Introduction Sarcopenia likely comprises muscle fiber denervation and re-innervation, resulting in clustering of muscle fibers of the same type (classified by myosin heavy chain isoform composition). Development of methodology to quantitatively evaluate clustering of muscle fibers according to fiber type is necessary. Methods Fiber type specific immunofluorescence histology was used to quantify fiber clustering in murine diaphragm muscle (n=15) at 6 and 24 months of age. Results With age, fiber type clustering is evidenced by fiber type specific changes in distances between fibers, specifically a 14% decrease to the closest fiber for type I and 24% increase for type IIx and/or IIb fibers (P<0.001). Additionally, a 34% increase to the 3 closest type IIx and/or IIb fibers was found (P<0.001). Discussion This novel method of analyzing fiber type clustering may be useful in examining pathophysiological conditions of motor unit loss in neuromuscular disorders, myopathies, dystrophies, injuries, or amyotrophic lateral sclerosis.

We aimed to test the hypothesis that self-selecting fluid intake but maintaining high exogenous CHO availability (60 g/h) does not compromise half-marathon performance. 15 participants completed 3 half-marathons while drinking a 6% CHO solution to guidelines (DRINK) or a non-caloric solution in self-selected volumes when consuming 3×glucose (20 g) gels (G-GEL) or glucose-fructose (13 g glucose+7 g fructose) gels (GF-GEL) per hour. Fluid intake (DRINK: 1 557±182, G-GEL: 473±234, GF-GEL: 404±144 ml) and percent body mass loss (DRINK: - 0.8±0.9, G-GEL: - 2.0±0.6, GF-GEL: -2.3±1.1) were different (P<0.05) between conditions, though race time did not differ (DRINK: 110.6±14.4, G-GEL: 110.3±14.6, GF-GEL: 113.7±12.8 min). In G-GEL, there was a positive correlation (P<0.05) between body mass loss and race time. Plasma glucose was lower (P<0.05) in GF-GEL compared with other conditions, and total CHO oxidation (DRINK: 3.2±0.5, G-GEL: 3.0±0.4, GF-GEL: 2.6±0.4 g/min) was lower (P=0.06) in this trial. Self-selecting fluid intake but maintaining high CHO availability does not impair half-marathon performance. Additionally, consuming glucose-fructose mixtures in sub-optimal amounts reduces plasma glucose and total rates of CHO oxidation.

Sarcopenia is the age‐related decline of skeletal muscle mass and function. Diaphragm muscle (DIAm) sarcopenia may contribute to respiratory complications, a common cause of morbidity and mortality in the elderly. From 6 to 24 months (mo) of age, representing ~100% and ~80% survival in C57BL/6 × 129 male and female mice, there is a significant reduction in DIAm force generation (~30%) and cross‐sectional area (CSA) of type IIx and/or IIb muscle fibers (~30%), impacting the ability to perform high force, non‐ventilatory behaviors. To date, there is little information available regarding DIAm sarcopenia in very old age groups. The present study examined DIAm sarcopenia in C57BL/6 × 129 male and female mice at 24, 27, and 30 mo, representing ~80%, ~60%, and ~30% survival, respectively. We hypothesized that survival into older ages will show no further worsening of DIAm sarcopenia and functional impairment in 30 mo mice compared to 24 or 27 mo C57BL/6 × 129 mice. Measurements included resting ventilation, transdiaphragmatic pressure (Pdi) generation across a range of motor behaviors, muscle fiber CSA, and proportion of type‐identified DIAm fibers. Maximum Pdi and resting ventilation did not change into very old age (from 24 to 30 mo). Type IIx and/or IIb fiber CSA and proportions did not change into very old age. The results of the study support a critical threshold for the reduction in DIAm force and Pdi such that survival into very old age is not associated with evidence of progression of DIAm sarcopenia or impairment in ventilation.

