Implementation of an ISO 15189 accredited next generation sequencing service for cell-free total nucleic acid (cfTNA) analysis to facilitate driver mutation reporting in blood: the experience of a clinical diagnostic laboratory.

AIMS: Next generation sequencing (NGS) on tumour tissue is integral to the delivery of personalised medicine and targeted therapy. NGS on liquid biopsy, a much less invasive technology, is an emerging clinical tool that has rapidly expanded clinical utility. Gene mutations in cell-free total nucleic acids (cfTNA) circulating in the blood are representative of whole tumour biology and can reveal different mutations from different tumour sites, thus addressing tumour heterogeneity challenges. METHODS: The novel Ion Torrent Genexus NGS system with automated sample preparation, onboard library preparation, templating, sequencing, data analysis and Oncomine Reporter software was used. cfTNA extracted from plasma was verified with the targeted pan-cancer (~50 genes) Oncomine Precision Assay (OPA). Assessment criteria included analytical sensitivity, specificity, limits of detection (LOD), accuracy, repeatability, reproducibility and the establishment of performance metrics. RESULTS: An ISO 15189 accredited, minimally invasive cfTNA NGS diagnostic service has been implemented. High sensitivity (>83%) and specificity between plasma and tissue were observed. A sequencing LOD of 1.2% was achieved when the depth of coverage was >22 000×. A reduction (>68%) in turnaround time (TAT) of liquid biopsy results was achieved: 5 days TAT for in-house analysis from sample receipt to a final report issued to oncologists as compared with >15 days from reference laboratories. CONCLUSION: Tumour-derived somatic variants can now be reliably assessed from plasma to provide minimally invasive tumour profiling. Successful implementation of this accredited service resulted in:Appropriate molecular profiling of patients where tumour tissue is unavailable or inaccessible.Rapid TAT of plasma NGS results.

A Cautionary Note on Pembrolizumab use in Patients with Ascending Aortic Aneurysms.

Case description: We describe a case of a patient treated with pembrolizumab (an immune checkpoint inhibitor) for metastatic scalp melanoma. He had a previous history of colorectal cancer, prostatic cancer and chronic polymyalgia rheumatica. The patient was known to have a stable ascending aortic aneurysm of 4.5 cm. However, he developed a rapid expansion of the ascending aortic aneurysm with the size crossing the threshold for surgery. The patient was referred to the cardiothoracic surgery service for intervention and he subsequently underwent surgery. The patient was electively admitted one week later for resection of aortic aneurysm, aortoplasty and external graft fixation. Pathologically, gross evidence of dissection was not identified; however, the histological analysis of the media showed laminar medial necrosis, multifocal in nature, with occasional clusters of histiocytic cells appreciated at their edge reminiscent of that seen in an inflammatory aortitis (granulomatous/giant cell type). Discussion: Immune checkpoint inhibitor-induced aortitis is becoming increasingly evident, and its presentation can vary. It has been discovered incidentally on surveillance imaging with the use of nivolumab. In other cases, patients have been symptomatic to severely symptomatic. Atezolizumab with carboplatin and etoposide has been reported to cause abdominal aortitis which was responsive to corticosteroids and subsequent discontinuation of atezolizumab. Pembrolizumab has been linked to a case of transverse aortic arch aortitis. In our case, the inflammatory aortitis due to pembrolizumab was the cause of the rapid expansion of the ascending aortic aneurysm. Conclusion: Patients with known aortic aneurysms should undergo careful surveillance when commencing immune-checkpoint inhibitor therapy. LEARNING POINTS: Immune checkpoint inhibitors are being increasingly used in the treatment of metastatic malignancy. However, they are a relatively new group of medications, and the side effect profile of each is yet to be fully recognised. Aortitis has occurred with several different immune checkpoint inhibitors.Patients with known aortic aneurysms should undergo careful surveillance when commencing immune checkpoint inhibitors.All interventional therapeutic options should be considered early in these patients on the development of aneurysmal expansion.

