Carpal tunnel syndrome and Raynaud's phenomenon: a narrative review.

BACKGROUND: Raynaud's phenomenon (RP) is a recognized symptom associated with carpal tunnel syndrome (CTS) and is also the vascular manifestation of hand arm vibration syndrome (HAVS). The symptoms of HAVS and CTS are such that there is a significant possibility of misdiagnosis and an incorrect attribution of vascular and sensory symptoms. An understanding of the relationship between RP and CTS is essential when undertaking health surveillance of vibration-exposed workers presenting with combined vascular and sensory symptoms. AIMS: To clarify the relationship between CTS and Raynaud's phenomenon. METHODS: A systematic search was undertaken of studies that reviewed links between CTS and Raynaud's phenomenon (RP). RESULTS: A total of 4170 papers were identified, with 21 articles that were then reviewed in full, including 1 meta-analysis of 8 studies. Eighteen papers, not included in the meta-analysis, were found including 3 case control studies, 9 case reports, 2 prospective studies and 4 retrospective reviews. Papers were reviewed on the basis of the diagnostic criteria used for CTS and RP. Our review of the literature confirms a substantial body of evidence of a relationship between RP and CTS. CONCLUSIONS: It is recommended that assessment of vibration exposed individuals who report concurrent RP and separate sensory symptoms suggestive of, or compatible with CTS, should formally exclude CTS before attributing symptoms to HAVS.

Rethinking efficiency: Growth curves as a proxy for inputs and impacts in finishing beef systems.

Quantifying and improving efficiency within beef systems is essential for economic and environmental sustainability. The industry standard for assessing efficiency is liveweight gain per day, however, this metric is limited in that it values each day of a growing animal's life as equally costly, despite the increasing maintenance requirements, inputs, and emissions associated with increasing liveweight. Quantifying the area under the growth curve (AUC) considers both time and liveweight as a cost and therefore may hold potential as a better estimate of cost, impact, and efficiency in beef systems. Liveweight data was taken from 439 finishing beef cattle split across three herds grazing on different pastures, known as 'farmlets'. Analysis was conducted in three parts: [1] Validation of AUC as a proxy for costs using data from a sub-set of 87 animals that had been part of a previous life cycle assessment (LCA) study in which dry matter intake (DMI), methane emissions (CH4), and nitrous oxide emissions (N2O) were calculated. [2] Calculation of AUC relative to liveweight gain (LWG AUC-1) and comparison of that metric against the industry standard of liveweight gain per day (LWG day-1). [3] Assessment of how LWG AUC-1 varied with breed, sex, and management. When comparing to LCA results, AUC correlated significantly with DMI (r = 0.886), CH4 (r = 0.788) and N2O (r = 0.575) emissions. Over the full dataset, there was a negative non-linear relationship between LWG AUC-1 and slaughter age (r = -0.809). There was a significant difference in LWG AUC-1 between breeds (p = 0.046) and farmlets (p = 0.028), but not sex (p = 0.388). LWG AUC-1 has the potential to act as a proxy for feed intake and emissions. In that regard it is superior to LWG day-1, whilst requiring no additional data. Results highlighted the decreasing efficiency of beef cattle over time and the potential benefits of earlier slaughter. The use of LWG AUC-1 could allow farmers to improve their understanding of efficiency within their herds, aiding informed management decision making.

Effects of Cooperation and Competition on Performance, Emotion, and Effort: Goal and Means Interdependence.

Social interdependence theory proposes that task structure influences performance via social interaction. Using this framework, we examined sport performance. Fifty-six males performed a basketball task under four conditions: as an individual (individual, perform your best) and as a member of a team of two (cooperation, where teammates sought to better their individual performance; means independent competition, where two teams competed sequentially to outperform the other team; means interdependent competition, where two teams competed simultaneously to outperform the other team). Task performance (points) was better during means independent competition than other conditions. Anxiety and effort peaked during the competitions and enjoyment was greater during competition and cooperation than during the individual condition. Emotions, effort, and actions are discussed as explanations for the performance effects. Social interdependence theory provides a valuable framework to understand emotion, motivation, and performance. Team competition can be used to promote effort and enhance performance in sport.

