-randomized to subsequent doses based on their initial response (ie, ≥30% pain reduction). A decision-analytic model was designed to incorporate costs and benefits associated with 8 different PCST dosing strategies. In the primary analysis, costs were limited to resources required to deliver PCST. Quality-adjusted life-years (QALYs) were modeled based on utility weights measured with the EuroQol-5 dimension 5-level at 4 assessments over 10 months. A probabilistic sensitivity analysis was performed to account for parameter uncertainty. Implementation of PCST initiated with the 5-session protocol was more costly ($693-853) than strategies initiated with the 1-session protocol ($288-496). QALYs for strategies beginning with the 5-session protocol were greater than for strategies beginning with the 1-session protocol. With the goal of implementing PCST as part of comprehensive cancer treatment and with willingness-to-pay thresholds ranging beyond $20,000 per QALY, the strategy most likely to provide the greatest number of QALYs at an acceptable cost was a 1-session PCST protocol followed by either 5 maintenance telephone calls for responders or 5 sessions of PCST for nonresponders. A PCST program with 1 initial session and subsequent dosing based on response provides good value and improved outcomes. PERSPECTIVE: This article presents the results of a cost analysis of the delivery of PCST, a nonpharmacological intervention, to women with breast cancer and pain. Results could potentially provide important cost-related information to health care providers and systems on the use of an efficacious and accessible nonmedication strategy for pain management. TRIALS REGISTRATION: ClinicalTrials.gov: NCT02791646, registered 6/2/2016.

The USMLE® STEP 1 Pass or Fail Era of the Vascular Surgery Residency Application Process: Implications for Structural Bias and Recommendations.

United States Medical Licensing Examination® (USMLE®) STEP 1 score reporting has been changed to a binary pass/fail format since January 26, 2022. The motives behind this change were (1) the questionable validity of using USMLE STEP 1 as a screening tool during the candidate selection process and (2) the negative impact of using standardized examination scores as an initial gatekeeping threshold for the underrepresented in medicine (URiM) candidates applying to graduate medical education programs, given their generally lower mean standardized exams scores compared to non-URiM students. The USMLE administrators justified this change as a tactic to enhance the overall educational experience for all students and to increase the representation of URiM groups. Moreover, they advised the program directors (PDs) to give more attention to other important qualities and components such as the applicant's personality traits, leadership roles and other extracurricular accomplishments, as part of a holistic evaluation strategy. At this early stage, it is unclear how this change will impact Vascular Surgery Integrated residency (VSIR) programs. Several questions are outstanding, most importantly, how VSIR PDs will evaluate applicants absent the variable which heretofore was the primary screening tool. Our previously published survey showed that VSIR PDs will move their attention to other measures such as USMLE STEP 2 Clinical Knowledge (CK) and letters of recommendation during the VSIR selection process. Furthermore, more emphasis on subjective measures such as the applicant's medical school rank and extracurricular student activities is expected. Given the expected higher weight of USMLE STEP 2CK in the selection process than ever, many anticipate that medical students will dedicate more of their limited time to its preparation at the expense of both clinical and nonclinical activities. Potentially leaving less time to explore specialty pathways and to determine whether Vascular Surgeons  is the appropriate career for them. The critical juncture in the VSIR candidate evaluation paradigm presents an opportunity to thoughtfully transform the process via current (Standardized Letter of Recommendation, USMLE STEP 2CK, and clinical research) and future (Emotional Intelligence, Structure Interview and Personality Assessment) measures which constitute a framework to follow in the USMLE STEP 1 pass/fail era.

Comparing the clinical and cost-effectiveness of remote (telehealth and online) cognitive behavioral therapy-based treatments for high-impact chronic pain relative to usual care: study protocol for the RESOLVE multisite randomized control trial.

