A framework for relating natural movement to length and quality of life in human and non-human animals.

Natural movement is clearly related to health, however, it is also highly complex and difficult to measure. Most attempts to measure it focus on functional movements in humans, and while this a valid and popular approach, assays focussed on particular movements cannot capture the range of natural movement that occurs outside them. It is also difficult to use current techniques to compare movement across animal species. Interspecies comparison may be useful for identifying conserved biomechanical and/ or computational principles of movement that could inform human and veterinary medicine, plus several other fields of research. It is therefore important that research develops a system for quantifying movement in freely moving animals in natural environments and relating it to length and quality of life (LQOL). The present text proposes a novel theoretical framework for doing so, based on screening movement ability (MA). MA is calculated from three major variables - Movement Quality, Movement Complexity, and Movement Quantity. These may represent the most important components of movement as it relates to LQOL, and offer insight into how and why differences in the relationship between movement and LQOL occur. A constrained version of the framework is validated in Drosophila, which suggests that MA may indeed represent a useful new paradigm for understanding the relationship between movement and length and quality of life.

Electrophysiological validation of monosynaptic connectivity between premotor interneurons and the aCC motoneuron in the Drosophila larval CNS.

The Drosophila connectome project aims to map the synaptic connectivity of entire larval and adult fly neural networks, which is essential for understanding nervous system development and function. So far, the project has produced an impressive amount of electron microscopy data that has facilitated reconstructions of specific synapses, including many in the larval locomotor circuit. While this breakthrough represents a technical tour-de-force, the data remain under-utilised, partly due to a lack of functional validation of reconstructions. Attempts to validate connectivity posited by the connectome project, have mostly relied on behavioural assays and/or GRASP or GCaMP imaging. While these techniques are useful, they have limited spatial or temporal resolution. Electrophysiological assays of synaptic connectivity overcome these limitations. Here, we combine patch clamp recordings with optogenetic stimulation in male and female larvae, to test synaptic connectivity proposed by connectome reconstructions. Specifically, we use multiple driver lines to confirm that several connections between premotor interneurons and the anterior corner cell (aCC) motoneuron are, as the connectome project suggests, monosynaptic. In contrast, our results also show that conclusions based on GRASP imaging may provide false positive results regarding connectivity between cells. We also present a novel imaging tool, based on the same technology as our electrophysiology, as a favourable alternative to GRASP. Finally, of eight Gal4 lines tested, five are reliably expressed in the premotors they are targeted to. Thus, our work highlights the need to confirm functional synaptic connectivity, driver line specificity, and use of appropriate genetic tools to support connectome projects.SIGNIFICANCE STATEMENTThe Drosophila connectome project aims to provide a complete description of connectivity between neurons in an organism that presents experimental advantages over other models. It has reconstructed over 80 percent of the fly larva's synaptic connections by manual identification of anatomical landmarks present in serial section transmission electron microscopy (ssTEM) volumes of the larval CNS. We use a highly reliable electrophysiological approach to verify these connections, so provide useful insight into the accuracy of work based on ssTEM. We also present a novel imaging tool for validating excitatory monosynaptic connections between cells, and show that several genetic driver lines designed to target neurons of the larval connectome exhibit non-specific and/or unreliable expression.

Energetics and Biomechanics of Uphill, Downhill and Level Running in Highly-Cushioned Carbon Fiber Midsole Plated Shoes.

Road-racing shoes recently experienced major changes. In the recent past, lightweight, thin midsole shoes were thought to help runners maximize their performance. But, in 2017, Nike released the Vaporfly shoe which transformed the thinking about racing shoe design. Incorporating a curved carbon fiber plate embedded in a thick, compliant and resilient midsole resulted in a reduced metabolic cost across a range of running speeds. We hypothesized the new style of shoes would be less effective uphill than downhill due to the larger ground reaction forces and hence greater elastic energy storage in the shoe during downhill running. Eighteen runners completed two days of testing, each comprising two trials of two shoe models (Saucony Endorphin Pro (EP) and Type A) and three grade conditions (uphill, level and downhill), i.e. 12 trials per day. Oxygen uptake, ground reaction forces, and lower-body kinematics were captured during each condition. Comparisons of the percent metabolic benefit were made between shoes for each grade. Stride rate, ground time, peak vertical force, and flight time were regressed with the percent metabolic benefit of the EP over the Type A shoe across grades. Metabolic benefits of the Endorphin Pro were similar across the three grade conditions (p = 0.778). No significant correlations were observed between how much benefit one runner got over another specific to grade. The new style of road-racing shoes effectively decreases metabolic cost equally across grades. Differences in running mechanics between runners did not explain greater individual metabolic benefits between shoe conditions during uphill or downhill running.

