John Young

At least 60% of adults over 40 experience symptoms related to the storage passage of urine that negatively affect their health and quality of life. Our research team is developing a device to deliver noninvasive long-term urine measures at the patient’s home or clinic. We employed a participatory-design approach to guide development in understanding end-user needs. We gathered data from 45 stakeholders through focus groups with clinicians (N = 40, including medical doctors (urologists), pelvic-floor physical therapists, and nurses) and semi-structured interviews with patients and caregivers (N = 5). Our results showed similarities (e.g., collecting urine storage and voiding data) and differences (e.g., the importance of pelvic-floor function for physical therapists, and the associated workload of using the device for nurses) among the three clinician groups. There were differences between clinicians and patients, the latter emphasizing the shame and discomfort associated with current diagnostic procedures. We gathered participants’ views on the advantages and disadvantages of the proposed device, considerations for use, and design suggestions. Our results emphasize the importance of including the end users in early design stages of a novel technology tailored to the target population.

Respiratory viruses cause airway inflammation, resulting in epithelial injury and repair. miRNAs, including miR-149-5p, regulate different pathological conditions. We aimed to determine how miR-149-5p functions in regulating pro-inflammatory IL-6 and p63, key regulators of airway epithelial wound repair, in response to viral proteins in bronchial (BEAS-2B) and alveolar (A549) epithelial cells. BEAS-2B or A549 cells were incubated with poly (I:C, 0.5 µg/mL) for 48 h or SARS-CoV-2 spike protein-1 or 2 subunit (S1 or S2, 1 μg/mL) for 24 h. miR-149-5p was suppressed in BEAS-2B challenged with poly (I:C), correlating with IL-6 and p63 upregulation. miR-149-5p was down-regulated in A549 stimulated with poly (I:C); IL-6 expression increased, but p63 protein levels were undetectable. miR-149-5p remained unchanged in cells exposed to S1 or S2, while S1 transfection increased IL-6 expression in BEAS-2B cells. Ectopic over-expression of miR-149-5p in BEAS-2B cells suppressed IL-6 and p63 mRNA levels and inhibited poly (I:C)-induced IL-6 and p63 mRNA expressions. miR-149-5p directly suppressed IL-6 mRNA in BEAS-2B cells. Hence, BEAS-2B cells respond differently to poly (I:C), S1 or S2 compared to A549 cells. Thus, miR-149-5p dysregulation may be involved in poly (I:C)-stimulated but not S1- or S2-stimulated increased IL-6 production and p63 expression in BEAS-2B cells.

Plasma biomarkers of inflammation, oxidative stress, endothelial function and damage were examined in 16 individuals with chronic NFCI (NFCI) and matched control participants with (COLD, n = 17) or without (CON, n = 14) previous cold exposure. Venous blood samples were collected at baseline to assess plasma biomarkers of endothelial function (nitrate, nitrite and endothelin‐1), inflammation [interleukin‐6 (IL‐6), interleukin‐10 (IL‐10), tumour necrosis factor alpha and E‐selectin], oxidative stress [protein carbonyl, 4‐hydroxy‐2‐nonenal (4‐HNE), superoxide dismutase and nitrotyrosine) and endothelial damage [von Willebrand factor, syndecan‐1 and tissue type plasminogen activator (TTPA)]. Immediately after whole‐body heating and separately, foot cooling, blood samples were taken for measurement of plasma [nitrate], [nitrite], [endothelin‐1], [IL‐6], [4‐HNE] and [TTPA]. At baseline, [IL‐10] and [syndecan‐1] were increased in NFCI (P < 0.001 and P = 0.015, respectively) and COLD (P = 0.033 and P = 0.030, respectively) compared with CON participants. The [4‐HNE] was elevated in CON compared with both NFCI (P = 0.002) and COLD (P < 0.001). [Endothelin‐1] was elevated in NFCI compared with COLD (P < 0.001) post‐heating. The [4‐HNE] was lower in NFCI compared with CON post‐heating (P = 0.032) and lower than both COLD (P = 0.02) and CON (P = 0.015) post‐cooling. No between‐group differences were seen for the other biomarkers. Mild to moderate chronic NFCI does not appear to be associated with a pro‐inflammatory state or oxidative stress. Baseline [IL‐10] and [syndecan‐1] and post‐heating [endothelin‐1] are the most promising candidates for diagnosing NFCI, but it is likely that a combination of tests will be required.

Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and progressive insulin resistance, leading to macro and microvascular dysfunction. Passive heating has potential to improve glucose homeostasis and act as an exercise mimetic. We assessed the effect of acute passive heating before or during an oral glucose tolerance test (OGTT) in people with T2DM. Twelve people with T2DM were randomly assigned to the following three conditions: 1) 3-h OGTT (control), 2) 1-h passive heating (40°C water) 30 min before an OGTT (HOT-OGTT), and 3) 1-h passive heating (40°C water) 30 min after commencing an OGTT (OGTT-HOT). Blood glucose concentration, insulin sensitivity, extracellular heat shock protein 70 (eHSP70), total energy expenditure (TEE), heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded. Passive heating did not alter blood glucose concentration [control: 1,677 (386) arbitrary units (AU), HOT-OGTT: 1,797 (340) AU, and OGTT-HOT: 1,662 (364) AU, P = 0.28], insulin sensitivity (P = 0.15), or SBP (P = 0.18) but did increase eHSP70 concentration in both heating conditions [control: 203.48 (110.81) pg·mL⁻¹; HOT-OGTT: 402.47 (79.02) pg·mL⁻¹; and OGTT-HOT: 310.00 (60.53) pg·mL⁻¹, P < 0.001], increased TEE (via fat oxidation) in the OGTT-HOT condition [control: 263 (33) kcal, HOT-OGTT: 278 (40) kcal, and OGTT-HOT: 304 (38) kcal, P = 0.001], increased HR in both heating conditions (P < 0.001), and reduced DBP in the OGTT-HOT condition (P < 0.01). Passive heating in close proximity to a glucose challenge does not alter glucose tolerance but does increase eHSP70 concentration and TEE and reduce blood pressure in people with T2DM. NEW & NOTEWORTHY This is the first study to investigate the timing of acute passive heating on glucose tolerance and extracellular heat shock protein 70 concentration ([eHSP70]) in people with type 2 diabetes. The principal novel findings from this study were that both passive heating conditions: 1) did not reduce the area under the curve or peak blood glucose concentration, 2) elevated heart rate, and 3) increased [eHSP70], which was blunted by glucose ingestion, while passive heating following glucose ingestion, 4) increased total energy expenditure, and 5) reduced diastolic blood pressure.

New Findings: What is the central question of this study? Are the urinary concentrations of NO and ATP, and their metabolites, associated with the severity of symptoms of overactive bladder? What is the main finding and its importance? The urinary ratios of [ATP/NO], [ADP/NO] and a combination of these, [ATP/Cr*ADP/Cr]/[NO/Cr], were correlated with overall OAB symptom severity, with the latter combination also being correlated with the severity of urinary frequency and urgency symptoms individually. Together, these data reveal changes in urothelial signalling that accompany the transition from physiology to pathology. Overactive bladder (OAB) is a highly prevalent symptom complex characterized by symptoms of urinary urgency and increased frequency and waking to void (nocturia), with or without urge incontinence and in the absence of proven infection or other obvious pathology. The underlying pathophysiology of idiopathic OAB is not clearly known, and the existence of several phenotypes has been proposed. Current diagnostic approaches are based on discordant measures, suffer from subjectivity and are incapable of detecting the proposed OAB phenotypes. Nitric oxide, ATP and their metabolites have previously been shown to underlie the perception of bladder fullness, with their release modifying the pathological perception of urgency. Therefore, in this study we assessed the concentrations of NO, ATP and associated metabolites in the urine of 113 consenting participants recruited from the general population. Recruited participants completed a questionnaire to measure the severity of OAB‐associated urinary symptoms and provided a mid‐stream urine sample. After identification of infection and haematuria using microbiology and microscopy, 95 samples were subjected to assays to measure NO, NO₂⁻, NO₃⁻, ATP, ADP and creatinine (Cr). There was no correlation between [NO/Cr], [NO₂⁻/Cr] or [NO₃⁻/Cr] and overall OAB symptom severity. In contrast, [ATP/NO], [ADP/NO] and a combination of these, [ATP/Cr*ADP/Cr]/[NO/Cr], were correlated with OAB symptom severity, and [ATP/Cr*ADP/Cr]/[NO/Cr] was also correlated with the severity of urinary frequency and urgency. This study adds to a growing literature that demonstrates the potential of urinary biomarkers and provides a foundation for a larger, longitudinal study.

Overactive bladder (OAB) is a highly prevalent symptom complex characterised by symptoms of urinary urgency, increased frequency, nocturia, with or without urge incontinence; in the absence of proven infection or other obvious pathology. The underlying pathophysiology of idiopathic OAB is not clearly known and the existence of several phenotypes has been proposed. Current diagnostic approaches are based on discordant measures, suffer from subjectivity and are incapable of detecting the proposed OAB phenotypes. In this study, cluster analysis was used as an objective approach for phenotyping participants based on their OAB characteristic symptoms and led to the identification of a low OAB symptomatic score group (cluster 1) and a high OAB symptomatic score group (cluster 2). Furthermore, the ability of several potential OAB urinary biomarkers including ATP, ACh, nitrite, MCP-1 and IL-5 and participants’ confounders, age and gender, in predicting the identified high OAB symptomatic score group was assessed. A combination of urinary ATP and IL-5 plus age and gender was shown to have clinically acceptable and improved diagnostic accuracy compared to urodynamically-observed detrusor overactivity. Therefore, this study provides the foundation for the development of novel non-invasive diagnostic tools for OAB phenotypes that may lead to personalised treatment.

