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Aims Heart failure with reduced ejection fraction (HFrEF) is characterized by sub‐clinical inflammation. Changes in selected biomarkers of inflammation concomitant with the release of pro‐inflammatory and anti‐inflammatory cytokines by neutrophils have not been investigated in patients with HFrEF. Methods and results Fifty‐two patients, aged 68.8 ± 1.7 years, with HFrEF and left ventricular ejection fraction 28.7 ± 1.0%, and 21 healthy controls (CTL) were recruited. Twenty‐five HF patients had type 2 diabetes. Venous blood samples from HF and CTL were collected once. Neutrophil‐derived pro‐inflammatory and anti‐inflammatory cytokine levels were assessed in plasma by ELISA. Plasma biomarkers assessed included: C‐reactive protein (CRP), vascular endothelial growth factor (VEGF), interleukins (IL)‐6, ‐8, ‐1 receptor antagonist (‐1RA), nitric oxide (NO), soluble intercellular adhesion molecule‐1 (sICAM‐1), vascular cell adhesion molecule 1 (sVCAM‐1) and E‐Selectin (sE‐Sel). Neutrophils were isolated and stimulated with various agonists to promote VEGF, IL‐6, IL‐8, and IL‐1RA release. Compared with CTL, HFrEF patients showed a marked decrease in circulating VEGF [178.0 (interquartile range; IQR 99.6; 239.2) vs. 16.2 (IQR 9.3; 20.2) pg/mL, P ≤ 0.001] and NO [45.2 (IQR 42.1; 57.6) vs. 40.6 (IQR 30.4; 47.1) pg/mL, P = 0.0234]. All other circulating biomarkers were significantly elevated. Neutrophils isolated from patients with HFrEF exhibited a greater IL‐8 release in response to LPS [1.2 ± 0.1 (CTL); 10.4 ± 1.6 ng/mL (HFrEF) and 12.4 ± 1.6 ng/mL (HFrEF and DM), P ≤ 0.001]. IL‐6 release in response to LPS was not changed in HFrEF patients without diabetes, whereas it was significantly increased in patients with HFrEF and diabetes [46.7 ± 3.9 (CTL) vs. 165.8 ± 48.0 pg/mL (HFrEF), P = 0.1713 and vs. 397.7 ± 67.4 pg/mL (HFrEF and DM), P ≤ 0.001]. In contrast, the release of VEGF and IL‐1RA was significantly reduced in HFrEF (VEGF; TNF‐α: 38.6 ± 3.1 and LPS: 25.3 ± 2.6 pg/mL; IL1RA; TNF‐α: 0.6 ± 0.04 and LPS: 0.3 ± 0.02 ng/mL) compared with CTL (VEGF; TNF‐α: 60.0 ± 9.4 and LPS: 41.2 ± 5.9 pg/mL; IL1RA; TNF‐α: 3.3 ± 0.2 and LPS: 2.3 ± 0.1 ng/mL). Conclusions Patients with HFrEF exhibit a significant decrease in circulating VEGF. The release of VEGF and both pro‐inflammatory and anti‐inflammatory cytokines from the stimulated neutrophils is markedly altered in these patients. The clinical significance of these findings deserves further investigation.

Background Neutrophils induce the synthesis and release of angiopoietin 1 (Ang1), a cytosolic growth factor involved in angiogenesis and capable of inducing several pro-inflammatory activities in neutrophils. Neutrophils also synthesize and release neutrophil extracellular traps (NETs), comprised from decondensed nuclear DNA filaments carrying proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), proteinase 3 (PR3) and calprotectin (S100A8/S100A9), which together, contribute to the innate immune response against pathogens (e.g., bacteria). NETs are involved in various pathological conditions through pro-inflammatory, pro-thrombotic and endothelial dysfunction effects and have recently been found in heart failure (HF) and type 2 diabetes (T2DM) patients. The aim of the present study was to investigate the role of NETs on the synthesis and release of Ang1 by the neutrophils in patients with T2DM and HF with preserved ejection fraction (HFpEF) (stable or acute decompensated; ADHFpEF) with or without T2DM. Results Our data show that at basal level (PBS) and upon treatment with LPS, levels of NETs are slightly increased in patients suffering from T2DM, HFpEF ± T2DM and ADHF without (w/o) T2DM, whereas this increase was significant in ADHFpEF + T2DM patients compared to healthy control (HC) volunteers and ADHFpEF w/o T2DM. We also observed that treatments with PMA or A23187 increase the synthesis of Ang1 (from 150 to 250%) in HC and this effect is amplified in T2DM and in all cohorts of HF patients. Ang1 is completely released (100%) by neutrophils of all groups and does not bind to NETs as opposed to calprotectin. Conclusions Our study suggests that severely ill patients with HFpEF and diabetes synthesize and release a greater abundance of NETs while Ang1 exocytosis is independent of NETs synthesis.

