Fasting pancreatic polypeptide predicts incident microvascular and macrovascular complications of type 2 diabetes: An observational study.

AIMS: Pancreatic polypeptide (PP) is elevated in people with vascular risk factors such as type 2 diabetes or increased visceral fat. We investigated potential relationships between PP and microvascular and macrovascular complications of diabetes. MATERIALS AND METHODS: Animal study: Subcutaneous PP infusion for 4 weeks in high fat diet mouse model. Retinal mRNA submitted for Ingenuity Pathway Analysis. Human study: fasting PP measured in 1478 participants and vascular complications recorded over median 5.5 (IQR 4.9-5.8) years follow-up. RESULTS: Animal study: The retinal transcriptional response to PP was indicative of cellular stress and damage, and this footprint matched responses described in previously published studies of retinal disease. Of mechanistic importance the transcriptional landscape was consistent with upregulation of folliculin, a recently identified susceptibility gene for diabetic retinopathy. Human study: Adjusting for established risk factors, PP was associated with prevalent and incident clinically significant retinopathy (odds ratio (OR) 1.289 (1.107-1.501) p = 0.001; hazard ratio (HR) 1.259 (1.035-1.531) p = 0.0213), albuminuria (OR 1.277 (1.124-1.454), p = 0.0002; HR 1.608 (1.208-2.141) p = 0.0011), and macrovascular disease (OR 1.021 (1.006-1.037) p = 0.0068; HR 1.324 (1.089-1.61), p = 0.0049), in individuals with type 2 diabetes, and progression to diabetes in non-diabetic individuals (HR 1.402 (1.081-1.818), p = 0.0109). CONCLUSIONS: Elevated fasting PP is independently associated with vascular complications of diabetes and affects retinal pathways potentially influencing retinal neuronal survival. Our results suggest possible new roles for PP-fold peptides in the pathophysiology of diabetes complications and vascular risk stratification.

Redefining ITT cortisol thresholds on Abbott platforms to prevent misdiagnosis of adrenal insufficiency.

BACKGROUND: Adrenal insufficiency (AI) is a life-threatening condition which requires long term glucocorticoid replacement. The insulin tolerance test (ITT) is the current gold standard test for diagnosis of secondary AI, but the widely accepted cut-off value of a peak cortisol of less than 500 nmol/L assumes that anyone who does not reach this value has AI and thus requires full replacement. The cut-off used to diagnose AI is also founded on outdated assays. Use of this cut-off in an era of more specific immunoassays therefore risks misdiagnosis, subsequent unnecessary glucocorticoid exposure and associated adverse effects with increased mortality risk. DESIGN, PATIENTS AND MEASUREMENTS: This retrospective analysis assessed 300 ITT cortisol responses using the Abbott Architect and Alinity analyser platforms in patients with suspected AI over a period of 12 years (August 2010 to January 2022), at a tertiary centre. RESULTS: Patients were classified as having AI or not, based on a comprehensive clinical review of electronic patient records from the point of test to the present day by a panel of pituitary and adrenal specialists. Using the current institutional cut-off value of 500 nmol/L, receiver operating characteristic analysis identified a 100.0% sensitivity and 43.6% specificity (area under the curve 0.979). Using a lower cortisol threshold value of 416 nmol/L on the Abbott analyser platform maintained a sensitivity of 100.0% and improved the specificity to 86.7%. CONCLUSION: This data supports lowering the Abbott analyser ITT peak cortisol threshold to 416 nmol/L. Use of this improved cut-off avoids unnecessary glucocorticoid replacement therapy in 104 (34.7%) of individuals in this study. All patients remained well with at least 1 year longitudinal follow up of glucocorticoid replacement.

Current Challenges and Future Directions in the Assessment of Glucocorticoid Status.

Glucocorticoid hormones (GC) are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels i.e. markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or non-specific. Current tools for assessing GC status, are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intra-individual variation, do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11ßeta-hydroxysteroid dehydrogenase (11ß-HSD) activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, miRNA, gene expression, epigenetic, and other novel biomarkers such as GDF-15 and osteocalcin, that could in future aid in the objective classification of GC status.

