AIP variant causing familial prolactinoma.

Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated.

British Society of Gastroenterology (BSG)-led multisociety consensus care bundle for the early clinical management of acute upper gastrointestinal bleeding.

Medical care bundles improve standards of care and patient outcomes. Acute upper gastrointestinal bleeding (AUGIB) is a common medical emergency which has been consistently associated with suboptimal care. We aimed to develop a multisociety care bundle centred on the early management of AUGIB. Commissioned by the British Society of Gastroenterology (BSG), a UK multisociety task force was assembled to produce an evidence-based and consensus-based care bundle detailing key interventions to be performed within 24 hours of presentation with AUGIB. A modified Delphi process was conducted with stakeholder representation from BSG, Association of Upper Gastrointestinal Surgeons, Society for Acute Medicine and the National Blood Transfusion Service of the UK. A formal literature search was conducted and international AUGIB guidelines reviewed. Evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation tool and statements were formulated and subjected to anonymous electronic voting to achieve consensus. Accepted statements were eligible for incorporation into the final bundle after a separate round of voting. The final version of the care bundle was reviewed by the BSG Clinical Services and Standards Committee and approved by all stakeholder groups. Consensus was reached on 19 statements; these culminated in 14 corresponding care bundle items, contained within 6 management domains: Recognition, Resuscitation, Risk assessment, Rx (Treatment), Refer and Review. A multisociety care bundle for AUGIB has been developed to facilitate timely delivery of evidence-based interventions and drive quality improvement and patient outcomes in AUGIB.

Physicians' real-world experience with IDegLira: results of a European survey.

OBJECTIVE: This study aimed to build on the current clinical findings and investigate physicians' experiences and level of satisfaction in using insulin degludec/liraglutide (IDegLira) to treat patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This multicountry, European online survey included respondents from primary (n=132) and secondary (n=103) care and examined physicians' use, confidence and satisfaction with IDegLira. To standardize responses, 24 of 28 questions pertained to an 'average patient' with T2D who has no major comorbidities, aged 35-70 years, with average cognitive ability/normal mental status and body mass index ≥25 kg/m2. RESULTS: The majority (70%) of respondents prescribe IDegLira in the same visit they first mention it, with uncontrolled glycated hemoglobin (HbA1c) (44%) and weight gain (22%) being the most common reasons. On average, physicians reported that patients weighed 95 kg and the HbA1c level was 9.0% at initiation. Physicians also reported the average HbA1c target set was 7.1%; 76% of patients achieved their target. On average, patients achieved their HbA1c target in <6 months, and the average dose of IDegLira in patients in glycemic control was 28 dose steps. Respondents were more satisfied with IDegLira than basal-bolus therapy across all parameters assessed, including reaching HbA1c targets (59%), number of injections (77%) and avoiding weight gain (84%). Correspondingly, 77% of physicians reported that IDegLira had more potential to improve patient motivation compared with basal-bolus to reach target blood glucose levels. CONCLUSIONS: Real-world experience of IDegLira is consistent with previous trials/studies, with no major differences between primary and secondary care. Importantly, the majority of respondents were more/much more satisfied with IDegLira than with basal-bolus therapy.

The management of type 2 diabetes with fixed-ratio combination insulin degludec/liraglutide (IDegLira) versus basal-bolus therapy (insulin glargine U100 plus insulin aspart): A short-term cost-effectiveness analysis in the UK setting.

AIM: To evaluate the cost-effectiveness of IDegLira versus basal-bolus therapy (BBT) with insulin glargine U100 plus up to 4 times daily insulin aspart for the management of type 2 diabetes in the UK. METHODS: A Microsoft Excel model was used to evaluate the cost-utility of IDegLira versus BBT over a 1-year time horizon. Clinical input data were taken from the treat-to-target DUAL VII trial, conducted in patients unable to achieve adequate glycaemic control (HbA1c <7.0%) with basal insulin, with IDegLira associated with lower rates of hypoglycaemia and reduced body mass index (BMI) in comparison with BBT, with similar HbA1c reductions. Costs (expressed in GBP) and event-related disutilities were taken from published sources. Extensive sensitivity analyses were performed. RESULTS: IDegLira was associated with an improvement of 0.05 quality-adjusted life years (QALYs) versus BBT, due to reductions in non-severe hypoglycaemic episodes and BMI with IDegLira. Costs were higher with IDegLira by GBP 303 per patient, leading to an incremental cost-effectiveness ratio (ICER) of GBP 5924 per QALY gained for IDegLira versus BBT. ICERs remained below GBP 20 000 per QALY gained across a range of sensitivity analyses. CONCLUSIONS: IDegLira is a cost-effective alternative to BBT with insulin glargine U100 plus insulin aspart, providing equivalent glycaemic control with a simpler treatment regimen for patients with type 2 diabetes inadequately controlled on basal insulin in the UK.

Deficits in Trabecular Bone Microarchitecture in Young Women With Type 1 Diabetes Mellitus.

