Tractography patterns of pedunculopontine nucleus deep brain stimulation.

Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson's disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = -0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.

The dynamics of cortical GABA in human motor learning.

KEY POINTS: The ability to learn new motor skills is supported by plasticity in the structural and functional organisation of the primary motor cortex in the human brain. Changes inhibitory to signalling by GABA are thought to be crucial in inducing motor cortex plasticity. This study used magnetic resonance spectroscopy (MRS) to quantify the concentration of GABA in human motor cortex during a period of motor learning, as well as during a period of movement and a period at rest. We report evidence for a reduction in the MRS-measured concentration of GABA specific to learning. Further, the GABA concentration early in the learning task was strongly correlated with the magnitude of subsequent learning: higher GABA concentrations were associated with poorer learning. The results provide initial insight into the neurochemical correlates of cortical plasticity associated with motor learning, specifically relevant in therapeutic efforts to induce cortical plasticity during recovery from stroke. ABSTRACT: The ability to learn novel motor skills is a central part of our daily lives and can provide a model for rehabilitation after a stroke. However, there are still fundamental gaps in our understanding of the physiological mechanisms that underpin human motor plasticity. The acquisition of new motor skills is dependent on changes in local circuitry within the primary motor cortex (M1). This reorganisation has been hypothesised to be facilitated by a decrease in local inhibition via modulation of the neurotransmitter GABA, but this link has not been conclusively demonstrated in humans. Here, we used 7 T magnetic resonance spectroscopy to investigate the dynamics of GABA concentrations in human M1 during the learning of an explicit, serial reaction time task. We observed a significant reduction in GABA concentration during motor learning that was not seen in an equivalent motor task lacking a learnable sequence, nor during a passive resting task of the same duration. No change in glutamate was observed in any group. Furthermore, M1 GABA measured early in task performance was strongly correlated with the degree of subsequent learning, such that greater inhibition was associated with poorer subsequent learning. This result suggests that higher levels of cortical inhibition may present a barrier that must be surmounted in order to achieve an increase in M1 excitability, and hence encoding of a new motor skill. These results provide strong support for the mechanistic role of GABAergic inhibition in motor plasticity, raising questions regarding the link between population variability in motor learning and GABA metabolism in the brain.

Automated volumetric breast density measures: differential change between breasts in women with and without breast cancer.

BACKGROUND: Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls. METHODS: Eligible cases (n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1-5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time. RESULTS: Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (- 0.26% and - 2.10 cm3) than the normal breast (- 0.39% and - 2.74 cm3) for a difference of 0.13% (p value < 0.001) and 0.63 cm3 (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (- 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54 (95% CI 0.52, 0.56) for VPD and 0.56 (95% CI, 0.54, 0.58) for DV. CONCLUSION: There is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer.

The Opioid Crisis and the Future of Addiction and Pain Therapeutics.

Opioid misuse and addiction are a public health crisis resulting in debilitation, deaths, and significant social and economic impact. Curbing this crisis requires collaboration among academic, government, and industrial partners toward the development of effective nonaddictive pain medications, interventions for opioid overdose, and addiction treatments. A 2-day meeting, The Opioid Crisis and the Future of Addiction and Pain Therapeutics: Opportunities, Tools, and Technologies Symposium, was held at the National Institutes of Health (NIH) to address these concerns and to chart a collaborative path forward. The meeting was supported by the NIH Helping to End Addiction Long-TermSM (HEAL) Initiative, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid crisis. The event was unique in bringing together two research disciplines, addiction and pain, in order to create a forum for crosscommunication and collaboration. The output from the symposium will be considered by the HEAL Initiative; this article summarizes the scientific presentations and key takeaways. Improved understanding of the etiology of acute and chronic pain will enable the discovery of novel targets and regulatable pain circuits for safe and effective therapeutics, as well as relevant biomarkers to ensure adequate testing in clinical trials. Applications of improved technologies including reagents, assays, model systems, and validated probe compounds will likely increase the delivery of testable hypotheses and therapeutics to enable better health outcomes for patients. The symposium goals were achieved by increasing interdisciplinary collaboration to accelerate solutions for this pressing public health challenge and provide a framework for focused efforts within the research community. SIGNIFICANCE STATEMENT: This article summarizes key messages and discussions resulting from a 2-day symposium focused on challenges and opportunities in developing addiction- and pain-related medications. Speakers and attendees came from 40 states in the United States and 15 countries, bringing perspectives from academia, industry, government, and healthcare by researchers, clinicians, regulatory experts, and patient advocates.

