A Relationship Between O-Serotype, Antibiotic Susceptibility and Biofilm Formation in Uropathogenic Escherichia coli

Microbial Drug Resistance, Ahead of Print.


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Molecular Characteristics of “BlaB-Like” Chromosomal Inducible Cephalosporinase of Yersinia enterocolitica Biotype 1A Strains

Microbial Drug Resistance, Ahead of Print.


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Diagnosis and Treatment Patterns in Celiac Disease

Abstract

Celiac disease (CD) is an immune-mediated gastrointestinal (GI) disorder driven by innate and adaptive immune responses to gluten. Presentation of CD has changed over time, with non-GI symptoms, such as anemia and osteoporosis, presenting more commonly. With improved screening and diagnostic methods, the reported prevalence of CD has increased globally, and there is considerable global variation in diagnostic and treatment practices. The objective of this study was to describe the current state of CD diagnosis and treatment patterns. A targeted review of literature from MEDLINE, Embase, the Cochrane Library, and screening of relevant conference abstracts was performed. The generally recommended diagnostic approach is GI endoscopy with small bowel biopsy; however, in selected patients, biopsy may be avoided and diagnosis based on positive serology and clinical symptoms. Diagnosis often is delayed; the average diagnostic delay after symptom onset is highly variable and can last up to 12 years. Barriers to accurate and timely diagnosis include atypical presentation, lack of physician awareness about current diagnostic criteria, misdiagnosis, and limited access to specialists. Currently, strict adherence to a gluten-free diet (GFD) is the only recommended treatment, which is not successful in all patients. Only one-third of patients are monitored regularly following diagnosis. Unmet needs for CD include improvements in the accuracy and timeliness of diagnosis, and the development of treatments for both refractory CD and GFD nonresponsive CD. Further research should investigate the impact of education about gluten-free eating and the availability of gluten-free foods support adherence and improve outcomes in patients with CD.

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The effect of severe and moderate hypoxia on exercise at a fixed level of perceived exertion

Abstract

Purpose

The purpose of this study was to determine the primary cues regulating perceived effort and exercise performance using a fixed-RPE protocol in severe and moderate hypoxia.

Methods

Eight male participants (26 ± 6 years, 76.3 ± 8.6 kg, 178.5 ± 3.6 cm, 51.4 ± 8.0 mL kg^− 1 min^− 1 \(\dot {V}\) O_2max) completed three exercise trials in environmental conditions of severe hypoxia (F_IO₂ 0.114), moderate hypoxia (F_IO₂ 0.152), and normoxia (F_IO₂ 0.202). They were instructed to continually adjust their power output to maintain a perceived effort (RPE) of 16, exercising until power output declined to 80% of the peak 30-s power output achieved.

Results

Exercise time was reduced (severe hypoxia 428 ± 210 s; moderate hypoxia 1044 ± 384 s; normoxia 1550 ± 590 s) according to a reduction in F_IO₂ (P < 0.05). The rate of oxygen desaturation during the first 3 min of exercise was accelerated in severe hypoxia (− 5.3 ± 2.8% min^− 1) relative to moderate hypoxia (− 2.5 ± 1.0% min^− 1) and normoxia (− 0.7 ± 0.3% min^− 1). Muscle tissue oxygenation did not differ between conditions (P > 0.05). Minute ventilation increased at a faster rate according to a decrease in F_IO₂ (severe hypoxia 27.6 ± 6.6; moderate hypoxia 21.8 ± 3.9; normoxia 17.3 ± 3.9 L min^− 1). Moderate-to-strong correlations were identified between breathing frequency (r = − 0.718, P < 0.001), blood oxygen saturation (r = 0.611, P = 0.002), and exercise performance.

Conclusions

The primary cues for determining perceived effort relate to progressive arterial hypoxemia and increases in ventilation.

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Generality of Genomic Findings on Blood Pressure Traits and Its Usefulness in Precision Medicine in Diverse Populations: A Systematic Review

Remarkable findings from genome wide association studies (GWAS) on blood pressure (BP) traits have made new insights for developing precision medicine towards more effective screening measures. However, generality of GWAS findings in diverse populations is hampered by some technical limitations. There is no comprehensive study to evaluate source(s) of the non‐generality of GWAS results on BP traits, so to fill the gap, this systematic review study was carried out. Using MeSH terms, 1545 records were detected through searching in 5 databases and 49 relevant full‐text articles were included in our review. Overall, 749 unique variants were reported, of those, majority of variants have been detected in Europeans and were associated to systolic and diastolic blood pressure traits. Frequency of genetic variants with same position was low in European and Non‐European populations (n=38). However, more than 200 (>25%) single nucleotide polymorphism were found on same loci or linkage disequilibrium blocks (r²≥80%). Investigating for locus position and linkage disequilibrium of infrequent unique variants showed modest to high reproducibility of findings in Europeans that in some extent was generalizable in other populations. Beyond theoretical limitations, our study addressed other possible sources of non‐generality of GWAS findings for BP traits in same and different origins.

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Telomeropathies: Aetiology, diagnosis, treatment and follow‐up. Ethical and legal considerations

Telomeropathies involve a wide variety of infrequent genetic diseases caused by mutations in the telomerase maintenance mechanism or the DNA damage response system (DDR). They are considered a family of rare diseases that often share causes, molecular mechanisms and symptoms. Generally, these diseases are not diagnosed until the symptoms are advanced, diminishing the survival time of patients. Although several related syndromes may still be unrecognized this work describes those that are known, highlighting that since they are rare diseases, physicians should be trained in their early diagnosis. The aetiology and diagnosis are discussed for each telomeropathy and the treatments when available, along with a new classification of this group of diseases. Ethical and legal issues related to this group of diseases are also considered.

This article is protected by copyright. All rights reserved.

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Endothelial‐cardiomyocyte cross‐talk in heart development and disease

Abstract

The cross‐talk between endothelial cells and cardiomyocytes has emerged as a requisite during normal cardiac development, but also a key pathogenic player during the onset and progression of cardiac disease. Endothelial cells and cardiomyocytes are in close proximity and communicate through the secretion of paracrine signals, as well as through direct cell‐to‐cell contact. Here, we provide an overview of the endothelial cell‐cardiomyocyte interactions controlling heart development and the main processes affecting the heart in normal and pathological conditions, including ischemia, remodeling and metabolic dysfunction. We also discuss the possible role of these interactions in cardiac regeneration and encourage the further improvement of in vitro models able to reproduce the complex environment of the cardiac tissue, in order to better define the mechanisms by which endothelial cells and cardiomyocytes interact and having the final aim to develop novel therapeutic opportunities.

Cardiomyocytes (labeled in red by anti‐α‐actinin antibodies) and endothelial cells (labeled in green by anti‐CD31 antibodies) crosstalk in multiple ways, including paracrine communication (dashed arrows) through either secreted molecules or vesicles (red circles), direct cell‐cell contact (hinges) and autocrine signaling (curved arrows). This crosstalk plays an important role during embryonic development, normal post‐natal life and several pathological conditions, thus representing a novel target for the treatment of cardiovascular disorders.2

This article is protected by copyright. All rights reserved

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Topical Review: Electrophysiology equipment for reliable study of kHz electrical stimulation

Abstract

Characterizing the cellular targets of kHz (1–10 kHz) electrical stimulation remains a pressing topic in neuromodulation because expanding interest in clinical application of kHz stimulation has surpassed mechanistic understanding. The presumed cellular targets of brain stimulation do not respond to kHz frequencies according to conventional electrophysiology theory. Specifically, the low‐pass characteristics of cell membranes are predicted to render kHz stimulation inert, especially given the use of limited‐duty‐cycle biphasic pulses. Precisely because kHz frequencies are considered supra‐physiological, conventional instruments designed for neurophysiological studies such as stimulators, amplifiers, and recording microelectrodes do not operate reliably at these high rates. Moreover, for pulsed waveforms, the signal frequency content is well above the pulse repetition rate. Thus, the very tools used to characterize the effects of kHz electrical stimulation may themselves be confounding factors. We illustrate custom equipment design that supports reliable electrophysiological recording during kHz‐rate stimulation. Given the increased importance of kHz stimulation in clinical domains and compelling possibilities that mechanisms of actions may reflect yet undiscovered neurophysiological phenomena, attention to suitable performance of electrophysiological equipment is pivotal.