Reduced exercise capacity can predispose solid organ transplant (SOT) recipients to higher risk of diabetes, cardiovascular complications, and mortality and impact their quality of life. This systematic review and meta-analysis investigated the effects of exercise training (versus no training) in adult SOT recipients. We conducted an electronic search of randomized controlled trials reporting on exercise interventions in SOT recipients. Primary outcomes were exercise capacity, quadriceps muscle strength, and health-related quality of life (HRQoL). Twenty-nine articles met the inclusion criteria. In 24 studies, there were either high risk of bias or some concerns about the potential risk of bias. There was an increase in exercise capacity (VO2 peak) (SMD: 0.40; 95%CI 0.22-0.57; P = 0.0) and quadriceps muscle strength (SMD: 0.38; 95%CI 0.16-0.60; P = 0.001) in the exercise vs control groups. There were also improvements in several domains of the SF-36. Diastolic blood pressure improved in the exercise group compared to controls (SMD: -0.22; 95%CI -0.41-0.03; P = 0.02). Despite the considerable variation in exercise training characteristics and high risk of bias in the included studies, exercise training improved maximal exercise capacity, quadriceps muscle strength, HRQoL, and diastolic blood pressure and should be an essential part of the post-transplant care.

Heart failure with preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation, which could be exacerbated by type 2 diabetes mellitus (DM). We hypothesized that neutrophils in patients with DM and patients with HFpEF with/without DM contribute to low-grade inflammation through the release of pro-inflammatory cytokines. Venous blood was withdrawn from patients with DM (n = 22), HFpEF (n = 15), HFpEF with DM (n = 13), and healthy controls (CTL) (n = 21). Levels of circulating cytokines and in vitro cytokines released by isolated neutrophils were assessed by enzyme-linked immunosorbent assay. Compared with CTL, there was a significant decrease in circulating nitric oxide in patients with DM (p ≤0.001), HFpEF (p ≤0.05), and HFpEF with DM (p ≤0.001) up to 44%. Circulating soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels increased (up to 2.5-fold and 1.9-fold, respectively; p ≤0.001) in patients with HFpEF and patients with HFpEF and DM, whereas soluble E-selectin only increased in patients with HFpEF and DM (1.4-fold, p ≤0.001). Circulating vascular endothelial growth factor levels were similar in CTL and patients with DM but were decreased in patients with HFpEF with/without DM (up to 94%; p ≤0.001). Circulating C-reactive protein, interleukin (IL)-8, IL-6, and IL-receptor antagonist increased in all patient groups with a maximum of 3.3-fold, 4.7-fold, 4.8-fold, and 1.6-fold, respectively, in patients with HFpEF and patients with DM. In vitro, lipopolysaccharide increased neutrophils IL-6 release from HFpEF with DM (3.7-fold; p ≤0.001), and IL-8 release from DM and HFpEF with DM versus CTL (2.8-fold and 10.1-fold, respectively; p ≤0.001). IL-1 receptor antagonist and vascular endothelial growth factor release from HFpEF neutrophils significantly decreased up to 87.0% and 92.2%, respectively, versus CTL. Neutrophils from patients with DM and HFpEF release more cytokines than CTL. This increase in pro-inflammatory status may explain the greater event rate in patients with HFpEF and DM.

Home-based exercise programs may offer a less costly alternative to providing exercise pre-transplant to a large number of patients. We describe the changes in 6-minute walk distance (6MWD) in lung transplant candidates who participated in a home-based exercise program and their relationship to post-transplant outcomes. Retrospectively, we investigated 159 individuals while awaiting transplantation who performed the surgery between 2011 and 2015. Primary outcome was 6MWD at time of assessment for transplant, last test prior to transplant and one-month post-transplant. 6MWD decreased by 28 ± 93.9 m between the time of assessment and the last 6MWD prior to transplantation (P < .001). Forty-one patients (25.8%) increased their 6MWD (mean + 85.8 ± 42.8 m); 72 patients (45.3%) decreased their 6MWD (mean -109.8 ± 71.2 m); and 46 patients (28.9%) had no change in 6MWD (-1.5 ± 15.7 m). There was a moderate correlation (r = .528; P < .001) between the last 6MWD prior to transplant and 6MWD post-transplant. Change in 6MWD prior to transplant weakly correlated with length of time on mechanical ventilation (r = -.185; P = .034). When adjusted for covariates, change in 6MWD prior to transplant was not associated with length of time on mechanical ventilation, total hospital LOS, or intensive care unit LOS. The majority of the patients were able to either increase or maintain their 6MWD while participating in a home-based pre-habilitation program during the waiting list period. Prospective research is needed to evaluate the effects of home-based pre-habilitation program for lung candidates.

BACKGROUND Many solid organ transplant (SOT) recipients fail to meet the recommended physical activity (PA) levels. "Physician recommendation" has previously been reported by SOT recipients as a key facilitator to being more physically active. The purpose of this study was to determine the proportion of Canadian SOT physicians providing PA counselling and identify barriers to including such counselling as part of the SOT recipients' routine care. MATERIAL AND METHODS We conducted a cross-sectional web-based survey study to evaluate physicians' PA counselling practices, including the prevalence and barriers to such practice. A survey link was sent to a convenience sample of transplant physicians who are members of the Canadian Society of Transplantation. RESULTS Thirty-four physicians (13.6%) participated in the survey. While 97% (n=33) of the participants reported providing PA counselling to their transplant patients, only 18% (n=6) responded they were very confident in PA counselling. Lack of time (n=19; 56%) and a lack of exercise guidelines (n=18; 53%) were identified as the main barriers to PA counselling. CONCLUSIONS Incorporating sufficient PA knowledge into physicians' educational curricula system, developing specific PA guidelines as well as establishing an easier referral system to exercise specialists might improve the frequency and quality of PA counselling post-transplant.

