ERK and c-Myc signaling in host-derived tumor endothelial cells is essential for solid tumor growth.

The limited efficacy of the current antitumor microenvironment strategies is due in part to the poor understanding of the roles and relative contributions of the various tumor stromal cells to tumor development. Here, we describe a versatile in vivo anthrax toxin protein delivery system allowing for the unambiguous genetic evaluation of individual tumor stromal elements in cancer. Our reengineered tumor-selective anthrax toxin exhibits potent antiproliferative activity by disrupting ERK signaling in sensitive cells. Since this activity requires the surface expression of the capillary morphogenesis protein-2 (CMG2) toxin receptor, genetic manipulation of CMG2 expression using our cell-type-specific CMG2 transgenic mice allows us to specifically define the role of individual tumor stromal cell types in tumor development. Here, we established mice with CMG2 only expressed in tumor endothelial cells (ECs) and determined the specific contribution of tumor stromal ECs to the toxin's antitumor activity. Our results demonstrate that disruption of ERK signaling only within tumor ECs is sufficient to halt tumor growth. We discovered that c-Myc is a downstream effector of ERK signaling and that the MEK-ERK-c-Myc central metabolic axis in tumor ECs is essential for tumor progression. As such, disruption of ERK-c-Myc signaling in host-derived tumor ECs by our tumor-selective anthrax toxins explains their high efficacy in solid tumor therapy.

Household Income and Parental Educational Level Affect Post-Operative Opioid Usage in Pediatric Orthopaedic Patients.

Opioid medications are commonly prescribed after pediatric orthopaedic surgery, but there is a critical need to optimize prescribing practice. This study identifies socio-economic characteristics, surgical characteristics, and patient reported psychological factors influencing postoperative opioid use in this population and found that post-operative opioid use in this pediatric orthopaedic population is multifactorial. Physicians should consider implementing protocols for initial opioid prescriptions to cover two to three days following common orthopaedic surgeries for most pediatric patients.

A longitudinal study examining uptake of new recreation infrastructure by inactive adults.

BACKGROUND: The built environment is reported to influence physical activity in populations, but longitudinal evidence about the impact of building new physical activity infrastructure is limited. This study aimed to prospectively investigate the uptake and usage of the newly established Peninsula Aquatic and Recreation Centre (PARC), a large multi-purpose recreation facility in Melbourne, Australia. METHODS: Physically inactive adults (n = 549) from the City of Frankston were recruited before the opening of PARC and followed up 12 months later to measure frequency of attendance at the Centre, and the purposes and barriers to use. Multivariable methods were used to identity the demographic, cognitive and social predictors of attendance, and the relationship between PARC use and improvements in leisure-time physical activity. RESULTS: Over 12 months 8.7% of the sampled residents used PARC once per month or more, 17.5% attended less than once per month, and 73.8% did not use the Centre. Lap swimming was the dominant purpose for attendance, and the major barriers were cost of transport and cost of entry. Independent predictors of usage were being female, having children, living within 5 km of the Centre, and expressing strong intentions for use prior to its opening. Use of PARC was not associated with progression to a higher level of total leisure-time physical activity. CONCLUSIONS: While installation of multi-purpose aquatic and recreation facilities may be considered an investment towards physical activity in populations, regular use by inactive people is likely to be low. Strategies to reduce barriers, including cost and transport, and to motivate use should be trialled in order to improve the public health impacts of this form of infrastructure.

Trends and Characteristics of Highly Cited Articles in Proximal Humerus Fracture Research.

As the treatment of proximal humerus fractures remains controversial in the literature, this study aims to identify highly cited articles and examine trends and characteristics. Scopus was used to identify the highest cited articles of proximal humerus fracture research. SPSS 23 was used for descriptive statistics and Pearson correlations for the relationship between citation count and density. Average citation count was 233 ± 164 with an annual citation density of 14 ± 7. Total citation count was associated with total citation density, 5-year citation count, and 5-year citation density. The Journal of Bone and Joint Surgery-American produced the most articles with 15 (30%). Thirty-five articles originated in Europe. The five most represented authors published three articles each. Finally, 13 (26%) papers appear in the American Shoulder and Elbow Surgeons Curriculum Guide. This study compiles a collection of articles investigating proximal humerus fractures for future review and demonstrates citation count to be an acceptable measure of an article's contemporary academic influence. (Journal of Surgical Orthopaedic Advances 28(3):180-188, 2019).

Trends and Characteristics of Highly Cited Articles in Shoulder Arthroplasty.

