Significant risk of repeat adverse outcomes in recurrent gestational diabetes pregnancy: a retrospective cohort study.

BACKGROUND: The risk of adverse outcomes in recurrent GDM pregnancy has not been well documented, particularly in women who have already had an adverse outcome. The aim of this study was to compare the risk of recurrent adverse delivery outcome (ADO) or adverse neonatal outcome (ANO) between consecutive gestational diabetes (GDM) pregnancies. METHODS: In this retrospective study of 424 pairs of consecutive ("index" and "subsequent") GDM pregnancies, we compared the risk of ADO (instrumental delivery, emergency Caesarean section) and ANO (large for gestational age (LGA and small for gestational age (SGA)) in women with and without a history of adverse outcome in their index pregnancy. RESULTS: Subsequent pregnancies had higher rates of elective Caesarean (30.4% vs 17.0%, p < 0.001) and lower rates of instrumental delivery (5% vs 13.9%, p < 0.001), emergency Caesarean (7.1% vs 16.3%, p < 0.001) and vaginal delivery (62.3% vs 66.3%, p = 0.01). Index pregnancy adverse outcome was associated with a higher risk of repeat outcome: RR 3.09 (95%CI:1.30,7.34) for instrumental delivery, RR 2.20 (95%CI:1.06,4.61) for emergency Caesarean, RR 4.55 (95%CI:3.03,6.82) for LGA, and RR 5.01 (95%CI:2.73,9.22) for SGA). The greatest risk factor for subsequent LGA (RR 3.13 (95%CI:2.20,4.47)) or SGA (RR 4.71 (95%CI:2.66,8.36)) was having that outcome in the index pregnancy. CONCLUSION: A history of an adverse outcome is a powerful predictor of the same outcome in the subsequent GDM pregnancy. These high-risk women may warrant more directed management over routine GDM care such as altered glucose targets or increased frequency of ultrasound assessment.

Metabolic changes in vitamin D receptor knockout mice.

VDR expression has been found in many cell types involved in metabolism, including the beta-cells of the pancreatic islets. Activated vitamin D and its interactions with the vitamin D receptor (VDR) are implicated in glucose homeostasis. We investigated the metabolic phenotype of the VDR-null (VDRKO) mouse at early and middle age. All offspring of heterozygote VDRKO breeding-pairs were fed 'rescue diet' from weaning to normalize calcium and phosphate levels in VDRKO and to avoid confounding by different diets. Glucose tolerance testing was performed at 7 and 24 weeks of age. Insulin tolerance testing, glucose-stimulated insulin secretion, body-composition studies and islet isolation were performed at 25-27 weeks. Glucose-stimulated insulin secretion was tested in isolated islets. VDRKO mice had reduced bone density, subcutaneous fat mass and muscle weights compared to WT mice. Despite reduced fat mass, glucose tolerance did not differ significantly. Male but not female VDRKO had improved insulin sensitivity. Global loss of VDR has significant effects on organs involved in energy metabolism and glucose homeostasis. In the setting of decreased fat mass, a clear effect on glucose tolerance was not present.

Asian Ethnicity and Femoral Geometry in Atypical Femur Fractures: Independent or Interdependent Risk Factors?

The earliest reports of atypical femur fractures (AFF) emerged from Asia. In the West, epidemiologic studies report a greater incidence of AFFs among subjects of Asian background. Asian ethnicity is an established risk factor for AFF, but clear mechanisms to explain this risk and implications for the general development of AFF are open questions. Ethno-specific differences in bisphosphonate action and femoral geometry have been proposed as hypotheses. In a retrospective cohort of 163 female patients presenting with AFFs or typical femur fractures (TFF), relative contributions of Asian ethnicity, proximal femoral geometry, and bisphosphonate use in AFF status were examined. There was a fourfold higher proportion of Asian subjects in the AFF compared with TFF groups (31.6%, 30/95 versus 7.4%, 5/68). Asian subjects had smaller femurs in femoral head, neck, and axial dimensions. A multiple logistic regression model for AFF status was fitted adding Asian ethnicity to three previously reported independent predictors of AFF including femoral geometry, which together comprise the Sydney AFF Score (age ≤80 years, femoral neck width <37 mm than non-Asian, lateral cortical width at lesser trochanter ≥5 mm). Asian ethnicity was a robust independent predictor of AFF, imparting sevenfold increase in the odds of AFF after adjusting for all three variables (95% confidence interval [CI] 2.2-23.2, p = 0.001) or for overall AFF score (95% CI 2.2-22.3 p = 0.001). Overall Asian subjects had higher rates of bisphosphonate use than non-Asian subjects (67.6% versus 47.2%, p = 0.034). Among AFF bisphosphonate users, Asian subjects had lower AFF scores than non-Asians (Sydney AFF Score ≤1, 45.5% Asian subjects versus 22.2% non-Asian subjects, p = 0.05). Asian ethnicity is a strong independent risk factor for AFF, unaccounted for by ethno-specific differences in proximal femoral geometry. Bisphosphonate use may be associated with a greater predisposition for AFF in Asian subjects compared with non-Asian subjects. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The Sydney AFF Score: A Simple Tool to Distinguish Females Presenting With Atypical Femur Fractures Versus Typical Femur Fractures.

