Protocol for a randomised controlled trial of ketamine versus ketamine and behavioural activation therapy for adults with treatment-resistant depression in the community.

INTRODUCTION: Although short-term benefits follow parenteral ketamine for treatment-resistant major depressive disorder (TR-MDD), there are challenges that prevent routine use of ketamine by clinicians. These include acute dissociative effects of parenteral ketamine, high relapse rates following ketamine dosing and the uncertain role of psychotherapy. This randomised controlled trial (RCT) seeks to establish the feasibility of evaluating repeated oral doses of ketamine and behavioural activation therapy (BAT), compared with ketamine treatment alone, for TR-MDD. We also aim to compare relapse rates between treatment arms to determine the effect size of adding BAT to oral ketamine. METHODS AND ANALYSIS: This is a prospectively registered, two-centre, single-blind RCT. We aim to recruit 60 participants with TR-MDD aged between 18 and 65 years. Participants will be randomised to 8 weeks of oral ketamine and BAT, or 8 weeks of oral ketamine alone. Feasibility will be assessed by tracking attendance for ketamine and BAT, acceptability of treatment measures and retention to the study follow-up protocol. The primary efficacy outcome measure is the Montgomery-Asberg Depression Rating Scale (MADRS) measured weekly during treatment and fortnightly during 12 weeks of follow-up. Other outcome measures will assess the tolerability of ketamine and BAT, cognition and activity (using actigraphy). Participants will be categorised as non-responders, responders, remitters and relapsed during follow-up. MADRS scores will be analysed using a linear mixed model. For a definitive follow-up RCT study to be recommended, the recruitment expectations will be met and efficacy outcomes consistent with a >20% reduction in relapse rates favouring the BAT and ketamine arm will be achieved. ETHICS AND DISSEMINATION: Ethics approval was granted by the New Zealand Central Health and Disability Ethics Committee (reference: 2023 FULL18176). Study findings will be reported to participants, stakeholder groups, conferences and peer-reviewed publications. TRIAL REGISTRATION NUMBER: UTN: U1111-1294-9310, ACTRN12623000817640p.

Methods of measurement for pneumothorax in pediatric patients: a systematic review.

Accurate measurement of pneumothorax (PTX) size is necessary to guide clinical decision making; however, there is no consensus as to which method should be used in pediatric patients. This systematic review seeks to identify and evaluate the methods used to measure PTX size with CXR in pediatric patients. A systematic review of the literature through 2021 following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was conducted using the following databases: Ovid/MEDLINE, Scopus, Cochrane Database of Controlled Trials, Cochrane Database of Systematic Reviews, and Google Scholar. Original research articles that included pediatric patients (< 18 years old) and outlined the PTX measurement method were included. 45 studies were identified and grouped by method (Kircher and Swartzel, Rhea, Light, Collins, Other) and societal guideline used. The most used method was Collins (n = 16; 35.6%). Only four (8.9%) studies compared validated methods. All found the Collins method to be accurate. Seven (15.6%) studies used a standard classification guideline and 3 (6.7%) compared guidelines and found significant disagreement between them. Pediatric-specific measurement guidelines for PTX are needed to establish consistency and uniformity in both research and clinical practice. Until there is a better method, the Collins method is preferred.

The impact of psychiatric comorbidity on Parkinson's disease outcomes: a systematic review and meta-analysis.

