Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1–6). It remains ...unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6Δ/Δ) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6Δ/Δ mice, but also in brown adipose tissue- (CerS6ΔBAT) and liver-specific (CerS6ΔLIVER) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition.
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•CERS6 expression in human WAT correlates with adiposity and insulin resistance•CerS6-deficient mice are protected from DIO and glucose intolerance•Both BAT- and liver-specific CerS6 deletion improves glucose tolerance•CerS6 inhibition provides a specific approach to treat glucose intolerance
Turpin et al. link alterations in the C16:0 ceramide-generating enzyme, CerS6, with obesity and diabetes in humans and mice and characterize the beneficial metabolic effects associated with loss of function in mice. Therapeutic CerS6 inhibition could circumvent the side effects of global ceramide synthesis inhibition.
Colorectal cancer (CRC) is one of the most lethal cancers worldwide in which the vast majority of cases exhibit little genetic risk but are associated with a sedentary lifestyle and obesity. Although ...the mechanisms underlying CRC and colitis-associated colorectal cancer (CAC) remain unclear, we hypothesised that obesity-induced inflammation predisposes to CAC development. Here, we show that diet-induced obesity accelerates chemically-induced CAC in mice via increased inflammation and immune cell recruitment. Obesity-induced interleukin-6 (IL-6) shifts macrophage polarisation towards tumour-promoting macrophages that produce the chemokine CC-chemokine-ligand-20 (CCL-20) in the CAC microenvironment. CCL-20 promotes CAC progression by recruiting CC-chemokine-receptor-6 (CCR-6)-expressing B cells and γδ T cells via chemotaxis. Compromised cell recruitment as well as inhibition of B and γδ T cells protects against CAC progression. Collectively, our data reveal a function for IL-6 in the CAC microenvironment via lymphocyte recruitment through the CCL-20/CCR-6 axis, thereby implicating a potential therapeutic intervention for human patients.
Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and ...leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.
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•Inflammatory signaling in AgRP neurons promotes obesity and insulin resistance•JNK and IKK activations in AgRP neurons have distinct metabolic consequences•JNK activation in AgRP neurons causes cellular and systemic leptin resistance•IKK activation in AgRP neurons leads to cellular and systemic insulin resistance
Inflammatory signaling in the CNS is crucial in the development of obesity-associated insulin and leptin resistance. Tsaousidou et al. demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons is sufficient to induce weight gain and leptin resistance in mice, whereas IKK2 activation fails to cause obesity but blunts insulin signaling and impairs systemic glucose homeostasis. The data reveal distinct effects of c-Jun N-terminal kinase (JNK)- and inhibitor of nuclear factor kappa-B kinase (IKK)-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.
Aging is a progressive decline of body function, during which many tissues accumulate few cells with high levels of deleted mitochondrial DNA (mtDNA), leading to a defect of mitochondrial functions. ...Whether this mosaic mitochondrial deficiency contributes to organ dysfunction is unknown. To investigate this, we generated mice with an accelerated accumulation of mtDNA deletions in the myocardium, by expressing a dominant-negative mutant mitochondrial helicase. These animals accumulated few randomly distributed cardiomyocytes with compromised mitochondrial function, which led to spontaneous ventricular premature contractions and AV blocks at 18 months. These symptoms were not caused by a general mitochondrial dysfunction in the entire myocardium, and were not observed in mice at 12 months with significantly lower numbers of dysfunctional cells. Therefore, our results suggest that the disposition to arrhythmia typically found in the aged human heart might be due to the random accumulation of mtDNA deletions and the subsequent mosaic respiratory chain deficiency.
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•Cardiomyocytes steadily accumulate mitochondrial DNA deletions with aging•This leads to the development of a tissue mosaic of mitochondrial deficiency•Impaired mitochondrial function in few cells promotes cardiac arrhythmia
Baris et al. test the idea of mosaic respiratory chain deficiency contributing to aging-related human cardiac disease. Using a genetic mouse model of accelerated accumulation of mtDNA deletions in the heart, they show that a few cardiomyocytes with mitochondrial DNA deletions progressively accumulate during aging, leading to cardiac arrhythmias.
