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Introduction Prescribing immune checkpoint inhibitors (ICIs) to cancer patients with an autoimmune disease (AID) is presumed safe when cautious adverse event management is applied. However, guidelines on immunosuppressant (IS) adaptations are limited and real-world evidence is scarce. Methods Current practice of IS adaptations is described in a case series of AID patients treated with ICIs in a tertiary university hospital in Belgium (1/1/2016–31/12/2021). Patient, drug and disease-related data were documented using retrospective chart review. A systematic search of the PubMed database was performed to identify similar cases (1/1/2010–30/11/2022). Results Sixteen patients were described in the case series (62% with active AID). Systemic IS were changed before ICI initiation in 5/9 patients. Four patients continued therapy, of which one achieved partial remission. Patients who had IS (partially) stopped before ICI start (n = 4) had AID flares in two cases; immune-related adverse events in three cases. In the systematic review, 37 cases were identified in 9 articles. Corticosteroids (n = 12) and non-selective IS (n = 27) were continued in, respectively, 66% and 68% of patients. Methotrexate was frequently discontinued (13/21). Biologicals, excluding tocilizumab and vedolizumab, were withheld during ICI treatment. Out of all patients with flares (n = 15), 47% had stopped IS therapy before ICI start and 53% had continued their AID drugs. Conclusions A detailed overview of IS management in patients with AID receiving ICI therapy is presented. Expanding the knowledge base germane to IS management with ICI therapy in the diverse population is essential to evaluate their mutual impact, thus advancing responsible patient care.

There are multiple imaging modalities in primary hyperparathyroidism. Ultrasound examination and subtraction scintigraphy are usually the first-line imaging techniques. When these results are negative or inconsistent, additional [11C]-methionine PET/CT (MET-PET/CT) or 4-dimensional computed tomography can be performed. ​This study aims to evaluate MET-PET/CT in comparison with other imaging techniques in primary hyperparathyroidism. This is a retrospective cohort study. Eighty-four patients with primary hyperparathyroidism, who underwent parathyroid surgery, were included. ​Imaging results have been correlated to the perioperative drop in parathyroid hormone level and to the pathological analysis. ​Descriptive statistics are used, supplemented with 95% Clopper–Pearson confidence intervals for sensitivity and specificity and a sub-analysis with the McNemar test on paired data only. The per-lesion sensitivity of MET-PET/CT seems higher than that of [99mTc]-sestamibi or [99mTc]-tetrofosmin and [99mTc]-pertechnetate subtraction scintigraphy. The McNemar test, on paired data only, shows significantly higher sensitivity of MET-PET/CT compared to ultrasound (p=0.039) and significantly higher specificity of ultrasound compared to subtraction scintigraphy (p=0.035).​ MET-PET/CT after inconclusive or negative ultrasound and/or subtraction scintigraphy has an additional value in 70% of the cases.​ Preoperative parathyroid hormone levels were higher in patients in whom MET-PET/CT correctly predicted the pathological parathyroid glands, compared to those where MET-PET/CT missed at least one adenoma. The same trend was seen for 4-dimensional computed tomography. In conclusion, MET-PET/CT seems a valuable imaging modality in primary hyperparathyroidism, at least as second line imaging approach, with a higher per-lesion sensitivity than ultrasound in such setting. Especially when ultrasound and/or subtraction scintigraphy are inconclusive or negative, MET-PET/CT directs the surgeon to the correct localization of the parathyroid adenoma.

Several studies have already explored individual and environmental risk factors for COVID-19 morality, however most study populations consisted of the overall population and mainly from China or the US. Our study focused on COVID-19 mortality in the elderly in seven European cities. Long-term exposure to air pollution was estimated through annual pollutant concentrations at the residential address averaged over the last two years of the study period between February and May 2020. We focused on the main outdoor air pollutants PM10, PM2.5, NO2 and O3. Short-term variations in air pollutants and weather parameters (e.g. temperature, UV, relative humidity) were also examined through a 20-day period before the confirmed PCR diagnostic of COVID-19. Individual risk factors such as smoking status, sex, body mass index (BMI), ischemic heart disease, diabetes, hypertension, chronic renal failure, history of cancer, COPD, and lung fibrosis, were taken into account. We found positive associations for diabetes and COVID-19 mortality (OR 2.2 CI 95% :1.1, 4.4). Using a multivariate logistic regression model adjusted for all patient characteristics and city, we fail to reject the null hypothesis of no association between COVID-19 mortality and long-term and short-term increase in PM2.5, PM10, NO2 and O3. Our study suffers from the fact that patient profiles strongly differ between high-polluted and less-polluted cities. Strong differences in COVID-19 mortalities were observed between cities, which could be due to differences in COVID-19 management and treatment, such as accessibility to reanimation and intensive units between cities. Overall, our study highlights the need to improve estimation of individual exposure to air pollution. Indeed, even with the high-efficiency modelisation systems used in our study, we were unable to estimate the effect of air pollution within each city, because variations in air pollution exposure were too small. Individual markers of air pollution exposure such as recently demonstrated with urinary black carbon or passive individual samplers, would be most suitable for future explorations. Concerning weather parameters, although previous studies concluded that increase in temperature and UV index could decrease COVID-19 morality, our data did not allow us to reject the null hypotheses.