Background: The burden of psychiatric symptoms in Parkinson's disease includes depression, anxiety, apathy, psychosis, and impulse control disorders. However, the relationship between psychiatric comorbidities and subsequent prognosis and neurological outcomes is not yet well understood. In this systematic review and meta-analysis, in individuals with Parkinson's disease, we aimed to characterise the association between specific psychiatric comorbidities and subsequent prognosis and neurological outcomes: cognitive impairment, death, disability, disease progression, falls or fractures and care home admission. Methods: We searched MEDLINE, Embase, PsycINFO and AMED up to 13th November 2023 for longitudinal observational studies which measured disease outcomes in people with Parkinson's disease, with and without specific psychiatric comorbidities, and a minimum of two authors extracted summary data. Studies of individuals with other parkinsonian conditions and those with outcome measures that had high overlap with psychiatric symptoms were excluded to ensure face validity. For each exposure-outcome pair, a random-effects meta-analysis was conducted based on standardised mean difference, using adjusted effect sizes-where available-in preference to unadjusted effect sizes. Study quality was assessed using the Newcastle-Ottawa Scale. Between-study heterogeneity was assessed using the I2 statistic and publication bias was assessed using funnel plots. PROSPERO Study registration number: CRD42022373072. Findings: There were 55 eligible studies for inclusion in meta-analysis (n = 165,828). Data on participants' sex was available for 164,514, of whom 99,182 (60.3%) were male and 65,460 (39.7%) female. Study quality was mostly high (84%). Significant positive associations were found between psychosis and cognitive impairment (standardised mean difference [SMD] 0.44, [95% confidence interval [CI] 0.23-0.66], I2 30.9), psychosis and disease progression (SMD 0.46, [95% CI 0.12-0.80], I2 70.3%), depression and cognitive impairment (SMD 0.37 [95% CI 0.10-0.65], I2 27.1%), depression and disease progression (SMD 0.46 [95% CI 0.18-0.74], I2 52.2), depression and disability (SMD 0.42 [95% CI 0.25-0.60], I2 7.9%), and apathy and cognitive impairment (SMD 0.60 [95% CI 0.02-1.19], I2 27.9%). Between-study heterogeneity was moderately high. Interpretation: Psychosis, depression, and apathy in Parkinson's disease are all associated with at least one adverse outcome, including cognitive impairment, disease progression and disability. Whether this relationship is causal is not clear, but the mechanisms underlying these associations require exploration. Clinicians should consider these psychiatric comorbidities to be markers of a poorer prognosis in people with Parkinson's disease. Future studies should investigate the underlying mechanisms and which treatments for these comorbidities may affect Parkinson's disease outcomes. Funding: Wellcome Trust, UK National Institute for Health Research (NIHR), National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospitals NHS Foundation Trust, National Brain Appeal.

Comparison of two bicycle handlebar trauma cases.

Handlebar injury is an uncommon mechanism of blunt injury with a recognised risk of injury to groin vasculature. We describe two cases involving bicycle handlebar injury to the groin and their different respective outcomes. Patient A sustained a significant limb-threatening injury following significant arterial and venous disruption. Surgical intervention was able to restore arterial flow via interpositional vein graft, while venous injuries were ligated. As a result, the patient was discharged with a viable limb and a non-disabling swelling from venous pathology. Patient B, of identical age, also sustained a bicycle handlebar injury to the groin but without the need for surgical intervention. Active observation and the use of repeat imaging suggested spontaneous cessation of any minor arterial bleeding; the patient made a rapid recovery and was discharged soon thereafter. These cases highlight the variability in outcome stemming from this injury mechanism and that early recognition is vital for limb viability.

Structure-activity relationships for alkyl-phenanthrenes support two independent but interacting synergistic models for PAC mixture potency.

Multiple lines of evidence at whole animal, cellular and molecular levels implicate polycyclic aromatic compounds (PACs) with three rings as drivers of crude oil toxicity to developing fish. Phenanthrene (P0) and its alkylated homologs (C1- through C4-phenanthrenes) comprise the most prominent subfraction of tricyclic PACs in crude oils. Among this family, P0 has been studied intensively, with more limited detail available for the C4-phenanthrene 1-methyl-7-isopropyl-phenanthrene (1-M,7-IP, or retene). While both compounds are cardiotoxic, P0 impacts embryonic cardiac function and development through direct blockade of K+ and Ca2+ currents that regulate cardiomyocyte contractions. In contrast, 1-M,7-IP dysregulates aryl hydrocarbon receptor (AHR) activation in developing ventricular cardiomyocytes. Although no other compounds have been assessed in detail across the larger family of alkylated phenanthrenes, increasing alkylation might be expected to shift phenanthrene family member activity from K+/Ca2+ ion current blockade to AHR activation. Using embryos of two distantly related fish species, zebrafish and Atlantic haddock, we tested 14 alkyl-phenanthrenes in both acute and latent developmental cardiotoxicity assays. All compounds were cardiotoxic, and effects were resolved into impacts on multiple, highly specific aspects of heart development or function. Craniofacial defects were clearly linked to developmental cardiotoxicity. Based on these findings, we suggest a novel framework to delineate the developmental toxicity of petrogenic PAC mixtures in fish, which incorporates multi-mechanistic pathways that produce interactive synergism at the organ level. In addition, relationships among measured embryo tissue concentrations, cytochrome P4501A mRNA induction, and cardiotoxic responses suggest a two-compartment toxicokinetic model that independently predicts high potency of PAC mixtures through classical metabolic synergism. These two modes of synergism, specific to the sub-fraction of phenanthrenes, are sufficient to explain the high embryotoxic potency of crude oils, independent of as-yet unmeasured compounds in these complex environmental mixtures.