Signal filtering (attenuation) caused by electrophysiology devices. (A) Illustration of the performance of an isolator during kHz pulsed stimulation verified using a resistive, capacitive, or electrode (non‐linear) load and high precision ammeter and voltmeter. (B) represents amplifiers performance (in response to 1 mV sinusoidal input), and (C) shows experimental testing of attenuation with frequency by applying sinusoidal current to an experimental lead in a saline bath and measuring voltage. (D) Illustration of significant waveform distortion (below 100 kHz) from conventional stimulator and isolator, amplifier, and microelectrode (A, B, and C), which can only be corrected by a custom circuitry here.2

This article is protected by copyright. All rights reserved

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An R Package for Bayesian Analysis of Multi-environment and Multi-trait Multi-environment Data for Genome-Gased Prediction

Evidence that genomic selection (GS) is a technology that is revolutionizing plant breeding continues to grow. However, it is very well documented that its success strongly depends on statistical models, which are used by GS to perform predictions of candidate genotypes that were not phenotyped. Because there is no universally better model for prediction and models for each type of response variable are needed (continuous, binary, ordinal, count, etc.), an active area of research aims to develop statistical models for the prediction of univariate and multivariate traits in GS. However, most of the models developed so far are for univariate and continuous (Gaussian) traits. Therefore, to overcome the lack of multivariate statistical models for genome-based prediction by improving the original version of the BMTME, we propose an improved Bayesian multi-trait and multi-environment (BMTME) R package for analyzing breeding data with multiple traits and multiple environments. We also introduce Bayesian multi-output regressor stacking (BMORS) functions that are considerably efficient in terms of computational resources. The package allows parameter estimation and evaluates the prediction performance of multi-trait and multi-environment data in a reliable, efficient and user-friendly way. We illustrate the use of the BMTME with real toy datasets to show all the facilities that the software offers the user. However, for large datasets, the BME() and BMTME() functions of the BMTME R package are very intense in terms of computing time; on the other hand, less intensive computing packages like the BMORS functions BMORS() and BMORS_Env() are also included in the R package.

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A Novel Root-Knot Nematode Resistance QTL on Chromosome Vu01 in Cowpea

The root-knot nematode (RKN) species Meloidogyne incognita and M. javanica cause substantial root system damage and suppress yield of susceptible cowpea cultivars. The narrow-based genetic resistance conferred by the Rk gene, present in some commercial cultivars, is not effective against Rk-virulent populations found in several cowpea production areas. The dynamics of virulence within RKN populations require a broadening of the genetic base of resistance in elite cowpea cultivars. As part of this goal, F₁ and F₂ populations from the cross CB46-Null (susceptible) x FN-2-9-04 (resistant) were phenotyped for M. javanica induced root-galling (RG) and egg-mass production (EM) in controlled growth chamber and greenhouse infection assays. In addition, F_2:3 families of the same cross were phenotyped for RG on field sites infested with Rk-avirulent M. incognita and M. javanica. The response of F₁ to RG and EM indicated that resistance to RKN in FN-2-9-04 is partially dominant, as supported by the degree of dominance in the F₂ and F_2:3 populations. Two QTLs associated with both RG and EM resistance were detected on chromosomes Vu01 and Vu04. The QTL on Vu01 was most effective against aggressive M. javanica, whereas both QTLs were effective against avirulent M. incognita. Allelism tests with CB46 x FN-2-9-04 progeny indicated that these parents share the same RKN resistance locus on Vu04, but the strong, broad-based resistance in FN-2-9-04 is conferred by the additive effect of the novel resistance QTL on Vu01. This novel resistance in FN-2-9-04 is an important resource for broadening RKN resistance in elite cowpea cultivars.

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Usefulness Criterion and Post-selection Parental Contributions in Multi-parental Crosses: Application to Polygenic Trait Introgression

Predicting the usefulness of crosses in terms of expected genetic gain and genetic diversity is of interest to secure performance in the progeny and to maintain long-term genetic gain in plant breeding. A wide range of crossing schemes are possible including large biparental crosses, backcrosses, four-way crosses, and synthetic populations. In silico progeny simulations together with genome-based prediction of quantitative traits can be used to guide mating decisions. However, the large number of multi-parental combinations can hinder the use of simulations in practice. Analytical solutions have been proposed recently to predict the distribution of a quantitative trait in the progeny of biparental crosses using information of recombination frequency and linkage disequilibrium between loci. Here, we extend this approach to obtain the progeny distribution of more complex crosses including two to four parents. Considering agronomic traits and parental genome contribution as jointly multivariate normally distributed traits, the usefulness criterion parental contribution (UCPC) enables to (i) evaluate the expected genetic gain for agronomic traits, and at the same time (ii) evaluate parental genome contributions to the selected fraction of progeny. We validate and illustrate UCPC in the context of multiple allele introgression from a donor into one or several elite recipients in maize (Zea mays L.). Recommendations regarding the interest of two-way, three-way, and backcrosses were derived depending on the donor performance. We believe that the computationally efficient UCPC approach can be useful for mate selection and allocation in many plant and animal breeding contexts.

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Pain and outcome prediction in muscle strength rehabilitation after knee injury in recreational athletes

Effects of rehabilitation on knee function, activity and health-related quality of life after soft-tissue knee injury have been widely studied in clinical trials, but there is still a lack of data on the relation between knee muscle strength and athlete's perceived performance to identify sports-risk modifiers. We performed a prospective observational clinical study of knee muscle strength and self-reported health during rehabilitation after unilateral knee soft-tissue injury in recreational sports. Forty-three patients performed isokinetic dynamometry and filled in the Short form Health Survey (SF-36) and the Oxford Knee Score questionnaires before and after 4 months of instructed home strengthening program. We observed significant improvement in peak torque deficit between two limbs during concentric extension (PTDE) and flexion, dynamic control ratio of the involved knee, most of the SF-36 subscales and the Oxford Knee Score values (P≤0.001). Dynamic control ratio of the uninvolved knee values remained below referential values and unchanged. Improvement of PTDE correlated positively with improvement of the bodily pain subscale of SF-36 score (r=0.51, P

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The International Classification of Functioning, Disability and Health-based factors related to physical activity level in adults with muscle diseases

The aim of this study was to investigate the physical activity (PA) level of adults with muscle diseases and the association of factors affecting PA behaviour. Forty-five adults with muscle diseases and 44 healthy participants were included. The PA was assessed by a SenseWear Armband and the International Physical Activity Questionnaire. The muscle strength, pain, fatigue severity, activity limitations, functional mobility level and quality of life were also assessed. Compared with the healthy group, adults with muscle diseases had significantly lower step counts and duration of moderate and vigorous PA (P

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Real-Time Ultrasound Improves Accuracy of Caudal Block in Children

BACKGROUND: Caudal block, the most common regional anesthetic in children, is predominantly performed using palpation to determine placement. The efficacy of the palpation technique is unknown with respect to block success. While ultrasound has been suggested for use during caudal block, its use is infrequent. METHODS: A single-blinded prospective observational trial was performed evaluating provider success rate of caudal blocks placed by palpation alone. After needle insertion and partial local anesthetic injection, an ultrasound was performed to confirm correct location. RESULTS: A total of 109 caudal blocks were performed during the prospective observational study. Success rate for caudal blocks done by palpation alone was 78.9% as confirmed by ultrasound. In 21.1% of caudal blocks, the provider incorrectly judged the needle to be in the caudal space as confirmed with ultrasound. CONCLUSIONS: Real-time ultrasound visualization of local anesthetic injection provides reliable and immediate confirmation during caudal block in children. Accepted for publication January 8, 2019. Funding: Departmental. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). This work was presented in abstract form at the 43rd Annual Regional Anesthesiology and Acute Pain Medicine Meeting, New York, NY, April 21, 2018. Reprints will not be available from the authors. Address correspondence to Adam C. Adler, MD, MS, FAAP, FASE, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin St, Suite #A3300, Houston, TX 77030. Address e-mail to adam.adler@bcm.edu. © 2019 International Anesthesia Research Society

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Hypertonic Saline in Human Sepsis: A Systematic Review of Randomized Controlled Trials

The role of hypertonic saline in sepsis remains unclear because clinical data are limited and the balance between beneficial and adverse effects is not well defined. In this systematic literature review, we searched PubMed and Embase to identify all randomized controlled trials up until January 31, 2018 in which hypertonic saline solutions of any concentration were used in patients of all ages with sepsis and compared to a cohort of patients receiving an isotonic fluid. We identified 8 randomized controlled trials with 381 patients who had received hypertonic saline. Lower volumes of hypertonic saline than of isotonic solutions were needed to achieve the desired hemodynamic goals (standardized mean difference, −0.702; 95% CI, −1.066 to −0.337; P

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Dose–Response Study of 4 Weight-Based Phenylephrine Infusion Regimens for Preventing Hypotension During Cesarean Delivery Under Combined Spinal–Epidural Anesthesia

BACKGROUND: Prophylactic IV infusion of phenylephrine has been recommended to prevent hypotension during spinal anesthesia for cesarean delivery. However, the optimal infusion dose is unknown. This study aimed to determine the infusion dose of phenylephrine that would be effective in preventing hypotension in 50% (ED50) and 90% (ED90) of patients when administered as a prophylactic infusion at a fixed rate based on the individual body weight. METHODS: Eighty parturients scheduled for elective cesarean delivery were randomly allocated to receive IV infusion of prophylactic phenylephrine at 0.25, 0.375, 0.5, or 0.625 µg/kg/min (n = 20 per group) started immediately after intrathecal injection of 10 mg hyperbaric bupivacaine and 5 µg sufentanil using a combined spinal–epidural technique. An effective dose was defined by the occurrence of no hypotension (defined as a decrease in systolic blood pressure by ≥20% below baseline and to