Summary: This study analyzed characteristics of hip fracture patients who did not undergo surgery within 24 hours after hospitalization, as recommended by the Belgian quality standards. Reasons for delay were analyzed. Delay in surgery for hip fracture was related to the medical condition of the patients. Introduction: To compare patients with optimal timing to patients with a delay in hip surgery, with respect to outcome (complications (postoperative) and mortality) and reasons for delay. Methods: A retrospective analysis of medical records compared patients operated on within 24h (Group A) to patients operated on more than 24h after admission (Group B). A follow-up period of 5 years after release or up to the time of data collection was used. Reasons for delay in relation with mortality were analyzed descriptively. Descriptive statistics were used for patient demographics and complications. Relationships causing a delayed surgery and mortality were analyzed using binary logistic regression. Additionally, a survival analysis was provided for overall mortality. Results: Respectively, 536 and 304 patients were included in Group A and B. The most prominent reason for delaying surgery was the patient not being medically fit (20.7%). Surgical delay was associated with more cardiovascular (p = 0.010), more pulmonary (p < 0.001), and less hematologic complications (p=0.037). Thirty-day mortality was higher with increasing age (p < 0.001), with hematologic (p < 0.001) or endocrine-metabolic complications (p = 0.001), and lower when no complications occurred (p = 0.004). Mortality at the end of data collection was higher for patients with delayed surgery (OR = 2.634, p < 0.001), an increased age (p = 0.006), male gender (p < 0.001), institutionalized patients (p = 0.009), pulmonary complication (p = 0.002), and having no endocrine-metabolic complications (p = 0.003). Survival analysis showed better survival for patients operated on within 24h (p < 0.001). Conclusions: Delayed surgery for patients with hip fractures was associated with bad additional medical conditions. Survival was higher for patients operated on within 24h of admission.

Background: Hypoglycemia, especially at old age, can lead to several major problems, such as falls and cognitive deficits. The aim of our study was to detect hypoglycemia in older persons with and without diabetes mellitus type 2 (T2DM).Methods: The frequency and duration of hypoglycemia/hyperglycemia was studied in ambulatory geriatric (>75 years), non-diabetic persons (Group 1, n=10), using real time Continuous Glucose Monitoring (CGM, Dexcom G6), and in age- and sex-matched cognitively-healthy, T2DM patients having HbA1c levels < 9.0% (Group 2, n=10). The device was used during 20 days per person, who was blinded for the values on the receiver (except in case of severe hypo- or hyperglycemia). Data were stored for further analysis on the Dexcom Clarity Portal.Results: Hypoglycemia occurred frequently in older persons without T2DM, despite absence of hypoglycemia-inducing medication. In this group, people had 0.50% (median value) of the time glycemic values below 70 mg/dL, most of the episodes happened during nighttime. Conclusions: Our study demonstrates that hypoglycemia occurs frequently in non-diabetic older persons. Further studies are needed to determine whether this could be part of the normal aging process, and to determine if hypoglycemia might contribute to cognitive deterioration.

Background Differentiated thyroid cancer (DTC) is a common malignancy with increasing incidence. Follow-up care for DTC includes thyroglobulin (Tg) measurement and ultrasound (US) of the neck, combined with 131I remnant ablation when indicated. Diagnostic precision has evolved with the introduction of the new high-sensitive Tg-assays (sensitivity ≤0.1 ng/mL). The aim of the study was to determine the prognostic utility of high-sensitive Tg and the need for other diagnostic tests in DTC. Methods This was a retrospective, observational study. Patients with pathologically confirmed DTC, treated with total thyroidectomy and 131I remnant ablation, who had their complete follow-up care in our institution were selected (October 2013–December 2018). Subjects with possible thyroglobulin autoantibody interference were excluded. Statistical analysis was performed using the IBM SPSS® Statistics 24 software package. Results Forty patients were eligible for analysis. A total of 24 out of the 40 patients (60%) had an undetectable high-sensitive Tg 6 months after total thyroidectomy. None of these patients had a stimulated Tg above 1 ng/mL, or remnant on the 123I Whole-Body Scan (WBS) after 1 year of follow-up. Ultrasound of the neck, performed between 6 and 12 months postoperative, was negative in 21 out of the 24 patients. Conclusions This study shows that an undetectable high-sensitive Tg can change the management of patients with DTC and decrease the use and need of stimulated Tg and 123I WBS.

