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We define a new family of similarity and distance measures on graphs, and explore their theoretical properties in comparison to conventional distance metrics. These measures are defined by the solution(s) to an optimization problem which attempts find a map minimizing the discrepancy between two graph Laplacian exponential matrices, under norm-preserving and sparsity constraints. Variants of the distance metric are introduced to consider such optimized maps under sparsity constraints as well as fixed time-scaling between the two Laplacians. The objective function of this optimization is multimodal and has discontinuous slope, and is hence difficult for univariate optimizers to solve. We demonstrate a novel procedure for efficiently calculating these optima for two of our distance measure variants. We present numerical experiments demonstrating that (a) upper bounds of our distance metrics can be used to distinguish between lineages of related graphs; (b) our procedure is faster at finding the required optima, by as much as a factor of 103; and (c) the upper bounds satisfy the triangle inequality exactly under some assumptions and approximately under others. We also derive an upper bound for the distance between two graph products, in terms of the distance between the two pairs of factors. Additionally, we present several possible applications, including the construction of infinite "graph limits" by means of Cauchy sequences of graphs related to one another by our distance measure.

Multigrid modeling algorithms are a technique used to accelerate iterative method models running on a hierarchy of similar graphlike structures. We introduce and demonstrate a new method for training neural networks which uses multilevel methods. Using an objective function derived from a graph-distance metric, we perform orthogonally-constrained optimization to find optimal prolongation and restriction maps between graphs. We compare and contrast several methods for performing this numerical optimization, and additionally present some new theoretical results on upper bounds of this type of objective function. Once calculated, these optimal maps between graphs form the core of multiscale artificial neural network (MsANN) training, a new procedure we present which simultaneously trains a hierarchy of neural network models of varying spatial resolution. Parameter information is passed between members of this hierarchy according to standard coarsening and refinement schedules from the multiscale modeling literature. In our machine learning experiments, these models are able to learn faster than training at the fine scale alone, achieving a comparable level of error with fewer weight updates (by an order of magnitude).

Energy expenditure during and after exercise is composed of aerobic and anaerobic bioenergetics and the energy demands of aerobic recovery. Current attempts to measure energy expenditure include an exercise oxygen uptake + oxygen debt (EPOC) measurement or, an oxygen deficit + exercise oxygen uptake measurement. This investigation illustrates how oxygen debt and oxygen deficit interpretation can effect a total energy expenditure measurement. It was hypothesized that the total energy expenditure for several intermittent bouts of exercise and recovery would be greater than for one bout of continuous exercise and recovery when equivalent work was compared. Exercise was performed under low-intensity and high-intensity conditions. Both oxygen debt and oxygen deficit methodology resulted in similar energy expenditure measurements for both intermittent and continuous exercise. This implies little to no recovery energy demand or considerable methodology errors. Differences in total energy expenditure were found when the oxygen deficit and parts of the oxygen debt (EPOC) were considered separate and independent (p < 0.05). These differences can be accounted for when the data are interpreted utilizing thermodynamic (2nd law) and engineering (in-series efficiency) concepts rather than the heat equivalent of carbohydrate oxidation (20.9 kJ equals one liter of O2). It is suggested that while oxygen uptake provides an excellent representation of aerobic metabolism during exercise and recovery, oxygen uptake may be an inadequate measure of the energetics of lactate production (fermentation). In application, energy expenditure differences appear realistic only for high-intensity, intermittent exercise rather than lower intensity exercise. [ABSTRACT FROM AUTHOR]

Goldspire™ is a personalized immunotherapy platform that combines whole tumor-derived cells with antisense oligonucleotide (IMV-001) against Insulin-Like Growth Factor-1 Receptor (IGF-1R) in biodiffusion chambers (BDCs; 0.1 μm pore). BDCs are exposed to 5-6 Gy and implanted at abdominal sites for ∼48 h to deliver an antigenic payload and immunostimulatory factors to train the immune system. Lead product IGV-001 was evaluated in newly diagnosed glioblastoma (ndGBM) patients in Phase 1a and 1b trials (NCT02507583). A Phase 2b study (NCT04485949) recently completed enrollment. Preventative treatment with tumor-specific products manufactured with Goldspire limited tumor progression and extended overall survival in mice challenged with bladder, pancreatic, ovarian, colorectal, or renal carcinomas. The benefit of this immunotherapy was enhanced with anti-PD-1; combination treatment was superior to either monotherapy in orthotopic GBM and melanoma models. Lastly, Goldspire elicited immune T cell activation and memory phenotypes against patient-derived endometrial tumor-derived products in co-cultures with matching immune cells., Competing Interests: Declaration of competing interest JZ, CU, DWA and MAE are/were employed by Imvax, Inc. CBS is a paid consultant of Imvax, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sex-differential selection (SDS), which occurs when the fitness effects of alleles differ between males and females, can have profound impacts on the maintenance of genetic variation, disease risk, and other key aspects of natural populations. Because the sexes mix their autosomal genomes each generation, quantifying SDS is not possible using conventional population genetic approaches. Here, we introduce a method that exploits subtle sex differences in haplotype frequencies resulting from SDS acting in the current generation. Using data from 300K individuals in the UK Biobank, we estimate the strength of SDS throughout the genome. While only a handful of loci under SDS are individually significant, we uncover highly polygenic signals of genome-wide SDS for both viability and fecundity. Selection coefficients of [Formula: see text] may be typical. Despite its ubiquity, SDS may impose a mortality load of less than 1%. An interesting life-history tradeoff emerges: Alleles that increase viability more strongly in females than males tend to increase fecundity more strongly in males than in females. Finally, we find marginal evidence of SDS on fecundity acting on alleles affecting arm fat-free mass. Taken together, our findings connect the long-standing evidence of SDS acting on human phenotypes with its impact on the genome., Competing Interests: Competing interests statement:The authors declare no competing interest.