Atypical femur fractures (AFF) are a rare but serious complication of long-term bisphosphonate use. Although clearly defined by ASBMR criteria, a proportion of patients with AFFs may go unrecognized and the use of qualitative fracture criteria may lead to uncertainty in AFF diagnosis, with significant therapeutic implications. A score that rapidly and accurately identifies AFFs among subtrochanteric femur fractures using quantitative, measurable parameters is needed. In a retrospective cohort of 110 female patients presenting with AFFs or typical femur fractures (TFFs), multiple logistic regression and decision tree analysis were used to develop the Sydney AFF score. This score, based on demographic and femoral geometry variables, uses three dichotomized independent predictors and adds one point for each: (age ≤80 years) + (femoral neck width <37 mm) + (lateral cortical width at lesser trochanter ≥5 mm), (score, 0 to 3). In an independent validation set of 53 female patients at a different centre in Sydney, a score ≥2 demonstrated 73.3% sensitivity and 69.6% specificity for AFF (area under the receiver-operating characteristic curve [AUC] 0.775, SE 0.063) and remained independently associated with AFF after adjustment for bisphosphonate use. The Sydney AFF score provides a quantitative means of flagging female patients with atraumatic femur fractures who have sustained an AFF as opposed to a TFF. This distinction has clear management implications and may augment current ASBMR diagnostic criteria. © 2021 American Society for Bone and Mineral Research (ASBMR).

ABCB1 and ABCC1 single-nucleotide polymorphisms in patients treated with clozapine.

Clozapine (CZ) has superior efficacy to other antipsychotic agents in the treatment of schizophrenia and has been extensively used in clinical practice. ATP-binding cassette (ABC) transporter proteins are responsible for the distribution of various molecules as well as drugs across extracellular and intracellular membranes, including the blood-brain barrier. Genetic variations in these proteins can account for differences in treatment response. We investigated the influence of ABCB1 rs1045642 and ABCC1 rs212090 single-nucleotide polymorphisms (SNPs) on CZ serum level, clinical outcome, and changes in body mass index (BMI) in the first year of CZ treatment. These polymorphisms influenced baseline BMI in males (p=0.009 and 0.054, B1 and C1, respectively), changes in BMI in males after 3 (p=0.026, ABCB1) and 12 months (p=0.022, ABCC1) of CZ treatment, and level of diastolic pressure (p=0.002 and 0.051, respectively). The combination of ABCB1 + ABCC1 homozygote SNPs was associated with increased CZ and norclozapine serum levels (p=0.054 and 0.010, respectively). ABC transporter SNPs could be potential biomarkers for CZ-induced weight gain and cardiovascular complications. Further pharmacogenetic research is warranted to help clinicians with their treatment decision, including concomitant use of drugs and prevention of side effects.

CYP2C19*17 protects against metabolic complications of clozapine treatment.

OBJECTIVES: Clozapine (CZ) is the most effective drug for managing treatment-resistant schizophrenic disorders. Its use has been limited due to adverse effects, which include weight gain and new-onset diabetes, but the incidence of these varies between patients. METHODS: We investigated 187 Clozapine Clinic patients (of whom 137 consented for genotyping) for the presence of CYP2C19*17 and its association with CZ and norclozapine (NCZ) levels, and clinical outcomes. RESULTS: Thirty-nine percent of genotyped patients were carriers of the CYP2C 19*17 polymorphism. This group demonstrated significantly higher NCZ serum levels, and significantly lower fasting glucose (5.66 ± 1.19 vs 6.72 ± 3.01 mmol/l, P = 0.009) and Hb1Ac (35.36 ± 4.78 vs 49.40 ± 20.60 mmol/mol, P = 0.006) levels compared to non-carriers of this polymorphism. CZ-treated patients with CYP2C19*17/*17 had a significantly lower prevalence of diabetes as well as a higher likelihood of clinical improvement of their schizophrenia, compared to those without this polymorphism (P = 0.012 and P = 0.031, respectively). CONCLUSIONS: Our data suggest that CYP2C19*17 ultra-rapid-metaboliser status is a protective factor against the development of diabetes during clozapine treatment, and increases the likelihood of improvement in schizophrenia. The role of NCZ in treatment response and side effects, including metabolic syndrome, warrants further pharmacogenetic, pharmacokinetic and pharmacodynamic studies.

