Cold-Water Immersion and Lower Limb Muscle Oxygen Consumption as Measured by Near-Infrared Spectroscopy in Trained Endurance Athletes.

CONTEXT: Cold-water immersion (CWI) has been reported to reduce tissue metabolism postimmersion, but physiological data are lacking regarding the muscle metabolic response to its application. Near-infrared spectroscopy (NIRS) is a noninvasive optical technique that can inform muscle hemodynamics and tissue metabolism. OBJECTIVE: To investigate the effects of CWI at 2 water temperatures (10°C and 15°C) on NIRS-calculated measurements of muscle oxygen consumption (mVO2). DESIGN: Crossover study. SETTING: University sports rehabilitation center. PATIENTS OR OTHER PARTICIPANTS: A total of 11 male National Collegiate Athletic Association Division II long-distance runners (age = 23.4 ± 3.4 years, height = 1.8 ± 0.1 m, mass = 68.8 ± 10.7 kg, mean adipose tissue thickness = 6.7 ± 2.7 mm). INTERVENTION(S): Cold-water immersion at 10°C and 15°C for 20 minutes. MAIN OUTCOME MEASURE(S): We calculated mVO2 preimmersion and postimmersion at water temperatures of 10°C and 15°C. Changes in tissue oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb), total hemoglobin (tHb), hemoglobin difference (Hbdiff), and tissue saturation index (TSI %) were measured during the 20-minute immersion at both temperatures. RESULTS: We observed a decrease in mVO2 after immersion at both 10°C and 15°C (F1,9 = 27.7801, P = .001). During the 20-minute immersion at both temperatures, we noted a main effect of time for O2Hb (F3,27 = 14.227, P = .001), HHb (F3,27 = 5.749, P = .009), tHb (F3,27 = 24.786, P = .001), and Hbdiff (F3,27 = 3.894, P = .020), in which values decreased over the course of immersion. Post hoc pairwise comparisons showed that these changes occurred within the final 5 minutes of immersion for tHb and O2Hb. CONCLUSIONS: A 20-minute CWI at 10°C and 15°C led to a reduction in mVO2. This was greater after immersion at 10°C. The reduction in mVO2 suggests a decrease in muscle metabolic activity (ie, O2 use after CWI). Calculating mVO2 via the NIRS-occlusion technique may offer further insight into muscle metabolic responses beyond what is attainable from observing the NIRS primary signals.

Longitudinal clusters of pain and stiffness in polymyalgia rheumatica: 2-year results from the PMR Cohort Study.

OBJECTIVES: To investigate potential subgroups of primary care-diagnosed patients with PMR based on self-reported pain and stiffness severity over time. METHODS: A total of 652 people with an incident PMR diagnosis were recruited from English general practices and completed a baseline postal questionnaire. They were followed up with a further six questionnaires over a 2 year period. A total of 446 people completed the 2 year follow-up. Pain and stiffness were reported on a 0-10 numerical rating scale. Latent class growth analysis was used to estimate the joint trajectories of pain and stiffness over time. A combination of statistical and clinical considerations was used to choose the number of clusters. Characteristics of the classes were described. RESULTS: Five clusters were identified. One cluster represented the profile of 'classical' PMR symptoms and one represented sustained symptoms that may not be PMR. The other three clusters displayed a partial recovery, a recovery followed by worsening and a slow, but sustained recovery. Those displaying classical PMR symptoms were in better overall health at diagnosis than the other groups. CONCLUSION: PMR is a heterogeneous condition, with a number of phenotypes. The spectrum of presentation, as well as varying responses to treatment, may be related to underlying health status at diagnosis. Future research should seek to stratify patients at diagnosis to identify those likely to have a poor recovery and in need of an alternative treatment pathway. Clinicians should be aware of the different experiences of patients and monitor symptoms closely, even where there is initial improvement.

Examining management and research priorities in patients with polymyalgia rheumatica: a primary care questionnaire survey.