In our clinical experience, we have encountered patients who developed hypomagnesemia after the introduction of teriparatide. Some trials have reported hypomagnesemia as an adverse event during teriparatide treatment, but this issue had never been studied specifically. Our objective was twofold: 1) determine the incidence of hypomagnesemia (serum magnesium

Purpose Home-based exercise programs offer an alternative way to provide exercise pre-transplant; it gives access to rehabilitation to a larger number of patients and it may be associated with lower healthcare cost. We described the changes in functional exercise capacity (6-minute walk distance (6MWD)) in lung transplant candidates who participated in a home-based exercise program and evaluated relationships between changes in functional exercise capacity pre-transplant and post-transplant variables. Methods Retrospective cohort study of 159 individuals who received a lung transplant between 2011-2015, who participated in a home-based exercise program while waiting for transplantation and had available pre-transplant data. Our primary outcome was 6MWD at 3 time points: time of assessment for transplant, last test prior to transplant and one-month post-transplant. Other variables included: age, sex, primary diagnosis, date of transplantation, body mass index (BMI), total hospital length of stay (LOS), intensive care unit (ICU) LOS and time on mechanical ventilation. Results The median LOS on the waiting list was 1.9 yrs. There was a mean decrease of 28±93.9m between the 6MWD at the time of assessment and the last 6MWD prior to transplantation (p Conclusion The majority of the patients (54.7%) were able to either increase or maintain their 6MWD by participating in a home-based pre-habilitation program while on the waiting list. These results are similar to what has been found for hospital-based programs in lung transplant candidates. *Financial support: Funded by the Canadian Society of Transplantation-Allied Health Group Research Grant (2017). Dr Massierer holds the Quebec Respiratory Health Network (RHN) Scholarship Supplement Program Award. Dr Janaudis-Ferreira holds FRQS Junior 1 career award.

Introduction: Bone loss is significant within the first 3 to 6 months after orthotopic liver transplantation (OLT) and is associated with high rates of fractures. Incident fractures after OLT are correlated with substantial decreased quality of life. To attempt preventing post-transplant fractures, the cornerstone of therapeutic management is bisphosphonates (BP). Objectives: The main objective of our study was to determine the incidence of fractures during the first three years after a first OLT in patients receiving BP. The secondary objective was to study the predictors of fractures in these patients. Methods: We conducted a retrospective study in a cohort of patients who underwent OLT between January 2012 and September 2016 at our center. All adult recipients who received BP after OLT were included in the study. Clinical, laboratory, bone mineral density (BMD) and fracture data were extracted from electronic medical records. Vertebral and non-vertebral fractures were included and all fractures were confirmed by a radiologist. Results: During the study period, 304 OLT were performed and 158 patients (median age 57 y.o.; 29.8% female) met the inclusion criteria. Prior to OLT, 14 patients (8.9%) met the criteria for osteoporosis (T-score ≤ -2.5) and a total of 24 patients (15.2%) had a past history of fractures (vertebral and non-vertebral). The cumulative incidence of fractures after OLT in patients treated with BP was 19.1% (26 patients) at 36 months, with a median time to first fracture of 6 months (Q1=2, Q3=20 months). Predictive factors of fractures in univariate analyses included: age > 60 y.o. (HR 2.46; 95% CI, 1.14-5.33), new onset diabetes after transplantation (NODAT) (HR 2.38; 95% CI, 1.10-5.15), narcotic use at 6 months after OLT (HR 2.19; 95% CI, 1.00-4.77) and length of hospital stays in the first year (days) (HR 1.01; 95% CI, 1.00-1.01). Previous fragility fracture was not associated with higher risk of post-transplant fracture. Multivariate analysis confirmed that age > 60 y.o. (HR 2.66; 95% CI, 1.23-5.79; p=0.01), narcotic use (HR 2.65; 95% CI, 1.20-5.84; p=0.02) and NODAT (HR 2.68; 95% CI, 1.23-5.84; p=0.01) were significant independent risk factors for fractures. BMD was available before and after transplant in 34 patients and there was a statistically significant decrease in mean absolute BMD (g/cm2) at the femoral neck (-0.07 g/cm2 vs. -0.04 g/cm2; p=0.02) and total hip (-0.07 g/cm2 vs. -0.02 g/cm2; p=0.02) in patients with incident fractures compared to patients without fracture during follow-up. Conclusion: Fractures are a frequent complication after OLT even in patients preemptively treated with BP. Special attention should be paid to BP treated older patients, narcotic users and patients with NODAT in order to prevent fractures after OLT. Further studies are needed to identify the best therapeutic strategy in this population.

