Aims/hypothesis
Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a ...major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown.
Methods
We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10–31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation.
Results
The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th–75th percentile: 25.0–32.7) kg/m
2
; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin–angiotensin–aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA
1c
, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 1.10, 1.47). On admission, dyspnoea (OR 2.10 1.31, 3.35), as well as lymphocyte count (OR 0.67 0.50, 0.88), C-reactive protein (OR 1.93 1.43, 2.59) and AST (OR 2.23 1.70, 2.93) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 1.74, 3.53), treated obstructive sleep apnoea (OR 2.80 1.46, 5.38), and microvascular (OR 2.14 1.16, 3.94) and macrovascular complications (OR 2.54 1.44, 4.50) were independently associated with the risk of death on day 7.
Conclusions/interpretations
In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days.
Trial registration
clinicaltrials.gov
NCT04324736.
Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. ...We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival.
Multicenter retrospective study by members of the French Society of Endocrinology.
Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (
= 23) or lactotroph (
= 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment.
The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (
= 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success.
Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.
Closed-loop insulin delivery systems are expected to become a standard treatment for patients with type 1 diabetes. We aimed to assess whether the Diabeloop Generation 1 (DBLG1) hybrid closed-loop ...artificial pancreas system improved glucose control compared with sensor-assisted pump therapy.
In this multicentre, open-label, randomised, crossover trial, we recruited adults (aged ≥18 years) with at least a 2 year history of type 1 diabetes, who had been treated with external insulin pump therapy for at least 6 months, had glycated haemoglobin (HbA
) of 10% or less (86 mmol/mol), and preserved hypoglycaemia awareness. After a 2-week run-in period, patients were randomly assigned (1:1) with a web-based system in randomly permuted blocks of two, to receive insulin via the hybrid closed-loop system (DBLG1; using a machine-learning-based algorithm) or sensor-assisted pump therapy over 12 weeks of free living, followed by an 8-week washout period and then the other intervention for 12 weeks. The primary outcome was the proportion of time that the sensor glucose concentration was within the target range (3·9-10·0 mmol/L) during the 12 week study period. Efficacy analyses were done in the modified intention-to-treat population, which included all randomly assigned patients who completed both 12 week treatment periods. Safety analyses were done in all patients who were exposed to either of the two treatments at least once during the study. This trial is registered with ClinicalTrials.gov, number NCT02987556.
Between March 3, 2017, and June 19, 2017, 71 patients were screened, and 68 eligible patients were randomly assigned to the DBLG1 group (n=33) or the sensor-assisted pump therapy group (n=35), of whom five dropped out in the washout period (n=1 pregnancy; n=4 withdrew consent). 63 patients completed both 12 week treatment periods and were included in the modified intention-to-treat analysis. The proportion of time that the glucose concentration was within the target range was significantly higher in the DBLG1 group (68·5% SD 9·4 than the sensor-assisted pump group (59·4% 10·2; mean difference 9·2% 95% CI 6·4 to 11·9; p<0·0001). Five severe hypoglycaemic episodes occurred in the DBLG1 group and three episodes occurred in the sensor-assisted pump therapy group, which were associated with hardware malfunctions or human error.
The DBLG1 system improves glucose control compared with sensor-assisted insulin pumps. This finding supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes.
French Innovation Fund, Diabeloop.