Automated and Clinical Breast Imaging Reporting and Data System Density Measures Predict Risk for Screen-Detected and Interval Cancers: A Case-Control Study.

Background: In 30 states, women who have had screening mammography are informed of their breast density on the basis of Breast Imaging Reporting and Data System (BI-RADS) density categories estimated subjectively by radiologists. Variation in these clinical categories across and within radiologists has led to discussion about whether automated BI-RADS density should be reported instead. Objective: To determine whether breast cancer risk and detection are similar for automated and clinical BI-RADS density measures. Design: Case-control. Setting: San Francisco Mammography Registry and Mayo Clinic. Participants: 1609 women with screen-detected cancer, 351 women with interval invasive cancer, and 4409 matched control participants. Measurements: Automated and clinical BI-RADS density assessed on digital mammography at 2 time points from September 2006 to October 2014, interval and screen-detected breast cancer risk, and mammography sensitivity. Results: Of women whose breast density was categorized by automated BI-RADS more than 6 months to 5 years before diagnosis, those with extremely dense breasts had a 5.65-fold higher interval cancer risk (95% CI, 3.33 to 9.60) and a 1.43-fold higher screen-detected risk (CI, 1.14 to 1.79) than those with scattered fibroglandular densities. Associations of interval and screen-detected cancer with clinical BI-RADS density were similar to those with automated BI-RADS density, regardless of whether density was measured more than 6 months to less than 2 years or 2 to 5 years before diagnosis. Automated and clinical BI-RADS density measures had similar discriminatory accuracy, which was higher for interval than screen-detected cancer (c-statistics: 0.70 vs. 0.62 [P < 0.001] and 0.72 vs. 0.62 [P < 0.001], respectively). Mammography sensitivity was similar for automated and clinical BI-RADS categories: fatty, 93% versus 92%; scattered fibroglandular densities, 90% versus 90%; heterogeneously dense, 82% versus 78%; and extremely dense, 63% versus 64%, respectively. Limitation: Neither automated nor clinical BI-RADS density was assessed on tomosynthesis, an emerging breast screening method. Conclusion: Automated and clinical BI-RADS density similarly predict interval and screen-detected cancer risk, suggesting that either measure may be used to inform women of their breast density. Primary Funding Source: National Cancer Institute.

Combining quantitative and qualitative breast density measures to assess breast cancer risk.

BACKGROUND: Accurately identifying women with dense breasts (Breast Imaging Reporting and Data System [BI-RADS] heterogeneously or extremely dense) who are at high breast cancer risk will facilitate discussions of supplemental imaging and primary prevention. We examined the independent contribution of dense breast volume and BI-RADS breast density to predict invasive breast cancer and whether dense breast volume combined with Breast Cancer Surveillance Consortium (BCSC) risk model factors (age, race/ethnicity, family history of breast cancer, history of breast biopsy, and BI-RADS breast density) improves identifying women with dense breasts at high breast cancer risk. METHODS: We conducted a case-control study of 1720 women with invasive cancer and 3686 control subjects. We calculated ORs and 95% CIs for the effect of BI-RADS breast density and Volpara™ automated dense breast volume on invasive cancer risk, adjusting for other BCSC risk model factors plus body mass index (BMI), and we compared C-statistics between models. We calculated BCSC 5-year breast cancer risk, incorporating the adjusted ORs associated with dense breast volume. RESULTS: Compared with women with BI-RADS scattered fibroglandular densities and second-quartile dense breast volume, women with BI-RADS extremely dense breasts and third- or fourth-quartile dense breast volume (75% of women with extremely dense breasts) had high breast cancer risk (OR 2.87, 95% CI 1.84-4.47, and OR 2.56, 95% CI 1.87-3.52, respectively), whereas women with extremely dense breasts and first- or second-quartile dense breast volume were not at significantly increased breast cancer risk (OR 1.53, 95% CI 0.75-3.09, and OR 1.50, 95% CI 0.82-2.73, respectively). Adding continuous dense breast volume to a model with BCSC risk model factors and BMI increased discriminatory accuracy compared with a model with only BCSC risk model factors (C-statistic 0.639, 95% CI 0.623-0.654, vs. C-statistic 0.614, 95% CI 0.598-0.630, respectively; P < 0.001). Women with dense breasts and fourth-quartile dense breast volume had a BCSC 5-year risk of 2.5%, whereas women with dense breasts and first-quartile dense breast volume had a 5-year risk ≤ 1.8%. CONCLUSIONS: Risk models with automated dense breast volume combined with BI-RADS breast density may better identify women with dense breasts at high breast cancer risk than risk models with either measure alone.