Fatigue might influence the losses in activities of daily living (ADL). When fatigue parameters are present before the experience of losses in ADL and gait speed they can be used as early warning signals. This study aimed to explore the predictive value of muscle endurance and fatigue on changes in ADL and gait speed in community-dwelling older adults aged 80 and over.324 community-dwelling older adults aged 80 and older of the BUTTERFLY study were assessed after one year for muscle endurance, self-perceived fatigue, Activities of Daily Living and gait speed. Exploratory factor analysis (EFA) was performed to explore, whether there is an underlying arrangement of the fatigue parameters. Mediating logistic regression analyses were used to investigate whether muscle endurance mediated by self-perceived fatigue predicts decline in gait speed and ADL after one year follow-up.Exploratory factor analysis indicated a 2-factor model (muscle endurance factor and self-perceived fatigue factor) and had a moderate fit (X 2: 374.81, df: 2, CFI; 0.710, TLI: 0.961, RSMEA(90%): 0.048 (0.00-0.90)). Muscle endurance mediated by self-perceived fatigue had an indirect effect on the prediction of decline in Basal- (-0.27), Instrumental-ADL (-0.25) and gait speed (-0.28) after one year follow-up.This study showed that low muscle endurance combined with high self-perceived fatigue can predict changes in ADL after one-year follow-up. These parameters might be very suitable for use in evaluating intrinsic capacity and can help to reduce the limitations in clinical usage of the vitality domain in the framework of intrinsic capacity.

Traditionally, geriatric patients with musculoskeletal or osteoarticular problems will be admitted to an orthopedic ward and will be treated by sur- geons. However, these patients often suffer from comorbidities requiring geriatric management. In this study, the orthogeriatric co-management (OG- CM) model is compared to traditional orthopedic care model in a retrospective pilot study. In this study, two patients groups were compared during two similar time periods : (1) Group 1 consisted of 119 geriatric patients admitted to an orthopedic (trauma) ward who were treated, with conventional geriatric care on demand (before OG- CM ; October 1-December 31, 2013) and (2) Group 2 consisted of 132 geriatric patients who were admitted after the implementation of the OG-CM model (after OG-CM ; October 1-December 31, 2014). Outcomes measured were : quality of care outcome, mortality and costs. After the introduction of OG-CM, the number of diagnoses increased (P = 0.011) adjusting for sex, age, length of stay (LOS), urgency and getting surgery (yes/ no). However, this did not lead to a significant higher severity of illness (SOI). The number of readmissions within a year were significantly lower after OG-CM (0.31 per patient) compared to before OG-CM (0.89 per patient) (P0.001). No significant difference in in-house and reported mortality after 3 months was observed. Costs increased, but no significant differences were found. The OG-CM model demonstrated an increase in quality of care. This was indicated by an increased number of medical diagnoses resulting in having less readmissions, without affecting the mortality rates and the LOS. Future randomized multi-centered studies are required to enable causal relationships.

Hypoparathyroidism is a rare endocrine disease with insufficient parathyroid hormone levels. Replacing the missing hormone is not yet a standard therapy. The objective of this retrospective cohort study was to evaluate if the usual therapy regimens of postsurgical hypoparathyroidism with calcitriol have a negative effect on renal function. We performed a chart analysis of patients who were seen in a tertiary care hospital in Brussels, Belgium. A total of 101 subjects were identified as patients with permanent post-surgical hypoparathyroidism, based on the hospital records of patients who underwent a total thyroidectomy between 1996 and 2016, while still being treated with calcitriol. Patients with pre-existing renal insufficiency and/or active malignancy were excluded. The cohort was predominantly female of Caucasian origin. Renal function was evaluated before and after surgery (with a maximum follow-up of 12 years), using the CKD-EPI equation. A multivariate linear regression model was used to correlate renal function decline with the duration of calcitriol therapy, while correcting for the mean calcium phosphate product and age. We found a statistically significant (p=0.027) relationship between the duration of calcitriol treatment and renal function decline at a rate of 1.06 ml/min/1.73 m2 per year of calcitriol therapy. Our study, although being retrospective, is the first one to demonstrate a relationship between the cumulative use of calcitriol therapy and renal function decline.