Citation calculations measure academic influence. This study sought to analyze highly cited shoulder arthroplasty articles and determine the best measure to assess their impact. Scopus identified the 50 most cited articles, and each was analyzed for citation number, authors, institution, country of origin, and journal of publication. SPSS 23 was used for descriptive statistics, and a Pearson correlation coefficient assessed the relationship between citation measures. The results revealed an average citation count of 259 ± 108 and a citation density (citation count/years since publication) of 18 ± 10 annually. Most articles originated in the United States (31) and France (9). Twelve surgeons were included on three or more articles. Forty-one studies were clinically based. Finally, correlation was demonstrated between citation count and citation density (r = 0.486, p < .001). In conclusion, this study revealed the trends of highly cited shoulder arthroplasty articles and found citation count and citation density to be acceptable measures of academic influence. (Journal of Surgical Orthopaedic Advances 28(1):10-17, 2019).

Predictive Accuracy of the ACS-NSQIP Surgical Risk Calculator for Pathologic Humerus Fracture Fixation.

Pathologic fractures are associated with poor outcomes. This article investigated the prevalence of underestimation of risk by the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Surgical Risk Calculator (SRC) in patients with pathologic humerus fractures. Two hundred seven (207) patients were identified and analyzed using the ACS-NSQIP SRC. Predicted and actual outcomes were then compared. Average hospitalization was 6 ± 10 days. Ten patients (5%) had a mild adverse event (AE), and 15 (7%) had a serious AE. The ACS-NSQIP SRC underestimated hospitalizations (p < 0.001), but not serious AE (p = 0.601), mild AE (p = 0.948), cardiac complications (p = 0.817), pneumonia (p = 0.713), surgical site infection (p = 0.692), urinary tract infection (p = 0.286), venous thromboembolism (p = 0.554), acute renal failure (p = 0.191), discharge to acute care facility (p = 0.865), readmission (p = 1.0), reoperation (0.956) or mortality (p = 0.872). Negative outcomes were limited in this cohort, and the SRC demonstrated acceptable accuracy. Future investigation of the calculator in other orthopaedic populations is warranted. (Journal of Surgical Orthopaedic Advances 28(4):250-256, 2019).

Con: Contrast-induced nephropathy-should we try to avoid contrast media in patients with chronic kidney disease?

The incidence of acute kidney injury (AKI) attributed to iodinated contrast has been over-estimated and this has led clinicians to withhold potentially life-saving diagnostic and therapeutic interventions. There is mounting evidence that iodinated contrast plays only a minor role in the development of AKI in comparison with more significant risk factors such as pre-existing renal dysfunction, hemodynamic instability and exposure to nephrotoxic drugs. We will present data which challenge the dogma of avoiding iodinated contrast in patients with reduced renal function. Based on a rational and individualized risk-benefit analysis, we believe it is preferable to utilize iodinated contrast if alternate diagnostic or therapeutic options are comparatively ineffective or hazardous.

Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy.

Recent studies have shown that autophagy mitigates the pathological effects of proteinopathies in the liver, heart, and skeletal muscle but this has not been investigated for proteinopathies that affect the lung. This may be due at least in part to the lack of an animal model robust enough for spontaneous pathological effects from proteinopathies even though several rare proteinopathies, surfactant protein A and C deficiencies, cause severe pulmonary fibrosis. In this report we show that the PiZ mouse, transgenic for the common misfolded variant α1-antitrypsin Z, is a model of respiratory epithelial cell proteinopathy with spontaneous pulmonary fibrosis. Intracellular accumulation of misfolded α1-antitrypsin Z in respiratory epithelial cells of the PiZ model resulted in activation of autophagy, leukocyte infiltration, and spontaneous pulmonary fibrosis severe enough to elicit functional restrictive deficits. Treatment with autophagy enhancer drugs or lung-directed gene transfer of TFEB, a master transcriptional activator of the autophagolysosomal system, reversed these proteotoxic consequences. We conclude that this mouse is an excellent model of respiratory epithelial proteinopathy with spontaneous pulmonary fibrosis and that autophagy is an important endogenous proteostasis mechanism and an attractive target for therapy.

Selected overtone mobility spectrometry.

