Predictive model of response to tafamidis in hereditary ATTR polyneuropathy

BACKGROUNDThe hereditary transthyretin (TTR) amyloidoses are a group of diseases for which several disease-modifying treatments are now available. Long-term effectiveness of these therapies is not yet fully known. Moreover, the existence of alternative therapies has resulted in an urgent need to identify patient characteristics that predict response to each therapy.METHODSWe carried out a retrospective cohort study of 210 patients with hereditary TTR amyloidosis treated with the kinetic stabilizer tafamidis (20 mg qd). These patients were followed for a period of 18-66 months, after which they were classified by an expert as responders, partial responders, or nonresponders. Correlations between baseline demographic and clinical characteristics, as well as plasma biomarkers and response to therapy, were investigated.RESULTS34% of patients exhibited an almost complete arrest of disease progression (classified by an expert as responders); 36% had a partial to complete arrest in progression of some but not all disease components (partial responders); whereas the remaining 30% continued progressing despite therapy (nonresponders). We determined that disease severity, sex, and native TTR concentration at the outset of treatment were the most relevant predictors of response to tafamidis. Plasma tafamidis concentration after 12 months of therapy was also a predictor of response for male patients. Using these variables, we built a model to predict responsiveness to tafamidis.CONCLUSIONOur study indicates long-term effectiveness for tafamidis, a kinetic stabilizer approved for the treatment of hereditary TTR amyloidosis. Moreover, we created a predictive model that can be potentially used in the clinical setting to inform patients and clinicians in their therapeutic decisions.info:eu-repo/semantics/publishedVersio

