Evaluation of a Combination Approach to Improving Muscle Tone and Decreasing Subcutaneous Tissue Thickness Using a Sequential, Dual-Modality, Energy-Based Device.

Background: The body shaping market has long been at the forefront of the aesthetic industry. With technological advances, patient demand for body sculpting in terms of reduction in subcutaneous tissue and enhancement of muscle has seen continual growth. Several devices have emerged in the space; however, few achieve both subcutaneous tissue reduction (SQR) and voluntary muscle increase (VMI) as measured by thickness, during the same treatment session. Objectives: This article presents the results of a pilot study on a unique approach to subcutaneous tissue reduction and increasing muscle thickness using a dual-modality, energy-based device. Methods: Twelve compliant patients (8 females and 4 males with an average age of 40 years) were enrolled in this single center, prospective study. All patients were treated with the dual-modality device (850 nm superluminescent diode matrix and electrical muscle stimulation), with external applicators being placed over the lower abdomen. The patients received 5 weekly treatments. Ultrasound measurements, photographs, weight, and waist measurements were taken at baseline, prior to the start of the fifth treatment, and at the 2-week and 2-month follow-up visits. Results: At the 2-month follow-up visit, the average SQR was 34.03% and the VMI measured 22.97% in all patients who completed the study. All patient and physician evaluations rated the results as satisfactory or better. There were no complications. Conclusions: Preliminary data show this dual-modality, electrical muscle stimulation/superluminescent diode matrix system provides both a safe and effective treatment for the reduction of subcutaneous tissue thickness and an increase in muscle definition and thickness. Objective and subjective evaluations demonstrated high levels of efficacy and satisfaction in all patients.

Net cost savings arising from patient completion of an active self-management program.

OBJECTIVE: The objective of this study is to investigate changes in willingness for total knee replacement (TKR) surgery following a randomised control trial (RCT) of an osteoarthritis management program, and to extrapolate orthopaedic cost consequences for private health insurers (PHI). METHODS: Willingness for surgery data from the RCT is analysed using a multinomial logistic regression model. A decision analytic model is used to conduct a break-even cost benefit analysis of the intervention from a PHI payer perspective. The analysis estimates the minimum probability of progression to surgery required for the intervention to be cost-neutral when considering savings limited to reduced orthopaedic costs. Cost data and orthopaedic pathway probabilities are sourced from payer data. RESULTS: At baseline, 39% of participants in the treatment and control group were willing for surgery. At 12 months, 16% of participants in the treatment group remained willing for surgery, versus 36% in the control group. Participants in the treatment group are 2.96 (95% CI: 1.01-8.66) times more likely than those in the control group to move from initially willing for surgery, to unsure or unwilling at 12 months. The analysis indicates that the intervention is likely to be cost saving when at least 60% of initially willing participants progress to surgery over a 5-year time horizon. CONCLUSION: Our study estimates that an education, exercise and weight loss intervention can deliver both improved participant outcomes and a return on investment to Australian PHIs through a reduction in TKR surgery incidence.

Engineering BioBricks for Deoxysugar Biosynthesis and Generation of New Tetracenomycins.