Carnosine supplementation improves glucose control in adults with pre-diabetes and type 2 diabetes: A randomised controlled trial.

BACKGROUND AND AIMS: Type 2 diabetes (T2DM) is a major cause of morbidity and mortality globally. Carnosine, a naturally occurring dipeptide, has anti-inflammatory, antioxidant, and anti-glycating effects, with preliminary evidence suggesting it may improve important chronic disease risk factors in adults with cardiometabolic conditions. METHODS AND RESULTS: In this randomised controlled trial, 43 adults (30%F) living with prediabetes or T2DM consumed carnosine (2 g) or a matching placebo daily for 14 weeks to evaluate its effect on glucose metabolism assessed via a 2-h 75 g oral glucose tolerance test. Secondary outcomes included body composition analysis by dual energy x-ray absorptiometry (DEXA), calf muscle density by pQCT, and anthropometry. Carnosine supplementation decreased blood glucose at 90 min (-1.31 mmol/L; p = 0.02) and 120 min (-1.60 mmol/L, p = 0.02) and total glucose area under the curve (-3.30 mmol/L; p = 0.04) following an oral glucose tolerance test. There were no additional changes in secondary outcomes. The carnosine group results remained significant before and after adjustment for age, sex, and change in weight (all>0.05), and in further sensitivity analyses accounting for missing data. There were no significant changes in insulin levels. CONCLUSION: This study provides preliminary support for larger trials evaluating carnosine as a potential treatment for prediabetes and the initial stages of T2DM. Likely mechanisms may include changes to hepatic glucose output explaining the observed reduction in blood glucose without changes in insulin secretion following carnosine supplementation.

Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma.

Glaucoma, a chronic neurodegenerative disease, is a leading cause of age-related blindness worldwide and characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Previously, we developed a novel epigenetic rejuvenation therapy, based on the expression of the three transcription factors Oct4, Sox2, and Klf4 (OSK), which safely rejuvenates RGCs without altering cell identity in glaucomatous and old mice after 1 month of treatment. In the current year-long study, mice with continuous or cyclic OSK expression induced after glaucoma-induced vision damage had occurred were tracked for efficacy, duration, and safety. Surprisingly, only 2 months of OSK fully restored impaired vision, with a restoration of vision for 11 months with prolonged expression. In RGCs, transcription from the doxycycline (DOX)-inducible Tet-On AAV system, returned to baseline 4 weeks after DOX withdrawal. Significant vision improvements remained for 1 month post switching off OSK, after which the vision benefit gradually diminished but remained better than baseline. Notably, no adverse effects on retinal structure or body weight were observed in glaucomatous mice with OSK continuously expressed for 21 months providing compelling evidence of efficacy and safety. This work highlights the tremendous therapeutic potential of rejuvenating gene therapies using OSK, not only for glaucoma but also for other ocular and systemic injuries and age-related diseases.