Effect of Menstrual Cycle Phase and Hormonal Contraceptives on Resting Metabolic Rate and Body Composition.

The cyclical changes in sex hormones across the menstrual cycle (MC) are associated with various biological changes that may alter resting metabolic rate (RMR) and body composition estimates. Hormonal contraceptive (HC) use must also be considered given their impact on endogenous sex hormone concentrations and synchronous exogenous profiles. The purpose of this study was to determine if RMR and dual-energy X-ray absorptiometry body composition estimates change across the MC and differ compared with HC users. This was accomplished during a 5-week training camp involving naturally cycling athletes (n = 11) and HC users (n = 7 subdermal progestin implant, n = 4 combined monophasic oral contraceptive pill, n = 1 injection) from the National Rugby League Indigenous Women's Academy. MC phase was retrospectively confirmed via serum estradiol and progesterone concentrations and a positive ovulation test. HC users had serum estradiol and progesterone concentrations assessed at the time point of testing. Results were analyzed using general linear mixed model. There was no effect of MC phase on absolute RMR (p = .877), relative RMR (p = .957), or dual-energy X-ray absorptiometry body composition estimates (p > .05). There was no effect of HC use on absolute RMR (p = .069), relative RMR (p = .679), or fat mass estimates (p = .766), but HC users had a greater fat-free mass and lean body mass than naturally cycling athletes (p = .028). Our findings suggest that RMR and dual-energy X-ray absorptiometry body composition estimates do not significantly differ due to changes in sex hormones in a group of athletes, and measurements can be compared between MC phases or with HC usage without variations in sex hormones causing additional noise.

Iron Absorption in Highly Trained Male Runners: Does it Matter When and Where You Eat Your Iron?

PURPOSE: We examined iron absorption and its regulation during two common scenarios experienced by endurance athletes. Our aims were to: (i) compare the effects of preexercise versus postexercise iron intake on iron absorption; and (ii) compare the impact of training at altitude (1800 m) on iron absorption preexercise. METHODS: Male runners (n = 18) completed three exercise trials over a 5-wk period, each preceded by 24 h of standardized low-iron diets. First, athletes completed two 60-min treadmill running trials at 65% V̇O2max at near sea-level (580 m). In a randomized order, preexercise and postexercise test meals labeled with 4 mg of 57Fe or 58Fe were consumed 30 min before or 30 min after exercise. Then, the same exercise trial was performed after living and training at altitude (~1800 m) for 7 d, with the labeled test meal consumed 30 min preexercise. We collected venous blood samples preexercise and postexercise for markers of iron status and regulation, and 14 d later to measure erythrocyte isotope incorporation. RESULTS: No differences in fractional iron absorption were evident when test meals were consumed preexercise (7.3% [4.4, 12.1]) or postexercise (6.2% [3.1, 12.5]) (n = 18; P = 0.058). Iron absorption preexercise was greater at altitude (18.4% [10.6, 32.0]) than at near sea-level (n = 17; P < 0.001) and hepcidin concentrations at altitude were lower at rest and 3 h postexercise compared with near sea level (P < 0.001). CONCLUSIONS: In an acute setting, preexercise and postexercise iron absorption is comparable if consumed within 30 min of exercise. Preexercise iron absorption increases 2.6-fold at altitude compared with near sea-level, likely due to the homeostatic response to provide iron for enhanced erythropoiesis and maintain iron stores.

Severe Aortic Valvular Incompetence From IgG4-Related Disease: An Unusual Entity.

IgG4-related disease (IgG4-RD) is a new clinical entity characterized by lymphoplasmacytic lesions rich in IgG4-positive plasma cells. Myocardial involvement is extremely rare and not a typical cardiovascular manifestation of IgG4-RD. We report a rare case of IgG4-RD-associated myocardial mass causing severe aortic incompetence, successfully treated with surgery and corticosteroids. (Level of Difficulty: Intermediate.).