Mammographic texture and risk of breast cancer by tumor type and estrogen receptor status.

BACKGROUND: Several studies have shown that mammographic texture features are associated with breast cancer risk independent of the contribution of breast density. Thus, texture features may provide novel information for risk stratification. We examined the association of a set of established texture features with breast cancer risk by tumor type and estrogen receptor (ER) status, accounting for breast density. METHODS: This study combines five case-control studies including 1171 breast cancer cases and 1659 controls matched for age, date of mammogram, and study. Mammographic breast density and 46 breast texture features, including first- and second-order features, Fourier transform, and fractal dimension analysis, were evaluated from digitized film-screen mammograms. Logistic regression models evaluated each normalized feature with breast cancer after adjustment for age, body mass index, first-degree family history, percent density, and study. RESULTS: Of the mammographic features analyzed, fractal dimension and second-order statistics features were significantly associated (p < 0.05) with breast cancer. Fractal dimensions for the thresholds equal to 10% and 15% (FD_TH_10 [corrected] and FD_TH_15) [corrected] were associated with an increased risk of breast cancer while thresholds from 60% to 85% (FD_TH_60 to FD_TH_85) [corrected] were associated with a decreased risk. Increasing the FD_TH_75 [corrected] and Energy feature values were associated with a decreased risk of breast cancer while increasing Entropy was associated with an increased [corrected] risk of breast cancer. For example, 1 standard deviation increase of FD_TH_75 [corrected] was associated with a 13% reduced risk of breast cancer (odds ratio = 0.87, 95% confidence interval 0.79-0.95). Overall, the direction of associations between features and ductal carcinoma in situ (DCIS) and invasive cancer, and estrogen receptor positive and negative cancer were similar. CONCLUSION: Mammographic features derived from film-screen mammograms are associated with breast cancer risk independent of percent mammographic density. Some texture features also demonstrated associations for specific tumor types. For future work, we plan to assess risk prediction combining mammographic density and features assessed on digital images.

Comparison of Clinical and Automated Breast Density Measurements: Implications for Risk Prediction and Supplemental Screening.

