The modulation of platelet function by growth hormone in growth hormone deficient Hypopituitary patients.

BACKGROUND: Growth hormone deficiency (GHD) has been implicated in increased cardiovascular and cerebrovascular disease risk seen in hypopituitarism, however the mechanism remains speculative. We hypothesise that platelet abnormalities may play a contributory role. Herein we examined platelet behaviour in GHD hypopituitary patients, pre- and post-growth hormone (GH) replacement. METHODS: This study utilizes a physiological flow-based assay to quantify platelet function in whole blood from patient cohorts under arterial shear. Thirteen GH Naïve hypopituitary adults with GHD and thirteen healthy matched controls were studied. Patients were assessed before and after GH treatment. All other pituitary replacements were optimised before the study. In addition to a full endocrine profile, whole blood was labelled and perfused over immobilised von Willibrand factor (vWF). Seven parameters of dynamic platelet-vWF interactions were recorded using digital image microscopy and analysed by customised platelet tracking software. RESULTS: We found a significantly altered profile of platelet-vWF interactions in GHD individuals compared to healthy controls. Specifically, we observed a marked increase in platelets shown to form associations such as tethering, rolling and adherence to immobilized vWF, which were reduced post GH treatment. Speed and distance platelets travelled across vWF was similar between controls and pre-therapy GHD patients, however, this was considerably increased post treatment. This may indicate reduced platelet signaling resulting in less stable adhesion of platelets post GH treatment. CONCLUSIONS: Taken together observed differences in platelet behaviour may contribute to an increased risk of thrombosis in GHD which can in part be reversed by GH therapy.

Risk assessments and structured care interventions for prevention of foot ulceration in diabetes: development and validation of a prognostic model.

BACKGROUND: Diabetes-related foot ulcers give rise to considerable morbidity, generate a high monetary cost for health and social care services and precede the majority of diabetes-related lower extremity amputations. There are many clinical prediction rules in existence to assess risk of foot ulceration but few have been subject to validation. OBJECTIVES: Our objectives were to produce an evidence-based clinical pathway for risk assessment and management of the foot in people with diabetes mellitus to estimate cost-effective monitoring intervals and to perform cost-effectiveness analyses and a value-of-information analysis. DESIGN: We developed and validated a prognostic model using predictive modelling, calibration and discrimination techniques. An overview of systematic reviews already completed was followed by a review of randomised controlled trials of interventions to prevent foot ulceration in diabetes mellitus. A review of the health economic literature was followed by the construction of an economic model, an analysis of the transitional probability of moving from one foot risk state to another, an assessment of cost-effectiveness and a value-of-information analysis. INTERVENTIONS: The effects of simple and complex interventions and different monitoring intervals for the clinical prediction rules were evaluated. MAIN OUTCOME MEASURE: The main outcome was the incidence of foot ulceration. We compared the new clinical prediction rules in conjunction with the most effective preventative interventions at different monitoring intervals with a 'treat-all' strategy. DATA SOURCES: Data from an electronic health record for 26,154 people with diabetes mellitus in one Scottish health board were used to estimate the monitoring interval. The Prediction Of Diabetic foot UlcerationS (PODUS) data set was used to develop and validate the clinical prediction rule. REVIEW METHODS: We searched for eligible randomised controlled trials of interventions using search strategies created for Ovid® (Wolters Kluwer, Alphen aan den Rijn, the Netherlands), MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. Randomised controlled trials in progress were identified via the International Standard Randomised Controlled Trial Number Registry and systematic reviews were identified via PROSPERO. Databases were searched from inception to February 2019. RESULTS: The clinical prediction rule was found to accurately assess the risk of foot ulceration. Digital infrared thermometry, complex interventions and therapeutic footwear with offloading devices were found to be effective in preventing foot ulcers. The risk of developing a foot ulcer did not change over time for most people. We found that interventions to prevent foot ulceration may be cost-effective but there is uncertainty about this. Digital infrared thermometry and therapeutic footwear with offloading devices may be cost-effective when used to treat all people with diabetes mellitus regardless of their ulcer risk. LIMITATIONS: The threats to the validity of the results in some randomised controlled trials in the review and the large number of missing data in the electronic health record mean that there is uncertainty in our estimates. CONCLUSIONS: There is evidence that interventions to prevent foot ulceration are effective but it is not clear who would benefit most from receiving the interventions. The ulceration risk does not change over an 8-year period for most people with diabetes mellitus. A change in the monitoring interval from annually to every 2 years for those at low risk would be acceptable. FUTURE WORK RECOMMENDATIONS: Improving the completeness of electronic health records and sharing data would help improve our knowledge about the most clinically effective and cost-effective approaches to prevent foot ulceration in diabetes mellitus. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016052324. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 62. See the NIHR Journals Library website for further project information.