Menstrual cycle hormones and oral contraceptives: a multimethod systems physiology-based review of their impact on key aspects of female physiology.

Hormonal changes around ovulation divide the menstrual cycle (MC) into the follicular and luteal phases. In addition, oral contraceptives (OCs) have active (higher hormone) and placebo phases. Although there are some MC-based effects on various physiological outcomes, we found these differences relatively subtle and difficult to attribute to specific hormones, as estrogen and progesterone fluctuate rather than operating in a complete on/off pattern as observed in cellular or preclinical models often used to substantiate human data. A broad review reveals that the differences between the follicular and luteal phases and between OC active and placebo phases are not associated with marked differences in exercise performance and appear unlikely to influence muscular hypertrophy in response to resistance exercise training. A systematic review and meta-analysis of substrate oxidation between MC phases revealed no difference between phases in the relative carbohydrate and fat oxidation at rest and during acute aerobic exercise. Vascular differences between MC phases are also relatively small or nonexistent. Although OCs can vary in composition and androgenicity, we acknowledge that much more work remains to be done in this area; however, based on what little evidence is currently available, we do not find compelling support for the notion that OC use significantly influences exercise performance, substrate oxidation, or hypertrophy. It is important to note that the study of females requires better methodological control in many areas. Previous studies lacking such rigor have contributed to premature or incorrect conclusions regarding the effects of the MC and systemic hormones on outcomes. While we acknowledge that the evidence in certain research areas is limited, the consensus view is that the impact of the MC and OC use on various aspects of physiology is small or nonexistent.

Real-world outcomes and toxicity of adjuvant chemotherapy in NSCLC: a single-center experience.

Aim: Adjuvant chemotherapy in NSCLC is associated with modest benefits and significant toxicity. We sought to evaluate the toxicity of adjuvant chemotherapy and disease-specific outcomes in a real-world population. Methods: We performed a retrospective analysis of patients undergoing adjuvant chemotherapy for NSCLC in an Irish center over a 7-year period. We described treatment-associated toxicity, recurrence-free survival and overall survival. Results: 62 patients underwent adjuvant chemotherapy. Treatment-associated hospitalisation occurred in 29% of patients. Relapse was recorded in 56% of patients and median recurrence-free survival was 27 months. Conclusion: High rates of disease recurrence and treatment-associated morbidity were observed in patients receiving adjuvant chemotherapy for NSCLC. Novel therapeutic strategies are required to improve outcomes in this population.

Early NSCLC is primarily managed with lung cancer surgery. Chemotherapy is offered to some patients with early NSCLC after surgery depending on the size of the tumor and lymph node involvement. The benefit of post-surgery (adjuvant) chemotherapy in reducing the chance of cancer recurrence has been shown to be relatively small in previous studies. Large studies of post-surgery chemotherapy in NSCLC have included limited numbers of older patients, and patients with significant medical issues. This study looked to evaluate the safety and treatment-associated side effects of adjuvant chemotherapy in a group of patients more reflective of everyday clinical practice, and to assess the rates of cancer recurrence in these patients. In our study of 62 patients who underwent adjuvant chemotherapy for NSCLC, nearly 1 in 3 patients required hospital admission due to treatment-associated side effects. Almost 40% of patients experienced significant blood test abnormalities (including anaemia, reduced platelets, and reduced white blood cells). Approximately 1 in 4 patients required a reduction in the doses of their treatment due to treatment-associated side effects. More than half of the patients in our study experienced a recurrence of their cancer. Our study demonstrates the significant side effects associated with adjuvant chemotherapy in NSCLC and highlights the need for better-tolerated treatment strategies to reduce cancer recurrence in early NSCLC.

The effect of caffeine on subsequent sleep: A systematic review and meta-analysis.