Acute Stress and Traumatic Stress in Type 2 Diabetes Mellitus

Hintergrund: Type 2 Diabetes ist eine der häufigsten chronischen Erkrankungen weltweit und die Prävalenzzahlen sowie diabetes-assoziierten Todesfälle steigen aktuell weiter an. In der Di- abetesforschung wird nun auch untersucht, welche Rolle psychologische Faktoren spielen, um so ein umfassenderes Verständnis der Erkrankung zu gewinnen. Chronischer und traumatischer Stress stellen dabei Forschungsschwerpunkte dar. Die vorliegenden Studie untersucht zwei, bisher wenig erforschte, Themenbereiche, die aus psychosomatischer Sicht von besonderem Interesse bei Typ 2 Diabetes Patient*innen sind: Die Stressreaktion des autonomen Nervensys- tems (ANS) und der Zusammenhang zwischen der psychologischen und physiologischen Stressreaktion und Vernachlässigungserfahrungen in der Kindheit. Weil das physiologische Stresssystem (die Hypothalamus-Hypophysen-Nebennierenrinden- Achse (HHNA) und das ANS) eng mit den physiologischen Systemen verbunden sind, die bei Typ 2 Diabetes von Bedeutung sind, könnte eine Untersuchung der Stressreaktion des ANS dazu beitragen, die Beziehung zwischen Typ 2 und Stress besser zu verstehen. Die Untersu- chung einer möglichen Beziehung zwischen der Stressreaktion und Vernachlässigungserfah- rungen in der Kindheit, ist von besonderem Interesse, weil bereits gezeigt werden konnte, dass Opfer von Kindesmisshandlung ein erhöhtes Risiko für Typ 2 Diabetes haben. Eine veränderte Stressreaktion könnte ein Teil des Mechanismus sein, der diesen Zusammenhang erklärt. Methode: In n=74 Typ 2 Diabetes Patienten und n=50 gesunden Kontrollpersonen wurden körperliche und emotionale Vernachlässigungserfahrungen erfasst. Der Trier sozialer Stress Test (TSST) wurde eingesetzt um eine Stressreaktion auszulösen. Dabei wurden die Herz Rate (HR) und die Herzratenvariabilität (HRV) zu sechs Messzeitpunkten vor, während und nach dem TSST gemessen. Weiterhin wurden die ACTH- und Cortisol Blutwerte vor, nach, sowie 30 und 60 Minuten nach dem TSST gemessen. Die psychologische Stressreaktion der Teilneh- mer*innen wurde vor, direkt nach, sowie 45 Minuten nach dem TSST erfragt. Die psychologi- sche Stressreaktion der Typ 2 Diabetes Patient*innen wurde mit der der gesunden Kontrollper- sonen verglichen und multiple Regressionen wurden verwendet, um die Veränderung in sub- jektiver Anspannung vorherzusagen. Anhand von Multilevelanalysen (MLA), wurde die Asso- ziation zwischen HR, Low Frequency (LF) und High Frequency (HF) HRV mit Typ 2 Diabetes über den zeitlichen Verlauf getestet. Diese Analyse wurde mit einer reduzierten Stichprobe, die nur Typ 2 Diabetes Patient*innen enthielt die an Folgeerkrankungen litten (n=51) wiederholt. Ebenfalls anhand von MLA wurde die Assoziation zwischen der autonomen Stressreaktion (HR, LF und HF), der Schwere früher Vernachlässigungserfahrungen und Typ 2 Diabetes sowie 76 Zusammenfassung der Stressreaktion der HHNA (ACTH und Cortisol), der Schwere früher Vernachlässigungser- fahrungen und Typ 2 Diabetes getestet. Ergebnisse: Der Vergleich der vollständigen Typ 2 Diabetes Gruppe (mit und ohne Folgeer- krankungen) mit gesunden Kontrollpersonen zeigte als einzigen Unterschied eine gestreckte LF HRV Kurve bei Typ 2 Diabetes Patient*innen. Als der Vergleich mit der reduzierten Stichprobe (mit Folgeerkrankungen) wiederholt wurde, zeigte sich bei Typ 2 Diabetes Patient*innen eine insgesamt niedrigere LF HRV sowie eine gestreckte HR Kurve, die auf eine schwächere Reak- tivität sowie eine verlangsamte Erholung hinweist. Dieses Muster fand sich auch in der psy- chologischen Stressreaktion der Typ 2 Diabetes Gruppe wieder. Assoziationen der psychologischen und der endokrinologischen (HHNA) Stressreaktion mit frühen Vernachlässigungserfahrungen fanden sich nur in Interaktion mit Typ 2 Diabetes. Dabei ergab sich ein Zusammenhang zwischen Vernachlässigungserfahrungen und einer stärkeren psychologischen Stressreaktion, eine positive Assoziation zwischen der Schwere emotionaler Vernachlässigung und insgesamt höheren ACTH Blutwerten sowie eine positive Assoziation zwischen einem stärkeren Cortisol Anstieg nach dem TSST und der Schwere körperlicher Ver- nachlässigungserfahrungen. Bei der autonomen Stressreaktion ergab sich nur eine Assoziation zwischen der Schwere emotionaler Vernachlässigungserfahrungen und einer gestreckten HR Kurve in beiden Gruppen. Eine negative Interaktion zwischen Type 2 Diabetes und der Schwere emotionaler Vernachlässigungserfahrungen zeigte, dass dieser Zusammenhang bei Typ 2 Dia- betes Patient*innen allerdings signifikant schwächer war. Diskussion: Auf der Basis der Ergebnisse dieser Studie kann angenommen werden, dass Ver- änderungen des ANS bei Typ 2 Diabetes Patient*innen bestimmte Aspekte der Stressreaktion beeinflussen. Allerdings besteht dieser Zusammenhang vor allem bei Typ 2 Diabetes Pati- ent*innen mit Folgeerkrankungen, was die Bedeutung von Folgeerkrankungen in diesem Kon- text unterstreicht. Die Ergebnisse zeigen außerdem, dass eine dysregulierte Stressreaktion bei Typ 2 Diabetes Patient*innen ein Teil des Mechanismus sein könnte, der Typ 2 Diabetes und frühe Vernachlässigungserfahrungen verbindet. Dabei kann vor allem für die gemessenen en- dokrinologischen und psychologischen Parameter ein Zusammenhang angenommen werden, während ein Zusammenhang mit der autonomen Stressreaktion unwahrscheinlicher ist. Wich- tige Limitation dieser Studie sind das querschnittliche Studiendesign, das keine Rückschlüsse auf kausale Zusammenhänge zulässt, sowie das Fehlen einer systematischen Diagnostik auto- nomer Neuropathie. Weitergehende Forschung in diesem Gebiet sollte das ANS miteinschlie- ßen und longitudinale Studiendesigns verwenden

The role of various risk factors in the prevalence of cardiac autonomic neuropathy and associated diseases