Tetracenomycins and elloramycins are polyketide natural products produced by several actinomycetes that exhibit antibacterial and anticancer activities. They inhibit ribosomal translation by binding in the polypeptide exit channel of the large ribosomal subunit. The tetracenomycins and elloramycins are typified by a shared oxidatively modified linear decaketide core, yet they are distinguished by the extent of O-methylation and the presence of a 2',3',4'-tri-O-methyl-α-l-rhamnose appended at the 8-position of elloramycin. The transfer of the TDP-l-rhamnose donor to the 8-demethyl-tetracenomycin C aglycone acceptor is catalyzed by the promiscuous glycosyltransferase ElmGT. ElmGT exhibits remarkable flexibility toward transfer of many TDP-deoxysugar substrates to 8-demethyltetracenomycin C, including TDP-2,6-dideoxysugars, TDP-2,3,6-trideoxysugars, and methyl-branched deoxysugars in both d- and l-configurations. Previously, we developed an improved host, Streptomyces coelicolor M1146::cos16F4iE, which is a stable integrant harboring the required genes for 8-demethyltetracenomycin C biosynthesis and expression of ElmGT. In this work, we developed BioBricks gene cassettes for the metabolic engineering of deoxysugar biosynthesis in Streptomyces spp. As a proof of concept, we used the BioBricks expression platform to engineer biosynthesis for d-configured TDP-deoxysugars, including known compounds 8-O-d-glucosyl-tetracenomycin C, 8-O-d-olivosyl-tetracenomycin C, 8-O-d-mycarosyl-tetracenomycin C, and 8-O-d-digitoxosyl-tetracenomycin C. In addition, we generated four new tetracenomycins including one modified with a ketosugar, 8-O-4'-keto-d-digitoxosyl-tetracenomycin C, and three modified with 6-deoxysugars, including 8-O-d-fucosyl-tetracenomycin C, 8-O-d-allosyl-tetracenomycin C, and 8-O-d-quinovosyl-tetracenomycin C. Our work demonstrates the feasibility of BioBricks cloning, with the ability to recycle intermediate constructs, for the rapid assembly of diverse carbohydrate pathways and glycodiversification of a variety of natural products.

How Does Exercise, With and Without Diet, Improve Pain and Function in Knee Osteoarthritis? A Secondary Analysis of a Randomized Controlled Trial Exploring Potential Mediators of Effects.

OBJECTIVE: To explore the mediators of effects of two 6-month telehealth-delivered exercise programs, including exercise with and without weight-loss diet, on pain and function improvements in knee osteoarthritis (OA). METHODS: Secondary analysis of 345 participants from a 3-arm randomized controlled trial of exercise (Exercise program) and exercise plus diet (Diet + Exercise program) versus information (Control program) was conducted. Outcomes were changes in pain (11-point numeric rating scale) and function (Western Ontario and McMaster Universities Osteoarthritis Index [score range 0-68]) at 12 months. Potential mediators were change at 6 months in attitudes toward self-management, fear of movement, arthritis self-efficacy, weight, physical activity, and willingness for knee surgery. For the Diet + Exercise program versus the Exercise program, only change in weight was evaluated. RESULTS: Possible mediators of the Exercise program versus the Control program included reduced fear of movement (accounting for -1.11 units [95% confidence interval (95% CI) -2.15, -0.07] improvement in function) and increased arthritis self-efficacy (-0.40 units [95% CI -0.75, -0.06] reduction in pain, -1.66 units [95% CI -3.04, -0.28] improvement in function). The Diet + Exercise program versus the Control program mediators included reduced fear of movement (-1.13 units [95% CI -2.17, -0.08] improvement in function), increased arthritis self-efficacy (-0.77 units [95% CI -1.26, -0.28] reduction in pain, -5.15 units [95% CI -7.34, -2.96] improvement in function), and weight loss (-1.20 units [95% CI -1.73, -0.68] reduction in pain, -5.79 units [95% CI -7.96, -3.63] improvement in function). Weight loss mediated the Diet + Exercise program versus the Exercise program (-0.89 units [95% CI -1.31, -0.47] reduction in pain, -4.02 units [95% CI -5.77, -2.26] improvement in function). CONCLUSION: Increased arthritis self-efficacy, reduced fear of movement, and weight loss may partially mediate telehealth-delivered exercise program effects, with and without diet, on pain and/or function in knee OA. Weight loss may partially mediate the effect of diet and exercise compared to exercise alone.

Affordable Care Act state Medicaid expansion and human papillomavirus vaccination among adolescent and young adult US women: A national study.