The consumption of caffeine in response to insufficient sleep may impair the onset and maintenance of subsequent sleep. This systematic review and meta-analysis investigated the effect of caffeine on the characteristics of night-time sleep, with the intent to identify the time after which caffeine should not be consumed prior to bedtime. A systematic search of the literature was undertaken with 24 studies included in the analysis. Caffeine consumption reduced total sleep time by 45 min and sleep efficiency by 7%, with an increase in sleep onset latency of 9 min and wake after sleep onset of 12 min. Duration (+6.1 min) and proportion (+1.7%) of light sleep (N1) increased with caffeine intake and the duration (-11.4 min) and proportion (-1.4%) of deep sleep (N3 and N4) decreased with caffeine intake. To avoid reductions in total sleep time, coffee (107 mg per 250 mL) should be consumed at least 8.8 h prior to bedtime and a standard serve of pre-workout supplement (217.5 mg) should be consumed at least 13.2 h prior to bedtime. The results of the present study provide evidence-based guidance for the appropriate consumption of caffeine to mitigate the deleterious effects on sleep.

IL-36 expression is increased in NSCLC with IL-36 stimulation of lung cancer cells promoting a pro-tumorigenic phenotype.

The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, and have been shown to play a role in the pathogenesis of respiratory diseases such as asthma and COPD. Given the common aetiological links between COPD and lung cancer development, as well as the involvement of other IL-1 family members in lung tumorigenesis, the aim of this work was to investigate the role of IL-36 cytokines in the pathogenesis of lung cancer. In this study we demonstrate that expression of IL-36 cytokines and receptor mRNA and protein are significantly increased in lung cancer tissue compared to adjacent non-tumour tissue. In vitro assays showed that stimulation of two lung cancer cell lines, SKMES-1 human squamous cell and LLC murine lung cancer, with IL-36R agonists resulted in increased cellular migration and proliferation. All IL-36 cytokines induced the expression of pro-inflammatory chemokines in both lung cancer cell lines with synergistic effects identified upon co-stimulation of cells with IL-17, IL-22 and TNFα. Furthermore, we report that IL-36 cytokines induce protein expression of the immune checkpoint inhibitor protein PD-L1 on lung cancer cells. Taken together, this data indicates that targeting IL-36R signalling may be a useful targeted therapy for lung cancer patients with IL-36R+ cancer cells.

Impact of the COVID-19 pandemic on cancer care in Ireland - Perspectives from a COVID-19 and Cancer Working Group.

Upon the COVID-19 pandemic onset in Ireland, cancer service disruptions occurred due to prioritisation of COVID-19 related care, redeployment of staff, initial pausing of screening, diagnostic, medical and surgical oncology procedures, staff shortages due to COVID-19 infection and impacts on the physical and mental health of cancer healthcare workers. This was coupled with reluctance among people with symptoms suspicious for cancer to attend for clinical evaluation, due to concerns of contracting the virus. This was further compounded by a cyber-attack on national health service IT systems on May 14th 2021. The Irish Cancer Society, a national cancer charity with a role in advocacy, research and patient supports, convened a multi-disciplinary stakeholder group (COVID-19 and Cancer Working Group) to reflect on and understand the impact of the pandemic on cancer patients and services in Ireland, and discuss potential mitigation strategies. Perspectives on experiences were gathered across domains including timeliness of data acquisition and its conversion into intelligence, and the resourcing of cancer care to address cancer service impacts. The group highlighted aspects for future research to understand the long-term pandemic impact on cancer outcomes, while also highlighting potential strategies to support cancer services, build resilience and address delayed diagnosis. Additional measures include the need for cancer workforce recruitment and retention, increased mental health supports for both patients and oncology professionals, improvements to public health messaging, a near real-time multimodal national cancer database, and robust digital and physical infrastructure to mitigate impacts of the current pandemic and future challenges to cancer care systems.

Implementation of an ISO15189 accredited next-generation sequencing service with the fully automated Ion Torrent Genexus: the experience of a clinical diagnostic laboratory.