Carnosine Did Not Affect Vascular and Metabolic Outcomes in Patients with Prediabetes and Type 2 Diabetes: A 14-Week Randomized Controlled Trial.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality in patients with prediabetes and type 2 diabetes mellitus (T2DM). Carnosine has been suggested as a potential approach to reduce ASCVD risk factors. However, there is a paucity of human data. Hence, we performed a 14-week double-blind randomized placebo-controlled trial to determine whether carnosine compared with placebo improves vascular and metabolic outcomes in individuals with prediabetes and T2DM. In total, 49 patients with prediabetes and T2DM with good glycemic control were randomly assigned either to receive 2 g/day carnosine or matching placebo. We evaluated endothelial dysfunction, arterial stiffness, lipid parameters, blood pressure, heart rate, hepatic and renal outcomes before and after the intervention. Carnosine supplementation had no effect on heart rate, peripheral and central blood pressure, endothelial function (logarithm of reactive hyperemia (LnRHI)), arterial stiffness (carotid femoral pulse wave velocity (CF PWV)), lipid parameters, liver fibroscan indicators, liver transient elastography, liver function tests, and renal outcomes compared to placebo. In conclusion, carnosine supplementation did not improve cardiovascular and cardiometabolic risk factors in adults with prediabetes and T2DM with good glycemic control. Therefore, it is improbable that carnosine supplementation would be a viable approach to mitigating the ASCVD risk in these populations. The trial was registered at clinicaltrials.gov (NCT02917928).

Biological Responses of Pacific Herring Embryos to Crude Oil Are Quantifiable at Exposure Levels Below Conventional Limits of Quantitation for PAHs in Water and Tissues.

Pacific herring (Clupea pallasii), a cornerstone of marine food webs, generally spawn on marine macroalgae in shallow nearshore areas that are disproportionately at risk from oil spills. Herring embryos are also highly susceptible to toxicity from chemicals leaching from oil stranded in intertidal and subtidal zones. The water-soluble components of crude oil trigger an adverse outcome pathway that involves disruption of the physiological functions of cardiomyocytes in the embryonic herring heart. In previous studies, impaired ionoregulation (calcium and potassium cycling) in response to specific polycyclic aromatic hydrocarbons (PAHs) corresponds to lethal embryolarval heart failure or subtle chamber malformations at the high and low ends of the PAH exposure range, respectively. Sublethal cardiotoxicity, which involves an abnormal outgrowth (ballooning) of the cardiac ventricular chamber soon after hatching, subsequently compromises juvenile heart structure and function, leading to pathological hypertrophy of the ventricle and reduced individual fitness, measured as cardiorespiratory performance. Previous studies have not established a threshold for these sublethal and delayed-in-time effects, even with total (∑)PAH exposures as low as 29 ng/g of wet weight (tissue dose). Here, we extend these earlier findings showing that (1) cyp1a gene expression provides an oil exposure metric that is more sensitive than typical quantitation of PAHs via GC-MS and (2) heart morphometrics in herring embryos provide a similarly sensitive measure of toxic response. Early life stage injury to herring (impaired heart development) thus occurs below the quantitation limits for PAHs in both water and embryonic tissues as a conventional basis for assessing oil-induced losses to coastal marine ecosystems.

A spectroscopic liquid biopsy for the earlier detection of multiple cancer types.

BACKGROUND: A rapid, low-cost blood test that can be applied to reliably detect multiple different cancer types would be transformational. METHODS: In this large-scale discovery study (n = 2092 patients) we applied the Dxcover® Cancer Liquid Biopsy to examine eight different cancers. The test uses Fourier transform infrared (FTIR) spectroscopy and machine-learning algorithms to detect cancer. RESULTS: Area under the receiver operating characteristic curve (ROC) values were calculated for eight cancer types versus symptomatic non-cancer controls: brain (0.90), breast (0.76), colorectal (0.91), kidney (0.91), lung (0.91), ovarian (0.86), pancreatic (0.84) and prostate (0.86). We assessed the test performance when all eight cancer types were pooled to classify 'any cancer' against non-cancer patients. The cancer versus asymptomatic non-cancer classification detected 64% of Stage I cancers when specificity was 99% (overall sensitivity 57%). When tuned for higher sensitivity, this model identified 99% of Stage I cancers (with specificity 59%). CONCLUSIONS: This spectroscopic blood test can effectively detect early-stage disease and can be fine-tuned to maximise either sensitivity or specificity depending on the requirements from different healthcare systems and cancer diagnostic pathways. This low-cost strategy could facilitate the requisite earlier diagnosis, when cancer treatment can be more effective, or less toxic. STATEMENT OF TRANSLATIONAL RELEVANCE: The earlier diagnosis of cancer is of paramount importance to improve patient survival. Current liquid biopsies are mainly focused on single tumour-derived biomarkers, which limits test sensitivity, especially for early-stage cancers that do not shed enough genetic material. This pan-omic liquid biopsy analyses the full complement of tumour and immune-derived markers present within blood derivatives and could facilitate the earlier detection of multiple cancer types. There is a low barrier to integrating this blood test into existing diagnostic pathways since the technology is rapid, simple to use, only minute sample volumes are required, and sample preparation is minimal. In addition, the spectroscopic liquid biopsy described in this study has the potential to be combined with other orthogonal tests, such as cell-free DNA, which could provide an efficient route to diagnosis. Cancer treatment can be more effective when given earlier, and this low-cost strategy has the potential to improve patient prognosis.