The objectives of this thesis were three-fold: The first aim was to investigate the roles of various markers in the prevalence and complications of CAN and associated diseases with emphasis on diabetes mellitus. Specifically, this study investigated the role of heart rate variability (HRV) markers as well as the roles of genetic and family history risk factors. The second aim of this study was to develop mechanisms to predict CAN disease occurrence. The third aim of this current study was to develop a model for predicting diabetes mellitus (DM) and cardiovascular disease (CVD) simultaneously using common risk factors

Doctor of Philosophy

dissertationType 2 diabetes mellitus (T2DM) is a well-known risk factor for atrial fibrillation (AF). The role of glycemic control in the development of AF is not clear in these patients. This study was conducted to find the association between glycemic control and AF in patients with T2DM receiving care through the US Veteran’s Affairs system. A case-control study was designed using US Veteran’s Affairs data in patients with T2DM receiving care between 2000 and 2014. The study included patients with T2DM as identified by diagnostic criteria or diabetes medication therapy, and with a minimum of two HbA1c values before the index date. Index date was defined as the AF diagnosis date for cases; for control patients, it was +/- 90 days of case’s index date. Incidence density sampling was used to select control patients who were matched with cases on diabetes duration and calendar year of T2DM diagnosis. Cases were defined as patients who were diagnosed with AF and controls were defined as patients who were not diagnosed with AF before the time period they were selected as control patients. A prior 12 month period before the index date was used to assess HbA1c values. HbA1C 11% were 0.96 times (95% CI, 0.81, 1.14; p = 0.642) as likely to be associated with AF. Numerous comorbidities were also associated with AF including congestive heart failure (OR: 2.29, 95% CI 2.20, 2.38; p < 0.001), coronary heart disease (OR: 1.72, 95% CI: 1.67, 1.78; p < 0.001), hypertension (OR: 2.03, 95% CI 1.96, 2.10; p < 0.001), myocardial infarction (OR: 1.97, 95% CI 1.80, 2.16; p < 0.001), left ventricular hypertrophy (OR: 1.51, 95% CI 1.38, 1.65; p < 0.001), and chronic kidney disease (OR: 1.14, 95% CI 1.09, 1.18; p < 0.001). We conclude that glycemic control is not associated with AF in patients with T2DM

Diabetes mellitus type 2; The incretin effect and interaction with the autonomic nervous system