AIMS: Next-generation sequencing (NGS) is integral to the delivery of personalised medicine for targeted cancer therapy. Average turnaround times (TAT) from reference laboratories with advanced expertise in sequencing are typically 2-3 weeks. Prolonged TAT for biomarker analysis can adversely affect patient outcomes. The project aim was to establish an accredited NGS service integrated within a routine clinical diagnostic laboratory, in a designated tertiary cancer centre with no previous experience in NGS or bioinformatics. METHODS: Platform selected was the novel Ion Torrent Genexus Sequencer with automated onboard library preparation, templating, sequencing and data analysis, with subsequent reporting using Oncomine Reporter software.Entire workflow validation was performed with a targeted panel, the Oncomine Precision Assay, on formalin-fixed paraffin embedded clinical tumour samples. Oncomine Reporter software was used to report on variants including mutations, copy number variations and fusions across 50 key genes.Samples included surgical resections, biopsies, cytology and commercial reference material. Assessment of criteria included analytical sensitivity, specificity, limit of detection, accuracy, repeatability and reproducibility, with the establishment of performance metrics and quality parameters. RESULTS: High sensitivity, specificity and reproducibility were achieved. DNA/RNA input requirements optimised to >10 ng, and sequencing performance established with a limit of detection of 5% when depth of coverage of 2500X was reached. This NGS service attained ISO15189 accreditation with no non-conformances and >56% reduction in TAT. CONCLUSION: Successful implementation, clinical validation and accreditation of a novel NGS technology was achieved in this institution, with a significantly improved TAT of results to oncologists.

Short-Term Carbohydrate Restriction Impairs Bone Formation at Rest and During Prolonged Exercise to a Greater Degree than Low Energy Availability.

Bone stress injuries are common in athletes, resulting in time lost from training and competition. Diets that are low in energy availability have been associated with increased circulating bone resorption and reduced bone formation markers, particularly in response to prolonged exercise. However, studies have not separated the effects of low energy availability per se from the associated reduction in carbohydrate availability. The current study aimed to compare the effects of these two restricted states directly. In a parallel group design, 28 elite racewalkers completed two 6-day phases. In the Baseline phase, all athletes adhered to a high carbohydrate/high energy availability diet (CON). During the Adaptation phase, athletes were allocated to one of three dietary groups: CON, low carbohydrate/high fat with high energy availability (LCHF), or low energy availability (LEA). At the end of each phase, a 25-km racewalk was completed, with venous blood taken fasted, pre-exercise, and 0, 1, 3 hours postexercise to measure carboxyterminal telopeptide (CTX), procollagen-1 N-terminal peptide (P1NP), and osteocalcin (carboxylated, gla-OC; undercarboxylated, glu-OC). Following Adaptation, LCHF showed decreased fasted P1NP (~26%; p < 0.0001, d = 3.6), gla-OC (~22%; p = 0.01, d = 1.8), and glu-OC (~41%; p = 0.004, d = 2.1), which were all significantly different from CON (p < 0.01), whereas LEA demonstrated significant, but smaller, reductions in fasted P1NP (~14%; p = 0.02, d = 1.7) and glu-OC (~24%; p = 0.049, d = 1.4). Both LCHF (p = 0.008, d = 1.9) and LEA (p = 0.01, d = 1.7) had significantly higher CTX pre-exercise to 3 hours post-exercise but only LCHF showed lower P1NP concentrations (p < 0.0001, d = 3.2). All markers remained unchanged from Baseline in CON. Short-term carbohydrate restriction appears to result in reduced bone formation markers at rest and during exercise with further exercise-related increases in a marker of bone resorption. Bone formation markers during exercise seem to be maintained with LEA although resorption increased. In contrast, nutritional support with adequate energy and carbohydrate appears to reduce unfavorable bone turnover responses to exercise in elite endurance athletes. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Dietary Inorganic Nitrate as an Ergogenic Aid: An Expert Consensus Derived via the Modified Delphi Technique.