Global serum profiling: an opportunity for earlier cancer detection.

The advances in cancer research achieved in the last 50 years have been remarkable and have provided a deeper knowledge of this disease in many of its conceptual and biochemical aspects. From viewing a tumor as a 'simple' aggregate of mutant cells and focusing on detecting key cell changes leading to the tumorigenesis, the understanding of cancer has broadened to consider it as a complex organ interacting with its close and far surroundings through tumor and non-tumor cells, metabolic mechanisms, and immune processes. Metabolism and the immune system have been linked to tumorigenesis and malignancy progression along with cancer-specific genetic mutations. However, most technologies developed to overcome the barriers to earlier detection are focused solely on genetic information. The concept of cancer as a complex organ has led to research on other analytical techniques, with the quest of finding a more sensitive and cost-effective comprehensive approach. Furthermore, artificial intelligence has gained broader consensus in the oncology community as a powerful tool with the potential to revolutionize cancer diagnosis for physicians. We herein explore the relevance of the concept of cancer as a complex organ interacting with the bodily surroundings, and focus on promising emerging technologies seeking to diagnose cancer earlier, such as liquid biopsies. We highlight the importance of a comprehensive approach to encompass all the tumor and non-tumor derived information salient to earlier cancer detection.

Bioretention filtration prevents acute mortality and reduces chronic toxicity for early life stage coho salmon (Oncorhynchus kisutch) episodically exposed to urban stormwater runoff.

As the human population of western North America continues to expand, widespread patterns of urban growth pose increasingly existential threats to certain wild stocks of Pacific salmon and steelhead (Oncorhynchus sp.). Rainfall previously absorbed into the soils of forests and grasslands falls instead on pavement and other hardened surfaces. This creates stormwater runoff that carries toxic metals, oil, and many other contaminants into salmon-bearing habitats. These include freshwater streams where coho salmon (O. kisutch) spawn in gravel beds. Coho salmon embryos develop within a thick eggshell (chorion) for weeks to months before hatching as alevins and ultimately emerging from the gravel as fry. Untreated urban runoff is highly toxic to older coho salmon (freshwater-resident juveniles and adult spawners), but the vulnerability of the earliest life stages remains poorly understood. To address this uncertainty, we fertilized eggs and raised them under an episodic stormwater exposure regimen, using runoff collected from a high-traffic arterial roadway from 15 discrete storm events. We monitored survival and morphological development, as well as molecular markers for contaminant exposure and cardiovascular stress. We also evaluated the benefit of treating runoff with green infrastructure (bioretention filtration) on coho salmon health and survival. Untreated runoff caused subtle sublethal toxicity in pre-hatch embryos with no mortality, followed by high rates of mortality from exposure at hatch. Bioretention filtration removed most measured contaminants (bacteria, dissolved metals, and polycyclic aromatic hydrocarbons), and the treated effluent was considerably less toxic - notably preventing mortality at the alevin stage. Our findings indicate that untreated urban runoff poses an important threat to early life stage coho salmon, in terms of both acute and delayed-in-time mortality. Moreover, while inexpensive management strategies involving bioinfiltration are promising, future green infrastructure effectiveness research should emphasize sublethal metrics for contaminant exposure and adverse health outcomes in salmonids.