BACKGROUND: Cognitive behavioral therapy for chronic pain (CBT-CP) is an effective but underused treatment for high-impact chronic pain. Increased access to CBT-CP services for pain is of critical public health importance, particularly for rural and medically underserved populations who have limited access due to these services being concentrated in urban and high income areas. Making CBT-CP widely available and more affordable could reduce barriers to CBT-CP use. METHODS: As part of the National Institutes of Health Helping to End Addiction Long-term® (NIH HEAL) initiative, we designed and implemented a comparative effectiveness, 3-arm randomized control trial comparing remotely delivered telephonic/video and online CBT-CP-based services to usual care for patients with high-impact chronic pain. The RESOLVE trial is being conducted in 4 large integrated healthcare systems located in Minnesota, Georgia, Oregon, and Washington state and includes demographically diverse populations residing in urban and rural areas. The trial compares (1) an 8-session, one-on-one, professionally delivered telephonic/video CBT-CP program; and (2) a previously developed and tested 8-session online CBT-CP-based program (painTRAINER) to (3) usual care augmented by a written guide for chronic pain management. Participants are followed for 1 year post-allocation and are assessed at baseline, and 3, 6, and 12 months post-allocation. The primary outcome is minimal clinically important difference (MCID; ≥ 30% reduction) in pain severity (composite of pain intensity and pain-related interference) assessed by a modified 11-item version of the Brief Pain Inventory-Short Form at 3 months. Secondary outcomes include pain severity, pain intensity, and pain-related interference scores, quality of life measures, and patient global impression of change at 3, 6, and 12 months. Cost-effectiveness is assessed by incremental cost per additional patient with MCID in primary outcome and by cost per quality-adjusted life year achieved. Outcome assessment is blinded to group assignment. DISCUSSION: This large-scale trial provides a unique opportunity to rigorously evaluate and compare the clinical and cost-effectiveness of 2 relatively low-cost and scalable modalities for providing CBT-CP-based treatments to persons with high-impact chronic pain, including those residing in rural and other medically underserved areas with limited access to these services. TRIAL REGISTRATION: ClinicalTrials.gov NCT04523714. This trial was registered on 24 August 2020.

Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation.

PURPOSE: Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%-50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA. EXPERIMENTAL DESIGN: We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues. RESULTS: This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD. CONCLUSIONS: Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.

Ninety-day oral toxicological profiling of Kolaviron (an extract of Garcinia kola) in male and female rats.

There remains an insufficiency of data on the long-term toxicological profile of Garcinia kola Heckel and its extract, Kolaviron (KV), despite several studies on its pharmacological effects. This research was designed to investigate the long-term histopathological, hematological, biochemical, hormonal, reproductive, and oxidative effects of 90 days administration of KV to male and female rats, as well as additional 30 days reversibility study to assess the potential for reversal of induced effects. Fifty-six male and female Wistar rats divided into four groups were treated orally with distilled water/propylene glycol, 20 mg/kg KV, 100 mg/kg KV, and 500 mg/kg KV for 90 days. At the end of 90 days and 30 additional days of reversibility study, 5 ml blood was collected from animals for relevant analyses. Vital organs were harvested for histopathological assessments. In this study, KV did not elicit any adverse effect on histopathological presentations of vital organs which were generally non-abnormal. There was significant increase (p < 0.05) in LEU, MON, EOS%, BAS%, HCT (male animals) and LYM%, EOS%, BAS%, RBC, hemoglobin and MCH (female animals). There was significant diminution (p < 0.05) in cholesterol, triglycerides, LDL, and VLDL levels, with significant increase (p < 0.05) in HDL level in both male and female animals. KV elicited a non-significant increase in sperm count accompanied by a significant increase (p < 0.05) in levels of Follicle stimulating hormone (FSH) and testosterone in male rats. Furthermore, KV elicited significant (p < 0.001-0.05) elevation in the levels of GSH, SOD and CAT, and diminution in the level of MDA. The findings in this study suggest that long-term administration of KV is considerably safe with some variations in response between male and female animals. The possible sustenance of observed effects after cessation of KV administration, lipid lowering, erythropoiesis inducing, and immune system boosting activities of KV were confirmed in this study.

Vascular surgery integrated resident selection criteria in the pass or fail era.

