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The deployment of machine learning for tasks relevant to complementing standard of care and advancing tools for precision health has gained much attention in the clinical community, thus meriting further investigations into its broader use. In an introduction to predictive modelling using machine learning, we conducted a review of the recent literature that explains standard taxonomies, terminology and central concepts to a broad clinical readership. Articles aimed at readers with little or no prior experience of commonly used methods or typical workflows were summarised and key references are highlighted. Continual interdisciplinary developments in data science, biostatistics and epidemiology also motivated us to further discuss emerging topics in predictive and data-driven (hypothesis-less) analytics with machine learning. Through two methodological deep dives using examples from precision psychiatry and outcome prediction after lymphoma, we highlight how the use of, for example, natural language processing can outperform established clinical risk scores and aid dynamic prediction and adaptive care strategies. Such realistic and detailed examples allow for critical analysis of the importance of new technological advances in artificial intelligence for clinical decision-making. New clinical decision support systems can assist in prevention and care by leveraging precision medicine.

Aims. Oral anticoagulation (OAC), predominantly with warfarin, is an effective treatment to prevent thromboembolic events. Serious bleeding is a frequent and feared treatment complication. In this ...

To investigate the risk of a first myocardial infarction (MI) and sudden cardiac death (SCD) amongst male snuff users.We used a prospective incident case-referent study design nested in the population-based Västerbotten Intervention Program and the Northern Sweden MONICA study.Tobacco habits and cardiovascular risk factors were assessed at baseline screening and compared in 525 male MI cases (including 93 SCD cases) and 1798 matched referents.Myocardial infarction occurred on average 4 years and 2 months after the baseline screening. No increased risk for MI was found amongst snuff users without a previous history of smoking compared with nontobacco users after adjustments for body mass index, leisure time physical activity, educational level and cholesterol level (OR 0.82; 95% CI, 0.46-1.43). For snuff users with a previous history of smoking, the adjusted OR was 1.25 (95% CI, 0.80-1.96). Significantly increased risk for MI was found in current smokers with or without current snuff use. For SCD cases with survival time24 h, the adjusted OR for snuff users without previous history of smoking was 1.18 (95% CI, 0.38-3.70) and for cases with survival time1 h the OR was 0.38 (95% CI, 0.08-1.89).We found no increased risk for MI amongst snuff users without a previous history of smoking. Amongst snuff users with a previous history of smoking, the tendency towards an increased risk for MI may reflect the residual risk from former smoking. This study does not support the hypothesis that the risk for SCD is increased amongst snuff users.

Skelleftea Hospital, and Umea University Hospital, Background. Unstable coronary artery disease (CAD) is a multi-factorial disease involving thrombotic and inflammatory processes. Short-term low molecular weight (LMW) heparin treatment reduces coagulation activity and clinical events. We investigated the influence of prolonged treatment on coagulation, fibrinolysis and inflammation. Methods and results. Serial blood samples were obtained from 555 of 2267 unstable CAD patients in the FRISC II study. Patients were treated with the LMW heparin dalteparin 120 IU kg -1 s.c. twice daily for 5-7 days and randomized to placebo (n = 285) or gender and weight-adjusted doses of dalteparin (5000 or 7500 IU) twice daily (n = 270) for 3 months. Dalteparin persistently depressed coagulation activity with, when compared with placebo, lower median levels of factor VIIa (63 IU mL -1 vs. 84 IU mL -1 ), prothrombin fragment 1 + 2 (0.86 nmol L -1 vs. 1.09 nmol L -1 ) and D-dimer (21 μg L -1 vs. 43 μg L -1 ) after 3 months, all P < 0.01. Reactivation of coagulation activity was observed after cessation of both short-term and prolonged dalteparin treatment. Higher levels of tPA/PAI-1 complex (11.7 μg L -1 vs. 6.5 μg L -1 , P < 0.001) and von Willebrand factor (162% vs. 136%, P < 0.001) were found during prolonged dalteparin treatment. Interleukin-6, C-reactive protein and fibrinogen levels were unaffected by dalteparin treatment. Conclusions. Three months dalteparin treatment resulted in a sustained and pronounced reduction of coagulation activity, which corresponds to the observed reduction in death and myocardial infarction during the initial 6 weeks in the FRISC II study. The persistently elevated levels of tPA/PAI-1 complex and von Willebrand factor might reflect effects on platelets and endothelial cells and thus contribute to the gradually decreased efficacy by prolonged dalteparin treatment in unstable CAD.

