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OBJECTIVE: We used machine learning to develop and validate a multivariable algorithm allowing the accurate and early prediction of postoperative hypocalcemia risk. SUMMARY BACKGROUND: Post-operative hypocalcemia is frequent after total thyroidectomy. An early and accurate individualized prediction of the risk of hypocalcemia could guide the selective prescription of calcium supplementation only to patients most likely to present with hypocalcemia after total thyroidectomy. METHODS: This retrospective study enrolled all patients undergoing total thyroidectomy in a single referral center between November 2019 and march 2022 (derivation cohort) and april 2022 and September 2022 (validation cohort) . The primary study outcome was post-operative hypocalcemia (serum calcium under 80 mg/L). Exposures were multiple clinical and biological variables prospectively collected and analyzed with various machine learning methods, to develop and validate a multi variable prediction algorithm. RESULTS: Among 610 / 118 participants in the derivation / validation cohorts, 100 (16.4%) / 26 (22%) presented post-operative hypocalcemia. The most accurate prediction algorithm was obtained with random forest, and combined intraoperative parathyroid hormone measurements with three clinical variables (age, sex and body mass index), to calculate a postoperative hypocalcemia risk for each patient. After multiple cross validation, the area under the receiver operative characteristic curve was 0.902 (0.829-0.970) in the derivation cohort, and 0.928 (95% CI : 0.86; 0.97) in the validation cohort. Postoperative hypocalcemia risk values of 7% (low threshold) and 20% ( high threshold) had respectively a sensitivity of 92% and a negative likelihood ratio of 0.11, and a specificity of 90% and a positive of 7.6 for the prediction of postoperative hypocalcemia. CONCLUSION: Using machine learning, we developed and validated a simple multivariable model which allowed the accurate prediction of postoperative hypocalcemia. The resulting algorithm could be used at the point of care to guide clinical management after total thyroidectomy.
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AIMS/HYPOTHESIS: Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process. METHODS: CD4+ T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1ß, TNF-α, IFN-γ) for 24-48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry. RESULTS: CNR1 expression was upregulated in circulating CD4+ T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function. CONCLUSIONS/INTERPRETATION: These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor. DATA AVAILABILITY: Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161 .
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BACKGROUND & AIMS: The value of non-invasive tests for monitoring the resolution of significant liver fibrosis after treatment is poorly investigated. We compared the performances of six non-invasive tests to predict the resolution of significant fibrosis after bariatric surgery. METHODS: Participants were individuals with obesity submitted to needle liver biopsy at the time of bariatric surgery, and 12 and/or 60 months after surgery. We calculated the fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), AST to platelet ratio index (APRI), Hepatic fibrosis score (HFS), Fibrotic NASH index (FNI), and Liver risk score (LRS) at each time point, and compared their performances for predicting significant fibrosis (F ≥ 2) and its resolution following surgery. RESULTS: At baseline, 2436 patients had liver biopsy, including 261 (10.7 %) with significant fibrosis. Overall, 672 patients had pre- and post-operative biopsies (564 at M12 and 328 at M60). The fibrosis stage decreased at M12 and M60 (p < 0.001 vs M0). Resolution of significant fibrosis occurred in 58/121 (47.9 %) at M12 and 32/50 (64 %) at M60. The mean value of all tests decreased after surgery, except for FIB-4. Performances for predicting fibrosis resolution was higher at M60 than at M12 for all tests, and maximal at M60 for FNI and LRS: area under the curve 0.843 (95%CI 0.71-0.95) and 0.92 (95%CI 0.84-1.00); positive likelihood ratio 3.75 (95 % CI 1.33-10.59) and 4.58 (95 % CI 1.65-12.70), respectively. CONCLUSIONS: Results showed the value and limits of non-invasive tests for monitoring the evolution of liver fibrosis after an intervention. Following bariatric surgery, the best performances to predict the resolution of significant fibrosis were observed at M60 with tests combining liver and metabolic traits, namely FNI and LRS.