Internal and External Oblique Muscle Asymmetry in Sprint Hurdlers and Sprinters: A Cross-Sectional Study.

The abdominal muscles are vital in providing core stability for functional movements during most activities. There is a correlation between side asymmetry of these muscles and dysfunction. Thus, the purpose of this study was to evaluate and compare trunk muscle morphology and trunk rotational strength between sprint hurdlers, an asymmetrical sport, and sprinters, a symmetrical sport. Twenty-one trained collegiate sprint hurdlers and sprinters were recruited for the study (Hurdlers: 4M, 7F; Sprinters: 8M, 2F), average age (years) hurdlers: 20 ± 1.2; sprinters: 20.4 ± 1.9, height (cm) hurdlers: 172.6 ± 10.2; sprinters: 181.7 ± 4.5, and weight (kg) hurdlers: 67.6 ± 12.0; sprinters: 73.9 ± 5.6. Using real-time ultrasound, panoramic images of the internal oblique (IO) and external oblique (EO) were obtained at rest and contracted (flexion and rotation) in a seated position for both right and left sides of the trunk. While wearing a specially crafted shoulder harness, participants performed three maximal voluntary trunk rotational contractions (MVC). The three attempts were then averaged to obtain an overall MVC score for trunk rotation strength. Average MVC trunk rotational strength to the right was greater among all participants, p < 0.001. The IO showed greater and significant thickness changes from resting to contracted state than the EO, this was observed in all participants. The IO side asymmetry was significantly different between groups p < 0.01. Hurdlers, involved in a unilaterally demanding sport, exhibited the expected asymmetry in muscle morphology and in trunk rotational strength. Interestingly, sprinters, although involved in a seemingly symmetrical sport, also exhibited asymmetrical trunk morphology and trunk rotational strength.

Acute effect of whole-body vibration on electromechanical delay and vertical jump performance.

OBJECTIVES: To determine if a change in vertical jump performance from acute whole-body vibration can be explained by indirectly assessing spindle sensitivity from electromechanical delay. METHODS: Using a counter-balanced design, twenty college-aged participants performed whole-body vibration (WBV) and control treatments. WBV included 10 intervals (26 Hz, 3.6 mm) of 60 s in a half-squat followed by 60 s of rest. After 5 intervals, participants rested for 6-minutes before commencing the final 5 intervals. For the control, the exact same protocol of whole-body vibration was performed but without vibration. Electromechanical delay and vertical jump were assessed at baseline, during the 6-minute rest period and immediately after whole-body vibration and control. RESULTS: There were no differences between treatments, for both electromechanical delay (F(2, 38)=1.385, p=0.263) and vertical jump (F(2, 38)=0.040, p<0.96). Whole-body vibration had no effect on vertical jump performance. CONCLUSION: The current whole-body vibration protocol is not effective for acute vertical jump or electromechanical delay enhancement. Also, since there was no effect on electromechanical delay, this suggests that whole-body vibration did not enhance muscle spindle sensitivity for the parameters examined.

Differences in Femoral Artery Occlusion Pressure between Sexes and Dominant and Non-Dominant Legs.

Background and Objectives: Blood flow restriction during low-load exercise stimulates similar muscle adaptations to those normally observed with higher loads. Differences in the arterial occlusion pressure (AOP) between limbs and between sexes are unclear. We compared the AOP of the superficial femoral artery in the dominant and non-dominant legs, and the relationship between blood flow and occlusion pressure in 35 (16 males, 19 females) young adults. Materials and Methods: Using ultrasound, we measured the AOP of the superficial femoral artery in both legs. Blood flow at occlusion pressures ranging from 0% to 100% of the AOP was measured in the dominant leg. Results: There was a significant difference in the AOP between males and females in the dominant (230 ± 41 vs. 191 ± 27 mmHg; p = 0.002) and non-dominant (209 ± 37 vs. 178 ± 21 mmHg; p = 0.004) legs, and between the dominant and non-dominant legs in males (230 ± 41 vs. 209 ± 37 mmHg; p = 0.009) but not females (191 ± 27 vs. 178 ± 21 mmHg; p = 0.053), respectively. Leg circumference was the most influential independent predictor of the AOP. There was a linear relationship between blood flow (expressed as a percentage of unoccluded blood flow) and occlusion pressure (expressed as a percentage of AOP). Conclusions: Arterial occlusion pressure is not always greater in the dominant leg or the larger leg. Practitioners should measure AOP in both limbs to determine if occlusion pressures used during exercise should be limb specific. Occlusion pressures used during blood flow restriction exercise should be chosen carefully.