INTRODUCTION: Dietary inorganic nitrate is a popular nutritional supplement, which increases nitric oxide bioavailability and may improve exercise performance. Despite over a decade of research into the effects of dietary nitrate supplementation during exercise there is currently no expert consensus on how, when and for whom this compound could be recommended as an ergogenic aid. Moreover, there is no consensus on the safe administration of dietary nitrate as an ergogenic aid. This study aimed to address these research gaps. METHODS: The modified Delphi technique was used to establish the views of 12 expert panel members on the use of dietary nitrate as an ergogenic aid. Over three iterative rounds (two via questionnaire and one via videoconferencing), the expert panel members voted on 222 statements relating to dietary nitrate as an ergogenic aid. Consensus was reached when > 80% of the panel provided the same answer (i.e. yes or no). Statements for which > 80% of the panel cast a vote of insufficient evidence were categorised as such and removed from further voting. These statements were subsequently used to identify directions for future research. RESULTS: The 12 panel members contributed to voting in all three rounds. A total of 39 statements (17.6%) reached consensus across the three rounds (20 yes, 19 no). In round one, 21 statements reached consensus (11 yes, 10 no). In round two, seven further statements reached consensus (4 yes, 3 no). In round three, an additional 11 statements reached consensus (5 yes, 6 no). The panel agreed that there was insufficient evidence for 134 (60.4%) of the statements, and were unable to agree on the outcome of the remaining statements. CONCLUSIONS: This study provides information on the current expert consensus on dietary nitrate, which may be of value to athletes, coaches, practitioners and researchers. The effects of dietary nitrate appear to be diminished in individuals with a higher aerobic fitness (peak oxygen consumption [V̇O2peak] > 60 ml/kg/min), and therefore, aerobic fitness should be taken into account when considering use of dietary nitrate as an ergogenic aid. It is recommended that athletes looking to benefit from dietary nitrate supplementation should consume 8-16 mmol nitrate acutely or 4-16 mmol/day nitrate chronically (with the final dose ingested 2-4 h pre-exercise) to maximise ergogenic effects, taking into consideration that, from a safety perspective, athletes may be best advised to increase their intake of nitrate via vegetables and vegetable juices. Acute nitrate supplementation up to ~ 16 mmol is believed to be safe, although the safety of chronic nitrate supplementation requires further investigation. The expert panel agreed that there was insufficient evidence for most of the appraised statements, highlighting the need for future research in this area.

Mitral valve replacement due to Libman-Sacks endocarditis: lower limb cellulitis as a red herring.

A 56-year-old woman was admitted due to new ulceration and acute digital ischaemia on a background of chronic leg ulcers bilaterally. Vasculitis screening returned strongly positive lupus anticoagulant levels and elevated anticardiolipin antibodies; these remained elevated at repeat testing. A diagnosis of antiphospholipid syndrome was made. Transthoracic echocardiogram identified a mitral valve lesion suggestive of vegetation and mild mitral valve regurgitation. Blood cultures taken throughout her inpatient admission were negative. Mechanical mitral valve replacement was performed 3 months later, and subsequent culture of the excised tissue returned as sterile. Histological examination showed no morphological signs of infective endocarditis.

Six Days of Low Carbohydrate, Not Energy Availability, Alters the Iron and Immune Response to Exercise in Elite Athletes.