Subject(s)
Bariatric Surgery , Non-alcoholic Fatty Liver Disease , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/surgery , Liver Cirrhosis/pathology , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/pathology , FibrosisABSTRACT
OBJECTIVE: Steatotic liver disease (SLD) is frequent in individuals with obesity. In this study, type 2 diabetes (T2D), sex, and menopausal status were combined to refine the stratification of obesity regarding the risk of advanced SLD and gain further insight into disease physiopathology. METHODS: This study enrolled 1446 participants with obesity from the ABOS cohort (NCT01129297), who underwent extensive phenotyping, including liver histology and transcriptome profiling. Hierarchical clustering was applied to classify participants. The prevalence of metabolic disorders associated with steatohepatitis (NASH) and liver fibrosis (F ≥ 2) was determined within each identified subgroup and aligned to clinical and biological characteristics. RESULTS: The prevalence of NASH and F ≥ 2 was, respectively, 9.5% (N = 138/1446) and 11.7% (N = 159/1365) in the overall population, 20.3% (N = 107/726) and 21.1% (N = 106/502) in T2D patients, and 3.4% (N = 31/920) and 6.1% (N = 53/863) in non-T2D patients. NASH and F ≥ 2 prevalence was 15.4% (33/215) and 15.5% (32/206) among premenopausal women with T2D vs. 29.5% (33/112) and 30.3% (N = 36/119) in postmenopausal women with T2D (p < 0.01); and 21.0% (21/100) / 27.0% (24/89) in men with T2D ≥ age 50 years and 17.9% (17/95) / 18.5% (17/92) in men with T2D < age 50 years (NS). The distinct contribution of menopause was confirmed by the interaction between sex and age with respect to NASH among T2D patients (p = 0.048). Finally, several NASH-associated biological traits (lower platelet count; higher serum uric acid; gamma-glutamyl transferase; aspartate aminotransferase) and liver expressed genes AKR1B10 and CCL20 were significantly associated with menopause in women with T2D but not with age in men with T2D. CONCLUSIONS: This study unveiled a remarkably high prevalence of advanced SLD after menopause in women with T2D, associated with a dysfunctional biological liver profile.
Subject(s)
Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Male , Humans , Female , Middle Aged , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/pathology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/metabolism , Retrospective Studies , Uric Acid/metabolism , Liver Cirrhosis/epidemiology , Liver Cirrhosis/complications , Liver Cirrhosis/pathology , Liver/metabolism , Obesity/complications , Obesity/epidemiology , Obesity/metabolism , MenopauseABSTRACT
Severe or repeated hypoglycemia events may favor memory complaints in type 1 diabetes (T1D). Pancreatic islet transplantation (IT) is an alternative option to exogenous insulin therapy in case of labile T1D, implying a maintenance immunosuppression regimen based on sirolimus or mycophenolate, associated with tacrolimus, that may also have neurological toxicity. The objective of this study was to compare a cognitive rating scale Mini-Mental State Examination (MMSE) between T1D patients with or without IT and to identify parameters influencing MMSE. Methods: This retrospective cross-sectional study compared MMSE and cognitive function tests between islet-transplanted T1D patients and nontransplanted T1D controls who were transplant candidates. Patients were excluded if they refused. Results: Forty-three T1D patients were included: 9 T1D patients before IT and 34 islet-transplanted patients (14 treated with mycophenolate and 20 treated with sirolimus). Neither MMSE score (P = 0.70) nor higher cognitive function differed between islet versus non-islet-transplanted patients, whatever the type of immunosuppression. In the whole population (N = 43), MMSE score was negatively correlated to glycated hemoglobin (r = -0.30; P = 0.048) and the time spent in hypoglycemia on the continuous glucose monitoring (r = -0.32; P = 0.041). MMSE score was not correlated to fasting C-peptide level, time spent in hyperglycemia, average blood glucose, time under immunosuppression, duration of diabetes, or beta-score (success score of IT). Conclusions: This first study evaluating cognitive disorders in islet-transplanted T1D patients argues for the importance of glucose balance on cognitive function rather than of immunosuppressive treatment, with a favorable effect of glucose balance improvement on MMSE score after IT.