The canonical basal ganglia model predicts that the substantia nigra pars reticulata (SNr) and the globus pallidus externa (GPe) will have specific effects on locomotion: the SNr inhibiting locomotion and the GPe enhancing it. In this manuscript, we use in vivo optogenetics to show that a projection-defined neural subpopulation within each structure exerts non-canonical effects on locomotion. These non-canonical subpopulations are defined by their projection to the pedunculopontine nucleus (PPN) and mediate opposing effects on reward. To understand how these structures differentially modulate the PPN, we use ex vivo whole-cell recording with optogenetics to comprehensively dissect the SNr and GPe connections to regionally- and molecularly-defined populations of PPN neurons. The SNr inhibits all PPN subtypes, but most strongly inhibits caudal glutamatergic neurons. The GPe selectively inhibits caudal glutamatergic and GABAergic neurons, avoiding both cholinergic and rostral cells. This circuit characterization reveals non-canonical basal ganglia pathways for locomotion and valence., Competing Interests: Declaration of Interests The authors declare no competing interests.

Coral bleaching, the stress-induced breakdown of coral-algal symbiosis, threatens reefs globally. Paradoxically, despite adverse fitness effects, corals bleach annually, even outside of abnormal temperatures. This generally occurs shortly after the once-per-year mass coral spawning. Here, we propose a hypothesis linking annual coral bleaching and the transmission of symbionts to the next generation of coral hosts. We developed a dynamic model with two symbiont growth strategies, and found that high sexual recruitment and low adult coral survivorship and growth favour bleaching susceptibility, while the reverse promotes bleaching resilience. Otherwise, unexplained trends in the Indo-Pacific align with our hypothesis, where reefs and coral taxa exhibiting higher recruitment are more bleaching susceptible. The results from our model caution against interpreting potential shifts towards more bleaching-resistant symbionts as evidence of climate adaptation-we predict such a shift could also occur in declining systems experiencing low recruitment rates, a common scenario on today's reefs., (© 2024 John Wiley & Sons Ltd.)

For sessile organisms at high risk from climate change, phenotypic plasticity can be critical to rapid acclimation. Epigenetic markers like DNA methylation are hypothesized as mediators of plasticity; methylation is associated with the regulation of gene expression, can change in response to ecological cues, and is a proposed basis for the inheritance of acquired traits. Within reef-building corals, gene-body methylation (gbM) can change in response to ecological stressors. If coral DNA methylation is transmissible across generations, this could potentially facilitate rapid acclimation to environmental change. We investigated methylation heritability in Acropora, a stony reef-building coral. Two Acropora millepora and two Acropora selago adults were crossed, producing eight offspring crosses (four hybrid, two of each species). We used whole-genome bisulfite sequencing to identify methylated loci and allele-specific alignments to quantify per-locus inheritance. If methylation is heritable, differential methylation (DM) between the parents should equal DM between paired offspring alleles at a given locus. We found a mixture of heritable and nonheritable loci, with heritable portions ranging from 44% to 90% among crosses. gBM was more heritable than intergenic methylation, and most loci had a consistent degree of heritability between crosses (i.e. the deviation between parental and offspring DM were of similar magnitude and direction). Our results provide evidence that coral methylation can be inherited but that heritability is heterogenous throughout the genome. Future investigations into this heterogeneity and its phenotypic implications will be important to understanding the potential capability of intergenerational environmental acclimation in reef building corals., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Background: IGV-001 is a personalized, autologous cancer cell-based immunotherapy conceived to deliver a tumor-derived antigenic payload in the context of immunostimulatory signals to patients with glioblastoma (GBM). IGV-001 consists of patient-derived GBM cells treated with an antisense oligodeoxynucleotide against insulin-like growth factor 1 receptor (IGF1R) and placed in proprietary biodiffusion chambers (BDCs). The BDCs are then exposed to 5-6 Gy radiation and implanted at abdominal sites for ~48 hours. IGV-001 has previously been shown to be generally safe with promising clinical activity in newly diagnosed GBM patients., Methods: Mouse ( m ) or human ( h ) variants of IGV-001 were prepared using GL261 mouse GBM cells or human GBM cells, respectively. BDCs containing vehicle or m IGV-001 were implanted in the flanks of C57BL/6 albino female mice in preventative and therapeutic experiments, optionally in combination with a programmed cell death 1 (PD-1) blocker. Bioactivity of the general approach was also measured against hepatocellular carcinoma Hepa 1-6 cells. Mice were followed for the growth of subsequently implanted or pre-existing tumors and survival. Draining lymph nodes from mice receiving m IGV-001 were immunophenotyped. m IGV-001 and h IGV-001 were analyzed for extracellular ATP and high mobility group box 1 (HMGB1) as indicators of immunogenic cell death (ICD), along with flow cytometric analysis of viability, surface calreticulin, and reactive oxygen species. Stress and cell death-related pathways were analyzed by immunoblotting., Results: IGV-001 causes oxidative and endoplasmic reticulum stress in GL261 cells, resulting in a cytotoxic response that enables the release of antigenic material and immunostimulatory, ICD-associated molecules including ATP and HMGB1 from BDCs. Immunophenotyping confirmed that IGV-001 increases the percentage of dendritic cells, as well as effector, and effector memory T cells in BDC-draining lymph nodes. Consistent with these observations, preventative IGV-001 limited tumor progression and extended overall survival in mice intracranially challenged with GL261 cells, a benefit that was associated with an increase in tumor-specific T cells with effector features. Similar findings were obtained in the Hepa 1-6 model. Moreover, therapeutically administered IGV-001 combined with PD-1 delayed progression in GBM-bearing mice., Conclusions: These results support treatment with IGV-001 to induce clinically relevant ICD-driven anticancer immune responses in patients with GBM., Competing Interests: Competing interests: CC, CU, KK, EAE, AZ, DWA, MAE, and JZ are/were employed by Imvax. CS is a paid consultant of Imvax. LG is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Motivation: Single-cell RNA sequencing (scRNA-seq) data, annotated by cell type, is useful in a variety of downstream biological applications, such as profiling gene expression at the single-cell level. However, manually assigning these annotations with known marker genes is both time-consuming and subjective., Results: We present a Graph Convolutional Network (GCN)-based approach to automate the annotation process. Our process builds upon existing labeling approaches, using state-of-the-art tools to find cells with highly confident label assignments through consensus and spreading these confident labels with a semi-supervised GCN. Using simulated data and two scRNA-seq datasets from different tissues, we show that our method improves accuracy over a simple consensus algorithm and the average of the underlying tools. We also compare our method to a nonparametric neighbor majority approach, showing comparable results. We then demonstrate that our GCN method allows for feature interpretation, identifying important genes for cell type classification. We present our completed pipeline, written in PyTorch, as an end-to-end tool for automating and interpreting the classification of scRNA-seq data., Availability and Implementation: Our code for conducting the experiments in this paper and using our model is available at https://github.com/lewinsohndp/scSHARP., (© The Author(s) 2023. Published by Oxford University Press.)