The Achilles Tendon Response to a Bout of Running is not affected by Triceps Surae Stretch Training in Runners.

An acute bout of distance running decreases Achilles tendon CSA. The purpose of this study was to examine if three-week stretch training of the Achilles tendon alters the Achilles tendon thinning response to running. Thirty-three recreational runners were divided into a control group (n = 17) and an intervention group (n = 16). The intervention included a three-week soleus stretch (knee flexed) and gastrocnemius stretch (knee extended). Three gastrocnemius stretches and three soleus stretches were performed each day, six days per week. Stretches were held for 30 s per repetition for a total duration of 180 s per leg per day. Achilles tendon CSA and range of motion measures were completed pre and post-run before and after the three-week stretching intervention. The runs prior to and following the three-week stretch training intervention both resulted in a 6% decrease in Achilles tendon CSA (p < 0.0001). There was no interaction across time between control and intervention groups in CSA (p = 0.446). Only the intervention group experienced a significant increase in dorsiflexion range of motion following the stretch training (p = 0.009). We therefore conclude that even when an increased dorsiflexion range of motion occurs, three weeks of triceps surae stretching does not alter the response of the Achilles tendon CSA.

Running economy, mechanics, and marathon racing shoes.

The choice of marathon racing shoes can greatly affect performance. The purpose of this study is to metabolically and mechanically compare the consumer version of the Nike Vaporfly 4% shoe to two other popular marathon shoes, and determine differences in running economy. Nineteen subjects performed two 5-minute trials at 4.44m/s wearing the Adidas Adios Boost (AB), Nike Zoom Streak (ZS), and Nike Vaporfly 4% (VP) in random order. Oxygen uptake was recorded during minutes 3-5 and averaged across both shoe trials. On a second day, subjects wore reflective markers, and performed a 3-minute trial in each shoe. Motion and force data were collected over the final 30 seconds of each trial. VP oxygen uptake was 2.8% and 1.9% lower than the AB and ZS. Stride length, plantar flexion velocity, and center of mass vertical oscillation were significantly different in the VP. The percent benefit of the VP over AB shoe was predicted by subject ground time. These results indicate that use of the VP shoe results in improved running economy, partially due to differences in running mechanics. Subject variation in running economy improvement is only partially explained by variation in ground time.

Outcomes of Closed Versus Open Defects After Local Excision of Rectal Neoplasms: A Multi-institutional Matched Analysis.

BACKGROUND: The management of the rectal wall defect after local excision of rectal neoplasms remains controversial, and the existing data are equivocal. OBJECTIVE: This study aimed to determine the effect of open versus closed defects on postoperative outcomes after local excision of rectal neoplasms. DESIGN: Data from 3 institutions were analyzed. Propensity score matching was performed in one-to-one fashion to create a balanced cohort comparing open and closed defects. SETTINGS: This study was conducted at high-volume specialist referral hospitals. PATIENTS: Adult patients undergoing local excision via transanal endoscopic surgery from 2004 to 2016 were included. Patients were assigned to open- and closed-defect groups, and further stratified by full- or partial-thickness excision. INTERVENTION: Closure of the rectal wall defect was performed at the surgeon's discretion. MAIN OUTCOME MEASURES: The primary outcome measured was the incidence of 30-day complications. RESULTS: A total of 991 patients were eligible (593 full-thickness excision with 114 open and 479 closed, and 398 partial-thickness excision with 263 open and 135 closed). After matching, balanced cohorts consisting of 220 patients with full-thickness excision and 210 patients with partial-thickness excision were created. Operative time was similar for open and closed defects for both full-and partial-thickness excision. The incidence of 30-day complications was similar for open and closed defects after full- (15% vs. 12%, p = 0.432) and partial-thickness excision (7% vs 5%, p = 0.552). The total number of complications was also similar after full- or partial-thickness excision. Patients undergoing full-thickness excision with open defects had a higher incidence of clinically significant bleeding complications (9% vs 3%, p = 0.045). LIMITATIONS: Data were obtained from 3 institutions with different equipment and perioperative management over a long time period. CONCLUSIONS: There was no difference in overall complications between open and closed defects for patients undergoing local excision of rectal neoplasms, but there may be more bleeding complications in open defects after full-thickness excision. A selective approach to defect closure may be appropriate. See Video Abstract at http://links.lww.com/DCR/A470.