OBJECTIVE: To ascertain the impact of Affordable Care Act (ACA) state Medicaid expansion on human papillomavirus (HPV) vaccination among both adolescent and young adult US women. DATA SOURCES: We used state-level data on ACA Medicaid expansion and individual-level data on US women aged 15-25 years living at or below 138% of the Federal Poverty Level (FPL) from the 2011-2017 waves of the National Survey of Family Growth (N = 2408). STUDY DESIGN: We conducted a quasi-experimental study examining the association between ACA state Medicaid expansion and HPV vaccination initiation among eligible adolescent and young adult US women. METHODS: We used linear probability modeling within a difference-in-differences approach, adjusting for individual- and state-level covariates. PRINCIPAL FINDINGS: Adjusting for individual- and state-level covariates, we found a negative association between Medicaid expansion and HPV vaccination among US women aged 15-25 years living in low-income households in the first year post-expansion (coefficient: -15.9 percentage points; 95% confidence interval [CI]: -30.1, -1.6 points). In contrast, we observed a positive association in the third year post-expansion (coefficient: 20.5 percentage points; 95% confidence interval [CI]: -1.8, 42.9 points). CONCLUSIONS: Medicaid expansion may have increased HPV vaccination among adolescent and young adult US women over time. Additional research is needed to identify the mechanisms and differential effects of Medicaid expansion on HPV vaccination among diverse subgroups of US women.

Comparing Video-Based, Telehealth-Delivered Exercise and Weight Loss Programs With Online Education on Outcomes of Knee Osteoarthritis : A Randomized Trial.

BACKGROUND: Scalable knee osteoarthritis programs are needed to deliver recommended education, exercise, and weight loss interventions. OBJECTIVE: To evaluate two 6-month, telehealth-delivered exercise programs, 1 with and 1 without dietary intervention. DESIGN: 3-group, parallel randomized (5:5:2) trial. (Australian New Zealand Clinical Trials Registry: ACTRN12618000930280). SETTING: Australian private health insurance members. PARTICIPANTS: 415 persons with symptomatic knee osteoarthritis and a body mass index between 28 and 40 kg/m2 who were aged 45 to 80 years. INTERVENTION: All groups received access to electronic osteoarthritis information (control). The exercise program comprised 6 physiotherapist consultations via videoconference for exercise, self-management advice, and behavioral counseling, plus exercise equipment and resources. The diet and exercise program included an additional 6 dietitian consultations for a ketogenic very-low-calorie diet (2 formulated meal replacements and a low-carbohydrate meal daily) followed by a transition to healthy eating, as well as nutrition and behavioral resources. MEASUREMENTS: Primary outcomes were changes in knee pain (numerical rating scale [NRS] of 0 to 10, higher indicating worse) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]; scale, 0 to 68, higher indicating worse) at 6 months (primary time point) and 12 months. Secondary outcomes were weight, physical activity, quality of life, mental health, global change, satisfaction, willingness to have surgery, orthopedic appointments, and knee surgery. RESULTS: A total of 379 participants (91%) provided 6-month primary outcomes, and 372 (90%) provided 12-month primary outcomes. At 6 months, both programs were superior to control for pain (between-group mean difference in change on NRS: diet and exercise, -1.5 [95% CI, -2.1 to -0.8]; exercise, -0.8 [CI, -1.5 to -0.2]) and function (between-group mean difference in change on WOMAC: diet and exercise, -9.8 [CI, -12.5 to -7.0]; exercise, -7.0 [CI, -9.7 to -4.2]). The diet and exercise program was superior to exercise (pain, -0.6 [CI, -1.1 to -0.2]; function, -2.8 [CI, -4.7 to -0.8]). Findings were similar at 12 months. LIMITATION: Participants and clinicians were unblinded. CONCLUSION: Telehealth-delivered exercise and diet programs improved pain and function in people with knee osteoarthritis and overweight or obesity. A dietary intervention conferred modest additional pain and function benefits over exercise. PRIMARY FUNDING SOURCE: Medibank, the Medibank Better Health Foundation Research Fund, and a National Health and Medical Research Council Centre of Research Excellence.

