Impact of a Public Health Emergency on Behavior, Stress, Anxiety and Glycemic Control in Patients With Pancreas or Islet Transplantation for Type 1 Diabetes.

A public health emergency such as the COVID-19 pandemic has behavioral, mental and physical implications in patients with type 1 diabetes (T1D). To what extent the presence of a transplant further increases this burden is not known. Therefore, we compared T1D patients with an islet or pancreas transplant (ß-cell Tx; n = 51) to control T1D patients (n = 272). Fear of coronavirus infection was higher in those with ß-cell Tx than without (Visual Analogue Scale 5.0 (3.0-7.0) vs. 3.0 (2.0-5.0), p = 0.004) and social isolation behavior was more stringent (45.8% vs. 14.0% reported not leaving the house, p < 0.001). A previous ß-cell Tx was the most important predictor of at-home isolation. Glycemic control worsened in patients with ß-cell Tx, but improved in control patients (ΔHbA1c +1.67 ± 8.74 vs. -1.72 ± 6.15 mmol/mol, p = 0.006; ΔTime-In-Range during continuous glucose monitoring -4.5% (-6.0%-1.5%) vs. +3.0% (-2.0%-6.0%), p = 0.038). Fewer patients with ß-cell Tx reported easier glycemic control during lockdown (10.4% vs. 22.6%, p = 0.015). All T1D patients, regardless of transplantation status, experienced stress (33.4%), anxiety (27.9%), decreased physical activity (42.0%), weight gain (40.5%), and increased insulin requirements (29.7%). In conclusion, T1D patients with ß-cell Tx are increasingly affected by a viral pandemic lockdown with higher fear of infection, more stringent social isolation behavior and deterioration of glycemic control. This trial has been registered in the clinicaltrials.gov registry under identifying number NCT05977205 (URL: https://clinicaltrials.gov/study/NCT05977205).

Investigating the Current Harmonization Status of Tumor Markers Using Global External Quality Assessment Programs: A Feasibility Study.

BACKGROUND: The harmonization status of most tumor markers (TMs) is unknown. We report a feasibility study performed to determine whether external quality assessment (EQA) programs can be used to obtain insights into the current harmonization status of the tumor markers α-fetoprotein (AFP), prostate specific antigen (PSA), carcinoembryonic antigen (CEA), cancer antigen (CA)125, CA15-3 and CA19-9. METHODS: EQA sample results provided by 6 EQA providers (INSTAND [Germany], Korean Association of External Quality Assessment Service [KEQAS, South Korea], National Center for Clinical Laboratories [NCCL, China], United Kingdom National External Quality Assessment Service [UK NEQAS, United Kingdom], Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek [SKML, the Netherlands], and the Royal College of Pathologists of Australasia Quality Assurance Programs [RCPAQAP, Australia]) between 2020 and 2021 were used. The consensus means, calculated from the measurement procedures present in all EQA programs (Abbott Alinity, Beckman Coulter DxI, Roche Cobas, and Siemens Atellica), was used as reference values. Per measurement procedure, the relative difference between consensus mean for each EQA sample and the mean of all patient-pool-based EQA samples were calculated and compared to minimum, desirable, and optimal allowable bias criteria based on biological variation. RESULTS: Between 19040 (CA15-3) and 25398 (PSA) individual results and 56 (PSA) to 76 (AFP) unique EQA samples were included in the final analysis. The mean differences with the consensus mean of patient-pool-based EQA samples for all measurement procedures were within the optimum bias criterion for AFP, the desirable bias for PSA, and the minimum bias criterion for CEA. However, CEA results <8 µg/L exceeded the minimum bias criterion. For CA125, CA15-3, and CA19-9, the harmonization status was outside the minimum bias criterion, with systematic differences identified. CONCLUSIONS: This study provides relevant information about the current harmonization status of 6 tumor markers. A pilot harmonization investigation for CEA, CA125, CA15-3, and CA19-9 would be desirable.

Screening for thyroid dysfunction with free T4 instead of thyroid stimulating hormone (TSH) improves efficiency in older adults in primary care.