Background: The differential diagnosis of adrenal incidentalomas is broad and includes benign or malignant primary adrenal lesions, metastases, myelolipomas, infections or hemorrhage. We present here a patient with a gastrointestinal stromal tumor (GIST) presenting as an adrenal incidentaloma. Clinical Case: A 64-year-old man was referred to Endocrinology for the work-up of a left adrenal incidentaloma discovered on an abdominal CT scan performed for left upper quadrant abdominal pain. His past medical history included well-controlled type 2 diabetes and hypertension. On subsequent imaging, the mass was described as a solid homogenous nodule with a density of 31 HU and an absolute contrast washout of 22%. Between 2017 and 2020, the mass’ size increased from 14 x 13 to 24 x 19 millimeters. Further functional imaging revealed no 131I-MIBG uptake but moderate hypermetabolism on FDG PET-CT with a SUVmax of 4.5. There was discordance regarding the mass’ localization between the various imaging modalities used preoperatively: some showed a left adrenal lesion whereas others suggested that it was adjacent to, but distinct from, the adrenal gland. Biochemical workup included normal 1-mg dexamethasone suppression test, serum potassium levels, 24-hour urine fractionated catecholamines, as well as plasma free metanephrines and normetanephrines. Chromogranin A levels were also normal. In light of these findings, laparoscopic tumor resection, with or without left adrenalectomy, was scheduled. During surgery, it was discovered that the tumor was intraperitoneal, located next to the splenic hilum and originating from the greater curvature of the stomach; a partial gastrectomy was therefore performed, without left adrenalectomy. Pathological evaluation revealed that the mass was a small spindle cell-type GIST. Genetic analysis of the tumoral DNA showed a somatic mutation in exon 11 of the KIT gene (c.1658_1669del, p.Tyr553_Gln556del). Conclusion: We report a rare case of gastric GIST initially mimicking a left adrenal incidentaloma. Localization of GISTs in the adrenal area is rare, with very few cases reported to date in the literature. Unlike other cases described previously, our patient underwent the right procedure thanks to adequate tumor localization during surgery. However, as some patients have experienced unnecessary adrenalectomy for similar clinical presentations, gastric GISTs should be kept in mind in the differential diagnosis of non-functional atypical adrenal masses, especially in the presence of suspicious PET scan imaging. References: 1. Hexi Du, Jun Zhou, Cheng Yang, Li Zhang, Chaozhao Liang: Gastrointestinal stromal tumor masquerading as an adrenal tumor: a case report with literature review. Int J Clin Exp Med 2017;10(10):14883-14887.

C-reactive protein (CRP) is recognized as a biomarker of chronic, low-grade inflammation associated with vascular disorders. Lately, the role of neutrophils and neutrophil extracellular traps (NETs) has been investigated as a potential source of chronic inflammation and cardiovascular complications. This study investigated NETs as a marker of inflammation in patients with symptomatic heart failure (HF) with or without type 2 diabetes (T2DM) and examined the correlation between NETs and CRP. We performed a noninterventional study including patients with HF with or without T2DM, T2DM, and a healthy control (HC) group. NETs and other inflammatory markers in serum were measured by ELISA. The release of NETs (NETosis) in vitro under various stimuli was measured by confocal microscopy. The levels of NETs in the serum of HF patients were significantly higher compared with HC (112%). Serum CRP concentrations were significantly increased in HF and HF plus T2DM patients compared with HC, and a positive correlation was observed between serum CRP and NETs levels. Neutrophils from HF and HF plus T2DM patients underwent in vitro NETs release faster than T2DM and HC without any stimuli. In vitro, serum collected from the HF and the HF plus T2DM group induced NETosis in healthy neutrophils significantly more when compared with HC and T2DM, which was prevented by depletion from CRP. We confirmed in vitro that CRP induces a concentration-dependent NETs synthesis. This study proposes a mechanism by which CRP increases the risk of future cardiovascular events and supports mounting evidences on the role of neutrophils in chronic low-grade inflammation associated with HF.

Metformin presents better survival rates than other oral antidiabetics in the treatment of type 2 diabetes. However, these benefits may be dampened by inadequate treatment adherence.We aimed to investigate the relationship between adherence level to metformin therapy and all-cause mortality over 10 years in incident metformin users.A nested case-control study was conducted using a large cohort of beneficiaries of the Quebec public drug insurance plan, aged 45 to 85 years, who initiated metformin between 2000 and 2009. Each case of all-cause death during follow-up was matched with up to 10 controls. Adherence to metformin was measured using the medication possession ratio (MPR). Conditional logistic regression models were used to estimate rate ratios (RRs) for mortality between adherent (MPR ≥ 80%) and nonadherent patients (MPR80%). Subgroup analyses were conducted according to age (45-64 and 65-85 years) and comedication use (antihypertensive/cardiovascular drugs and statins).The cohort included 82 720 incident metformin users, followed up for 2.4 [0.8-4.4] years (median [interquartile range]) and 4747 cases of all-cause deaths. Analyses revealed decreased mortality risks after long-term adherence to metformin. Specifically, RRs were 0.84 (95% CI = [0.71-0.98]) and 0.69 [0.57-0.85] after 4 to 6 and ≥6 years of adherence to metformin, respectively. Survival benefits of long-term adherence (≥4 years) were also observed across most subgroups and particularly in patients using neither antihypertensive/cardiovascular drugs nor statins (0.57 [0.41-0.77]).Long-term adherence to metformin is associated with decreased risks of all-cause mortality in incident metformin users. Further research should investigate whether survival benefits vary according to the comorbidity burden of patients.