Reporting of Randomized Controlled Trials With Statistically Nonsignificant Primary Outcomes Published in High-impact Surgical Journals.

OBJECTIVE: To determine the nature and frequency of distorted presentation or "spin" (ie, specific reporting strategies which highlight that the experimental treatment is beneficial, despite a statistically nonsignificant difference for the primary outcome, or distract the reader from statistically nonsignificant results) in published reports of randomized controlled trials (RCTs) with statistically nonsignificant results for primary outcomes in surgical journals. BACKGROUND: Multiple reports have suggested that interpretation of RCT results in medical journals can be distorted by authors of published reports. METHODS: Using a defined search strategy, RCTs with clearly nonsignificant results for the primary outcome (P > 0.05) form 10 high-impact factor surgical journals (Annals of Surgery, Journal of Neurology, Neurosurgery and Psychiatry, Journal of Heart and Lung Transplantation, American Journal of Transplantation, British Journal of Surgery, Journal of Bone and Joint Surgery, Journal of the American College of Surgeons, Endoscopy, Archives of Surgery, and Liver transplantation), published between July 2013 to July 2015, were identified. Two reviewers independently appraised each selected article using a validated, standardized data abstraction form. RESULTS: In all, 110 eligible RCTs with nonsignificant primary outcomes were appraised. The title was reported with spin in 8 (7%) articles. Forty-four (40%) included abstracts and 39 (35%) main texts were classified as having spin in at least 1 section. The level of spin was high in 16 (14%) abstract and 19 (19%) main-text "Conclusions" sections. Twenty-five articles (23%) recommended the intervention of interest despite a nonsignificant primary outcome. There was no relationship between trial funding source, use of statistician and article section, and the presence of spin. CONCLUSIONS: In RCTs with statistically nonsignificant primary outcomes published in surgical journals, the reporting and interpretation of findings was frequently inconsistent with the results.

Quality of Local Excision for Rectal Neoplasms Using Transanal Endoscopic Microsurgery Versus Transanal Minimally Invasive Surgery: A Multi-institutional Matched Analysis.

BACKGROUND: There are no data comparing the quality of local excision of rectal neoplasms using transanal endoscopic microsurgery and transanal minimally invasive surgery. OBJECTIVE: The purpose of this study was to compare the incidence of tumor fragmentation and positive margins for patients undergoing local excision of benign and malignant rectal neoplasms using transanal endoscopic microsurgery versus transanal minimally invasive surgery. DESIGN: This was a multi-institutional cohort study using coarsened exact matching. SETTINGS: The study was conducted at high-volume tertiary institutions with specialist colorectal surgeons. PATIENTS: Patients undergoing full-thickness local excision for benign and malignant rectal neoplasms were included. INTERVENTIONS: Transanal endoscopic microsurgery and transanal minimally invasive surgery were the included interventions. MAIN OUTCOME MEASURES: The incidence of poor quality excision (composite measure including tumor fragmentation and/or positive resection margin) was measured. RESULTS: The matched cohort consisted of 428 patients (247 with transanal endoscopic microsurgery and 181 with transanal minimally invasive surgery). Transanal minimally invasive surgery was associated with shorter operative time and length of stay. Poor quality excision was similar (8% vs 11%; p = 0.233). There were also no differences in peritoneal violation (3% vs 3%; p = 0.965) and postoperative complications (11% vs 9%; p = 0.477). Cumulative 5-year disease-free survival for patients undergoing transanal endoscopic microsurgery was 80% compared with 78% for patients undergoing transanal minimally invasive surgery (log rank p = 0.824). The incidence of local recurrence for patients with malignancy who did not undergo immediate salvage surgery was 7% (8/117) for transanal endoscopic microsurgery and 7% (7/94) for transanal minimally invasive surgery (p = 0.864). LIMITATIONS: All of the procedures were also performed at high-volume referral centers by specialist colorectal surgeons with slightly differing perioperative practices and different time periods. CONCLUSIONS: High-quality local excision for benign and rectal neoplasms can be equally achieved using transanal endoscopic microsurgery or transanal minimally invasive surgery. The choice of operating platform for local excisions of rectal neoplasms should be based on surgeon preference, availability, and cost. See Video Abstract at http://links.lww.com/DCR/A382.