Bakgrunn: Inkretineffekten er kroppens evne til økt insulinsekresjon når glukose inntas peroralt sammenliknet med administrert intravenøst, utløst av spesifikke hormoner fra tarmen. En redusert inkretineffekt leder til forhøyet blodsukker etter måltid, og er et tidlig fenomen ved diabetes type 2, også påvist i forstadier til diabetes, såkalt prediabetes, og ved fedme. En bevart inkretineffekt ser delvis ut til å være avhengig av et intakt autonomt nervesystem. Autonom nevropati har vært betraktet som en sen komplikasjon til diabetes mellitus, men det er økende evidens for at nevropati også kan oppstå tidlig i forløpet. Kjennskap til disse faktorene ledet oss til en hypotese om at tidlig autonom nevropati kan bidra til den reduserte inkretineffekten ved diabetes type 2. Mål: Vårt primære mål var å undersøke om det var assosiasjon mellom inkretineffekt og grad av autonom nevropati. Sekundære mål var å se på inkretineffekten relatert til grad av hyperglykemi og varighet av diabetes, og sammenlikne en ny test som innebærer ballongdilatasjon i rektum, som mål for tarmens sensitivitet og videre signaloverføring, med mer etablerte tester for nevropati. Et siste sekundærmål var å undersøke gjennomførbarheten av en norsk versjon av spørreskjemaet, «Composite Autonomic Symptom Score» (COMPASS) 31, som kan påvise mulige symptomer fra autonom dysfunksjon, og vi testet om dette var assosiert med øvrige nerveundersøkelser. Metode: Tre grupper ble inkludert; en gruppe med diabetes type 2 varighet >10 år, en gruppe med nyoppdaget type 2 diabetes siste året, uten behov for medikamentell behandling, og en kontrollgruppe matchet for alder, kjønn og kroppsmasseindeks. Inkretineffekten ble kalkulert fra c-peptid (areal under kurven) ved oral glukosebelastning sammenliknet med intravenøs isoglykemisk glukose infusjon. Gastrointestinal glukose-håndtering (GIGD) ble kalkulert fra glukose gitt oralt sammenliknet med glukose tilført intravenøst. Tester for nevropati inkluderte kardiovaskulære reflekstester, hjertefrekvensvariabilitet, svettefunksjon, nerveledningshastighet i nervus suralis og monofilament test. Som mål på gastrointestinal visceral nervefunksjon utførte vi rektal ballongdilatasjon med registrering av trykk for første følelse av dilatasjon og ubehagelig følelse av dilatasjon. Evokerte hjernepotensial ble målt som respons på ballongdilatasjon ved gjentatte stimuli av nevnte trykk. Spørreskjemaet COMPASS 31 ble besvart digitalt. Resultat: Deltakerne med diabetes trengte høyere trykk for å oppnå første følelse av ballongdilatasjon i rektum, uavhengig av diabetesvarighet. Økt behov for trykk korrelerte med nedsatt GIGD, men ikke med inkretineffekt. Økt behov for trykk korrelerte også med nedsatt følelse på monofilament test. GIGD og inkretineffekt korrelerte signifikant med både grad av hyperglykemi og diabetesvarighet. Det ble funnet få tilfeller av nevropati totalt sett, og få forskjeller mellom gruppene. Det var en tendens til at lenger latenstid og mindre amplituder på evokerte hjernepotensial var assosiert med lavere hjertefrekvensvariabilitet og kardiovaskulære reflekstester, sural nerveledning og monofilament test, men ikke statistisk signifikant etter korreksjon for multippel testing. Høyere score på COMPASS 31 ble funnet hos dem med langvarig diabetes og hos kvinner, med best sensitivitet og negativ prediktiv verdi for score <10. Konklusjon: Vi fant rektal hyposensitivitet både ved langvarig og tidlig type 2 diabetes og dette var assosiert med redusert GIGD, men ikke med redusert inkretineffekt. Dette kan tyde på at adekvat nervefunksjon i tarmen er viktig for andre faktorer enn inkretineffekten i håndteringen av glukose. Redusert GIGD og inkretineffekt er assosiert med økende hyperglykemi og varighet av diabetes, som viser et kontinuum i tarmens glukosehåndtering fra normo- til hyperglykemi. Vi fant klinisk plausible tegn på at sentral nerveledning er assosiert med perifer nervefunksjon, men resultatene må tolkes med forsiktighet, gitt multippel testing. Rektal ballongdilatasjon med måling av sensitivitet og evokerte hjernepotensial synes å være en lovende metode for undersøkelse av nervefunksjon i tarmen, også når øvrige autonome tester er normale. Til sist finner vi spørreskjemaet COMPASS 31 lovende til bruk både i forskning, men også i den kliniske hverdag, hvor autonome symptomer ofte er neglisjert. I en liknende populasjon som vår vil en score på 10 poeng eller mindre nærmest utelukke kardiovaskulær autonom nevropati.Background: The incretin effect refers to the amplified insulin response when glucose is administered orally compared to intravenously. A reduced incretin effect is found at early stages of type 2 diabetes, even in prediabetes and obesity, but the mechanisms behind are unknown. Evidence suggests that part of the effect of incretin hormones are mediated through vagal nerve transmission. Diabetic autonomic neuropathy is considered a late complication of diabetes mellitus, but there is an increasing awareness that neuropathy can exist in both prediabetes and early stages of diabetes. This led us to the hypothesis that the incretin effect could be affected by early autonomic neuropathy because of a reduced transmission of signals. Aims: Our main objective was to explore whether a reduced incretin effect could be associated with autonomic neuropathy. Secondarily, we aimed to explore the incretin effect in relation to degree of dysglycemia and the duration of diabetes. Other secondary objectives were to explore a novel test of gut visceral sensitivity and central transmission of peripheral signals, and to compare it with established tests for diabetic neuropathy, including assessment of symptoms using the Composite Autonomic Symptom Score (COMPASS) 31. Methods: This was case-control study including three groups of participants: People with type 2 diabetes for >10 years (longstanding), people with newly discovered type 2 diabetes within the last year, without the need for antidiabetic medication (early), and a group of matched controls in age, sex, and body mass index. An oral glucose tolerance test followed by an intravenous isoglycemic glucose infusion were performed to calculate the incretin effect (from c-peptide area under the curve). Gastrointestinal-mediated glucose disposal (GIGD) was calculated as an estimate of the body’s ability to cope with the challenge of a carbohydrate ingestion. Neuropathy tests included cardiovascular reflex tests, heart rate variability, sudomotor function, sural nerve, and the monofilament test. Rapid rectal balloon distention measuring visceral sensitivity and evoked potentials was performed as a proxy for gut autonomic nerve function. The COMPASS 31 questionnaire was distributed and answered online. Results: Both groups of diabetes were hyposensitive to first sensation performing rapid rectal balloon distention. Also, those with reduced sensation performing the monofilament test showed hyposensitivity. A correlation was found between rectal hyposensitivity at the first sensation and reduced GIGD, but not with the incretin effect. Both GIGD and the incretin effect were found to correlate with degree of dysglycaemia and duration of diabetes, and were comparable to previous studies. Overall, few cases of confirmed neuropathy were detected, and there were few differences between groups regarding established neuropathy tests. Longer evoked potential latencies and smaller amplitudes plausibly correlated with lower heart rate variability and cardiovascular reflex test score, reduced parameters in the sural nerve test and monofilament sensation, but not statistically significant considering multiple testing. Higher scores in COMPASS 31 were correlated with longstanding diabetes and female sex. We found an acceptable negative predictive value for cardiovascular autonomic neuropathy at a 10-point cut-off . Conclusions: Rectal hyposensitivity may be an early manifestation of type 2 diabetes, and associated with GIGD, but not with the incretin effect. GIGD and the incretin effect are associated with degree of dysglycemia and duration of diabetes, indicating a continuum in the diminished effect. Central neuronal signal processing appears to be affected in parallel with peripheral neuronal function, but the results must be interpreted with caution. In general, we found that investigating evoked potentials following rapid rectal balloon distention may be a useful research tool for evaluating gut autonomic neuropathy, also when other autonomic neuropathy tests are normal. The Norwegian version of COMPASS 31 was easy to use and for assessing autonomic neuropathy in diabetes, and we suggest a cut off at ten points for screening purposes. Symptoms of autonomic neuropathy seems to be more frequent in people with longstanding diabetes and in women.Doktorgradsavhandlin

