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The article presents a study which examines the results of the INHERITANCE project funded by the European Commission which aims to implement information technology solutions to support the research on genetic screening. It notes that several advanced biomedical informatics tools and layer of software instruments were used to support the project team. It cites that the data warehouse of the project was completely established as well as the text mining tools for automatic literature analysis.

The risk profiles of post-acute sequelae of COVID-19 (PASC) have not been well characterized in multi-national settings with appropriate controls. We leveraged electronic health record (EHR) data from 277 international hospitals representing 414,602 patients with COVID-19, 2.3 million control patients without COVID-19 in the inpatient and outpatient settings, and over 221 million diagnosis codes to systematically identify new-onset conditions enriched among patients with COVID-19 during the post-acute period. Compared to inpatient controls, inpatient COVID-19 cases were at significant risk for angina pectoris (RR 1.30, 95% CI 1.09-1.55), heart failure (RR 1.22, 95% CI 1.10-1.35), cognitive dysfunctions (RR 1.18, 95% CI 1.07-1.31), and fatigue (RR 1.18, 95% CI 1.07-1.30). Relative to outpatient controls, outpatient COVID-19 cases were at risk for pulmonary embolism (RR 2.10, 95% CI 1.58-2.76), venous embolism (RR 1.34, 95% CI 1.17-1.54), atrial fibrillation (RR 1.30, 95% CI 1.13-1.50), type 2 diabetes (RR 1.26, 95% CI 1.16-1.36) and vitamin D deficiency (RR 1.19, 95% CI 1.09-1.30). Outpatient COVID-19 cases were also at risk for loss of smell and taste (RR 2.42, 95% CI 1.90-3.06), inflammatory neuropathy (RR 1.66, 95% CI 1.21-2.27), and cognitive dysfunction (RR 1.18, 95% CI 1.04-1.33). The incidence of post-acute cardiovascular and pulmonary conditions decreased across time among inpatient cases while the incidence of cardiovascular, digestive, and metabolic conditions increased among outpatient cases. Our study, based on a federated international network, systematically identified robust conditions associated with PASC compared to control groups, underscoring the multifaceted cardiovascular and neurological phenotype profiles of PASC., (© 2022. The Author(s).)