Normocalcemic primary hyperparathyroidism (NPHPT) is a formally recognized variant of primary hyperparathyroidism (PHPT), characterized by normal total and ionized serum calcium concentrations and elevated parathyroid hormone (PTH) levels, in the absence of secondary causes for hyperparathyroidism. NPHPT has been studied previously, but data are limited and confounded. We aimed to compare the clinical and biochemical data of normocalcemic and hypercalcemic subjects in a hospital-based population.We retrospectively analysed the medical records of 131 subjects diagnosed with PHPT at the university hospital Brussels (UZ Brussel) between January 1st 2007 and December 31st 2016, including 25 normocalcemic and 106 hypercalcemic subjects.The mean values of age, BMI, sex, serum 25-OH vitamin D levels and urinary phosphate excretion were comparable between both groups. Subjects diagnosed with NPHPT had significantly lower plasma PTH levels, lower urinary calcium excretion and lower serum creatinine levels compared to the hypercalcemic subjects with PHPT. Corresponding eGFR values were higher in the normocalcemic group. Normocalcemic subjects (NPHPT) presented with a high prevalence of nephrolithiasis (36%), fragility fractures (12%) and osteoporosis (25%). Clinical manifestations and BMD measurements revealed no statistically significant differences between both groups.Our data show a relative prevalence of 19% NPHPT in PHPT. NPHPT may present the earliest form of PHPT with an extension in time, but is not an indolent disease state. Normocalcemic subjects should be managed as hypercalcemic subjects with PHPT. Further research regarding the pathophysiology and natural course of NPHPT is required.

Background Orthostatic hypotension (OH) in geriatric patients frequently involves a component of autonomic failure (AF). The combination of OH with nocturnal hypertension (NHT) is indicative of AF, which is described as pure (PAF), when neurologic symptoms are absent, or as multisystem atrophy (MSA), when combined with motor disturbance (Parkinsonism or Parkinson disease). Case presentation An 87-year-old man presented with long-lasting OH. He frequently fell, causing several fractures, and he developed heart failure. Blood pressure (BP) registration revealed a reversal of the day-night rhythm with NHT. An 18-FDG PET brain CT scan showed cerebellar hypometabolism, indicating MSA. Conclusions This case demonstrates the use of continuous BP registration in geriatric patients with OH for diagnosing NHT. It illustrates the usefulness of 18-FDG PET brain CT scan to specify the nature of the AF. The case also illustrates the difficulty of managing the combination of OH and NHT.

OBJECTIVES: Antihypertensive drugs (AHTD) and statins have been shown to have effects beyond their primarily designed purpose; here we investigate their possible effect on muscle performance and strength in older adults following a physical exercise programme. DESIGN: The Senior PRoject INtensive Training (SPRINT) study is a randomised, controlled clinical trial designed to evaluate the effects of physical exercise on the immune system and muscle performance in older adults. PARTICIPANTS: In this secondary analysis, we included 179 independent participants (aged 65 years and above). We applied further categorisation based on medication use: AHTD (including, angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARB], β-blockers, and other AHTD) and statins. INTERVENTION: Participants were allocated randomly to one of the three exercise protocols: intensive strength training 3 times/week (3 × 10 repetitions at 80% of one-repetition maximum), strength endurance training (2 × 30 repetitions at 40% of one-repetition maximum), or control (passive stretching exercise) for 6 weeks. MEASUREMENTS: The change in maximal hand grip strength (GS), muscle fatigue resistance (FR), Muscle Strength Index (MSI), the 6-min walk test (6MWT), and Timed Up and Go Test (TUG) were assessed before and after 6 weeks of training. RESULTS: After 6 weeks, muscle strength (MSI and TUG) improved significantly in all training groups compared to baseline, independently of AHTD use. Moreover, AHTD had no effect on exercise improvements, with no significant differences between medication groups, except for TUG in ARB users, which exhibited a significantly lower performance. On the other hand, statin users presented a significantly longer FR time, indicating better performance compared to non-users. Finally, medication did not affect the participants' commitment to the training programme. CONCLUSION: Our study showed that statins and ARB usage might affect participant's response to strength training. Nevertheless, 6 weeks of training significantly improved muscle strength and performance irrespective of AHTD or statin use.