Electroencephalographic neurofeedback training can decrease conscious motor control and increase single and dual-task psychomotor performance.

The control of human movements is thought to automize with repetition, promoting consistent execution and reduced dual-task costs. However, contingencies such as illness or constraints to regular movement patterns can promote conscious motor control, which can reduce movement proficiency and make dual-task situations more difficult. This experiment evaluated whether electroencephalographic neurofeedback training can reduce the adverse effects of conscious motor control. Twenty-five participants completed the timed-up-and-go task while wearing a leg brace to de-automize their regular movement, under both single and dual-task (walking + serial sevens) conditions, both before and after 30-min of neurofeedback training. Three different types of neurofeedback were prescribed across three laboratory visits. We hypothesised that training to decrease central EEG alpha-power at scalp sites above the supplementary motor area would facilitate performance compared to opposite (increase central EEG alpha-power) or sham neurofeedback training. Results revealed a pre-test to post-test improvement in performance on the single-task and on both aspects of the dual-task when participants were trained to decrease central EEG alpha-power. There were no benefits of opposite or sham neurofeedback training. Mediation analyses revealed that the improvement in dual-task motor performance was mediated by the improvement in cognitive performance. This suggests that the neurofeedback protocol was beneficial because it helped to reduce conscious control of the motor task. The findings could have important implications for rehabilitation and high-performance (e.g., elite sport) domains; neurofeedback could be prescribed to help alleviate the problems that can arise when individuals exert conscious motor control.

Design and synthesis of novel proline based factor XIa selective inhibitors as leads for potential new anticoagulants.

A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC50 = 1 nM and FXIa IC50 = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.

Identification of potent inhibitors of the sortilin-progranulin interaction.

High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.

Structural characterization of nonactive site, TrkA-selective kinase inhibitors.

Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of-but adjacent to-the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.

I Am Great, but Only When I Also Want to Dominate: Maladaptive Narcissism Moderates the Relationship Between Adaptive Narcissism and Performance Under Pressure.

Narcissism-performance research has focused on grandiose narcissism but has not examined the interaction between its so-called adaptive (reflecting overconfidence) and maladaptive (reflecting a domineering orientation) components. In this research, the authors tested interactions between adaptive and maladaptive narcissism using two motor tasks (basketball and golf in Experiments 1 and 2, respectively) and a cognitive task (letter transformation in Experiment 3). Across all experiments, adaptive narcissism predicted performance under pressure only when maladaptive narcissism was high. In the presence of maladaptive narcissism, adaptive narcissism also predicted decreased pre-putt time in Experiment 2 and an adaptive psychophysiological response in Experiment 3, reflecting better processing efficiency. Findings suggest that individuals high in both aspects of narcissism perform better under pressure thanks to superior task processing. In performance contexts, the terms "adaptive" and "maladaptive"-adopted from social psychology-are oversimplistic and inaccurate. The authors believe that "self-inflated narcissism" and "dominant narcissism" are better monikers for these constructs.

Anxiety and Ironic Errors of Performance: Task Instruction Matters.

Five experiments that examined Wegner's theory of ironic processes of mental control in reactive motor performance under pressure are presented for the first time. In Experiments 1, 2, and 4, the authors conducted specific examinations of the incidence of an ironic error using a reactive motor task. In Experiments 3 and 5, they provided the first tests of whether task instruction moderates the incidence of ironic errors. The task required participants to react to a series of three primary-colored balls as they rolled down a chute under low- and high-anxiety conditions. Measures of anxiety, heart rate, heart-rate variability, and muscle activity confirmed the effectiveness of the anxiety manipulation. Experiments 1, 2, and 4 revealed that anxiety increased the number of ironic errors. In Experiments 3 and 5, the authors provided the first evidence that instructional interventions can reduce the incidence of anxiety-induced ironic performance errors in reactive motor tasks.

Chunking, Conscious Processing, and EEG During Sequence Acquisition and Performance Pressure: A Comprehensive Test of Reinvestment Theory.

