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11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool.
No full textAndrogens are the obligatory precursors of estrogens. In humans, classic androgen biosynthesis yields testosterone, thought to represent the predominant circulating active androgen both in men and women. However, recent work has shown that 11-ketotestosterone, derived from the newly described 11-oxygenated androgen biosynthesis pathway, makes a substantial contribution to the active androgen pool in women. Considering that classic androgens are the obligatory substrates for estrogen biosynthesis catalyzed by cytochrome P450 aromatase, we hypothesized that 11-oxygenated androgens are aromatizable. Here we use steroid analysis by tandem mass spectrometry to demonstrate that human aromatase generates 11-oxygenated estrogens from 11-oxygenated androgens in 3 different cell-based aromatase expression systems and in human ex vivo placenta explant cultures. We also show that 11-oxygenated estrogens are generated as a byproduct of the aromatization of classic androgens. We show that 11β-hydroxy-17β-estradiol binds and activates estrogen receptors α and β and that 11β-hydroxy-17β-estradiol and the classic androgen pathway-derived active estrogen, 17β-estradiol, are equipotent in stimulating breast cancer cell line proliferation and expression of estrogen-responsive genes. 11-oxygenated estrogens were, however, not detectable in serum from individuals with high aromatase levels (pregnant women) and elevated 11-oxygenated androgen levels (patients with congenital adrenal hyperplasia or adrenocortical carcinoma). Our data show that while 11-oxygenated androgens are aromatizable in vitro and ex vivo, the resulting 11-oxygenated estrogens are not detectable in circulation, suggesting that 11-oxygenated androgens function primarily as androgens in vivo
Telemetric monitoring in idiopathic intracranial hypertension demonstrates intracranial pressure in a case with sight-threatening disease.
No full textThe understanding of raised intracranial pressure (ICP) is increasing with the directed use of intracranial telemetric ICP monitors. This case uniquely observed ICP changes by telemetric monitoring in a patient with idiopathic intracranial hypertension (IIH), who developed rapid sight-threatening disease. A lumbar drain was inserted, as a temporising measure, and was clamped prior to surgery. This resulted in a rapid rise in ICP, which normalised after insertion of a ventriculoperitoneal shunt. This case highlighted the utility of the ICP monitor and the lumbar drain as a temporising measure to control ICP prior to a definitive procedure as recommended by the IIH consensus guidelines
The Impact of Bariatric Surgery on Incident Microvascular Complications in Patients With Type 2 Diabetes: A Matched Controlled Population-Based Retrospective Cohort Study.
No full textOBJECTIVE
To assess the impact of bariatric surgery (BS) on incident microvascular complications of diabetes-related foot disease (DFD), sight-threatening diabetic retinopathy (STDR), and chronic kidney disease (CKD) in patients with type 2 diabetes and obesity.
RESEARCH DESIGN AND METHODS
A retrospective matched, controlled population-based cohort study was conducted of adults with type 2 diabetes between 1 January 1990 and 31 January 2018 using IQVIA Medical Research Data (IMRD), a database of primary care electronic records. Each patient with type 2 diabetes who subsequently had BS (surgical group) was matched on the index date with up to two patients with type 2 diabetes who did not have BS (nonsurgical group) within the same general practice by age, sex, preindex BMI, and diabetes duration.
RESULTS
Included were 1,126 surgical and 2,219 nonsurgical participants. In the study population 2,261 (68%) were women. Mean (SD) age was 49.87 (9.3) years vs. 50.12 (9.3) years and BMI was 46.76 (7.96) kg/m vs. 46.14 (7.49) kg/m in the surgical versus nonsurgical group, respectively. In the surgical group, 22.1%, 22.7%, 52.2%, and 1.1% of patients had gastric band, sleeve gastrectomy, Roux-en-Y gastric bypass (RYGB), and duodenal switch, respectively. Over a median follow-up of 3.9 years (interquartile range 1.8-6.4), BS was associated with reduction in incident combined microvascular complications (adjusted hazard ratio 0.53, 95% CI 0.43-0.66, < 0.001), DFD (0.61, 0.50-0.75, < 0.001), STDR (0.66, 0.44-1.00, = 0.048), and CKD (0.63, 0.51-0.78, < 0.001). Analysis based on the type of surgery showed that all types of surgery were associated with a favorable impact on the incidence of composite microvascular complications, with the greatest reduction for RYGB.
CONCLUSIONS
BS was associated with a significant reduction in incident diabetes-related microvascular complications
Character failings in the surgeon fallen from grace: a thematic analysis of disciplinary hearings against surgeons 2016-2020.