Influence of Tennis Racquet Kinematics on Ball Topspin Angular Velocity and Accuracy during the Forehand Groundstroke.

Forehand groundstroke effectiveness is important for tennis success. Ball topspin angular velocity (TAV) and accuracy are important for forehand groundstroke effectiveness, and have been extensively studied, previously; despite previous, quality studies, it was unclear whether certain racquet kinematics relate to ball TAV and shot accuracy during the forehand groundstroke. This study evaluated potential relationships between (1) ball TAV and (2) forehand accuracy, and five measures of racquet kinematics: racquet head impact angle (i.e., closed or open face), horizontal and vertical racquet head velocity before impact, racquet head trajectory (resultant velocity direction, relative to horizontal) before impact, and hitting zone length (quasi-linear displacement, immediately before and after impact). Thirteen collegiate-level tennis players hit forehand groundstrokes in a biomechanics laboratory, where racquet kinematics and ball TAV were measured, and on a tennis court, to assess accuracy. Correlational statistics were used to evaluate potential relationships between racquet kinematics, and ball TAV (mixed model) and forehand accuracy (between-subjects model; α = 0.05). We observed an average (1) racquet head impact angle, (2) racquet head trajectory before impact, relative to horizontal, (3) racquet head horizontal velocity before impact, (4) racquet head vertical velocity before impact, and (5) hitting zone length of 80.4 ± 3.6˚, 18.6 ± 4.3˚, 15.4 ± 1.4 m·s-1, 6.6 ± 2.2 m·s-1, and 79.8 ± 8.6 mm, respectively; and an average ball TAV of 969 ± 375 revolutions per minute. Only racquet head impact angle and racquet head vertical velocity, before impact, significantly correlated with ball TAV (p < 0.01). None of the observed racquet kinematics significantly correlated to the measures of forehand accuracy. These results confirmed mechanical logic and indicate that increased ball TAV is associated with a more closed racquet head impact angle (ranging from 70 to 85˚, relative to the ground) and increased racquet head vertical velocity before impact.

A Systematic Review of Outcomes After Transanal Mesorectal Resection for Rectal Cancer.

BACKGROUND: Transanal mesorectal resection has been developed to facilitate minimally invasive proctectomy for rectal cancer. OBJECTIVE: The purpose of this study was to evaluate the evidence regarding technical parameters, oncological outcomes, morbidity, and mortality after transanal mesorectal resection. DATA SOURCES: The Cochrane Library, PubMed, and MEDLINE databases were reviewed. STUDY SELECTION: Systematic review of the literature from January 2005 to September 2015 was used for study selection. INTERVENTION: Intervention included transanal mesorectal resection for rectal cancer. MAIN OUTCOME MEASURES: Technical parameters, histological outcomes, morbidity, and mortality were the outcomes measured. RESULTS: Fifteen predominately retrospective studies involving 449 patients were included (mean age, 64.3 years; 64.1% men). Different platforms were used. The operative mortality rate was 0.4% and the cumulative morbidity rate 35.5%. Circumferential resection margins were clear in 98%, and the resected mesorectum was grade III in 87% of patients. Median follow-up was 14.7 months. There were 4 local recurrences (1.5%) and 12 patients (5.6%) with metastatic disease. No study followed patients long enough to report on 5-year overall and disease-free survival rates. Functional outcome was only reported in 3 studies. LIMITATIONS: A low number of procedures were performed by expert early adopters. There are no comparative or randomized data included in this study and inconsistent reporting of outcome variables. CONCLUSIONS: Transanal mesorectal resection for rectal cancer may enhance negative circumferential margin rates with a reasonable safety profile. Contemporary randomized, controlled studies are required before there can be universal recommendation.

Tailoring specialized metabolite production in streptomyces.

Streptomycetes are prolific producers of a plethora of medically useful metabolites. These compounds are made by complex secondary (specialized) metabolic pathways, which utilize primary metabolic intermediates as building blocks. In this review we discuss the evolution of specialized metabolites and how expansion of gene families in primary metabolism has lead to the evolution of diversity in these specialized metabolic pathways and how developing a better understanding of expanded primary metabolic pathways can help enhance synthetic biology approaches to industrial pathway engineering.