Dobutamine effects on systolic and diastolic left ventricular long-axis excursion and timing - significance for the interpretation of s' and e'.

BACKGROUND: Dobutamine effects on the relationships of the peak velocity of left ventricular (LV) long-axis systolic motion (s') with systolic excursion (SExc), systolic duration (SDur) and heart rate, of LV long-axis early diastolic excursion (EDExc) with SExc, and of the peak velocity of LV long-axis early diastolic motion (e') with EDExc, early diastolic duration (EDDur) and isovolumic relaxation time (IVRT') are unknown. METHODS: Two groups of adult subjects, one young and healthy (n = 10), and one with impaired LV long-axis function (n = 10), were studied, with the aim of identifying consistent findings for the two groups and for the septal and lateral walls. Dobutamine was infused at doses of 5 and 10 µg/kg/min. The relationships between tissue Doppler imaging (TDI) variables acquired before and during dobutamine infusion were analysed using mixed effect multivariate regression modelling. RESULTS: In both groups, heart rate increased and SDur decreased during dobutamine infusion, and there were independent inverse correlations of SDur with heart rate and dobutamine dose. In contrast, there was no change in EDDur during dobutamine infusion, and no consistent changes in IVRT' independent of heart rate. s' was positively correlated with SExc and inversely correlated with SDur, and there were positive correlations between EDExc and SExc and between e' and EDExc. CONCLUSION: Dobutamine increases s' due to effects on both systolic excursion and duration and it increases e' due to the associated increases in systolic and early diastolic excursion. A lack of effect on diastolic times does not support the presence of a lusitropic effect of dobutamine.

Peri-Coronary Adipose Tissue Is a Predictor of Stent Failure in Patients Undergoing Percutaneous Coronary Intervention.

PURPOSE: Coronary inflammation is postulated as a driver of atherosclerosis and dysfunctional arterial healing which may trigger stent failure. Pericoronary adipose tissue (PCAT) attenuation, detected on computer tomography coronary angiography (CTCA), is an emerging non-invasive marker of coronary inflammation. This propensity matched study assessed the utility of both lesion specific (PCATLesion) and standardized PCAT attenuation as assessed in the proximal RCA (PCATRCA) as a predictor of stent failure in patients undergoing elective percutaneous coronary intervention. This is the first study to our knowledge that assesses the association of PCAT with stent failure. METHODS: Patients undergoing CTCA assessment for coronary artery disease with subsequent stent insertion within 60 days and repeat coronary angiography for any clinical reason within 5 years were included in the study. Stent failure was defined as binary restenosis of >50 % on quantitative coronary angiography analysis or stent thrombosis. Both PCATLesion and PCATRCA was assessed utilizing semi-automated proprietary software on baseline CTCA. Patients with stent failure were propensity matched utilizing age, sex, cardiovascular risk factors and procedural characteristics. RESULTS: One hundred and fifty-one patients met inclusion criteria. Of these, 26 (17.2 %) had study-defined failure. A significant difference in PCATLesion attenuation between patients with and without failure was observed (-79.0 ± 12.6 vs. -85.9 ± 10.3HU, p = 0.035). There was no significant difference in PCATRCA attenuation between the two groups (-79.5 ± 10.1 vs -81.0 ± 12.3HU, p = 0.50). Univariate regression analysis showed PCATLesion attenuation was independently associated with stent failure (OR 1.06, 95 % CI 1.01-1.12, P = 0.035). CONCLUSIONS: Patients with stent failure exhibit significantly increased PCATLesion attenuation at baseline. These data suggest that baseline plaque inflammation may be an important driver for coronary stent failure.

Liquid biopsies: the future of cancer early detection.

Cancer is a worldwide pandemic. The burden it imposes grows steadily on a global scale causing emotional, physical, and financial strains on individuals, families, and health care systems. Despite being the second leading cause of death worldwide, many cancers do not have screening programs and many people with a high risk of developing cancer fail to follow the advised medical screening regime due to the nature of the available screening tests and other challenges with compliance. Moreover, many liquid biopsy strategies being developed for early detection of cancer lack the sensitivity required to detect early-stage cancers. Early detection is key for improved quality of life, survival, and to reduce the financial burden of cancer treatments which are greater at later stage detection. This review examines the current liquid biopsy market, focusing in particular on the strengths and drawbacks of techniques in achieving early cancer detection. We explore the clinical utility of liquid biopsy technologies for the earlier detection of solid cancers, with a focus on how a combination of various spectroscopic and -omic methodologies may pave the way for more efficient cancer diagnostics.

