Glucose metabolism in preclinical type 1 diabetes

Abstract Type 1 diabetes is considered to be a T cell-mediated autoimmune disease characterized by destruction of the pancreatic beta cells. Its prediction is currently based on diabetes-associated autoantibodies, giving a cumulative risk of 84% during 15 years of follow-up since seroconversion. Prediction of the timing of clinical onset has remained challenging, however. This thesis examines glucose metabolism in autoantibody-positive children with a high risk of developing type 1 diabetes. Out of a total of 14,876 children with an increased genetic risk followed up from birth in the Finnish DIPP study, 567 developed ≥2 autoantibodies during the follow-up and 255 of these (45%) were diagnosed with type 1 diabetes until the end of December 2011. The glucose parameters measured were HbA1c, OGTT and random plasma glucose with 3 to 12 months interval. Seven-day continuous glucose monitoring (CGM) was performed on an age and sex-matched cohort. We showed that rising HbA1c, impaired glucose tolerance in OGTT, random plasma glucose values of ≥7.8mmol/l and potentially CGM can predict type 1 diabetes with a median time to diagnosis of approximately one year. Our results suggest that especially HbA1c and random plasma glucose are cost-effective and improve the prediction of diabetes. These markers may be useful for monitoring the response to treatment in prevention studies.Tiivistelmä Tyypin 1 diabetesta pidetään T-soluvälitteisenä autoimmuunitautina, joka johtaa haiman beetasolujen tuhoutumiseen. Tyypin 1 diabeteksen ennustaminen perustuu tällä hetkellä diabetekseen assosioituviin vasta-aineisiin, jotka antavat 84% kumulatiivisen riskin 15 vuoden seurannassa. Taudin puhkeamisen ajankohdan ennustaminen on kuitenkin edelleen vaikeaa. Tämä väitöskirja käsittelee glukoosiaineenvaihduntaa vasta-ainepositiivisilla lapsilla, joilla on suurentunut riski sairastua tyypin 1 diabetekseen. Suomalaisessa DIPP-tutkimuksessa vasta-aineiden kehittymistä on seurattu yhteensä 14876 lapselta. Seurannan aikana 567 lasta kehitti ≥2 autovasta-ainetta ja näistä 255 (45%) sairastui tyypin 1 diabetekseen joulukuun loppuun 2011 mennessä. Glukoosiaineenvaihduntaa seurattiin tutkimalla HbA1c, OGTT ja satunnaisia verensokeriarvoja 3-12 kuukauden välein. Ikä ja sukupuolivakioidussa kohortissa tehtiin jatkuvan sokeripitoisuuden seuranta (CGM). Tutkimuksessamme nouseva HbA1c, heikentynyt sokerin sieto OGTT-kokeessa, satunnainen verensokeri ≥7.8 mmol/l ja mahdollisesti CGM ennustavat tyypin 1 diabeteksen puhkeamista. Tulostemme perusteella erityisesti kustannustehokkaat HbA1c ja satunnainen verensokeri parantavat diabeteksen ennustamista. Nämä parametrit saattavat olla hyödyllisiä myös preventiotutkimuksissa hoitovasteen seurannassa