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Road to Perioperative Medicine: A Perspective From China

With the development of anesthesiology, patient safety has been remarkably improved, but the postoperative mortality rate at 30 days is still as high as 0.56%–4%, and the morbidity is even higher. Three years ago, the Chinese Society of Anesthesiology proposed that the direction of the anesthesiology development should be changed to perioperative medicine in China. Anesthesiologists should pay more attention to the long-term outcome. In this article, we introduced what we have done, what the challenges are, and what we should do in the future with regard to the practice of perioperative medicine in China. Accepted for publication January 8, 2019 Funding: This study was partly supported by the National Natural Science Foundation of China (Grant No. 81842018). The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Lize Xiong, MD, PhD, Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China 710032. Address e-mail to mzkxlz@126.com. © 2019 International Anesthesia Research Society

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Culture-Negative and Culture-Positive Sepsis: A Comparison of Characteristics and Outcomes

BACKGROUND: The primary objective of this study was to compare the characteristics of culture-positive and culture-negative status in septic patients. We also determined whether culture status is associated with mortality and whether unique variables are associated with mortality in culture-positive and culture-negative patients separately. METHODS: Utilizing patient records from intensive care units, emergency department, and general care wards in a large academic medical center, we identified adult patients with suspected infection and ≥2 systemic inflammatory response syndrome criteria between January 1, 2007, and May 31, 2014. We compared the characteristics between culture-positive and culture-negative patients and used binary logistic regression to identify variables independently associated with culture status and mortality. We also did sensitivity analyses using patients with Sequential Organ Failure Assessment and quick Sequential Organ Failure Assessment criteria for sepsis. RESULTS: The study population included 9288 culture-negative patients (89%) and 1105 culture-positive patients (11%). Culture-negative patients received more antibiotics during the 48 hours preceding diagnosis but otherwise demonstrated similar characteristics as culture-positive patients. After adjusting for illness severity, a positive culture was not independently associated with mortality (odds ratio = 1.01 [95% CI, 0.81–1.26]; P = .945). The models predicting mortality separately in culture-negative and culture-positive patients demonstrated very good and excellent discrimination (C-statistic ± SD, 0.87 ± 0.01 and 0.92 ± 0.01), respectively. In the sensitivity analyses using patients with sepsis by Sequential Organ Failure Assessment and quick Sequential Organ Failure Assessment criteria, after adjustments for illness severity, positive cultures were still not associated with mortality (odds ratio = 1.13 [95% CI, 0.86–1.43]; P = .303; and odds ratio = 1.05 [95% CI, 0.83–1.33]; P = .665), respectively. In all models, physiological derangements were associated with mortality. CONCLUSIONS: While culture status is important for tailoring antibiotics, culture-negative and culture-positive patients with sepsis demonstrate similar characteristics and, after adjusting for severity of illness, similar mortality. The most important factor associated with negative cultures is receipt of antibiotics during the preceding 48 hours. The risk of death in patients suspected of having an infection is most associated with severity of illness. This is aligned with the Sepsis-3 definition using Sequential Organ Failure Assessment score to better identify those suspected of infection at highest risk of a poor outcome. Accepted for publication January 8, 2019. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Matthew J. G. Sigakis, MD, Division of Critical Care Medicine, Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109. Address e-mail to msigakis@med.umich.edu. © 2019 International Anesthesia Research Society

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Customizable Curriculum to Enhance Resident Communication Skills

Communication remains challenging to teach and evaluate. We designed an online patient survey to assess anesthesia residents' communication skills from August 2014 to July 2015. In December 2014, we implemented a customized, simulation-based curriculum. We calculated an overall rating for each survey by averaging the ratings for the individual questions. Based on the Hodges–Lehmann 2-sample aligned rank-sum test, overall ratings, reported as the median (interquartile range) of residents' average overall ratings, differed significantly between the preintervention (3.86 [3.76–3.94]) and postintervention (3.91 [3.84–3.95]) periods (P = .025). Future studies should assess the intervention's effectiveness and generalizability. Accepted for publication January 16, 2019. Funding: This study was funded by the Department of Anesthesia, Critical Care and Pain Medicine at Beth Israel Deaconess Medical Center, Boston, MA. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to John D. Mitchell, MD, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, 1 Deaconess Rd, RB-470, Boston, MA 02215. Address e-mail to jdmitche@bidmc.harvard.edu. © 2019 International Anesthesia Research Society

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Anesthetic Implications of the New Guidelines for Button Battery Ingestion in Children

Button battery ingestions result in significant morbidity and mortality in children—before, during, and even after removal. The injuries created by a button battery lodged in the esophagus develop rapidly and can be severe. The current of the button battery, conducted through saliva and the tissue drives a highly alkaline caustic injury, leading to liquefactive tissue necrosis. In June 2018, new guidelines were released from the National Capital Poison Center, which include the use of preoperative protective, pH-neutralizing and viscous barrier interventions with honey and/or sucralfate administered within 12 h of ingestion. In addition, the use of postremoval irrigation of the esophagus with 50–150 mL 0.25% acetic acid is done in the operating room to help neutralize the site of tissue injury. Given that anesthesiologists play an important role in the management of esophageal foreign body removal, the entire specialty needs to be aware of the supporting data behind this and general perioperative considerations for management and potential complications of button battery ingestion. Accepted for publication December 13, 2018. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Debnath Chatterjee, MD, FAAP, Department of Anesthesiology, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 E 16th Ave, B090, Aurora, CO 80045. Address e-mail to debnath.chatterjee@childrenscolorado.org. © 2019 International Anesthesia Research Society

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Proliferator-Activated Receptor-Gamma Coactivator-1α Haploinsufficiency Promotes Pain Chronification After Burn Injury

BACKGROUND: Tissue injuries such as surgery and trauma are usually accompanied by simultaneous development of acute pain, which typically resolves along with tissue healing. However, in many cases, acute pain does not resolve despite proper tissue repair; rather, it transitions to chronic pain. In this study, we examined whether proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondria biogenesis, is implicated in pain chronification after burn injury in mice. METHODS: We used PGC-1α+/+ and littermates PGC-1α+/− mice of both sex. Burn injury was induced on these mice. Hindpaw mechanical withdrawal thresholds and thermal withdrawal latency were examined. RESULTS: Hindpaw mechanical withdrawal thresholds and thermal withdrawal latencies were comparable at baseline between PGC-1α+/− and PGC-1α+/+ mice. After burn injury, both PGC-1α+/+ and PGC-1α+/− mice exhibited an initial dramatic decrease of withdrawal parameters at days 3 and 5 after injury. While PGC-1α+/+ mice fully recovered their withdrawal parameters to preinjury levels by days 11–14, PGC-1α+/− mice failed to recover those parameters during the same time frame, regardless of sex. Moreover, we found that PGC-1α+/− mice resolved tissue inflammation in a similar fashion to PGC-1α+/+ mice using a chemiluminescence-based reactive oxygen species imaging technique. CONCLUSIONS: Taken together, our data suggest that PGC-1α haploinsufficiency promotes pain chronification after burn injury. Accepted for publication January 16, 2019. J. Miao and X. Zhou contributed equally and share first authorship. The authors declare no conflicts of interest. Funding: J.M. is supported by R01DE02290 and R01DA039925. S.S. is supported by the Foundation of Anesthesia Education and Research, National Institute of General Medical Sciences R35-GM1286928, and research fund from the Department of Anesthesia, Critical Care and Pain Medicine at the Massachusetts General Hospital. Reprints will not be available from the authors. Address correspondence to Shiqian Shen, MD, Department of Anesthesia, Critical Care and Pain Medicine, Center for Translational Pain Research, Massachusetts General Hospital, Harvard Medical School, Jackson Bldg 458, 55 Fruit St, Boston, MA 02121. Address e-mail to sshen2@mgh.harvard.edu. © 2019 International Anesthesia Research Society

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Retrospective Analysis of Obstetric Intensive Care Unit Admissions Reveals Differences in Etiology for Admission Based on Mode of Conception