Alterations in arterial CO2 rather than pH affect the kinetics of neurovascular coupling in humans.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3- ]. The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+ ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg PaCO2 and the absolute peak change was reduced by -19% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ]. The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness. ABSTRACT: Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial PCO2 ( PaCO2 ) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, PaCO2 would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus-evoked NVC test during matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO3 (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P < 0.001) and [HCO3- ] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27-38% with -10 mmHg PaCO2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO3 (all P > 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of PaCO2 (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P < 0.001). Overall, these findings indicate that temporal patterns in NVC are acutely regulated by PaCO2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans.

Arterial carbon dioxide and bicarbonate rather than pH regulate cerebral blood flow in the setting of acute experimental metabolic alkalosis.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acutely elevated arterial pH and bicarbonate ([HCO3- ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in PaCO2 (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO3- ) to acutely elevate arterial pH and [HCO3- ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of PaCO2 , indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. The cerebrovascular responses to changes in arterial H+ /pH were altered in keeping with the altered relationship between PaCO2 and H+ /pH following NaHCO3- infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO3- infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO3- independent of PaCO2 levels. ABSTRACT: Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial PCO2 ( PaCO2 ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in PaCO2 or intravascular bicarbonate ([HCO3- ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO3- ; 8.4%, 50 mEq 50 mL-1 ) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P < 0.001) and [HCO3- ] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L-1 ; P < 0.001). Absolute CBF was not different at each stage of CO2 reactivity (P = 0.629) following NaHCO3- , irrespective of a higher pH (P < 0.001) at each matched stage of PaCO2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg PaCO2 ; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg PaCO2 ; P = 0.151) reactivity to PaCO2 were altered pre- to post-NaHCO3- . When indexed against arterial [H+ ], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO3- , respectively. These changes in reactivity to [H+ ] were, however, explained by alterations in buffering between PaCO2 and arterial H+ /pH consequent to NaHCO3- . Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min-1 , 7% ± 12%; P = 0.047) following NaHCO3- during isocapnic breathing providing support for a direct influence of HCO3- on cerebrovascular tone independent of PaCO2 . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by PaCO2 rather than arterial pH.

Better Knee, Better Me™: effectiveness of two scalable health care interventions supporting self-management for knee osteoarthritis - protocol for a randomized controlled trial.

BACKGROUND: Although education, exercise, and weight loss are recommended for management of knee osteoarthritis, the additional benefits of incorporating weight loss strategies into exercise interventions have not been well investigated. The aim of this study is to compare, in a private health insurance setting, the clinical- and cost-effectiveness of a remotely-delivered, evidence- and theory-informed, behaviour change intervention targeting exercise and self-management (Exercise intervention), with the same intervention plus active weight management (Exercise plus weight management intervention), and with an information-only control group for people with knee osteoarthritis who are overweight or obese. METHODS: Three-arm, pragmatic parallel-design randomised controlled trial involving 415 people aged ≥45 and ≤ 80 years, with body mass index ≥28 kg/m2 and < 41 kg/m2 and painful knee osteoarthritis. Recruitment is Australia-wide amongst Medibank private health insurance members. All three groups receive access to a bespoke website containing information about osteoarthritis and self-management. Participants in the Exercise group also receive six consultations with a physiotherapist via videoconferencing over 6 months, including prescription of a strengthening exercise and physical activity program, advice about management, and additional educational resources. The Exercise plus weight management group receive six consultations with a dietitian via videoconferencing over 6 months, which include a very low calorie ketogenic diet with meal replacements and resources to support behaviour change, in addition to the interventions of the Exercise group. Outcomes are measured at baseline, 6 and 12 months. Primary outcomes are self-reported knee pain and physical function at 6 months. Secondary outcomes include weight, physical activity levels, quality of life, global rating of change, satisfaction with care, knee surgery and/or appointments with an orthopaedic surgeon, and willingness to undergo surgery. Additional measures include adherence, adverse events, self-efficacy, and perceived usefulness of intervention components. Cost-effectiveness of each intervention will also be assessed. DISCUSSION: This pragmatic study will determine whether a scalable remotely-delivered service combining weight management with exercise is more effective than a service with exercise alone, and with both compared to an information-only control group. Findings will inform development and implementation of future remotely-delivered services for people with knee osteoarthritis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12618000930280 (01/06/2018).