This study was designed to test the theorized link between reinvestment, motor chunks, and conscious processing, to provide a thorough examination of reinvestment theory. The authors measured electroencephalographic power and connectivity alongside self-reported conscious processing and behavioral indices of chunking in a 2 (group) × 5 (block) mixed-model design. A total of 55 individuals acquired a motor sequence (blocks A1, A2, A3, and A4) by relatively explicit (errorful) or implicit (errorless) paradigms. Then they performed in a pressure condition (block T). Results confirmed that chunking characterizes both modes of acquisition. However, explicit acquisition resulted in quicker chunking, reduced conscious processing, and increased cortical efficiency (left-temporal high-alpha power). In support of reinvestment theory, self-reported conscious processing tended to increase under pressure among explicit trainees only. In contrast to reinvestment theory, this had no adverse effect on performance. The results endorse explicit acquisition as an effective mode of training and provide a new neurophysiological explanation of this phenomenon.

Design, synthesis and SAR of substituted indoles as selective TrkA inhibitors.

A series of substituted indoles were examined as selective inhibitors of tropomyosin-related kinase receptor A (TrkA), a therapeutic target for the treatment of pain. An SAR optimization campaign based on ALIS screening lead compound 1 is reported.

Imidazopyridyl compounds as aldosterone synthase inhibitors.

The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1.

Discovery of highly potent and selective orexin 1 receptor antagonists (1-SORAs) suitable for in vivo interrogation of orexin 1 receptor pharmacology.

While a correlation between blockade of the orexin 2 receptor (OX2R) with either a dual orexin receptor antagonist (DORA) or a selective orexin 2 receptor antagonist (2-SORA) and a decrease of wakefulness is well established, less is known about selective blockade of the orexin 1 receptor (OX1R). Therefore, a highly selective orexin 1 antagonist (1-SORA) with suitable properties to allow in vivo interrogation of OX1R specific pharmacology in preclinical species remains an attractive target. Herein, we describe the discovery of an optimized 1-SORA series in the piperidine ether class. Notably, a 4,4-difluoropiperidine core coupled with a 2-quinoline ether linkage provides OX1R selective compounds. The combination with an azabenzimidazole or imidazopyridine amide substituent leads to analogs 47 and 51 with >625-fold functional selectivity for OX1R over OX2R in rat. Compounds 47 and 51 possess clean off-target profiles and the required pharmacokinetic and physical properties to be useful as 1-SORA tool compounds.

Asthma and chronic obstructive pulmonary disease inhalers: Techniques for proper use.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) affect millions of Americans. Inhalers are necessary to manage these diseases, but physicians and patients often struggle to use them correctly. OBJECTIVE: To simplify inhaler use for patients and physicians. METHODS: This article compares the various inhalers used to treat asthma and COPD, their techniques for use, and the steps necessary to prime the inhaler if required. The authors provide a suggested standardized technique for the use of metered-dose inhalers, dry powder inhalers, and soft-mist inhalers to provide for a more universal approach for the use of these medications and summarizes how each product is to be used per the U.S. Food and Drug Administration approved package insert. RESULTS AND CONCLUSIONS: The simplified techniques proposed in this article for the use of metered-dose inhalers, dry powder inhalers, and soft mist inhalers used to treat asthma and COPD may limit inhaler misuse and aid in proper medication delivery and treatment.

Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant.

Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.

Sensitivity and Specificity of Emergency Physicians and Trainees for Identifying Internally Concealed Drug Packages on Abdominal Computed Tomography Scan: Do Lung Windows Improve Accuracy?