Antibacterial peptides are the effector molecules of innate immunity. Generally they contain 15-45 amino acid residues and the net charge is positive. The cecropin type of linear peptides without cysteine were found first in insects, whilst the defensin type with three disulphide bridges were found in rabbit granulocytes. Now a database stores more than 800 sequences of antibacterial peptides and proteins from the animal and plant kingdoms. Generally, each species has 15-40 peptides made from genes, which code for only one precursor. The dominating targets are bacterial membranes and the killing reaction must be faster than the growth rate of the bacteria. Some antibacterial peptides are clearly multifunctional and an attempt to predict this property from the hydrophobicity of all amino acid side chains are given. Gene structures and biosynthesis are known both in the fruit fly Drosophila and several mammals. Humans need two classes of defensins and the cathelicidin-derived linear peptide LL-37. Clinical cases show that deficiencies in these peptides give severe symptoms. Examples given are morbus Kostmann and atopic allergy. Several antibacterial peptides are being developed as drugs.

Johansson A, Boman K, Cederquist K, Forsberg H, Olsson T (Umea University Hospital, Umea, Skelleftea County Hospital, Skelleftea, and Boden Hospital, Boden, Sweden). Increased levels of tPA antigen and tPA/PAI-1 complex in myotonic dystrophy. J Intern Med 2001; 249: 503–510. Objective. To assess the fibrinolytic system in myotonic dystrophy (DM1), a disease connected to features of the metabolic syndrome, including a prominent insulin resistance, increased body fat mass, and hypertriglyceridaemia. We hypothesized that abnormalities in the fibrinolytic system are linked to metabolic dysfunction in DM1. Design. Circulating morning levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1) antigens, tPA/PAI-1 complex, lipids and insulin were determined. Genetic analyses, including calculation of allele size, were performed in all patients. Body fat mass was estimated with bioelectrical impedance analysis. Setting. Out-patient clinic in collaboration with Umea University Hospital. Subjects. A total of 42 otherwise healthy patients with DM1 (22 men, 20 women; median age 41.5 years) and 50 controls (27 men, 23 women; median age 42.0 years). Main outcome measures. The tPA and PAI-1 antigens, tPA/PAI-1 complex, blood lipids and body fat mass. Results. The tPA antigen and tPA/PAI-1 complex levels were significantly increased in DM1 patients (P

Diabetes mellitus and obstructive sleep apnoea (OSA) are two prevalent medical problems. Both are strongly associated with obesity and hypertension. The aim of this study was to investigate whether the association between OSA and diabetes is entirely dependent on obesity in hypertensive men.A population-based study.The municipality of Uppsala, Sweden. Subjects and methods. In 1994, 2668 men aged 40-79 years answered a questionnaire regarding snoring, sleep disturbances and somatic diseases. An age-stratified sample of 116 hypertensive men was selected for a whole-night sleep study. Twenty-five of them had diabetes, defined as reporting regular medical controls for diabetes or having a fasting blood glucoseor =6.1 mmol L(-1).The prevalence of severe OSA, defined as apnoea-hypopnoea index (AHI)or =20 h(-1) was significantly higher in diabetic patients than in normoglycaemic subjects (36 vs. 14.5%, P0.05). The sample was divided into four groups based on the presence or absence of severe OSA and the presence or absence of central obesity, defined as waist-to-hip ratio (WHR)or =1.0. In a logistic regression model with the non-OSA, WHR1.0 as the reference group, the adjusted odds ratio (95% confidence interval) for diabetes was 11.8 (2.0-69.8) in the OSA, WHRor =1.0 group, whilst it was 3.6 (0.9-14.8) in the non-OSA, WHRor =1.0 group and 5.7 (0.3-112) in the OSA, WHR1.0 group. In a linear regression model, after adjustment for WHR, there was a significant relationship between variables of sleep-disordered breathing and fasting insulin, glucose and haemoglobin A1c.We conclude that, in hypertensive men, although obesity is the main risk factor for diabetes, coexistent severe OSA may add to this risk. Sleep breathing disorders, independent of central obesity, may influence plasma insulin and glycaemia.