Purpose To compare the classification of breast density with two automated methods, Volpara (version 1.5.0; Matakina Technology, Wellington, New Zealand) and Quantra (version 2.0; Hologic, Bedford, Mass), with clinical Breast Imaging Reporting and Data System (BI-RADS) density classifications and to examine associations of these measures with breast cancer risk. Materials and Methods In this study, 1911 patients with breast cancer and 4170 control subjects matched for age, race, examination date, and mammography machine were evaluated. Participants underwent mammography at Mayo Clinic or one of four sites within the San Francisco Mammography Registry between 2006 and 2012 and provided informed consent or a waiver for research, in compliance with HIPAA regulations and institutional review board approval. Digital mammograms were retrieved a mean of 2.1 years (range, 6 months to 6 years) before cancer diagnosis, with the corresponding clinical BI-RADS density classifications, and Volpara and Quantra density estimates were generated. Agreement was assessed with weighted κ statistics among control subjects. Breast cancer associations were evaluated with conditional logistic regression, adjusted for age and body mass index. Odds ratios, C statistics, and 95% confidence intervals (CIs) were estimated. Results Agreement between clinical BI-RADS density classifications and Volpara and Quantra BI-RADS estimates was moderate, with κ values of 0.57 (95% CI: 0.55, 0.59) and 0.46 (95% CI: 0.44, 0.47), respectively. Differences of up to 14% in dense tissue classification were found, with Volpara classifying 51% of women as having dense breasts, Quantra classifying 37%, and clinical BI-RADS assessment used to classify 43%. Clinical and automated measures showed similar breast cancer associations; odds ratios for extremely dense breasts versus scattered fibroglandular densities were 1.8 (95% CI: 1.5, 2.2), 1.9 (95% CI: 1.5, 2.5), and 2.3 (95% CI: 1.9, 2.8) for Volpara, Quantra, and BI-RADS classifications, respectively. Clinical BI-RADS assessment showed better discrimination of case status (C = 0.60; 95% CI: 0.58, 0.61) than did Volpara (C = 0.58; 95% CI: 0.56, 0.59) and Quantra (C = 0.56; 95% CI: 0.54, 0.58) BI-RADS classifications. Conclusion Automated and clinical assessments of breast density are similarly associated with breast cancer risk but differ up to 14% in the classification of women with dense breasts. This could have substantial effects on clinical practice patterns. (©) RSNA, 2015 Online supplemental material is available for this article.

A reappraisal of adult thoracic and abdominal surface anatomy in Iranians in vivo using computed tomography.

Surface anatomy is a core component of human anatomy in clinical practice. It allows clinicians to assess patients accurately and quickly; however, recent studies have revealed variability among individuals and ethnicities. The aim of this study is to investigate possible variations in adult thoracic and abdominal surface anatomy landmarks in an Iranian population. This study used 100 thoracoabdominal CT scans (mean age: 47 ± 17 years, age range: 20-77 years, 47% females), noted the most common locations of clinically relevant surface markings, and analyzed correlations between these variables and age or gender. While many common surface markings in Iranians were consistent with the evidence-based literature, there were some differences. In relation to the corresponding segments of the vertebral column, the superior vena cava formation and the lower border of the pleura adjacent to the vertebral column and right kidney tended to be at higher levels in adult Iranians than a Caucasian population. There were also discrepancies between the Iranian population and commonly-referenced medical textbooks and recent evidence-based literature concerning the vertebral levels of the diaphragmatic openings of the esophagus, aorta, and inferior vena cava. This study emphasizes the need to consider evidence-based reappraisals of surface anatomy to guide clinical practice. Much of our current knowledge of surface anatomy is based on older studies of cadavers rather than living people, and does not take ethnic and individual variations into consideration.

Whole egg and alevin changes of cortisol and interrenal tissue differences in rainbow trout Oncorhynchus mykiss exposed to different stocking densities during early development.