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BACKGROUND: Allogeneic islet transplantation is a validated therapy in type 1 diabetes; however, there is decline of transplanted islet graft function over time and the mechanisms underlying this decline are unclear. We evaluated the distinct association between primary graft function (PGF) and 5-year islet transplantation outcomes. METHODS: In this retrospective, multicentre, observational cohort study, we enrolled all patients from the Collaborative Islet Transplant Registry who received islet transplantation alone (ITA recipients) or islet-after-kidney transplantation (IAK recipients) between Jan 19, 1999, and July 17, 2020, with a calculable PGF (exposure of interest), measured 28 days after last islet infusion with a validated composite index of islet graft function (BETA-2 score). The primary outcome was cumulative incidence of unsuccessful islet transplantation, defined as an HbA1c of 7·0% (53 mmol/mol) or higher, or severe hypoglycaemia (ie, requiring third-party intervention to correct), or a fasting C-peptide concentration of less than 0·2 ng/mL. Secondary outcomes were graft exhaustion (fasting C-peptide <0·3 ng/mL); inadequate glucose control (HbA1c ≥7·0% [53 mmol/mol] or severe hypoglycaemia); and requirement for exogenous insulin therapy (≥14 consecutive days). Associations between PGF and islet transplantation outcomes were explored with a competing risk analysis adjusted for all covariates suspected or known to affect outcomes. A predictive model based on PGF was built and internally validated by using bootstraps resampling method. FINDINGS: In 39 centres worldwide, we enrolled 1210 patients with a calculable PGF (of those without missing data, mean age 47 years [SD 10], 712 [59·5%] were female, and 865 (97·9%) were White), who received a median of 10·8 thousand islet-equivalents per kg of bodyweight (IQR 7·4-13·5). 986 (82·4%) were ITA recipients and 211 (17·6%) were IAK recipients. Of 1210 patients, 452 (37·4%) received a single islet infusion and 758 (62·6%) received multiple islet infusions. Mean PGF was 14·3 (SD 8·8). The 5-year cumulative incidence of unsuccessful islet transplantation was 70·7% (95% CI 67·2-73·9), and was inversely and linearly related to PGF, with an adjusted subhazard ratio (sHR) of 0·77 (95% CI 0·72-0·82) per 5-unit increase of BETA-2 score (p<0·0001). Secondary endpoints were similarly related to PGF. The model-adjusted median C-statistic values of PGF for predicting 5-year cumulative incidences of unsuccessful islet transplantation, graft exhaustion, inadequate glucose control, and exogenous insulin therapy were 0·70 (range 0·69-0·71), 0·76 (0·74-0·77), 0·65 (0·64-0·66), and 0·72 (0·71-0·73), respectively. INTERPRETATION: This global multicentre study reports a linear and independent association between PGF and 5-year clinical outcomes of islet transplantation. The main study limitations are its retrospective design and the absence of analysis of complications. FUNDING: Public Health Service Research, National Institutes of Health, Juvenile Diabetes Research Foundation International, Agence National de la Recherche, Fondation de l'Avenir, and Fonds de Dotation Line Renaud-Loulou Gasté.