Background: Many countries have experienced 2 predominant waves of COVID-19-related hospitalizations. Comparing the clinical trajectories of patients hospitalized in separate waves of the pandemic enables further understanding of the evolving epidemiology, pathophysiology, and health care dynamics of the COVID-19 pandemic., Objective: In this retrospective cohort study, we analyzed electronic health record (EHR) data from patients with SARS-CoV-2 infections hospitalized in participating health care systems representing 315 hospitals across 6 countries. We compared hospitalization rates, severe COVID-19 risk, and mean laboratory values between patients hospitalized during the first and second waves of the pandemic., Methods: Using a federated approach, each participating health care system extracted patient-level clinical data on their first and second wave cohorts and submitted aggregated data to the central site. Data quality control steps were adopted at the central site to correct for implausible values and harmonize units. Statistical analyses were performed by computing individual health care system effect sizes and synthesizing these using random effect meta-analyses to account for heterogeneity. We focused the laboratory analysis on C-reactive protein (CRP), ferritin, fibrinogen, procalcitonin, D-dimer, and creatinine based on their reported associations with severe COVID-19., Results: Data were available for 79,613 patients, of which 32,467 were hospitalized in the first wave and 47,146 in the second wave. The prevalence of male patients and patients aged 50 to 69 years decreased significantly between the first and second waves. Patients hospitalized in the second wave had a 9.9% reduction in the risk of severe COVID-19 compared to patients hospitalized in the first wave (95% CI 8.5%-11.3%). Demographic subgroup analyses indicated that patients aged 26 to 49 years and 50 to 69 years; male and female patients; and black patients had significantly lower risk for severe disease in the second wave than in the first wave. At admission, the mean values of CRP were significantly lower in the second wave than in the first wave. On the seventh hospital day, the mean values of CRP, ferritin, fibrinogen, and procalcitonin were significantly lower in the second wave than in the first wave. In general, countries exhibited variable changes in laboratory testing rates from the first to the second wave. At admission, there was a significantly higher testing rate for D-dimer in France, Germany, and Spain., Conclusions: Patients hospitalized in the second wave were at significantly lower risk for severe COVID-19. This corresponded to mean laboratory values in the second wave that were more likely to be in typical physiological ranges on the seventh hospital day compared to the first wave. Our federated approach demonstrated the feasibility and power of harmonizing heterogeneous EHR data from multiple international health care systems to rapidly conduct large-scale studies to characterize how COVID-19 clinical trajectories evolve., (©Griffin M Weber, Harrison G Zhang, Sehi L'Yi, Clara-Lea Bonzel, Chuan Hong, Paul Avillach, Alba Gutiérrez-Sacristán, Nathan P Palmer, Amelia Li Min Tan, Xuan Wang, William Yuan, Nils Gehlenborg, Anna Alloni, Danilo F Amendola, Antonio Bellasi, Riccardo Bellazzi, Michele Beraghi, Mauro Bucalo, Luca Chiovato, Kelly Cho, Arianna Dagliati, Hossein Estiri, Robert W Follett, Noelia García Barrio, David A Hanauer, Darren W Henderson, Yuk-Lam Ho, John H Holmes, Meghan R Hutch, Ramakanth Kavuluru, Katie Kirchoff, Jeffrey G Klann, Ashok K Krishnamurthy, Trang T Le, Molei Liu, Ne Hooi Will Loh, Sara Lozano-Zahonero, Yuan Luo, Sarah Maidlow, Adeline Makoudjou, Alberto Malovini, Marcelo Roberto Martins, Bertrand Moal, Michele Morris, Danielle L Mowery, Shawn N Murphy, Antoine Neuraz, Kee Yuan Ngiam, Marina P Okoshi, Gilbert S Omenn, Lav P Patel, Miguel Pedrera Jiménez, Robson A Prudente, Malarkodi Jebathilagam Samayamuthu, Fernando J Sanz Vidorreta, Emily R Schriver, Petra Schubert, Pablo Serrano Balazote, Byorn WL Tan, Suzana E Tanni, Valentina Tibollo, Shyam Visweswaran, Kavishwar B Wagholikar, Zongqi Xia, Daniela Zöller, The Consortium For Clinical Characterization Of COVID-19 By EHR (4CE), Isaac S Kohane, Tianxi Cai, Andrew M South, Gabriel A Brat. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 11.10.2021.)

i2b2 data-warehouse could be a useful tool to support the enrollment phase of clinical studies. The aim of this work is to evaluate its performance on two clinical trials. We developed also an i2b2 extension to help in suggesting eligible patients for a study. The work showed good results in terms of ability to implement inclusion/exclusion criteria, but also in terms of identified patients actually enrolled and high number of patients suggested as potentially enrollable.

Global pandemics call for large and diverse healthcare data to study various risk factors, treatment options, and disease progression patterns. Despite the enormous efforts of many large data consortium initiatives, scientific community still lacks a secure and privacy-preserving infrastructure to support auditable data sharing and facilitate automated and legally compliant federated analysis on an international scale. Existing health informatics systems do not incorporate the latest progress in modern security and federated machine learning algorithms, which are poised to offer solutions. An international group of passionate researchers came together with a joint mission to solve the problem with our finest models and tools. The SCOR Consortium has developed a ready-to-deploy secure infrastructure using world-class privacy and security technologies to reconcile the privacy/utility conflicts. We hope our effort will make a change and accelerate research in future pandemics with broad and diverse samples on an international scale., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across five countries (www.covidclinical.net). Contributors utilized the Informatics for Integrating Biology and the Bedside (i2b2) or Observational Medical Outcomes Partnership (OMOP) platforms to map to a common data model. The group focused on temporal changes in key laboratory test values. Harmonized data were analyzed locally and converted to a shared aggregate form for rapid analysis and visualization of regional differences and global commonalities. Data covered 27,584 COVID-19 cases with 187,802 laboratory tests. Case counts and laboratory trajectories were concordant with existing literature. Laboratory tests at the time of diagnosis showed hospital-level differences equivalent to country-level variation across the consortium partners. Despite the limitations of decentralized data generation, we established a framework to capture the trajectory of COVID-19 disease in patients and their response to interventions., Competing Interests: Competing interestsR.B. and A.M. are shareholders of Biomeris s.r.l., (© The Author(s) 2020.)

Unstructured clinical notes contain a huge amount of information. We investigated the possibility of harvesting such information through an NLP-based approach. A manually curated ontology is the only resource required to handle all the steps of the process leading from clinical narrative to a structured data warehouse (i2b2). We have tested our approach at the Papa Giovanni XXIII hospital in Bergamo (Italy) on pathology reports collected since 2008.