OBJECTIVES: Vascular surgery integrated residency (VSIR) programs are highly competitive; however, criteria for resident selection remain opaque and non-standardized. The already unclear selection criteria will be further impacted by the impending transition of the United States Medical Licensing Examination (USMLE) Step 1 from numeric scores to a binary pass/fail outcome. The purpose of this study was to investigate the historical and anticipated selection criteria of VSIR applicants. METHODS: This was a cross-sectional, nationwide, 59-item survey that was sent to all VSIR program directors (PDs). Data was analyzed using the Fisher exact test if categorical and the Mann-Whitney U test and the Kruskal-Wallis test if ordinal. RESULTS: Forty of 69 PDs (58%) responded to the survey. University-based programs constituted 85% of responders. Most VSIR PDs (65%) reported reviewing between 101 to 150 applications for 1 to 2 positions annually. Forty-two percent of the responding PDs reported sole responsibility for inviting applicants to interview, whereas 50% had a team of faculty responsible for reviewing applications. On a five-point Likert scale, letters of recommendation (LOR) from vascular surgeons or colleagues (a person the PD knows) were the most important objective criteria. Work within a team structure was rated highest among subjective criteria. The majority of respondents (72%) currently use the Step 1 score as a primary method to screen applicants. Regional differences in use of Step 1 score as a primary screening method were: Midwest (100%), Northeast (76%), South (43%), and West (40%) (P = .01). PDs responded that that they will use USMLE Step 2 score (42%) and LOR (10%) to replace USMLE Step 1 score. The current top ranked selection criteria are letters from a vascular surgeon, USMLE Step 1 score and overall LOR. The proposed top ranked selection criteria after transition of USMLE Step 1 to pass/fail include LOR overall followed by Step 2 score. CONCLUSIONS: This is the first study to evaluate the selection criteria used by PDs for VSIR. The landscape of VSIR selection criteria is shifting and increasing transparency is essential to applicants' understanding of the selection process. The transition of USMLE Step 1 to a pass/fail report will shift the attention to Step 2 scores and elevate the importance of other relatively more subjective criteria. Defining VSIR program selection criteria is an important first step toward establishing holistic review processes that are transparent and equitable.

Improving treatment of patients with psychosis in low-and-middle-income countries in Southeast Europe: Results from a hybrid effectiveness-implementation, pragmatic, cluster-randomized clinical trial (IMPULSE).

BACKGROUND: In Southeast Europe (SEE) standard treatment of patients with psychosis is largely based on pharmacotherapy with psychosocial interventions rarely available. DIALOG+ is a digital psychosocial intervention designed to make routine care therapeutically effective. This trial simultaneously examined effectiveness of DIALOG+ versus standard care on clinical and social outcomes (Aim 1) and explored intervention fidelity (Aim 2). METHODS: A hybrid type II effectiveness-implementation, cluster-randomized trial was conducted in five SEE countries: Bosnia and Herzegovina, Kosovo*, Montenegro, North Macedonia, and Serbia. The intervention was offered to patients six times across 12 months instead of routine care. The outcomes were subjective quality of life (primary), clinical symptoms, satisfaction with services, and economic costs. Intervention fidelity was operationalized as adherence to the protocol in terms of frequency, duration, content, and coverage. Data were analyzed using multilevel regression. RESULTS: A total of 81 clinicians and 468 patients with psychosis were randomized to DIALOG+ or standard care. The intervention was delivered with high fidelity. The average number of delivered sessions was 5.5 (SD = 2.3) across 12 months. Patients in the intervention arm had better quality of life (MANSA) at 6 months (p = 0.03). No difference was found for other outcomes at 6 months. Due to disruptions caused by the COVID-19 pandemic, 12-month data were not interpretable. CONCLUSIONS: DIALOG+ improved subjective quality of life of individuals with psychosis at 6 months (after four sessions), albeit with small effect size. The intervention has the potential to contribute to holistic care of patients with psychosis.

Adalimumab Mitigates Lumbar Radiculopathy in a Case of Ankylosing Spondylitis.