BACKGROUND: The use of in vitro fertilization is increasing. The incidence of adverse outcomes is greater for women who undergo in vitro fertilization, potentially leading to intensive care unit admission. This study aimed to assess the etiology and course of intensive care unit admission in women who underwent in vitro fertilization compared to those who did not, with specific focus on intensive care unit admission due to postpartum hemorrhage. METHODS: In this retrospective study, medical records of patients admitted to the intensive care unit during pregnancy or the peripartum period at 2 medical centers (2005–2016 at Mount Sinai Hospital, New York, NY, and 2005–2013 at Shaare Zedek Medical Center, Jerusalem, Israel) were analyzed. Demographic, past medical and obstetric history, and details regarding delivery and intensive care unit stay were collected, as was information regarding mode of conception (in vitro fertilization versus non–in vitro fertilization) for the current pregnancy. The primary outcome measure was difference in etiology of intensive care unit admission between in vitro fertilization and non–in vitro fertilization groups. Secondary outcome measures included differences in prepregnancy characteristics, incidence, severity, and management of postpartum hemorrhage, as well as incidence of other clinical major morbidity events and delivery-related complications. Multivariable logistic regression was performed to study the relationship between in vitro fertilization and the odds of having been admitted to the intensive care unit due to hemorrhage. RESULTS: During the study period, there were nearly 192,000 deliveries, with 428 pregnant and peripartum women admitted to the intensive care unit. Of the 409 cases analyzed, 60 had conceived following in vitro fertilization and 349 had conceived without in vitro fertilization. The non–in vitro fertilization group was more likely to have multiple medical comorbidities, and the in vitro fertilization group was more likely to have multiple gestations. The groups also differed in etiology of intensive care unit admission; more women in the in vitro fertilization group were admitted due to a pregnancy-related complication. Intensive care unit admission for postpartum hemorrhage was more frequent in the in vitro fertilization group (60.0% vs 43.1%, P = .014), with a 2-fold increase in the incidence of hemorrhagic shock. Logistic regression analysis revealed a 2-fold increase in the odds that intensive care unit admission was due to hemorrhage in women undergoing in vitro fertilization, a finding that was not statistically significant when multiple gestation was added to the model. CONCLUSIONS: Among patients admitted to the intensive care unit, patients with different modes of conception had dissimilar etiologies for intensive care unit admission with intensive care unit admission due to hemorrhage greater in those with in vitro fertilization. Higher rates of multiple gestation pregnancies may explain this difference. Differences in pregnancies conceived via in vitro fertilization versus without in vitro fertilization may affect the obstetric intensive care unit case mix. Accepted for publication January 2, 2019. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Diana N. Romano, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl, Box 1010 New York, NY 10029. Address e-mail to diana.romano@mountsinai.org. © 2019 International Anesthesia Research Society

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Core Topics in Preoperative Anaesthetic Assessment and Management

No abstract available

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Minocycline Relieves Depressive-Like Behaviors in Rats With Bone Cancer Pain by Inhibiting Microglia Activation in Hippocampus

BACKGROUND: Pain and depression are highly prevalent symptoms in cancer patients. They tend to occur simultaneously and affect each other and share biological pathways and neurotransmitters. In this study, we investigated the roles of microglia in the hippocampus in the comorbidity of bone cancer pain and depressive-like behaviors in an animal model of bone cancer pain. METHODS: Bone cancer pain was induced by injection of Walker 256 mammary gland carcinoma cells into the tibia of rats. The effects of intracerebroventricular administration of microglia inhibitor minocycline were examined. RESULTS: Carcinoma intratibia injection caused comorbidity of mechanical allodynia and depressive-like behaviors in rats and activation of microglia in the hippocampus. Both mechanical allodynia and depressive-like behaviors were attenuated by minocycline. Enzyme-linked immunosorbent assay analysis showed that the enhanced expressions of M1 microglia marker (CD 86) and the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the hippocampus of cancer-bearing rats were decreased by minocycline. On the other hand, minocycline also increased the expressions of M2 microglia marker (MRC1) and anti-inflammatory cytokine interleukin-10. CONCLUSIONS: The results suggest that the activation of microglia in the hippocampus plays an important role in the development of pain and depressive-like behaviors in bone cancer condition. Accepted for publication January 3, 2019. The authors declare no conflicts of interest. Funding: Nature Science Foundation of Hunan Province (2018JJ3836 to S.Z.), National Nature Science Foundation of China (81300958 to S.Z.), and Nature Science Foundation of Hunan Province (S2016J504F2145 to Z.J.). Reprints will not be available from the authors. Address correspondence to Zongbin Song, MD, PhD, Department of Anesthesiology, Xiangya Hospital, Central S. University, Hunan, China. Address e-mail to songzb2001@163.com. © 2019 International Anesthesia Research Society

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Methylprednisolone Does Not Reduce Acute Postoperative Pain After Cardiac Surgery: Subanalysis of a Randomized Clinical Trial

BACKGROUND: Pain after cardiac surgery is largely treated with opioids, but their poor safety profile makes nonopioid medications attractive as part of multimodal pathways. Anti-inflammatory drugs reduce acute postoperative pain, but the role of steroids in reducing acute poststernotomy pain is unclear. We evaluated the association between the intraoperative administration of methylprednisolone and postoperative analgesia, defined as a composite of pain scores and opioid consumption, during the initial 24 hours after cardiac surgery. METHODS: We conducted a post hoc retrospective analysis of a large clinical trial in which adults having cardiac surgery were randomized 1:1 to receive 2 intraoperative doses of 250 mg IV methylprednisolone or placebo. Pain scores and opioid consumption were collected during the initial 24 hours after surgery. Methylprednisolone was considered to be associated with better pain control than placebo if proven noninferior (not worse) on both pain scores (defined a priori with delta of 1 point) and opioid consumption (delta of 20%) and superior to placebo in at least 1 of the 2 outcomes. This test was repeated in the opposite direction (testing whether placebo is better than methylprednisolone on postoperative pain management). RESULTS: Of 251 eligible patients, 127 received methylprednisolone and 124 received placebo. Methylprednisolone was noninferior to placebo on pain with difference in mean (CI) pain scores of −0.25 (−0.71 to 0.21); P

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Gupta and Gelb’s Essentials of Neuroanesthesia and Neurointensive Care

No abstract available

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Early Treatment With Metformin in a Mice Model of Complex Regional Pain Syndrome Reduces Pain and Edema

BACKGROUND: Metformin, an adenosine monophosphate (AMP)–activated protein kinase activator, as well as a common drug for type 2 diabetes, has previously been shown to decrease mechanical allodynia in mice with neuropathic pain. The objective of this study is to determine if treatment with metformin during the first 3 weeks after fracture would produce a long-term decrease in mechanical allodynia and improve a complex behavioral task (burrowing) in a mouse tibia fracture model with signs of complex regional pain syndrome. METHODS: Mice were allocated into distal tibia fracture or nonfracture groups (n = 12 per group). The fracture was stabilized with intramedullary pinning and external casting for 21 days. Animals were then randomized into 4 groups (n = 6 per group): (1) fracture, metformin treated, (2) fracture, saline treated, (3) nonfracture, metformin treated, and (4) nonfracture, saline treated. Mice received daily intraperitoneal injections of metformin 200 mg/kg or saline between days 14 and 21. After cast removal, von Frey force withdrawal (every 3 days) and burrowing (every 7 days) were tested between 25 and 56 days. Paw width was measured for 14 days after cast removal. AMP-activated protein kinase downregulation at 4 weeks after tibia fracture in the dorsal root ganglia was examined by immunohistochemistry for changes in the AMP-activated protein kinase pathway. RESULTS: Metformin injections elevated von Frey thresholds (reduced mechanical allodynia) in complex regional pain syndrome mice versus saline-treated fracture mice between days 25 and 56 (difference of mean area under the curve, 42.5 g·d; 95% CI of the difference, 21.0–63.9; P

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Suppression of Human Natural Killer Cells by Different Classes of Opioids

BACKGROUND: The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized. METHODS: After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester–labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction. RESULTS: Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5]enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells. CONCLUSIONS: Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not overserved after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with μ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by μ- and κ-receptor agonism and that suppression is similar with many clinically used opioids. Accepted for publication January 3, 2018. Funding: D.P.M. received funding from the Blaustein Pain Research Fund Grant and National Institutes of Health (NIH) Grant 5T32GM075774. N.M.H. receives funding from NIH Grant R01 HL124477. No copyrighted material from outside sources was used in preparation of this manuscript. This study has not been previously presented. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Dermot P. Maher, MD, MS, Johns Hopkins Blaustein Pain Treatment Center, Johns Hopkins University School of Medicine, 601 N Caroline St, Baltimore, MD 21205. Address e-mail to dmaher3@jhmi.edu. © 2019 International Anesthesia Research Society

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Ultrasound-Guided Erector Spinae Plane Block in Patients Undergoing Open Epigastric Hernia Repair: A Prospective Randomized Controlled Study

BACKGROUND: Hernia repair is associated with considerable postoperative pain. We studied the analgesic efficacy of bilateral ultrasound-guided erector spinae plane block in patients undergoing open midline epigastric hernia repair (T6–T9). METHODS: Sixty patients 18–65 years of age were randomly allocated into 2 groups. Patients in the erector spinae plane block group received bilateral ultrasound-guided erector spinae plane block at the level of T7 transverse process using 20 mL of bupivacaine 0.25% on each side, while the control group received bilateral sham erector spinae plane block using 1 mL of normal saline. All patients underwent general anesthesia for surgery. Pain severity (visual analog scale), consumption of intraoperative fentanyl, time to first request of rescue analgesia, and postoperative pethidine consumption were recorded over the first 24 hours postoperatively. RESULTS: At 2 hours postoperatively, the visual analog scale pain score was significantly lower in the erector spinae plane block group compared to the control group (estimated main effect of 2.53; P

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In Response

No abstract available

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Association of Preoperative Frailty With Intraoperative Hemodynamic Instability and Postoperative Mortality