Medical reports often contain a lot of relevant information in the form of free text. To reuse these unstructured texts for biomedical research, it is important to extract structured data from them. In this work, we adapted a previously developed information extraction system to the oncology domain, to process a set of anatomic pathology reports in the Italian language. The information extraction system relies on a domain ontology, which was adapted and refined in an iterative way. The final output was evaluated by a domain expert, with promising results.

The i2b2 software is a widely adopted solution for secondary use of clinical data for clinical research, specifically designed for cohort identification. i2b2 is still lacking functionalities for data analysis. The aim of this work is to empower the i2b2 framework enabling clinical researchers to perform statistical analyses for accelerating the process of hypothesis testing. To this aim we have developed a flexible extension of i2b2 able to exploit different statistical engines. We have implemented some first applications for basic statistics and survival analyses, exploiting this extension and accessible through suitable user interfaces designed with a special consideration for usability.

The INHERITANCE project, funded by the European Commission, is aimed at studying genetic or inherited Dilated cardiomyopathies (DCM) and at understanding the impact and management of the condition within families that suffer from heart conditions that are caused by DCMs. The project is supported by a number of advanced biomedical informatics tools, including data warehousing, automated literature search and decision support. The paper describes the design of these tools and the current status of implementation.

Background: This retrospective and descriptive 4-year study was undertaken to describe cardiac changes in subclinical and overt hyperthyroidism., Methods: We revised the charts of 386 consecutive cardiopathic women whose blood samples were referred to the Radioimmunoassay Laboratory to evaluate thyroid function from 1 January 1997 through 31 December 2000., Results: After excluding women because euthyroid or hypothyroid, or taking amiodarone and women with hypertension, rheumatic disease, myocardial infarction, a total of 31 hyperthyroid women were thus selected for the study: 19 with subclinical hyperthyroidism and 12 with overt hyperthyroidism. The prevalence of atrial fibrillation did not differ between subclinical (48%) and overt (67%) hyperthyroid women, as well as left atrial dimension; the latter was larger in hyperthyroid (27.8+/-7.8 cm(2)/m(2)) than in control women (18.9+/-2.8 cm(2)/m(2)) (P<0.001). In the subclinical and overt hyperthyroidism, the heart rate (HR) was increased and left ventricular end diastolic (LVED) volume was reduced; in addition, only in overt hyperthyroidism, left ventricular (LV) mass was increased. A significant correlation between LV mass and free triiodothyronine was found., Conclusion: HR increase and LVED decrease, both in subclinical and overt hyperthyroidism, indicate a global impairment of diastolic heart performance, complicated in overt hyperthyroidism by LV concentric hypertrophy. So, in our opinion, subclinical hyperthyroidism, far from being considered a simple laboratory finding, in clinical practice should be taken into serious consideration.

Background: To examine the prevalence of atrial fibrillation (AF) in cardiopathic patients with hyperthyroidism., Methods: The data concerning the patients had been derived from registers of the Laboratory of Radioimmunoassay where cardiopathic patients' blood samples were referred from the Cardiology Unit to evaluate thyroid function, consecutively from January 1992 to December 1997. Of the 443 patients, 303 (68.4%) were classified as being euthyroid, 23 (5.2%) hypothyroid, 117 (26.4%) hyperthyroid. Thyroid function was diagnosed clinically and confirmed by serum TSH and free thyroid hormone (FT3, FT4), levels., Results: Among hyperthyroid patients, the more frequent arrhythmia was AF (54.7%). After excluding from the study those hyperthyroid patients with rheumatic disease, hypertension, myocardial infarction, 37 hyperthyroid patients were selected; 18 (48.6%), (mean age 63.4 +/- 10.8 yrs), showed sinus rhythm and 19 (51.4%), (mean age 66.0 +/- 12.1 yrs), showed AF. FT3 and FT4 were higher in patients with AF than in those without AF, whereas TSH was not significantly different between the groups. Left ventricular (LV) mass index was significantly increased in hyperthyroid women with AF compared with hyperthyroid women without AF (109.80 +/- 22.33 g/m2 vs 84.50 +/- 6.20 g/m2; p < 0.005). A significant correlation was found between FT3 levels and LV mass index in the hyperthyroid women with and without AF (r = 0.77; p < 0.001)., Conclusions: In this study the prevalence of AF is 51.4% in hyperthyroid patients. FT3 is higher in patients with AF than in those without AF. Finally, the correlation between FT3 and LV mass index suggests that cardiac hypertrophy is associated with thyroid hyperfunction.