INTRODUCTION/OBJECTIVES: Polymyalgia rheumatica (PMR) is a common inflammatory disorder that is usually managed with oral glucocorticoids, which although effective can cause significant adverse events. Support group survey data suggests length of glucocorticoid treatment and managing side effects are key priority areas of management for patients. Recognising that not all patients will access patient support organisations, our objective was to identify priorities for PMR management and research among primary care PMR patients. METHOD: All adults aged ≥ 50 years registered with 150 English general practices who had a first read code for PMR in their medical records in the preceding 3 years were mailed a self-completion questionnaire (n = 704). Survey items included questions regarding patient priorities for PMR management (from a pre-defined list of 10 items) and suggestions for future research (8 items, plus a free-text option), which were developed in collaboration with PMRGCAuk. RESULTS: Five hundred fifty patients responded (78%). The mean (SD) age was 74.1 (8.5) years and 361 (66%) were female. Priority research areas were focused on how to better manage pain, stiffness and fatigue (431, 78%), improving the diagnosis of PMR (393, 71%) and steroid management (342, 62%). CONCLUSIONS: This survey of PMR patients suggests that symptom management, early diagnosis and managing medication are key areas for patients for future research. Researchers and funding organisations should be aware of these priorities if we are to generate research findings that are relevant to the widest range of stakeholders.

Bioengineered AAV Capsids with Combined High Human Liver Transduction In Vivo and Unique Humoral Seroreactivity.

Existing recombinant adeno-associated virus (rAAV) serotypes for delivering in vivo gene therapy treatments for human liver diseases have not yielded combined high-level human hepatocyte transduction and favorable humoral neutralization properties in diverse patient groups. Yet, these combined properties are important for therapeutic efficacy. To bioengineer capsids that exhibit both unique seroreactivity profiles and functionally transduce human hepatocytes at therapeutically relevant levels, we performed multiplexed sequential directed evolution screens using diverse capsid libraries in both primary human hepatocytes in vivo and with pooled human sera from thousands of patients. AAV libraries were subjected to five rounds of in vivo selection in xenografted mice with human livers to isolate an enriched human-hepatotropic library that was then used as input for a sequential on-bead screen against pooled human immunoglobulins. Evolved variants were vectorized and validated against existing hepatotropic serotypes. Two of the evolved AAV serotypes, NP40 and NP59, exhibited dramatically improved functional human hepatocyte transduction in vivo in xenografted mice with human livers, along with favorable human seroreactivity profiles, compared with existing serotypes. These novel capsids represent enhanced vector delivery systems for future human liver gene therapy applications.

Symptom Recognition and Perceived Urgency of Help-Seeking for Rheumatoid Arthritis and Other Diseases in the General Public: A Mixed Method Approach.

OBJECTIVE: Clinical outcomes in rheumatoid arthritis (RA) are improved if the disease is treated early. However, treatment is often significantly delayed as a result of delayed help-seeking by patients who fail to recognize its symptoms or the need for rapid medical attention. Two studies were conducted to investigate the role of symptom recognition in help-seeking for the symptoms of RA, and compared this to symptom recognition and help-seeking in angina and bowel cancer. METHODS: A qualitative interview study with 31 individuals and a survey of 1,088 members of the general public (all without RA) were conducted. Both studies used vignettes describing the symptoms of RA, bowel cancer, and angina. Participants made causal attributions and rated the perceived seriousness of the symptoms and the urgency with which they would seek medical help if confronted with these symptoms. RESULTS: Only a small proportion of participants in both studies recognized the symptoms of RA, whereas the symptoms of bowel cancer and angina were readily recognized by many participants and considered to be more serious and to require more rapid medical attention (Z = 14.7-34.2, P < 0.001). CONCLUSION: Accurate symptom attribution and the perception that symptoms are indicative of a serious underlying condition are both important drivers for rapid help-seeking. In the case of angina and bowel cancer, recent campaigns have promoted not only recognition of symptoms and their seriousness, but also emphasized the consequences of not seeking timely help. Our results suggest that these consequences should also be addressed in any public health campaign for RA.

Targeting oxidative stress in embryonal rhabdomyosarcoma.

Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.