Somatostatin Receptor Imaging with [18F]FET-ßAG-TOCA PET/CT and [68Ga]Ga-DOTA-Peptide PET/CT in Patients with Neuroendocrine Tumors: A Prospective, Phase 2 Comparative Study.

There is a clinical need for 18F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]-octreotate ([18F]FET-ßAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-ßAG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-ßAG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6-180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-ßAG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-ßAG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor-to-background ratio of [18F]FET-ßAG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [18F]FET-ßAG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in routine clinical practice given the longer half-life and availability of the cyclotron-produced fluorine radioisotope.

Pituitary hypophysitis in granulomatosis with polyangiitis (GPA): a case series.

Granulomatosis with polyangiitis (GPA) rarely involves the pituitary gland. Pituitary involvement has been reported in ~ 1% of all cases of GPA. Most commonly, pituitary swelling and inflammation results in symptoms due to pituitary mass effect and arginine vasopressin deficiency. To date, there are no pituitary-specific treatment guidelines for this rare condition. We present three patients with GPA-related hypophysitis highlighting the spectrum of pituitary involvement. All three patients were successfully treated with immunosuppressive regimens that included rituximab (RTX). Following remission induction with high-dose glucocorticoids, patients received 6 monthly RTX for remission maintenance. RTX was well tolerated without significant side effects.

Adrenal Vein Sampling: Does the Location of the Non-adrenal Venous Sample Matter?

PURPOSE: Adrenal vein sampling (AVS) is used to lateralise and differentiate unilateral from bilateral aldosterone production in primary aldosteronism. The adrenal venous samples are standardised to a peripheral or low inferior vena cava (IVC) sample and compared. It is unknown whether the location of the non-adrenal sample affects the results. This study compares AVS results standardised to the low IVC and right external iliac vein (REIV). METHODS: Patients who underwent AVS between March 2021 and May 2023 were included. All procedures were undertaken by a single operator (AA). Demographic data and AVS results were collected from patients' electronic records. Catheterisation success and lateralisation were assessed using both low IVC and REIV samples. Equivalence test was used to compare the cortisol and aldosterone levels. RESULTS: Eighty-one patients, (M: F = 38:43), aged between 29 and 74 were included. Bilateral successful adrenal vein cannulation was achieved in 79/81 (97.5%) cases. The mean cortisol levels from the REIV were statistically equivalent although there was a small and not biologically significant difference from the low IVC (respective geometric means 183 nmol/l vs. 185 nmol/l, p = 0.015). This small difference in cortisol may be due to accessory adrenal venous drainage into the IVC. The aldosterone and aldosterone/cortisol ratios were statistically equivalent. There was no discordance in selectivity or lateralisation when the IVC or REIV measurements were used. CONCLUSION: The IVC and REIV samples may be used interchangeably during AVS.

Global Barriers to Accessing Off-Patent Endocrine Therapies: A Renaissance of the Orphan Disease?

CONTEXT: Clinical endocrinology encompasses many diseases requiring long-term drug therapy. Prohibitive pricing of some endocrine drugs classified as essential by the World Health Organization has created suboptimal care of patients with endocrine disorders. EVIDENCE ACQUISITION: This review is based on evidence obtained from several databases and search engines including PubMed, Google, and Google Scholar; reference searches; manual searching for web pages of international regulatory bodies; and the authors' experience from different healthcare settings. EVIDENCE SYNTHESIS: After the expiry of a patent, generic versions with the opportunity for increased availability and a price reduction are expected. There are access barriers worldwide for many off-patent endocrine drugs. The high price is the main issue for several medicines including insulin, hydrocortisone, testosterone, and gonadotropins. This is caused by several factors including the market monopoly due to the lack of registered generics or suppliers limiting the benefit of competition and a complex supply chain. Additionally, the lack of some medicines has been concerning due to market factors such as the relatively small number of patients, making it less attractive for the manufacturers. Commissioning of nonprofit manufacturers and state manufacturing as well as strict price control measures could alleviate this situation. CONCLUSION: Lack of availability and disproportionate price inflation affecting essential off-patent endocrine therapies is common due to several interrelated factors. Global collaboration among healthcare organizations with the support of policymaking bodies might be needed to mitigate this.