The Effect of Training in Minimalist Running Shoes on Running Economy.

The purpose of this study was to examine the effect of minimalist running shoes on oxygen uptake during running before and after a 10-week transition from traditional to minimalist running shoes. Twenty-five recreational runners (no previous experience in minimalist running shoes) participated in submaximal VO2 testing at a self-selected pace while wearing traditional and minimalist running shoes. Ten of the 25 runners gradually transitioned to minimalist running shoes over 10 weeks (experimental group), while the other 15 maintained their typical training regimen (control group). All participants repeated submaximal VO2 testing at the end of 10 weeks. Testing included a 3 minute warm-up, 3 minutes of running in the first pair of shoes, and 3 minutes of running in the second pair of shoes. Shoe order was randomized. Average oxygen uptake was calculated during the last minute of running in each condition. The average change from pre- to post-training for the control group during testing in traditional and minimalist shoes was an improvement of 3.1 ± 15.2% and 2.8 ± 16.2%, respectively. The average change from pre- to post-training for the experimental group during testing in traditional and minimalist shoes was an improvement of 8.4 ± 7.2% and 10.4 ± 6.9%, respectively. Data were analyzed using a 2-way repeated measures ANOVA. There were no significant interaction effects, but the overall improvement in running economy across time (6.15%) was significant (p = 0.015). Running in minimalist running shoes improves running economy in experienced, traditionally shod runners, but not significantly more than when running in traditional running shoes. Improvement in running economy in both groups, regardless of shoe type, may have been due to compliance with training over the 10-week study period and/or familiarity with testing procedures. Key pointsRunning in minimalist footwear did not result in a change in running economy compared to running in traditional footwear prior to 10 weeks of training.Both groups (control and experimental) showed an improvement in running economy in both types of shoes after 10 weeks of training.After transitioning to minimalist running shoes, running economy was not significantly different while running in traditional or minimalist footwear.

Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering.

Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad-spectrum antibiotic lead was generated with significantly improved activity, including against all Gram-negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering.

Registration rates, adequacy of registration, and a comparison of registered and published primary outcomes in randomized controlled trials published in surgery journals.

OBJECTIVE: To determine the proportion of registered trials published in the surgical literature, to compare, in registered trials, the primary outcomes registered with those published and to determine whether outcome-reporting bias favored significant primary outcomes. BACKGROUND: Trial protocol registration before patient enrolment for randomized controlled trials (RCTs) is a perquisite for many journals in attempt to decrease publication and selective reporting bias. Analysis of the medical literature demonstrates poor registration rates with discrepancies between reported and registered primary outcomes. This has not been evaluated in contemporary surgical journals. METHODS: RCTs were identified for 2009 and 2010 from 10 high-impact factor surgical journals. One investigator identified all RCTs and extracted primary and secondary outcomes, dates of commencement and completion of study, funding source, and trial registration number. Trial registers were searched using the trial registration number for primary and secondary outcomes, dates of commencement and completion of study, and date of registration. Trial registration rates and registration adequacy were recorded. Register and published primary outcomes were then compared. RESULTS: A total of 246 papers were analyzed, among which 86 (34.9%) were not registered and 52 (21%) were inadequately registered. Of the 108 adequately registered trials, 32 (29%) had a discrepancy between the published primary outcome and that registered in trial register. In the 24 published studies where it was possible to assess, the discrepancy favored a statistically significant primary outcome in 22 (91.7%) whereas in 2 (8.3%) the discrepancy produced a statistically insignificant result. CONCLUSIONS: Less than half of all RCTs published in general surgical journals were adequately registered, and approximately 30% had discrepancies in the registered and published primary outcome with 90% of those assessable favoring a statistically positive result.

Does achilles tendon cross sectional area differ after downhill, level and uphill running in trained runners?