The pathophysiological mechanism of increased fractures in young adults with type 1 diabetes mellitus (T1DM) is unclear. We conducted a case-control study of trabecular bone microarchitecture and vertebral marrow adiposity in young women with T1DM. Thirty women with T1DM with a median age (range) age of 22.0 years (16.9, 36.1) attending one outpatient clinic with a median age at diagnosis of 9.7 years (0.46, 14.8) were compared with 28 age-matched healthy women who acted as controls. Measurements included MRI-based assessment of proximal tibial bone volume/total volume (appBV/TV), trabecular separation (appTb.Sp), vertebral bone marrow adiposity (BMA), and abdominal adipose tissue and biochemical markers of GH/IGF-1 axis (IGF-1, IGFBP3, ALS) and bone turnover. Median appBV/TV in cases and controls was 0.3 (0.22, 0.37) and 0.33 (0.26, 0.4), respectively (p = 0.018) and median appTb.Sp in T1DM was 2.59 (2.24, 3.38) and 2.32 (2.03, 2.97), respectively (p = 0.012). The median appBV/TV was 0.28 (0.22, 0.33) in those cases with retinopathy (n = 15) compared with 0.33 (0.25, 0.37) in those without retinopathy (p = 0.02). Although median visceral adipose tissue in cases was higher than in controls at 5733 mm(3) (2030, 11,144) and 3460 mm(3) (1808, 6832), respectively (p = 0.012), there was no difference in median BMA, which was 31.1% (9.9, 59.9) and 26.3% (8.5, 49.8) in cases and controls, respectively (p = 0.2). Serum IGF-1 and ALS were also lower in cases, and the latter showed an inverse association to appTbSp (r = -0.30, p = 0.04). Detailed MRI studies in young women with childhood-onset T1DM have shown clear deficits in trabecular microarchitecture of the tibia. Underlying pathophysiological mechanisms may include a microvasculopathy.

Cross-cultural validity of the thyroid-specific quality-of-life patient-reported outcome measure, ThyPRO.

BACKGROUND AND PURPOSE: Thyroid diseases are common and often affect quality of life (QoL). No cross-culturally validated patient-reported outcome measuring thyroid-related QoL is available. The purpose of the present study was to test the cross-cultural validity of the newly developed thyroid-related patient-reported outcome ThyPRO, using tests for differential item functioning (DIF) according to language version. METHODS: The ThyPRO consists of 85 items summarized in 13 multi-item scales and one single item. Scales cover physical and mental symptoms, well-being and function as well as social and daily function and cosmetic concerns. Translation applied standard forward-backward methodology with subsequent cognitive interviews and reviews. Responses (N = 1,810) to the ThyPRO were collected in seven countries: UK (n = 166), The Netherlands (n = 147), Serbia (n = 150), Italy (n = 110), India (n = 148), Denmark (n = 902) and Sweden (n = 187). Translated versions were compared pairwise to the English version by examining uniform and nonuniform DIF, i.e., whether patients from different countries respond differently to a particular item, although they have identical level of the concept measured by the item. Analyses were controlled for thyroid diagnosis. DIF was investigated by ordinal logistic regression, testing for both statistical significance and magnitude (ΔR (2) > 0.02). Scale level was estimated by the sum score, after purification. RESULTS: For twelve of the 84 tested items, DIF was identified in more than one language. Eight of these were small, but four were indicative of possible low translatability. Twenty-one instances of DIF in single languages were identified, indicating potential problems with the particular translation. However, only seven were of a magnitude which could affect scale scores, most of which could be explained by sample differences not controlled for. CONCLUSION: The ThyPRO has good cross-cultural validity with only minor cross-cultural invariance and is recommended for use in international multicenter studies.

Mutant prolactin receptor and familial hyperprolactinemia.

Hyperprolactinemia that is not associated with gestation or the puerperium is usually due to tumors in the anterior pituitary gland and occurs occasionally in hereditary multiple endocrine neoplasia syndromes. Here, we report data from three sisters with hyperprolactinemia, two of whom presented with oligomenorrhea and one with infertility. These symptoms were not associated with pituitary tumors or multiple endocrine neoplasia but were due to a heterozygous mutation in the prolactin receptor gene, PRLR, resulting in an amino acid change from histidine to arginine at codon 188 (His188Arg). This substitution disrupted the high-affinity ligand-binding interface of the prolactin receptor, resulting in a loss of downstream signaling by Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Thus, the familial hyperprolactinemia appears to be due to a germline, loss-of-function mutation in PRLR, resulting in prolactin insensitivity.

Strategies to reduce oxidative stress in cardiovascular disease.

A multitude of studies in experimental animals, together with clinical data, provide evidence that increased production of ROS (reactive oxygen species) are involved in the development and progression of cardiovascular disease. As ROS appear to have a critical role in atherosclerosis, there has been considerable interest in identifying the enzyme systems involved and in developing strategies to reduce oxidative stress. Prospective clinical trials with vitamins and hormone replacement therapy have not fulfilled earlier promises, although there is still interest in other dietary supplements. Superoxide dismutase mimetics, thiols, xanthine oxidase and NAD(P)H oxidase inhibitors are currently receiving much interest, while animal studies using gene therapy show promise, but are still at an early stage. Of the drugs in common clinical use, there is evidence that ACE (angiotensin-converting enzyme) inhibitors and AT1 (angiotensin II type 1) receptor blockers have beneficial effects on oxidative stress above their antihypertensive properties, whereas statins, in addition to improving lipid profiles, may also lower oxidative stress.