BACKGROUND Ankylosing spondylitis (AS) is an immune-mediated chronic inflammatory condition grouped under spondyloarthritis (SpA), which is an umbrella term for a group of interrelated inflammatory rheumatic conditions with characteristic radiographic findings such as erosions and ankylosis of the sacroiliac joint. Unfortunately, there is an average delay of 8-9 years between the onset of the symptoms and diagnosis due to infrequent consideration of this disease in the differential diagnosis of patients with low back pain and unusual or incomplete presenting clinical symptoms. CASE REPORT We describe the case of a 37-year-old male patient with no significant past medical history and surgical history of bilateral hip arthroplasty secondary to idiopathic aseptic necrosis of the bilateral femoral head and bilateral rotator cuff repaired surgery due to multiple motor vehicle accidents (MVA) with a chief concern of chronic low back pain. In this case of ankylosing spondylitis presenting with low back pain and radicular symptoms, his symptoms were resistant to multiple opioid medications, trigger point injections, and epidural steroid injections. Initiation of adalimumab subsequently relieved the patient's symptoms and restored his ability to perform daily activities. CONCLUSIONS This is an unusual presentation of AS with radiographic evidence of bilateral sacroiliitis. The neurological manifestations in AS are not uncommon, and they can occur during the quiescent stage of the disease. It should be emphasized that early diagnosis is essential to prevent progression of the disease and avoid unnecessary treatment for the patient.

A Primary Care-Based Cognitive Behavioral Therapy Intervention for Long-Term Opioid Users With Chronic Pain : A Randomized Pragmatic Trial.

BACKGROUND: Chronic pain is common, disabling, and costly. Few clinical trials have examined cognitive behavioral therapy (CBT) interventions embedded in primary care settings to improve chronic pain among those receiving long-term opioid therapy. OBJECTIVE: To determine the effectiveness of a group-based CBT intervention for chronic pain. DESIGN: Pragmatic, cluster randomized controlled trial. (ClinicalTrials.gov: NCT02113592). SETTING: Kaiser Permanente health care systems in Georgia, Hawaii, and the Northwest. PARTICIPANTS: Adults (aged ≥18 years) with mixed chronic pain conditions receiving long-term opioid therapy. INTERVENTION: A CBT intervention teaching pain self-management skills in 12 weekly, 90-minute groups delivered by an interdisciplinary team (behaviorist, nurse, physical therapist, and pharmacist) versus usual care. MEASUREMENTS: Self-reported pain impact (primary outcome, as measured by the PEGS scale [pain intensity and interference with enjoyment of life, general activity, and sleep]) was assessed quarterly over 12 months. Pain-related disability, satisfaction with care, and opioid and benzodiazepine use based on electronic health care data were secondary outcomes. RESULTS: A total of 850 patients participated, representing 106 clusters of primary care providers (mean age, 60.3 years; 67.4% women); 816 (96.0%) completed follow-up assessments. Intervention patients sustained larger reductions on all self-reported outcomes from baseline to 12-month follow-up; the change in PEGS score was -0.434 point (95% CI, -0.690 to -0.178 point) for pain impact, and the change in pain-related disability was -0.060 point (CI, -0.084 to -0.035 point). At 6 months, intervention patients reported higher satisfaction with primary care (difference, 0.230 point [CI, 0.053 to 0.406 point]) and pain services (difference, 0.336 point [CI, 0.129 to 0.543 point]). Benzodiazepine use decreased more in the intervention group (absolute risk difference, -0.055 [CI, -0.099 to -0.011]), but opioid use did not differ significantly between groups. LIMITATION: The inclusion of only patients with insurance in large integrated health care systems limited generalizability, and the clinical effect of change in scores is unclear. CONCLUSION: Primary care-based CBT, using frontline clinicians, produced modest but sustained reductions in measures of pain and pain-related disability compared with usual care but did not reduce use of opioid medication. PRIMARY FUNDING SOURCE: National Institutes of Health.

Ameliorative effect of Kolaviron, an extract of Garcinia kola seeds, on induced hypertension.