Subclinical hypothyroidism (SCHT) is defined as a consistently elevated thyroid stimulating hormone (TSH) with a free T4 (fT4) within the reference range. This diagnosis may lead to additional monitoring, levothyroxine therapy and increased patient concerns, despite lack of evidence of treatment benefit in older adults. In order to avoid this diagnosis, we evaluated the efficiency of fT4-based screening for thyroid dysfunction, in older adults in primary care and compared it with TSH-based screening. Individuals aged >65years in primary care were selected for this retrospective study when both TSH and fT4 were individually requested irrespective of the TSH value. Exclusion criteria were C-reactive protein > 10 mg/l or a history of thyroid hormone monitoring in the previous year. Screening based on fT4 instead of TSH decreased reflex testing from 23.8% to 11.2%. The positive predictive value (PPV) for clinical hypothyroidism increased from 17.3% to 52.2%. The negative predictive value was 96.1% with TSH-based screening versus 97.8% with fT4-based screening. Elevation of the TSH cutoff value from 4.2 to 6.5 mU/l resulted in a reflex test percentage of 12.5% and a PPV of 31.0%. Our results suggest that screening for thyroid dysfunction in older individuals in primary care can be improved by screening based on fT4 instead of TSH or by adjusting the TSH cutoff value. Adjustment of the screening strategy may be of interest to health policy makers because of potential cost reduction. From a patient perspective, medical concerns and unnecessary biochemical follow-up might be reduced by circumventing the diagnosis SCHT.

Increased stress, weight gain and less exercise in relation to glycemic control in people with type 1 and type 2 diabetes during the COVID-19 pandemic.

INTRODUCTION: Lockdown measures have a profound effect on many aspects of daily life relevant for diabetes self-management. We assessed whether lockdown measures, in the context of the COVID-19 pandemic, differentially affect perceived stress, body weight, exercise and related this to glycemic control in people with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a short-term observational cohort study at the Leiden University Medical Center. People with type 1 and type 2 diabetes ≥18 years were eligible to participate. Participants filled out online questionnaires, sent in blood for hemoglobin A1c (HbA1c) analysis and shared data of their flash or continuous glucose sensors. HbA1c during the lockdown was compared with the last known HbA1c before the lockdown. RESULTS: In total, 435 people were included (type 1 diabetes n=280, type 2 diabetes n=155). An increase in perceived stress and anxiety, weight gain and less exercise was observed in both groups. There was improvement in glycemic control in the group with the highest HbA1c tertile (type 1 diabetes: -0.39% (-4.3 mmol/mol) (p<0.0001 and type 2 diabetes: -0.62% (-6.8 mmol/mol) (p=0.0036). Perceived stress was associated with difficulty with glycemic control (p<0.0001). CONCLUSIONS: An increase in perceived stress and anxiety, weight gain and less exercise but no deterioration of glycemic control occurs in both people with relatively well-controlled type 1 and type 2 diabetes during short-term lockdown measures. As perceived stress showed to be associated with glycemic control, this provides opportunities for healthcare professionals to put more emphasis on psychological aspects during diabetes care consultations.

Men Have a Stronger Monocyte-Derived Cytokine Production Response upon Stimulation with the Gram-Negative Stimulus Lipopolysaccharide than Women: A Pooled Analysis Including 15 Study Populations.

The incidence of bacterial infections and sepsis, as well as the mortality risk from sepsis, is sex specific. These clinical findings have been attributed to sex differences in immune responsiveness. The aim of the present study was to investigate sex differences in monocyte-derived cytokine production response upon stimulation with the gram-negative stimulus lipopolysaccharide (LPS) using cytokine data from 15 study populations. Individual data on ex vivo cytokine production response upon stimulation with LPS in whole blood were available for 4,020 subjects originating from these 15 study populations, either from the general population or from patient populations with specific diseases. Men had a stronger cytokine production response than women to LPS for tumour necrosis factor-α, interleukin (IL)-6, IL-12, IL-1ß, IL-1RA, and IL-10, but not for interferon-γ. The granulocyte-macrophage colony-stimulating factor production response was lower in men than in women. These sex differences were independent of chronological age. As men had higher monocyte concentrations, we normalized the cytokine production responses for monocyte concentration. After normalization, the sex differences in cytokine production response to LPS disappeared, except for IL-10, for which the production response was lower in men than in women. A sex-based approach to interpreting immune responsiveness is crucial.

Associations of Elevated Antithyroperoxidase Antibodies with Thyroid Function, Survival, Functioning, and Depressive Symptoms in the Oldest Old: The Leiden 85-plus Study.