Quality of care in incident type 2 diabetes and initial presentation of vascular complications: Prospective cohort study using linked electronic health records from CALIBER research platform

Background. Numbers of new cases of type 2 diabetes (T2D) are increasing rapidly. Early and continuing intervention after T2D presentation is crucial for best possible outcomes, ensuring that the existing high burden of T2D will not be aggravated. Identification of patterns of continuous care and predictors for meeting key targets for T2D management can improve quality of care. Glycaemic control is particularly important for primary prevention of vascular complications but its relationship with contemporary cardiovascular diseases (CVDs) has been less explored. More importantly, long-term glycaemic control can be assessed from routine monitoring, potentially providing new insight into T2D management to prevent vascular complications. Linked electronic health records are invaluable data resources for investigating these issues. Objective. To examine the quality of care in an incident T2D cohort through assessment of temporal trends of care, predictors of glycaemic, blood pressure and lipid control, and associations of short-term and long-term glycaemic control with chronic vascular complications. Methods. The data source for studies in this thesis was CALIBER which links electronic health records from primary care, hospitalisation, myocardial infarction and mortality registries. Patients newly diagnosed with T2D between 1998 and 2010 were followed-up until a censoring administrative date or initial occurrence of vascular complications. Trends in receipt of care and attainment of glycaemic, blood pressure and total cholesterol targets were examined. Predictors for meeting the targets were explored using multinomial logistic regressions. Association of early glycaemic control with a range of specific cardiovascular complications were investigated using Cox regressions. A longitudinal metric for glycaemic control was developed by quantifying time spent at target during follow-up and was tested for its association with cardiovascular and microvascular outcomes using mixed logistic regressions. Results. A total of 52,379 incident T2D patients were identified with a median follow-up of over 4 years. Positive trends were observed for blood pressure and total cholesterol control, but not for glycaemic control, whilst attainment of HbA1c and blood pressure targets over time consistently fell short. Older age at diagnosis was an important predictor for meeting the key targets. In 36,149 patients free from prior CVD, early glycaemic and blood pressure control was associated with lower risk for heart failure and peripheral arterial disease, whereas cholesterol control with myocardial infarction and transient ischaemic attack. Shorter duration at glycaemic target was associated with higher risk of major adverse cardiovascular events, cardiovascular death and diabetic retinopathy. Conclusions. This thesis highlights missed opportunities and inequality in T2D care. Both short-term and long-term glycaemic control are important for reducing risk of vascular complications. Limitations and implications of the findings for clinical practice and research were discussed