People with diabetes sometimes have problems with their feet that can become serious and make getting around harder and life less enjoyable. We have developed a test based on a simple score to find out a person's risk of getting a foot ulcer. We also wanted to know how often the test needs to be done. People who have been tested and learn that they might go on to have foot problems rightly expect to be given treatment that stops the problem happening in the first place. In this project, we read many written reports about the best treatments to prevent foot ulcers. We found that some things can prevent foot ulcers, such as wearing special shoes and insoles, taking the temperature of the skin of the foot and resting when the temperature rises, and receiving specialist care from diabetes foot care teams. However, we also looked at the costs of the test and treatments and found that some treatments are better value for money than others. By using people's health data from NHS computers, we discovered that very few people with diabetes develop a worse risk score for foot ulcers as time goes on, and it seems that being tested every year is not necessary for everyone. New clinical trials might help to improve foot health for people with diabetes, but if all of the researchers who have collected data from people in clinical trials shared their data it would be possible to find out more about who will gain most from these treatments without spending a lot on new research. It is clear that better input of patients' health data into NHS computers will benefit diabetes research in the future.

Preventing foot ulceration in diabetes: systematic review and meta-analyses of RCT data.

AIMS/HYPOTHESIS: Foot ulceration is a serious complication for people with diabetes that results in high levels of morbidity for individuals and significant costs for health and social care systems. Nineteen systematic reviews of preventative interventions have been published, but none provides a reliable numerical summary of treatment effects. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to make the best possible use of the currently available data. METHODS: We conducted a systematic review and meta-analysis of RCTs of preventative interventions for foot ulceration. OVID MEDLINE and EMBASE were searched to February 2019 and the Cochrane Central Register of Controlled Trials to October 2018. RCTs of interventions to prevent foot ulcers in people with diabetes who were free from foot ulceration at trial entry were included. Two independent reviewers read the full-text articles and extracted data. The quality of trial reporting was assessed using the Cochrane Risk of Bias tool. The primary outcome of foot ulceration was summarised using pooled relative risks in meta-analyses. RESULTS: Twenty-two RCTs of eight interventions were eligible for analysis. One trial of digital silicone devices (RR 0.07 [95% CI 0.01, 0.55]) and meta-analyses of dermal infrared thermometry (RR 0.41 [95% CI 0.19, 0.86]), complex interventions (RR 0.59 [95% CI 0.38, 0.90], and custom-made footwear and offloading insoles (RR 0.53 [95% CI 0.33, 0.85]) showed beneficial effects for these interventions. CONCLUSIONS/INTERPRETATION: Four interventions were identified as being effective in preventing foot ulcers in people with diabetes, but uncertainty remains about what works and who is most likely to benefit.

Hyponatraemia in patients with community-acquired pneumonia; prevalence and aetiology, and natural history of SIAD.