The aim of this study is to assess differences in patient characteristics, tumour characteristics and hormone levels between acromegalic patients with and without hyperprolactinemia. 44 patients of the University Hospital of Brussels, Belgium with acromegaly who were diagnosed between January 2007 and July 2018 were included in this study. Nineteen patients were classified in the hyperprolactinemia group and 25 patients were classified in the normoprolactinemia group. No significant differences between acromegalic patients with and without hyperprolactinemia were found in age at diagnosis, gender, presence of hyperprolactinemia symptoms, insulin-like growth factor 1, growth hormone and testosterone levels, tumour volume, tumour invasiveness, immunohistochemistry of growth hormone and prolactin, Ki-67 index and mitotic index. However, for a cut-off of 10% of prolactin-positive cells, there was a trend towards a higher percentage of prolactin-positive tumours in hyperprolactinemia patients (p=0.054) and higher mean prolactin level in case of positive prolactin immunostaining (p=0.007)). In our study there were no differences in characteristics between acromegaly patients with hyper- and normoprolactinemia. An association between the serum prolactin level and the positivity of prolactin immunohistochemistry of the adenoma tissue was found. The absence of a difference in tumour volume between patients with hyper- and normoprolactinemia suggests that the hyperprolactinemia is likely to be caused by the co-secretion of growth hormone and prolactin by the tumour. Finally, for the first time, the cut-off of 10% of prolactin cells was validated for the diagnosis of somatolactotroph tumours in acromegaly.

Background Hematologic malignancies can spread to the central nervous system (CNS), either as focal lesions or as leptomeningeal disease. Marginal zone lymphoma (MZL) is a low-grade non-Hodgkin lymphoma and generally presents as an indolent disease. This case report illustrates an unexpected diagnosis of leptomeningeal metastasis in an MZL, presenting as a delirium without B symptoms, pronounced hematologic progression or abnormalities on cerebral imaging. Case presentation An 80-year-old patient with a medical history of monoclonal B-cell lymphocytosis (MBL) with a clone indicative for an MZL, presented to the emergency and the geriatric departments with a recent cognitive deterioration and behavioral changes. MMSE score was 18/30. After excluding the most common etiologies through classical work-up including a normal head magnetic resonance imaging, a lumbar puncture was performed. In the cerebrospinal fluid an elevated protein level and increased lymphocyte count were identified, whereas beta-amyloid and tau protein levels were normal. Immunophenotyping of the lymphocytes confirmed CNS invasion by the MZL clone. Staging revealed mild splenomegaly. Prednisolone, intrathecal and systemic chemotherapy were initiated, leading to quick cognitive improvement with a final MMSE score of 28/30. Conclusions To the best of our knowledge a delirium in an older patient due to leptomeningeal disease in MZL has never been described. To date, rare reports of CNS invasion by MZL describe focal intracranial lesions. After exclusion of common etiologies, physicians should remain vigilant when confronted with a patient with history of MBL presenting neurological symptoms. This case illustrates the importance of low threshold for lumbar punctures in this population, also for those patients with normal imaging studies.

Background: Hypothyroidism due to non-compliance with levothyroxine therapy (pseudomalabsorption) is rare. The diagnosis is considered in patients with persistent severe hypothyroidism despite treatment with large doses of levothyroxine. Intestinal malabsorption, drug and dietary interference with levothyroxine absorption and nephrotic syndrome should be excluded. The diagnosis of pseudomalabsorption can be demonstrated by using “an oral 1,000 µg of levothyroxine test” showing a rapid decrease in thyroid-stimulating hormone and increase in thyroxine. There are however few data on the sensitivity and specificity of the test in large cohorts of hypothyroid patients. Treatment of pseudomalabsorption is controversial, with reports using parenteral, intramuscular or single weekly oral dosing of levothyroxine. Cases: We report 3 patients who presented with persistent clinical and biochemical signs of hypothyroidism despite replacement therapy with high doses of levothyroxine. Pseudomalabsorption was diagnosed by a systematic approach, including prior exclusion of digestive, liver and kidney diseases. A peroral challenge test was positive in all cases. Patients denied non-compliance, and a psychiatric approach was elusive. Two of the patients were treated successfully with a single supervised weekly 1,000-µg administration of levothyroxine, while non-supervised weekly administration resulted in hypothyroidism confirming pseudomalabsorption. Conclusions: Non-compliance with medical therapy should be considered in patients with treatment-refractory hypothyroidism. Supervised once weekly levothyroxine treatment is a safe and well-tolerated treatment option, obviating the need for parenteral administration of the drug. Apart from the medical treatment, there is also a need for psychiatric evaluation and care.

Objective To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs). Design and methods We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy. Results Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population. Conclusion ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.