Background: Elevated levels of antithyroperoxidase antibodies (TPOAbs) have been associated with progression of subclinical thyroid dysfunction, extrathyroidal diseases, and decrease in functional status. However, TPOAb as determinant of future thyroid dysfunction and other clinical outcomes has not been studied well for adults aged 85 years and over. This study aimed to assess associations of TPOAb levels with thyroid function, survival, physical function, disability in activities of daily living (ADL), cognitive function, and depressive symptoms in the oldest old. Methods: Data from a population-based cohort study (Leiden 85-plus Study) of residents of Leiden, the Netherlands, aged 85 and older were used. Baseline serum TPOAb levels were available for 488 participants (82% of the total cohort). We considered levels ≥35 IU/mL as elevated. Thyroid function (thyrotropin [TSH] and free thyroxine) was assessed at age 85 (baseline), 87, and 88 years. Survival, physical function, disability in ADL, cognitive function, and depressive symptoms were assessed from age 85 through 90 years. Results: At baseline, 64 of the 85-year old participants (13.1%) had elevated TPOAb levels. They were more often female, had higher TSH levels, and a higher prevalence of overt or subclinical hypothyroidism than participants with normal TPOAb levels. Over time, elevated TPOAb levels were independently associated with a lower mortality risk (hazard ratio 0.72, [95% confidence interval 0.53-0.99]), but were not associated with changes in thyroid function, nor with physical function, disability in ADL, cognitive function, or depressive symptoms. Conclusions: In community-dwelling oldest old, elevated TPOAb levels are cross-sectionally associated with higher TSH levels. Over time, elevated TPOAb levels are associated with a survival benefit but are not associated with changes in thyroid function, functional status, or depressive symptoms in old age. The added clinical value of TPOAb tests in oldest old persons with thyroid dysfunction is limited.

Endogenous sex hormones and risk of venous thromboembolism in young women.

BACKGROUND: The risk of venous thromboembolism (VTE) in young women can predominantly be attributed to exogenous hormone use. The influence of (abnormalities in) endogenous sex hormones, as in polycystic ovary syndrome (PCOS) or primary ovarian insufficiency (POI), on VTE risk is uncertain. OBJECTIVES: Th assess the association between endogenous sex hormone levels and VTE risk. METHODS: Women aged ≤45 years from the MEGA case-control study who provided a blood sample in the absence of exogenous hormone exposure or pregnancy were included. Sex hormone-binding globulin (SHBG), estradiol, follicle-stimulating hormone (FSH) and testosterone were measured. The free androgen index (FAI) and estradiol to testosterone ratio (E:T) were calculated. VTE risk was assessed according to quartiles (Qs) of levels and clinical cut-offs as proxies for PCOS (FAI > 4.5) and POI (FSH > 40 U/L). Logistic regression models were used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Six hundred and sixty-five women (369 cases; 296 controls) were eligible for the analyses. Testosterone and FSH levels, E:T and POI (FSH > 40 U/L vs FSH ≤ 40 U/L) were not associated with VTE risk. For estradiol, VTE risk was increased with levels in Q4 vs Q1 (OR 1.6; 95% CI 1.0-2.5). There was a dose-response relationship between SHBG levels and VTE risk, with the highest OR at Q4 vs Q1: 2.0 (95% CI 1.2-3.3). FAI > 4.5 (PCOS proxy) vs FAI ≤ 4.5 was associated with increased VTE risk (OR 3.3; 95% CI 0.9-11.8). CONCLUSIONS: Estradiol, SHBG and FAI were associated with VTE risk, suggesting a role for endogenous sex hormones in the pathophysiology of VTE in young women.

Increased cardiovascular disease risk in women with a history of recurrent miscarriage.

