Cardiorespiratory fitness and circadian rhythms in adolescents: a pilot study.

Although cardiorespiratory fitness (CRF), an important marker of youth health, is associated with earlier sleep/wake schedule, its relationship with circadian rhythms is unclear. This study examined the associations between CRF and rhythm variables in adolescents. Eighteen healthy adolescents (10 females and 8 males; Mage = 14.6 ± 2.3 yr) completed two study visits on weekdays bracketing an ambulatory assessment during summer vacation. Visit 1 included in-laboratory CRF assessment (peak V̇o2) using a ramp-type progressive cycle ergometry protocol and gas exchange measurement, which was followed by 7-14 days of actigraphy to assess sleep/wake patterns and 24-h activity rhythms. During Visit 2, chronotype, social jetlag (i.e., the difference in midsleep time between weekdays and weekends), and phase preference were assessed using a questionnaire, and hourly saliva samples were collected to determine the dim light melatonin onset (DLMO) phase. All analyses were adjusted for sex, pubertal status, and physical activity. Greater peak V̇o2 was associated with earlier sleep/wake times and circadian phase measures, including acrophase, UP time, DOWN time, last activity peak (LAP) time, and chronotype (all P < 0.05). Peak V̇o2 was negatively associated with social jetlag (P = 0.02). In addition, the mixed-model analysis revealed a significant interaction effect between peak V̇o2 and actigraphy-estimated hour-by-hour activity patterns (P < 0.001), with the strongest effects observed at around the time of waking (0600-1000). In healthy adolescents, better CRF was associated with an earlier circadian phase and increased activity levels notably during the morning. Future studies are needed to investigate the longitudinal effects of the interactions between CRF and advanced rhythms on health outcomes.NEW & NOTEWORTHY In healthy adolescents, better cardiorespiratory fitness, as assessed by the gold standard measure [laboratory-based assessment of peak oxygen consumption (V̇o2)], was associated with earlier circadian timing of sleep/wake patterns, rest-activity rhythms and chronotype, and less social jetlag. These findings highlight the close interrelationships between fitness and rhythms and raise the possibility that maintaining higher cardiorespiratory fitness levels alongside earlier sleep/wake schedule and activity rhythms may be important behavioral intervention targets to promote health in adolescents.

Rapid, non-invasive measurement of gastric emptying rate using transcutaneous fluorescence spectroscopy.

Gastric emptying rate (GER) signifies the rate at which the stomach empties following ingestion of a meal and is relevant to a wide range of clinical conditions. GER also represents a rate limiting step in small intestinal absorption and so is widely assessed for research purposes. Despite the clinical and physiological importance of gastric emptying, methods used to measure GER possess a series of limitations (including being invasive, slow or unsuitable for certain patient populations). Here, we present a new technique based on transcutaneous (through-the-skin) fluorescence spectroscopy that is fast, non-invasive, and does not require the collection of samples or laboratory-based analysis. Thus, this approach has the potential to allow immediate reporting of clinical results. Using this new method, participants receive an oral dose of a fluorescent contrast agent and a wearable probe detects the uptake of the agent from the gut into the blood stream. Analysis of the resulting data then permits the calculation of GER. We compared our spectroscopic technique to the paracetamol absorption test (a clinically approved GER test) in a clinical study of 20 participants. Results demonstrated good agreement between the two approaches and, hence, the clear potential of transcutaneous fluorescence spectroscopy for clinical assessment of GER.

A unique case of progressive hemifacial microsomia or Parry-Romberg syndrome associated with limb and brain anomalies with normal neurological findings: A review of the literature.

In this report, we describe an unusual case of progressive hemifacial atrophy or Parry-Romberg syndrome in a 10-year-old girl with progressive hemifacial microsomia and limb anomalies who had brain magnetic resonance imaging (MRI) findings of white matter hyper-intensities. Patients typically present with neurological manifestations such as epilepsy, facial pain, and migraines and ophthalmological symptoms in conjunction with white matter lesions. The patient demonstrated normal cognition and psychomotor development despite the presence of white matter lesions in her frontal lobe that is commonly associated with neurological symptoms. This report brings attention to the complicated relationship between facial, limb and brain imaging findings in Parry-Romberg syndrome and differentiates it from hemifacial microsomia syndrome.

Transcutaneous fluorescence spectroscopy as a tool for non-invasive monitoring of gut function: first clinical experiences.