BACKGROUND: Suspected body packers may be brought to emergency departments (EDs) close to international airports for abdominal computed tomography (CT) scanning. Senior emergency clinicians may be asked to interpret these CT scans. Missing concealed drug packages have important clinical and forensic implications. The accuracy of emergency clinician interpretation of abdominal CT scans for concealed drugs is not known. Limited evidence suggests that accuracy for identification of concealed packages can be increased by viewing CT images on "lung window" settings. OBJECTIVES: To determine the accuracy of senior emergency clinicians in interpreting abdominal CT scans for concealed drugs, and to determine if this accuracy was improved by viewing scans on both abdominal and lung window settings. METHODS: Emergency clinicians blinded to all patient identifiers and the radiology report interpreted CT scans of suspected body packers using standard abdominal window settings and then with the addition of lung window settings. The reference standard was the radiologist's report. RESULTS: Fifty-five emergency clinicians reported 235 CT scans. The sensitivity, specificity, and accuracy of interpretation using abdominal windows was 89.9% (95% confidence interval [CI] 83.0-94.7), 81.9% (95% CI 73.7-88.4), and 86.0% (95% CI 81.5-90.4), respectively, and with both window settings was 94.1% (95% CI 88.3-97.6), 76.7% (95% CI 68.0-84.1), 85.5% (95% CI 81.0-90.0), respectively. Diagnostic accuracy was similar regardless of the clinician's experience. Interrater reliability was moderate (kappa 0.46). CONCLUSION: The accuracy of interpretation of abdominal CT scans performed for the purpose of detecting concealed drug packages by emergency clinicians is not high enough to safely discharge these patients from the ED. The use of lung windows improved sensitivity, but at the expense of specificity.

Three-month outcome of patients with suspected acute coronary syndrome using point-of-care cardiac troponin-T testing compared with laboratory-based cardiac troponin-T testing: a randomised trial.

OBJECTIVE: The aim of this randomised trial was to determine clinical outcomes in patients suspected of an acute coronary syndrome (ACS) who had cardiac troponin-T measured by point-of-care (POC) compared with laboratory-based cardiac troponin-T testing. A secondary aim was to describe the correlation between the two troponin assays. METHODS: Adults suspected of ACS were allocated to have troponin processed by POC or laboratory analyser. The primary outcome was a composite of acute myocardial infarction, coronary revascularisation, cardiac arrest and mortality at 3 months. Paired troponins taken on participants allocated to POC were used to determine correlation between troponin values obtained from laboratory and POC analysers. RESULTS: There were 452 participants. 30 (13.1%) of 229 participants allocated to POC had at least one primary outcome event compared with 29 (13.0%) of 223 allocated to laboratory testing, a difference of 0.1% (95% CI -6.2% to 6.4%, p=0.98). Of 215 available paired troponins results, both analysers gave congruent results in 196 (91%) cases. The POC troponin was negative when the laboratory sample was positive in 16 (7%) cases. The POC troponin was positive when the laboratory sample was negative in 3 (1%) samples. Passing-Bablok regression analysis demonstrated both a constant and proportional difference between the two analytic methods. CONCLUSIONS: Among patients suspected of an ACS, we found no evidence for a difference in adverse outcome when POC troponin was used in comparison with laboratory troponin. Due to the small sample size, an absolute difference of up to 6% in adverse outcome is possible. TRIAL REGISTRATION NUMBER: ANZCTR#12612000319875.

Some pressures are more equal than others: Effects of isolated pressure on performance.

It is commonly assumed that performance is impaired by pressure and that different types of individual situational factors can produce equivalent pressure. Our aim was to explore the psychophysiological effects of pressure to test this assumption. Eighty-one novices completed a golf putting task under control and eight individual pressure conditions: time, difficulty, video, team, goal, fame, shame, and distraction. Performance was measured by the number of holed putts and ball-hole distance. Psychological, physiological and kinematic measures were collected. Performance was impaired by time and difficulty conditions but improved by team, goal and shame conditions compared to control. Perceived pressure and effort were higher than control in all conditions except distraction. Conscious processing was greater than control in all conditions except distraction and time constraint. Heart rate was faster with time, team, fame and shame. Heart rate variability and muscle activity were largely unaffected. Putter kinematics provided evidence of swing profiles slowing and/or becoming constrained in conditions where conscious processing increased, while the swing became faster in the time-pressure condition where conscious processing was decreased. Taken together, these results reveal heterogenous effects of pressure on performance, with performance impaired, unaffected, and improved by individual pressure situations. Similarly, heterogeneity characterized the effects of pressure on psychological, physiological and kinematic responses associated with task performance. In sum, the evidence challenges the standard tacit assumptions about the pressure-performance relationship in sport.

