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Biological age measures outperform chronological age in predicting various aging outcomes, yet little is known regarding genetic predisposition. We performed genome‐wide association scans of two age‐adjusted biological age measures (PhenoAgeAcceleration and BioAgeAcceleration), estimated from clinical biochemistry markers (Levine et al., 2018; Levine, 2013) in European‐descent participants from UK Biobank. The strongest signals were found in the APOE gene, tagged by the two major protein‐coding SNPs, PhenoAgeAccel—rs429358 (APOE e4 determinant) (p = 1.50 × 10−72); BioAgeAccel—rs7412 (APOE e2 determinant) (p = 3.16 × 10−60). Interestingly, we observed inverse APOE e2 and e4 associations and unique pathway enrichments when comparing the two biological age measures. Genes associated with BioAgeAccel were enriched in lipid related pathways, while genes associated with PhenoAgeAccel showed enrichment for immune system, cell function, and carbohydrate homeostasis pathways, suggesting the two measures capture different aging domains. Our study reaffirms that aging patterns are heterogeneous across individuals, and the manner in which a person ages may be partly attributed to genetic predisposition. A genome‐wide association study for differences in aging rates was performed in the UK Biobank sample using two previously established aging measures. Results suggest that one was associated with genes involved in lipid metabolism and blood pressure, while the other was associated with genes involved in immune functioning. APOE e4 was associated with faster aging in the measure reflecting lipid age, yet paradoxically, was associated with reduced aging in the measure reflecting immune functioning and inflammation.

Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging‐related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40–70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow‐up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate‐adjusted p‐values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92–0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06–1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age‐related health outcomes. Telomere lengthening may offer little gain in later‐life health status and face increasing cancer risks. We estimated associations between measured telomere length (TL) and several aging outcomes by using TL‐associated inherited genetic variants, which are robust to later environmental exposures (confounders)(top X). Genetically determined TL was associated with increased risks of cancers and reduced risks of cardiovascular disease, but little change in other studied age‐related health outcomes. There was genetic evidence consistent with these findings being caused through telomere length itself, rather than through another (unknown) pathway (bottom X).

Measuring vital physiological pressures is important for monitoring health status, preventing the buildup of dangerous internal forces in impaired organs, and enabling novel approaches of using mechanical stimulation for tissue regeneration. Pressure sensors are often required to be implanted and directly integrated with native soft biological systems. Therefore, the devices should be flexible and at the same time biodegradable to avoid invasive removal surgery that can damage directly interfaced tissues. Despite recent achievements in degradable electronic devices, there is still a tremendous need to develop a force sensor which only relies on safe medical materials and requires no complex fabrication process to provide accurate information on important biophysiological forces. Here, we present a strategy for material processing, electromechanical analysis, device fabrication, and assessment of a piezoelectric Poly-L-lactide (PLLA) polymer to create a biodegradable, biocompatible piezoelectric force sensor, which only employs medical materials used commonly in Food and Drug Administration-approved implants, for the monitoring of biological forces. We show the sensor can precisely measure pressures in a wide range of 0–18 kPa and sustain a reliable performance for a period of 4 d in an aqueous environment. We also demonstrate this PLLA piezoelectric sensor can be implanted inside the abdominal cavity of a mouse to monitor the pressure of diaphragmatic contraction. This piezoelectric sensor offers an appealing alternative to present biodegradable electronic devices for the monitoring of intraorgan pressures. The sensor can be integrated with tissues and organs, forming self-sensing bionic systems to enable many exciting applications in regenerative medicine, drug delivery, and medical devices.

In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework ‘ T riangulation WI thin a ST udy’ (TWIST)’ in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.