Differences between risk factors for falling in homebound diabetics and non-diabetics

The purpose of this study was to identify the differences in fall risk factors between diabetic and non-diabetic homebound adults in a population identified at high risk for falls. The sample compared 210 non-diabetic homebound adults to 74 diabetic homebound adults. Five research hypotheses supported this study. It was hypothesized that, 1) incidence and severity of somatosensory changes in the feet of diabetics surpassed that of non-diabetics; 2) incidence of lower leg and foot pain in diabetics surpassed that of non-diabetics; 3) deficits in sensory integration would be greater in diabetics than non-diabetics; 4) balance deficits were more evident in diabetics and non-diabetics; and 5) fear of falling was more prominent in diabetics than in non-diabetics. An one-way ANOVA showed a significant difference in sensation between groups, with diabetics reporting less sensation than non-diabetics in all age categories. A small effect size limited external validity. No other significant differences emerged for the other fall risk factors. Gender and age category failed to influence differences between diagnostic groups

Factors predicting mortality in type 2 diabetes. With special reference to physical exercise, blood pressure, proteinuria, inflammation and P wave duration

Background: Type 2 diabetes patients have a 2-4 fold risk of cardiovascular disease (CVD) compared to the general population. In type 2 diabetes, several CVD risk factors have been identified, including obesity, hypertension, hyperglycemia, proteinuria, sedentary lifestyle and dyslipidemia. Although much of the excess CVD risk can be attributed to these risk factors, a significant proportion is still unknown. Aims: To assess in middle-aged type 2 diabetic subjects the joint relations of several conventional and non-conventional CVD risk factors with respect to cardiovascular and total mortality. Subjects and methods: This thesis is part of a large prospective, population based East-West type 2 diabetes study that was launched in 1982-1984. It includes 1,059 middle-aged (45-64 years old) participants. At baseline, a thorough clinical examination and laboratory measurements were performed and an ECG was recorded. The latest follow-up study was performed 18 years later in January 2001 (when the subjects were 63-81 years old). The study endpoints were total mortality and mortality due to CVD, coronary heart disease (CHD) and stroke. Results: Physically more active patients had significantly reduced total, CVD and CHD mortality independent of high-sensitivity C-reactive protein (hs-CRP) levels unless proteinuria was present. Among physically active patients with a hs-CRP level >3 mg/L, the prognosis of CVD mortality was similar to patients with hs-CRP levels ≤3 mg/L. The worst prognosis was among physically inactive patients with hs-CRP levels >3 mg/L. Physically active patients with proteinuria had significantly increased total and CVD mortality by multivariate analyses. After adjustment for confounding factors, patients with proteinuria and a systolic BP <130 mmHg had a significant increase in total and CVD mortality compared to those with a systolic BP between 130 and 160 mmHg. The prognosis was similar in patients with a systolic BP <130 mmHg and ≥160 mmHg. Among patients without proteinuria, a systolic BP <130 mmHg was associated with a non-significant reduction in mortality. A P wave duration ≥114 ms was associated with a 2.5-fold increase in stroke mortality among patients with prevalent CHD or claudication. This finding persisted in multivariable analyses. Among patients with no comorbidities, there was no relationship between P wave duration and stroke mortality. Conclusions: Physical activity reduces total and CVD mortality in patients with type 2 diabetes without proteinuria or with elevated levels of hs-CRP, suggesting that the anti-inflammatory effect of physical activity can counteract increased CVD morbidity and mortality associated with a high CRP level. In patients with proteinuria the protective effect was not, however, present. Among patients with proteinuria, systolic BP <130 mmHg may increase mortality due to CVD. These results demonstrate the importance of early intervention to prevent CVD and to control all-cause mortality among patients with type 2 diabetes. The presence of proteinuria should be taken into account when defining the target systolic BP level for prevention of CVD deaths. A prolongation of the duration of the P wave was associated with increased stroke mortality among high-risk patients with type 2 diabetes. P wave duration is easy to measure and merits further examination to evaluate its importance for estimation of the risk of stroke among patients with type 2 diabetes.Siirretty Doriast

Towards Early Risk Stratification in Children and Adolescents with Type 1 Diabetes

The general objective of this thesis is to improve this risk stratification in children and adolescents with type 1 diabetes, aiming to fill a scientific gap by studying some underexposed complication fields in pediatrics