Standardizing Clinical Response to Results of Lead Screening: A Quality Improvement Study.

BACKGROUND AND OBJECTIVES: Lead exposure remains common and is associated with adverse intellectual and behavioral outcomes. Despite quality improvement used to increase screening rates, clinical response to elevated lead levels remains variable. Our aim was to increase provider adherence to published guidelines for addressing elevated lead levels. METHODS: We created a protocol for addressing elevated lead levels on the basis of published guidelines. The protocol included ordering multivitamins with iron and follow-up lead testing, educating families about identifying and reducing sources of lead exposure, and referring to a specialty environmental health clinic when indicated. We used quality improvement methods to increase provider adherence to the protocol in a large, academic primary care center among patients 9 to 27 months old. The outcome measure was the percentage of elevated lead levels for which providers adhered to all elements of the protocol. This measure was plotted on a control chart. Statistical process control was used to determine a significant change to system performance. RESULTS: Adherence to the protocol rose from 5% to 90%. Key interventions included decision support in the e-health records and weekly review of reports of lead levels. These interventions were supported by staffing adjustments and individualized feedback to create accountability. CONCLUSIONS: Simple process changes dramatically improved adherence to complex guidelines for addressing lead exposure in primary care. These changes could be used to similarly standardize clinical responses to other screens.

Integrating Psychological Screening Into Medical Care for Youth With Abdominal Pain.

BACKGROUND: Pediatric functional abdominal pain disorders are common, costly, and disabling. Clinical anxiety is highly prevalent and is associated with increased pain and functional disability. Thus, a psychological screening process is recommended but is infrequently used in current practice. METHODS: A screening process for patient-reported anxiety (Screen for Child Anxiety and Related Disorders), functional disability (Functional Disability Inventory), and pain levels was implemented in a large gastroenterology division within a major medical center. Quality improvement methods and traditional analytic approaches were used to test the feasibility and outcomes of routine screening in patients ages 8 to 18 with abdominal pain. RESULTS: Screening rates increased from <1% to >80%. A total of 1291 patients who reported having abdominal pain completed the screening during the first 6 months. Clinically significant anxiety (43.1%), at least moderate disability (45%), and elevated pain (61.5%) were common in children with abdominal pain. The presence of clinically significant anxiety corresponded with higher pain and pain-related disability. Twenty-one percent of youth had clinical elevations in all 3 areas. In such instances, medical providers received an automated prompt to tailor care, including to consider a psychological referral. After the project implementation, psychological referral rates increased from 8.3 per 1000 patients to 15.2 per 1000 patients. CONCLUSIONS: Systematic screening for anxiety, pain, and pain-related disability as a routine part of medical care can be reliably implemented with clinically meaningful results. Future directions include examining the role of anxiety over the long-term and reducing clinician burden.

Oral contraceptives modulate the muscle metaboreflex in healthy young women.

There are known sex differences in blood pressure regulation. The differences are related to ovarian hormones that influence ß-adrenergic receptors and the transduction of muscle sympathetic nerve activity. Oral contraceptives (OC) modulate the ovarian hormonal profile in women and therefore may alter the cardiovascular response. We questioned if OC would alter the absolute pressor response to static exercise and influence the day-to-day variability of the response. Healthy men (n = 11) and women (n = 19) completed a familiarization day and 2 experimental testing days. Women were divided into those taking (W-OC, n = 10) and not taking (W-NC, n = 9) OC. Each experimental testing day involved isometric handgripping exercise, at 30% of maximal force, followed by circulatory occlusion to isolate the metaboreflex. Experimental days in men were 7-14 days apart. The first experimental testing in W-OC occurred 2-7 days after the start of the active phase of their OC. Women not taking OC were tested during the early and late follicular phase of the menstrual cycle as determined by commercial ovulation monitor. The increase in mean arterial pressure (MAP) during exercise was significantly lower in W-NC (95 ± 4 mm Hg) compared with men (114 ± 4 mm Hg) and W-OC (111 ± 3 mm Hg) (P < 0.05), with the differences preserved during circulatory occlusion. The rise in MAP was significantly correlated between the 2 testing days in men (r = 0.72, P < 0.01) and W-OC (r = 0.77, P < 0.05), but not in W-NC (r = 0.17, P = 0.67), indicating greater day-to-day variation in W-NC. In conclusion, OC modulate the exercise pressor response in women and minimize day-to-day variability in the exercise metaboreflex.