Background The functionality of cryopreserved parathyroid autotransplantation (CPAT) has been evaluated in few studies, mostly conducted by experienced single-institution centers that have reported ...different success rates ranging from 17% to 83%. In France, CPAT are rare and their functionality has never been evaluated. Moreover, French tissue banks are facing an accumulation of ungrafted samples. The aim of our work was to evaluate the implantation rate of cryopreserved parathyroid samples and the functionality of CPAT in a multicenter study. Methods Data from 9 French tissue banks were analyzed. CPAT functionality was defined as fully functional (normal parathyroid hormone PTH and calcium levels without treatment), partially functional (normal PTH levels but need for treatment to maintain normocalcemia), and nonfunctional (low PTH levels and need for treatment). For dialyzed patients, CPAT was considered nonfunctional if the PTH level in the nongrafted arm was less than 20 pg/mL, partially functional if the PTH level was between 20 and 50 pg/mL, and fully functional if the PTH level was between 50 and 300 pg/mL. Results The 9 centers had cryopreserved 1376 samples of parathyroid tissue and only 22 (1.6%) had been autografted in 20 patients (65% renal hyperparathyroidism, 20% multiple endocrine neoplasia type 1, 15% “other”) by 12 different surgical teams. The median duration of storage was 11.1 months (range, 0.4–28.5). Only 2 autografts (10%) were fully functional, 2 (10%) were partially functional, and 17 (80%) were nonfunctional at 26 months median follow-up. Conclusion The reimplantation rate is low, and the functionality of CPAT is less than those published by experienced centers. Logistical and technical problems occurring in less experienced centers are probably the main reasons for nonfunctioning implants. Considering the results of this study, we suggest that cryopreservation of parathyroid glands should be abandoned when not performed in very large experimented centers, that CPAT should be used only for patients with hyperplasic parathyroid tissue, and that tissue samples should be systematically destroyed when patients do not have hypoparathyroidism or after 1 year of storage.
Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection ...mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.
Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less ...clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins.
Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61).
Maximal cortisol secretion rate (CSRmax) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24–0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33–0.46), and CSRmax was negatively correlated with CP score (r = −0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min−1) compared with that in the CP ≤8 group (0.21 ± 0.21 min−1), and free cortisol elimination rates were negatively correlated with CP score (r = −0.23, p = 0.01). A significant correlation between CSRmax and free cortisol elimination rate (r = 0.88, p <0.001) was observed.
CSRmax and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSRmax estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis.
We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis.
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•Free cortisol appearance and elimination rates were obtained by computer-assisted numerical analysis.•Maximal cortisol secretion rates, a measure of adrenocortical function, were inversely related to severity of cirrhosis.•Variation in concentrations of cortisol binding proteins bias measures of adrenocortical function that rely on total cortisol.•Chronically reduced rate of free cortisol elimination in patients with cirrhosis may contribute to the pathophysiology of subnormal adrenocortical function.•Evidence of subnormal adrenocortical function supports the hepatoadrenal syndrome hypothesis.
Objective: Because over 90% of serum cortisol is bound to albumin and corticosteroid‐binding globulin (CBG), changes in these proteins can affect measures of serum total cortisol levels in cirrhotics ...without altering serum‐free and salivary cortisol concentrations.
Methods: We assessed basal (T0) and post‐synacthen (T60) serum total cortisol, serum‐free and salivary cortisol in 125 consecutive cirrhotics (95 non‐septic and 30 septic patients with a Child>8).
Results: Serum total cortisol levels significantly decreased from the Child A–C non‐septic group, as did albumin and CBG levels, with a non‐significant rise in serum‐free cortisol concentrations. Non‐septic patients with low albumin (≤25 g/L) or CBG levels (≤35 mg/L) had lower T0 serum total cortisol levels than patients with near‐normal albumin (303.4 vs. 382.6 nmol/L; P=0.0035) or with normal CBG levels (289.9 vs. 441.4 nmol/L; P<0.0001), respectively, despite similar serum‐free cortisol or salivary cortisol concentrations. Subnormal T60 serum total cortisol concentrations (<510.4 nmol/L) were measured in 7.2% of all patients (Child C: 14.5% vs. Child A and B: 0%; P=0.0013) but no patients exhibited symptoms suggesting adrenal insufficiency. Patients with or without subnormal T60 total cortisol had similar T0 salivary cortisol and serum‐free cortisol concentrations. A trend was observed towards high serum‐free cortisol concentrations and mortality in multivariate analysis.
Conclusions: Serum total cortisol levels overestimated the prevalence of adrenal dysfunction in cirrhotics with end‐stage liver disease. Since serum‐free cortisol cannot be measured routinely, salivary cortisol testing could represent a useful approach but needs to be standardized.
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