Breast Cancer Polygenic-Risk Score Influence on Risk-Reducing Endocrine Therapy Use: Genetic Risk Estimate (GENRE) Trial 1-Year and 2-Year Follow-Up.

Refinement of breast cancer risk estimates with a polygenic-risk score (PRS) may improve uptake of risk-reducing endocrine therapy (ET). A previous clinical trial assessed the influence of adding a PRS to traditional risk estimates on ET use. We stratified participants according to PRS-refined breast cancer risk and evaluated ET use and ET-related quality of life (QOL) at 1-year (previously reported) and 2-year follow-ups. Of 151 participants, 58 (38.4%) initiated ET, and 22 (14.6%) discontinued ET by 2 years; 42 (27.8%) and 36 (23.8%) participants were using ET at 1- and 2-year follow-ups, respectively. At the 2-year follow-up, 39% of participants with a lifetime breast cancer risk of 40.1% to 100.0%, 18% with a 20.1% to 40.0% risk, and 16% with a 0.0% to 20.0% risk were taking ET (overall P = 0.01). Moreover, 40% of participants whose breast cancer risk increased by 10% or greater with addition of the PRS to a traditional breast cancer-risk model were taking ET versus 0% whose risk decreased by 10% or greater (P = 0.004). QOL was similar for participants taking or not taking ET at 1- and 2-year follow-ups, although most who discontinued ET did so because of adverse effects. However, these QOL results may have been skewed by the long interval between QOL surveys and lack of baseline QOL data. PRS-informed breast cancer prevention counseling has a lasting, but waning, effect over time. Additional follow-up studies are needed to address the effect of PRS on ET adherence, ET-related QOL, supplemental breast cancer screening, and other risk-reducing behaviors. PREVENTION RELEVANCE: Risk-reducing medications for breast cancer are considerably underused. Informing women at risk with precise and individualized risk assessment tools may substantially affect the incidence of breast cancer. In our study, a risk assessment tool (IBIS-polygenic-risk score) yielded promising results, with 39% of women at highest risk starting preventive medication.

Opportunities to improve goat production and food security in Botswana through forage nutrition and the use of supplemental feeds.

Goats fulfil a central role in food and nutritional security across Africa with over half of households owning or rearing goats in rural areas. However, goat performance is poor and mortality high. This study assessed the nutritional quality of commonly used feeds and proposes feed-baskets to enhance goat nutrition and health. Feeds were collected from 11 areas within the Central District of Botswana, and macronutrient analyses were conducted, including crude protein, fibre fractions, ash, and metabolizable energy (ME). Forage nutrition was compared across seasons and soil types. Additionally, seasonal supplementation trials were conducted to evaluate consumption rates of various supplements, including crop residues, pellets, Lablab purpureus, and Dichrostachys cinerea. Each supplement was provided ad libitum for a 24-h period, and consumption rates determined. Findings revealed significant differences in nutrition among various feed sources, across seasons, and in relation to soil types (p < 0.001). Consumption rates of supplements were higher during the dry season, possibly due to reduced forage availability. Supplement consumption rates varied across supplement type, with crop residues accounting for approximately 1% of dry matter intake, compared to up to 45% for pellets, 13% for L. purpureus, and 15% for D. cinerea. While wet season feed baskets exhibited higher ME values compared to dry-season feed-baskets, the relative impact of supplementation was more pronounced during the dry season. These results highlight the potential for optimizing goat diets through improved grazing and browsing management, especially during the reduced nutritional availability in the dry season in Botswana. Such diet optimisation may improve goat health and productivity, which may positively impact the food and financial security of smallholders by providing both increased yields and increased resilience. Importantly, rural communities can experience some of the lowest food security levels in the region. The interventions explored in this study utilise natural capital, often freely available, which can be deployed through existing husbandry systems, potentially making them accessible and practical to smallholders.