A new means of acquiring overtone mobility spectrometry (OMS) data sets that allows distributions of ions for a prescribed overtone number is described. In this approach, the drift fields applied to specific OMS drift regions are varied to make it possible to select different ions from a specific overtone that is resonant over a range of applied frequencies. This is accomplished by applying different fields for fixed ratios of time while scanning the applied frequency. The ability to eliminate peaks from all but a single overtone region overcomes a significant limitation associated with OMS analysis of unknowns, especially in mixtures. Specifically, a priori knowledge via selection of the overtone used to separate ions makes it possible to directly determine ion mobilities for unknown species and collision cross sections (assuming that the ion charge state is known). We refer to this selection method of operation as selected overtone mobility spectrometry (SOMS). A simple theoretical description of the SOMS approach is provided. Simulations are carried out and discussed in order to illustrate the advantages and disadvantages of SOMS compared with traditional OMS. Finally, the SOMS method (and its distinction from OMS) is demonstrated experimentally by examining a mixture of peptides generated by enzymatic digestion of the equine cytochrome c with trypsin.

Gas molecule scattering & ion mobility measurements for organic macro-ions in He versus N2 environments.

A pending issue in linking ion mobility measurements to ion structures is that the collisional cross section (CCS, the measured structural parameter in ion mobility spectrometry) of an ion is strongly dependent upon the manner in which gas molecules effectively impinge on and are reemitted from ion surfaces (when modeling ions as fixed structures). To directly examine the gas molecule impingement and reemission processes and their influence, we measured the CCSs of positively charged ions of room temperature ionic liquids 1-ethyl-3-methylimidazolium dicyanamide (EMIM-N(CN)2) and 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIM-BF4) in N2 using a differential mobility analyzer-mass spectrometer (DMA-MS) and in He using a drift tube mobility spectrometer-mass spectrometer (DT-MS). Cluster ions, generated via electrosprays, took the form (AB)N(A)z, spanning up to z = 20 and with masses greater than 100 kDa. As confirmed by molecular dynamics simulations, at the measurement temperature (∼300 K), such cluster ions took on globular conformations in the gas phase. Based upon their attained charge levels, in neither He nor N2 did the ion-induced dipole potential significantly influence gas molecule-ion collisions. Therefore, differences in the CCSs measured for ions in the two different gases could be primarily attributed to differences in gas molecule behavior upon collision with ions. Overwhelmingly, by comparison of predicted CCSs with selected input impingement-reemission laws to measurements, we find that in N2, gas molecules collide with ions diffusely--they are reemitted at random angles relative to the gas molecule incoming angle--and inelastically. Meanwhile, in He, gas molecules collide specularly and elastically and are emitted from ion surfaces at determined angles. The results can be rationalized on the basis of the momentum transferred per collision; in the case of He, individual gas molecule collisions minimally perturb the atoms within a cluster ion (internal motion), while in the case of N2, individual gas molecules have sufficiently large momentum to alter the internal motion in organic ions.

The MOVE study: a study protocol for a randomised controlled trial assessing interventions to maximise attendance at physical activity facilities.

BACKGROUND: Physical activity is associated with a host of health benefits, yet many individuals do not perform sufficient physical activity to realise these benefits. One approach to rectifying this situation is through modifying the built environment to make it more conducive to physical activity, such as by building walking tracks or recreational physical activity facilities. Often, however, modifications to the built environment are not connected to efforts aimed at encouraging their use. The purpose of the Monitoring and Observing the Value of Exercise (MOVE) study is to evaluate the effectiveness of two interventions designed to encourage the ongoing use of a new, multi-purpose, community-based physical activity facility. METHODS/DESIGN: A two-year, randomised controlled trial with yearly survey points (baseline, 12 months follow-up, 24 months follow-up) will be conducted among 1,300 physically inactive adult participants aged 18-70 years. Participants will be randomly assigned to one of three groups: control, intervention 1 (attendance incentives), or intervention 2 (attendance incentives and tailored support following a model based on customer relationship management). Primary outcome measures will include facility usage, physical activity participation, mental and physical wellbeing, community connectedness, social capital, friendship, and social support. Secondary outcome measures will include stages of change for facility usage and social cognitive decision-making variables. DISCUSSION: This study will assess whether customer relationship management systems, a tool commonly used in commercial marketing settings, can encourage the ongoing use of a physical activity facility. Findings may also indicate the population segments among which the use of such systems are most effective, as well as their cost-effectiveness. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12615000012572 (registered 9 January 2015).

Characterizing intermediates along the transition from polyproline I to polyproline II using ion mobility spectrometry-mass spectrometry.