To determine whether plasma endothelin, a potent vasoconstrictive peptide, is elevated in NIDDM patients, we compared a group of 15 NIDDM patients with macroangiopathy of mean age 60.60 +/- 2.33 years with 15 NIDDM randomly selected matched patients without macroangiopathy. Plasma endothelin levels were significantly increased in NIDDM patients with macroangiopathy (4.22 +/- 0.57 pmol/L) and in NIDDM patients without macroangiopathy (3.81 +/- 0.51 pmol/L). Although endothelin values did not differ between NIDDM groups, both represented significant difference from control values (2.46 +/- 0.24 pmol/L). No significant correlations were found between plasma endothelin and age (rs = 0.11), duration of diabetes mellitus (rs = 0.06), BMI (rs = 0.19), plasma glucose (rs = 0.15), plasma fructosamine (rs = 0.02). These findings confirm that in diabetes mellitus a primary disturbance in endothelin production from vascular endothelium exists as an early phenomenon rather than a result of advanced stage of the disease.

Conflicting evidence has been reported on the metabolic fate of glucose following oral ingestion. We measured the metabolic pattern of gluconeogenic substrates as alanine, predominantly produced by muscle, and lactate after an oral glucose load in ten normal subjects and in eighteen non-insulin dependent diabetes mellitus (NIDDM) subjects. Neither in normal or NIDDM subjects were significant increases in plasma alanine observed, whereas a significant increase in plasma lactate was observed at 60, 90 and 120 min after a glucose load. Although a similar behaviour in plasma alanine and lactate between normal and NIDDM subjects was found, in NIDDM significantly higher levels of plasma alanine and lactate were found at each time. From these observations we conclude: 1) when glucose is ingested under post-absorptive conditions, since plasma alanine levels do not change concurrently with lactate increase, muscle tissue does not play a predominant role in glucose disposal 2) after an oral glucose load, the pattern of gluconeogenic precursors (alanine and lactate) is similar in normal and NIDDM subjects 3) the main cause of fasting and post-prandial hyperglycemia in NIDDM subjects may be due to an overproduction of alanine as well as lactate.

Lipoprotein(a) [Lp(a)] has been added to the list of independent risk factors for cardiovascular disease (CVD), whose incidence is greater in obese subjects. There are few data available on the serum Lp(a) concentrations in obese individuals with or without insulin dependent diabetes mellitus (NIDDM). We selected 31 obese men with normal glucose tolerance (NGT) tests, 15 obese diabetic men, 14 non obese diabetic men and 17 healthy men as controls. We measured serum total cholesterol, HDL cholesterol, triglycerides, glucose, insulin and Lp(a). The mean Lp(a) levels in NGT obese men were 70.00 +/- 13.40 mg/l, which were similar to those found in normal controls (75.98 +/- 24.70 mg/l); significantly higher mean Lp(a) levels were found in obese diabetic men (168.84 +/- 56.43 mg/l) and in non obese diabetic men (240.85 +/- 63.35 mg/l). No significant correlation between Lp(a) levels and age, body mass index (BMI), total cholesterol, HDL cholesterol, triglycerides, insulin, was found; only a significant positive correlation between Lp(a) levels and glucose could be revealed (P < 0.05). Since higher levels of Lp(a) were found in NIDDM subjects with or without obesity, we conclude that hyperglycemia may influence the levels of serum Lp(a) facilitating its glycosylation in the liver with the consequence of a decline in its catabolic rate.

Several clinical and epidemiological evidences support the increased risk of cardiovascular disease (CVD) in pathological conditions as obesity, hypertension, non-insulin-dependent diabetes mellitus, which have hyperinsulinemia as a common feature. In this study, we assessed basal plasma insulin (IRI) and C-peptide (CPR) concentrations in 297 volunteers who participated in a survey concerning risk factors of CVD. We found a stepwise increase in fasting insulin and C-peptide levels in normal subjects (IRI 9.10 +/- 0.41 microU/ml; CPR 1.79 +/- 0.08 ng/ml), in obese subjects (IRI 11.31 +/- 0.38 microU/ml; CPR 2.54 +/- 0.07 ng/ml) in obese hypertensive subjects (IRI 14.17 +/- 0.72 microU/ml; CPR 2.64 +/- 0.09 ng/ml), in obese hypertensive diabetic subjects (IRI 22.57 +/- 2.62 microU/ml; CPR 3.33 +/- 0.27 ng/ml). Thus, we found increasing levels of IRI and CPR as normal conditions changed towards progressively more severe pathological conditions. Although several other factors contribute to determine CVD, we conclude that increasing levels of insulin and C-peptide could play an important role in causing CVD.