Treatment of chronic lower back pain (CLBP) should be stratified for best medical and economic outcome. To improve the targeting of potential participants for exclusive therapy offers from payers, ...Freytag et al. developed a tool to classify back pain chronicity classes (CC) based on claim data. The aim of this study was to evaluate the criterion validity of the model. Administrative claim data and self-reported patient information from 3,506 participants (2014-2021) in a private health insurance health management programme in Germany were used to validate the tool. Sensitivity, specificity, and Matthews' correlation coefficient (MCC) were calculated comparing the prediction with actual grades based on von Korff's graded chronic pain scale (GCPS). The secondary outcome was an updated view on direct health care costs (€) of patients with back pain (BP) grouped by GCPS. Results showed a fair correlation between predicted CC and actual GCPS grades. A total of 69.7% of all cases were correctly classified. Sensitivity and specificity rates of 54.6 and 76.4% underlined precision. Correlation between CC and GCPS with an MCC of 0.304 also indicated a fair relationship between prediction and observation. Cost data could be clearly grouped by GCPS: the higher the grade, the higher the costs and the use of health care. This was the first study to compare the predicted severity of BP using claim data with the actual severity of BP by GCPS. Based on the results, the usage of CC as a single tool to determine who receives CLBP treatment cannot be recommended. CC is a good tool to segment candidates for specific types of intervention in BP. However, it cannot replace a medical screening at the beginning of an intervention, as the rate of false negatives is too high. Trial registration The study was conducted using routinely collected data from an intervention, which was previously evaluated and registered retrospectively in the German Registry of Clinical Trials under DRKS00015463 (04/09/2018). Informed consent and the self-reported questionnaire have remained unchanged since the study and, therefore, are still valid according to the ethics proposal.
Abstract
Background
Nonspecific chronic low back pain (CLBP) is a complex symptom with numerous possible causes and influencing factors. Understanding how modifiable factors affect the course of CLBP ...is important for preventing progression. As the COVID-19 pandemic has changed the lifestyle of many people, this study paper assessed whether it also changed the influence of modifiable lifestyle factors (regular exercise and sedentary behaviour) and mental health factors (anxiety and depression) on CLBP pain intensity and disability by comparing the strength of these associations before and during the pandemic. We hypothesised that the importance of regular physical activity and good mental health for CLBP patients would increase during the pandemic.
Methods
These questions were investigated in a cross-sectional study of insurance claims data and self-reported data from various questionnaires from 3,478 participants in a German CLBP health intervention (2014–2021) by calculating pre- and intra-pandemic odds ratios (OR) and 95% confidence intervals (CI) for each variable of interest and outcome. Potential confounders were also considered. Pandemic status was treated as an effect modifier. Based on the date of enrolment, participants were classified as “pre-pandemic” or “pandemic”.
Results
Regularly exercising ≥ 4 h/week significantly reduced the odds of high disability for men (OR 0.49, 95% CI 0.31 – 0.79,
p
= 0.003) and women (OR 0.30, 95% CI 0.14 – 0.563,
p
= 0.002) and reduced the probability of severe pain in women (OR 0.37, 95% CI 0.21 – 0.65,
p
< 0.001). Each one-point increase in PHQ-4 score for anxiety and depression increased the OR of high pain intensity by 1.25 points (95% CI 1.18 – 1.34,
p
< 0.001). A clear impact of COVID-19 lockdowns was observed. In individuals who exercised ≥ 4 h/week the OR of high disability was 0.57 (95% CI 0.36 – 0.92,
p
= 0.021) in the pre-pandemic group compared to 0.29 (95% CI 0.12 – 0.56,
p
= 0.002) in the pandemic group. The probability of high disability increased from an OR of 1.42 (95% CI 1.33 – 1.52,
p
< 0.001) per marginal increase in the PHQ-4 scale before the pandemic, to an OR of 1.73 (95% CI 1.58 – 1.89,
p
< 0.001) during the pandemic.
Conclusions
The magnitude of association of the factors that influenced high pain intensity and disability increased during the pandemic. On the one hand, the protective effect of regular exercising was greater in participants surveyed during lockdown. On the other hand, a higher risk through anxiety or depression during the lockdown was identified. An additional study with objective measures of sedentary behaviour and physical activity is needed to validate these results. More in-depth investigation of lockdown-induced associations between reduced daily physical activity, increased levels of anxiety and depression, and their effects on CLPB could also be worthwhile.
Trial registration
This study used routinely collected data from a CLBP intervention that was previously evaluated and registered in the German Registry of Clinical Trials under DRKS00015463 (04/09/2018). The original ethics approval, informed consent and self-reported questionnaire have remained unchanged and are still valid.
