Biological ageing and the human genome.

Age is a crucial prognostic factor across clinical specialities with significant implications for medical practice. Increasingly, "biological age" is being used as a more relevant age marker in a clinical context and is heavily integrated into the medical use of AI. This review describes the current knowledge about molecular biological and genetic aging-related changes associated with the genome and epigenome, used for biological age determination. It explores the potential causes of these changes and provides an update on treatment status and "rejuvenation" of these genome-related factors.

Perception by Palpation: Development and Testing of a Haptic Ferrogranular Jamming Surface.

Tactile hands-only training is particularly important for medical palpation. Generally, equipment for palpation training is expensive, static, or provides too few study cases to practice on. We have therefore developed a novel haptic surface concept for palpation training, using ferrogranular jamming. The concept's design consists of a tactile field spanning 260 x 160 mm, and uses ferromagnetic granules to alter shape, position, and hardness of palpable irregularities. Granules are enclosed in a compliant vacuum-sealed chamber connected to a pneumatic system. A variety of geometric shapes (output) can be obtained by manipulating and arranging granules with permanent magnets. The tactile hardness of the palpable output can be controlled by adjusting the chamber's vacuum level. A psychophysical experiment (N = 28) investigated how people interact with the palpable surface and evaluated the proposed concept. Untrained participants characterized irregularities with different position, form, and hardness through palpation, and their performance was evaluated. A baseline (no irregularity) was compared to three irregularity conditions: two circular shapes with different hardness (Hard Lump and Soft Lump), and an Annulus shape. 100% of participants correctly identified an irregularity in the three irregularity conditions, whereas 78.6% correctly identified baseline. Overall agreement between participants was high (κ= 0.723). The Intersection over Union (IoU) for participants sketched outline over the actual shape was IoU Mdn = 79.3% for Soft Lump, IoU Mdn = 68.8% for Annulus, and IoU Mdn = 76.7% for Hard Lump. The distance from actual to drawn center was Mdn = 6.4 mm (Soft Lump), Mdn = 5.3 mm (Annulus), and Mdn = 7.4 mm (Hard Lump), which are small distances compared to the size of the field. The participants subjectively evaluated Soft Lump to be significantly softer than Hard Lump and Annulus. Moreover, 71% of participants thought they improved their palpation skills throughout the experiment. Together, these results show that the concept can render irregularities with different position, form, and hardness, and that users are able to locate and characterize these through palpation. Participants experienced an improvement in palpation skills throughout the experiment, which indicates the concepts feasibility as a palpation training device.

[Personalised medicine requires a paradigm shift in the concept of evidence].

Personalised medicine via a central biobank will require the introduction of a paradigm shift navigating by detecting pattern and correlation, instead of evidence of limited use in our complex environment. Accordingly, to make sense, population-wide data comprising "deep phenotype" including genetics, must be submitted to evaluation by "machine intelligence", based on "unsupervised learning" - the algorithm concomitantly improving its power with increasing mass of data. A system not based on deductive logic cannot be checked by logic but must be taken on face value.

Involvement of interleukin-1 genotypes in the association of coronary heart disease with periodontitis.