Fyysisen suorituskyvyn merkitys ruokatorvi- ja keuhkosyövän leikkaushoidossa

Tiivistelmä JOHDANTO: Tutkimuksessamme arvioitiin porrastestin hyötyjä vakavien komplikaatioiden ja kuolleisuuden ennustajana vaativassa syöpäkirurgiassa. POTILAAT JA MENETELMÄT: Aineiston muodostivat Keski-Suomen keskussairaalassa vuosina 2012–2021 leikatut 495 ruokatorvi- ja keuhkosyöpäpotilasta. Porrastestistä muodostettiin kolme ryhmää: yli 14 metriä (neljä kerrosta), 10–14 metriä (3–4 kerrosta) ja alle kymmenen metriä (alle kolme kerrosta) nousevat. Potilaat vastasivat myös suorituskykykyselyyn. Päätemuuttujat olivat vakavat komplikaatiot, kuolleisuus 90 vuorokauden kuluessa, viiden vuoden kokonaiskuolleisuus sekä kuolemat muuhun kuin syöpään. TULOKSET: Vakavia komplikaatioita ilmaantui eniten huonon (alle 10 m) suorituskyvyn ryhmässä (23 %) verrattuna 10–14 metrin (12 %) ja yli 14 metrin (11 %) ryhmiin (p = 0,037). Yhdeksänkymmenen vuorokauden kuolleisuus oli vastaavasti 10 %, 4,1 % ja 0,7 % (p < 0,001), ja viiden vuoden elossaolo-osuudet olivat 45 %, 36 % ja 69 % (p < 0,001). Kun tarkasteltiin muita kuin syövästä johtuvia kuolemia, elossaolo-osuudet olivat 47 %, 66 % ja 88 % (p < 0,001). Monimuuttujamallissa porrastestitulos oli kuolleisuuden lisääntymisen itsenäinen riskitekijä. PÄÄTELMÄT: Suorituskyky vaikuttaa ruokatorvi- ja keuhkosyöpäkirurgiassa potilaan hoitolinjaukseen, leikkauskomplikaatioihin ja pitkän ajan tuloksiin

Fragility Index, power, strength and robustness of findings in sports medicine and arthroscopic surgery:a secondary analysis of data from a study on use of the Fragility Index in sports surgery

Abstract Background: A recent study concluded that most findings reported as significant in sports medicine and arthroscopic surgery are not “robust” when evaluated with the Fragility Index (FI). A secondary analysis of data from a previous study was performed to investigate (1) the correctness of the findings, (2) the association between FI, p-value and post hoc power, (3) median power to detect a medium effect size, and (4) the implementation of sample size analysis in these randomized controlled trials (RCTs). Methods: In addition to the 48 studies listed in the appendix accompanying the original study by Khan et al. (2017) we did a follow-up literature search and 18 additional studies were found. In total 66 studies were included in the analysis. We calculated post hoc power, p-values and confidence intervals associated with the main outcome variable. Use of a priori power analysis was recorded. The median power to detect small (h > 0.2), medium (h > 0.5), or large effect (h > 0.8) with a baseline proportion of events of 10% and 30% in each study included was calculated. Three simulation data sets were used to validate our findings. Results: Inconsistencies were found in eight studies. A priori power analysis was missing in one-fourth of studies (16/66). The median power to detect a medium effect size with a baseline proportion of events of 10% and 30% was 42% and 43%, respectively. The FI was inherently associated with the achieved p-value and post hoc power. Discussion: A relatively high proportion of studies had inconsistencies. The FI is a surrogate measure for p-value and post hoc power. Based on these studies, the median power in this field of research is suboptimal. There is an urgent need to investigate how well research claims in orthopedics hold in a replicated setting and the validity of research findings

Ruokatorven korroosiovammat:tunnista vaikeat

Tiivistelmä Myrkytystietokeskukseen tulee vuosittain noin 30 puhelua, joissa syövyttävää happoa tai emästä on otettu suun kautta, ja noin 200 puhelua, joissa tiedetään tai epäillään, että henkilö on niellyt pariston. Oireettomissa ja lievissä happo- ja emäsaltistuksissa päivystyskäynti ei usein ole tarpeellinen tai potilas voidaan kotiuttaa lyhyen seurannan jälkeen. Merkittävissä altistuksissa päivystyksellinen tietokonekuvantaminen on tarkin keino vamman laajuuden arvioinnissa. Pinnalliset nekroosit aiheuttavat parantuessaan ruokatorven ahtaumia. Jos ruokatorvi puhkeaa korroosiovamman seurauksena, joudutaan päivystykselliseen leikkaushoitoon. Merkittäviin ruokatorven korroosiovammoihin liittyy kohonnut syöpäriski, joskin latenssiaika on yli 20 vuotta. Vaikeiden korroosiovammojen akuuttivaiheen ja myöhäiskomplikaatioiden hoito kuuluu ruokatorvikirurgian keskuksiin

Tutkimustulokset eivät toistu:missä syy?

