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Abstract Background Radiotherapy is commonly used to treat childhood cancers and can have adverse effects on muscle function, but the underlying mechanisms have yet to be fully elucidated. We hypothesized that endurance exercise following radiation treatment would improve skeletal muscle function. Methods We utilized the Small Animal Radiation Research Platform (SARRP) to irradiate juvenile male mice with a clinically relevant fractionated dose of 3× (every other day over 5 days) 8.2 Gy X-ray irradiation locally from the knee to footpad region of the right hindlimb. Mice were then singly housed for 1 month in cages equipped with either locked or free-spinning voluntary running wheels. Ex vivo muscle contractile function, RT-qPCR analyses, resting cytosolic and sarcoplasmic reticulum (SR) store Ca2+ levels, mitochondrial reactive oxygen species levels (MitoSOX), and immunohistochemical and biochemical analyses of muscle samples were conducted to assess the muscle pathology and the relative therapeutic impact of voluntary wheel running (VWR). Results Irradiation reduced fast-twitch extensor digitorum longus (EDL) muscle-specific force by 27% compared to that of non-irradiated mice, while VWR post-irradiation improved muscle-specific force by 37%. Radiation treatment similarly reduced slow-twitch soleus muscle-specific force by 14% compared to that of non-irradiated mice, while VWR post-irradiation improved specific force by 18%. We assessed intracellular Ca2+ regulation, oxidative stress, and mitochondrial homeostasis as potential mechanisms of radiation-induced pathology and exercise-mediated rescue. We found a significant reduction in resting cytosolic Ca2+ concentration following irradiation in sedentary mice. Intriguingly, however, SR Ca2+ store content was increased in myofibers from irradiated mice post-VWR compared to mice that remained sedentary. We observed a 73% elevation in the overall protein oxidization in muscle post-irradiation, while VWR reduced protein nitrosylation by 35% and mitochondrial reactive oxygen species (ROS) production by 50%. Finally, we found that VWR significantly increased the expression of PGC1α at both the transcript and protein levels, consistent with an exercise-dependent increase in mitochondrial biogenesis. Conclusions Juvenile irradiation stunted muscle development, disrupted proper Ca2+ handling, damaged mitochondria, and increased oxidative and nitrosative stress, paralleling significant deficits in muscle force production. Exercise mitigated aberrant Ca2+ handling, mitochondrial homeostasis, and increased oxidative and nitrosative stress in a manner that correlated with improved skeletal muscle function after radiation.

Abstract Background As paediatric cancer survivors are living into adulthood, they suffer from the age‐related, accelerated decline of functional skeletal muscle tissue, termed sarcopenia. With ionizing radiation (radiotherapy) at the core of paediatric cancer therapies, its direct and indirect effects can have lifelong negative impacts on paediatric growth and maintenance of skeletal muscle. Utilizing our recently developed preclinical rhabdomyosarcoma mouse model, we investigated the late effects of paediatric radiation treatment on skeletal muscles from late adolescent (8 weeks old) and middle‐aged (16 months old) mice. Methods Paediatric C57BL/6J male mice (3 weeks old) were injected with rhabdomyosarcoma cells into their right hindlimbs, and then fractionated irradiation (3 × 8.2 Gy) was administered to those limbs at 4 weeks old to eliminate the tumours. Radiation‐alone and tumour‐irradiated mice were assessed at either 8 weeks (3 weeks post‐irradiation) or 16 months (14 months post‐irradiation) of age for muscle physiology, myofibre characteristics, cell loss, histopathology, fibrosis, inflammatory gene expression, and fibrotic gene expression. Results Mice that received only paediatric radiation demonstrated reduced muscle mass (−17%, P