Posttransplant weight gain is common after orthotopic liver transplantation. We sought to determine the extent of weight gain at 5 years after transplantation in patients with nonalcoholic fatty liver disease (NAFLD) cirrhosis versus patients with other types of cirrhosis (non-NAFLD). We studied 126 liver transplants performed between 2005 and 2007 at Saint Luc Hospital, University of Montreal. Seventeen of the 126 patients (13.5%) had NAFLD cirrhosis. Ascites volume was difficult to assess, so we used the body mass index (BMI) at 3 months as the reference BMI. All patients gained weight after transplantation, but BMI increased significantly more and earlier among the NAFLD patients [4.8 versus 1.5 kg/m2 at 1 year (P = 0.001), 5.0 versus 2.3 kg/m2 at 2 years (P = 0.01), and 5.6 versus 2.6 kg/m2 at 5 years (P = 0.009)] in comparison with non-NAFLD patients in unadjusted analyses. The greatest BMI increase over time was investigated with univariate and multivariate logistic regression analyses. The BMI increase was divided into tertiles for each period of time observed. The greatest BMI increase over time was defined as the top tertile of BMI increase. After adjustments for potential confounders (ie, total cholesterol, diabetes, and length of hospital stay), NAFLD was no longer associated with a risk of a greater BMI increase [odds ratio (OR) = 3.73 at 1 year (P = 0.11), OR = 2.15 at 2 years (P = 0.34), and OR = 2.87 at 5 years (P = 0.30)]. These findings suggest the need for multidisciplinary, early, and close weight monitoring for all patients. All patients could benefit from pretransplant counseling regarding weight gain and its consequences. Liver Transpl 20:1266-1274, 2014. © 2014 AASLD.

Both diabetes and fractures are prevalent in adults. The relationship between diabetes and osteoporosis is complex and, although it has been investigated extensively, the subject remains controversial. While low bone mineral density (BMD) is consistently observed in type 1 diabetes, the relationship is less clear in type 2 diabetes, with some studies reporting modestly increased or unchanged BMD. Both type 1 and type 2 diabetes have been associated with a higher risk of fractures. Despite discrepancies between BMD and fracture rates, clinical trials uniformly support the fact that new bone formation and bone microarchitecture and, thus, bone quality, are altered in both types of diabetes. Although a causal association between diabetes and osteoporosis cannot be established on the basis of existing data, it is possible to conclude from many studies and from a better understanding of the physiopathology of diabetes that it can increase the risk of fractures through skeletal (decreased BMD and bone quality) and extraskeletal (increased risk of falls) factors. Even though osteoporosis screening or prophylactic treatment in all patients with type 1 and type 2 diabetes is not being recommended at present, such patient populations should be given general guidelines regarding calcium and vitamin D intakes, exercise and the avoidance of potential risk factors for osteoporosis. The extent of diagnostic and therapeutic interventions should be based on the individual's risk profile for fractures.

To assess the risk of fractures after a solid organ transplantation among diabetic versus nondiabetic patients, we conducted a nested case-control study. Pretransplant diabetes was associated with a 2-fold increase in post-transplant fractures. Introduction: Diabetes has been associated with osteoporosis in the general population. However, among patients receiving solid organ transplantation, the association between pretransplant diabetes and post-transplant fractures is not clear, although both diabetes and fractures are prevalent among this patient population. We aimed to determine whether pretransplant diabetes increases the risk of fractures among patients receiving solid organ transplantation. Materials and Methods: We conducted a nested case-control study in a cohort of subjects 18 years and older, enrolled in the Quebec Drug Insurance Plan, who received a first solid organ transplantation between January 1986 and December 2005. Cases had sustained a fracture between the date of discharge from the hospitalization for solid organ transplantation and the end of the study period. All remaining patients were eligible controls. The fracture date was the case index date. Cases were matched to up to four controls on the type of organ transplanted and the date of transplantation. The index date of a control patient was that of his/her matched case. Crude and adjusted ORs were obtained with univariate and multivariate conditional logistic regression models. Results: The study included 238 cases and 873 controls. Pretransplant diabetes was present in 30% of the cases and 22% of the controls (crude OR: 2.16; 95% CI: 1.7–2.8). After adjusting for age, sex, previous fractures, past hyperthyroidism, hospitalization duration, use of narcotics, benzodiazepines, antidepressants, loop diuretics, thiazide diuretics, glucocorticoids, immunosuppressants, estrogens, bisphosphonates, calcium, vitamin D, and calcitonin, pretransplantation diabetes remained a significant risk factor for fractures (adjusted OR: 1.94; 95% CI: 1.5–2.6). Use of narcotics (OR: 3.0; 95% CI: 2.0–4.4) and antidepressants (OR: 1.9; 95% CI: 1.2–3.1) in the month preceding the index date and use of loop diuretics in the year preceding the index date (OR: 1.4; 95% CI: 1.1–1.9) were also associated with increased risks of fractures. Conclusions: Pretransplant diabetes seemed to significantly increase post-transplant fractures among adults receiving solid organ transplantation. Pretransplant fracture prophylaxis should be considered in these patients.