Polyproline exists predominately as the all-cis polyproline I (PPI) helix in aliphatic alcohols, whereas the all-trans polyproline II (PPII) helix is favored in aqueous solutions. Previous ion mobility spectrometry-mass spectrometry (IMS-MS) work demonstrates that the gas-phase conformations of polyproline ions can be related to the corresponding PPI and PPII helices in solution [J. Phys. Chem. B 2004, 108, 4885]. Here, we use IMS-MS to examine the detailed intermediate steps associated with the process of Polyproline-13 (Pro13) conversion from the PPI helix to the PPII helix upon solvent exchange. Collision cross section distributions of Pro13 [M + 2H](2+) ions obtained at different transition times indicate the presence of two major conformers, identified as the PPI and PPII helices, and six conformers that appear as subpopulations of polyproline. Further analysis shows a transition mechanism with sequential cis-trans isomerizations followed by a parallel process to establish PPII and two smaller subpopulations at equilibrium. Temperature-dependent studies are used to obtain Arrhenius activation parameters for each step of the mechanism, and molecular dynamics simulations provide insight about the structures of the intermediates. It appears that prolines sequentially flip from cis to trans starting from the N-terminus. However, after the first few transitions, possible steps take place at the center of the peptide chain; subsequently, several pathways appear to be accessible at the same time. Our results reflect the existence of stable subpopulations in polyprolines and provide new insight into the structural changes during the transition process of polyproline peptides converting from PPI to PPII in aqueous solution.

Knowledge about sports-related concussion: is the message getting through to coaches and trainers?

AIM: The need for accurate diagnosis and appropriate return-to-play decisions following a concussion in sports has prompted the dissemination of guidelines to assist managing this condition. This study aimed to assess whether key messages within these guidelines are reflected in the knowledge of coaches and sports trainers involved in community sport. METHODS: An online knowledge survey was widely promoted across Australia in May-August 2012 targeting community Australian Football (AF) and Rugby League (RL) coaches and sports trainers. 260 AF coaches, 161 AF sports trainers, 267 RL coaches and 228 RL sports trainers completed the survey. Knowledge scores were constructed from Likert scales and compared across football codes and respondent groups. RESULTS: General concussion knowledge did not differ across codes but sports trainers had higher levels than did coaches. There were no significant differences in either concussion symptoms or concussion management knowledge across codes or team roles. Over 90% of respondents correctly identified five of the eight key signs or symptoms of concussion. Fewer than 50% recognised the increased risk of another concussion following an initial concussion. Most incorrectly believed or were uncertain that scans typically show damage to the brain after a concussion occurs. Fewer than 25% recognised, and >40% were uncertain that younger players typically take longer to recover from concussion than adults. CONCLUSIONS: The key messages from published concussion management guidelines have not reached community sports coaches and sports trainers. This needs to be redressed to maximise the safety of all of those involved in community sport.

Structural Insights into Linkage-Specific Ubiquitin Chains Using Ion Mobility Mass Spectrometry.

The structural characterization and differentiation of four types of oligoubiquitin conjugates [linear (Met1)-, Lys11-, Lys48-, Lys63-linked di-, tri-, and tetraubiquitin chains] using ion mobility mass spectrometry are reported. A comparison of collision cross sections for the same linkage of di-, tri-, and tetraubiquitin chains shows differences in conformational elongation for higher charge states due to the interplay of linkage-derived structure and Coulombic repulsion. For di- and triubiquitin chains, this elongation results in a single narrow feature representing an elongated conformation type for multiple higher charge state species. In contrast, higher charge state tetraubiquitin species do not form a single conformer type as readily. A comparison of different linkages in tetraubiquitin chains reveals greater similarity in conformation type at lower charge states; with increasing charge state, the four linkage types diverge in the relative proportions of elongated conformer types with Met1- ≥ Lys11- > Lys63- > Lys48-linkage. These differences in conformational trends could be discussed with respect to biological functions of linkage-specific polyubiquitinated proteins.

Gridless overtone mobility spectrometry.

A novel overtone mobility spectrometry (OMS) instrument utilizing a gridless elimination mechanism and cooperative radio frequency confinement is described. The gridless elimination region uses a set of mobility-discriminating radial electric fields that are designed so that the frequency of field application results in selective transmission and elimination of ions. To neutralize ions with mobilities that do not match the field application frequency, active elimination regions radially defocus ions toward the lens walls. Concomitantly, a lens-dependent radio frequency waveform is applied to the transmission regions of the drift tube resulting in radial confinement for mobility-matched ions. Compared with prior techniques, which use many grids for ion elimination, the new gridless configuration substantially reduces indiscriminate ion losses. A description of the apparatus and elimination process, including detailed simulations showing how ions are transmitted and eliminated is presented. A prototype 28 cm long OMS instrument is shown to have a resolving power of 20 and is capable of attomole detection limits of a model peptide (angiotensin I) spiked into a complex mixture (in this case peptides generated from digestion of ß-casein with trypsin).