BACKGROUND: Frailty, a state of decreased physiological reserve, is strongly associated with perioperative mortality in older adults. However, the mechanism by which frailty is associated with mortality is not yet understood. Autonomic dysfunction in the form of decreased intraoperative hemodynamic variability has been shown to be associated with increased mortality. We aimed to see whether frail patients have less hemodynamic variability under anesthesia and whether variability mediates the relationship between frailty and 30-day mortality. METHODS: We performed a single-center retrospective study of 1223 patients ≥65 years of age undergoing surgery between July 2008 and December 2012. We used markers of frailty: age >70, preoperative body mass index 2.0 mg/dL. We modeled the outcome of 30-day mortality with number of frailty conditions adjusting for gender, length of surgery, American Society of Anesthesiologists class, and need for transfusion. Intraoperative hemodynamic variability was defined as the count of episodes of absolute change >15% in fractional mean arterial pressure (MAP) between consecutive 5-minute intervals. We evaluated the role of intraoperative hemodynamic variability as a mediator (modifier) of the relationship between frailty and mortality, checking for 3 conditions: (1) frailty must affect episodes of absolute change >15% in fractional MAP; (2) episodes of absolute change >15% in fractional MAP must affect 30-day mortality; and (3) mediation effect is significant. We used the product method, in which the mediation effect was estimated as the product of the first 2 relationships. Then we applied the percentile bootstrap method to obtain the 95% CI for the estimate of mediation effect. RESULTS: Number of frailty conditions and episodes of absolute change >15% in fractional MAP were inversely proportional. Presence of ≥4 frailty conditions was associated with >40% reduction of the number of episodes of absolute change >15% in fractional MAP. Regarding mortality, episodes of absolute change >15% in fractional MAP were protective. The addition of absolute change >15% in fractional MAP in the mortality model resulted in a decrease in the frailty odds ratio from 10.6 to 9.1 (4+ conditions), suggesting that episodes of absolute change >15% in fractional MAP are indeed a mediator. The mediation effect was modest; 5 episodes of absolute change >15% in fractional MAP was 5.2%, 6.4%, 6.9%, and 9.0% for frailty conditions from 1 to 4+, respectively. CONCLUSIONS: Frailty is associated with less intraoperative blood pressure variation, and the relationship of frailty with 30-day mortality is partially mediated by episodes of absolute change >15% in fractional MAP. This suggests that autonomic dysregulation may be a modest part of the mechanism behind the association between frailty and perioperative mortality. Our finding is consistent with recent literature, suggesting that an intact autonomic nervous system confers lower perioperative mortality. Accepted for publication January 16, 2019. Funding: This work was supported by National Institute on Aging (K23 AG17-015; S.G.D.), Optimizing Postoperative Cognition in the Elderly, (American Federation of Aging Beeson Scholar Program; S.G.D.), and the American Federation for Aging Research, Medical Student Training in Aging Research (L.A.J.). Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Stacie G. Deiner, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, c/o S Deiner, Box 1010, 1 Gustave L. Levy Pl, New York, NY 10029. Address e-mail to stacie.deiner@mssm.edu. © 2019 International Anesthesia Research Society

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Use of Preoperative Salivary Cortisol AM/PM Ratio for Prediction of Early Postoperative Cognitive Dysfunction

No abstract available

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Long Intravascular Persistence of 20% Albumin in Postoperative Patients

BACKGROUND: Albumin may persist intravascularly for a shorter time in patients after major surgery than in healthy volunteers due to a surgery-induced breakdown (shedding) of the endothelial glycocalyx layer. METHODS: In this nonrandomized clinical trial, an IV infusion of 3 mL/kg of 20% albumin was given at a constant rate during 30 minutes to 15 patients on the first day after major open abdominal surgery (mean operating time 5.9 h) and to 15 conscious volunteers. Blood samples and urine were collected during 5 h and mass balance calculations used to estimate the half-lives of the administered albumin molecules and the induced plasma volume expansion, based on measurements of hemodilution and the plasma albumin concentration. RESULTS: At the end of the infusions, albumin had diluted the plasma volume by 13.3% ± 4.9% (mean ± SD) in the postoperative patients and by 14.2% ± 4.8% in the volunteers (mean difference −0.9, 95% CI, −4.7 to 2.9; 1-way ANOVA P = .61), which amounted to twice the infused volume. The intravascular half-life of the infused albumin molecules was 9.1 (5.7–11.2) h in the surgical patients and 6.0 (5.1–9.0) h in the volunteers (Mann-Whitney U test, P = .26; geometric mean difference 1.2, 95% CI, 0.8–2.0). The half-life of the plasma volume expansion was 10.3 (5.3–17.6; median and interquartile range) h in the surgical patients and 7.6 (3.5–9.0) h in the volunteers (P = .10; geometric mean difference 1.5, 95% CI, 0.8–2.8). All of these parameters correlated positively with the body mass index (correlation coefficients being 0.42–0.47) while age and sex did not affect the results. CONCLUSIONS: Twenty percent albumin caused a long-lasting plasma volume expansion of similar magnitude in postoperative patients and volunteers. Accepted for publication December 28, 2018. Funding: The study was supported by a grant from Mats Kleberg Foundation. The authors declare no conflicts of interest. ClinicalTrials.com, identifier NCT02556580. Reprints will not be available from the authors. Address correspondence to Robert G. Hahn, MD, PhD, Research Unit, Södertälje Hospital, 152 86 Södertälje, Sweden. Address e-mail to r.hahn@telia.com. © 2019 International Anesthesia Research Society

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Exercise-induced bilateral rectus femoris injury

No abstract available

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Minimal Clinically Important Difference of Shoulder Outcome Measures and Diagnoses: A Systematic Review

Objective Patient-reported outcome scales determine response to treatment. The minimal clinically important difference (MCID) of these scales is a measure of responsiveness: the smallest change in a score associated with a clinically important change to the patient. This study sought to summarize the literature on MCID for the most commonly reported shoulder outcome scales. Design A literature search of PubMed and EMBASE databases identified 193 citations, twenty-seven of which met the inclusion/exclusion criteria. Results For rotator cuff tears, a MCID range of 9-26.9 was reported for American Shoulder and Elbow Surgeons (ASES), 8 or 10 for Constant, and 282.6-588.7 for the Western Ontario Rotator Cuff Index (WORC). For patients who underwent arthroplasty, a MCID range of 6.3-20.9 was reported for ASES, 5.7-9.4 for Constant, and 14.1-20.6 for the Shoulder Pain and Disability Index (SPADI). For proximal humeral fractures, a MCID range of 5.4-11.6 was reported for Constant and 8.1-13.0 for Disability of the Arm, Shoulder, and Hand (DASH). Conclusion A wide range of MCID values was reported for each patient population and instrument. In the future, a uniform outcome instrument and MCID will be useful to measure clinically meaningful change across practices and the spectrum of shoulder diagnoses. Corresponding Author: Nitin B. Jain, MD, MSPH, Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, 2201 Children's Way, Suite 1318, Nashville, TN 37212, United States of America, Phone: (615) 936-8508; Fax: (615) 322-7454, Email: nitin.jain@vanderbilt.edu Source of Funding: Dr. Jain is/was supported by funding from NIAMS 1K23AR059199 and 1U34AR069201. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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Assessing the Accuracy of Ultrasound Guided Needle Placement in Sacroiliac Joint Injections

Objective The aim of this study was to assess the accuracy of ultrasound guided needle placement for sacroiliac joint injections. Design Institutional Review Board (IRB) approval was gained for a prospective cohort study of fifty patients (N=50). Study patients who were referred for sacroiliac joint injections for sacroiliac joint mediate pain, and met inclusion/exclusion criteria, were enrolled in the study. Each patient underwent needle placement with ultrasound guidance in the procedure suite. After the needle was placed with the ultrasound guidance, fluoroscopy was utilized to confirm correct placement via contrast injection confirming a sacroiliac joint arthrogram. The arthrogram was confirmed via the performing physician and radiologist. Results The placement of the needle with ultrasound guidance into the sacroiliac joint was confirmed successful in 96% (48/50) patients by fluoroscopic arthrogram. The two patients with unsuccessful arthrograms following initial placement of the needle with ultrasound were morbidly obese. There was intra-vascular uptake during the arthrogram of one patient who had a successful arthrogram. Conclusions Ultrasound-guided injection of the sacroiliac joint is successful and accurate upon confirmation of fluoroscopic arthrogram and should be utilized as an imaging modality for needle guidance. Correspondence: Arthur Jason De Luigi, DO, MHSA, 10825 N. 140th Way, Scottsdale, AZ 85259, 301793-2136, ajweege@yahoo.com Competing Interests-None for any author Funding or grants or equipment provided for the project from any source-None for any author Financial benefits to the authors-None to any author Details of any previous presentation of the research, manuscript, or abstract in any form: None Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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Caloric intake relative to total daily energy expenditure using a spinal cord injury-specific correction factor: an analysis by level of injury