The Impact of Obesity on the Resolution of Hypertension Following Adrenalectomy for Primary Hyperaldosteronism.

BACKGROUND: This study aims to determine the impact of patient obesity on the resolution of hypertension and pill burden post-adrenalectomy for PA. Primary hyperaldosteronism (PA) is the most common cause of secondary hypertension that may be remedied with surgery (unilateral adrenalectomy). Obesity may independently cause hypertension through several mechanisms including activation of the renin-angiotensin-aldosterone pathway. The influence of obesity on the efficacy of adrenalectomy in PA has not been established. METHODS: This is a retrospective analysis of prospectively collected data on patients undergoing adrenalectomy for PA at a single, tertiary-care surgical centre from January 2015 to December 2020. Electronic health records of patients were screened to collect relevant data. The primary outcomes of the study include post-operative blood pressure, the reduction in the number of anti-hypertensive medications and potassium supplementation burden post-adrenalectomy. RESULTS: Fifty-three patients were included in the final analysis. There was a significant reduction in the blood pressure and the number of anti-hypertensive medications in all patients after adrenalectomy (p < 0.001). Of the 34 patients (64.2%) with pre-operative hypokalaemia, all became normokalaemic and were able to stop supplementation. However obese patients required more anti-hypertensive medications to achieve an acceptable blood pressure than overweight or normal BMI patients (p < 0.01). Multivariate logistic regression analysis showed that male gender and BMI were independent predictors of resolution of hypertension (p <0.01). CONCLUSION: Unilateral adrenalectomy improves the management of hypertension and hypokalaemia when present in patients with PA. However, obesity has an independent deleterious impact on improvement in blood pressure post-adrenalectomy for PA.

Clinical characteristics of functioning gonadotroph adenoma in women presenting with ovarian hyperstimulation: Audit of UK pituitary centres.

OBJECTIVE: Functioning gonadotroph adenomas (FGAs) are rare pituitary tumours stimulating ovarian function with potential life-threatening consequences in women. However, a lack of aggregated clinical experience of FGAs impairs management in affected women. The aim of this study is to present the clinical course of FGA-induced ovarian hyperstimulation syndrome (OHSS) cases as identified by some of the largest UK pituitary endocrine tertiary centres with a view to increasing awareness and improving diagnosis and management of women with FGA. DESIGN: A retrospective observational study; audit of eight UK regional pituitary centres for cases of FGAs. SETTING: Specialist neuroendocrine centres in the United Kingdom. PATIENTS AND MEASUREMENTS: Women diagnosed with FGA-induced OHSS. Description of their clinical course. RESULTS: Seven cases of FGA were identified in women, all causing OHSS. Mean age was 33.4 years at diagnosis. Abdominal pain, irregular periods, headache, and visual disturbances were reported at presentation by 100%, 71%, 57% and 43% of women, respectively. Three of seven women underwent ovarian surgery before FGA diagnosis. Six women underwent transsphenoidal surgery (TSS) with incomplete tumour resection in five of those, but all showed improvement or resolution in symptoms and biochemistry postoperatively. CONCLUSION: FGA is a rare cause of spontaneous OHSS. TSS improves clinical and biochemical features of ovarian hyperstimulation in FGAs. Improved awareness of FGA will prevent inappropriate emergency ovarian surgery.

Optimising prednisolone or prednisone replacement in adrenal insufficiency.

Context: Patients with adrenal insufficiency (AI) have a higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with twice- or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance through its convenience. Objectives: Prednisolone day curves can be used to accurately downtitrate patients to the minimum effective dose. This study aimed to review prednisolone day curves and determine therapeutic ranges at different time points after administration. Methods: Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. Spearman's correlation coefficient was used to determine the relationship between 2-, 4-, and 6-h prednisolone levels compared to the previously validated standard 8-h prednisolone level (15-25 µg/L). Results: The median dose was 4 mg of prednisolone once daily. There was a strong correlation between the 4- and 8-h (R = 0.8829, P ≤ 0.0001) and 6- and 8-h prednisolone levels (R = 0.9530, P ≤ 0.0001). Target ranges for prednisolone were 37-62 µg/L at 4 h, 24-39 µg/L at 6 h, and 15-25 µg/L at 8 h. Prednisolone doses were successfully reduced in 21 individuals, and of these, 3 were reduced to 2 mg once daily. All patients were well upon follow-up. Conclusion: This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low-dose prednisolone of 2-4 mg is safe and effective in most patients with AI. Doses can be titrated with either 4-, 6-, or 8-h single time point drug levels.