Subject(s)
Diabetes Mellitus, Type 1 , Hypoglycemia , Islets of Langerhans Transplantation , Humans , Female , Middle Aged , Male , Diabetes Mellitus, Type 1/surgery , Diabetes Mellitus, Type 1/complications , Islets of Langerhans Transplantation/methods , Blood Glucose , Retrospective Studies , C-Peptide/therapeutic use , Glycated Hemoglobin , Treatment Outcome , Transplantation, Homologous , Insulin/therapeutic use , Hypoglycemia/complications , RegistriesABSTRACT
In islet transplantation (ITx), primary graft function (PGF) or beta cell function measured early after last infusion is closely associated with long term clinical outcomes. We investigated the association between PGF and 5 year insulin independence rate in ITx and pancreas transplantation (PTx) recipients. This retrospective multicenter study included type 1 diabetes patients who underwent ITx in Lille and PTx in Nantes from 2000 to 2022. PGF was assessed using the validated Beta2-score and compared to normoglycemic control subjects. Subsequently, the 5 year insulin independence rates, as predicted by a validated PGF-based model, were compared to the actual rates observed in ITx and PTx patients. The study enrolled 39 ITx (23 ITA, 16 IAK), 209 PTx recipients (23 PTA, 14 PAK, 172 SPK), and 56 normoglycemic controls. Mean[SD] PGF was lower after ITx (ITA 22.3[5.2], IAK 24.8[6.4], than after PTx (PTA 38.9[15.3], PAK 36.8[9.0], SPK 38.7[10.5]), and lower than mean beta-cell function measured in normoglycemic control: 36.6[4.3]. The insulin independence rates observed at 5 years after PTA and PAK aligned with PGF predictions, and was higher after SPK. Our results indicate a similar relation between PGF and 5 year insulin independence in ITx and solitary PTx, shedding new light on long-term transplantation outcomes.
Subject(s)
Diabetes Mellitus, Type 1 , Islets of Langerhans Transplantation , Pancreas Transplantation , Humans , Diabetes Mellitus, Type 1/surgery , Retrospective Studies , Cohort Studies , Insulin/therapeutic use , Pancreas Transplantation/methods , Pancreas , Graft SurvivalABSTRACT
Islet transplantation is a unique paradigm in organ transplantation, since multiple donors are required to achieve complete insulin-independence. Preformed or de novo Donor Specific Antibodies (DSA) may target one or several donor islets, which adds complexity to the analysis of their impact. Adult patients with type 1 diabetes transplanted with pancreatic islets between 2005 and 2018 were included in a single-center observational study. Thirty-two recipients with available sera tested by solid-phase assays for anti-HLA antibodies during their whole follow-up were analyzed. Twenty-five recipients were islet-transplantation-alone recipients, and 7 islet-after-kidney recipients. Seven recipients presented with DSA at any time during follow-up (two with preformed DSA only, one with preformed and de novo DSA, 4 with de novo DSA only). Only islet-transplantation-alone recipients presented with de novo DSA. Three clinical trajectories were identified according to: 1/the presence of preformed DSA, 2/early de novo DSA or 3/late de novo DSA. Only late de novo DSA were associated with unfavorable outcomes, depicted by a decrease of the ß-score. Islet transplantation with preformed DSA, even with high MFI values, is associated with favorable outcomes in our experience. On the contrary, de novo DSA, and especially late de novo DSA, may be associated with allograft loss.
Subject(s)
Islets of Langerhans Transplantation , Isoantibodies , Adult , Graft Rejection , Graft Survival , HLA Antigens , Humans , Retrospective Studies , Tissue DonorsABSTRACT
BACKGROUND: A novel data-driven classification of type 2 diabetes has been proposed to personalise anti-diabetic treatment according to phenotype. One subgroup, severe insulin-resistant diabetes (SIRD), is characterised by mild hyperglycaemia but marked hyperinsulinaemia, and presents an increased risk of diabetic nephropathy. We hypothesised that patients with SIRD could particularly benefit from metabolic surgery. METHODS: We retrospectively related the newly defined clusters with the response to metabolic surgery in participants with type 2 diabetes from independent cohorts in France (the Atlas Biologique de l'Obésite Sévère [ABOS] cohort, n=368; participants underwent Roux-en-Y gastric bypass or sleeve gastrectomy between Jan 1, 2006, and Dec 12, 2017) and Brazil (the metabolic surgery cohort of the German Hospital of San Paulo, n=121; participants underwent Roux-en-Y gastric bypass between April 1, 2008, and March 20, 2016). The study