Ancient DNA (aDNA) has been applied to evolutionary questions across a wide variety of taxa. Here, for the first time, we utilized aDNA from millennia-old fossil coral fragments to gain new insights into a rapidly declining western Atlantic reef ecosystem. We sampled four Acropora palmata fragments (dated 4215 BCE to 1099 CE) obtained from two Florida Keys reef cores. From these samples, we established that it is possible both to sequence aDNA from reef cores and place the data in the context of modern-day genetic variation. We recovered varying amounts of nuclear DNA exhibiting the characteristic signatures of aDNA from the A. palmata fragments. To describe the holobiont sensu lato, which plays a crucial role in reef health, we utilized metagenome-assembled genomes as a reference to identify a large additional proportion of ancient microbial DNA from the samples. The samples shared many common microbes with modern-day coral holobionts from the same region, suggesting remarkable holobiont stability over time. Despite efforts, we were unable to recover ancient Symbiodiniaceae reads from the samples. Comparing the ancient A. palmata data to whole-genome sequencing data from living acroporids, we found that while slightly distinct, ancient samples were most closely related to individuals of their own species. Together, these results provide a proof-of-principle showing that it is possible to carry out direct analysis of coral holobiont change over time, which lays a foundation for studying the impacts of environmental stress and evolutionary constraints., (© 2022 John Wiley & Sons Ltd.)

Background: Tafenoquine is a long-acting 8-aminoquinoline approved for antimalarial prophylaxis for ≤6 months. Additional data is needed to establish the drug's longer-term safety profile, including potential ophthalmic or neuropsychiatric effects., Method: This was a randomized, double-blind, placebo-controlled trial in 600 healthy adults. Eligible subjects were randomized 1:1 to receive tafenoquine 200 mg weekly (antimalarial prophylactic regimen) or placebo for 52 weeks. Scheduled safety visits occurred at Weeks 4, 12, 24, 52 (dosing completed), and 64 (final follow-up). Safety assessments included ophthalmic changes, general and neuropsychiatric adverse events (AEs), and laboratory value changes., Results: The percentage of subjects with a protocol-defined Serious Ophthalmic Safety Event was lower in the Tafenoquine Group (18.2%) versus the Placebo Group (19%, p = 0.308). There was no significant difference between the percentages of subjects with at least one AE in the Tafenoquine Group (91.0%) versus Placebo (89.9%, p = 0.65). Common AEs seen at a significantly higher incidence for tafenoquine included reversible cornea verticillata (54.5%) and nausea (13.0%), leading to 0.0% and 0.7% discontinuations. Psychiatric AEs occurred at similar percentages in both study groups. Reversible changes in hemoglobin, methemoglobin, creatinine, and blood urea nitrogen (BUN) were noted., Conclusions: This study supports the safety of extended 52-week tafenoquine prophylaxis. CLINICAL TRIAL REGISTRATION NUMBER/CLINICALTRIALS., Gov Identifier: NCT03320174., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma., Patients and Methods: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies., Results: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall ( n = 22; P = 0.001) and 17.1 months at the highest exposure ( n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O 6 -methylguanine-DNA methyltransferase promoter ( n = 10) demonstrated median PFS of 38.4 months ( P = 0.0008). Evidence of immune activation was noted., Conclusions: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583)., (©2021 American Association for Cancer Research.)

Comparing risks against benefits of adolescent idiopathic scoliosis (AIS) patients participating in sports represents a controversial topic in the literature. Previous studies have reported sports participation as a possible risk factor for AIS development, while others describe its functional benefits for AIS athletes. The objective of this study was to determine if sports participation had an impact on pain, function, mental status, and self-perception of deformity in patients and their parents. Patients had full spine radiographs and completed baseline surveys of demographics, socioeconomics, and patient-reported outcomes (PRO): Scoliosis Research Society (SRS)-30, Body Image Disturbance Questionnaire, and Spinal Appearance Questionnaire (SAQ: Children and Parent). Patients were grouped by their participation (sports) or nonparticipation (no-sports) in noncontact sports. Demographics, radiographic parameters, and PRO were compared using parametric/nonparametric tests with means/medians reported. Linear regression models identified significant predictors of PRO. Forty-nine patients were included (sports: n=29, no-sports: n=20). Both groups had comparable age, sex, BMI, bracing status, and history of physical therapy (all P>0.05). Sports and no-sports also had similar coronal deformity (major Cobb: 31.1° vs. 31.5°). Sagittal alignment profiles (pelvic incidence, pelvic incidence minus lumbar lordosis, thoracic kyphosis, and sagittal vertical axis) were similar between groups (all P>0.05). Sports had better SRS-30 (Function, Self-image, and Total) scores, SAQ-Child Expectations, and SAQ-Parent Total Scores (P<0.05). Regression models revealed major Cobb angle (β coefficient: -0.312) and sports participation (β coefficient: 0.422) as significant predictors of SRS-30 Function score (R=0.434, P<0.05). Our data show that for AIS patients with statistically similar bracing status and coronal and sagittal deformities, patients who participated in sports were more likely to have improved functionality, self-image, expectations, and parental perception of deformity. Further investigation is warranted to acquire a comprehensive understanding of the relationship between AIS and patient participation in sports. Maintaining moderate levels of physical activity and participating in safe sports may benefit treatment outcomes. Level of Evidence III - Retrospective Comparative Study.