BACKGROUND: Epidemiologic studies demonstrated an association between periodontitis (PE) and coronary heart disease (CHD). The coexistence of the two disease entities could be dependent on mutual risk factors, and polymorphism of the interleukin (IL)-1 gene cluster associated with the severity of PE might also be involved in the pathogenesis of CHD. METHODS: The study consisted of 225 dentate white subjects, including 97 patients with CHD and 128 controls. Patients with confirmed diagnoses of CHD were recruited after being discharged from a cardiology department, and controls without CHD were recruited consecutively from the Copenhagen City Heart Study. Mean alveolar bone level (ABL) was measured on radiographs. ABL was stratified into ABL1 (ABL < or = 2 mm), ABL2 (2 mm 4 mm). Genotypes were analyzed by amplifying the polymorphic regions of the IL-1 gene cluster using polymerase chain reaction, followed by restriction digestion and gel electrophoresis. RESULTS: In the univariate analysis, allele 2 of IL-1B+3954 and IL-1B-511 was associated with ABL (P = 0.040 and P = 0.039, respectively), whereas no association was found with allele 2 of IL-1A+4845 or IL-1RN variable number tandem repeat (VNTR) (P = 0.445 and P = 0.375, respectively). A lower ABL was associated with the occurrence of allele 2 of IL-1B-511. The multiple logistic regression analysis also showed a significant association of allele 1 of IL-1B-511 with high ABL (P = 0.049) and of allele 2 of IL-1A+4845 with high ABL among individuals with CHD (P = 0.050). There was no association between any of the polymorphisms of IL-1 and CHD in the univariate or multiple analyses. However, in a binary multiple logistic regression model, carriage of allele 1 of IL-1RN VNTR was found to be associated with the occurrence of both CHD and ABL3 (P = 0.016). CONCLUSION: Allele 1 of IL-1RN VNTR may be associated with the coexistence of CHD and PE in a multiple regression model.

Hospital-based comprehensive cardiac rehabilitation versus usual care among patients with congestive heart failure, ischemic heart disease, or high risk of ischemic heart disease: 12-month results of a randomized clinical trial.

BACKGROUND: Current guidelines broadly recommend comprehensive cardiac rehabilitation (CCR), although evidence for this is still limited. We investigated the 12-month effect of hospital-based CCR versus usual care (UC) for a broadly defined group of cardiac patients within the modern therapeutic era of cardiology. METHODS: We conducted a centrally randomized single-center clinical trial with blinded assessment of the primary outcome: registry-based composite of total mortality, myocardial infarction, or acute first-time readmission due to heart disease. Other outcomes were hospitalization, risk profile, and quality of life. The trial included 770 participants (20-94 years) with congestive heart failure (12%), ischemic heart disease (58%), or high risk of ischemic heart disease (30%). Comprehensive cardiac rehabilitation is composed of 6 weeks of intensive intervention and systematic follow-up for 10.5 months. RESULTS: We randomized 380 patients to CCR versus 390 to UC. Randomization was well balanced. The primary outcome occurred in 31% of both groups (relative risk 0.96, 95% confidence interval 0.78-1.26). Compared with the UC group, CCR significantly reduced length of stay by 15% (95% confidence interval 1.1%-27.1%, P = .04), mean number of cardiac risk factors above target (4.5 vs 4.1, P = .01), patients with systolic blood pressure below target (P = .003), physically inactivity (P = .01), and unhealthy dietary habits (P = .0003). Short-Form-36 and Hospital Anxiety and Depression Scale did not differ significantly. CONCLUSION: At 12 months, the CCR and UC groups did not differ regarding the primary composite outcome. Comprehensive cardiac rehabilitation significantly reduced length of hospital stay and improved cardiac risk factors.

[Mutations in the heart's pacemaker channels--a new cause of sick sinus node syndrome and long-QT syndrome]. / Mutationer i hjertets pacemakerkanaler--ny årsag til syg sinus-syndrom og langt QT-syndrom.

The sinus node hyperpolarization-activated If current generated by the cardiac pacemaker channels HCN2 and HCN4 determines the autonomous beating of the heart. Cardiac arrhythmias, like long-QT syndrome, are often caused by irregularities of the heart action potential generated by mutations in cardiac ion channel genes. Mutations in the HCN4 gene have been associated with sick sinus syndrome and long-QT syndrome. The identification of cardiac arrhythmia disease-associated genes makes possible new therapeutic strategies based on gene-specific drug treatment and gene therapy.

Mutations in the Kv1.5 channel gene KCNA5 in cardiac arrest patients.