outcomes were type 2 diabetes remission and improvement of estimated glomerular filtration rate (eGFR). FINDINGS: At baseline, 34 (9%) of 368 patients, 314 (85%) of 368 patients, and 17 (5%) of 368 patients were classified as having SIRD, mild obesity-related diabetes (MOD), and severe insulin deficient diabetes (SIDD) in the ABOS cohort, respectively, and in the São Paulo cohort, ten (8%) of 121 patients, 83 (69%) of 121 patients, and 25 (21%) of 121 patients were classified as having SIRD, MOD, and SIDD, respectively. At 1 year, type 2 diabetes remission was reported in 26 (81%) of 32 and nine (90%) of ten patients with SIRD, 167 (55%) of 306 and 42 (51%) of 83 patients with MOD, and two (13%) of 16 and nine (36%) of 25 patients with SIDD, in the ABOS and São Paulo cohorts, respectively. The mean eGFR was lower in patients with SIRD at baseline and increased postoperatively in these patients in both cohorts. In multivariable analysis, SIRD was associated with more frequent type 2 diabetes remission (odds ratio 4·3, 95% CI 1·8-11·2; p=0·0015), and an increase in eGFR (mean effect size 13·1 ml/min per 1·73 m2, 95% CI 3·6-22·7; p=0·0070). INTERPRETATION: Patients in the SIRD subgroup had better outcomes after metabolic surgery, both in terms of type 2 diabetes remission and renal function, with no additional surgical risk. Data-driven classification might help to refine the indications for metabolic surgery. FUNDING: Agence Nationale de la Recherche, Investissement d'Avenir, Innovative Medecines Initiative, Fondation CÅur et Artères, and Fondation Francophone pour la Recherche sur le Diabète.
Subject(s)
Bariatric Surgery , Diabetes Mellitus, Type 2 , Gastric Bypass , Insulin Resistance , Obesity, Morbid , Brazil , Cohort Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/surgery , Gastric Bypass/adverse effects , Humans , Insulin , Obesity, Morbid/complications , Obesity, Morbid/epidemiology , Obesity, Morbid/surgery , Retrospective Studies , Treatment OutcomeABSTRACT
INTRODUCTION: In animal research, obtaining efficient and constant pain control is regulatory but challenging. The gold standard pain management consists of opioid analgesic administration, such as buprenorphine or fentanyl extended-release patches. However, as in all drugs with a short half-life time, repeated buprenorphine administrations are needed, leading to multiple injections that affect the research protocol. On the other hand, fentanyl patch efficacy is discussed in some species. These elements highlight the need of an optimal formulation of analgesic drugs for laboratory animals. In this study, we investigated how Recuvyra®, a fentanyl transdermal solution (FTS), validated in dog perioperative pain management, could provide sustained analgesia after a single topical administration in pigs in a surgical context. METHODS: A total of 11 minipigs were used in this study. As a preliminary experiment, two different doses were tested as a single application on five pigs: two pigs at full dose (2.6 mg/kg) and three pigs at half dose (1.3 mg/kg). Plasma fentanyl dosages were performed during 4 consecutive days, using liquid chromatography with tandem mass spectrometry detection. The efficacy of FTS was then evaluated in a perioperative period. Six minipigs benefited from a surgical intervention comprising a laparotomy. The FTS was blotted on the skin in a single application 20 min before the surgical incision and plasma fentanyl dosages, clinical examination (body weight, food intake, heart rate, and body temperature) and pain assessment were performed for 7 consecutive days. RESULTS: During the preliminary experiment, all fentanyl concentrations reached the minimum effective concentration (MEC) extrapolated in pigs (fentanylemia ≥0.2 ng/mL) throughout the 4 days. The half dose was chosen for the next step of the study. After the surgical intervention, all plasma fentanyl concentrations remained above the MEC up to 7 days post administration. Pig clinical examinations and pain evaluations showed efficient and constant pain control at the half dose, and few adverse events were observed. DISCUSSION AND CONCLUSION: This study confirms the pharmacological and clinical efficacy of FTS at 1.3 mg/kg in pigs throughout at least 7 postoperative days following laparotomy. The clinical analgesic effect of FTS appears more efficient and well-tolerated than the one observed with repeated injections of buprenorphine. This analgesic drug formulation could be universally used in animal research to provide optimal perioperative pain management and long-term analgesia.
