Impaired muscle oxygen use at onset of exercise in peripheral arterial disease

ObjectivesIn patients with peripheral arterial disease (PAD), abnormal muscle metabolism and impaired oxygen delivery distal to the arterial occlusions may contribute to the exercise limitation observed in this population. Muscle tissue hemoglobin saturation (StO2), measured with near-infrared spectroscopy, reflects the relative contributions of oxygen delivery and oxygen use. Thus differences in the kinetics of StO2 in response to exercise may yield important insight into the potential mechanisms associated with the PAD exercise impairment. The purposes of this study were to characterize the muscle oxygenation responses in patients with PAD and in healthy control subjects at the onset of exercise, and to compare the kinetics of StO2 desaturation. We hypothesized that at the onset of exercise the kinetics of StO2 desaturation would be slowed in PAD compared with control responses.Material and methodsSix patients with PAD and 6 healthy control subjects from a university center were examined in a prospective cross-sectional analysis that evaluated the desaturation kinetics of StO2 at the onset of walking exercise. On separate visits subjects performed graded treadmill exercise and 3 constant work rate treadmill tests equivalent to ∼60% (low), ∼80% (medium), and 100% (peak) of their peak exercise work rate. Gastrocnemious muscle StO2 response profiles (InSpectra tissue spectrometer) were measured at rest and across the rest to exercise transition. Muscle StO2 responses were characterized by an exponential mathematical model. The end point value was taken as the time constant of StO2 desaturation after onset of exercise (ie, equivalent to time to reach approximately 63% of StO2 decrease).ResultsThe patients with PAD and the control subjects were of similar age and activity level. The qualitative patterns of StO2 responses at onset of exercise were also similar between patients and control subjects at all work rates. However, the kinetic time constants of StO2 desaturation were prolonged in patients with PAD versus control subjects (averaged time constant across all work rates, 21.9 ± 9.4 seconds vs 4.9 ± 2.2 seconds; P < .01).ConclusionsThe slowed muscle StO2 kinetics in PAD are consistent with an impairment in muscle oxygen use at the onset of walking exercise. Impaired muscle metabolism may contribute to the altered physiologic responses to exercise and to exercise impairment in patients with PAD

A review of the Namaqua gecko, Pachydactylus namaquensis (Reptilia: Gekkonidae) from southern Africa, with the description of two new species

An analysis of morphological and allozyme variation in the Namaqua gecko, Pachydactylus namaquensis from southern Africa is presented. Three separately evolving lineages, well defined by morphology and allozyme variation, are identified. The isolated southern population, occurring on the southern escarpment and Cape Fold Mountains surrounding the western Little Karoo, is named P. kladamderma sp. nov., and is characterized by a slit-like ear opening, low number of granules bordering the mental (3-6) and mental and adjacent infralabials (513), the frequent (79%) occurence of the supralabial entering the nostril, and its drab brown base colouration. A northern population, occurring in southern Namibia and the Richtersveld is named P. haackei sp. nov., and is characterized by its more rounded or squared ear opening; high number of granules bordering the mental and adjacent infralabials (11-19), the general exclusion of the supralabial from the nostril (only 3.7% entry), and brighter, lighter colouration. It is further differentiated from P. kladaroderma on the basis of fixed differences at 11 allozyme loci. Both new species differ from P. namaquensis,  which is mainly restricted to Little Namaqualand, but is sympatric with P. haackei in the Lower Orange River region, by their more heterogenous dorsal scalation, smaller cloacal spurs, lack of spine-like tubercles on the lateral surfaces of the tail, and more fragile skin. The type locality of P. namaquensis is restricted to ‘the vicinity of Springbok, Little Namaqualand, Northern Cape Province, South Africa’

Testing Modules for Experiments in Stellar Astrophysics (MESA)

Regular, automated testing is a foundational principle of modern software development. Numerous widely-used continuous integration systems exist, but they are often not suitable for the unique needs of scientific simulation software. Here we describe the testing infrastructure developed for and used by the Modules for Experiments in Stellar Astrophysics (MESA) project. This system allows the computationally-demanding MESA test suite to be regularly run on a heterogeneous set of computers and aggregates and displays the testing results in a form that allows for the rapid identification and diagnosis of regressions. Regularly collecting comprehensive testing data also enables longitudinal studies of the performance of the software and the properties of the models it generates.Comment: 12 page, 7 figures, Accepted to ApJ

Effect of Combination Folic Acid, Vitamin B6 , and Vitamin B12 Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial.