Tiivistelmä Tieteellisten havaintojen toistettavuus on keskeisin luotettavan tutkimuksen ominaisuus. Tutkimuslöydös on uskottava, jos se on toistettavissa aina uudelleen. Toistettavuusongelmalla tarkoitetaan, että aiemmin julkaistut tutkimuslöydökset eivät ole vahvistettavissa tai todennettavissa uusissa, riippumattomissa tutkimuksissa. Toistettavuusongelman tärkeimpiä syitä ovat tilastollisen merkitsevyyden tarkoitushakuinen etsiminen ("kalastelu"), virheelliset tilastolliset menetelmät ja toimintatavat, pieni tilastollinen voima sekä erilaiset harhakäsitykset. Tieteellisiä tutkimuksia lukevan on tärkeää ymmärtää, millaiset keinot toisaalta vahvistavat ja toisaalta heikentävät tutkimustulosten toistettavuutta.Abstract Reproducibility of scientific findings and results is in the core of modern science. Issue of irreproducibility is raised when previous finding cannot be replicated or reproduced in a new, separate experiment. Major issues resulting in problems with reproducibility are fishing, flawed statistical methods and procedures, low statistical power and misconceptions in general. Clinicians and researchers who read and assimilate scientific research papers must understand which factors are crucial for reproducibility of the studies and which factors should be a cause for concern

Early glucose metabolism in children at risk for type 1 diabetes based on islet autoantibodies compared to low-risk control groups

Abstract Background: Anatomic variation or early differences in glucose metabolism have been linked to the development of type 1 diabetes. We aimed to describe early glucose metabolism based on HbA1c, oral glucose tolerance test (OGTT), and random plasma glucose years before the presentation of type 1 diabetes in five risk groups based on autoantibody combinations. For the first time, we were able to include for comparison children with very low risk of progression to type 1 diabetes. Methods: The Finnish Diabetes Prediction and Prevention birth cohort study screened newborn infants for HLA susceptibility to type 1 diabetes since 1994. Those carrying a risk genotype were prospectively followed up with islet autoantibody testing. Glucose parameters were obtained starting from the time of seroconversion. By 31 August 2014, 1162 children had developed at least one islet autoantibody and were included in the current study. Type 1 diabetes was diagnosed in 335 children (progressors). In the non-progressor groups, 207 developed multiple (≥2) biochemical islet autoantibodies, 229 a single biochemical autoantibody, 370 ICA only, and 64 transient autoantibodies. Children were divided into five risk groups. Glucose metabolism was evaluated. Results: We observed lower HbA1c values in early follow-up 4.5 to 6.0 years before diagnosis in the progressors when compared to the same time in children with a single biochemical autoantibody or low-risk (ICA only and transient) participants, who did not progress to clinical type 1 diabetes. However, no such differences were observed in OGTTs or random plasma glucose. The variation was minimal in glucose values in the low-risk groups. Conclusion: We report the possibility of early alteration in glucose metabolism in future progressors. This could suggest early defects in multiple glucose-regulating hormones

CD3⁺, CD8⁺, CD4⁺ and FOXP3⁺ T cells in the immune microenvironment of small bowel neuroendocrine tumors

Abstract The role of inflammation in neuroendocrine tumors is poorly known. The purpose of this study was to characterize the densities of CD3⁺, CD8⁺, CD4⁺ and FOXP3⁺ T cells in small bowel neuroendocrine tumors (SB-NETs), SB-NET lymph node metastases and gastric neuroendocrine tumors (G-NETs) to assess the prognostic role of immune cell infiltrates in SB-NETs. The final cohort included 113 SB-NETs, 75 SB-NET lymph node metastases and 19 G-NETs from two Finnish hospitals. CD3⁺- and CD8⁺-based immune cell score (ICS), and other T cell densities were evaluated. Survival analyses of SB-NETs and SB-NET lymph node metastases were performed with the Kaplan-Meier method and Cox regression adjusted for confounders. The primary outcome was disease-specific survival (DSS). No significant difference in DSS was seen between low and high ICS groups in SB-NETs at 5 years (92.6% vs. 87.8%) or 10 years (53.8% vs. 79.4%), p = 0.507, or in SB-NET lymph node metastases at 5 years (88.9% vs. 90.4%) or 10 years (71.1% vs. 59.8%), p = 0.466. Individual densities of the examined T cell types showed no correlation with prognosis either. SB-NETs and lymph node metastases had similar inflammatory cell profiles, whereas in G-NETs CD3⁺ and CD8⁺ T cells were particularly more abundant. In SB-NETs, ICS or T cell densities showed no correlation with prognosis