Short metacarpals and/or metatarsals are typically observed in pseudohypoparathyroidism (PHP) type Ia (PHP1A) or pseudo-PHP (PPHP), disorders caused by inactivating GNAS mutations involving exons encoding the alpha-subunit of the stimulatory G protein (Gsα). Skeletal abnormalities similar to those in PHP1A/PPHP were present in several members of an extended Belgian family without evidence for abnormal calcium and phosphate regulation. Direct nucleotide sequencing of genomic DNA from an affected individual (190/III-1) excluded GNAS mutations. Instead, whole exome analysis revealed a novel heterozygous A>G change at nucleotide -3 upstream of PTHLH exon 3 that encodes the last two amino acids of the prosequence and the mature PTHrP. The same nucleotide change was also found in her affected mother and maternal aunt (190/II-2, 190/II-1), and her affected twin sons (190/IV-1, 190/IV-2), but not in her unaffected daughter (190/IV-3) and sister (190/III-2). Complementary DNA derived from immortalized lymphoblastoid cells from 190/IV-2 (affected) and 190/IV-3 (unaffected) was PCR-amplified using forward primers located either in PTHLH exon 1 (noncoding) or exon 2 (presequence and most of the prosequence), and reverse primers located in the 3'-noncoding regions of exons 3 or 4. Nucleotide sequence analysis of these amplicons revealed for the affected son 190/IV-2, but not for the unaffected daughter 190/IV-3, a heterozygous insertion of genomic nucleotides -2 and -1 causing a frameshift after residue 34 of the pre/prosequence and thus 29 novel residues without homology to PTHrP or any other protein. Our findings extend previous reports indicating that PTHrP haploinsufficiency causes skeletal abnormalities similar to those observed with heterozygous GNAS mutations. © 2018 American Society for Bone and Mineral Research.

Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programed cell death 1 (PD-1), or its ligand (PD-L1) have become the mainstay for advanced malignancies. The incidence of endocrine adverse events provoked by these immune checkpoint inhibitors (ICI) is based on data from randomized controlled trials, which have their drawbacks. PubMed was searched through August 22nd, 2017, by 2 reviewers independently (J.d.F. and C.E.A.). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. The weighted incidence and risk ratio were estimated for hypophysitis, primary thyroid disease, primary adrenal insufficiency, and diabetes mellitus. Their management is discussed in a systematic review. A total of 101 studies involving 19 922 patients were included. Ipilimumab-treated patients experienced hypophysitis in 5.6% (95% CI, 3.9–8.1), which was higher than nivolumab (0.5%; 95% CI, 0.2–1.2) and pembrolizumab (1.1%; 95% CI, 0.5–2.6). PD-1/PD-L1 inhibitors had a higher incidence of thyroid dysfunction – particularly hypothyroidism (nivolumab, 8.0%; 95% CI, 6.4–9.8; pembrolizumab, 8.5%; 95% CI, 7.5–9.7; PD-L1, 5.5%; 95% CI, 4.4–6.8; ipilimumab, 3.8%; 95% CI, 2.6–5.5). Combination therapy was associated with a high incidence of hypothyroidism (10.2–16.4%), hyperthyroidism (9.4–10.4%), hypophysitis (8.8–10.5%), and primary adrenal insufficiency (5.2–7.6%). Diabetes mellitus and primary adrenal insufficiency were less frequent findings on monotherapy. Our meta-analysis shows a high incidence of endocrine adverse events provoked by single agent checkpoint blockade, further reinforced by combined treatment.

Objectives Several markers of iron metabolism have been associated with insulin resistance (IR) and type 2 diabetes mellitus in cross-sectional studies. However, prospective data on these associations are scarce, and it is currently unclear in which tissues iron metabolism may contribute to IR. Therefore, we investigated whether markers of iron metabolism were associated with IR in muscle, liver, and adipocytes, and with glucose intolerance over a 7-year follow-up period. Design and methods Serum ferritin, transferrin, total iron, non-transferrin-bound iron, and transferrin saturation were determined at baseline of a prospective cohort study in 509 individuals (60 % men, age 59 ± 6.9 years, body mass index 28.5 ± 4.3). Both at baseline and after a 7-year follow-up (n = 386), measures of glucose, insulin (during glucose tolerance tests), and non-esterified fatty acids were obtained. Using generalized estimating equations, we investigated associations between baseline iron markers and indices of muscle, liver, and adipocyte insulin resistance (adipocyte IR), as well as glucose intolerance, over the 7-year period. Results Over a 7-year period, baseline serum ferritin (per 10 µg/L increase) was positively associated with homeostasis model assessment insulin resistance (HOMA2-IR) [ß = 0.77 % (95 % CI 0.50–1.03)], hepatic insulin resistance (hepatic IR) [ß = 0.39 % (0.23–0.55)], adipocyte IR [ß = 1.00 % (0.65–1.35)], and AUCglucose [ß = 0.32 % (0.18–0.46)] after adjustment for several covariates, including inflammatory markers (all p

ObjectivesThe aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). MethodsAn open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naive patients with CD4 count 350 cells/L and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA ResultsFor the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA 400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. ConclusionsA single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