Knowledge Attainment and Engagement Among Medical Students: A Comparison of Three Forms of Online Learning.

Objective: This study compared knowledge attainment and student enjoyment and engagement between clinical case vignette, patient-testimony videos and mixed reality (MR) teaching via the Microsoft HoloLens 2, all delivered remotely to third year medical students. The feasibility of conducting MR teaching on a large scale was also assessed. Setting & Participants: Medical students in Year 3 at Imperial College London participated in three online teaching sessions, one in each format. All students were expected to attend these scheduled teaching sessions and to complete the formative assessment. Inclusion of their data used as part of the research trial was optional. Primary and Secondary Outcome Measures: The primary outcome measure was performance on a formative assessment, which served to compare knowledge attainment between three forms of online learning. Moreover, we aimed to explore student engagement with each form of learning via a questionnaire, and also feasibility of applying MR as a teaching tool on a large scale. Comparisons between performances on the formative assessment between the three groups were investigated using a repeated measures two-way ANOVA. Engagement and enjoyment were also analysed in the same manner. Results: A total of 252 students participated in the study. Knowledge attainment of students using MR was comparable with the other two methods. Participants reported higher enjoyment and engagement (p<0.001) for the case vignette method, compared with MR and video-based teaching. There was no difference in enjoyment or engagement ratings between MR and the video-based methods. Conclusion: This study demonstrated that the implementation of MR is an effective, acceptable, and feasible way of teaching clinical medicine to undergraduate students on a large scale. However, case-based tutorials were found to be favoured most by students. Future work could further explore the best uses for MR teaching within the medical curriculum.

The impact of patient skin colour on diagnostic ability and confidence of medical students.

Previous literature has explored unconscious racial biases in clinical education and medicine, finding that people with darker skin tones can be underrepresented in learning resources and managed differently in a clinical setting. This study aimed to examine whether patient skin colour can affect the diagnostic ability and confidence of medical students, and their cognitive reasoning processes. We presented students with 12 different clinical presentations on both white skin (WS) and non-white skin (NWS). A think aloud (TA) study was conducted to explore students' cognitive reasoning processes (n = 8). An online quiz was also conducted where students submitted a diagnosis and confidence level for each clinical presentation (n = 185). In the TA interviews, students used similar levels of information gathering and analytical reasoning for each skin type but appeared to display increased uncertainty and reduced non-analytical reasoning methods for the NWS images compared to the WS images. In the online quiz, students were significantly more likely to accurately diagnose five of the 12 clinical presentations (shingles, cellulitis, Lyme disease, eczema and meningococcal disease) on WS compared to NWS (p < 0.01). With regards to students' confidence, they were significantly more confident diagnosing eight of the 12 clinical presentations (shingles, cellulitis, Lyme disease, eczema, meningococcal disease, urticaria, chickenpox and Kawasaki disease) on WS when compared to NWS (p < 0.01). These findings highlight the need to improve teaching resources to include a greater diversity of skin colours exhibiting clinical signs, to improve students' knowledge and confidence, and ultimately, to avoid patients being misdiagnosed due to the colour of their skin.

Time for preference-informed foundation allocation?

Successful completion of year 1 of the UK Foundation Programme is a General Medical Council requirement that newly qualified doctors must achieve in order to gain full registration for licence to practise in the UK. We present compelling evidence that both sections of the UK Foundation Programme allocation process, consisting of the Educational Performance Measure and Situational Judgement Test scores, are not fit for purpose. The ranking process drives competitive behaviours among medical students and undermines NHS teamworking values. Furthermore, data from 2013-2020 show that UK minority ethnic students consistently receive significantly lower SJT scores than White students. The current process in the UK allocates lower ranked students, who often need more academic and social support, to undersubscribed regions. This can lead to vacancies in less popular regions, ultimately worsening health inequality. A preference-informed allocation process will improve trainee access to support and help retain trainees in underserved regions. We aim to summarise the flaws of the current system and report a potential radical solution.