Gastro-intestinal function plays a vital role in conditions ranging from inflammatory bowel disease and HIV through to sepsis and malnutrition. However, the techniques that are currently used to assess gut function are either highly invasive or unreliable. Here we present an alternative, non-invasive sensing modality for assessment of gut function based on fluorescence spectroscopy. In this approach, patients receive an oral dose of a fluorescent contrast agent and a fibre-optic probe is used to make fluorescence measurements through the skin. This provides a readout of the degree to which fluorescent dyes have permeated from the gut into the blood stream. We present preliminary results from our first measurements in human volunteers demonstrating the potential of the technique for non-invasive monitoring of multiple aspects of gastro-intestinal health.

Strong social relationships are associated with decreased longevity in a facultatively social mammal.

Humans in strong social relationships are more likely to live longer because social relationships may buffer stressors and thus have protective effects. However, a shortcoming of human studies is that they often rely on self-reporting of these relationships. By contrast, observational studies of non-human animals permit detailed analyses of the specific nature of social relationships. Thus, discoveries that some social animals live longer and healthier lives if they are involved in social grooming, forage together or have more affiliative associates emphasizes the potential importance of social relationships on health and longevity. Previous studies have focused on the impact of social metrics on longevity in obligately social species. However, if sociality indeed has a key role in longevity, we might expect that affiliative relationships should also influence longevity in less social species. We focused on socially flexible yellow-bellied marmots (Marmota flaviventer) and asked whether female longevity covaries with the specific nature of social relationships. We quantified social relationships with social network statistics that were based on affiliative interactions, and then estimated the correlation between longevity and sociality using bivariate models. We found a significant negative phenotypic correlation between affiliative social relationship strength and longevity; marmots with greater degree, closeness and those with a greater negative average shortest path length died at younger ages. We conclude that sociality plays an important role in longevity, but how it does so may depend on whether a species is obligately or facultatively social.

Sea anemones modify their hiding time based on their commensal damselfish.

Animals often retreat to refugia when alarmed and the time they spend hiding reflects an economic decision that trades off reducing predation risk with other beneficial activities. Typically, refugia such as burrows are static, but some refugia are dynamic. For species with defensive mutualisms, hiding might be contingent on their mutualist's behaviour. We disturbed and quantified hiding time in magnificent sea anemones, Heteractis magnifica, and their associated domino damselfish, Dascyllus trimaculatus. We found that sea anemone hiding behaviour was dependent on the number and behaviour of their commensal fish: anemones emerged sooner when they had more associated fish and faster returning fish. Together, these results demonstrate that hiding behaviour can be influenced by the behaviour of a commensal; such dynamic mutualisms may be found in other systems.

PD-1 inhibition and treatment of advanced melanoma-role of pembrolizumab.

Remarkable clinical responses have been seen in patients with metastatic melanoma with targeted therapy (BRAFi vemurafenib, MEKi) and with modern immune cell-based approaches such as TCR engineered adoptive cell transfer (ACT) and earlier experiences with high-dose IL-2. The proximal mediators of these immune therapies are tumor-reactive CTL. Various mechanisms of resistance to immune-mediated apoptotic signals have been described, including phenotypic changes, effector cell exhaustion, functional tolerance, deficiencies in Ag processing and presentation, and mutation or down-regulation of antigenic epitopes. The immune system and drugs eradicate tumors via apoptosis. Therefore, tumors' resistance to apoptosis may be a determining factor that limits the efficacy of immunotherapies. It is predicted that these therapies have limited efficacy in patients whose melanomas have developed resistance to targeted therapy such as vemurafenib. Upregulation of the immune checkpoint molecule CTLA-4 on activated T cells and its interaction with CD80/86 blocks T cell activation. The fully humanized mAb ipilimumab blocks this interaction, resulting in sustained T cell stimulation. Likewise, the programmed death receptor 1 (PD-1) is another member of the B7:CD28 family of costimulatory molecules that regulates T cell activation, whose ligand (PD-L1) is expressed on melanomas. The human anti-PD-1 mAb, Pembrolizumab, overcomes tolerance, has a favorable pharmacokinetics profile with minimal undesired toxic side effects and has shown remarkable improvement in melanoma therapy. This review focuses on recent advances in the development of various anti-PD-1 checkpoint blockade antibodies and will summarize recent clinical data using immune checkpoint blocking antibodies.