OBJECTIVE: Hyponatraemia is common in community-acquired pneumonia (CAP) and is associated with increased mortality. The mechanism of hyponatraemia in CAP is not completely understood and treatment is therefore ill-defined. We aimed to define the causation of hyponatraemia in CAP. DESIGN: Prospective, single-centre, observational study of all patients with CAP and hyponatraemia (≤ 130 mmol/L) during a 9-month period. PATIENTS: The prevalence of each subtype of hyponatraemia, and the associated mortality, was determined in 143 admissions with CAP (Study 1). A sub-cohort of patients with SIAD (n = 10) was prospectively followed, to document the natural history of SIAD associated with CAP (Study 2). MEASUREMENTS: In Study 2, blood and urine were collected on day 1, 3, 5 and 7 following admission for measurement of plasma vasopressin, sodium, osmolality and urine osmolality. RESULTS: In study 1, 143/1723(8.3%) of CAP patients had hyponatraemia (≤130 mmol/L). About 66 had SIAD (46%), 60(42%) had hypovolaemic hyponatraemia (HON), 13(9%) had hypervolaemic hyponatraemia (HEN) and 4(3%) patients had hyponatraemia due to glucocorticoid hormone deficiency. Mortality was higher in the HEN than in the HON, SIAD or normonatraemic groups (P < 0.01). In Study 2, plasma sodium concentration normalized in 8/10 (80%) by day 7. Two patients with persistent hyponatraemia were discovered to have underlying bronchiectasis. CONCLUSIONS: Hyponatraemia in CAP is most commonly secondary to SIAD or hypovolaemia. HEN is less common, but has worse prognosis. Prospective observation demonstrates that in SIAD, plasma AVP and sodium concentrations normalize with antimicrobials; failure of reversal of suggests underlying lung disease, such as bronchiectasis.

Author Correction: Analysis of inflammatory cytokine and TLR expression levels in Type 2 Diabetes with complications.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Analysis of inflammatory cytokine and TLR expression levels in Type 2 Diabetes with complications.

The pathogenesis and complications of type 2 diabetes (T2DM) are closely linked with defective glucose metabolism, obesity, cardiovascular disease and an inability to mount an effective immune response to certain pathogenic organisms. Perturbations in key innate immune receptors known as Toll-like receptors (TLRs) and inflammatory mediators such as IL-6, TNFα and IL-1ß have been linked with T2DM. Herein, we sought to establish whether patients with T2DM and underlying complications exhibit perturbations in cytokine and TLR expression. Serum cytokine and mRNA levels of cytokines/TLRs in monocytes (M) and neutrophils (N) were measured in a cohort of 112 diabetic patients: good glycaemic control without complications (GC), good glycaemic control with complications (GCC), poor glycaemic control without complications (PC) and poor glycaemic control with complications (PCC) and compared them with 34 non-diabetic volunteers (NGT). Serum cytokine levels were normal in all study participants. In the GC group, cytokine and TLR gene expression were enhanced compared to NGT. In contrast, suppressed cytokine and TLR gene expression were evident in PC, GCC & PCC groups when compared to the GC. In conclusion, whereas serum pro-inflammatory cytokine levels are unaltered in T2DM patients, differences in inflammatory gene profiles exist among the T2DM patient groups.

Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: Results of a prospective observational study.

OBJECTIVE: Hyponatraemia is associated with increased mortality, but the mortality associated specifically with SIAD is not known. We hypothesized that mortality in SIAD was elevated, but that it was less than in hypervolaemic (HEN) or hypovolaemic (HON) hyponatraemia. DESIGN: Mortality rates are presented as risk ratios (RR),with 95% confidence intervals (CI), and compared to normonatraemic controls (NN). METHODS: Prospective, single centre, noninterventional study of all patients with hyponatraemia (≤130 mmol/L) admitted to hospital. RESULTS: A total of 1323 admissions with hyponatraemia were prospectively evaluated and 1136 contemporaneous NN controls. 431(32.6%) hyponatraemic patients had HON, 573(43.3%) had SIAD and 275(20.8%) patients had HEN. In patient mortality was higher in hyponatraemia than NN (9.1% vs 3.3%, P<.0001). The RRs for in-hospital mortality compared to NN were: SIAD, 1.76 (95% CI 1.08-2.8, P=.02), HON 2.77 (95% CI 1.8-4.3, P<.0001) and HEN, 4.9 (95% CI 3.2-7.4, P<.0001). The mortality rate was higher in HEN (RR 2.85; 95% CI 1.86-4.37, P<.0001) and in HON, (RR 1.6; 95% CI 1.04-2.52; P=.03), when compared to SIAD. The Charlson Comorbidity Index was lower in SIAD than in eunatraemic patients (P<.0001). 9/121(7.4%) patients died with plasma sodium <125 mmol/L and 4(3.3%) with plasma sodium <120 mmol/L. However, 69/121(57%) patients died with a plasma sodium above 133 mmol/L. CONCLUSIONS: We confirmed higher all-cause mortality in hyponatraemia than in NN. Mortality was higher in SIAD than in normonatraemia and was not explained on the basis of co-morbidities. Mortality was higher in HON and HEN than in SIAD. Mortality rates reported for all-cause hyponatraemia in the medical literature are not applicable to SIAD.