Aim: To characterize purinergic signaling in overactive bladder (OAB).Methods: Mucosal biopsies were taken by flexible cystoscopy from patients with storage symptoms referred to Urology Departments of collaborating hospitals. Immunohistochemistry (n = 12) and Western blot analysis (n = 28) were used to establish the qualitative and quantitative expression profile of P2Y6 in human mucosa. Participants from the general population provided a mid‐stream urine sample. Bioluminescent assays were used to quantify adenosine triphosphate (ATP; n = 66) and adenosine diphosphate (ADP; n = 60) concentrations, which were normalized to creatinine (Cr) concentration. All participants completed a questionnaire (International Consultation on Incontinence Questionnaire – Overactive Bladder) to score urinary symptoms of OAB.Results: P2Y6 immunoreactivity, more prominent in the urothelium (colocalized with the uroepithelial marker pan‐cytokeratin), was more greatly expressed in OAB compared to age‐ and sex‐matched controls (benign prostatic hyperplasia) without OAB symptoms. Mucosal P2Y6 was positively correlated only with incontinence (P = .009). Both urinary ATP and its hydrolysis product, ADP, an agonist to P2Y6, were positively correlated with total OAB symptom score (P = .010 and P = .042, respectively).Conclusions: The positive correlation of P2Y6 only with incontinence may indicate a different phenotype in OAB wet and warrants further investigation. Positive correlations of ATP and ADP with total OAB symptom score demonstrate upregulation in purinergic signaling in OAB; shown previously only in animal models. Further research is required to validate whether purinoceptors are indeed new therapeutic targets for this highly prevalent symptom complex.

New Findings: What is the central question of this study? What are the mechanisms responsible for the decline in cognitive performance following exposure to acute normobaric hypoxia? What are the main findings and their importance? We found that (1) performance of a complex central executive task (n‐back) was reduced at 0.12; (2) there was a strong correlation between performance of the n‐back task and reductions in and cerebral oxygenation; and (3) plasma adrenaline, noradrenaline, cortisol and copeptin were not correlated with cognitive performance. It is well established that hypoxia impairs cognitive function; however, the physiological mechanisms responsible for these effects have received relatively little attention. This study examined the effects of graded reductions in fraction of inspired oxygen () on oxygen saturation (), cerebral oxygenation, cardiorespiratory variables, activity of the sympathoadrenal system (adrenaline, noradrenaline) and hypothalamic–pituitary–adrenal axis (cortisol, copeptin), and cognitive performance. Twelve healthy males [mean (SD), age: 22 (4) years, height: 178 (5) cm, mass: 75 (9) kg, FEV₁/FVC ratio: 85 (5)%] completed a four‐task battery of cognitive tests to examine inhibition, selective attention (Eriksen flanker), executive function (n‐back) and simple and choice reaction time (Deary–Liewald). Tests were completed before and following 60 min of exposure to 0.2093, 0.17, 0.145 and 0.12. Following 60 min of exposure, response accuracy in the n‐back task was significantly reduced in 0.12 compared to baseline [82 (9) vs. 93 (5)%; P < 0.001] and compared to all other conditions at the same time point [ 0.2093: 92 (3)%; 0.17: 91 (6)%; 0.145: 85 (10)%; 12: 82 (9)%; all P < 0.05]. The performance of the other tasks was maintained. Δaccuracy and Δreaction time of the n‐back task was correlated with both Δ [r(9) = 0.66, P < 0.001 and r(9) = −0.36, P = 0.037, respectively] and Δcerebral oxygenation [r(7) = 0.55, P < 0.001 and r(7) = −0.38, P = 0.045, respectively]. Plasma adrenaline, noradrenaline, cortisol and copeptin were not significantly elevated in any condition or correlated with any of the tests of cognitive performance. These findings suggest that reductions in peripheral oxygen saturation and cerebral oxygenation, and not increased activity of the sympathoadrenal system and hypothalamic–pituitary–adrenal axis, as previously speculated, are responsible for a decrease in cognitive performance during normobaric hypoxia.

Unlike most excitable cells, certain syncytial smooth muscle cells are known to exhibit spontaneous action potentials of varying shapes and sizes. These differences in shape are observed even in electrophysiological recordings obtained from a single cell. The origin and physiological relevance of this phenomenon are currently unclear. The study presented here aims to test the hypothesis that the syncytial nature of the detrusor smooth muscle tissue contributes to the variations in the action potential profile by influencing the superposition of the passive and active signals. Data extracted from experimental recordings have been compared with those obtained through simulations. The feature correlation studies on action potentials obtained from the experimental recordings suggest the underlying presence of passive signals, called spontaneous excitatory junction potentials (sEJPs). Through simulations, we are able to demonstrate that the syncytial organization of the cells, and the variable superposition of the sEJPs with the “native action potential”, contribute to the diversity in the action potential profiles exhibited. It could also be inferred that the fraction of the propagated action potentials is very low in the detrusor. It is proposed that objective measurements of spontaneous action potential profiles can lead to a better understanding of bladder physiology and pathology.