Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice

The α-ketoglutarate–dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is an HIF target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. Although PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about the effects of this highly conserved enzyme in insulin-secreting β cells in vivo. Here, we show that the deletion of PHD3 specifically in β cells (βPHD3KO) was associated with impaired glucose homeostasis in mice fed a high-fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewired, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in βPHD3KO islets was associated with impaired glucose-stimulated ATP/ADP rises, Ca(2+) fluxes, and insulin secretion. Thus, PHD3 might be a pivotal component of the β cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Flank position is associated with higher skin-to-surface interface pressures in men versus women: Implications for laparoscopic renal surgery and the risk of rhabdomyolysis

Background and Purpose: There have been several reports of rhabdomyolysis occurring after prolonged laparoscopic procedures in the flank position. Accordingly, we evaluated interface pressures between the skin and three commonly used operating room table surfaces. The aim of our study was to determine if pressure changes could be related to body mass index (BMI), sex, position, and/or the table surface material. Patients and Methods: Ten men and 10 women were grouped according to BMI = 25, with five participants in each group. Subjects were placed in the left lateral decubitus position with the operating table flat, half flexed, fully flexed, half flexed with the kidney rest elevated, and fully flexed with the kidney rest elevated. Interface pressures were recorded, using an X-Sensor pressure sensing mat, for 5-minute periods in each of the described positions on each surface. Results: Sex and BMI were statistically significant predictors of increased pressures ( P = 0.0042 and 0.0402, respectively). The parameter estimate for the difference between men and women was 4.63 mm Hg ( P = 0.0002), and the difference for BMI >= 25 compared with < 25 was also significant ( P < 0.0209). Full table flexion (50-degree) produced significantly higher pressures than both flat ( P = 0.0001) and the half-flexed ( 25-degree) position ( P < 0.0001). Positions with the kidney rest elevated were associated with significantly higher pressures than without elevation ( P < 0.0001). With regard to the surface used, egg crate provided lower pressures than gel pads ( P = 0.0117). Conclusion: Women have significantly lower interface pressures when compared with men. BMI >= 25 also increases interface pressures. The use of the kidney rest is associated with markedly increased pressure; use of a half-flexed position is preferable to a full-flexed position. These data have implications for patient positioning and identification of persons at risk for rhabdomyolysis during laparoscopic renal surgery

Current and future funding streams for paediatric postmortem imaging: European Society of Paediatric Radiology survey results

Background: Perinatal and childhood postmortem imaging has been accepted as a noninvasive alternative or adjunct to autopsy. However, the variation in funding models from institution to institution is a major factor prohibiting uniform provision of this service. Objective: To describe current funding models employed in European and non-European institutions offering paediatric postmortem imaging services and to discuss the perceived barriers to future postmortem imaging service provision. Materials and methods: A web-based 16-question survey was distributed to members of the European Society of Paediatric Radiology (ESPR) and ESPR postmortem imaging task force over a 6-month period (March-August 2021). Survey questions related to the radiologic and autopsy services being offered and how each was funded within the respondent’s institute. Results: Eighteen individual responses were received (13/18, 72.2% from Europe). Only one-third of the institutions (6/18, 33.3%) have fully funded postmortem imaging services, with the remainder receiving partial (6/18, 33.3%) or no funding (5/18, 27.8%). Funding (full or partial) was more commonly available for forensic work (13/18, 72%), particularly where this was nationally provided. Where funding was not provided, the imaging and reporting costs were absorbed by the institute. Conclusion: Increased access is required for the expansion of postmortem imaging into routine clinical use. This can only be achieved with formal funding on a national level, potentially through health care commissioning and acknowledgement by health care policy makers and pathology services of the value the service provides following the death of a fetus or child. Funding should include the costs involved in training, equipment, reporting and image acquisition

Analysis of the periodicity of synaptic events in neurones in the superior cervical ganglion of anaesthetized rats

The patterns of on-going synaptic events recorded intracellularly in neurones of superior cervical ganglia (SCG)of anaesthetized female rats were analysed by constructing inter-event interval histograms, autocorrelograms, ln-survivor curves and histograms triggered by the arterial pulse wave and by the intercostal EMG.In 11/12 cells with on-going frequencies > 0.5 Hz, one or two inputs were strong (i.e. always suprathreshold). In five cells, action potentials also arose from synaptic potentials with amplitudes close to threshold.Synaptic events in 5/11 neurones tested were phase-related to the arterial pressure wave (i.e. had cardiac rhythmicity, CR).Synaptic events in 9/10 neurones tested (including all with CR) were phase-related to the intercostal EMG and/or their autocorrelograms showed peaks at multiples of the respiratory interval (i.e. had respiratory rhythmicity, RR).The intervals between all synaptic events were exponentially distributed in 8/12 neurones although intervals between single strong events showed peaks related to the respiratory cycle. Bursts occurred only by chance.Event patterns could be simulated by combining events from several respiration-modulated inputs with their timing distributed over nearly half the cycle. From the simulations, the mean number of active preganglionic inputs was estimated to be ≈6 with mean discharge frequency ≈0.4 Hz.We conclude that, in the spontaneously breathing anaesthetized rat, most preganglionic neurones to the SCG fire with relatively low probability in relation to the respiratory cycle. Rhythms in a postganglionic neurone reflect the activity of its suprathreshold preganglionic inputs