PURPOSE: To quantify the effects of a short-term (6-d) low carbohydrate (CHO) high fat (LCHF), and low energy availability (LEA) diet on immune, inflammatory, and iron-regulatory responses to exercise in endurance athletes. METHODS: Twenty-eight elite male race walkers completed two 6-d diet/training phases. During phase 1 (Baseline), all athletes consumed a high CHO/energy availability (CON) diet (65% CHO and ~40 kcal·kg-1 fat-free mass (FFM)·d-1). In phase 2 (Adaptation), athletes were allocated to either a CON (n = 10), LCHF (n = 8; <50 g·d-1 CHO and ~40 kcal·kg-1·FFM-1·d-1), or LEA diet (n = 10; 60% CHO and 15 kcal·kg-1·FFM-1·d-1). At the end of each phase, athletes completed a 25-km race walk protocol at ~75% V˙O2max. On each occasion, venous blood was collected before and after exercise for interleukin-6, hepcidin, cortisol, and glucose concentrations, as well as white blood cell counts. RESULTS: The LCHF athletes displayed a greater IL-6 (P = 0.019) and hepcidin (P = 0.011) response to exercise after Adaptation, compared with Baseline. Similarly, postexercise increases in total white blood cell counts (P = 0.026) and cortisol levels (P < 0.001) were larger compared with Baseline after LCHF Adaptation. Decreases in blood glucose concentrations were evident postexercise during Adaptation in LCHF (P = 0.049), whereas no change occurred in CON or LEA (P > 0.05). No differences between CON and LEA were evident for any of the measured biological markers (all P > 0.05). CONCLUSIONS: Short-term adherence to a LCHF diet elicited small yet unfavorable iron, immune, and stress responses to exercise. In contrast, no substantial alterations to athlete health were observed when athletes restricted energy availability compared with athletes with adequate energy availability. Therefore, short-term restriction of CHO, rather than energy, may have greater negative impacts on athlete health.

The Hyperhydration Potential of Sodium Bicarbonate and Sodium Citrate.

Buffering agents have not been comprehensively profiled in terms of their capacity to influence water retention prior to exercise. The purpose of this investigation was to profile the fluid retention characteristics of sodium bicarbonate (BIC) and sodium citrate (CIT) to determine the efficacy of these buffering mediums as hyperhydrating agents. Nineteen volunteers (13 males and six females; age = 28.3 ± 4.9 years) completed three trials (randomized and cross-over design). For each trial, a baseline measurement of body mass, capillary blood, and urine was collected prior to ingestion of their respective condition (control condition [CON] = 25 ml/kg artificially sweetened water; BIC condition = CON + 7.5 g/L of sodium in the form of BIC; CIT condition = CON + 7.5 g/L of sodium in the form of CIT). The fluid loads were consumed in four equal aliquots (0, 20, 40 and 60 min; fluid intake was 1.972 ± 361 ml [CON]; 1.977 ± 360 ml [BIC]; 1.953 ± 352 ml [CIT]). Samples were recorded at 20 (body mass and urine) and 60 min (blood) intervals for 180 min. Blood buffering capacity (HCO3-) was elevated (p < .001) in both BIC (32.1 ± 2.2 mmol/L) and CIT (28.9 ± 3.8 mmol/L) at 180 min compared with CON (25.1 ± 1.8 mmol/L). Plasma volume expansion was greater (p < .001) in both BIC (8.1 ± 1.3%) and CIT (5.9 ± 1.8%) compared with CON (-1.1 ± 1.4%); whereas, total urine production was lower in BIC and CIT at 180 min (BIC vs. CON, mean difference of 370 ± 85 ml; p < .001; CIT vs. CON, mean difference of 239 ± 102 ml; p = .05). There were no increases observed in body mass (p = .9). Under resting conditions, these data suggest BIC and CIT induce a greater plasma hypervolemic response as compared with water alone.

Sequential Submaximal Training in Elite Male Rowers Does Not Result in Amplified Increases in Interleukin-6 or Hepcidin.

Previous research investigating single bouts of exercise have identified baseline iron status and circulating concentrations of interleukin-6 (IL-6) as contributors to the magnitude of postexercise hepcidin increase. The current study examined the effects of repeated training bouts in close succession on IL-6 and hepcidin responses. In a randomized, crossover design, 16 elite male rowers completed two trials, a week apart, with either high (1,000 mg) or low (<50 mg) calcium pre-exercise meals. Each trial involved two, submaximal 90-min rowing ergometer sessions, 2.5 hr apart, with venous blood sampled at baseline; pre-exercise; and 0, 1, 2, and 3 hr after each session. Peak elevations in IL-6 (approximately 7.5-fold, p < .0001) and hepcidin (approximately threefold, p < .0001) concentrations relative to baseline were seen at 2 and 3 hr after the first session, respectively. Following the second session, concentrations of both IL-6 and hepcidin remained elevated above baseline, exhibiting a plateau rather than an additive increase (2 hr post first session vs. 2 hr post second session, p = 1.00). Pre-exercise calcium resulted in a slightly greater elevation in hepcidin across all time points compared with control (p = .0005); however, no effect on IL-6 was evident (p = .27). Performing multiple submaximal training sessions in close succession with adequate nutritional support does not result in an amplified increase in IL-6 or hepcidin concentrations following the second session in male elite rowers. Although effects of calcium intake require further investigation, athletes should continue to prioritize iron consumption around morning exercise prior to exercise-induced hepcidin elevations to maximize absorption.