We determined erythrocyte glucose, ATP and lactate contents in diabetic subjects using an experimental design in which red blood cells (RBCs) were incubated over four hours in their own plasma and in plasma from normal subjects. The results indicated that baseline RBC glucose and lactate concentrations were higher in diabetic RBCs than in the controls, while ATP content was similar. After incubation, in diabetic RBCs glucose decreased significantly but more markedly when RBCs were incubated in normal plasma; lactate increased markedly in diabetic erythrocytes in their own plasma, but increased to the same extent as controls when incubated in normal plasma. ATP levels were similar to baseline values in diabetic RBCs in their own plasma, but decreased significantly when incubated in normal plasma. Since we found such a different metabolic behaviour in diabetic RBCs changing from diabetic to normal plasma, the important role of blood glucose in regulating RBC glycolysis is again confirmed.

Forty obese subjects with normal glucose tolerance test (NGTT) thirteen diabetic obese subjects and sixteen normal subjects were studied to evaluate the possible interactions between beta-endorphin (B-Ep) and glucose homeostasis. On the basis of baseline B-Ep levels, two subgroups were selected: one group with normal mean values of B-Ep (7.02 +/- 0.59 pmol/l); another group with elevated mean values of B-Ep (18.95 +/- 1.52 pmol/l). No differences between these subgroups were found as regards body mass index (BMI), insulin and glucagon levels. Normal B-Ep values were found in diabetic obese subjects. No significant correlation was found between B-Ep and BMI, insulin or glucagon. Considering that B-Ep is involved in eating behavior and on the basis of our results, we suggest that elevated B-Ep levels can be found only in those obese NGTT subjects whose obesity is probably related to an abnormal modulation of food intake, such as hyperphagia.

We determined red blood cell (RBC) lactate concentrations in NIDDM subjects using an experimental protocol in which diabetic RBCs were incubated over 8 hours both with own plasma and with normal plasma. Furthermore, normal RBCs were incubated both with own plasma and with diabetic plasma. The results indicate that the increased lactate concentrations in RBCs from NIDDM subjects decreased significantly when the same RBCs were incubated in normal plasma. Conversely, lactate concentrations in normal RBCs increased significantly when RBCs were incubated in diabetic plasma. Thus, other than muscle and adipose tissue, RBCs may contribute to increase lactate release for hepatic gluconeogenesis in NIDDM and we suggest that there may be extrinsic plasmatic factor(s) capable of stimulatory effect on diabetic RBC glycolytic pathway.

To evaluate calcium hormones in diabetic pregnancy, eleven diabetic pregnant women were studied by measuring serum total calcium, phosphorus by conventional methods, and parathyroid hormone, calcitonin and 25-hydroxycholecalciferol, by radioimmunologic methods, serially every four weeks, beginning at 16th week throughout 36th week of gestation. Serum total calcium, phosphorus and parathyroid hormone levels dit not differ between diabetic and non diabetic pregnant women, nor between all pregnant women and age-matched non pregnant healthy women. Serum calcitonin levels, although significantly higher than those of age-matched non pregnant women, did not differ between diabetic and non diabetic pregnant women, maintaining constant with the progression of pregnancy. Serum 25-hydroxycholecalciferol levels, although contained within the normal range, increased significantly in the third trimester of gestation both in non diabetic pregnant women and, even though later, in diabetic pregnant women.