Objectives New-onsetdiabetes after transplant (NODAT) is a major contributor to cardiovascular disease after transplantation. Kidney transplantation (KT) recipients have low levels of exercise capacity. Resistance training (RT) might be of special benefit in this population because underlying disease and immunosuppressive drugs favour muscle loss and insulin resistance. The aim of this study was to assess the feasibility of implementing an RT program within a population of KT recipients and its impact on the incidence of NODAT and cardiometabolic risk factors. Methods This pilot study was an open-randomized study. We randomized 24 patients with a 1:1 allocation to 2 parallel groups, the exercise group (E) or the control group (C). The E group was submitted to RT 3 times a week for 16 weeks. Anthropometric, body composition, cardiometabolic risk factors, muscle strength, cardiorespiratory fitness and well-being were measured before and after 16 weeks. Results Of the 24 recruited participants, 20 completed the study (10 in the E group and 10 in the C group). No injuries were reported. The intervention was associated with a significant increase in muscle strength (p=0.003). A significant group effect, in favour of the E group, was detected for the well-being score (p=0.03). However, no changes in body composition, cardiometabolic risk factors or cardiorespiratory fitness were noted for either group after the intervention. Conclusions This pilot study suggests that RT appears to be secure and feasible and improves strength and well-being in patients after KT. However, it does not improve cardiometabolic risk factors.

RESUME Foot ulcers are a significant source of morbidity, mortality and diminished quality of life for patients with diabetes. Hyperbaric oxygen therapy (HBOT) has been proposed as a possible treatment. In this technical review, the results of clinical trials on the use of HBOT for diabetic foot ulcers are reviewed. Many of the studies examining the role of HBOT in the treatment of diabetic ulcers have been retrospective, nonrandomized and noncontrolled. In addition, most studies have included small patient populations with heterogeneous classes of ulcers. However, results of these studies suggest that HBOT may accelerate wound healing and reduce amputation in a subset of patients with diabetic ulcers. Most patients with Wagner grade 1 and 2 ulcers will heal with carefully administered conventional care (local wound care and efficacious offloading). Appropriate candidates for HBOT are patients with long-standing nonhealing Wagner grade 3 or higher ulcers with an adequately perfused capillary bed in the wound area (best assessed by the transcutaneous oxygen tension [TcPO 2] response to 100% oxygen challenge).

The quantitative evaluation of circulating PTH peaks revealed by PTH assays after HPLC separation constitutes the best way to study the behavior of PTH molecular forms, but it is also impractical.The objective of the study was to investigate the regulation of circulating PTH molecular forms by calcium through the use of PTH fragments/PTH (1-84) ratios derived from PTH assays with different specificities before and after HPLC separation of circulating PTH.CaCl2 and Na citrate were infused in eight volunteers. PTH was measured in serum and HPLC fractions at different calcium concentrations in PTH assays reacting with regions 1-2 (CA), 12-18 (T), and 65-69 (C) of the PTH structure.From hypo- to hypercalcemia, the C/CA ratio had the highest range (1.92 to 9.75; P0.001), and the C/T ratio had a higher range (1.69 to 6.11; P0.01) than the T/CA ratio (1.15 to 1.86). Human (h) PTH (1-84) represented 32.7 and 4.3% of circulating PTH in hypo- and hypercalcemic HPLC profiles, respectively. These numbers were 5 and 0.9% for amino-terminal (N)-PTH, an amino-terminal form of PTH distinct from hPTH (1-84), 7.3 and 6.8% for non-(1-84) PTH or large C-PTH fragments with a partially preserved N structure, and 54.9 and 88.1% for C-PTH fragments missing a N structure. The HPLC C-PTH fragments to hPTH (1-84) ratio had the most extensive range (1.67 to 20.58). Despite their quantitative differences, all ratios identified identical behavior of PTH fragments relative to PTH (1-84).PTH assay ratios are an adequate tool to investigate the modulation of PTH molecular forms, even if all PTH assays show some undesirable cross-reactivity with certain circulating forms of PTH.