Abstract Background Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which is responsible for ~30% of patient deaths. While the established paradigm to explain SMW posits that muscle catabolism from systemic inflammation and nutritional deficiencies, the cause of death, and the cellular and molecular mechanisms responsible remain to be elucidated. To address this, we investigated the relationship between tumour burden and survival in the KCKO murine PDAC model. Methods Female C57BL/6J mice 6–8 weeks of age underwent orthotopic injection with KCKO‐luc tumour cells. Solid tumour was verified on Day 5, post‐tumour inoculation. In vivo, longitudinal lean mass and tumour burden were assessed via dual‐energy X‐ray absorptiometry and IVIS imaging, respectively, and total body weight was assessed, weekly. Animals were sacrificed at a designated end point of ‘failure to thrive’. After sacrifice, lower limb hind muscles were harvested for histology and RNA extraction. Results We found a strong correlation between primary tumour size and survival (r2 = 0.83, P

Increased wildfire frequency and size has led to a surge in flammability research, most of which investigates landscape-level patterns and wildfire dynamics. There has been a recent shift towards organism-scale mechanisms that may drive these patterns, as more studies focus on flammability of plants themselves. Here, we examine methods developed to study tissue-level flammability, comparing a novel hot-plate-based method to existing methods identified in a literature review. Based on a survey of the literature, we find that the hot plate method has advantages over alternatives when looking at the specific niche of small-to-intermediate live fuel samples—a size range not addressed in most studies. In addition, we directly compare the hot plate method to the commonly used epiradiator design by simultaneously conducting flammability tests along a moisture gradient, established with a laboratory benchtop drydown. Our design comparison addresses two basic issues: (1) the relationship between hydration and flammability and (2) relationships between flammability metrics. We conclude that the hot plate method compares well to the epiradiator method, while allowing for testing of bigger samples.

Chronic inflammation is a feature of age-related regenerative decline in skeletal muscles, but how it directly affects resident muscle stem cell fate and function is unclear. Here, the authors show that Ccr2 signaling in muscle stem cell derived progenitors represses terminal myogenic differentiation, and that targeting Ccr2 on aged myogenic progenitors rejuvenates aged skeletal muscle healing and function.

During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function impacting mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs); however, the relationship between MuSCs and innervation has not been established. Herein, we administered severe neuromuscular trauma to a transgenic murine model that permits MuSC lineage tracing. We show that a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ), the synapse between myofibers and motor neurons, in healthy young adult muscles. In aging and in a mouse model of neuromuscular degeneration (Cu/Zn superoxide dismutase knockout – Sod1-/-), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in Sod1-/- mice reestablished integrity of the NMJ in a manner akin to young muscle and partially restored MuSC ability to engraft into positions proximal to the NMJ. Using single cell RNA-sequencing of MuSCs isolated from aged muscle, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury and share similarity to synaptic myonuclei. Collectively, these data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors.

Summary: During prepubertal development, muscle stem cells (satellite cells, SCs) actively contribute to myofiber growth. Because some SCs are active during this time, they may be particularly susceptible to damage. Using a Small Animal Radiation Research Platform (SARRP), we investigated the effects of local fractionated radiation treatment on prepubertal SCs. Immediately after this regimen, there was a reduction in SC number. Although surviving SCs had deficiencies in function, some myogenic potential remained. Indeed, some muscle regenerative capacity persisted immediately after irradiation. Lastly, we assessed the long-term consequences of radiation-induced SC loss during prepuberty. We observed a reduction of myofiber size and corresponding loss of nuclei in both fast- and slow-contracting muscles 14 months post-irradiation. Notably, prepubertal SC depletion mimicked these lifelong deficits. This work highlights the susceptibility of prepubertal SCs to radiation exposure. We also reveal the importance of prepubertal SC contribution to the lifelong maintenance of skeletal muscle.