OBJECTIVES: Early diagnosis and management of known cardiovascular disease risk attributes such as hypertension lessens morbidity and mortality as well as increase quality of life of patients. This present study was modelled to investigate the ameliorative effect of Kolaviron, an extract of Garcinia kola Heckel seeds, in ethanol- and sucrose-induced hypertension. METHODS: Test animals were divided into six groups of six animals each for each hypertensive model. Animals were treated daily with distilled water (10 ml/kg); 35% ethanol (3 g/kg) or sucrose (5-7%); Kolaviron (50, 100 and 200 mg/kg) separately plus ethanol or sucrose and Amlodipine (0.14 mg/kg) separately plus ethanol or sucrose for 8 weeks. Systolic, diastolic and mean arterial pressures were determined using non-invasive BP system after 8 weeks. Blood was obtained for the assessment of biochemical parameters, lipid profile and antioxidant indices. Vital organs were collected for approximation of tissue antioxidant levels. RESULTS: Results show that Kolaviron at various doses and Amlodipine significantly reduced (p<0.05-0.001) the elevated systolic, diastolic, and mean arterial pressures produced by ethanol and sucrose administration. Additionally, Kolaviron and Amlodipine significantly overturned (p<0.05-0.001) the reduction in GSH, SOD and CAT, and elevation in MDA levels elicited by ethanol and sucrose. Furthermore, Kolaviron and Amlodipine produced significant reduction (p<0.001) in levels of cholesterol, triglycerides and low-density lipoproteins, as well as significant increase (p<0.01-0.001) in levels of high-density lipoproteins. CONCLUSIONS: Results from this study demonstrate that Kolaviron possibly possesses significant antihypertensive effect which may possibly be attributed to its antioxidant effects and relative improvement of lipid profile.

Historical biogeography of Pomaderris (Rhamnaceae): Continental vicariance in Australia and repeated independent dispersals to New Zealand.

AIM: Gondwanan biogeographic patterns include a combination of old vicariance events following the breakup of the supercontinent, and more recent long-distance dispersals across the southern landmasses. Floristic relationships between Australia and New Zealand have mostly been attributed to recent dispersal events rather than vicariance. We assessed the biogeographic history of Pomaderris (Rhamnaceae), which occurs in both Australia and New Zealand, by constructing a time-calibrated molecular phylogeny to infer (1) phylogenetic relationships and (2) the relative contributions of vicariance and dispersal events in the biogeographic history of the genus. LOCATION: Australia and New Zealand. METHODS: Using hybrid capture and high throughput sequencing, we generated nuclear and plastid data sets to estimate phylogenetic relationships and fossil calibrated divergence time estimates for Pomaderris. BioGeoBEARS and biogeographical stochastic mapping (BSM) were used to assess the ancestral area of the genus and the relative contributions of vicariance vs dispersal, and the directionality of dispersal events. RESULTS: Our analyses indicate that Pomaderris originated in the Oligocene and had a widespread Australian distribution. Vicariance of western and eastern Australian clades coincides with the uplift of the Nullarbor Plain c. 14 Ma, followed by subsequent in-situ and within-biome diversification with little exchange across regions. A rapid radiation of southeastern Australian taxa beginning c. 10 Ma was the source for at least six independent long-distance dispersal events to New Zealand during the Pliocene-Pleistocene. MAIN CONCLUSIONS: Our study demonstrates the importance of dispersal in explaining not only the current cross-Tasman distributions of Pomaderris, but for the New Zealand flora more broadly. The pattern of multiple independent long-distance dispersal events for Pomaderris, without significant radiation within New Zealand, is congruent with other lowland plant groups, suggesting that this biome has a different evolutionary history compared with the younger alpine flora of New Zealand, which exhibits extensive radiations often following single long distance dispersal events.

Yoga Practice Predicts Improvements in Day-to-Day Pain in Women With Metastatic Breast Cancer.

CONTEXT: Women with metastatic breast cancer (MBC) experience a significant symptom burden, including cancer pain. Yoga is a mind-body discipline that has shown promise for alleviating cancer pain, but few studies have included patients with metastatic disease or examined the acute effects of yoga practice. OBJECTIVES: To determine whether daily pain changed significantly during a randomized controlled trial of the Mindful Yoga program among women with MBC and whether time spent in yoga practice was related to daily pain. METHODS: On alternate weeks during the intervention period, we collected daily measures of pain from a subset of 48 women randomized to either yoga (n = 30) or a support group condition (n = 18). We also assessed daily duration of yoga practice among patients randomized to yoga. RESULTS: Pain levels were low for women in both conditions, and no differential treatment effects were found on daily pain. However, among women randomized to yoga, a dose/response relationship was found between yoga practice duration and daily pain. When patients had spent relatively more time practicing yoga across two consecutive days, they were more likely to experience lower pain on the next day. This finding is consistent with an earlier MBC study. Meditation practice showed the strongest association with lower daily pain. CONCLUSION: Findings suggest that yoga practice (meditation practice in particular) is associated with acute improvements in cancer pain, and that yoga interventions may be more impactful if tested in a sample of patients with advanced cancer in which pain is relatively elevated.