Summary Objective Rare patients with severe primary hyperparathyroidism present with large parathyroid tumours, severe hypercalcaemia, very high PTH levels and osteitis fibrosa cystica. Some of these patients display a large amount of C-PTH fragments in circulation and present with a higher C-PTH/I-PTH ratio than seen in less severe cases of primary hyperparathyroidism. We wanted to determine how PTH levels and circulating PTH high-performance liquid chromatography (HPLC) profiles analysed with PTH assays having different epitopes could be affected by medical and surgical treatment in such patients. Design A 55-year-old man with severe hypercalcaemia (Ca2+: 2·01 mmol/l), very high PTH levels (CA-PTH 82·1 and T-PTH 72 pmol/l) caused by a large parathyroid tumour (7·35 g) and accompanied by significant bone involvement (alkaline phosphatase of 185 UI/l and subperiostal bone resorption of hands) was referred to us. Blood was obtained at various time points during his medical treatment, before and after surgery, to measure parameters of calcium and phosphorus metabolism, and of bone turnover. HPLC separations of circulating PTH molecular forms were performed and analysed with PTH assays having 1–4 (CA), 12–18 (T), 26–32 (E) and 65–84 (C) epitopes. Results Before surgery, serum Ca2+ was nearly normalized with hydratation, intravenous (IV) pamidronate and oral vitamin D administration. Despite a decrease in Ca2+ to 1·31 mmol/l, CA-PTH and T-PTH levels decreased by half in relation to a threefold increase in basal 1,25-dihydroxyvitamin D [1,25(OH)2D] level (94 to 337 pmol/l). After this initial positive response, hypercalcaemia and elevated CA- and T-PTH levels recurred even if 1,25(OH)2D levels remained elevated. The tumour was removed surgically and proved to be poorly differentiated with nuclear atypia and mitosis. After surgery, the Ca2+ level and PTH secretion normalized. The higher CA-PTH level relative to the T-PTH level observed before surgery in this patient was related to the oversecretion of an amino-terminal (N) form of PTH recognized by PTH assays with (1–4) or (26–32) epitopes but not by the T-PTH assay with a (12–18) epitope. This molecular form represented 50% of CA-PTH measured in this patient, but only 7% in less severe cases of primary hyperparathyroidism. It was unaffected by medical therapy and disappeared after surgery. Conclusion The relationship between the overexpression of this N-PTH molecular form and severe primary hyperparathyroidism remains unclear. Further studies will be required in these rare patients to see whether N-PTH is a marker of less well differentiated parathyroid tumours and/or relates to the overproduction of C-PTH fragments in the presence of severe hypercalcaemia.

Background: Non-(1–84) parathyroid hormone (PTH) fragments are large C-terminal fragments of PTH with a partially preserved N-terminal structure. They differ from other C-terminal PTH fragments, which do not have an N-terminal structure and do not react in intact PTH assays. We aimed to identify the minimal N-terminal structure common to all non-(1–84) PTH fragments.Methods: Sera obtained from six healthy individuals and six patients with primary hyperparathyroidism, and six serum pools from dialysis patients with different PTH concentrations were fractionated by HPLC and analyzed by four different PTH assays. Each assay was characterized by saturation analysis of its detection antibody and capacity to react with different PTH fragments. Human PTH(1–84) [hPTH(1–84)] calibrators were normalized to an in-house hPTH(1–84) calibrator.Results: The cyclase-activating PTH (CA-PTH) assay had an early (1, 2,) epitope and reacted only with hPTH(1–84). The other assays had epitopes in region (13–34). Total and intact PTH assays had epitopes proximal to position 18 and reacted equally well with hPTH(1–84) and hPTH(7–84), and the Elecsys PTH assay had an epitope distal to position 19, being saturable by hPTH(18–48) and also reacting with [Tyr34]hPTH(19–84). The HPLC profiles obtained with these assays showed that non-(1–84) PTH fragments did not react in the CA-PTH assay, as expected. The amount of non-(1–84) PTH detected by the other three assays was similar when the assay results were normalized to a common calibrator.Conclusions: The results suggest that the amount of non-(1–84) PTH detected by epitopes proximal or distal to position 19 of the PTH structure is identical, indicating a common minimum structure starting before position 19. This in turn points to a probable high-affinity interaction with the C-PTH receptor, as observed previously with [Tyr34]hPTH(19–84) in various cell lines and in mouse osteocytes with PTH/PTHrP type I receptor ablation.

A population-based cohort study design was used to estimate persistence rate, re-initiation rate after discontinuation, and adherence level among incident users of oral antidiabetics (OADs), and to investigate predictors of non-persistence and non-adherence.Incident OAD users were identified using healthcare databases of residents covered by the public drug insurance plan of the Province of Quebec, Canada. Patients initiated OAD therapy between January 2000 and October 2009 and were aged 45-85 years at cohort entry. Persistence rate, re-initiation after discontinuation, and adherence level were assessed over 2 years. Predictors of non-persistence and non-adherence were analyzed using Cox and logistic regression models, respectively.The cohort included 160,231 incident OAD users at entry. One year after OAD initiation, persistence rate was 51 % and adherence level 67 %. Among those deemed non-persistent, 80.6 % re-initiated OAD therapy within 12 months of discontinuation; a proportion increasing with primary persistence duration. The 1-year persistence rate varied according to OAD classes; being the highest for thiazolidinediones (62 %) and the lowest for alpha-glucosidase inhibitors (30 %). The likelihood for non-persistence was 39-54 % higher when drug copayments were required. Conversely, OAD discontinuation was least likely for patients with schizophrenia [hazard ratio 0.70 (95 % CI 0.67-0.73)], dyslipidemia [0.85 (0.84-0.87)], anticoagulation [0.86 (0.83-0.88)], hypertension [0.87 (0.85-0.88)], and ≥7 medications [0.90 (0.88-0.91)]. Predictors of non-adherence were similar.Non-persistence and non-adherence to OAD therapy were common, although re-initiation rate was high. OAD classes, drug copayments, comorbidities and co-medications may help identifying those who were more likely to benefit from counseling.