Previously, we found that brain‐derived neurotrophic factor (BDNF) signaling through the high‐affinity tropomyosin‐related kinase receptor subtype B (TrkB) enhances neuromuscular transmission in the diaphragm muscle. However, there is an age‐related loss of this effect of BDNF/TrkB signaling that may contribute to diaphragm muscle sarcopenia (atrophy and force loss). We hypothesized that chronic treatment with 7,8‐dihydroxyflavone (7,8‐DHF), a small molecule BDNF analog and TrkB agonist, will mitigate age‐related diaphragm neuromuscular transmission failure and sarcopenia in old mice. Adult male Trk BF 616A mice (n = 32) were randomized to the following 6‐month treatment groups: vehicle‐control, 7,8‐DHF, and 7,8‐DHF and 1NMPP1 (an inhibitor of TrkB kinase activity in Trk BF 616A mice) cotreatment, beginning at 18 months of age. At 24 months of age, diaphragm neuromuscular transmission failure, muscle‐specific force, and fiber cross‐sectional areas were compared across treatment groups. The results did not support our hypothesis in that chronic 7,8‐DHF treatment did not improve diaphragm neuromuscular transmission or mitigate diaphragm muscle sarcopenia. Taken together, these results do not exclude a role for BDNF/TrkB signaling in aging‐related changes in the diaphragm muscle, but they do not support the use of 7,8‐DHF as a therapeutic agent to mitigate age‐related neuromuscular dysfunction.

Rational and objective Prognosis provides critical knowledge for shared decision making between patients and clinicians. While several prognostic indices for mortality in dialysis patients have been developed, their performance among elderly patients initiating dialysis is unknown, despite great need for reliable prognostication in that context. To assess the performance of 6 previously validated prognostic indices to predict 3 and/or 6 months mortality in a cohort of elderly incident dialysis patients. Study design Validation study of prognostic indices using retrospective cohort data. Indices were compared using the concordance (“c”)-statistic, i.e. area under the receiver operating characteristic curve (ROC). Calibration, sensitivity, specificity, positive and negative predictive values were also calculated. Setting & participants Incident elderly (age ≥75 years; n = 349) dialysis patients at a tertiary referral center. Established predictors Variables for six validated prognostic indices for short term (3 and 6 month) mortality prediction (Foley, NCI, REIN, updated REIN, Thamer, and Wick) were extracted from the electronic medical record. The indices were individually applied as per each index specifications to predict 3- and/or 6-month mortality. Results In our cohort of 349 patients, mean age was 81.5±4.4 years, 66% were male, and median survival was 351 days. The c-statistic for the risk prediction indices ranged from 0.57 to 0.73. Wick ROC 0.73 (0.68, 0.78) and Foley 0.67 (0.61, 0.73) indices performed best. The Foley index was weakly calibrated with poor overall model fit (p <0.01) and overestimated mortality risk, while the Wick index was relatively well-calibrated but underestimated mortality risk. Limitations Small sample size, use of secondary data, need for imputation, homogeneous population. Conclusion Most predictive indices for mortality performed moderately in our incident dialysis population. The Wick and Foley indices were the best performing, but had issues with under and over calibration. More accurate indices for predicting survival in older patients with kidney failure are needed.

IntroductionThere is a considerable implementation gap in managing early stage chronic kidney disease (CKD) in primary care despite the high prevalence and risk for increased morbidity and mortality associated with CKD. This systematic review aims to synthesise the evidence of efficacy of implementation interventions aimed at primary care practitioners (PCPs) to improve CKD identification and management. We further aim to describe the interventions’ behavioural change components.Methods and analysisWe will conduct a systematic review of studies from 2000 to October 2017 that evaluate implementation interventions targeting PCPs and which include at least one clinically meaningful CKD outcome. We will search several electronic data bases and conduct reference mining of related systematic reviews and publications. An interdisciplinary team will independently and in duplicate, screen publications, extract data and assess the risk of bias. Clinical outcomes will include all clinically meaningful medical management outcomes relevant to CKD management in primary care such as blood pressure, chronic heart disease and diabetes target achievements. Quantitative evidence synthesis will be performed, where possible. Planned subgroup analyses include by (1) study design, (2) length of follow-up, (3) type of intervention, (4) type of implementation strategy, (5) whether a behavioural or implementation theory was used to guide study, (6) baseline CKD severity, (7) patient minority status, (8) study location and (9) academic setting or not.Ethics and disseminationApproval by research ethics board is not required since the review will only include published and publicly accessible data. Review findings will inform a future trial of an intervention to promote uptake of CKD diagnosis and treatment guidelines in our primary care setting and the development of complementary tools to support its successful adoption and implementation. We will publish our findings in a peer-reviewed journal and develop accessible summaries of the results.PROSPERO registration numberCRD42018102441.