Decrements of mobility and power in recreationally active septuagenarians is related to loss of force, but not slowing of the muscle: a 5-year longitudinal study.

A lesser 6-min walk distance (6MWD) and timed up-and-go (TUG) in old compared with young adults was previously linked to slowing of muscle contractile properties. The purpose of the present study was to determine whether any further reductions in 6MWD and TUG over a 5-year period in septuagenarians are associated with further slowing of muscle contractile properties. We measured muscle function by a countermovement jump, isometric maximal knee extensor strength (MVC) on a dynamometer and quadriceps muscle size by magnetic resonance imaging (MRI) in 17 older women (71.1 ± 2.8 y) and 17 older men (71.3 ± 4.1y). Performance in TUG and 6MWD were reduced over the 5-year period, irrespective of sex (P < 0.001), and both were correlated with power at both baseline and follow-up (R ≥ 0.53; P ≤ 0.001). Jump take-off velocity (VCMJ) was slower at follow-up (P < 0.01) and correlated with 6MWD and TUG at both baseline and follow-up in both sexes (R ≥ 0.54; P ≤ 0.001). However, the relationship between 'body mass: maximal muscle force ratio' with VCMJ was not significantly changed, indicating that the lower VCMJ was attributable to muscles working at a higher relative load, hence a lower part of the force-velocity relationship, due to a reduction in MVC (body mass had not changed significantly), rather than slowing of the muscle. The lower VCMJ in women than men (P < 0.001) was likewise attributable to a lower MVC rather than slower contractile properties in women. In conclusion, the decrement in 6MWD and TUG in septuagenarians is due to a loss of muscle mass, rather than further loss of muscle quality.

How to do an open midline extraperitoneal bilateral retroperitoneal lymph node dissection for non-seminomatous germ cell tumour.

Retroperitoneal lymph node dissection, remains a crucial step in the management of patients with non-seminomatous germ cell tumours who have undergone chemotherapy. It is a technically challenging operation with a number of techniques that have been advocated. We outline the midline, extraperitoneal approach to perform a bilateral template lymph node dissection.

Characterization of age-associated B cells in early drug-naïve rheumatoid arthritis patients.

Age-associated B cells (ABCs) are an immune cell subset linked to autoimmunity, infection and ageing, and whose pathophysiological importance was recently highlighted using single cell synovial tissue profiling. To elucidate their pathophysiological relevance, peripheral blood (PB) ABCs from early rheumatoid arthritis (eRA) patients naïve to disease-modifying anti-rheumatic drugs (DMARDs) were compared with their synovial fluid (SF) counterparts, and to PB ABCs from psoriatic arthritis patients and healthy controls. PB and SF B-cell subsets were phenotyped by multi-parameter flow cytometry, sorted and subjected to gene expression profiling (NanoString nCounter® Immunology V2 Panel) and functional characterization (stimulated cytokine measurements by immunoassay). PB ABCs of eRA patients, which are transcriptionally distinct from those of control cohorts, express chemokine receptors and adhesion molecules, such as CXCR3, that favour homing to inflammatory sites over lymphoid tissue. These cells are an activated, class-switched B-cell subset expressing high levels of HLA-DR, co-stimulatory molecules and T-bet. Their secretion profile includes IL-12p70 and IL-23 but low levels of IL-10. High surface expression of FcRL family members, including FcRL3, furthermore suggests a role for these cells in autoimmunity. Finally, and unlike in the periphery where they are rare, ABCs are the predominant B-cell subsets in SF. These observations indicate the predilection of ABCs for inflammatory tissue in RA, where their propensity for antigen presentation and pro-inflammatory phenotype may support autoimmune pathology. Their potential as a therapeutic target therefore warrants further study.