Occurrence and Treatment of Bone Atrophic Non-Unions Investigated by an Integrative Approach

Recently developed atrophic non-union models are a good representation of the clinical situation in which many nonunions develop. Based on previous experimental studies with these atrophic non-union models, it was hypothesized that in order to obtain successful fracture healing, blood vessels, growth factors, and (proliferative) precursor cells all need to be present in the callus at the same time. This study uses a combined in vivo-in silico approach to investigate these different aspects (vasculature, growth factors, cell proliferation). The mathematical model, initially developed for the study of normal fracture healing, is able to capture essential aspects of the in vivo atrophic non-union model despite a number of deviations that are mainly due to simplifications in the in silico model. The mathematical model is subsequently used to test possible treatment strategies for atrophic non-unions (i.e. cell transplant at post-osteotomy, week 3). Preliminary in vivo experiments corroborate the numerical predictions. Finally, the mathematical model is applied to explain experimental observations and identify potentially crucial steps in the treatments and can thereby be used to optimize experimental and clinical studies in this area. This study demonstrates the potential of the combined in silico-in vivo approach and its clinical implications for the early treatment of patients with problematic fractures

HbA1c and fasting plasma glucose levels are equally related to incident cardiovascular risk in a high CVD risk population without known diabetes

OBJECTIVES: Type 2 diabetes (T2DM) is associated with increased risk for cardiovascular disease (CVD). Whether screen-detected T2DM, based on fasting plasma glucose (FPG) or on HbA 1c, are associated with different risks of incident CVD in high-risk populations and which one is preferable for diabetes screening in these populations, remains unclear. METHODS: 8,274 high-risk CVD participants were included from the UCC-SMART cohort. Participants were divided into groups based on prior T2DM diagnosis, and combinations of elevated/non-elevated FPG and HbA 1c (cut-offs at 7 mmol/L and 48 mmol/mol, respectively): Group 0: known T2DM; group 1: elevated FPG/HbA 1c; group 2: elevated FPG, non-elevated HbA 1c; group 3: non-elevated FPG, elevated HbA 1c; group 1 + 2: elevated FPG, regardless of HbA 1c; group 1 + 3: elevated HbA 1c, regardless of FPG; and group 4 (reference), non-elevated FPG/HbA 1c. RESULTS: During a median follow-up of 6.3 years (IQR 3.3-9.8), 712 cardiovascular events occurred. Compared to the reference (group 4), group 0 was at increased risk (HR 1.40; 95 % CI 1.16-1.68), but group 1 (HR 1.16; 95 % CI 0.62-2.18), 2 (HR 1.18; 95 % CI 0.84-1.67), 3 (HR 0.61; 95 % CI 0.15-2.44), 1 + 2 (HR 1.17; 95 % CI 0.86-1.59) and 1 + 3 (HR 1.01; 95 % CI 0.57-1.79) were not. However, spline interpolation showed a linearly increasing risk with increasing HbA 1c/FPG, but did not allow for identification of other cut-off points. CONCLUSIONS: Based on current cut-offs, FPG and HbA 1c at screening were equally related to incident CVD in high-risk populations without known T2DM. Hence, neither FPG, nor HbA 1c, is preferential for diabetes screening in this population with respect to risk of incident CVD. </p

Is the number of ideal cardiovascular health metrics in midlife associated with lower risk of cancer? Evidence from 3 European prospective cohorts

BACKGROUND: Primordial prevention may be a relevant strategy for the prevention of cancer. Given the commonality of risk factors and mechanisms between cancer and cardiovascular disease, we examined the associations between the number of ideal cardiovascular health metrics in midlife and incident cancer. METHODS: In 3 European cohorts (NutriNet-Santé and GAZEL, France; Whitehall II, United Kingdom), the number of ideal cardiovascular health metrics was determined at baseline (range 0-7). Follow-up for cancer events was until October 2020 (NutriNet-Santé), March 2017 (Whitehall II) and December 2015 (GAZEL). Cox regression was conducted in each cohort, and results were thereafter pooled using a random-effects model. RESULTS: Data were available on 39 718 participants. A total of 16 237 were from NutriNet-Santé (mean age 51.3 yr; 28% men), 9418 were from Whitehall II (mean age 44.8 yr; 68% men) and 14 063 were from GAZEL (mean age 45.2 yr; 75% men). The median follow-up was 8.1 years in NutriNet-Santé, 29.6 years in Whitehall II and 24.8 years in GAZEL, and yielded a total of 4889 cancer events. A greater number of ideal cardiovascular health metrics was associated with a lower overall cancer risk in each cohort, with an aggregate hazard ratio (HR) per 1 increment in number of ideal metrics of 0.91 (95% confidence interval [CI] 0.88-0.93). This association remained after removal of the smoking metric (aggregate HR per unit increment in number of ideal metrics: 0.94, 95% CI 0.90-0.97), and site-specific analysis demonstrated a significant association with lung cancer. INTERPRETATION: A greater number of ideal cardiovascular health metrics in midlife was associated with lower cancer risk, notably lung cancer. Primordial prevention of cardiovascular risk factors in midlife may be a complementary strategy to prevent the onset of cancer