Background Type 2 diabetes is a major healthcare problem. Glucose-, lipid-, and blood pressure-lowering strategies decrease the risk of micro- and macrovascular complications. However, a substantial residual risk remains. To unravel the etiology of type 2 diabetes and its complications, large-scale, well-phenotyped studies with prospective follow-up are needed. This is the goal of the DiaGene study. In this manuscript, we describe the design and baseline characteristics of the study. Methods The DiaGene study is a multi-centre, prospective, extensively phenotyped type 2 diabetes cohort study with concurrent inclusion of diabetes-free individuals at baseline as controls in the city of Eindhoven, The Netherlands. We collected anthropometry, laboratory measurements, DNA material, and detailed information on medication usage, family history, lifestyle and past medical history. Furthermore, we assessed the prevalence and incidence of retinopathy, nephropathy, neuropathy, and diabetic feet in cases. Using logistic regression models, we analyzed the association of 11 well known genetic risk variants with type 2 diabetes in our study. Results In total, 1886 patients with type 2 diabetes and 854 controls were included. Cases had worse anthropometric and metabolic profiles than controls. Patients in outpatient clinics had higher prevalence of macrovascular (41.9% vs. 34.8%; P = 0.002) and microvascular disease (63.8% vs. 20.7%) compared to patients from primary care. With the exception of the genetic variant in KCNJ11, all type 2 diabetes susceptibility variants had higher allele frequencies in subjects with type 2 diabetes than in controls. Conclusions In our study population, considerable rates of macrovascular and microvascular complications are present despite treatment. These prevalence rates are comparable to other type 2 diabetes populations. While planning genomics, we describe that 11 well-known type 2 diabetes genetic risk variants (in TCF7L2, PPARG-P12A, KCNJ11, FTO, IGF2BP2, DUSP9, CENTD2, THADA, HHEX, CDKAL1, KCNQ1) showed similar associations compared to literature. This study is well-suited for multiple omics analyses to further elucidate disease pathophysiology. Our overall goal is to increase the understanding of the underlying mechanisms of type 2 diabetes and its complications for developing new prediction, prevention, and treatment strategies. Electronic supplementary material The online version of this article (doi:10.1186/s13098-017-0245-x) contains supplementary material, which is available to authorized users.

Study question Does thyroid autoimmunity (TAI) predict live birth rate in euthyroid women after one treatment cycle in IUI patients? Summary answer TAI as such does not influence pregnancy outcome after IUI treatment. What is known already The role of TAI on pregnancy outcome in the case of IVF/ICSI is largely debated in the literature. This is the first study to address this issue in the case of IUI. Study design, size, duration This was a retrospective cohort study. A two-armed study design was performed: patients anti-thyroid peroxidase (TPO)+ and patients anti-TPO-. All patients who started their first IUI cycle in our fertility center between 1 January 2010 and 31 December 2014 were included. After exclusion of those patients with or being treated for thyroid dysfunction, 3143 patients were finally included in the study. Participants/materials, setting, methods After approval by the institutional review board we retrospectively included all patients who started their first IUI cycle in our center between 1 January 2010 and 31 December 2014 with follow-up of outcome until 31 December 2015. Patients with clinical thyroid dysfunction were excluded (thyroid-stimulating hormone (TSH) 5 mIU/l) as were patients under treatment with levothyroxine or anti-thyroid drugs. These patients were then divided into two main groups: patients anti-TPO+ and patients anti-TPO- (= control group). Live birth delivery after 25 weeks of gestation was taken as the primary endpoint of our study. As a secondary endpoint, we evaluated differences in live birth delivery after IUI according to different upper limits of preconception TSH thresholds (

Objective: To investigate whether an adverse body composition is associated with endothelial dysfunction (ED) and the extent to which any such association could be explained by low-grade inflammation (LGI) and/or insulin resistance (HOMA2-IR). Methods: We studied 475 individuals from the Hoorn Study [mean (range) age, 68.9 (60-87) years, 245 women). Body composition was assessed by whole body dual-energy absorptiometry. Endothelial dysfunction was measured functionally, by flow-mediated dilation (FMD) and by circulating biomarkers. Associations were examined with multiple linear regression models and mediation analyses according to the ab product of coefficients method. Results: After adjustment for age, sex, glucose metabolism status, prior cardiovascular disease and lifestyle factors, total and central fat mass were positively associated with the ED score [beta = 0.16 (95% CI 0.04-0.29) and b 0.18 (0.05-0.31), respectively] and inversely, although not statistically significantly, with FMD. Peripheral fat mass was not associated with the ED score or FMD. There was a significant favourable association between peripheral lean mass and FMD [beta = 0.13 (0.00-0.26)], but not with the ED score. The association between total and central fat mass and the ED score was, to a great extent, mediated by LGI and HOMA2-IR. In contrast, LGI or HOMA2-IR did not mediate the association between peripheral lean mass and FMD. Conclusion: Higher levels of central, but not peripheral fat mass were adversely associated with ED, which was attributable to body composition-related LGI and insulin resistance. In contrast, peripheral lean mass was beneficially associated with ED, but this seemed to be unrelated to LGI or insulin resistance. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials.