Areg Grigorian, Joshua K Livingston, Sebastian D Schubl, Bima J Hasjim, Daniel Mayers, Eric Kuncir, Cristobal Barrios, Victor Joe, Jeffry Nahmias Division of Trauma, Burns and Surgical Critical Care, Department of Surgery, University of California, Irvine, Orange County, CA, USA Background: To provide a descriptive analysis of scrotal and testicular trauma in the USA. Additionally, we hypothesized that motorcycle collision would have a higher association with scrotal or testicular trauma and subsequent scrotal or testicular operation, compared to a bicycle collision.Methods: The National Trauma Data Bank (2007–2015) was queried to identify adult male patients with scrotal or testicular trauma. A multivariable logistic regression analysis was performed.Results: A total of 8,030 patients (0.23%) had scrotal/testicular injury, with 44.6% involved in blunt trauma. A penetrating mechanism occurred in 50.5% of cases, with assault by firearm (75.8%) being the most common. The median age of the patients was 31 years and the median injury severity score was 8. Most had isolated scrotal or testicular trauma (74.5%), with 48.3% requiring scrotal or testicular operation, most commonly repair of laceration (37.3%). Patients involved in a motorcycle collision had higher risk for scrotal/testicular trauma (OR=5.40, CI=4.40–6.61, p=0.0004) and subsequent scrotal/testicular surgery (OR=4.93, CI=3.82–6.36, p=0.0005), compared to bicycle collision.Conclusion: Scrotal or testicular trauma is rare but occurs most commonly after assault by firearm. Most patients only have isolated scrotal or testicular trauma, but nearly half require subsequent scrotal or testicular operation. Trauma patients presenting after a motorcycle collision have a higher association of scrotal or testicular trauma and subsequent surgery when compared to those involved in a bicycle collision. Keywords: scrotal trauma, testicular trauma, testes, scrotal surgery, testicular surgery

International experts have recommended actions that funders can take to improve the value of research investments. They state that self-assessment and public sharing are the basis for accountability and improvement. We examined our policies and practice to determine the extent to which the Patient-Centered Outcomes Research Institute’s (PCORI) policies and practices as a research funder align with international best practice recommendations. A self-audit of current policies and practice against 17 recommendations and 35 sub-recommendations representing five major stages of research production, based on adapted methods used for self-assessment by another funder, was performed. Fit of existing PCORI policies and practices with 35 sub-recommendations, qualitative assessment of adequacy (area of strength; area of partial strength; area of growth; not applicable) for 17 recommendations for five stages of research production was assessed. Of the 17 recommendations, 15 were applicable to PCORI’s research mission and focus. PCORI has policies and practices in place for all elements of six recommendations (“area of strength”) and policies that address each element but with some still in active development for three (“area of partial strength”). PCORI is partially addressing six of the 15 relevant recommendations (“area of growth”). Areas for growth include making study protocols publicly available, improving policies on data sharing, and enhancing collaboration with other funders to reduce redundant funding. A voluntary consortium of international funders is underway to encourage further progress, including additional self-assessment and public sharing for accountability. These findings indicate PCORI has undertaken efforts to align its funding practices with international recommendations to ensure the value of public dollars invested in research. Further efforts will likely require additional coordination and collaboration between funders and stakeholders.

International experts have recommended actions that funders can take to improve the value of research investments. They state that self-assessment and public sharing are the basis for accountability and improvement. We examined our policies and practice to determine the extent to which the Patient-Centered Outcomes Research Institute’s (PCORI) policies and practices as a research funder align with international best practice recommendations. A self-audit of current policies and practice against 17 recommendations and 35 sub-recommendations representing five major stages of research production, based on adapted methods used for self-assessment by another funder, was performed. Fit of existing PCORI policies and practices with 35 sub-recommendations, qualitative assessment of adequacy (area of strength; area of partial strength; area of growth; not applicable) for 17 recommendations for five stages of research production was assessed. Of the 17 recommendations, 15 were applicable to PCORI’s research mission and focus. PCORI has policies and practices in place for all elements of six recommendations (“area of strength”) and policies that address each element but with some still in active development for three (“area of partial strength”). PCORI is partially addressing six of the 15 relevant recommendations (“area of growth”). Areas for growth include making study protocols publicly available, improving policies on data sharing, and enhancing collaboration with other funders to reduce redundant funding. A voluntary consortium of international funders is underway to encourage further progress, including additional self-assessment and public sharing for accountability. These findings indicate PCORI has undertaken efforts to align its funding practices with international recommendations to ensure the value of public dollars invested in research. Further efforts will likely require additional coordination and collaboration between funders and stakeholders.

Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age-associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (Liu et al., 2015). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of age-related neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and post-synaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline.

Skeletal muscle regenerative potential declines with age, in part due to deficiencies in resident stem cells (satellite cells, SCs) and derived myogenic progenitors (MPs); however, the factors responsible for this decline remain obscure. TGFβ superfamily signaling is an inhibitor of myogenic differentiation, with elevated activity in aged skeletal muscle. Surprisingly, we find reduced expression of Smad4, the downstream cofactor for canonical TGFβ superfamily signaling, and the target Id1 in aged SCs and MPs during regeneration. Specific deletion of Smad4 in adult mouse SCs led to increased propensity for terminal myogenic commitment connected to impaired proliferative potential. Furthermore, SC-specific Smad4 disruption compromised adult skeletal muscle regeneration. Finally, loss of Smad4 in aged SCs did not promote aged skeletal muscle regeneration. Therefore, SC-specific reduction of Smad4 is a feature of aged regenerating skeletal muscle and Smad4 is a critical regulator of SC and MP amplification during skeletal muscle regeneration.

The transfer entropy has proven a useful measure of coupling among components of a dynamical system. This measure effectively captures the influence of one system component on the transition probabilities (dynamics) of another. The original motivation for the measure was to quantify such relationships among signals collected from a nonlinear system. However, we have found the transfer entropy to also be a useful concept in describing linear coupling among system components. In this work we derive the analytical transfer entropy for the response of coupled, second order linear systems driven with a Gaussian random process. The resulting expression is a function of the auto- and cross-correlation functions associated with the system response for different degrees-of-freedom. We show clearly that the interpretation of the transfer entropy as a measure of "information flow" is not always valid. In fact, in certain instances the "flow" can appear to switch directions simply by altering the degree of linear coupling. A safer way to view the transfer entropy is as a measure of the ability of a given system component to predict the dynamics of another.

Skeletal muscle maintenance depends on motor innervation at neuromuscular junctions (NMJs). Multiple mechanisms contribute to NMJ repair and maintenance; however muscle stem cells (satellite cells, SCs), are deemed to have little impact on these processes. Therefore, the applicability of SC studies to attenuate muscle loss due to NMJ deterioration as observed in neuromuscular diseases and aging is ambiguous. We employed mice with an inducible Cre, and conditionally expressed DTA to deplete or GFP to track SCs. We found SC depletion exacerbated muscle atrophy and type transitions connected to neuromuscular disruption. Also, elevated fibrosis and further declines in force generation were specific to SC depletion and neuromuscular disruption. Fate analysis revealed SC activity near regenerating NMJs. Moreover, SC depletion aggravated deficits in reinnervation and post-synaptic morphology at regenerating NMJs. Therefore, our results propose a mechanism whereby further NMJ and skeletal muscle decline ensues upon SC depletion and neuromuscular disruption.

Important controversies exist about the extent to which people's health status as adults is shaped by their living conditions in early life compared to adulthood. These debates have important policy implications, and one obstacle to resolving them is the relative lack of sufficient high-quality data on childhood and adult socioeconomic position and adult health status. We accordingly compared the health status among monozygotic and dizygotic women twin pairs who lived together through childhood (until at least age 14) and subsequently were discordant or concordant on adult socioeconomic position. This comparison permitted us to ascertain the additional impact of adult experiences on adult health in a population matched on early life experiences.Our study employed data from a cross-sectional survey and physical examinations of twins in a population-based twin registry, the Kaiser Permanente Women Twins Study Examination II, conducted in 1989 to 1990 in Oakland, California, United States. The study population was composed of 308 women twin pairs (58% monozygotic, 42% dizygotic); data were obtained on childhood and adult socioeconomic position and on blood pressure, cholesterol, post-load glucose, body mass index, waist-to-hip ratio, physical activity, and self-rated health. Health outcomes among adult women twin pairs who lived together through childhood varied by their subsequent adult occupational class. Cardiovascular factors overall differed more among monozygotic twin pairs that were discordant compared to concordant on occupational class. Moreover, among the monozygotic twins discordant on adult occupational class, the working class twin fared worse and, compared to her professional twin, on average had significantly higher systolic blood pressure (mean matched difference = 4.54 mm Hg; 95% confidence interval [CI], 0.10-8.97), diastolic blood pressure (mean matched difference = 3.80 mm Hg; 95% CI, 0.44-7.17), and low-density lipoprotein cholesterol (mean matched difference = 7.82 mg/dl; 95% CI, 1.07-14.57). By contrast, no such differences were evident for analyses based on educational attainment, which does not capture post-education socioeconomic position.These results provide novel evidence that lifetime socioeconomic position influences adult health and highlight the utility of studying social plus biological aspects of twinship.