INTRODUCTION: Cardiovascular disease is the leading cause of death in women. Observational studies suggest that women with a history of recurrent miscarriage have an increased risk of cardiovascular disease. MATERIAL AND METHODS: Women who visited the recurrent miscarriage clinic at Leiden University Medical Center between 2000 and 2010 and who had their third consecutive miscarriage before the age of 31 years, were invited to participate in this follow-up study (between 2012 and 2014). The reference group consisted of women with at least one uncomplicated pregnancy and no miscarriage, matched by zip code, age, and date of pregnancy. All women were invited for risk factor screening, including physical examination and blood collection. Main outcome measures were the (extrapolated) 10- and 30-year cardiovascular risk scores using the Framingham risk score. A subanalysis was performed for women with idiopathic recurrent miscarriage. RESULTS: Thirty-six women were included in both groups. Mean follow up was 7.5 years. Women with recurrent miscarriage had a significantly higher extrapolated 10-year cardiovascular risk score (mean 6.24%, SD 5.44) compared with women with no miscarriage (mean 3.56%, SD 1.82, P = .007) and a significantly higher 30-year cardiovascular risk score (mean 9.86%, SD 9.10) compared with women with no miscarriage (mean 6.39%, SD 4.20, P = .04). Similar results were found in women with idiopathic recurrent miscarriage (n = 28). CONCLUSIONS: Women with a history of recurrent miscarriage differ in cardiovascular risk profile at a young age compared with women with no miscarriage. The findings support an opportunity to identify women at risk of cardiovascular disease later in life and a possible moment for intervention.

Determinants of Advanced Bone Age in Childhood Obesity
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BACKGROUND: Childhood obesity is associated with advanced bone age (BA). Previous studies suggest that androgens, oestrogens, sex hormone-binding globulin, and insulin are responsible for this phenomenon, but results are contradictory and might be biased by confounders. We aim to elucidate this matter by applying a multivariate approach. METHOD: We performed a correlation analysis of BA standard deviation score (SDS) with age- and sex-specific SDS for androgens, oestrogens, and with indicators of insulin secretion derived from oral glucose tolerance testing, in a group of obese children. A multivariate analysis was performed to investigate which parameters were independently predictive of BA SDS. RESULTS: In this cohort (n = 101; mean age 10.9 years; mean BA 11.8 years; mean BMI SDS 3.3), BMI SDS was significantly correlated to BA SDS (r = 0.55, p < 0.001). In a regression analysis in the total cohort (B = 0.27, p < 0.001) as well as in females (B = 0.34, p = 0.042), males (B = 0.31, p = 0.006), and pubertal children (B = 0.32, p = 0.046), dehydroepiandrosterone sulphate (DHEAS) showed a positive, independent association with BA SDS. No association with indicators of insulin secretion was found. CONCLUSION: BMI SDS is highly correlated to BA SDS in obese children. Increased DHEAS has a central role in advanced BA in obese children.
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Pituitary Hormone Secretion Profiles in IGSF1 Deficiency Syndrome.

BACKGROUND: Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked syndrome of central hypothyroidism, macroorchidism, delayed pubertal testosterone rise, variable prolactin deficiency and variable partial GH deficiency in childhood. The clinical features and gene expression pattern suggest a pivotal role for IGSF1 in the pituitary, but detailed knowledge on pituitary hormone secretion in this syndrome is lacking. We therefore aimed to study the 24-hour pituitary hormone secretion in male patients with IGSF1 deficiency. METHODS: We collected blood samples every 10 min for 24 h in eight adult male IGSF1-deficient patients and measured circulating TSH, prolactin and gonadotropins. Deconvolution, modified cosinor and approximate entropy analyses were applied to quantify secretion rates, diurnal rhythmicity and regularity of hormone release. Results were compared to healthy controls matched for age and body mass index. RESULTS: Compared to healthy controls, IGSF1-deficient patients showed decreased pulsatile secretion of TSH with decreased disorderliness and reduced diurnal variation. Basal and pulsatile secretion of FSH was increased by over 200%, while LH secretion did not differ from healthy controls. We observed a bimodal distribution of prolactin secretion, i.e. severe deficiency in three and increased basal and total secretion in the other five patients. CONCLUSION: The altered TSH secretion pattern is consistent with the previously hypothesized defect in thyrotropin-releasing hormone signaling in IGSF1 deficiency. However, the phenotype is more extensive and includes increased FSH secretion without altered LH secretion as well as either undetectable or increased prolactin secretion.

Long-term ketogenic diet causes glucose intolerance and reduced ß- and α-cell mass but no weight loss in mice.