No full textSurgeons are commonly evaluated with respect to outcomes and adherence to rules and regulations, rather than a true holistic examination of the character of the surgeon in question. We sought to examine the character failings of surgeons who faced fitness to practice enquiries under the Medical Practitioner Tribunal Service in the UK. In particular, we examined the absence of virtue as perceived through the lens of Aristotelian ethics using thematic analysis of tribunal hearing transcripts from 2016 to 2020. We identified three overarching themes that are explored in depth: 'the god complex', 'reputation over integrity' and 'wounded pride'. We hope to use this as the foundation for a re-examination of the place of phronesis in postgraduate surgical education, which we argue should be perceived as an exercise in character development and reformation rather than the simplistic teaching of skills to standardised outcomes
Experiences and perceptions of dietitians for obesity management: a general practice qualitative study.
No full textBACKGROUND
Multi-component lifestyle interventions are the first line treatment for obesity. Dietitians are ideally placed healthcare professionals to deliver such interventions. However, only a small proportion of patients with obesity are referred by general practice to dietitians, and the reasons for this are not clear. The present study aimed to explore general practice healthcare professionals' (GPHCPs) experiences and perceptions of dietitians in the context of obesity management.
METHODS
A convenience sample of GPHCPs practicing in the UK was recruited via a targeted social media strategy, using virtual snowball sampling. Data were collected using semi-structured interviews and analysed using framework analysis.
RESULTS
In total, 20 participants were interviewed (11 general practice nurses and nine general practitioners). Experiences of referring patients with obesity for dietetic intervention resulted in two main themes: (i) access barriers and (ii) the dietetic consult experience. Three themes emerged from participants' perceptions of a role for general practice dietitians: (i) utilising dietetic expertise; (ii) access to dietitian; and (iii) time. Participants experienced barriers to accessing dietitians for obesity management and felt that having a dietitian working within their general practice team would help address this. Having a dietitian embedded within their general practice team was perceived to have the potential to alleviate GPHCPs' clinical time pressures, offer opportunities for upskilling, and may improve patient engagement with obesity management.
CONCLUSIONS
GPHCPs perceived that embedding a dietitian within their general practice team would be valuable and beneficial for obesity management. Our findings provide support for the funding of general practice dietitian roles in the UK
Association of british clinical diabetologists and renal association guidelines on the detection and management of diabetes post solid organ transplantation.
No full textPost-transplant diabetes mellitus (PTDM) is common after solid organ transplantation (SOT) and associated with increased morbidity and mortality for allograft recipients. Despite the significant burden of disease, there is a paucity of literature with regards to detection, prevention and management. Evidence from the general population with diabetes may not be translatable to the unique context of SOT. In light of emerging clinical evidence and novel anti-diabetic agents, there is an urgent need for updated guidance and recommendations in this high-risk cohort. The Association of British Clinical Diabetologists (ABCD) and Renal Association (RA) Diabetic Kidney Disease Clinical Speciality Group have undertaken a systematic review and critical appraisal of the available evidence. Areas of focus are; 1) Epidemiology, 2) Pathogenesis, 3) Detection, 4) Management, 5) Modification of immunosuppression, 6) Prevention, and 7) PTDM in the non-renal setting. Evidence-graded recommendations are provided for the detection, management, and prevention of PTDM, with suggested areas for future research and potential audit standards. The guidelines are endorsed by Diabetes UK, the British Transplantation Society and the Royal College of Physicians of London. The full guidelines are available freely online for the diabetes, renal and transplantation community using the link below. The aim of this review article is to introduce an abridged version of this new clinical guideline. https://abcd.care/sites/abcd.care/files/site_uploads/Resources/Position-Papers/ABCD-RA%20PTDM%20v14.pdf
A comparison of the demographics, injury patterns and outcome data for patients injured in motor vehicle collisions who are trapped compared to those patients who are not trapped.
No full textBACKGROUND
Motor vehicle collisions (MVCs) are a common cause of major trauma and death. Following an MVC, up to 40% of patients will be trapped in their vehicle. Extrication methods are focused on the prevention of secondary spinal injury through movement minimisation and mitigation. This approach is time consuming and patients may have time-critical injuries. The purpose of this study is to describe the outcomes and injuries of those trapped following an MVC: this will help guide meaningful patient-focused interventions and future extrication strategies.
METHODS
We undertook a retrospective database study using the Trauma Audit and Research Network database. Patients were included if they were admitted to an English hospital following an MVC from 2012 to 2018. Patients were excluded when their outcomes were not known or if they were secondary transfers.
RESULTS
This analysis identified 426,135 cases of which 63,625 patients were included: 6983 trapped and 56,642 not trapped. Trapped patients had a higher mortality (8.9% vs 5.0%, p < 0.001). Spinal cord injuries were rare (0.71% of all extrications) but frequently (50.1%) associated with other severe injuries. Spinal cord injuries were more common in patients who were trapped (p < 0.001). Injury Severity Score (ISS) was higher in the trapped group 18 (IQR 10-29) vs 13 (IQR 9-22). Trapped patients had more deranged physiology with lower blood pressures, lower oxygen saturations and lower Glasgow Coma Scale, GCS (all p < 0.001). Trapped patients had more significant injuries of the head chest, abdomen and spine (all p < 0.001) and an increased rate of pelvic injures with significant blood loss, blood loss from other areas or tension pneumothorax (all p < 0.001).