Objective: This study evaluated incidence over time, any association between race and demographics, and hospital-related parameters in pediatric patients with septic hip or knee arthritis., Methods: The Kids' Inpatient Database was used to identify all children with a diagnosis of septic hip or knee arthritis who underwent incision and drainage (1997-2012)., Results: Between 1997 and 2012, overall incidence of septic arthritis of the knee (0.20-0.33 per 100,000) and hip (0.12-0.18 per 100,000) increased., Conclusion: Incidence of pediatric septic joint arthritis, an emergent orthopaedic condition, has increased over time. Patient demographics may vary with respect to both age and race.

Pediatric intrasubstance anterior cruciate ligament (ACL) tears have a significant epidemiologic impact as their numbers continue to grow globally. This review focuses on true pediatric intrasubstance ACL tears, which occur >400,000 times annually. Modifiable and non-modifiable risk factors include intercondylar notch width, ACL size, gender, landing mechanisms, and hormonal variations. The proposed mechanisms of injury include anterior tibial shear and dynamic valgus collapse. ACL tears can be associated with soft tissue and chondral defects. History and physical examination are the most important parts of evaluation, including the Lachman test, which is considered the most accurate physical examination maneuver. Imaging studies should begin with AP and lateral radiographs, but magnetic resonance imaging is very useful in confirming the diagnosis and preoperative planning. ACL injury prevention programs targeting high risk populations have been proven to reduce the risk of injury, but lack uniformity across programs. Pediatric ACL injuries were conventionally treated nonoperatively, but recent data suggest that early operative intervention produces best long term outcomes pertaining to knee stability, meniscal tear risk, and return to previous level of play. Current techniques in ACL reconstruction, including more vertically oriented tunnels and physeal sparing techniques, have been described to reduce the risk of physeal arrest and limb angulation or deformity. Data consistently show that autograft is superior to allograft regarding failure rate. Mean durations of postoperative therapy and return to sport were 7 ± 3 and 10 ± 3 months, respectively. These patients have good functional outcomes compared to the general population yet are at increased risk of additional ACL injury. Attempts at primary ACL repair using biological scaffolds are under investigation., Competing Interests: There are no conflicts of interest.

Study Design: This is a meta-analysis., Objective: To establish rates of (1) neurological complications, (2) bony-related complications, (3) complications delaying recovery, (4) reoperation, and (5) fatalities following posterior cervical arthrodesis in Down syndrome (DS) patients with atlantoaxial subluxation. To determine if presenting symptoms had any relationship to postoperative complications., Summary of Background Data: Posterior arthrodesis is commonly utilized to correct cervical instability secondary to atlantoaxial instability in DS patients. However, there has never been a global evaluation of postoperative complications associated with posterior cervical spinal arthrodesis in DS patients., Methods: A comprehensive search of Medline/PubMed, EMBASE, and Ovid databases between January 1980 and July 2017 was utilized to identify DS patients with atlantoaxial subluxation who underwent posterior cervical arthrodesis. Data were sorted by neurological complications, complications delaying recovery, bony-related complications, reoperations, and fatalities. Patients were sorted into 2 groups based on presentation with or without neurological deficits., Results: Twelve studies met inclusion criteria, including 128 DS patients. Mean age was 13.8 years (range: 6.7-32.7 y; 47.8% male). Mean follow-up was 31.7 months (range: 14.9-77 mo). All patients underwent primary posterior cervical arthrodesis with an average of 2.5 vertebrae fused. A total of 39.6% of patients had bony-related complications [95% confidence interval (CI), 31.4%-48.5%], 23.3% had neurological deficits (95% CI, 16.6%-31.6%), and 26.4% experienced complications delaying recovery (95% CI, 19.4%-34.9%). The reoperation rate was 34.9% (95% CI, 25.5%-45.6%). The mortality rate was 3.9% (95% CI, 1.5%-9.7%). Neurological complications were 4-fold (P<0.05) and reoperation was 5.5-fold (P<0.05) more likely in patients presenting with neurological deficits compared with those without., Conclusions: This study detailed global complication rates of posterior arthrodesis for DS patients, identifying bony-related complications and reoperations among the most common. Patients presenting with neurological symptoms and cervical instability have increased postoperative rates of neurological complications and reoperations than patients with instability alone. Further investigation into how postoperative complications effect patient independence is warranted.

Introduction: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA)., Methods: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude., Results: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts., Discussion: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018., (© 2017 Wiley Periodicals, Inc.)

The aim of this study was to compare the values of oxygen uptake (VO2) during and after strength training exercises (STe) and ergometer exercises (Ee), matched for intensity and exercise time. Eight men (24 ± 2.33 years) performed upper and lower body cycling Ee at the individual's ventilatory threshold (VE/VCO2). The STe session included half squats and the bench press which were performed with a load at the individual blood lactate concentration of 4 mmol/l. Both sessions lasted 30 minutes, alternating 50 seconds of effort with a 10 second transition time between upper and lower body work. The averaged overall VO2 between sessions was significantly higher for Ee (24.96 ± 3.6 ml·kg·min -1 ) compared to STe (21.66 ± 1.77 ml·kg·min -1 ) (p = 0.035), but this difference was only seen for the first 20 minutes of exercise. Absolute VO2 values between sessions did not reveal differences. There were more statistically greater values in Ee compared to STe, regarding VO2 of lower limbs (25.44 ± 3.84 ml·kg·min -1 versus 21.83 ± 2·24 ml·kg·min -1 ; p = 0.038) and upper limbs (24.49 ± 3.84 ml·kg·min -1 versus 21.54 ± 1.77 ml·kg·min -1 ; p = 0.047). There were further significant differences regarding the moment effect (p<0.0001) of both STe and Ee sessions. With respect to the moment × session effect, only VO2 5 minutes into recovery showed significant differences (p = 0.017). In conclusion, although significant increases in VO2 were seen following Ee compared to STe, it appears that the load/intensity, and not the material/equipment used for the execution of an exercise, are variables that best influence oxygen uptake.