International experts have recommended actions that funders can take to improve the value of research investments. They state that self-assessment and public sharing are the basis for accountability and improvement. We examined our policies and practice to determine the extent to which the Patient-Centered Outcomes Research Institute's (PCORI) policies and practices as a research funder align with international best practice recommendations. A self-audit of current policies and practice against 17 recommendations and 35 sub-recommendations representing five major stages of research production, based on adapted methods used for self-assessment by another funder, was performed.  Fit of existing PCORI policies and practices with 35 sub-recommendations, qualitative assessment of adequacy (area of strength; area of partial strength; area of growth; not applicable) for 17 recommendations for five stages of research production was assessed. Of the 17 recommendations, 15 were applicable to PCORI's research mission and focus.  PCORI has policies and practices in place for all elements of six recommendations ("area of strength") and policies that address each element but with some still in active development for three ("area of partial strength"). PCORI is partially addressing six of the 15 relevant recommendations ("area of growth"). Areas for growth include making study protocols publicly available, improving policies on data sharing, and enhancing collaboration with other funders to reduce redundant funding. A voluntary consortium of international funders is underway to encourage further progress, including additional self-assessment and public sharing for accountability. These findings indicate PCORI has undertaken efforts to align its funding practices with international recommendations to ensure the value of public dollars invested in research.  Further efforts will likely require additional coordination and collaboration between funders and stakeholders.

BackgroundStudies have associated thiazolidinedione (TZD) treatment with cardiovascular disease (CVD) and questioned whether the two available TZDs, rosiglitazone and pioglitazone, have different CVD risks. We compared CVD incidence, cardiovascular (CV), and all-cause mortality in type 2 diabetic patients treated with rosiglitazone or pioglitazone as their only TZD.MethodsWe analyzed survey, medical record, administrative, and National Death Index (NDI) data from 1999 through 2003 from Translating Research Into Action for Diabetes (TRIAD), a prospective observational study of diabetes care in managed care. Medications, CV procedures, and CVD were determined from health plan (HP) administrative data, and mortality was from NDI. Adjusted hazard rates (AHR) were derived from Cox proportional hazard models adjusted for age, sex, race/ethnicity, income, history of diabetic nephropathy, history of CVD, insulin use, and HP.ResultsAcross TRIAD's 10 HPs, 1,815 patients (24%) filled prescriptions for a TZD, 773 (10%) for only rosiglitazone, 711 (10%) for only pioglitazone, and 331 (4%) for multiple TZDs. In the seven HPs using both TZDs, 1,159 patients (33%) filled a prescription for a TZD, 564 (16%) for only rosiglitazone, 334 (10%) for only pioglitazone, and 261 (7%) for multiple TZDs. For all CV events, CV, and all-cause mortality, we found no significant difference between rosiglitazone and pioglitazone.ConclusionsIn this relatively small, prospective, observational study, we found no statistically significant differences in CV outcomes for rosiglitazone- compared to pioglitazone-treated patients. There does not appear to be a pattern of clinically meaningful differences in CV outcomes for rosiglitazone- versus pioglitazone-treated patients.