Objectives Evaluate the influence of level of spinal cord injury (SCI) on caloric intake relative to total daily energy expenditure (TDEE) and body composition (BC), and develop a SCI-specific correction factor for the TDEE estimation. Design Individuals with paraplegia (PARA; n=28) and tetraplegia (TETRA; n=13) were analyzed. Daily caloric intake, basal metabolic rate (BMR), and TDEE were obtained using dietary recall, indirect calorimetry, and prediction equations, respectively. Caloric intake and TDEE were adjusted to bodyweight. BC was assessed using dual energy x-ray absorptiometry. Results Total caloric (PARA 1516.4±548.4, TETRA 1619.1±564.3 kcal/d), fat (PARA 58.6±27.4, TETRA 65.8±29.7 g), and protein (PARA 62.7±23.2, TETRA 71.5±30.9 g) intake were significantly higher in TETRA versus PARA (P

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“Medial Epicondyle Fracture leading to Snapping Elbow with Ulnar Neuropathy”

No abstract available

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Improved mobility, cognition and disease severity in Corticobasal Degeneration of an African-American male after 12 weeks of Adapted tango: a case study

Corticobasal degeneration (CBD) has no available treatment to slow disease progression and generally resists drug therapy. CBD has symptoms and decreased quality of life similar to Parkinson's disease. Adapted Tango, a successful rehabilitation for Parkinson's, may address CBD. A 63-year-old African-American male with CBD (alias: YD; CBD duration=2 years) was evaluated for motor, cognitive and psychosocial function before, immediately after, one-month after and six-months after 12 weeks of 20, bi-weekly 90-minute AT lessons. After intervention, disease-related motor symptoms improved and YD reported fewer problems in non-motor experiences of daily living, which include mood, cognition, pain, fatigue, etc. Motor symptoms remained above baseline at six-month posttest. YD's balance confidence improved post-intervention, but declined below baseline at six-month posttest. Quality of life was maintained despite worsened depression. YD improved or maintained executive function, and visuospatial function and attention at posttest and one-month posttest. At posttest, YD maintained mobility and improved on dynamic balance. At one-month posttest, most mobility measures had improved relative to baseline. Yet, YD showed executive function and overall motor decline six months post-intervention. AT may have temporarily slowed disease progression, and improved or maintained mobility and cognition. Gains were poorly maintained after six months. Further study is warranted. Corresponding Author: Hayley Silverstein, BA, Research Assistant, Emory University School of Medicine, Division of General Medicine and Geriatrics. E-mail: hsilve3@emory.edu, hayleyas96@gmail.com. There are no competing interests or financial benefits to disclose. The Department of Veterans Affairs R&D Service Career Development Award N0780W supported this work and ME Hackney. The Emory Center for Health in Aging supported the study. This study was also supported by National Center for Advancing Translational Sciences, National Institutes of Health Award UL1TR000454. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was previously presented as a poster at Emory University's Department of Medicine Day of Research in 2016. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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Understanding measures of association: A primer with examples from rehabilitation research

Understanding measures of associations, how they are calculated, what they mean, and how to compare them is an important part of understanding clinical and health research. The relative risk (RR) and odds ratio (OR) are the two most common used measures of association in medical research. The appropriate use of these statistics to estimate the association between treatment or risk factor and outcome in research studies depends on the methodology and design of the study. The aim of this article is to cover basics of odds ratio and relative risk as the most important measures for the association between an exposure and an outcome. We use a clinical scenario as an example of their uses and demonstrate their calculation. Corresponding author: Dinesh Kumbhare, MD, PhD, FRCPC, FAAPMR, 550 University Avenue, Suite 7-131, Toronto, Ontario M5G 2A2, dinesh.kumbhare@uhn.ca, Telephone: 416-597-3422 x 4612 Author Disclosures: All the authors report no conflict of interest for the completion of this manuscript. Also, no funding was received. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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Bone Biomarker Response to Walking under Different Thermal Conditions in Older Adults

Endurance exercise can cause a decrease in serum ionized calcium (iCa) and increases in parathyroid hormone (PTH) and c-terminal telopeptide of type I collagen (CTX), which may be due to Ca loss in sweat. PURPOSE To determine if exercise in a warm environment exaggerates the decrease in iCa and increases in PTH and CTX compared to a cool environment in older adults. METHODS Twelve women and men aged 61-78 y performed two identical 60-minute treadmill bouts at ~75% of maximal heart rate under warm and cool conditions. Serum iCa, PTH, and CTX were measured every 15 minutes starting 15 minutes before and continuing for 60 minutes after exercise. Sweat Ca loss was estimated from sweat volume and sweat Ca concentration. RESULTS Sweat volume was low and variable; there were no differences in sweat volume or Ca concentration between conditions. iCa decreased after 15 minutes of exercise and the change was similar in both conditions. Increases in PTH (Warm: 16.4, 95% CI: 6.2, 26.5 pg/mL; Cool: 17.3, 95% CI: 8.1, 26.4 pg/mL) and CTX (Warm: 0.08, 95% CI: 0.05, 0.11 ng/mL; Cool: 0.08, 95% CI: 0.01, 0.16 ng/mL) from before to immediately after exercise were statistically significant and similar between conditions. Adjusting for plasma volume shifts did not change the results. CONCLUSION The increases in PTH and CTX, despite the low sweat volume, suggest that dermal Ca loss is not a major factor in the decrease in iCa and increases in PTH and CTX observed during exercise in older adults. ADDRESS FOR CORRESPONDANCE: Sarah J. Wherry, PhD, Division of Geriatric Medicine, University of Colorado Anschutz Medical Campus, Mail Stop B179, 12631 E. 17th Avenue, Room 8111, Aurora, CO 80045, 720-848-6475 (O), 720-848-7382 (F). Sarah.wherry@ucdenver.edu Funding Sources: This study was supported in part by NIH awards UL1 TR002535, T32 AG000279, K23 AR070275 and P30 DK048520 and the VA Eastern Colorado Geriatric Research, Education, and Clinical Center (GRECC). Contents are the sole responsibility of the authors and may not represent official views of the NIH or VA. The authors have no conflicts of interest to declare. Accepted for Publication: 25 February 2019 © 2019 American College of Sports Medicine

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A Statistical Timetable for the Sub-2-Hour Marathon

Introduction Breaking the sub-2 hour marathon in an official event has attracted growing interest in recent times with commercial and international momentum building. Here it is shown that predicting how likely, and when, the sub-2 hour barrier will be broken are statistically coupled considerations. Methods Using a non-linear limiting exponential model and calculating prediction intervals, a statistical timetable for the sub-2 hour event is produced over a range of likelihoods. Results At the benchmark odds level (1 in 10, or 10% likely), the expected sub-2 hour arrival time is found to be May, 2032. By estimating the model for male and female world record progressions, I find that limiting marathon times for males and females (at 1 in 10) are 1hr 58min 5s and 2hr 5min 31s respectively. These times equate to a performance gap of 2.9% and 8.6% respectively. The male estimate has remarkable similarity (~ 7s) to Joyner's 1991 limiting human physiological estimate. Finally, I provide an estimate of the equivalent 'sub-2h' threshold for females, and argue that a threshold of 130min ('sub-130') could be an appropriate choice. Conclusion The study is the first to address all three related aspects of world record marathon performance (sub-2 hour, limits, gender equivalence) in a single, unified modeling framework and provides many avenues for further exploration and insight. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. The author declares no conflict of interest regarding the study. The results of the present study do not constitute endorsement by the ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Correspondence: Simon D. Angus Dept. of Economics, Monash University, Wellington Road, Clayton 3800 VIC Australia. E-mail: Simon.angus@monash.edu, Submitted for publication November 2018. Accepted for publication February 2019. © 2019 American College of Sports Medicine

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Physical Activity and Cerebral Small Vein Integrity in Older Adults

Identifying promoters of cerebral small vein integrity is important to counter vascular contributions to cognitive impairment and dementia. Purpose In this preliminary investigation, the effects of a randomized 24-month physical activity (PA) intervention on changes in cerebral small vein integrity were compared to those of a health education (HE) control. Methods Cerebral small vein integrity was measured in 24 older adults (n=8, PA; n=16, HE) using ultra-high field MRI before and at the end of the 24-month intervention. Deep medullary veins were defined as straight or tortuous; percent change in straight length, tortuous length, and tortuosity ratio were computed. Microbleed count and white matter hyperintensities were also rated. Results Accelerometry-based values of PA increased by 17.2% in the PA group but declined by 28.0% in the HE group. The PA group, but not the HE group, had a significant increase in straight vein length from baseline to 24-month follow-up (p=.02 and p=.21, respectively); the between group difference in percent change in straight length was significant (median (IQR) increase: 93.6%(112.9) for PA, 28.4%(90.6) for HE; p=.07). Between group differences in other markers were non-significant. Conclusion Increasing PA in late-life may promote cerebral small vein integrity. This should be confirmed in larger studies. Clinicaltrials.gov Identifier: NCT01072500. Corresponding author: C. Elizabeth Shaaban PhD, MPH; Department of Epidemiology, Graduate School of Public Health, 130 DeSoto Street, 5121B Public Health Building, Pittsburgh, PA 15261; Phone: (412)-383-2623; E-mail: Beth.Shaaban@pitt.edu This work was supported by the National Institute on Aging [Grant Numbers U01 AG022376, F31 AG054084 (CES), R01 AG044474 (CR), and P30 AG024827 and the National Institute of General Medical Sciences [Grant Number T32 GM081760]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Authors declare that they have no conflicts of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 5 February 2019 © 2019 American College of Sports Medicine