Context: Physicians overestimate survival in patients with advanced cancer. Patient-reported outcomes could provide another way to estimate survival. We previously reported four prognostic groups based on Karnofsky Performance Status, Functional Assessment of Cancer Therapy physical well-being subscale, and Memorial Symptom Assessment Scale-Short Form physical symptom distress subscale scores., Objectives: To determine the validity of these four prognostic groups., Methods: We performed prospective surveys. Data from a total of 880 Veterans Affairs Medical Center patients, 417 in the First Cohort and 463 in the Validation Cohort, were analyzed. Both inpatients and outpatients were prospectively recruited in Institutional Review Board-approved studies from August 1999 to September 2009. Survival was measured from the date of entry until death or December 1, 2009. Patients completed self-assessments with the Functional Assessment of Cancer Therapy and Memorial Symptom Assessment Scale-Short Form. Analysis of variance was used to test differences between groups in continuous variables; a generalized Wilcoxon test was used for differences between groups for survival., Results: The average age in the Validation Cohort was 66.5 years and 98% were men. The majority of patients had metastatic cancer (90%), with lung (28%) and prostate (26%) cancers being predominant. The median Karnofsky Performance Status was 70. Median survival was 33, 46.5, 124, and 209.5 days for the four prognostic groups (P < 0.0001, all pair-wise comparisons P < 0.02)., Conclusion: The four prognostic groups remained distinct in the prospective cohort. Small differences in patient-reported physical well-being can halve survival estimates. Patient-reported outcomes can correct for physician overestimate of prognosis. This study provides a way to use patient-reported outcomes for prognosis in patients with advanced cancer, with important implications for assessment., (Published by Elsevier Inc.)

While no doubt thought about for thousands of years, it was Antoine Lavoisier in the late 18th century who is largely credited with the first "modern" investigations of biological energy exchanges. From Lavoisier's work with combustion and respiration a scientific trend emerges that extends to the present day: the world gains a credible working hypothesis but validity goes missing, often for some time, until later confirmed using proper measures. This theme is applied to glucose/glycogen metabolism where energy exchanges are depicted as conversion from one form to another and, transfer from one place to another made by both the anaerobic and aerobic biochemical pathways within working skeletal muscle, and the hypothetical quantification of these components as part of an oxygen (O2) uptake measurement. The anaerobic and aerobic energy exchange components of metabolism are represented by two different interpretations of O2 uptake: one that contains a glycolytic component (1 L O2 = 21.1 kJ) and one that does not (1 L O2 = 19.6 kJ). When energy exchange transfer and oxygen-related expenditures are applied separately to exercise and recovery periods, an increased energy cost for intermittent as compared to continuous exercise is hypothesized to be a direct result.

Children with type I spinal muscular atrophy commonly demonstrate reduced bone mineral density. Our objectives were to evaluate and assess adequacy of vitamin D intake, serum levels, and association with bone mineral density. Assessments were completed using 3-day food records and dual energy x-ray absorptiometry scans. The spinal muscular atrophy type I cohort included 22 males and 18 females (N = 40), with a mean age of 18.6 months. Data collection occurred from 2001 to 2011. Seventy-five percent of patients had inadequate intake of vitamin D at the initial visit. Using mixed-effects analyses, vitamin D and calcium intakes correlated positively with bone mineral density (r = 0.31 and r = 0.53, respectively). Increased vitamin D and calcium consumption were associated with an increase in bone mineral density (P = .04 and P = .01, respectively). Vitamin D intake correlated positively with serum levels (r = 0.65). Further study is needed to determine optimal intakes of vitamin D and calcium in the spinal muscular atrophy type I population.

Introduction: An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults., Methods: There were 33 subjects, aged 20–55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10–20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes., Results: Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months., Conclusions: VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.

A modified larval migration inhibition assay was used to determine if redberry juniper (Juniperus pinchotii Sudw.) can reduce Haemonchus contortus in vitro motility and increase ivermectin (IVM) efficacy. Ruminal fluid was mixed with buffer solution and either no material (CNTL) or Tifton 85 Bermudagrass hay (T85), dried juniper (DRY), fresh juniper (FRE), or distilled juniper terpenoid oil (OIL) to make treatment solutions and anaerobically incubated for 16 h. For Trial 1, larvae were incubated in CNTL, T85, DRY, or IVM. During Trial 2, larvae were incubated in CNTL, DRY, FRE, or OIL for 4h. Trials 3 (CNTL or OIL) and 4 (CNTL, DRY or FRE) evaluated larvae after incubation in treatment solution for 2h, then incubated an additional 2h in various IVM doses (0, 0.1, 1, 3, and 6 μg/mL IVM) and placed onto a screen. Larvae that passed through the 20-μm screen within a 96-well plate were considered motile. Larvae incubated in CNTL or T85 had similar (P=0.12) motility, but larvae incubated in DRY were less (P<0.02) motile than larvae incubated in CNTL or T85 (Trial 1). During Trial 2, adding DRY, FRE, or OIL reduced (P<0.001) larval motility as compared to CNTL. A treatment×IVM dose interaction (P=0.02) was observed during Trial 3, due to OIL unexpectedly decreasing IMV efficacy at IVM concentrations of 1 (P=0.07), 3, and 6 (P<0.002)μg/mL. No treatment×IVM dose interaction (P=0.57) was observed during Trial 4, but larvae incubated in DRY had less (P<0.004) total motility than larvae incubated in CNTL or FRE. Juniper forage material reduced in vitro H. contortus larval motility, but IVM efficacy was increased only by initially incubating larvae in DRY., (Copyright © 2013 Elsevier B.V. All rights reserved.)