Late-night salivary cortisol and cortisone should be the initial screening test for Cushing's syndrome.

Endogenous Cushing's syndrome (CS) poses considerable diagnostic challenges. Although late-night salivary cortisol (LNSC) is recommended as a first-line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low-dose dexamethasone suppression test and 24-h urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients). LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/L the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home. We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS.

Understanding concepts of generalism and specialism amongst medical students at a research-intensive London medical school.

BACKGROUND: Many prominent UK medical organisations have identified a need for more generalist clinicians to address the complex requirements of an aging society. We sought to clarify attitudes towards "Specialists" and "Generalists" amongst medical students and junior doctors at Imperial College School of Medicine. METHODS: A survey exploring medical students' beliefs was followed up by qualitative analysis of focus groups of medical students and Imperial-graduate foundation year doctors. RESULTS: First year medical students associated specialists with academia and higher income, and generalists with ease of training and job availability. Senior (Years 5/6) medical students associated specialists even more firmly with broader influence and academic work, whilst generalists were assigned lower prestige but the same workload as specialists. The medical student focus group discussed concepts of Generalism pertaining only to Primary Care. In contrast, the foundation year doctor focus group revealed that Generalism was now seen to include some hospital care, and the perception that generalists sat lower in a knowledge hierarchy had been challenged. CONCLUSION: Perceptions that Generalism is associated with lower prestige in the medical profession are already present at the very start of medical school and seem to be reinforced during undergraduate training. In early postgraduate clinical practice, the perceived knowledge and prestige hierarchy lessens. These findings can help inform curriculum redesign and the promotion of Generalism as a rewarding career aspiration.

Ramadan Fasting and Changes in Thyroid Function in Hypothyroidism: Identifying Patients at Risk.

Background: Ramadan fasting (RF) is associated with major changes in meal times. This can affect thyroxine absorption and thyroid function (TF) in patients with hypothyroidism. We aimed to examine the short- and long-term impact of RF on TF in patients with primary hypothyroidism on levothyroxine. Methods: TF tests in patients with primary hypothyroidism attending an endocrine center in the United Arab Emirates were retrospectively analyzed. The impact of RF on TF, namely serum thyrotropin (TSH) TSH, free thyroxine (fT4) and free triiodothyronine (fT3), was investigated in 481 patients within 3 months before Ramadan (BR), 1-2 weeks (PR1), and 3-6 months (PR2) post-Ramadan. Controlled TF was defined as TSH between 0.45 and 4.5 µIU/mL. Inadequate control was defined as TSH >4.5 µIU/mL. Loss of control was defined as having controlled TF at BR and inadequate control at PR1. Multivariable regression analyses were used to assess the association of baseline TSH, baseline levothyroxine dose, and medication use with loss of thyroid control in Ramadan. Results: TSH increased significantly from a median of 2.0 (0.8-3.7) µIU/mL at BR to 2.9 (1.4-5.6) µIU/mL at PR1 (p < 0.001). This was accompanied by a fall in fT4 and fT3 at PR1 (p < 0.001). 25.5% of patients with previously controlled TF at BR had deterioration in TF at PR1. Sixty-one percent of patients with previously uncontrolled TF at BR remained uncontrolled at PR1. Baseline TSH was significantly associated with loss of thyroid control in Ramadan with an odds ratio (95% confidence interval) of 1.5 (1.17-1.92) (p < 0.001), whereas other variables, including medications known to affect levothyroxine absorption were not associated with loss of control. TSH, fT4, and fT3 levels returned to normal at PR2. Conclusions: RF can negatively affect TF of patients on levothyroxine replacement. Although this effect is modest and transitory in most patients, a significant minority exhibit more pronounced, and clinically relevant changes. The latter includes those with higher TSH BR, and a smaller group whose thyroid disease appears to be particularly affected by the mealtime and lifestyle changes of Ramadan.