Ohgren B, Weinehall L, Stegmayr B, Boman K, Hallmans G, Wall S (Umea University and Skelleftea County Hospital, Umea, Sweden). What else adds to hypertension in predicting stroke? An incident case–referent study. J Intern Med 2000; 248: 475–482. Objectives. To examine to what extent traditional biomedical risk factors and social factors can predict, separately or jointly, first-ever stroke event, and to explore to what extent other risk factors might add to hypertension/elevated blood pressure as a stroke risk factor. Design. An incident case–referent study. Setting. The study was nested within the Vasterbotten Intervention Program (VIP) and the Northern Sweden MONICA cohorts. Subjects. The study involves 129 stroke cases with two randomly selected referents per case from the same study cohorts. Results. History of diabetes, daily smoking, obesity (body mass index ≥ 30 kg m−2), hypertension and living as an unmarried person were associated with an increased risk in univariate analysis. However, in the multivariate logistic regression analysis, only hypertension, diabetes and single marital status remained significant. There was a statistically significant interaction between hypertension and smoking and stroke. Interaction of possible clinical relevance was also observed between hypertension, history of diabetes and stroke. Conclusions. The study both emphasizes the multifactorial nature of stroke and illustrates that knowledge of interactions offers different strategic approaches when preventing stroke in clinical work. It is important, but not enough, to focus on blood pressure control. Diabetes prevention as well as prevention of smoking must also be considered as factors of major importance.

There are many similarities between diabetes (mainly type 2) and sleep breathing disturbances regarding risk factors, anthropometric criteria and consequences of morbidity and mortality. The aim of this study was to investigate whether the association between habitual snoring and diabetes is entirely dependent on obesity.A population-based prospective study.The municipality of Uppsala, Sweden.In 1984 and in 1994, 2668 men aged 30-69 years at baseline answered questionnaires concerning sleep breathing disturbances and somatic diseases.Of those with habitual snoring in 1984, 5.4% reported that they had developed diabetes during the 10-year period compared with 2.4% of those without habitual snoring (P0.001). Amongst obese snorers, 13.5% developed diabetes compared with 8.6% of obese non-snorers (P = 0.17). In a multiple logistic regression model, the odds ratio (95% confidence interval) for development of diabetes was higher in obese snorers [7.0 (2.9-16.9)] than in obese non-snorers [5.1 (2.7-9.5)] after adjustment for age, weight gain, smoking, alcohol dependence and physical inactivity.We conclude that, in males aged 30-69 years, habitual snoring is associated with an increased incidence of diabetes within 10 years. Although obesity is the main risk factor for developing diabetes, coexistent habitual snoring may add to this hazard.

To study the geographical variation in daytime sleepiness, snoring and disrupted breathing during sleep and to identify and compare risk factors using the same method in four European cities.A cross-sectional, multicentre epidemiological survey.Reykjavik in Iceland, Uppsala and Göteborg in Sweden and Antwerp in Belgium.A random population sample of 2202 subjects who participated in the European Community Respiratory Health Survey.Sleep disturbances and daytime symptoms.At all the centres, 5% of the men and 2-3% of the women reported snoring every night. Daytime sleepiness (DS) was more often reported in Uppsala [odds ratio (OR) and 95% confidence interval: 1.6 (1.2-2.1)] than in the other centres, whilst daytime tiredness (DT) was most common in Reykjavik [ OR 1.8 (1.4-2.1)]. Snoring was positively correlated with age, male gender and body-mass index in all areas. Symptoms of gastro-oesophageal reflux were associated with DS: OR 2.6 (1.5 4.4) and DT: OR 4.5 (2.7-7.6) and disrupted breathing: OR 3.8 (1.4-10). DS and DT were reported more often by women than by men.The prevalence of snoring was about the same in all four areas, whilst there was a geographical variation in daytime sleepiness and tiredness. As complaints of DS and DT and disrupted breathing were more common in subjects who reported symptoms of gastro-oesophageal reflux, we suggest that polysomnographic studies comparing sleep patterns in adult patients with and without reflux should be conducted.