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B12 or B6 , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. © 2017 American Society for Bone and Mineral Research

Development and assessment of a clinical calculator for estimating the likelihood of recurrence and survival among patients with locally advanced rectal cancer treated with chemotherapy, radiotherapy, and surgery

Importance: Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed. Objective: To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score. Design, Setting, and Participants: This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using Cox proportional hazards and multivariable regression analyses with restricted cubic splines. Because patients with complete pathological response to neoadjuvant therapy had uniformly favorable outcomes, their predictions were obtained separately. The study included 1400 patients with stage II or III rectal cancer who received treatment with chemotherapy, radiotherapy, and surgery at 2 comprehensive cancer centers (Memorial Sloan Kettering [MSK] Cancer Center and Siteman Cancer Center [SCC]) between January 1, 1998, and December 31, 2017. Patients from the MSK cohort received chemoradiation, surgery, and adjuvant chemotherapy from January 1, 1998, to December 31, 2014; these patients were randomly assigned to either a model training group or an internal validation group. Models were externally validated using data from the SCC cohort, who received either chemoradiation, surgery, and adjuvant chemotherapy (chemoradiotherapy group) or short-course radiotherapy, consolidation chemotherapy, and surgery (total neoadjuvant therapy with short-course radiotherapy group) from January 1, 2009, to December 31, 2017. Data were analyzed from March 1, 2020, to January 10, 2021. Exposures: Chemotherapy, radiotherapy, chemoradiotherapy, and surgery. Main Outcomes and Measures: Recurrence-free survival and OS were the outcome measures, and the discriminatory performance of the clinical calculators was measured with concordance index and calibration plots. The ability of the clinical calculators to predict RFS and OS was compared with that of the AJCC staging system and the NAR score. The models for RFS and OS among patients with incomplete pathological response included postoperative pathological tumor category, number of positive lymph nodes, tumor distance from anal verge, and large- and small-vessel venous and perineural invasion; age was included in the risk model for OS. The final clinical calculators provided RFS and OS estimates derived from Kaplan-Meier curves for patients with complete pathological response and from risk models for patients with incomplete pathological response. Results: Among 1400 total patients with locally advanced rectal cancer, the median age was 57.8 years (range, 18.0-91.9 years), and 863 patients (61.6%) were male, with tumors at a median distance of 6.7 cm (range, 0-15.0 cm) from the anal verge. The MSK cohort comprised 1069 patients; of those, 710 were assigned to the model training group and 359 were assigned to the internal validation group. The SCC cohort comprised 331 patients; of those, 200 were assigned to the chemoradiotherapy group and 131 were assigned to the total neoadjuvant therapy with short-course radiotherapy group. The concordance indices in the MSK validation data set were 0.70 (95% CI, 0.65-0.76) for RFS and 0.73 (95% CI, 0.65-0.80) for OS. In the external SCC data set, the concordance indices in the chemoradiotherapy group were 0.71 (95% CI, 0.62-0.81) for RFS and 0.72 (95% CI, 0.59-0.85) for OS; the concordance indices in the total neoadjuvant therapy with short-course radiotherapy group were 0.62 (95% CI, 0.49-0.75) for RFS and 0.67 (95% CI, 0.46-0.84) for OS. Calibration plots confirmed good agreement between predicted and observed events. These results compared favorably with predictions based on the AJCC staging system (concordance indices for MSK validation: RFS = 0.69 [95% CI, 0.64-0.74]; OS = 0.67 [95% CI, 0.58-0.75]) and the NAR score (concordance indices for MSK validation: RFS = 0.56 [95% CI, 0.50-0.63]; OS = 0.56 [95% CI, 0.46-0.66]). Furthermore, the clinical calculators provided more individualized outcome estimates compared with the categorical schemas (eg, estimated RFS for patients with AJCC stage IIIB disease ranged from 7% to 68%). Conclusions and Relevance: In this prognostic study, clinical calculators were developed and validated; these calculators provided more individualized estimates of the likelihood of RFS and OS than the AJCC staging system or the NAR score among patients with rectal cancer who received multimodal treatment. The calculators were easy to use and applicable to both short- and long-course radiotherapy regimens, and they may be used to inform surveillance strategies and facilitate future clinical trials and statistical power calculations