Subject(s)
Analgesia , Analgesics, Opioid , Buprenorphine , Fentanyl , Administration, Cutaneous , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/therapeutic use , Animals , Buprenorphine/therapeutic use , Dogs , Fentanyl/administration & dosage , Fentanyl/therapeutic use , Pain , Pain Management , Swine , Swine, MiniatureABSTRACT
CONTEXT: The Igls criteria were developed to provide a consensus definition for outcomes of ß-cell replacement therapy in the treatment of diabetes during a January 2017 workshop sponsored by the International Pancreas & Islet Transplant Association (IPITA) and the European Pancreas & Islet Transplant Association. In July 2019, a symposium at the 17th IPITA World Congress was held to examine the Igls criteria after 2 years in clinical practice, including validation against continuous glucose monitoring (CGM)-derived glucose targets, and to propose future refinements that would allow for comparison of outcomes with artificial pancreas system approaches. EVIDENCE ACQUISITION: Utilization of the criteria in various clinical and research settings was illustrated by population as well as individual outcome data of 4 islet and/or pancreas transplant centers. Validation against CGM metrics was conducted in 55 islet transplant recipients followed-up to 10 years from a fifth center. EVIDENCE SYNTHESIS: The Igls criteria provided meaningful clinical assessment on an individual patient and treatment group level, allowing for comparison both within and between different ß-cell replacement modalities. Important limitations include the need to account for changes in insulin requirements and C-peptide levels relative to baseline. In islet transplant recipients, CGM glucose time in range improved with each category of increasing ß-cell graft function. CONCLUSIONS: Future Igls 2.0 criteria should consider absolute rather than relative levels of insulin use and C-peptide as qualifiers with treatment success based on glucose assessment using CGM metrics on par with assessment of glycated hemoglobin and severe hypoglycemia events.
Subject(s)
Blood Glucose Self-Monitoring/standards , Diabetes Mellitus/therapy , Insulin-Secreting Cells/transplantation , Islets of Langerhans Transplantation/standards , Outcome Assessment, Health Care/standards , Blood Glucose/analysis , Glycated Hemoglobin/analysis , Humans , Treatment OutcomeABSTRACT
OBJECTIVE: Previous studies have unveiled a relationship between the severity of coronavirus disease 2019 (COVID-19) pneumonia and obesity. The aims of this multicenter retrospective cohort study were to disentangle the association of BMI and associated metabolic risk factors (diabetes, hypertension, hyperlipidemia, and current smoking status) in critically ill patients with COVID-19. METHODS: Patients admitted to intensive care units for COVID-19 in 21 centers (in Europe, Israel, and the United States) were enrolled in this study between February 19, 2020, and May 19, 2020. Primary and secondary outcomes were the need for invasive mechanical ventilation (IMV) and 28-day mortality, respectively. RESULTS: A total of 1,461 patients were enrolled; the median (interquartile range) age was 64 years (40.9-72.0); 73.2% of patients were male; the median BMI was 28.1 kg/m2 (25.4-32.3); a total of 1,080 patients (73.9%) required IMV; and the 28-day mortality estimate was 36.1% (95% CI: 33.0-39.5). An adjusted mixed logistic regression model showed a significant linear relationship between BMI and IMV: odds ratio = 1.27 (95% CI: 1.12-1.45) per 5 kg/m2 . An adjusted Cox proportional hazards regression model showed a significant association between BMI and mortality, which was increased only in obesity class III (≥40; hazard ratio = 1.68 [95% CI: 1.06-2.64]). CONCLUSIONS: In critically ill COVID-19 patients, a linear association between BMI and the need for IMV, independent of other metabolic risk factors, and a nonlinear association between BMI and mortality risk were observed.