Mechanical performance of auxetic meta-biomaterials

The innovative design of orthopedic implants could play an important role in the development of life-lasting implants, by improving both primary and secondary implant fixations. The concept of meta-biomaterials aims to achieve a unique combination of mechanical, mass transport, and biological properties through optimized topological design of additively manufactured (AM) porous biomaterials. In this study, we primarily focused on a specific class of meta-biomaterials, namely auxetic meta-biomaterials. Their extraordinary behavior of lateral expansion in response to axial tension could potentially improve implant-bone contact in certain orthopedic applications. In this work, a multitude of auxetic meta-biomaterials were rationally designed and printed from Ti–6Al–4V using a commercially available laser powder bed fusion process called selective laser melting. The re-entrant hexagonal honeycomb unit cell was used as a starting point, which was then parametrically tuned to obtain a variety of mechanical and morphological properties. In this two-step study, the morphology and quasi-static properties of the developed meta-biomaterials were assessed using mechanical experiments accompanied with full-field strain measurements using digital image correlation. In addition, all our designs were computationally modelled using the finite element method. Our results showed the limits of the AM processes for the production of auxetic meta-biomaterials in terms of which values of the design parameters (e.g., re-entrant angle, relative density, and aspect ratio) could be successfully manufactured. We also found that the AM process itself imparts significant influence on the morphological and mechanical properties of the resulting auxetic meta-biomaterials. This further highlights the importance of experimental studies to determine the actual mechanical properties of such metamaterials. The elastic modulus and strength of many of our designs fell within the range of those reported for both trabecular and cortical bone. Unprecedented properties like these could be used to simultaneously address the different challenges faced in the mechanical design of orthopedic implants

Associations of plasma NfL, GFAP, and t-tau with cerebral small vessel disease and incident dementia: longitudinal data of the AGES-Reykjavik Study

We investigated the associations of plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (t-tau) with markers of cerebral small vessel disease (SVD) and with incident dementia. We also investigated whether associations of NfL, GFAP, and t-tau with incident dementia were explained by SVD. Data are from a random subsample (n = 1069) of the population-based AGES-Reykjavik Study who underwent brain MRI and in whom plasma NfL, GFAP, and t-tau were measured at baseline (76.1 ± 5.4 years/55.9% women/baseline 2002-2006/follow-up until 2015). A composite SVD burden score was calculated using white matter hyperintensity volume (WMHV), subcortical infarcts, cerebral microbleeds, and large perivascular spaces. Dementia was assessed in a 3-step process and adjudicated by specialists. Higher NfL was associated with a higher SVD burden score. Dementia occurred in 225 (21.0%) individuals. The SVD burden score significantly explained part of the association between NfL and incident dementia. WMHV mostly strongly contributed to the explained effect. GFAP was not associated with the SVD burden score, but was associated with WMHV, and WMHV significantly explained part of the association between GFAP and incident dementia. T-tau was associated with WMHV, but not with incident dementia. In conclusion, the marker most strongly related to SVD is plasma NfL, for which the association with WMHV appeared to explain part of its association with incident dementia. This study suggests that plasma NfL may reflect the contribution of co-morbid vascular disease to dementia. However, the magnitude of the explained effect was relatively small, and further research is required to investigate the clinical implications of this finding

Variability in benefit from intensive insulin therapy on cardiovascular events in individuals with type 1 diabetes: A post hoc analysis of the DCCT/EDIC study

Aim: To evaluate presence of treatment effect heterogeneity of intensive insulin therapy (INT) on occurrence of major adverse cardiovascular events (MACE) in individuals with type 1 diabetes. Methods: In participants from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, individual treatment effect of INT (≥3 daily insulin injections/insulin pump therapy) versus conventional therapy (once/twice daily insulin) on the risk of MACE was estimated using a penalized Cox regression model including treatment-by-covariate interaction terms. Results: In 1441 participants, 120 first MACE events were observed and 1279 individuals (89%) were predicted to benefit from INT with regard to MACE risk reduction. The study population was divided into four groups based on predicted treatment effect: one group with no predicted benefit and three tertiles with predicted treatment benefit. The median absolute reduction in 30-year risk of MACE across groups of predicted treatment effect ranged from −0.2% (i.e. risk increase; interquartile range [IQR] −0.1% to −0.3%) in the group with no predicted benefit to 6.6% (i.e. risk reduction; IQR 3.8%–10.9%; number needed to treat 15) in the highest tertile of predicted benefit. The observed benefit of preventing microvascular complications was stable across all subgroups of predicted MACE benefit. Conclusions: Although INT reduces the risk of MACE in the majority of individuals with type 1 diabetes, benefit varies substantially. These individual differences in the effect of INT underline the necessity for a better understanding of the individual response to intensive treatment

Association of hearing impairment with incident depressive symptoms: a community-based prospective study