Predicting Weight Gain in Patients Treated With Clozapine: The Role of Sex, Body Mass Index, and Smoking.

OBJECTIVES: Weight gain on clozapine is highly variable and poorly predictable. Its mechanisms are not well understood. This study explores the factors that predict weight gain between 3 and 12 months of clozapine therapy in community-dwelling patients. METHODS: We conducted a retrospective audit of patients attending an outpatient clozapine clinic. Weight change from 3 to 12 months of therapy was recorded, expressed as a percentage of the 3-month weight. Univariate analyses compared percent weight change according to sex, smoking status, country of birth, and baseline body mass index. Correlations between weight gain, age, and clozapine dose were explored. A general linear model identified independent predictors of weight gain. RESULTS: The mean weight change from 3 to 12 months in 117 patients was +3.1% (range, -17% to +30%). Females gained more weight than males (+5.5% vs +1.3%, P = 0.01), smokers gained more than nonsmokers (+5.1% vs +1.2%, P = 0.02), and obese patients gained less than normal or overweight individuals (0.15% vs 4.6% and 5.2%, respectively, P = 0.01). Age and clozapine dose had no relation to weight change. On multivariate analysis, baseline BMI and smoking status remained independent predictors of percent weight change in females. These 2 predictors explained 25% of weight change in females in the first 3 to 12 months of therapy. These associations were not observed in males. CONCLUSIONS: We hypothesize that smoking affects weight change by promoting clozapine metabolism to norclozapine via cytochrome P450 enzymes. Verifying this hypothesis and exploring the mechanisms underpinning the sex dichotomy are areas for further research.

Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:

Effects of vitamin D in skeletal muscle: falls, strength, athletic performance and insulin sensitivity.

Accompanying the high rates of vitamin D deficiency observed in many countries, there is increasing interest in the physiological functions of vitamin D. Vitamin D is recognized to exert extra-skeletal actions in addition to its classic roles in bone and mineral homeostasis. Here, we review the evidence for vitamin D's actions in muscle on the basis of observational studies, clinical trials and basic research. Numerous observational studies link vitamin D deficiency with muscle weakness and sarcopaenia. Randomized trials predominantly support an effect of vitamin D supplementation and the prevention of falls in older or institutionalized patients. Studies have also examined the effect of vitamin D in athletic performance, both inferentially by UV radiation and directly by vitamin D supplementation. Effects of vitamin D in muscle metabolic function, specifically insulin sensitivity, are also addressed in this review. At a mechanistic level, animal studies have evaluated the roles of vitamin D and associated minerals, calcium and phosphate, in muscle function. In vitro studies have identified molecular pathways by which vitamin D regulates muscle cell signalling and gene expression. This review evaluates evidence for the various roles of vitamin D in skeletal muscle and discusses controversies that have made this a dynamic field of research.

Serum 25-hydroxyvitamin D and glycated haemoglobin levels in women with gestational diabetes mellitus.

OBJECTIVE: To test the hypothesis that lower 25-hydroxyvitamin D (25[OH]D) levels in late pregnancy are associated with poorer glucose control in gestational diabetes mellitus (GDM). DESIGN AND SETTING: Retrospective cross-sectional study, in a GDM clinic at a tertiary referral centre. PATIENTS: Women attending the GDM clinic at Westmead Hospital from 1 February 2007 to 1 February 2008, excluding those with prepregnancy glucose intolerance. MAIN OUTCOME MEASURES: Levels of glycated haemoglobin (HbA(1c)) and 25(OH)D measured during the third trimester; maternal age, ethnicity, body mass index (BMI) and occupational status; and results of oral glucose tolerance testing (OGTT). RESULTS: 147 women with a mean gestational age of 35 ± 2 weeks were included, of whom 41% had insufficient or deficient levels of 25(OH)D (≤ 50 nmol/L). Ethnicity, occupational status and season significantly influenced 25(OH)D levels (P < 0.01 for all) but BMI did not. 25(OH)D levels were inversely associated with fasting and 2-hour blood glucose levels during OGTT (Spearman r = - 0.16; P = 0.05 for both) and with log[HbA(1c)] (Spearman r = - 0.32; P < 0.001). BMI and insulin doses were also associated with HbA(1c) levels. Multivariable analysis identified 25(OH)D and blood glucose levels during the OGTT as independent predictors of HbA(1c) levels. CONCLUSIONS: Lower 25(OH)D levels are independently associated with poorer glycaemic control. Future randomised trials are needed to determine whether vitamin D plays a role in glycaemic control in GDM. Regardless, maternal vitamin D insufficiency has adverse effects including neonatal hypocalcaemia and rickets. The 41% prevalence of inadequate 25(OH)D levels in the women in our study is unacceptably high. We propose routine 25(OH)D testing of all pregnant women at screening for GDM or earlier, and treatment of women who are found to be deficient.