Brain Morphological Signatures for Chronic Pain

Chronic pain can be understood not only as an altered functional state, but also as a consequence of neuronal plasticity. Here we use in vivo structural MRI to compare global, local, and architectural changes in gray matter properties in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA), relative to healthy controls. We find that different chronic pain types exhibit unique anatomical ‘brain signatures’. Only the CBP group showed altered whole-brain gray matter volume, while regional gray matter density was distinct for each group. Voxel-wise comparison of gray matter density showed that the impact on the extent of chronicity of pain was localized to a common set of regions across all conditions. When gray matter density was examined for large regions approximating Brodmann areas, it exhibited unique large-scale distributed networks for each group. We derived a barcode, summarized by a single index of within-subject co-variation of gray matter density, which enabled classification of individual brains to their conditions with high accuracy. This index also enabled calculating time constants and asymptotic amplitudes for an exponential increase in brain re-organization with pain chronicity, and showed that brain reorganization with pain chronicity was 6 times slower and twice as large in CBP in comparison to CRPS. The results show an exuberance of brain anatomical reorganization peculiar to each condition and as such reflecting the unique maladaptive physiology of different types of chronic pain

Multiwavelength Observations of the Second Largest Known FR II Radio Galaxy, NVSS 2146+82

We present multi-frequency VLA, multicolor CCD imaging, optical spectroscopy, and ROSAT HRI observations of the giant FR II radio galaxy NVSS 2146+82. This galaxy, which was discovered by the NRAO VLA Sky Survey (NVSS), has an angular extent of nearly 20' from lobe to lobe. The radio structure is normal for an FR II source except for its large size and regions in the lobes with unusually flat radio spectra. Our spectroscopy indicates that the optical counterpart of the radio core is at a redshift of z=0.145, so the linear size of the radio structure is ~4 h_50^-1 Mpc. This object is therefore the second largest FR II known (3C 236 is ~6 h_50^-1 Mpc). Optical imaging of the field surrounding the host galaxy reveals an excess number of candidate galaxy cluster members above the number typically found in the field surrounding a giant radio galaxy. WIYN HYDRA spectra of a sample of the candidate cluster members reveal that six share the same redshift as NVSS 2146+82, indicating the presence of at least a ``rich group'' containing the FR II host galaxy. ROSAT HRI observations of NVSS 2146+82 place upper limits on the X-ray flux of 1.33 x 10^-13 ergs cm^-2 s^-1 for any hot IGM and 3.52 x 10^-14 ergs cm^-2 s^-1 for an X-ray AGN, thereby limiting any X-ray emission at the distance of the radio galaxy to that typical of a poor group or weak AGN. Several other giant radio galaxies have been found in regions with overdensities of nearby galaxies, and a separate study has shown that groups containing FR IIs are underluminous in X-rays compared to groups without radio sources. We speculate that the presence of the host galaxy in an optically rich group of galaxies that is underluminous in X-rays may be related to the giant radio galaxy phenomenon.Comment: 46 pages, 15 figures, AASTeX aaspp4 style, accepted for publication in A