Fifteen insulin-dependent diabetic (White's class B-C) and 10 healthy pregnant women were examined from the 12th to the 36th wk. Every 4 wk, a blood sample was drawn to determine total estriol, progesterone, placental lactogen and prolactin. Throughout the pregnancy, total estriol and progesterone in diabetic and non-diabetic women are very similar. On the contrary, the PRL levels are constantly lower in diabetic pregnant women, even though the difference is statistically significant only for the 24th wk determination. The hPL level is instead significantly lower in diabetic pregnant women at the 12th, 20th, 24th, 32nd and 36th wk. A negative correlation exists between the hPL value and the mean blood glucose level, performed the same day as the hormonal test. This correlation is statistically significant at the 12th, 16th, 20th, 28th and 36th wk. No significant difference is found between the two groups examined for the delivery week, the placental weight, the birth weight and the fetal body weight index. To conclude, while estriol and progesterone are not affected by the higher variability of glucose levels during pregnancy in diabetics, compared to normals, hPL and perhaps also PRL may be influenced by the mild hyperglycemia consequent to diabetes.

The effect of prolonged gliclazide treatment on diabetic metabolic control was studied in 10 subjects with non-insulin dependent diabetes mellitus. Patients were examined before, after 15 days of treatment with diet alone and, again, after 60 days of treatment with diet plus gliclazide. Gliclazide did not restore the abnormality of blood glucose, free insulin and C-peptide response to an intensive stimulus of glucose load, although fasting and after-load blood glucose, fasting glycosylated haemoglobin, alanine and lactate significantly decreased after prolonged treatment with diet plus gliclazide, but not with diet alone. These findings support the assumption that the efficacy of prolonged treatment with gliclazide might be related to its extrapancreatic effects on glucose homeostasis.

Blood prolactin levels (PRL) rise significantly in man following stress or the administration of many drugs. This finding led the authors to study variations in PRL during anaesthesia with Enflurane or Alfatesine. Repeated estimations of PRL were made in 38 subjects: in 8 cases (3 female and 5 male) under anaesthesia with Enflurane only, in 10 cases (6 female and 4 male) with Alfatesine only, in 10 cases (5 female and 5 male) with Enflurane and surgery and in 10 other cases (5 female and 5 male) with Alfatesine with surgery. No significant increase in PRL was seen during the administration of anaesthesia without surgery. By contrast, significant changes were seen when surgery was performed. No significant difference was seen in the results between the two sexes in each group. Taking into account the results of earlier experiments, the authors conclude that Enflurane or Alfatesine alone do not influence the hypothalamo-pituitary axis, but do not protect it during surgical and/or pharmacological stress.

The insulin secretory action of gastrin during O.G.T.T. has been assessed. The insulinaemic and gastrinaemic curves were evaluated in a group of normal subjects submitted to oral glucose load, using radioimmunological measurement techniques. At a later stage, the insulinaemic values were considered in the same subjects after administration of a gastrin analogue (pentagastrin) by the subcutaneous route in a dose such as to provoke a maximal gastric acid response. The data suggest that any participation of gastrin in the regulation of insulin secretion following a glucose meal can be excluded.

Metabolic effects of muscular exercise were studied in eleven subjects with type I diabetes mellitus during poor metabolic control, and again during good metabolic control, and in ten healthy control subjects. All the subjects were submitted to a submaximal gradual triangular test on an electrically braked bicycle ergometer; glucose, FFA, alanine and lactate were measured at rest, and after exercise. In poorly controlled patients, glucose and FFA were unchanged after exercise, whereas blood alanine and lactate increased by a percentage similar to that of the controls, and well-controlled diabetic patients. Baseline alanine concentrations were lower and lactate concentrations higher than in the controls and well-controlled patients. After adequate metabolic control was achieved, in the well-controlled diabetic patients a normalization of pre-exercise alanine and lactate levels and a decrease in blood glucose and FFA after exercise was observed.

Type I diabetes mellitus represents a metabolic disorder in which intracellular glycolytic pathway is inhibited by insulin deficiency, with the subsequent decreased availability of energetic substrates such as ATP. Some aspects of the energetic metabolism in response to an intensive demand (muscular exercise) were investigated, in a group of 10 ketotic diabetic patients, by measuring erythrocyte adenosine triphosphate (ATP) and blood glucose, free fatty acids (FFA) and lactate levels. In the diabetic subjects, in comparison with normal subjects, the decreased levels of erythrocyte ATP at rest did not increase after exercise, while the increased levels of FFA at rest did not diminish after exercise. The results show that the impaired erythrocyte glycolysis may produce reduced levels of ATP not only at rest, but also after exercise, when muscular contraction results in a manifold increase in cellular energy requirements. In addition, other metabolic systems providing energy for the exercising muscle, such as FFA utilization, are impaired in the ketotic diabetic patients.