CONCLUSION
Trapped patients are more likely to die than those who are not trapped. The frequency of spinal cord injuries is low, accounting for < 0.7% of all patients extricated. Patients who are trapped are more likely to have time-critical injuries requiring intervention. Extrication takes time and when considering the frequency, type and severity of injuries reported here, the benefit of movement minimisation may be outweighed by the additional time taken. Improved extrication strategies should be developed which are evidence-based and allow for the expedient management of other life-threatening injuries
Resuscitation and emergency care in drowning: A scoping review.
No full textBACKGROUND
The ILCOR Basic Life Support Task Force and the international drowning research community considered it timely to undertake a scoping review of the literature to identify evidence relating to the initial resuscitation, hospital-based interventions and criteria for safe discharge related to drowning.
METHODS
Medline, PreMedline, Embase, Cochrane Reviews and Cochrane CENTRAL were searched from 2000 to June 2020 to identify relevant literature. Titles and abstracts and if necessary full text were reviewed in duplicate. Studies were eligible for inclusion if they reported on the population (adults and children who are submerged in water), interventions (resuscitation in water / boats, airway management, oxygen administration, AED use, bystander CPR, ventilation strategies, ECMO, protocols for hospital discharge (I), comparator (standard care) and outcomes (O) survival, survival with a favourable neurological outcome, CPR quality, physiological end-points).
RESULTS
The database search yielded 3242 references (Medline 1104, Pre-Medline 202, Embase 1722, Cochrane reviews 12, Cochrane CENTRAL 202). After removal of duplicates 2377 papers were left for screening titles and abstracts. In total 65 unique papers were included. The evidence identified was from predominantly high-income countries and lacked consistency in the populations, interventions and outcomes reported. Clinical studies were exclusively observational in nature.
CONCLUSION
This scoping review found that there is very limited evidence from observational studies to inform evidence based clinical practice guidelines for drowning. The review highlights an urgent need for high quality research in drowning
Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial.
No full textBACKGROUND
Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial.
METHODS
ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146.
FINDINGS
Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6-54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2-28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1-20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8-23·4; 544 events) and 9·7 months (5·8-14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response.
INTERPRETATION
The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient's clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response.
FUNDING
Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia
Association of Bone Metastatic Burden With Survival Benefit From Prostate Radiotherapy in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial.
No full textImportance
Prostate radiotherapy (RT) improves survival in men with low-burden metastatic prostate cancer. However, owing to the dichotomized nature of metastatic burden criteria, it is not clear how this benefit varies with bone metastasis counts and metastatic site.
Objective
To evaluate the association of bone metastasis count and location with survival benefit from prostate RT.
Design, Setting, and Participants
This exploratory analysis of treatment outcomes based on metastatic site and extent as determined by conventional imaging (computed tomography/magnetic resonance imaging and bone scan) evaluated patients with newly diagnosed metastatic prostate cancer randomized within the STAMPEDE trial's metastasis M1 RT comparison. The association of baseline bone metastasis counts with overall survival (OS) and failure-free survival (FFS) was assessed using a multivariable fractional polynomial interaction procedure. Further analysis was conducted in subgroups.
Interventions
Patients were randomized to receive either standard of care (androgen deprivation therapy with or without docetaxel) or standard of care and prostate RT.
Main Outcomes and Measures
The primary outcomes were OS and FFS.
Results
A total of 1939 of 2061 men were included (median [interquartile range] age, 68 [63-73] years); 1732 (89%) had bone metastases. Bone metastasis counts were associated with OS and FFS benefit from prostate RT. Survival benefit decreased continuously as the number of bone metastases increased, with benefit most pronounced up to 3 bone metastases. A plot of estimated treatment effect indicated that the upper 95% CI crossed the line of equivalence (hazard ratio [HR], 1) above 3 bone metastases without a detectable change point. Further analysis based on subgroups showed that the magnitude of benefit from the addition of prostate RT was greater in patients with low metastatic burden with only nonregional lymph nodes (M1a) or 3 or fewer bone metastases without visceral metastasis (HR for OS, 0.62; 95% CI, 0.46-0.83; HR for FFS, 0.57; 95% CI, 0.47-0.70) than among patients with 4 or more bone metastases or any visceral/other metastasis (HR for OS, 1.08; 95% CI, 0.91-1.28; interaction P = .003; HR for FFS, 0.87; 95% CI, 0.76-0.99; interaction P = .002).
Conclusions and Relevance
In this exploratory analysis of a randomized clinical trial, bone metastasis count and metastasis location based on conventional imaging were associated with OS and FFS benefit from prostate RT in M1 disease.
Trial Registration
ClinicalTrials.gov Identifier: NCT00268476; ISRCTN.com Identifier: ISRCTN78818544