Frailty in patients with aortic stenosis awaiting intervention.

Aortic stenosis (AS) is a common valvular disease in older age. Definitive interventions include surgical aortic valve replacement or transcatheter aortic valve implantation (TAVI). In high-risk patients, frailty is observed in up to 50% awaiting TAVI. Frailty is now an established predictor of outcomes in patients with AS who undergo intervention. There is currently no consensus definition for frailty. It is widely described as a syndrome of loss in physiological reserve predisposing to increased vulnerability for death or dependency. Frailty encompasses a holistic view including domains of physical function, cognition, depression, nutrition and medical comorbidities. Individual components of frailty have been shown to significantly predict mortality, functional recovery and quality of life after TAVI. The addition of frailty components to conventional risk prediction models traditionally used in cardiac surgery has been shown to augment overall prediction for post-operative mortality and morbidity. Identifying patients who are frail at baseline provides an opportunity to modify dynamic aspects of frailty prior to, and after definitive intervention for AS. A multidisciplinary approach including comprehensive geriatric pre-operative assessment will likely become standard of care to identify and optimise frail patients awaiting TAVI. In this review, we discuss the definition and measurement of frailty in patients with AS, evaluate recent data on risk prediction associated with frailty, and outline approaches to optimisation of dynamic components of frailty to improve outcomes after AS intervention.

Prevention and treatment of SHIVAD8 infection in rhesus macaques by a potent d-peptide HIV entry inhibitor.

Cholesterol-PIE12-trimer (CPT31) is a potent d-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a simian-HIV chimeric virus AD8 (SHIVAD8) macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ∼2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising candidate for HIV prevention and treatment.

Khat (Catha edulis) upregulates lipolytic genes in white adipose tissue of male obese mice (C57BL/6J).

ETHNOPHARMACOLOGICAL RELEVANCE: Khat (Catha edulis (Vahl) Forssk.) is a herb from the Celastraceae family (also known as qat, gaad, or mirra) that is widely-consumed in East Africa and in the Arabian peninsula. The green leaves and small stems are consumed primarily at recreational and social gatherings, and medicinally for their antidiabetic and appetite-suppression effects. AIMS: The objectives of this study were to determine the effects of khat and its active alkaloid, cathinone, on food intake and body weight in mice maintained on a high-fat diet, and to investigate its mechanism of action in white adipose tissue and in the hypothalamus. MATERIALS & METHOD: Adult male mice (C57BL/6J) were fed a high fat diet (HFD) for 8 weeks (n = 30), then divided into 5 groups and treated daily for a further 8 weeks with HFD + vehicle [control (HFD)], HFD + 15 mg/kg orlistat (HFDO), HFD + 200 mg/kg khat extract (HFDK200), HFD + 400 mg/kg khat extract (HFDK400) and HFD + 3.2 mg/kg cathinone (HFDCAT). Treatments were carried out once daily by gastric gavage. Blood and tissue samples were collected for biochemical, hormonal and gene expression analyses. RESULTS: Khat extracts and orlistat treatment significantly reduced weight gain as compared to control mice on HFD, and cathinone administration completely prevented weight gain in mice fed on HFD. Khat treatment caused a marked reduction in body fat and in serum triglycerides. A dose-dependent effect of khat was observed in reducing serum leptin concentrations. Analysis of gene expression in adipose tissue revealed a significant upregulation of two lipolysis pathway genes:(adipose triglyceride lipase (PNPLA-2) and hormone-sensitive lipase (LIPE). In the hypothalamic there was a significant (P < 0.05) upregulation of agouti-related peptide (AgRP) and cocaine-amphetamine regulated transcript (CART) genes in the HFDK400 and HFDCAT groups. CONCLUSION: Cathinone treatment blocked body weight gain, while high dose khat extract significantly reduced the weight gain of mice on an obesogenic diet through stimulation of lipolysis in white adipose tissue.