Objectives. To test whether von Willebrand factor, a new cardiovascular risk factor, belongs to the group of risk factors forming part of the insulin resistance syndrome. Design. A population-based, age-stratified, cross-sectional study. Setting. A primary health care centre. Subjects. All subjects aged 35, 45, 55, and 65 years in Norsjo municipality (n = 265) were invited, and 68% (82 males, 93 females) entered and completed the study. Results. von Willebrand factor did not correlate with any measured lipid, anthropometric, or glucose metabolism variable. The higher levels of cardiovascular risk factors found in the subgroup of patients with electrocardiographical signs of ischaemic heart disease did not confound this result. Conclusion. von Willebrand factor plasma concentration is unrelated to the metabolic factors involved in the insulin resistance syndrome. Thus, it may be difficult to reduce elevated von Willebrand factor levels by conventional non-pharmacological cardiovascular high-risk intervention schemes.

Oral anticoagulation (OAC), predominantly with warfarin, is an effective treatment to prevent thromboembolic events. Serious bleeding is a frequent and feared treatment complication. In this longitudinal cohort study of OAC-treated patients, we aimed to evaluate the relationship between von Willebrand factor (VWF) levels and risk of bleeding complications, cardiovascular mortality and all-cause mortality.A total of 719 patients receiving warfarin treatment were observed for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified into clinically relevant bleeding (CRB) and major bleeding. Ischaemic stroke, peripheral arterial embolism, myocardial infarction, and death were also recorded. We identified 113 cases of CRB and 73 of major bleeding. In total, 161 deaths occurred during follow-up with cardiovascular disease identified as the cause of death in 110 patients. Patients in the highest tertile of VWF had a significantly increased risk of bleeding complications: hazard ratio (HR) 2.53 (95% CI 1.41-4.56) for major bleeding and HR 2.19 (95% CI 1.38-3.48) for CRB. VWF, expressed either in tertiles or as a continuous variable, showed a significant association with cardiovascular mortality (HR 1.68, 95% CI 1.40-2.01) and all-cause mortality (HR 1.77, 95% CI 1.52-2.05). In multivariate Cox regression analysis, the findings remained significant after adjusting for age, high-sensitivity C-reactive protein and creatinine.Patients with high levels of VWF had an increased risk of bleeding complications, cardiovascular mortality and all-cause mortality during OAC treatment. Our findings imply that the use of VWF as a risk marker for thromboembolic events is complicated by the association of VWF with bleeding complications.

To test the hypothesis that increased blood pressure and hyperlipidaemia result in changes in the fibrinolytic system, 84 subjects with both hypertension and elevated serum cholesterol levels (the high risk group) were compared with 55 controls matched with respect to age, sex and body mass index (BMI). Plasminogen activator inhibitor (PAI-1), and tissue plasminogen activator (tPA) antigen and activity were measured before and after venous occlusion. In the high risk group, tPA activity was significantly lower both before and after venous occlusion and PAI-1 levels were significantly higher. In a multivariate analysis the triglyceride levels, diastolic blood pressure and cholesterol levels were independently associated with the PAI-1 levels. Diastolic blood pressure was independently and inversely associated with resting tPA activity. We conclude that patients with hypertension and hyperlipidaemia have a reduced activity of the fibrinolytic system, an effect which is unrelated to differences in age, sex, smoking or BMI.