OBJECTIVE Patient-physician race/ethnicity concordance can improve care for minority patients. However, its effect on cardiovascular disease (CVD) care and prevention is unknown. We examined associations of patient race/ethnicity and patient-physician race/ethnicity concordance on CVD risk factor levels and appropriate modification of treatment in response to high risk factor values (treatment intensification) in a large cohort of diabetic patients. RESEARCH DESIGN AND METHODS The study population included 108,555 adult diabetic patients in Kaiser Permanente Northern California in 2005. Probit models assessed the effect of patient race/ethnicity on risk factor control and treatment intensification after adjusting for patient and physician-level characteristics. RESULTS African American patients were less likely than whites to have A1C

BackgroundDespite the availability of effective hypertension, hyperlipidemia, and hyperglycemia therapies, target levels of systolic blood pressure (SBP), LDL-cholesterol (LDL-c), and hemoglobin A1c control are often not achieved.ObjectiveTo examine the relative importance of patient medication nonadherence versus clinician lack of therapy intensification in explaining above target cardiovascular disease (CVD) risk factor levels.DesignCross-sectional assessment.ParticipantsIn 2005, 161,697 Kaiser Permanente Northern California adult diabetes patients were included in the study.Measurement"Above target" was defined as most recent A1c >/=7.0% for hyperglycemia, LDL-c >/=100 mg/dL for hyperlipidemia, and SBP >/=130 mmHg for hypertension. Poor adherence was defined as medication gaps for >/=20% of days covered for all medications for each condition separately. Treatment intensification was defined as an increase in the number of drug classes, increased dosage of a class, or a switch to a different class within the 3 months before or after notation of above target levels.ResultsPoor adherence was found in 20-23% of patients across the 3 conditions. No evidence of poor adherence with no treatment intensification was found in 30% of hyperglycemia patients, 47% of hyperlipidemia patients, and 36% of hypertension patients. Poor adherence or lack of therapy intensification was evident in 53-68% of patients above target levels across conditions.ConclusionsBoth nonadherence and lack of treatment intensification occur frequently in patients above target for CVD risk factor levels; however, lack of therapy intensification was somewhat more common. Quality improvement efforts should focus on these modifiable barriers to CVD risk factor control.

BackgroundAlthough disease management programs are widely implemented, little is known about their effectiveness.ObjectiveTo determine whether disease management by physician groups is associated with diabetes care processes, control of intermediate outcomes, or the amount of medication used when intermediate outcomes are above target levels.DesignCross-sectional study.SettingPatients were randomly sampled from 63 physician groups nested in 7 health plans sponsored by Translating Research into Action for Diabetes (87%) and from 4 health plans with individual physician contracts (13%).Patients8661 adults with diabetes who completed a survey (2000-2001) and had medical record data.MeasurementsPhysician group and health plan directors described their organizations' use of physician reminders, performance feedback, and structured care management on a survey; their responses were used to determine measures of intensity of disease management. The current study measured 8 processes of care, including most recent hemoglobin A1c level, systolic blood pressure, serum low-density lipoprotein cholesterol level, and several measures of medication use.ResultsIncreased use of any of 3 disease management strategies was significantly associated with higher adjusted rates of retinal screening, nephropathy screening, foot examinations, and measurement of hemoglobin A1c levels. Serum lipid level testing and influenza vaccine administration were associated with greater use of structured care management and performance feedback. Greater use of performance feedback correlated with an increased rate of foot examinations (difference, 5 percentage points [95% CI, 1 to 8 percentage points]), and greater use of physician reminders was associated with an increased rate of nephropathy screening (difference, 15 percentage points [CI, 6 to 23 percentage points]). No strategies were associated with intermediate outcome levels or level of medication management.LimitationsPhysician groups were not randomly sampled from population-based listings, and disease management strategies were not randomly allocated across groups.ConclusionsDisease management strategies were associated with better processes of diabetes care but not with improved intermediate outcomes or level of medication management. A greater focus on direct measurement, feedback, and reporting of intermediate outcome levels or of level of medication management may enhance the effectiveness of these programs.