The Neuroeconomics of Tobacco Demand: An Initial Investigation of the Neural Correlates of Cigarette Cost-Benefit Decision Making in Male Smokers.

How the brain processes cigarette cost-benefit decision making remains largely unknown. Using functional magnetic resonance imaging (fMRI), this study investigated the neural correlates of decisions for cigarettes (0-10 cigarettes) at varying levels of price during a Cigarette Purchase Task (CPT) in male regular smokers (N = 35). Differential neural activity was examined between choices classified as inelastic, elastic, and suppressed demand, operationalized as consumption unaffected by cost, partially suppressed by cost, and entirely suppressed by cost, respectively. Decisions reflecting elastic demand, putatively the most effortful decisions, elicited greater activation in regions associated with inhibition and planning (e.g., middle frontal gyrus and inferior frontal gyrus), craving and interoceptive processing (anterior insula), and conflict monitoring (e.g., anterior cingulate cortex). Exploratory examination in a harmonized dataset of both cigarette and alcohol demand (N = 59) suggested common neural activation patterns across commodities, particularly in the anterior insula, caudate, anterior cingulate, medial frontal gyrus, and dorsolateral prefrontal cortex. Collectively, these findings provide initial validation of a CPT fMRI paradigm; reveal the interplay of brain regions associated with executive functioning, incentive salience, and interoceptive processing in cigarette decision making; and add to the literature implicating the insula as a key brain region in addiction.

The effectiveness of passive physical modalities for the management of soft tissue injuries and neuropathies of the wrist and hand: a systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) collaboration.

OBJECTIVE: The purpose of this systematic review was to determine the effectiveness of passive physical modalities compared to other interventions, placebo/sham interventions, or no intervention in improving self-rated recovery, functional recovery, clinical outcomes and/or administrative outcomes (eg, time of disability benefits) in adults and/or children with soft tissue injuries and neuropathies of the wrist and hand. METHODS: We systematically searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials, accessed through Ovid Technologies, Inc, and CINAHL Plus with Full Text, accessed through EBSCO host, from 1990 to 2015. Our search strategies combined controlled vocabulary relevant to each database (eg, MeSH for MEDLINE) and text words relevant to our research question and the inclusion criteria. Randomized controlled trials, cohort studies, and case-control studies were eligible. Random pairs of independent reviewers screened studies for relevance and critically appraised relevant studies using the Scottish Intercollegiate Guidelines Network criteria. Studies with low risk of bias were synthesized following best evidence synthesis principles. RESULTS: We screened 6618 articles and critically appraised 11 studies. Of those, 7 had low risk of bias: 5 addressed carpal tunnel syndrome (CTS) and 2 addressed de Quervain disease. We found evidence that various types of night splints lead to similar outcomes for the management of CTS. The evidence suggests that a night wrist splint is less effective than surgery in the short term but not in the long term. Furthermore, a night wrist splint and needle electroacupuncture lead to similar outcomes immediately postintervention. Finally, low-level laser therapy and placebo low-level laser therapy lead to similar outcomes. The evidence suggests that kinesio tape or a thumb spica cast offers short-term benefit for the management of de Quervain disease. Our search did not identify any low risk of bias studies examining the effectiveness of passive physical modalities for the management of other soft tissue injuries or neuropathies of the wrist and hand. CONCLUSIONS: Different night orthoses provided similar outcomes for CTS. Night orthoses offer similar outcomes to electroacupuncture but are less effective than surgery in the short term. This review suggests that kinesio tape or a thumb spica cast may offer short-term benefit for the management of de Quervain disease.