Cortisol level changes in response to stocking density in the early stages of rainbow trout were measured. Eggs were exposed to low, normal, and high (2.55, 5.10 and 7.65 eggs cm(-2)) densities during the incubation period. Cortisol of maternal origin was found in pre-fertilized eggs (5.09 ± 0.12 ng g(-1)) of rainbow trout. In newly fertilized eggs, resting Cortisol levels (3.68 ± 0.14 ng g(-1)) decreased to 0.58 ± 0.08, 0.60 ± 0.12, and 0.57 ± 0.16 ng g(-1) at low, normal and high densities by day 10 (organo-genesis), respectively. Resting Cortisol levels remained constant until the eyed stage (day 18). Then, Cortisol showed an increase at hatching to 1.16 ± 0.11, 1.20 ± 0.12, and 1.21 ± 0.14 ng g(-1) at low, normal, and high densities, respectively. The pattern of change in Cortisol level was similar in all three densities. Interrenal cells were observed in 1-day old alevins at all three densities. Hematopoietic tissue, renal tubules and nucleated red blood cells were clarified through the head part of kidney. Higher numbers and larger interrenal cells were observed at high-density groups. Chronic density stress test conducted on embryonic stages of rainbow trout revealed no differences in Cortisol levels, but had an effect on the abundance and size of the interrenal cells. Densities were equaled after hatching (200 alevins per replicate) to investigate the different densities of eggs on stress indices in rainbow trout alevins. An acute stress (air exposure of eggs for five minutes) was applied in three treatments two weeks after hatching, and samples were taken at 0, 1, 3, 6, and 24 hps (hours post stress). Cortisol content increased under low density in 1 hps and reached from 5.21 ± 0.13 ng g(-1) to 6.01 ± 0.18 ng g(-1) (P < 0.05). Cortisol levels increased under normal density in 1 hps from 6.03 ± 0.28 ng g(-1) to 10.84 ± 0.18 ng g(-1) (P < 0.05). In high density also Cortisol increased from 6.83 ± 0.23 ng g(-1) to 8.86 ± 0.26 ng g(-1) (P < 0.05). At 3 hps;, Cortisol level was returned to basal level under low (P > 0.05) and normal (P > 0.05) densities, but significantly decreased (P < 0.05) under high density. Results revealed that the Cortisol biosynthesis was observed in rainbow trout between eyeing to the hatching stage. An increase in the density of eggs until 7.65 egg cm(-2) impaired Cortisol secretion and feedback system in alevins. However, more studies are needed to identify the exact time for Cortisol synthesis ability from eyeing to hatching in this species.

The Design of Brainstem Interfaces: Characterisation of Physiological Artefacts and Implications for Closed-loop Algorithms.

Surgical neuromodulation through implantable devices allows for stimulation delivery to subcortical regions, crucial for symptom control in many debilitating neurological conditions. Novel closed-loop algorithms deliver therapy tailor-made to endogenous physiological activity, however rely on precise sensing of signals such as subcortical oscillations. The frequency of such intrinsic activity can vary depending on subcortical target nucleus, while factors such as regional anatomy may also contribute to variability in sensing signals. While artefact parameters have been explored in more 'standard' and commonly used targets (such as the basal ganglia, which are implanted in movement disorders), characterisation in novel candidate nuclei is still under investigation. One such important area is the brainstem, which contains nuclei crucial for arousal and autonomic regulation. The brainstem provides additional implantation targets for treatment indications in disorders of consciousness and sleep, yet poses distinct anatomical challenges compared to central subcortical targets. Here we investigate the region-specific artefacts encountered during activity and rest while streaming data from brainstem implants with a cranially-mounted device in two patients. Such artefacts result from this complex anatomical environment and its interactions with physiological parameters such as head movement and cardiac functions. The implications of the micromotion-induced artefacts, and potential mitigation, are then considered for future closed-loop stimulation methods.

The association between penile cancer and HIV infection: A literature review.

Penile cancer is a rare malignancy which HIV infection appears to increase the risk of. The magnitude of this risk and the pathogenesis remain unclear. A comprehensive review of the literature was undertaken using conventional search strategies. Twenty-four publications were identified by this methodology, of which nine were case reports and 15 were observational studies. These studies were highly heterogeneous, with varying study designs, populations, and objectives. The risk of penile cancer within HIV-positive individuals is significantly greater than in those without HIV (RR = 3 .7 to 5.8, 3 studies; SIR = 3.8 to 11.1, 4 studies). HIV is also shown to influence disease characteristics, with a four-fold increased risk of death from penile cancer. Moreover, progression from intraepithelial neoplasia occurs earlier in HIV, six years sooner than in HIV-negative men. HIV-positive men have a higher prevalence of HPV infection. Ethnicity is also shown to modulate the relationship between HIV and penile carcinoma, with a higher risk of cancer in Hispanic, compared with Caucasian, HIV-positive men. This review has collated data from diverse sources to improve understanding of the relationship between HIV and penile cancer. This relationship has been quantitatively and qualitatively characterised and highlights areas deserving further enquiry.