Volumetric muscle loss (VML) is the traumatic loss of muscle tissue that results in reduced regenerative capacity and long‐term functional deficits. In fact, in comparison to the mass of muscle removed from the VML injury, the functional deficits observed are disproportionally greater. Clinically, it is estimated that nearly 30% of VML injured patients are further impacted by some ongoing degree of peripheral nerve damage in the injured limb. These findings suggest that VML injury has a significant impact on the neuromuscular system that extends beyond the defect area. This is further supported by our recent finding that VML injury results in chronic motor neuron axotomy of ~75% through 21 days post‐VML; however, how this impacts individual muscle fibers is not yet clear. As such, the purpose of this study was to systematically quantify the neuromuscular junctions (NMJs) surrounding the VML injury site. We hypothesized that VML injury would result in a reduced NMJ area, altered innervation and an irregular morphology that ultimately impairs skeletal muscle function. A standard VML surgery was performed by removing approximately 20% of the middle third of the tibialis anterior (TA) muscle in adult male inbred Lewis rats (n=32). Full thickness injuries were performed unilaterally so that the non‐injured leg served as an intra‐animal control. The TA muscles were harvested at 0, 3, 7, 14, 21, and 48 days post injury and ~50 individual NMJs per muscle were evaluated. Pre‐ and post‐synaptic were identified immunohistochemically and quantitative confocal microscopy was used to evaluate 2‐ and 3‐D synaptic area, fiber denervation and morphologic characteristics. As expected, the mass of the TA muscle was 20–30% of the contralateral over the 48 days post‐VML; which is supported by an ~40% loss in contractile protein content over this same period. The muscle remaining after VML indicates a significant number of denervated (reduced overlap of pre‐ and post‐synaptic structures) NMJs after injury. Additionally, substantial changes in the NMJ morphological characteristics were identified in the muscle remaining after VML. Specifically, poly‐innervation and sprouting of individual NMJs, which suggest that motor unit reorganization may be occurring after VML injury. While the most obvious consequence of VML injury is the loss of contractile protein content and muscle fibers, the disorientate changes at both the motor neuron and NMJ may exacerbate the decline in muscle function following VML injury. This work is foundational to support future work to identify interventions to support maintenance of NMJ innervation following VML injury. Support or Funding Information Supported by W81XWH‐19‐1‐0075.

Sarcopenia is the age‐related decline of skeletal muscle function. Sarcopenia involves loss of motor neurons and the subsequent denervation of muscle fibers. Denervated muscle fibers can be re‐innervated through terminal axonal sprouting of neighboring axons. Given the predominant role of motor neurons in establishing muscle fiber type, we hypothesized that sarcopenia (and the associated partial denervatin effects) result in clustering of muscle fibers of the same type (classified by myosin heavy chain isoform composition). Fiber type specific immunofluorescence histology was used to quantify fiber clustering in murine diaphragm muscle (n=15) at 6 and 24 months of age. Clustering was analyzed using the distance between fibers of the same fiber type as well as quantification of the number of type‐identified fibers in a cluster. There was a 14% decrease to the closest fiber for type I and a 24% increase for type IIx and/or IIb fibers (P<0.001) in old vs. young mice. Additionally, a 34% increase to the 3 closest type IIx and/or IIb fibers was found (P<0.001). Changes in the interfiber distances for type‐identified fibers reveals important effects that consider changes in fiber size and proportion across disease conditions. This novel method of analyzing fiber type clustering may be useful in examining pathophysiological conditions of motor unit loss in neuromuscular disorders, myopathies, dystrophies, injuries, or amyotrophic lateral sclerosis.Supported by R01‐AG044615, T32‐HL105355, and the Mayo Clinic.