Subject(s)
Body Mass Index , COVID-19 , Pneumonia , COVID-19/mortality , Critical Illness , Europe , Female , Humans , Israel , Male , Middle Aged , Pneumonia/mortality , Retrospective Studies , United StatesABSTRACT
One century after the discovery of insulin, the French Health regulations have just authorized the reimbursement for islet transplantation. Intraportal islet allotransplantation from a pancreatic donor is indicated in patients with type 1 diabetes (T1D) complicated with lability or hypoglycemia unawareness, or in case of a functioning kidney graft; islet auto-transplantation may be indicated after pancreatic surgery.Compared with insulin even administered in closed-loop pumps, the specificity of islet allotransplantation is the restoration of C-peptide secretion. Long-term insulin-independence is observed when the engrafted islet mass is sufficient, at the cost of immunosuppression. Fewer low-glucose events and less glucose variability, are observed even with minimal functional islet graft, after islet transplantation as at onset of T1D, when a residual C-peptide secretion is maintained, an objective currently approached with less aggressive immuno-modulating therapies than in the past. Therefore, restoration or preservation of endogen insulin secretion is an important goal, allowing to maintain a long-term glucose balance with more than 70% of time in range 3.9-10mmol/L and less than 3% of time <3.9mmol/L, thus reducing the occurrence of diabetic complications. In the clinical setting, - the preservation of C-peptide at early stage of T1D, - the use of technological ressources (multi-injections, sensors, insulin pump, closed-loop systems) at later stages, - and islet transplantation when hypoglycemia awareness becomes impaired are complementary for a personalized care all along the life of T1D patients.
Subject(s)
Diabetes Mellitus, Type 1/therapy , Insulin , Islets of Langerhans Transplantation , C-Peptide , Diabetes Mellitus, Type 1/history , France , Glycemic Control , History, 20th Century , History, 21st Century , Humans , Insulin/administration & dosage , Insulin/history , Insulin/therapeutic useABSTRACT
OBJECTIVE: The COVID-19 pandemic is rapidly spreading worldwide, notably in Europe and North America where obesity is highly prevalent. The relation between obesity and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has not been fully documented. METHODS: This retrospective cohort study analyzed the relationship between clinical characteristics, including BMI, and the requirement for invasive mechanical ventilation (IMV) in 124 consecutive patients admitted in intensive care for SARS-CoV-2 in a single French center. RESULTS: Obesity (BMI > 30) and severe obesity (BMI > 35) were present in 47.6% and 28.2% of cases, respectively. Overall, 85 patients (68.6%) required IMV. The proportion of patients who required IMV increased with BMI categories (P < 0.01, χ2 test for trend), and it was greatest in patients with BMI > 35 (85.7%). In multivariate logistic regression, the need for IMV was significantly associated with male sex (P < 0.05) and BMI (P < 0.05), independent of age, diabetes, and hypertension. The odds ratio for IMV in patients with BMI > 35 versus patients with BMI < 25 was 7.36 (1.63-33.14; P = 0.02). CONCLUSIONS: The present study showed a high frequency of obesity among patients admitted in intensive care for SARS-CoV-2. Disease severity increased with BMI. Obesity is a risk factor for SARS-CoV-2 severity, requiring increased attention to preventive measures in susceptible individuals.
Subject(s)
Betacoronavirus , Coronavirus Infections/therapy , Hospitalization/statistics & numerical data , Obesity/epidemiology , Pneumonia, Viral/therapy , Respiration, Artificial/statistics & numerical data , Adult , Aged , Body Mass Index , COVID-19 , Coronavirus Infections/complications , Female , France/epidemiology , Humans , Male , Middle Aged , Obesity/virology , Pandemics , Pneumonia, Viral/complications , Prevalence , Retrospective Studies , Risk Factors , SARS-CoV-2 , Young AdultABSTRACT
OBJECTIVE: The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft. RESEARCH DESIGN AND METHODS: We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43-92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function. RESULTS: The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22-57) and 28% (13-45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62-92) and 78% (57-89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence. CONCLUSIONS: Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.