Impact of potential pregabalin or duloxetine drug-drug interactions on health care costs and utilization among Medicare members with fibromyalgia.

PURPOSE: To examine the impact of newly initiated pregabalin or duloxetine treatment on fibromyalgia (FM) patients' encounters with potential drug-drug interactions (DDIs), the health care cost and utilization consequences of those interactions, and the impact of treatment on opioid utilization. PATIENTS AND METHODS: Subjects included those with an FM diagnosis, a pregabalin or duloxetine prescription claim (index event), ≥1 inpatient or ≥2 outpatient medical claims, and ≥12 months preindex and ≥6 postindex enrollment. Propensity score matching was used to help balance the pregabalin and duloxetine cohorts on baseline demographics and comorbidities. Potential DDIs were defined based on Micromedex 2.0 software and were identified by prescription claims. RESULTS: No significant differences in baseline characteristics were found between matched pregabalin (n=794) and duloxetine cohorts (n=794). Potential DDI prevalence was significantly greater (P<0.0001) among duloxetine subjects (71.9%) than among pregabalin subjects (4.0%). There were no significant differences in all-cause health care utilization or costs between pregabalin subjects with and without a potential DDI. By contrast, duloxetine subjects with a potential DDI had higher mean all-cause costs ($9,373 versus $7,228; P<0.0001) and higher mean number of outpatient visits/member (16.0 versus 13.0; P=0.0009) in comparison to duloxetine subjects without a potential DDI. There was a trend toward a statistically significant difference between pregabalin and duloxetine subjects in their respective pre- versus post-differences in use of ≥1 long-acting opioids (1.6% and 3.4%, respectively; P=0.077). CONCLUSION: The significantly higher prevalence of potential DDIs and potential cost impact found in FM duloxetine subjects, relative to pregabalin subjects, underscore the importance of considering DDIs when selecting a treatment.

Clarifying the neural basis for incentive salience of tobacco cues in smokers.

In functional magnetic resonance imaging (fMRI) studies, smoking cues have been found to elicit increases in brain activity in regions associated with processing rewarding and emotional stimuli. However, most smoking cue studies to date have reported effects relative to neutral control stimuli with no incentive properties, making it unclear whether the observed activation pertains to value in general or the value of cigarettes in particular. The current fMRI study sought to clarify the neural activity reflecting tobacco-specific incentive value versus domain-general incentive value by examining smoking cues, neutral cues, and a third set of cues, monetary cues, which served as an active control condition. Participants were 42 male daily smokers. Compared to neutral cues, significantly greater activation was found in the left ventral striatum in response to tobacco and money cues. Monetary cues also elicited significantly increased activation in the right inferior frontal gyrus and cuneus compared to the other two cue types. Overall, the results suggest that the salience of monetary cues was the highest and, as a result, might have reduced the incentive salience of tobacco cues.

Social-emotional problems in preschool-aged children: opportunities for prevention and early intervention.

OBJECTIVES: To estimate the prevalence of positive screens for social-emotional problems among preschool-aged children in a low-income clinical population and to explore the family context and receptivity to referrals to help guide development of interventions. DESIGN: Observational, cross-sectional study. SETTING: Two urban primary care clinics. PARTICIPANTS: A total of 254 parents of 3- and 4-year-old children at 2 urban primary care clinics. MAIN OUTCOME MEASURES: Score on a standardized screen for social-emotional problems (Ages and Stages Questionnaire: Social-Emotional) and answers to additional survey questions about child care arrangements, parental depressive symptoms, and attitudes toward preschool and behavioral health referrals. RESULTS: Twenty-four percent (95% CI, 16.5%-31.5%) of children screened positive for social-emotional problems. Among those screening positive, 45% had a parent with depressive symptoms, and 27% had no nonparental child care. Among parents of children who screened positive for social-emotional problems, 79% reported they would welcome or would not mind a referral to a counselor or psychologist; only 16% reported a prior referral. CONCLUSIONS: In a clinical sample, 1 in 4 low-income preschool-aged children screened positive for social-emotional problems, and most parents were amenable to referrals to preschool or early childhood mental health. This represents an opportunity for improvement in primary prevention and early intervention for social-emotional problems.