Study protocol for a multicenter randomized controlled trial of personalized exercise therapy and self-management support for people with multimorbidity: The MOBILIZE study.

Background: Despite the great individual and societal burden associated with multimorbidity, little is known about how to effectively manage it. Objective: The aim of this multicenter randomized controlled trial (RCT) is to investigate the 12-month effects of a personalized exercise therapy and self-management support program in addition to usual care in people with multimorbidity. Design: This is a protocol for a pragmatic, parallel-group (1:1 ratio), superiority RCT conducted at five intervention sites (two hospitals, a private practice physiotherapy clinic and two municipal rehabilitation centers) in Region Zealand, Denmark. A total of 228 persons with multimorbidity aged 18 years or older, will be randomly allocated to one of two groups. Both groups will receive usual care, defined as routine care for multimorbidity at the discretion of the treating doctor, while the intervention group will also participate in a 12-week exercise therapy and self-management support program tailored to people with multimorbidity at one of the intervention sites. The primary outcome will be the between-group difference in change in EQ-5D-5L from baseline to the follow-up at 12 months. Secondary outcomes include objectively-measured physical function and physical activity, inflammatory markers, disease and treatment burden, anxiety, depression, stress, sleep, pain and other self-reported parameters. In parallel with the RCT, an observational cohort will follow persons aged ≥18 years with multimorbidity not adhering to all eligibility criteria, as well as people fulfilling all eligibility criteria, but unwilling to participate in the RCT. This study was approved by the Regional Committee on Health Research Ethics for Region Zealand (SJ-857) and results will be communicated in scientific papers, at relevant conferences and to a broader audience. Discussion: Exercise therapy and self-management support is safe and effective in people with single conditions. However, it is still unclear whether this holds true for individuals with multimorbidity. This pragmatic, multicenter RCT will provide high-quality evidence on the benefits and harms of exercise therapy and self-management support and, if the results support it, lead to the development of a plan for implementation in clinical practice.

Effect of stretch frequency and sex on the rate of gain and rate of loss in muscle flexibility during a hamstring-stretching program: a randomized single-blind longitudinal study.

This study evaluated the effects of 4 different weekly stretching protocols on the rate of gain and decline in hamstring flexibility over an 8-week period, across sex. Using a randomized single-blind design, 53 healthy subjects aged 18-46 years were assigned to 1 of 4 stretching protocols or a control group. The stretching protocols consisted of either daily or 3 times per week stretching and performed once or twice each day. These protocols differed in terms of frequency and total weekly stretching time. All the subjects stretched their hamstring muscles for 4 weeks and were measured weekly for their hip range of motion (ROM). Stretching ceased the final 4 weeks as the weekly measurements continued. The results revealed no significant differences in the rate of gain or the rate of loss between the different stretching protocols (2-way analysis of variance, F = 2.60, p > 0.05). All the stretching groups gained in hip ROM from pre to week 4 (F = 269.24, p < 0.001). After cessation, the rate of loss was similar for all the 4 stretching groups (F = 102.86, p < 0.001); all the groups retained significant gains at the end of the study (p < 0.001). The control group did not change over time. Those who stretched at least 6 times per week gained more than those who stretched 3 times per week (24 and 16.8%, respectively, F = 5.20, p < 0.05). Subject sex did not influence ROM changes (p > 0.05). Stretching appears to be equally effective, whether performed daily or 3 times per week, provided individuals stretch at least 2 times each day. Moreover, although women are more flexible than men are, there was no sex difference in terms of stretching response.

A focus on the neural exposome.

Many neurological disorders have complex etiologies that include noninheritable factors, collectively called the neural exposome. The National Institute of Neurological Disorders and Stroke is developing a new office with goals to advance our understanding of the multiple causes of neurological illness and to enable the development of more effective interventions.

Preclinical target validation for non-addictive therapeutics development for pain.