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Neuromuscular Fatigue and Metabolism during High-Intensity Intermittent Exercise

Purpose To examine the degree of neuromuscular fatigue development along with changes in muscle metabolism during two work-matched high-intensity intermittent exercise protocols in trained individuals. Methods In a randomized, counter-balanced, crossover design, eleven endurance-trained men performed high-intensity intermittent cycle exercise protocols matched for total work and including either multiple short- (18×5 s; SS) or long-duration (6×20 s; LS) sprints. Neuromuscular fatigue was determined by pre- to post-exercise changes in maximal voluntary contraction force (MVC), voluntary activation level and contractile properties of the quadriceps muscle. Metabolites and pH were measured in vastus lateralis muscle biopsies taken before and after the first and last sprint of each exercise protocol. Results Peak power output (11±2 vs. 16±8%, P

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Development and Testing of an Integrated Score for Physical Behaviors

Purpose Interest in a variety of physical behaviors (e.g., exercise, sitting time, sleep) in relation to health outcomes creates a need for new statistical approaches to analyze the joint effects of these distinct but inter-related physical behaviors. We developed and tested an integrated physical behavior score (PBS). Methods NIH-AARP Diet and Health Study participants (N=163,016) completed a questionnaire (2004-2006) asking about time spent in five exercise and non-exercise physical activities, two sedentary behaviors (television and non-television), and sleep. In half of the sample, we used shape constrained additive regression to model the relationship between each behavior and survival. Maximum logit scores from each of the eight behavior-survival functions were summed to produce a PBS that was proportionally rescaled to range from 0-100. We examined predictive validity of the PBS in the other half-sample using Cox Proportional Hazards models after adjustment for covariates for all-cause and cause-specific mortality. Results In the testing sample, over an average of 6.6y of follow-up, 8,732 deaths occurred. We found a strong graded decline in risk of all-cause mortality across quintiles of PBS (Q5 vs Q1 hazard ratio [95%CI] = 0.53 [0.49, 0.57]). Risk estimates for the PBS were higher than any of the components in isolation. Results were similar but stronger for cardiovascular disease (Q5 vs Q1 = 0.42 [0.39, 0.48]) and other mortality (Q5 vs Q1 = 0.42 [0.36, 0.48]). The relationship between PBS and mortality was observed in stratified analyses by median age, sex, BMI and health status. Conclusions We developed a novel statistical method generated a composite physical behavior that is predictive of mortality outcomes. Future research is needed to test this approach in an independent sample. Corresponding author: Sarah Kozey Keadle, 1 Grand Ave, San Luis Obispo, CA 93407, 805-756-1785 (phone), 805-756-7273 (fax), skeadle@calpoly.edu (email) This work was supported by National Cancer Institute (U01-CA057030 to R.J.C), and the Intramural Research Program at the National Institutes of Health (C.E.M). The funders had no role in the study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. The results of the present study do not constitute an endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation and the authors declare no conflicts of interest. Accepted for Publication: 15 February 2019 © 2019 American College of Sports Medicine

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Dynamics of Locomotor Fatigue during Supra-critical Power Exercise

PURPOSE We aimed to measure 1) the dynamics of locomotor fatigue during constant supra-critical power cycling, and 2) the magnitude of any reserve in locomotor power at intolerance to constant and ramp-incremental cycling in recreationally-active volunteers. METHODS Fifteen participants (7 women and 8 men, 22±3 yr, 3.34±0.67 L.min-1 V[Combining Dot Above]O2peak) completed ramp-incremental and very-heavy constant power (205±46 W) exercise to the limit of tolerance. Immediately following intolerance, the ergometer was switched into the isokinetic mode and participants completed a short (~5 s) maximal isokinetic effort at 70 rpm. The time course of locomotor fatigue during constant supra-critical power exercise was characterized with these short maximal isokinetic sprints at 30, 60, 120, 180 s and at the limit of tolerance. Each bout was terminated following the isokinetic sprint. RESULTS Constant power exercise duration was 312±37 s. Isokinetic power production at 30, 60, 120, 180 s and the limit of tolerance (at 312±37 s) was 609±165, 503±195, 443±157, 449±133, and 337±94 W, respectively. Of the total decline in isokinetic power, ~36% occurred within the first minute of exercise and significant (p

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VO2peak, Body Composition, and Neck Strength of Elite Motor Racing Drivers

PURPOSE Automobile racing is widely known to be physically demanding, however there is no published information comparing the physical fitness variables of elite level race car drivers across various competitive championships. METHODS We documented the body composition, peak oxygen consumption (VO2peak), and isometric neck strength in a sample of elite race car drivers currently competing in Formula 1, IndyCar, NASCAR, and International Motor Sports Association sports car racing (IMSA GTD), in order to determine current human performance benchmarks and establish goals for drivers wishing to compete in these series. RESULTS Percent body fat was significantly (P

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Objectively Measured Physical Activity Is Associated with Vertebral Size in Midlife

Background Vertebral fractures reduce the quality of life and are a major burden to the health care sector. Small vertebral size is associated with increased vertebral fracture risk. Previous studies have investigated the relationship between physical activity and vertebral size, but their results seem somewhat contradictory. In this population-based birth cohort study, we aimed to evaluate the relationship between objectively measured physical activity (PA) and vertebral size. Methods The study population consisted of 1202 cohort participants who underwent PA and vertebral size measurements at the age of 46–48. Moderate-to-vigorous physical activity (MVPA, ≥ 3.5 METs) was measured by a wrist-worn accelerometer (Polar Active, Polar Electro, Finland) for 14 days. The vertebral axial cross-sectional area (CSA) of the L4 vertebra was measured and calculated from lumbar magnetic resonance imaging (MRI) scans at 46–48 years. We analyzed the association between the daily amount of MVPA (min/day) and vertebral CSA using multivariable linear regression analysis. Results The daily amount of MVPA was significantly and positively associated with CSA in both sexes. For every minute/day of MVPA, men had 0.71 mm2 (95% CI 0.36–1.06) and women 0.90 mm2 (95% CI 0.58–1.21) larger CSA. Conclusion PA of at least moderate intensity is positively associated with vertebral size and may thus prevent future vertebral fractures. Address for Corresponding author: Mahsa Modarress-Sadeghi, PO Box 21, 90029 OYS, Clinic of Physiatry, Oulu University Hospital, Oulu, Finland. +358408480811. mahsa.modarress@oulu.fi The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation, and statement that results of the present study do not constitute endorsement by ACSM. NFBC1966 received financial support through University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, and ERDF European Regional Development Fund Grant no. 539/2010 A31592. The study has been financially supported by the Ministry of Education and Culture in Finland, grant numbers OKM/86/626/2014, OKM/43/626/2015 and OKM/17/626/2016, and Infotech Oulu, Finland. The authors declare that they have no conflict of interest. Accepted for publication: 20 February 2019. © 2019 American College of Sports Medicine

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Effects of Static Stretching and Foam Rolling on Ankle Dorsiflexion Range of Motion

Introduction Static stretching (SS) has been used for inducing acute and long-term increases in range of motion (ROM). Foam rolling (FR) has recently gained popularity for acutely increasing ROM. However, the long-term effects of FR on ROM have not been thoroughly evaluated. Therefore, the purpose of this study was to investigate the acute and long-term changes in dorsiflexion range of motion (ROM) as a result of six weeks of FR, SS, and FR followed by SS (FR + SS). Methods Participants (n = 44) were randomly assigned to FR, SS, and FR + SS groups. FR group foam rolled the triceps surae. SS group performed a wall stretch for both legs. FR + SS performed FR immediately followed by SS. All groups completed 12 training sessions in six weeks. Dorsiflexion ROM was assessed before and after the first training session, before the second session of week three, before and after the last session in week six, and at week seven. Results There was a 4.0% acute increase in ROM at week six (p = 0.004) for all three groups. ROM increased 8.4% from week three to week seven for all three groups (p

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Lower Extremity Stiffness Predicts Ground Reaction Force Loading Rate in Heel-Strike Runners

Purpose High vertical ground reaction force (vGRF) loading rates are thought to contribute to lower extremity injuries in runners. Given that elevated lower extremity stiffness has been reported to be associated with increased GRFs, the purpose of the current study was to determine if overall lower extremity stiffness, or individual joint angular excursions and/or torsional stiffness are predictive of the average vGRF loading rate during running. Methods Forty heel-strike runners (20 males and 20 females) ran overground at a speed of 3.4 m·s-1. Average vGRF loading rate, lower extremity stiffness, as well as hip, knee and ankle joint excursions and torsional stiffness from initial contact to the first peak of the vGRF were quantified. Step-wise multiple linear regression was performed to determine the best predictor(s) of average vGRF loading rate. Results Lower extremity stiffness was found to the best predictor of average vGRF loading rate (R2=0.68, p