Ion trapping for ion mobility spectrometry measurements in a cyclical drift tube.

A new ion trapping technique, involving the accumulation of ions in a cyclical drift tube, as a means of enhancing ion signals for scanning ion cyclotron mobility measurements has been modeled by computational simulations and demonstrated experimentally. In this approach, multiple packets of ions are periodically released from a source region into the on ramp region of the cyclical drift tube and these pulses are accumulated prior to initiation of the mobility measurements. Using this ion trapping approach, it was possible to examine ions that traversed between 1.83 and 182.86 m (from 1 to 100 cycles). Overall, we observe that instrumental resolving power improves with increasing cycle numbers; at 100 cycles, a resolving power in excess of 1000 can be achieved. The utility of this method as a means of distinguishing between analytes is demonstrated by examining the well-characterized model peptides substance P, angiotensin II, and bradykinin.

The patient-centered medical home solution to the cost-quality conundrum.

The U.S. healthcare system has been plagued by rising costs while achieving relatively poor-quality outcomes, and the situation continues to worsen. One solution is the patient-centered medical home (PCMH) model of primary care. This model focuses on care coordination and development of long-term physician-patient relationships that are expected to lead to better quality care and higher rates of patient satisfaction than have previously been achieved. Although the PCMH features a number of core principles, significant differences are seen across models. Three of the most prevalent models are those offered by the American Academy of Family Physicians, National Demonstration Project, and National Committee for Quality Assurance (NCQA). After analysis, the NCQA approach emerged as the recommended model due to its specificity and comprehensiveness. Research suggests that the PCMH, and specifically the NCQA model, can achieve both increases in quality and reductions in cost. However, this finding is tempered by the challenges inherent in implementation.

Lateral Extra-articular Tenodesis with Iliotibial Band Using Knotless All-Suture Anchor Femoral Fixation.

Common injuries, such as anterior cruciate ligament (ACL) tears, can result in both anterior and rotational instability of the knee. An arthroscopic anterior cruciate ligament reconstruction (ACLR) method has been shown to be effective in restoring anterior translational stability, but this could be followed by persistent rotational instability by means of residual pivot shifts or repeat instability episodes. Alternative techniques, such as a lateral extraarticular tenodesis (LET), has been proposed as a technique for preventing persistent rotational instability following ACLR. This article presents a case of a LET using an autologous central slip of iliotibial (IT) band with fixation to the femur using a 1.8-mm knotless all-suture anchor.

The Mechanism of Anterior Cruciate Ligament Injuries in the National Football League: A Systematic Video Review.

Introduction Anterior cruciate ligament (ACL) injuries are common among American football athletes, although few studies have performed video analyses of ACL injuries to better understand the injury mechanism. This work aims to characterize the mechanism of ACL injury during professional football competitions using video analysis. We hypothesize that football-specific injury trends will emerge, including high rates of contact injuries and associations with shallow knee and hip flexion angles (0°-30°). Methods Videos of professional football players suffering ACL injuries from 2007 to 2016 were analyzed. Injured players were identified using the injured reserve (IR) lists of the National Football League (NFL), and videos were discovered via a systematic Google search. Descriptive statistics and frequency analyses were performed on all variables using the Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM SPSS Statistics, Armonk, NY, USA). Results Of the 429 ACL injuries identified, 53 (12%) videos were available. Deceleration was the most common injury maneuver, present in 32 (60%) athletes. Thirty-one (58%) players suffered contact injuries. Twenty-eight (53%) injuries demonstrated valgus collapse of the knee, and 26 (49%) had neutral knee rotation. Defensive backs (26%) and wide receivers (23%) were the most frequently injured positions. Conclusion Overall, we found that most ACL injuries had preceding contact, deceleration, shallow hip and knee flexion, and heel strike, and subsequent valgus collapse and neutral knee rotation. This understanding of American football-specific ACL tear mechanisms could help direct the focus of future injury prevention training modalities.

Primary Repair of Peroneus Longus Myofascial Herniation With Symptomatic Superficial Peroneal Nerve Compression.

Symptomatic myofascial herniations of the extremities occur infrequently; however, they can contribute to significant pain, weakness, and neuropathy with activity. Muscle herniation typically occurs through either a traumatic or congenital focal defect in the deep overlying fascia. Patients may present with an intermittently palpable subcutaneous mass and may have neuropathic symptoms, depending on the degree of nerve involvement. Patients are initially treated with conservative modalities, whereas surgery is reserved for patients who demonstrate persistent functional limitations and neurologic symptoms. Here, we demonstrate a technique for primary repair of a symptomatic lower-leg fascial defect.