First-emerging islet autoantibody and glucose metabolism:search for type 1 diabetes subtypes

Abstract Objectives: Subtypes in type 1 diabetes pathogenesis have been implicated based on the first-appearing autoantibody (primary autoantibody). We set out to describe the glucose metabolism in preclinical diabetes in relation to the primary autoantibody in children with HLA-conferred disease susceptibility. Design and methods: Dysglycemic markers are defined as a 10% increase in HbA1c in a 3–12 months interval or HbA1c ≥5.9% (41 mmol/mol) in two consecutive samples, impaired fasting glucose or impaired glucose tolerance, or a random plasma glucose value ≥7.8 mmol/L. A primary autoantibody could be detected in 295 children who later developed at least 1 additional biochemical autoantibody. These children were divided into three groups: insulin autoantibody (IAA) multiple (n  = 143), GAD antibody (GADA) multiple (n  = 126) and islet antigen 2 antibody (IA-2A) multiple (n  = 26). Another 229 children seroconverted to positivity only for a single biochemical autoantibody and were grouped as IAA only (n  = 87), GADA only (n   = 114) and IA-2A only (n  = 28). Results: No consistent differences were observed in selected autoantibody groups during the preclinical period. At diagnosis, children with IAA only showed the highest HbA1c (P < 0.001 between groups) and the highest random plasma glucose (P = 0.005 between groups). Children with IA-2A only progressed to type 1 diabetes as frequently as those with IA-2A multiple (46% vs 54%, P = 0.297) whereas those with IAA only or GADA only progressed less often than children with IAA multiple or GADA multiple (22% vs 62% (P < 0.001) and 7% vs 43% (P < 0.001)), respectively. Conclusions: The phenotype of preclinical diabetes defined by the primary autoantibody is not associated with any discernible differences in glucose metabolism before the clinical disease manifestation

Results of intention-to-treat pulmonary metastasectomies in northern Finland revealing significant number of new lung primary carcinomas:time to move on from wedge resections?

Abstract Background: A considerable proportion of intended pulmonary metastasectomies is known to turn out as new incidental primary lung cancers in final pathology. We aimed to analyse the trends and results of pulmonary metastasectomies using the intention-to-treat approach with an emphasis on final histopathological findings. Methods: All intention-to-treat pulmonary metastasectomies performed in Oulu University Hospital between 2000 and 2020 were included in the study. Long term survival was analysed with the Kaplan-Meier method and log-rank tests. A binary logistic regression analysis was performed to calculate odds ratios for incidental primary lung cancer in final histology. Results: A total of 154 intended pulmonary metastasectomies were performed to 127 individual patients. There was an increasing trend in pulmonary metastasectomies during the study period. Despite the increasing trend in comorbidities of the operated patients, the length of hospital stays decreased, and the postoperative complication rates remained stable. In final pathology reports, 9.7% were new primary lung cancers and 13.0% were benign nodules. A long disease-free interval (≥24 months) and smoking history were associated with incidental primary lung cancer in final histology. The short-term 30- and 90-day mortalities after pulmonary metastasectomy were 0.7%. The 5-year survival after pulmonary metastasectomy from all histologies was 52.8%, and from colorectal cancer metastasectomies (n=34) it was 73.5%. Conclusions: The significant amount of new primary lung cancer lesions in pulmonary metastasectomy specimens highlight the diagnostic importance of pulmonary metastasectomy. A segmentectomy could be considered as a primary procedure in pulmonary metastasectomy in patients with a long disease-free interval and a heavy smoking history