Behavioral economic analysis of withdrawal- and cue-elicited craving for tobacco: an initial investigation.

INTRODUCTION: The role of craving in nicotine dependence remains controversial and may be a function of measurement challenges. The current study used behavioral economic approach to test the hypotheses that subjective craving from acute withdrawal and exposure to tobacco cues dynamically increases the relative value of cigarettes. METHODS: Using a 2 (1-hr/12-hr deprivation) × 2 (neutral/tobacco cues) within-subjects design, 33 nicotine dependent adults completed 2 laboratory sessions. Assessment included subjective craving and behavioral economic indices of cigarette demand, namely Intensity (i.e., cigarette consumption at zero cost), O(max) (i.e., maximum total expenditure), Breakpoint (i.e., highest acceptable price for cigarettes), P(max) (i.e., price at which consumption becomes sensitive to price), and elasticity (i.e., price sensitivity). Behavioral economic indices were generated using a Cigarette Purchase Task in which participants selected between cigarettes for a subsequent 2-hr self-administration period and money. RESULTS: Main effects of deprivation and tobacco cues were present for subjective craving and multiple behavioral economic indices of cigarette demand. Interestingly, deprivation significantly increased Breakpoint (p ≤ .01) and P(max) (p ≤ .05) and had trend-level effects on Intensity and O(max) (p ≤ .10); whereas cues significantly reduced elasticity (p ≤ .01), reflecting lower sensitivity to increasing prices. Heterogeneous associations were evident among the motivational variables but with aggregations suggesting variably overlapping motivational channels. CONCLUSIONS: These findings further support a behavioral economic approach to craving and a multidimensional conception of acute motivation for addictive drugs. Methodological considerations, including potential order effects, and the need for further refinement of these findings are discussed.

Complications of axial lumbar interbody fusion.

OBJECT: Axial lumbar interbody fusion (AxiaLIF) is a novel minimally invasive approach for fusion of L4-5 and L5-S1. This technique uses the presacral space for percutaneous access to the anterior sacrum. The AxiaLIF procedure has the potential to decrease patient recovery time, length of hospital stay, and overall occurrence of surgical complications. It can be used alone or in combination with minimally invasive or traditional open fusion procedures. The purpose of this study was to evaluate complications of the AxiaLIF procedure at the authors' institutions. METHODS: Patients who underwent AxiaLIF surgery between October 2005 and June 2009 at the authors' institutions were identified. The authors retrospectively reviewed these patients' charts, including operative reports and postoperative medical records, to determine what complications were encountered. RESULTS: A total of 68 patients underwent AxiaLIF surgery, with an average follow-up time of 34 months. Sixteen patients (23.5%) experienced a total of 18 complications (26.5%); this group included 8 men and 8 women (mean age 52.1 years). These complications included pseudarthrosis (8.8%), superficial infection (5.9%), sacral fracture (2.9%), pelvic hematoma (2.9%), failure of wound closure (1.5%), transient nerve root irritation (1.5%), and rectal perforation (2.9%). CONCLUSIONS: The complication rate associated with AxiaLIF in the present study was relatively low (26.5%). The most common complications were superficial infection and pseudarthrosis. There were 2 cases of rectal perforation associated with AxiaLIF; one case was found intraoperatively and the other presented 4 days postoperatively. Both patients underwent emergency repair by a general surgeon and had no long-term sequelae as a result of the rectal injuries. It is important for surgeons to be aware of the potential for these complications. Many of these complications can probably be avoided with proper patient selection and operative planning. Preoperative MR imaging, a detailed patient physical examination and history, full bowel preparation, and the use of live fluoroscopy can all help to prevent complications with AxiaLIF surgery.

Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases.

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.