High-fat, low-carbohydrate ketogenic diets (KD) are used for weight loss and for treatment of refractory epilepsy. Recently, short-time studies in rodents have shown that, besides their beneficial effect on body weight, KD lead to glucose intolerance and insulin resistance. However, the long-term effects on pancreatic endocrine cells are unknown. In this study we investigate the effects of long-term KD on glucose tolerance and ß- and α-cell mass in mice. Despite an initial weight loss, KD did not result in weight loss after 22 wk. Plasma markers associated with dyslipidemia and inflammation (cholesterol, triglycerides, leptin, monocyte chemotactic protein-1, IL-1ß, and IL-6) were increased, and KD-fed mice showed signs of hepatic steatosis after 22 wk of diet. Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from ß-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in ß-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also α-cell mass was markedly decreased, resulting in a lower α- to ß-cell ratio. Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in ß- and α-cell mass, but no weight loss. This indicates that long-term high-fat, low-carbohydrate KD lead to features that are also associated with the metabolic syndrome and an increased risk for type 2 diabetes in humans.

Discomfort in children undergoing unsedated MRI.

Magnetic resonance imaging (MRI) scans for research purposes usually do not directly benefit the children scanned, so that review boards need to assess whether the risk of harm or discomfort is minimal. This study aimed at providing empirical data on discomfort related to unsedated MRI in children aged 5-12 years. Secondary objectives were to determine whether lower age is associated with higher levels of discomfort and to investigate which other characteristics of subjects and/or procedures may be associated with higher levels of discomfort. Self-report scores, observation scores, heart rate standard deviation scores, and incremental salivary cortisol levels were obtained from 54 children aged 5-12 years with non-acute conditions undergoing diagnostic MRI. Of the 54 children, 10 scored relatively high values on the self-report score and on one or two of the other measures, and another 15 scored relatively high on the self-report score alone. Rather than an age effect, associations were found between parents' trait anxiety and observation score values and between use of contrast fluid (requiring the insertion of a venous cannula) and high incremental salivary cortisol levels. In conclusion, MRI-related discomfort may be regarded as minimal for more than half of children aged 5-12.

False-positive serum human chorionic gonadotropin (HCG) in a male patient with a malignant germ cell tumor of the testis: a case report and review of the literature.

A 39-year-old male patient with a favorable prognosis stage IIB metastatic malignant germ cell tumor (GCT) and elevated pre- and postorchiectomy serum human chorionic gonadotropin (hCG) was treated with three courses of combination chemotherapy resulting in a rapid normalization of his serum hCG. Within 2 months after the cessation of chemotherapy, his serum hCG increased again, suggesting tumor recurrence. Pathological examination of the resected residual retroperitoneal lymph nodes revealed no vital tumor cells. Based on the further rise in his serum hCG and enlargement of mediastinal lymph nodes on computed tomography scan, the patient underwent second- and third-line chemotherapy, which did not result in normalization of his serum hCG. Reanalysis of stored serum samples with other immunoassays revealed that the elevated serum hCG levels collected before first-line chemotherapy were indeed elevated, but those collected after first-line chemotherapy were all falsely positive. Currently, the patient is still alive and disease free. This is the first report of a male cancer patient who received unneeded second- and third-line chemotherapy for relapse based on false-positive hCG results. We discuss the pitfalls of false-positive serum hCG measurements, including heterophilic antibodies, as in our IgA-deficient patient, and review the literature.

Elevated levels of mannose-binding lectin at clinical manifestation of type 1 diabetes in juveniles.

Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL polymorphisms have been described that are associated with MBL serum concentration, impaired function, and diabetic complications. We investigated 86 new-onset juvenile type 1 diabetic patients and compared these with their nondiabetic siblings and healthy unrelated control subjects. Polymorphisms of MBL exon 1 and promoter were determined, and serum concentration and MBL-complex activity were measured. Although the genetic polymorphisms of MBL were not different between patients and control subjects, MBL serum concentration as well as MBL complex activity was significantly higher in new-onset diabetic patients compared with their siblings matched for high-producing MBL genotypes (P = 0.0018 and P = 0.0005, respectively). The increase in MBL complex activity in high-MBL-producing patients could only partially be explained by high MBL production, as demonstrated by an increased MBL complex activity-to-MBL concentration ratio (P = 0.004). We conclude that MBL serum concentration and complex activity are increased in early-onset diabetic patients upon manifestation independently of genetic predisposition to high MBL production, indicating a possible role in the immunopathogenesis of type 1 diabetes, in addition to the adaptive islet autoimmunity.