The Validity of Ultrasound Technology in Providing an Indirect Estimate of Muscle Glycogen Concentrations Is Equivocal.

Researchers and practitioners in sports nutrition would greatly benefit from a rapid, portable, and non-invasive technique to measure muscle glycogen, both in the laboratory and field. This explains the interest in MuscleSound®, the first commercial system to use high-frequency ultrasound technology and image analysis from patented cloud-based software to estimate muscle glycogen content from the echogenicity of the ultrasound image. This technique is based largely on muscle water content, which is presumed to act as a proxy for glycogen. Despite the promise of early validation studies, newer studies from independent groups reported discrepant results, with MuscleSound® scores failing to correlate with the glycogen content of biopsy-derived mixed muscle samples or to show the expected changes in muscle glycogen associated with various diet and exercise strategies. The explanation of issues related to the site of assessment do not account for these discrepancies, and there are substantial problems with the premise that the ratio of glycogen to water in the muscle is constant. Although further studies investigating this technique are warranted, current evidence that MuscleSound® technology can provide valid and actionable information around muscle glycogen stores is at best equivocal.

Solitary fibrous tumour of mediastinum: an often asymptomatic neoplasm.

Solitary fibrous tumours (SFTs) are rare neoplasms derived from mesenchymal cell lines. They are often asymptomatic, follow an indolent growth pattern and are more often benign than malignant. Here, we present a case of a very large, asymptomatic mediastinal SFT in an otherwise healthy man. A 67-year-old Irish man was referred for workup of an asymptomatic murmur. Auscultation of the lung fields revealed diminished breath sounds on the right side. Chest X-ray identified a 20 cm mass localised within the thorax. CT of the thorax confirmed a pleural based, solid lesion with no local invasion. CT-guided core biopsies were reported as consistent with SFT. Primary excision of the lesion was undertaken via median sternotomy. Histological examination confirmed a diagnosis of SFT. The patient remains well at this time. Primary excisive surgery is a safe and effective treatment modality for SFTs.

Antiglomerular basement membrane (anti-GBM) disease with clinical and histological features that bridge the typical to atypical spectrum.

We describe antiglomerular basement membrane (anti-GBM) disease with rapidly progressive glomerulonephritis and concurrent parainfluenza pneumonia. Circulating anti-GBM antibodies were barely detectable and disappeared rapidly following corticosteroids, cyclophosphamide and plasma exchange. Kidney biopsy demonstrated strong linear GBM staining for IgG and IgG4 and unusually prominent endocapillary hypercellularity, suggesting 'atypical anti-GBM disease', although glomerular necrosis and crescents were also seen. When kidney function deteriorated further, despite persistently absent circulating anti-GBM antibodies, a repeat kidney biopsy was performed, showing crescents in 100% of glomeruli with ongoing endocapillary hypercellularity and strong IgG and IgG4 GBM staining. This case highlights complexities in the diagnosis of anti-GBM disease, with clinical and histological features bridging the atypical to typical anti-GBM disease spectrum. We hypothesise that these findings might be explained by the presence of IgG4 (rather than traditional IgG1 or IgG3) autoantibodies. To our knowledge, this is also the first report of parainfluenza associated with anti-GBM disease.