Mutations in one of the ion channels shaping the cardiac action potential can lead to action potential prolongation. However, only in a minority of cardiac arrest cases mutations in the known arrhythmia-related genes can be identified. In two patients with arrhythmia and cardiac arrest, we identified the point mutations P91L and E33V in the KCNA5 gene encoding the Kv1.5 potassium channel that has not previously been associated with arrhythmia. We functionally characterized the mutations in HEK293 cells. The mutated channels behaved similarly to the wild-type with respect to biophysical characteristics and drug sensitivity. Both patients also carried a D85N polymorphism in KCNE1, which was neither found to influence the Kv1.5 nor the Kv7.1 channel activity. We conclude that although the two N-terminal Kv1.5 mutations did not show any apparent electrophysiological phenotype, it is possible that they may influence other cellular mechanisms responsible for proper electrical behaviour of native cardiomyocytes.

Periodontal disease and coronary heart disease.

BACKGROUND: Several epidemiological studies have demonstrated an association between periodontal disease and coronary heart disease (CHD). The association could be a result of confounding by mutual risk factors. The present study was undertaken in a Danish population to reveal the significance of common risk factors. METHODS: The investigation was conducted as a case-control study comprising 250 individuals: 110 individuals with verified CHD from a Department of Cardiovascular Medicine and 140 control individuals without CHD from the Copenhagen City Heart Study. Information on diabetic status, smoking habits, alcohol consumption, physical activity, school attendance, household income, body weight and height, triglyceride, and serum cholesterol was obtained. Full-mouth probing depth (PD), clinical attachment loss (CAL), bleeding on probing (BOP), and alveolar bone level (ABL) on radiographs were registered. ABL was stratified into ABL1=ABL2 to 4 mm. Multiple logistic regression models with stepwise backward elimination were used allowing variables with P<0.15 to enter the multivariate analysis. RESULTS: The CHD group had a significantly lower outcome with respect to PD, BOP, CAL, and ABL. For participants<60 years old, only risk factors such as smoking and diabetic status entered the multivariate analysis. For the ABL3 group, there was a significant association with CHD for participants<60 years old, the odds ratio being 6.6 (1.69 to 25.6). For participants>or=60 years old, there was no association. CONCLUSIONS: The present study showed a positive association between periodontal disease and CHD in agreement with several other studies. The association was highly age dependent and could only be attributed to diabetes and smoking to some extent.

A randomized clinical trial of hospital-based, comprehensive cardiac rehabilitation versus usual care for patients with congestive heart failure, ischemic heart disease, or high risk of ischemic heart disease (the DANREHAB trial)--design, intervention, and population.

BACKGROUND: Current guidelines broadly recommend comprehensive cardiac rehabilitation (CR), although evidence for this is still limited. It is not known whether evidence from before 1995 is still valid. STUDY DESIGN: The DANish Cardiac ReHABilitation (DANREHAB) trial was designed as a centrally randomized clinical trial to clarify whether hospital-based comprehensive CR is superior to usual care for patients with congestive heart failure, ischemic heart disease, or high risk for ischemic heart disease. A combined primary outcome measure included total mortality, myocardial infarction, or readmissions due to heart disease based on linkage to public registries. The CR was an individually tailored, multidisciplinary program (6 weeks of intensive CR and 12 months of follow-up) including patient education, exercise training, dietary counseling, smoking cessation, psychosocial support, risk factor management, and clinical assessment. STUDY POPULATION: Of 5060 discharged patients, 1614 (32%) were eligible for the trial and 770 patients were randomized (47% of those eligible). Participants were younger (P < .001) and had less comorbidity than nonparticipants (P < .03). CONCLUSION: Our trial shows that a large-scale, centrally randomized clinical trial on comprehensive CR can be conducted among a broadly defined patient group, but reaching the stipulated number of 1800 patients was difficult. Although the study included relatively many women and older people, elderly patients and patients with high comorbidity were underrepresented, which may influence the external validity.