Objective: The aim was to investigate the potential association between hearing impairment and incident depressive symptoms.Methods: Using a prospective community-based cohort study in France (the Paris Prospective Study III), participants aged 50-75 years were recruited between 2008 and 2012 and thereafter followed up every 2 years up to 2018. Hearing impairment, measured at study recruitment by audiometry testing, was defined as a pure tone average >25 decibels in the better ear. Incident depressive symptoms, measured using the validated 13-item Questionnaire of Depression 2nd version, was assessed during follow-up. Multivariate generalized estimating equations were used to compute odds ratio (OR) and 95% confidence intervals (CI).Results: Among 7591 participants free of depressive symptoms at baseline (mean age 59.8 years, 63% of men), 14.3% had hearing impairment. Over 6 years of follow-up, 479 subjects (6.3%) had incident depressive symptoms. The OR for incident depressive symptoms was 1.36 for subjects with baseline hearing impairment (95% CI, 1.06-1.73). A pooled analysis of 4 published prospective studies yielded a multivariable relative risk of baseline hearing impairment for incident depressive symptoms of 1.29 (95% CI, 1.09-1.53).Conclusions: In this community-based prospective cohort study of participants aged 50 to 75 years, baseline hearing impairment was associated with a 36% increased odds of incident depressive symptoms

Carotid artery stiffness and incident depressive symptoms: The Paris Prospective Study III

Background: Arterial stiffness may contribute to late-life depression via cerebral microvascular damage, but evidence is scarce. No longitudinal study has evaluated the association between arterial stiffness and risk of depressive symptoms. Therefore, we investigated the association between carotid artery stiffness and incident depressive symptoms in a large community-based cohort study.Methods: This longitudinal study included 7013 participants (mean age 59.7 ± 6.3 years; 35.8% women) free of depressive symptoms at baseline. Carotid artery stiffness (high-resolution echo tracking) was determined at baseline. Presence of depressive symptoms was determined at baseline and at 4 and 6 years of follow-up, and was defined as a score ≥7 on the validated Questionnaire of Depression, Second Version, Abridged and/or new use of antidepressant medication. Logistic regression and generalized estimating equations were used.Results: In total, 6.9% (n = 484) of the participants had incident depressive symptoms. Individuals in the lowest tertile of carotid distensibility coefficient (indicating greater carotid artery stiffness) compared with those in the highest tertile had a higher risk of incident depressive symptoms (odds ratio: 1.43; 95% confidence interval: 1.10-1.87), after adjustment for age, sex, living alone, education, lifestyle, cardiovascular risk factors, and baseline Questionnaire of Depression, Second Version, Abridged scores. Results were qualitatively similar when we used carotid Young's elastic modulus as a measure of carotid stiffness instead of carotid distensibility coefficient, and when we used generalized estimating equations instead of logistic regression.Conclusions: Greater carotid stiffness is associated with a higher incidence of depressive symptoms. This supports the hypothesis that carotid stiffness may contribute to the development of late-life depression

HbA1cand fasting plasma glucose levels are equally related to incident cardiovascular risk in a high CVD risk population without known diabetes

Objectives: Type 2 diabetes (T2DM) is associated with increased risk for cardiovascular disease (CVD). Whether screen-detected T2DM, based on fasting plasma glucose (FPG) or on HbA1c, are associated with different risks of incident CVD in high-risk populations and which one is preferable for diabetes screening in these populations, remains unclear. Methods: A total of 8,274 high-risk CVD participants were included from the UCC-SMART cohort. Participants were divided into groups based on prior T2DM diagnosis, and combinations of elevated/non-elevated FPG and HbA1c (cut-offs at 7 mmol/L and 48 mmol/mol, respectively): Group 0: known T2DM; group 1: elevated FPG/HbA1c; group 2: elevated FPG, non-elevated HbA1c; group 3: non-elevated FPG, elevated HbA1c; group 1 + 2: elevated FPG, regardless of HbA1c; group 1 + 3: elevated HbA1c, regardless of FPG; and group 4 (reference), non-elevated FPG/HbA1c. Results: During a median follow-up of 6.3 years (IQR 3.3–9.8), 712 cardiovascular events occurred. Compared to the reference (group 4), group 0 was at increased risk (HR 1.40; 95 % CI 1.16–1.68), but group 1 (HR 1.16; 95 % CI 0.62–2.18), 2 (HR 1.18; 95 % CI 0.84–1.67), 3 (HR 0.61; 95 % CI 0.15–2.44), 1 + 2 (HR 1.17; 95 % CI 0.86–1.59) and 1 + 3 (HR 1.01; 95 % CI 0.57–1.79) were not. However, spline interpolation showed a linearly increasing risk with increasing HbA1c/FPG, but did not allow for identification of other cut-off points. Conclusions: Based on current cut-offs, FPG and HbA1c at screening were equally related to incident CVD in high-risk populations without known T2DM. Hence, neither FPG, nor HbA1c, is preferential for diabetes screening in this population with respect to risk of incident CVD