In this study we examined how hill running affects the Achilles tendon, a common location for injuries in runners. Twenty females ran for 10 min on each of three randomly ordered grades (-6%, 0 and +6%) at speeds selected to match the metabolic rates. Achilles tendon (AT) cross-sectional area (CSA) was imaged using Doppler ultrasound and peak vertical forces were analyzed using an instrumented treadmill. A metabolic cart and gas analyzer ensured a similar metabolic cost across grades. Data were analyzed using a forward selection regression. Results showed similar decreases in AT CSA from pre- to post-run for all three conditions of ~5 to 7% (p = 0.0001). Active peak vertical forces were different across grades (p = 0.0001) with the largest occurring during downhill running and smallest during uphill running. Since changes in AT CSA were not different between grades, each form of running appears equal and acceptable in regards to how the Achilles tendon reacts. That is, the results suggest that the Achilles tendon is affected by downhill, level, and uphill running and a decrease in CSA appears to be a normal response. Key PointsDownhill (- 6%), level and uphill (+ 6%) running at different speeds each caused a statistically significant decrease in the Achilles tendon cross-sectional area in healthy, trained runners.The magnitude of change in Achilles tendon cross-sectional area did not differ between grades when metabolic cost of running was matched.Downhill running resulted in the largest peak vertical force, while uphill running resulted in the smallest.

Balance of activity during a critical period tunes a developing network.

Developing neural circuits are influenced by activity and are especially sensitive to changes in activity during critical periods (CPs) of development. Changes occurring during a CP often become 'locked in' so that they affect the mature network. Indeed, several neurodevelopmental disorders have been linked to excessive activity during such periods. It is, therefore, important to identify those aspects of neural circuit development that are influenced by neural activity during a CP. In this study, we take advantage of the genetic tractability of Drosophila to show that activity perturbation during an embryonic CP permanently alters properties of the locomotor circuit. Specific changes we identify include increased synchronicity of motoneuron activity and greater strengthening of excitatory over inhibitory synaptic drive to motoneurons. These changes are sufficient to reduce network robustness, evidenced by increased sensitivity to induced seizure. We also show that we can rescue these changes when increased activity is mitigated by inhibition provided by mechanosensory neurons. Similarly, we demonstrate a dose-dependent relationship between inhibition experienced during the CP and the extent to which it is possible to rescue the hyperexcitable phenotype characteristic of the parabss mutation. This suggests that developing circuits must be exposed to a properly balanced sum of excitation and inhibition during the CP to achieve normal mature network function. Our results, therefore, provide novel insight into how activity during a CP shapes specific elements of a circuit, and how activity during this period is integrated to tune neural circuits to the environment in which they will likely function.

Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus.

Most biosynthetic gene clusters (BGC) encoding the synthesis of important microbial secondary metabolites, such as antibiotics, are either silent or poorly expressed; therefore, to ensure a strong pipeline of novel antibiotics, there is a need to develop rapid and efficient strain development approaches. This study uses comparative genome analysis to instruct rational strain improvement, using Streptomyces rimosus, the producer of the important antibiotic oxytetracycline (OTC) as a model system. Sequencing of the genomes of two industrial strains M4018 and R6-500, developed independently from a common ancestor, identified large DNA rearrangements located at the chromosome end. We evaluated the effect of these genome deletions on the parental S. rimosus Type Strain (ATCC 10970) genome where introduction of a 145 kb deletion close to the OTC BGC in the Type Strain resulted in massive OTC overproduction, achieving titers that were equivalent to M4018 and R6-500. Transcriptome data supported the hypothesis that the reason for such an increase in OTC biosynthesis was due to enhanced transcription of the OTC BGC and not due to enhanced substrate supply. We also observed changes in the expression of other cryptic BGCs; some metabolites, undetectable in ATCC 10970, were now produced at high titers. This study demonstrated for the first time that the main force behind BGC overexpression is genome rearrangement. This new approach demonstrates great potential to activate cryptic gene clusters of yet unexplored natural products of medical and industrial value.IMPORTANCEThere is a critical need to develop novel antibiotics to combat antimicrobial resistance. Streptomyces species are very rich source of antibiotics, typically encoding 20-60 biosynthetic gene clusters (BGCs). However, under laboratory conditions, most are either silent or poorly expressed so that their products are only detectable at nanogram quantities, which hampers drug development efforts. To address this subject, we used comparative genome analysis of industrial Streptomyces rimosus strains producing high titers of a broad spectrum antibiotic oxytetracycline (OTC), developed during decades of industrial strain improvement. Interestingly, large-scale chromosomal deletions were observed. Based on this information, we carried out targeted genome deletions in the native strain S. rimosus ATCC 10970, and we show that a targeted deletion in the vicinity of the OTC BGC significantly induced expression of the OTC BGC, as well as some other silent BGCs, thus suggesting that this approach may be a useful way to identify new natural products.