Multidisciplinary biopsychosocial rehabilitation (MBR) is highly recommended for chronic lower back pain (CLBP) treatment, but its economic benefit remains to be clearly demonstrated. The purpose of ...this study is to analyse the effect of a 12-month MBR programme of behavioural change coaching and device-supported exercise on direct medical costs, sick leave and health-related quality of life (HRQOL) at 24 months.
An incremental cost-effectiveness analysis was conducted in Germany from a private health insurance perspective using data from a multi-centre, two-arm randomised controlled trial with parallel-group Zelen's randomisation and 24-month follow-up. After removing dissimilarities in characteristics between MBR and usual care (control) via propensity score matching, treatment effects were calculated using a difference-in-difference approach.
Base-case analysis of the MBR (n=112) and usual care group (n=111) showed an incremental cost-effectiveness ratio (ICER) of €8,296 per quality-adjusted life year (QALY) gained, indicating that the intervention was cost-effective. Compared to the controls, MBR reduced economically unaccounted sick leave due to back pain in the last six months by 17.5 days (p = 0.001) and had a positive effect on health-related quality of life (HRQOL) (0.046, p=0.026). Subgroup analysis of participants with major impairment demonstrated that a dominant intervention was possible, as reflected by an ICER of - €7,302 per QALY. Savings were driven by a - €1,824 reduction in back pain-specific costs. Moreover, sick leave was 27 days (p = 0.006) less in the MBR group.
This first cost-effectiveness study with combined data from a private health insurer and a controlled trial in Germany demonstrated that long term MBR for the treatment of CLBP is cost-effective. Subgroups with major impairment from back pain benefitted more from the intervention than those with minor impairment. MBR significantly reduced sick leave in all participants. Hence, it is a profitable intervention from a societal point of view.
The trial of the evaluation study was retrospectively registered in the German Clinical Trials Register under trial number DRKS00015463 retrospectively (dated 4 Sept 2018).
Pathogen outbreaks (i.e., outbreaks of bacteria and viruses) in hospitals can cause high mortality rates and increase costs for hospitals significantly. An outbreak is generally noticed when the ...number of infected patients rises above an endemic level or the usual prevalence of a pathogen in a defined population. Reconstructing transmission pathways back to the source of an outbreak - the patient zero or index patient - requires the analysis of microbiological data and patient contacts. This is often manually completed by infection control experts. We present a novel visual analytics approach to support the analysis of transmission pathways, patient contacts, the progression of the outbreak, and patient timelines during hospitalization. Infection control experts applied our solution to a real outbreak of Klebsiella pneumoniae in a large German hospital. Using our system, our experts were able to scale the analysis of transmission pathways to longer time intervals (i.e., several years of data instead of days) and across a larger number of wards. Also, the system is able to reduce the analysis time from days to hours. In our final study, feedback from twenty-five experts from seven German hospitals provides evidence that our solution brings significant benefits for analyzing outbreaks.
To facilitate access to evidence-based care for back pain, a German private medical insurance offered a health program proactively to their members. Feasibility and long-term efficacy of this ...approach were evaluated.
Using Zelen's design, adult members of the health insurance with chronic back pain according to billing data were randomized to the intervention (IG) or the control group (CG). Participants allocated to the IG were invited to participate in the comprehensive health program comprising medical exercise therapy and life style coaching, and those allocated to the CG to a longitudinal back pain survey. Primary outcomes were back pain severity (Korff's Chronic Pain Grade Questionnaire) as well as health-related quality of life (SF-12) assessed by identical online questionnaires at baseline and 2-year follow-up in both study arms. In addition to analyses of covariance, a subgroup analysis explored the heterogeneity of treatment effects among different risks of back pain chronification (STarT Back Tool).
Out of 3462 persons selected, randomized and thereafter contacted, 552 agreed to participate. At the 24-month follow-up, data on 189 of 258 (73.3%) of the IG were available, in the CG on 255 of 294 (86.7%). Significant, small beneficial effects were seen in primary outcomes: Compared to the CG, the IG reported less disability (1.6 vs 2.0; p = 0.025; d = 0.24) and scored better at the SF-12 physical health scale (43.3 vs 41.0; p < 0.007; d = 0.26). No effect was seen in back pain intensity and in the SF-12 mental health scale. Persons with medium or high risk of back pain chronification at baseline responded better to the health program in all primary outcomes than the subgroup with low risk at baseline.
After 2 years, the proactive health program resulted in small positive long-term improvements. Using risk screening prior to inclusion in the health program might increase the percentage of participants deriving benefits from it.
The trial was registered at the German Clinical Trials Register under DRKS00015463 retrospectively (dated 4 Sept 2018).
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