DM (diabetes mellitus) is present in 20-40% of patients with liver cirrhosis, but its prognostic impact is unclear. Therefore, in the present study, we investigated whether the presence of DM in patients with cirrhosis was associated with increased mortality, and/or with increased incidence of SBP (spontaneous bacterial peritonitis). We reviewed medical and laboratory data of 230 patients with cirrhosis from the period 2001-2011, for whom data were complete in n=226. Follow-up for the outcomes mortality and SBP was performed until May 2012, with only 13 patients lost to follow-up. DM was present at baseline in 78 patients (35%). Median follow-up was 6.2 (interquartile range, 3.1-9.3) years, during which 118 patients died [47 out of 78 with DM (60%), and 71 out of 148 without DM (48%)]. The presence of DM at baseline was not associated with increased mortality after adjustment for age {HR (hazard ratio), 1.00 [95% CI (confidence interval), 0.67-1.50]}. Further adjustment for sex, aetiology of cirrhosis, platelet count and the Child-Pugh or MELD (model for end-stage liver disease) score did not change this finding. During follow-up, 37 patients developed incident SBP (19 with DM and 18 without DM). DM at baseline was associated with incident SBP, even after adjustment for age, sex, aetiology, platelet count and the Child-Pugh [HR, 2.39 (95% CI, 1.10-5.18)] or MELD score [HR, 2.50 (95% CI, 1.16-5.40)]. In conclusion, the presence of DM at baseline in patients with cirrhosis was associated with an increased risk of SBP, which may represent an increased susceptibility to infections. On the other hand, DM was not clearly associated with increased mortality in these patients. © The Authors Journal compilation. © 2013 Biochemical Society.

OBJECTIVE Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron metabolism–related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin. RESEARCH DESIGN AND METHODS Serum ferritin, transferrin, total iron, non–transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 individuals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers. RESULTS Serum ferritin (β = 1.00% increase in adipocyte IR per 10 μg/L [95% CI 0.66–1.34]), transferrin (4.18% per 0.1 g/L [2.88–5.50]), total iron (1.36% per μmol/L [0.61–2.12]), and NTBI (5.14% per μmol/L [1.88–8.52]) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P < 0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P < 0.01). CONCLUSIONS The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM.

Objective To investigate the role of low-grade inflammation and insulin resistance (HOMA2-IR) in adiposity-related increases in serum complement factor 3 (C3). Although C3 has been linked to type 2 diabetes and cardiovascular diseases, and C3 levels are closely related to body fat, the underlying mechanisms explaining this association are still unknown. Methods Adiposity measures (including BMI, waist circumference (WC), sagittal diameter and several skinfolds), HOMA2-IR and markers of inflammation (hs-CRP, IL-6, SAA, haptoglobin, ceruloplasmin, sICAM-1) were determined in 532 individuals (62% men, mean age 59 ± 6.9 yrs) from the Cohort on Diabetes and Atherosclerosis Maastricht study. Markers of inflammation were standardized and compiled into an averaged inflammation score. Cross-sectional associations between adiposity measures and C3 and the mediating role of low-grade inflammation and/or HOMA2-IR herein were analysed with multiple linear regression models. Results Adiposity measurements were significantly associated with C3 levels, with the strongest (adjusted) associations found for WC (β = 0.383; 95%CI 0.302–0.464) and sagittal diameter (β = 0.412; 95%CI 0.333-0.490). Further adjustment for inflammation and HOMA2-IR attenuated these associations to β = 0.115 (95%CI 0.030-0.200) and β = 0.163 (95%CI 0.082-0.244) respectively. Multiple mediation analyses showed that inflammation [β = 0.090 (95%CI 0.060–0.126)] and HOMA2-IR [β = 0.179 (95%CI 0.128–0.236)] each explained, independently of one another, a significant portion of the association between WC and C3 (23% and 47%, respectively). Similar mediation by inflammation (19-27%) and HOMA2-IR (37-56%) was found for other adiposity measures. Conclusion Systemic low-grade inflammation and insulin resistance may represent two independent pathways by which body fat leads to elevated C3 levels.