Subject(s)
Diabetes Mellitus, Type 1/surgery , Islets of Langerhans Transplantation/methods , Kidney Transplantation/methods , Adult , Blood Glucose/metabolism , Combined Modality Therapy , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Female , Glycated Hemoglobin/analysis , Humans , Hypoglycemia/epidemiology , Hypoglycemia/etiology , Hypoglycemic Agents/administration & dosage , Immunosuppression Therapy/methods , Insulin/administration & dosage , Islets of Langerhans Transplantation/adverse effects , Kidney Transplantation/adverse effects , Male , Middle Aged , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Prospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Total pancreatectomy with intraportal islet autotransplantation (TPIAT) rather than partial pancreatectomy could represent a major shift in the management of patients with resectable pancreatic ductal adenocarcinoma (PDAC) when risks of postoperative pancreatic fistula are well identified. This approach provides a theoretical risk of tumor cell dissemination when islet cells are transplanted into the portal vein. Our objective was to explore the safety of TPIAT in PDAC in a mouse preclinical model of subcutaneous xenotransplantation of human cells isolated from pancreatic specimen during partial pancreatectomy performed for PDAC. METHODS: Patients requiring pancreatectomy for PDAC were prospectively included. Immunocompromised mice were transplanted with pancreatic cells isolated from the nonmalignant part of the surgical specimen (experimental group). Results were compared with pancreatic tumor implants (control group). Pancreatic grafts were explanted at 6 weeks for histological analyses. RESULTS: Nine patients were included, and 31 mice were transplanted. In the experimental group, explants were microscopically devoid of tumor cell, and no metastasis was observed. In the control group, all explants were composed of tumor. CONCLUSIONS: We report in a preclinical model the absence of local and distant spreading of malignant cells after pancreatic islets xenograft isolated from PDAC patients. These data supports the oncological safety of TPIAT as valuable alternative to partial pancreatectomy for PDAC patients with a high risk of postoperative pancreatic fistula.
Subject(s)
Carcinoma, Pancreatic Ductal/surgery , Islets of Langerhans Transplantation , Pancreatectomy , Pancreatic Neoplasms/surgery , Pancreaticoduodenectomy , Aged , Animals , Carcinoma, Pancreatic Ductal/pathology , Female , Humans , Islets of Langerhans Transplantation/adverse effects , Male , Mice, Nude , Middle Aged , Pancreatic Neoplasms/pathology , Prospective Studies , Risk Assessment , Time Factors , Transplantation, Autologous , Transplantation, HeterologousABSTRACT
BACKGROUND: The most feared complication of laparoscopic cholecystectomy (LC) is biliary tract injuries (BTI). We conducted a prospective study to evaluate the role of preoperative magnetic resonance cholangiopancreatography (MRCP) in describing the biliary tract anatomy and to investigate its potential benefit to prevent BTI. MATERIALS AND METHODS: From January 2012 to December 2016, 402 patients who underwent LC with preoperative MRCP were prospectively included. Routine intraoperative cholangiography was not performed. Patients' characteristics, preoperative diagnosis, biliary anatomy, conversion to laparotomy, and the incidence of BTI were analyzed. RESULTS: Preoperative MRCP was performed prospectively in 402 patients. LC was indicated for cholecystitis and pancreatitis, respectively, in 119 (29.6%) and 53 (13.2%) patients. One hundred and five (26%) patients had anatomical variations of biliary tract. Three BTI (0.75%) occurred with a major BTI (Strasberg E) and two bile leakage from the cystic stump (Strasberg A). For these 3 patients, biliary anatomy was modal on MRCP. No BTI occurred in patients presenting "dangerous" biliary anatomical variations. CONCLUSION: MRCP could be a valuable tool to study preoperatively the biliary anatomy and to recognize "dangerous" anatomical variations. Subsequent BTI might be avoided. Further randomized trials should be designed to assess its real value as a routine investigation before LC.