To date, steady state models represent the only acceptable methodology for the estimation of exercise energy costs. Conversely, comparisons made between continuous and intermittent exercise generally reveal major physiological discrepancies, leading to speculation as to why steady state energy expenditure models should be applied to intermittent exercise. Under intermittent conditions, skeletal muscle invokes varying aerobic and anaerobic metabolic responses, each with the potential to make significant contributions to overall energy costs. We hypothesize that if the aerobic-only energetic profile of steady state exercise can be used to estimate the energetics of non-steady state and intermittent exercise, then the converse also must be true. In fact, reasonable estimates of energy costs to work volumes or work rates can be demonstrated under steady state, non-steady state and intermittent conditions; the problem with the latter two is metabolic variability. Using resistance training as a model, estimates of both aerobic and anaerobic energy cost components, as opposed to one or the other, have reduced the overall energetic variability that appears inherent to brief, intense, intermittent exercise models.

We examined the aerobic and anaerobic energy expenditures of weight lifting (bench press); submaximal work was kept constant among protocols. Ten male subjects (age, 23.2 ± 3.1 years; height, 177.3 ± 5.3 cm; weight, 82.1 ± 11.5 kg) were randomly assigned to 3 lifting sessions of 3 sets of 5 repetitions at 70% 1 repetition maximum (1RM) using 3 lifting cadences: 1.5 s down and 1.5 s up (15 s per set), 4 s down and 1 s up (25 s per set), and 1 s down and 4 s up (25 s per set). No differences were found among the aerobic exercise energy expenditures for each lifting cadence. However, anaerobic energy expenditure was significantly different among protocols: 1.5 down-1.5 up, 16.5 ± 8.1 kJ; 4 down-1 up, 21.6 ± 8.1 kJ; and 1 down-4 up, 26.7 ± 7.2 kJ (p = 0.001). Excess postexercise oxygen consumption (EPOC; after each set) was lower for 1.5 down-1.5 up, 38.6 ± 17.8 kJ; versus 4 down-1 up, 50.2 ± 23.5 kJ; and 1 down-4 up, 50.0 ± 22.6 kJ (p = 0.002). Total energy expenditure also was significantly less for 1.5 up-1.5 down, 60.2 ± 23.8 kJ; versus 4 down-1 up, 80.0 ± 27.7 kJ; and 1 down-4 up, 84.2 ± 28.3 kJ (p = 0.001). Differences in EPOC and total energy expenditure with submaximal lifting were based not on the amount of work performed or with a particular eccentric-concentric cadence, but on the time to completion of the weight lifting exercise - time-under-tension; longer submaximal lifting times had greater energy expenditure.

For both respiration and combustion, the energy loss difference between glucose and fat oxidation often is referenced to the efficiency of the fuel. Yet, the addition of anaerobic metabolism with ATP resynthesis to complete respiratory glucose oxidation further contributes to energy loss in the form of entropy changes that are not measured or quantified by calorimetry; combustion and respiratory fat/lactate oxidation lack this anaerobic component. Indeed, the presence or absence of an anaerobic energy expenditure component needs to be applied to the estimation of energy costs in regard to glucose, lactate, and fuel oxidation, especially when the measurement of oxygen uptake alone may incorrectly define energy expenditure.

Objective: To develop and validate a functional measure, the Movement and Activity in Physical Space (MAPS) score, that encompasses both physical activity and environmental interaction., Design: Observational matched-pair cohort with 2-month follow-up., Setting: General community under free-living conditions., Participants: Adult participants (N=18; n=9 postsurgical, n=9 matched control; mean age ± SD, 28.9 ± 12.0y) were monitored by an accelerometer and global positioning system receiver for 3 days within 1 week (4.1 ± 2.8d) after knee surgery (T=0) and 2 months later (T+2). The healthy controls were matched for age, sex, smoking, perceived physical activity level, and occupation of a postsurgical participant. Correlation, t test (with Bonferroni adjustment: α=.05/2), analysis of variance, and intraclass correlation coefficient were used to establish validity and reliability evidence., Interventions: Not applicable., Main Outcome Measure: MAPS scores., Results: MAPS scores were moderately correlated with the Knee Injury and Osteoarthritis Outcome Score (P<.05). There was a significant group difference at T = 0 for MAPS (t(9.9)=-3.60; P=.01). Analysis of variance results for the MAPS indicated a time and group interaction (F(1,12)=4.60, P=.05). Reliability of 3 days of MAPS scores ranged from 0.75 to 0.81 (postsurgical and control), and 2-month test-retest reliability in the control group was 0.94., Conclusions: The results provide a foundation of convergent and known-group difference validity evidence along with reliability evidence for the use of MAPS as a functional outcome measure., (Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) ≤30 months of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also studied., Methods: Twenty-two children with SMA type II [mean age (SD) = 20 (5) months, range 9-30 months) were tested twice using the MHFMS. Twenty-five TD children [mean age (SD) = 18 (7) months, range 9-30 months) were tested once., Results: The average difference between MHFMS scores for SMA children was 0.18 [first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8)]. Reliability was excellent (ICC(1,3) = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean (SD) = 39.2 (1.2)] and achieved maximum test scores at 12 months of age., Discussion: MHFMS scores in young children with SMA type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up., (Copyright © 2011 Wiley Periodicals, Inc.)

We use a new approach to the estimation of energy expenditure for resistance training involving nonsteady state measures of work (weight × displacement), exercise O2 uptake, blood lactate, and recovery O2 uptake; all lifts were performed to muscular failure. Our intent was to estimate and compare absolute and relative aerobic and anaerobic exercise energy expenditure and recovery energy expenditure. Single-set bench press lifts of ∼ 37, ∼ 46, and ∼ 56% (muscular endurance-type exercise) along with 70, 80, and 90% (strength-type exercise) of a 1 repetition maximum were performed. Collectively, the muscular endurance lifts resulted in larger total energy expenditure (60.2 ± 14.5 kJ) as compared with the strength lifts (43.2 ± 12.5 kJ) (p = 0.001). Overall work also was greater for muscular endurance (462 ± 131 J) as opposed to strength (253 ± 93 J) (p = 0.001); overall work and energy expenditure were related (r = 0.87, p = 0.001). Anaerobic exercise and recovery energy expenditure were significantly larger for all strength lifts as compared with aerobic exercise energy expenditure (p < 0.001). For the muscular endurance lifts, anaerobic energy expenditure was larger than recovery energy expenditure (p < 0.001) that in turn was larger than aerobic exercise energy expenditure (p < 0.001). We conclude that for a single set of resistance training to fatigue, the anaerobic and recovery energy expenditure contributions can be significantly larger than aerobic energy expenditure during the exercise. To our surprise, recovery energy expenditure was similar both within strength and muscular-endurance protocols and between protocols; moreover, recovery energy expenditure had little to no relationship with aerobic and anaerobic exercise energy expenditure or work.