This study was performed to evaluate hypothalamic-pituitary hormone regulation in patients with familial amyloidotic polyneuropathy. Twenty-two patients without clinically overt endocrinological dysfunction were studied. A thyrotropin-releasing hormone test revealed abnormal growth hormone regulation in 9 of 17 (53%) patients, and abnormal prolactin regulation in 9 of 18 (50%) patients. Abnormalities in either growth hormone or prolactin regulation were found in 12 of 17 (71%) patients. Serum somatomedin C levels were normal in all 22 patients. In 3 of 18 (17%) patients the plasma arginine vasopressin levels were low relative to the serum osmolality levels. Thus abnormalities in hypothalamic-pituitary hormone regulation may be common in familial amyloidotic polyneuropathy.

To evaluate tissue plasminogen activator (tPA) activity as a measure of fibrinolytic response to treatment with streptokinase (SK) and to relate this to the effect of pretreatment SK antibodies and to successful reperfusion assessed by continuous computerized vectorcardiography (VCG).Umeå University Hospital.A total of 104 patients with acute myocardial infarction (AMI) treated with SK and no history of previous SK treatment were studied. The tPA activity was measured 4 h after the start of treatment. The effect of pre-existing neutralizing antibodies to SK was analysed with a functional assay in pretreatment samples. Reperfusion was evaluated with VCG.Successful reperfusion.Fifty-five patients (53%) were classified as successfully reperfused. The risk for failed reperfusion was calculated in logistic regression models. In a univariate model, a borderline significant increase in the risk of failed reperfusion was observed in intermediate levels of SK neutralizing antibodies, but not in the highest levels. In a multivariate model, only high tPA activity,25 U mL(-1), at 4 h (OR 0.17: 95% CI: 0.06-0.51) was associated with a higher rate of reperfusion whilst longer time to treatment (OR 1.17; 95% CI: 1.02-1.35) was associated with a higher risk of failed reperfusion. There was no significant correlation between neutralizing antibodies to SK and tPA activity at 4 h.The SK treatment of AMI induced high levels of tPA activity which were associated with successful reperfusion. The effect of pre-existing SK antibodies had no significant influence on reperfusion and were not correlated to the fibrinolytic activity obtained.

Objectives To assess the importance of biomedical risk factors, social factors and self-reported health in the prediction of the first event of acute myocardial infarction (AMI) in an apparently healthy middle-aged population. Design An incident case–control study. Setting The study was nested within the Vasterbotten Intervention Program and the Northern Sweden MONICA cohorts. Subjects The study consists of 78 AMI cases with two randomly selected controls per case from the same study cohorts. Results Significant odds ratios were found for history of diabetes, daily smoking, cholesterol, body–mass index, hypertension, lower education and perceived ill health. In multivariate logistic regression smoking, hypertension and cholesterol of ≥7.8 mmol L−1 remained significant. An interaction was observed between number of biomedical risk factors and perceived health. Conclusions Smoking, hypertension and hypercholesterolaemia explain a major share of incident AMI events in a Swedish middle-aged population. The study further illustrates that perceived ill health negatively modifies the impact of these risk factors.

Intravenous immunoglobulin (IVIG) has been successfully used to treat autoimmune diseases. We report dramatic, rapid and sustained responses to its use in two cases of vasculitis: a patient with primary angitis of the central nervous system: and a patient with hepatitis-B-antigen-related polyarteritis nodosa, who failed treatment with corticosteroids. Improvement in gait and a marked decrease in serum creatinine, respectively, were observed within 24 h of the first dose of IVIG. Both patients remained stable for several months. We conclude that IVIG should be considered in patients with vasculitis who fail corticosteroids, or when a rapid response is required.

This study was performed to evaluate thyroid and adrenal function in patients with familial amyloidotic polyneuropathy. Twenty-four patients without any clinical overt endocrinological dysfunction were studied. None of the patients showed laboratory evidences of hypo- or hyperthyroidism. A short ACTH-stimulation test was performed in 17 of the patients. A low cortisol response to ACTH stimulation, suggesting adrenocortical insufficiency, was found in four (24%) of the patients, and an intermediate response interpreted as suspected hypofunction was found in three (18%) patients. Low serum dehydroepiandrosterone sulphate levels, suggesting adrenal hypofunction, were found in six (25%) of the patients. We believe that the possibility of glucocorticoid insufficiency should always be considered in patients with familial amyloidotic polyneuropathy.