Posttransplant weight gain is common after orthotopic liver transplantation. We sought to determine the extent of weight gain at 5 years after transplantation in patients with nonalcoholic fatty liver disease (NAFLD) cirrhosis versus patients with other types of cirrhosis (non-NAFLD). We studied 126 liver transplants performed between 2005 and 2007 at Saint Luc Hospital, University of Montreal. Seventeen of the 126 patients (13.5%) had NAFLD cirrhosis. Ascites volume was difficult to assess, so we used the body mass index (BMI) at 3 months as the reference BMI. All patients gained weight after transplantation, but BMI increased significantly more and earlier among the NAFLD patients [4.8 versus 1.5 kg/m(2) at 1 year (P = 0.001), 5.0 versus 2.3 kg/m(2) at 2 years (P = 0.01), and 5.6 versus 2.6 kg/m(2) at 5 years (P = 0.009)] in comparison with non-NAFLD patients in unadjusted analyses. The greatest BMI increase over time was investigated with univariate and multivariate logistic regression analyses. The BMI increase was divided into tertiles for each period of time observed. The greatest BMI increase over time was defined as the top tertile of BMI increase. After adjustments for potential confounders (ie, total cholesterol, diabetes, and length of hospital stay), NAFLD was no longer associated with a risk of a greater BMI increase [odds ratio (OR) = 3.73 at 1 year (P = 0.11), OR = 2.15 at 2 years (P = 0.34), and OR = 2.87 at 5 years (P = 0.30)]. These findings suggest the need for multidisciplinary, early, and close weight monitoring for all patients. All patients could benefit from pretransplant counseling regarding weight gain and its consequences.

The aim of the study was to examine the association between total adiponectin and high molecular weight (HMW) adiponectin levels with cardio-metabolic risk factors in a population of sedentary, overweight, and obese postmenopausal women. Cross-sectional study was carried out on 55 nondiabetic sedentary overweight and obese postmenopausal women aged between 50 and 70 years. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp technique. Body composition and visceral fat were measured using dual X-ray absorptiometry and computed tomography, respectively. Other cardio-metabolic risk factors included: plasma lipids, hsC-reactive protein, energy expenditure (doubly labeled water), peak oxygen consumption, muscle strength (using weight training equipment) as well as total and HMW adiponectin. Correlations of total and HMW adiponectin with various cardio-metabolic risk factors were comparable. In addition, regression analysis results showed similar independent predictors of total and HMW adiponectin. Finally, the receiver operator characteristic (ROC) curves for total and HMW adiponectin to predict insulin sensitivity showed no difference between the areas under curve (AUC) (AUC total adiponectin=0.80 [95% CI: 0.66-0.95] versus AUC HMW adiponectin=0.76 [95% CI: 0.60-0.91], p=0.36). The present study indicates that HMW adiponectin does not seem to provide additional information than total adiponectin in relation to cardio-metabolic risk factors in overweight/obese postmenopausal women.

With improvements in patient and graft survival, increasing attention has been placed on complications that contribute to long-term patient morbidity and mortality. New-onset diabetes after transplantation (NODAT) is a common complication of solid-organ transplantation, and is a strong predictor of graft failure and cardiovascular mortality in the transplant population. Risk factors for NODAT in transplant recipients are similar to those in non-transplant patients, but transplant-specific risk factors such as hepatitis C (HCV) infection, corticosteroids and calcineurin inhibitors play a dominant role in NODAT pathogenesis. Management of NODAT is similar to type 2 diabetes management in the general population. However, adjusting the immunosuppressant regimen to improve glucose tolerance must be weighed against the risk of allograft rejection. Lifestyle modification is currently the strategy with the least risk and the most benefit.

Cystic fibrosis-related diabetes (CFRD) prevalence has increased dramatically with the improved life expectancy of patients with cystic fibrosis (CF). Glycated haemoglobin (HbA(1c)) is an important tool for monitoring blood glucose control but, unlike in type 1 and type 2 diabetes, a correlation between HbA(1c), fructosamine and mean plasma glucose has not been clearly established in CF. This study aimed to examine the relationship between mean plasma glucose and HbA(1c) or fructosamine in stable patients with CFRD.Fifteen type 1 diabetes and 13 CFRD patients (HbA(1c)9.0%; no anaemia), matched for age and body mass index (BMI), provided 72 capillary blood glucose profiles taken 3days/month for three months. At the end of this time, HbA(1c) and fructosamine were measured. Mean plasma glucose was estimated using the Diabetes Control and Complications Trial (DCCT) conversion formula, and linear regressions carried out to establish its relationship with HbA(1c) and fructosamine.In type 1 diabetes patients, mean plasma glucose correlated significantly with HbA(1c) (r=0.68; P=0.005). In CFRD patients, no correlation was found between mean plasma glucose and HbA(1c) (r=0.24; P=0.460). Also, no association was found between mean plasma glucose, representing the month before blood sampling, and fructosamine in either group.Unlike in type 1 diabetes, HbA(1c) did not correlate with mean plasma glucose in CFRD subjects. Thus, having a normal HbA(1c) may not be sufficient to indicate a low risk of diabetes complications in CFRD. Further studies are required to explain such a discrepancy.