As opposed to steady state aerobic-type exercise involving long duration, continuous, rhythmic, large muscle group activities that consume large volumes of oxygen, a resistance training set is brief, intermittent, uses multiple and isolated muscles, and is considered anaerobic in description. Because differences are evident between aerobic- and anaerobic-type exercise, it is proposed that the methods used for estimating resistance training energy expenditure should be different as compared with walking, jogging, cycling, etc. After a single set of weight lifting, for example, oxygen uptake is greater in the recovery from lifting as opposed to during the actual exercise; likewise, the anaerobic energy expenditure contribution to lifting may exceed exercise oxygen uptake. Recovery energy expenditure also does not appear well related to the anaerobic energy expenditure of the previous exercise. Based on this evidence, it is suggested that anaerobic-type exercise should not be based on aerobic-type models. In terms of excess postexercise oxygen consumption, a hypothesis is presented in regard to how non-steady-state energy expenditure in the immediate recovery from intense exercise should be properly quantified (e.g., in-between resistance training sets). The proposed concept is based on possible substrate or fuel use differences during intense exercise and aerobic recovery and the biochemistry and bioenergetics of glucose, lactate, and fat oxidation. It is proposed that immediately after a single weight lifting bout or in-between resistance training sets, as O2 uptake plummets rapidly back toward pre-exercise levels, a separate energy expenditure conversion is required for recovery that differs from non-steady-state exercise, that is, 1 L of recovery oxygen uptake = 19.6 kJ (4.7 kcal) (not the standard exercise conversion of 1 L of oxygen uptake = 21.1 kJ) (5.0 kcal).

Anthelmintic effects of plant secondary compounds may be occurring in the rumen, but in vitro larvae migration inhibition (LMI) methods using rumen fluid and forage material have not been widely used. Forage material added to an in vitro system can affect rumen pH, ammonia N, and volatile fatty acids, which may affect larvae viability (LV). Validating a LMI assay using rumen fluid and a known anthelmintic drug (Ivermectin) and a known anthelmintic plant extract (Quebracho tannins; QT) is important. Rumen fluid was collected and pooled from 3 goats, mixed with buffer solution and a treatment (1 jar/treatment), and placed into an anaerobic incubator for 16h. Ensheathed larvae (<3 months old) were then anaerobically incubated with treatment rumen fluid for 2, 4, or 16h depending on the trial. Larvae (n=15-45) were then transferred onto a screen (n=4-6 wells/treatment) within a multi-screen 96-well plate that contained treatment rumen fluid. Larvae were incubated overnight and those that passed through the 20-μm screen were considered viable. Adding dry or fresh juniper material reduced (P<0.05) pH, ammonia N, and isobutyric, butyric, isovaleric, and valeric acids, and increased (P<0.001) acetic, propionic, and total VFA. Including 4.5% (w/v) polyethylene glycol (PEG) in rumen fluid mixture with or without forage material reduced (P<0.01) LV. However, LV was similar at all PEG concentrations tested (0-2%, w/v; 89.4, 78.9, 76.5, 75.5, and 77.5% viable). Q. tannin concentrations from 0 to 1.2% (w/v) quadratically reduced (P<0.001) LV; 89.4, 65.5, 22.8, and 9.2%. Ivermectin concentrations from 0 to 15μg/mL quadratically reduced (P<0.001) LV; 90.2, 82.6, 73.6, 66.3, 51.9, 56.5, 43.5, 41.9, 29.3, and 19.9% viable, respectively. Effects of altering in vitro rumen fluid pH, ammonia N, and VFA and using PEG when evaluating LV need to be further investigated. In vitro rumen fluid assays using QT and Ivermectin resulted in decreased LV, validating the efficacy of this technique for measuring Haemonchus contortus larval viability., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We investigated the work performed and energy expenditure characteristics within and among 2 sets of the bench press at 70%, 80%, and 90% of 1 repetition maximum (1RM). For both sets fatigue was the end point. We asked: do multiple sets affect subsequent work output along with aerobic, anaerobic, and excess postexercise oxygen consumption (EPOC) contributions? Ten males participated. Work was significantly less for the 2nd set within the 70% and 80% protocols, but not the 90% protocol. Anaerobic (glycolytic) energy expenditure was less for the 2nd set within all protocols. However, within all protocols, the work / energy expenditure ratio was not different between sets. Overall work was significantly different among protocols, becoming less as the weight lifted was increased: 70%, 637.1 ± 122.4 J; 80%, 512.4 ± 93.4 J; 90%, 324.7 ± 92.6 J (p < 0.001). EPOC was not different among protocols after the 1st set, 2nd set, or combined overall. Moreover, the overall EPOC did not correlate with overall work performed (r = 0.31, p = 0.11). EPOC overall did correlate with aerobic (r = 0.68, p < 0.001) and anaerobic (r = 0.65, p < 0.001) energy expenditures. In terms of a work / energy expenditure ratio, the least amount of completed work at 90% 1RM required greater energy expenditure as compared with 70% and 80% because of an EPOC that is similar for all. As more work is completed (i.e., lower weight, more repetitions), aerobic and anaerobic exercise energy expenditures appear to increase accordingly, yet absolute EPOC remains essentially unchanged, contributing less to the overall energy expenditure.