INTRODUCTION: The Helping to End Addiction Long-termSM Initiative supports a wide range of programs to develop new or improved prevention and opioid addiction treatment strategies. An essential component of this effort is to accelerate development of non-opioid pain therapeutics. In all fields of medicine, therapeutics development is an arduous process and late-stage translational efforts such as clinical trials to validate targets are particularly complex and costly. While there are plentiful novel targets for pain treatment, successful clinical validation is rare. It is therefore crucial to develop processes whereby therapeutic targets can be reasonably 'de-risked' prior to substantial late-stage validation efforts. Such rigorous validation of novel therapeutic targets in the preclinical space will give potential private sector partners the confidence to pursue clinical validation of promising therapeutic concepts and compounds. AREAS COVERED: In 2020, the National Institutes of Health (NIH) held the Target Validation for Non-Addictive Therapeutics Development for Pain workshop to gather insights from key opinion leaders in academia, industry, and venture-financing. EXPERT OPINION: The result was a roadmap for pain target validation focusing on three modalities: 1) human evidence; 2) assay development in vitro; 3) assay development in vivo.

Antishivering effects of two different doses of intrathecal meperidine in caesarean section: a prospective randomised blinded study.

BACKGROUND AND OBJECTIVE: Shivering causes various adverse disturbances and interferes with monitoring. The optimal dose of intrathecal meperidine to prevent shivering without producing other side-effects remains unknown. This prospective randomised double-blinded study was conducted to compare the antishivering effects of two different doses of intrathecal meperidine. METHODS: Seventy two parturients, scheduled for elective caesarean section under spinal anaesthesia, were enrolled in three different groups. Spinal anaesthesia consisted of bupivacaine 0.5% (10 mg) for the control group (M0), and the same dose of bupivacaine with meperidine 12.5 or 25 mg for the experimental groups (M1, M2). Blood pressure, heart rate, skin and core temperatures, sensory level, capnometry, pulse oximetry, Apgar scores, shivering intensity and intrathecal opioid-related side-effects were evaluated and recorded by a blinded observer. Data were analysed using analysis of variance, χ² test, Kruskal-Wallis H-test and Mann-Whitney U-test. A P value less than 0.05 was considered to be significant. RESULTS: Shivering was more intense in group M0 than in groups M1 and M2 with P values of 0.003 and less than 0.001, respectively. The intensity of shivering was comparable in groups M1 and M2. As regards the incidence of significant shivering, it was found to be highest in M0 (4/24 ≈16.7%) in comparison with M1 (0/24) and M2 (0/24) (P = 0.03). Nausea and vomiting occurred more frequently with higher doses of meperidine (P < 0.001 and P = 0.003, respectively). Other complications were comparable. CONCLUSION: The use of intrathecal meperidine for caesarean section during spinal anaesthesia for the prevention of shivering cannot be recommended as its use is associated with increased incidence of nausea and vomiting.

Pregnancy-related uterine arteriovenous malformations: experience from a single medical center.

PURPOSE: The purpose of this article was to investigate clinical ultrasonographic findings and the outcomes of post-pregnancy patients with acquired uterine vascular abnormalities including arteriovenous malformations (AVMs). MATERIALS AND METHODS: We performed a computerized database search for all patients with ultrasonographic findings of a vascular abnormality including AVM in our referral center between 2000-2008. An ultrasound finding of vascular abnormality was defined as an area of strong hypervascularity within the myometrium and the presence of marked turbulence. The inclusion criteria for angiography were abnormal vaginal bleeding in a hemodynamically stable patient, bhCG serum levels ≤ 30 mIU/ml, and ultrasound demonstration of large (≥ 15 mm on the larger side of the vessel) or multiple vascular lesions. RESULTS: 16 women were identified, of whom 10 (63 %) underwent uterine artery embolization. Angiography confirmed the pre-interventional ultrasound diagnosis of AVM in all cases. AVM feeding arteries were on the left side of the uterus in 80 % of the cases. Residual tissue was ultrasonographically detected in five patients: 2 underwent hysteroscopy and guided curettage following embolization and three received methotrexate. All tissue samples were benign. One small vascular abnormality resolved spontaneously. CONCLUSION: An acquired uterine vascular abnormality including AVM should be considered in the work-up of post-pregnancy vaginal bleeding.