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The Impact of Cycling Cadence on Respiratory and Hemodynamic Responses to Exercise

Purpose The physiological consequences of freely chosen cadence (FCC) during cycling remains poorly understood. We sought to determine the effect of cadence on the respiratory and hemodynamic response to cycling exercise. Methods Eleven cyclists (10M:1F; age=27±6yr; V[Combining Dot Above]O2max=60.8±3.7ml·kg-1·min-1) completed four, 6-min constant-load cycling trials at 10% below their previously determined gas exchange threshold (i.e., 63±5% peak power) while pedaling at 60, 90, and 120rpm, and a FCC (94.3±6.9rpm), in randomized order. Standard cardiorespiratory parameters were measured and an esophageal electrode balloon catheter was used to assess electromyography of the diaphragm (EMGdi) and the work of breathing (Wb). Leg blood flow index (BFI) was determined on four muscles using near-infrared spectroscopy (NIRS) with indocyanine green dye injections. Results Oxygen uptake (V[Combining Dot Above]O2) increased as a function of increasing cadence (all pairwise comparisons, p0.05). Conclusions High cadence cycling at submaximal exercise intensities is metabolically inefficient and increases EMGdi, Wb, and leg muscle blood flow relative to slower cadences. Corresponding Author: Jordan A. Guenette, Ph.D. UBC Centre for Heart Lung Innovation Room 166 – 1081 Burrard Street Vancouver, British Columbia, Canada, V6Z-1Y6 Email: jordan.guenette@hli.ubc.ca No conflict of interest, financial or otherwise, are declared by the authors. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. This work was funded by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada (NSERC). RAM was supported by a postgraduate doctoral scholarship from the NSERC. AHR was supported by a NSERC Alexander Graham Bell Canada Graduate Scholarship. RAM and AHR were also supported by four-year doctoral fellowships from the University of British Columbia. JAG was supported by a Canadian Institutes of Health Research Clinical Rehabilitation New Investigator Award and a Scholar Award from the Michael Smith Foundation for Health Research. Submitted for publication November 2018. Accepted for publication February 2019. © 2019 American College of Sports Medicine

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The Reconstitution of W′ Depends on Both Work and Recovery Characteristics

Purpose This study aimed to investigate the effects of different work and recovery characteristics on the W' reconstitution and to test the predictive capabilities of the W'BAL model. Methods Eleven male participants (22±3 yr, 55±4 mL.min-1.kg-1) completed three to five constant work rate tests to determine CP and W'. Subsequently, subjects performed twelve experimental trials, each comprising two exhaustive constant work rate bouts (i.e., WB1 and WB2), interspersed by an active recovery interval. In each trial, work bout characteristics (P4 or P8, i.e., the work rate predicted to result in exhaustion in 4 and 8 min, respectively), recovery work rate (33% CP or 66% CP) and recovery duration (2, 4 or 6 min) were varied. Actual (W'ACT) and model-predicted (W'PRED) reconstitution of W' were calculated. Results After 2, 4 and 6 min recovery, W'ACT averaged 46±2.7%, 51.2±3.3% and 59.4±4.1%, respectively (P=0.003). W'ACT was 9.4% higher after recovery at 33% CP than at 66% CP (56.9±3.9% vs. 47.5±3.2%) (P=0.019). P4 exercise yielded a 11.3 % higher W'ACT than P8 exercise (57.8±3.9% vs. 46.5±2.7%) (P=0.001). W'ACT was higher than W'PRED in the conditions P4-2min (+29.7%), P4-4min (+18.4%) and P8-2min (+18%) (P

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Effect of the Wii Sports Resort on the improvement in attention, processing speed and working memory in moderate stroke

Stroke is the most common neurological disease in the world. After the stroke, some people suffer a cognitive disability. Commercial videogames have been used after stroke for physical rehabilitation; however,...

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Will behavioral treatments for cognitive impairment in multiple sclerosis become standards-of-care?

Publication date: Available online 28 February 2019

Source: International Journal of Psychophysiology

Author(s): Brian M. Sandroff, John DeLuca

Abstract

Cognitive impairment is common and debilitating in persons with multiple sclerosis (MS), and further is poorly-managed by pharmacotherapy. Cognitive rehabilitation and exercise training have been identified as promising behavioral approaches for managing MS-related cognitive impairment based on systematic reviews and meta-analyses. However, each body of literature is associated with similar sets of methodological shortcomings, as has been identified by periodic systematic reviews and meta-analyses. Thus, there is little generalizability or transportability research supporting either behavioral approach for managing cognitive dysfunction in this population under real-world conditions (i.e., as a standard-of-care). To that end, this paper aims to catalyze the advancement of cognitive rehabilitation and exercise training research in MS, respectively, towards the successful implementation of generalizability/transportability trials. This first involves critical examinations of the respective cognitive rehabilitation and exercise training literatures in MS from a chronological perspective, with particular emphasis on how the fields have each evolved in response to systematic reviews and meta-analyses. Accordingly, the current paper then provides a roadmap for harmonizing research in those areas to systematically and efficiently inform the development of generalizability/transportability trials for behavioral approaches to manage MS-related cognitive dysfunction. This involves the recognition of overlapping facilitators and impediments for progress in each field, including considerations for the implementation of neuroimaging. Ultimately, the provision of such a framework aims to shorten the timeline for research to influence clinical practice and improve the lives of cognitively-impaired persons with MS.

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Handover of anesthesia care is associated with an increased risk of delirium in elderly after major noncardiac surgery: results of a secondary analysis

Abstract

In patients undergoing major surgery, complete handover of intraoperative anesthesia care is associated with adverse postoperative outcomes including high mortality and more major complications. The purpose of this study was to explore the association between the intraoperative complete handover between anesthesiologists and the occurrence of postoperative delirium. This was a secondary analysis of the database of a previously published clinical trial. Seven hundred patients aged 65 years or older, who were admitted to the intensive care unit after noncardiac surgery, were included. Delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit twice daily during the first 7 postoperative days. Other postoperative outcomes were also monitored. The association between the intraoperative complete handover of anesthesia care and the development of postoperative delirium was analyzed with a logistic regression model. Of the 700 enrolled patients, 111 (15.9%) developed postoperative delirium within 7 days. After correction for confounding factors, intraoperative complete handover between anesthesiologists was associated with an increased risk of postoperative delirium (OR 1.787, 95% CI 1.012–3.155, P = 0.046). Patients with intraoperative complete handover also had higher incidence of non-delirium complications (P = 0.003) and stayed longer in hospital after surgery (P = 0.002). For elderly patients admitted to the intensive care unit after noncardiac surgery, intraoperative complete handover of anesthesia care was associated with an increased risk of postoperative delirium. Chinese Clinical Trial Registry (http://www.chictr.org.cn): ChiCTR-TRC-10000802.

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Botulinum neurotoxin serotype D - a potential treatment alternative for BoNT/A and B non-responding patients

Publication date: Available online 28 February 2019

Source: Clinical Neurophysiology

Author(s): Anna Kutschenko, Jasmin Weisemann, Katja Kollewe, Thiemo Fiedler, Sascha Alvermann, Sebastian Böselt, Claus Escher, Niklas Garde, Stefan Gingele, Stefan-Benno Kaehler, Ralf Karatschai, Tillmann H.C. Krüger, Stefan Sikorra, Pawel Tacik, Florian Wegner, Johannes Wollmann, Hans Bigalke, Kai Wohlfarth, Andreas Rummel

Abstract

Objectives

Botulinum neurotoxin serotypes A and B (BoNT/A & B) are highly effective medicines to treat hyperactive cholinergic neurons. Due to neutralizing antibody formation, some patients may become non-responders. In these cases, the serotypes BoNT/C-G might become treatment alternatives. BoNT/D is genetically least related to BoNT/A & B and thereby circumventing neutralisation in A/B non-responders. We produced BoNT/D and compared its pharmacology with BoNT/A ex vivo in mice tissue and in vivo in human volunteers.

Methods

BoNT/D was expressed recombinantly in E. coli, isolated by chromatography and its ex vivo potency was determined at mouse phrenic nerve hemidiaphragm preparations. Different doses of BoNT/D or incobotulinumtoxinA were injected into the extensor digitorum brevis (EDB) muscles (n=30) of human volunteers. Their compound muscle action potentials were measured 11 times by electroneurography within 220 days.

Results

Despite a 3.7-fold lower ex vivo potency in mice, a 110-fold higher dosage of BoNT/D achieved the same clinical effect as incobotulinumtoxinA while showing a 50% shortened duration of action.

Conclusions

BoNT/D blocks dose-dependently acetylcholine release in human motoneurons upon intramuscular administration, but its potency and duration of action is inferior to approved BoNT/A based drugs.

Significance

BoNT/D constitutes a potential treatment alternative for BoNT/A & B non-responders.

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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Abstract

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10^− 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10^− 4, replication P = 6.7 × 10^− 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.

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