Background: Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children., Methods: This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores., Results: Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful., Conclusions: This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

Background: Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo., Methods: Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures., Results: At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007)., Conclusions: This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials., Trial Registry: Clinicaltrials.gov NCT00227266.

We examined the reliability and validity of non-steady-state aerobic and anaerobic estimations of energy expenditure during and after bouts of the bench press exercise. A Smith machine, not free weights, was used. On different days, 8 subjects (28.4 +/- 9.0 years; 170.4 +/- 11.9 cm; 68.4 +/- 14.0 kg) were randomly assigned to 3 lifting sessions of 7, 14, and 21 reps at 50% of the 1-repetition maximum (9 total sessions). No differences were found in any of the triplicate measures within 7, 14, and 21 reps. Coefficients of variation for 7, 14, and 21 reps were, respectively, for resting blood lactate, 20.3, 24.3, and 26.7%; for anaerobic exercise energy expenditure, 47.9, 29.1, and 14.2%; for aerobic exercise energy expenditure, 47.4, 28.3, and 18.4%; for excess postexercise O2 consumption, 33.0, 26.5, and 29.2%; for total energy expenditure, 21.0, 15.4, and 15.1%; and, for work, 4.5, 5.0, and 5.4%. Anaerobic energy expenditure made a significant contribution to exercise energy expenditure for all lifts (p < 0.05). Changes (Delta) in work were related to changes in energy expenditure (Delta aerobic exercise energy expenditure, r = 0.54; Delta anaerobic exercise energy expenditure, r = 0.88; Delta total energy expenditure, r = 0.88; p < 0.001). Although variability is evident and often considerable during exercise and recovery in this heterogonous sample, we suggest that non-steady-state estimates of aerobic and anaerobic exercise energy expenditure with excess postexercise O2 consumption provide a reasonable estimate of the energy cost of a single bout of weight lifting. Our results agree with those of others, without the need for multiple steady-state measurements or for the assumption of proportional increases between work and O2 uptake.

Unlabelled: Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p

Background: The purpose of this investigation was to identify the onset of the thermic effect of feeding (TEF) after ingestion of a high carbohydrate (CHO) and a high protein (PRO) 1255 kJ (300 kcal) drink., Methods: Resting metabolic rate (RMR) and TEF were measured over 30-minute periods via indirect calorimetry using a ventilated hood technique. Eighteen subjects (7 men and 11 women) completed two randomized, double-blind trials. Data were collected in 1-minute measurement intervals. RMR was subtracted from TEF and the time of onset was obtained when two consecutive data points exceeded 5% and 10% of resting metabolic rate., Results: At 5% above RMR the onset of TEF for CHO was 8.4 +/- 6.2 minutes and was not different as compared to PRO, 8.6 +/- 5.2 minutes (p = 0.77). Likewise, no differences were found with a 10% increase above RMR: CHO, 14.1 +/- 7.5 min; PRO, 16.7 +/- 6.7 min (p = 0.36). Several subjects did not show a 10% increase within 30-min., Conclusion: We conclude that the onset of TEF is variable among subjects but is initiated within about 5 to 20-min for most subjects after ingestion of a 1255 kJ liquid meal. No differences were found between CHO or PRO liquid meals.

Purpose: To identify factors that are predictive of satisfactory acute and long-term pulmonary tolerance of definitive irradiation and, conversely, factors that are predictive of excessive impairment of pulmonary functions. To determine if there is any correlation between early elevation of biochemical markers obtained in blood of irradiated patients and subsequent pulmonary abnormalities as detected by clinical findings, pulmonary function tests, and/or radiographic findings of pneumonitis/fibrosis., Materials and Methods: This was a multi-institutional prospective trial sponsored by the Radiation Therapy Oncology Group. Eligible patients had surgically unresectable or medically inoperable stage II or III non-small cell lung cancer. Pretreatment evaluation included baseline dyspnea index (BDI) and pulmonary function tests (PFT). Radiation therapy consisted of once-daily treatment with 2 Gy to a total of 60 to 66 Gy. A quantitative nuclear medicine perfusion study was correlated to the radiation therapy portals to assess the proportion of lung irradiated. Blood for serum markers (surfactant apoprotein, procollagen type III, interleukin [IL]-1, interleukin-6, and tumor necrosis factor-alpha) was drawn prior to the beginning of radiation therapy and then weekly during treatment (at 10, 20, 30, 40, 50, and 60 Gy). Post-treatment follow-up included PFT every 3 months for 1 year and then annually. The BDI was reevaluated at the same intervals., Results: There were 127 analyzable patients. Squamous cell carcinoma was the predominant histology and 93% of the patients had AJCC stage III disease. The median survival time is 10.9 months with 43% of patients living 1 year and 10% living 3 years. Grade >or=2 acute lung toxicity was seen in 18% of patients; patients least likely to develop lung toxicity are those with undetectable levels of IL-6 at 10 Gy and diffusing capacity of the lung for carbon monoxide percent (DLCO%) >54. Patients most likely to develop acute toxicity are those with elevated IL-6 and age >60 years. Grade >or=2 late lung toxicity was seen in 30% of patients. Karnofsky performance status was the only pretreatment factor predictive of late lung toxicity. The proportion of lung within the irradiated field, BDI indices, physician-assessed baseline dyspnea, and baseline PFT were not predictive of pulmonary toxicity. Using grade >or=2 toxicity as an event, age >60 years, gender, and a surfactant level <797 at 20 Gy were predictive of late lung toxicity., Conclusions: Elevated levels of serum IL-6 after 10 Gy of lung irradiation appear to predict grade >or=2 acute lung toxicity, and high serum levels of surfactant apoproteins at 20 Gy correlated with grade >or=2 late pulmonary toxicity. These findings need to be confirmed but could be useful in a model to predict risk of pulmonary injury with high doses of radiation. For future studies, it is necessary to evaluate serum markers at multiple time-points during treatment, and quality control is critical during the collection, storage, and analysis of these serum markers.

Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.