The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study.

OBJECTIVE: The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia. Data on SIAD are mainly derived from retrospective studies, often with poor ascertainment of the minimum criteria for the correct diagnosis. Reliable data on the incidence of adrenal failure in SIAD are therefore unavailable. The aim of the study was to describe the aetiology of SIAD and in particular to define the prevalence of undiagnosed adrenal insufficiency. DESIGN: Prospective, single centre, noninterventional, observational study of patients admitted to Beaumont Hospital with euvolaemic hyponatraemia (plasma sodium ≤ 130 mmol/l) between January 1st and October 1st 2015. PATIENTS: A total of 1323 admissions with hyponatraemia were prospectively evaluated; 576 had euvolaemic hyponatraemia, with 573 (43·4%) initially classified as SIAD. MAIN OUTCOME MEASURES: (i) Aetiology of SIAD, defined by diagnostic criteria; (ii) Incidence of adrenal insufficiency. RESULTS: Central nervous system diseases were the commonest cause of SIAD (n = 148, 26%) followed by pulmonary diseases (n = 111, 19%), malignancy (n = 105, 18%) and drugs (n = 47, 8%). A total of 22 patients (3·8%), initially diagnosed as SIAD, were reclassified as secondary adrenal insufficiency on the basis of cortisol measurements and clinical presentation; 9/22 cases had undiagnosed hypopituitarism; 13/22 patients had secondary adrenal insufficiency due to exogenous steroid administration. CONCLUSIONS: In a large, prospective and well-defined cohort of euvolaemic hyponatraemia, undiagnosed secondary adrenal insufficiency co-occurred in 3·8% of cases initially diagnosed as SIAD. Undiagnosed pituitary disease was responsible for 1·5% of cases presenting as euvolaemic hyponatraemia.

ACTH and gonadotropin deficiencies predict mortality in patients treated for nonfunctioning pituitary adenoma: long-term follow-up of 519 patients in two large European centres.

CONTEXT AND OBJECTIVE: Nonfunctioning pituitary adenomas (NFPAs) are the most common subtype of pituitary tumour. Hypopituitarism is observed in NFPAs due to tumour- or treatment-related factors and may increase mortality risk. Here, we analysed the associations of hypopituitarism, hormone replacement and mortality in a large NFPA cohort derived from two large European centres. DESIGN, SETTING AND PARTICIPANTS: Case note review of all patients treated for NFPA in University Hospitals Birmingham and Beaumont Hospital Dublin between 1999 and 2014 was performed. MAIN OUTCOME MEASURES: Clinical presentation, treatment strategies, pituitary function and vitality status were recorded in each patient. A multivariate Cox regression model was used to examine the association between hypopituitarism, hormone replacement and premature mortality. RESULTS: A total of 519 patients were included in the analysis. Median duration of follow-up was 7·0 years (0·5-43). A total of 81 deaths were recorded (15·6%). On multivariate analysis, adrenocorticotropic hormone (ACTH) and gonadotropin (Gn) deficiencies were associated with an increased relative risk of death (OR 2·26, 95% CI 1·15-4·47, P = 0·01 and OR 2·56, 95% CI 1·10-5·96, P = 0·01, respectively). Increased hydrocortisone (HC) (P-trend = 0·02) and lower levothyroxine (LT4) doses (P-trend = 0·03) were associated with increased risk of death. Mortality increased with the degree of pituitary failure observed (P-trend = 0·04). CONCLUSION: ACTH and gonadotropin-deficient patients have higher mortality rates compared to those with intact hormonal axes. Excessive HC and suboptimal LT4 replacement may also increase risk of death. Complex associations between hormone deficiency and replacement underpin the increased mortality risk in NFPA patients.