ObjectivesTo evaluate the dental and skeletal effects that occur in the correction of anterior open bite with clear aligners.Materials and methodIn this single-center retrospective study, the mechanism of anterior open bite closure using clear aligners (Invisalign, Align Technology, Santa Clara, CA, USA) was evaluated by cephalometric superimposition based on records of patients consecutively treated by a single, experienced Invisalign provider. Inclusion criteria consisted of anterior open bite (overbite < 0.5 mm), adult patients (18+) at the beginning of treatment, consecutive records, and good quality pre- and post-treatment records, where the required landmarks were clearly visible.ResultsA total of 45 patients were included for data analysis with a mean age of 30.73 ± 8.0 years and initial open bite of − 1.21 ± 1.15 mm. During treatment, the upper incisors showed significant (p < 0.05) retraction [U1-SN′(°) = − 10.91 ± 6.95°], [U1-SN′perp(mm) = − 2.57 ± 1.75 mm] and extrusion [U1-SN′(mm) = 1.45 ± 0.89 mm]. The lower incisors also showed significant retraction [IMPA(°) = − 3.73 ± 4.91°), (ΔL1-MP′perp (mm) = − 1.08 ± 1.59] and extrusion (ΔL1-MP′(mm) = 0.53 ± 0.74). Regarding molar position, no significant changes were noted in the anteroposterior position of the upper [ΔU6-SN′perp(mm) = 0.01 ± 1.08 mm] and lower molar [ΔL6-MP′perp(mm) = 0.03 ± 0.87 mm]; however, there was a statistically significant intrusion of the upper [ΔU6-SN′(mm) = − 0.47 ± 0.59 mm] and lower molar [ΔL6-MP′(mm) = − 0.39 ± 0.76 mm].ConclusionOpen bite closure with clear aligners occurred due to a combination of maxillary and mandibular incisor extrusion and maxillary and mandibular molar intrusion, with slight mandibular auto rotation. Significant retraction of maxillary and mandibular incisors was also observed with treatment. Clear aligners are effective in reducing/controlling the vertical dimension in open bite patients.

Beyond mere prognostication, optimal biomarkers of aging provide insights into qualitative and quantitative features of biological aging and might, therefore, offer useful information for the testing and, ultimately, clinical use of gerotherapeutics. We aimed to develop a proteomic aging clock (PAC) for all‐cause mortality risk as a proxy of biological age. Data were from the UK Biobank Pharma Proteomics Project, including 53,021 participants aged between 39 and 70 years and 2923 plasma proteins assessed using the Olink Explore 3072 assay®. 10.9% of the participants died during a mean follow‐up of 13.3 years, with the mean age at death of 70.1 years. The Spearman correlation between PAC proteomic age and chronological age was 0.77. PAC showed robust age‐adjusted associations and predictions for all‐cause mortality and the onset of various diseases in general and disease‐free participants. The proteins associated with PAC proteomic age deviation were enriched in several processes related to the hallmarks of biological aging. Our results expand previous findings by showing that biological age acceleration, based on PAC, strongly predicts all‐cause mortality and several incident disease outcomes. Particularly, it facilitates the evaluation of risk for multiple conditions in a disease‐free population, thereby, contributing to the prevention of initial diseases, which vary among individuals and may subsequently lead to additional comorbidities. We developed a proteomic aging clock (PAC) for all‐cause mortality risk as a surrogate of BA. PAC showed robust age‐adjusted associations and predictions for all‐cause mortality and the onset of various diseases in general and disease‐free participants. Our results expand previous findings by showing that age acceleration, based on PAC, strongly predicts all‐cause mortality and several incident disease outcomes.

Background Telomere attrition may share common biological mechanisms with bone and muscle loss with aging. Here, we investigated the association between these hallmarks of aging using data from UK Biobank, a large observational study. Methods Leukocyte telomere length (LTL as T/S ratio) was measured using a multiplex qPCR assay at baseline (2006–2010). Bone mineral density (whole body and regional; via dual‐energy X‐ray absorptiometry), trabecular bone score (via lumbar‐spine dual‐energy X‐ray absorptiometry images), fat‐free muscle volume (thighs; via magnetic resonance imaging), and muscle fat infiltration (thighs; via magnetic resonance imaging) were measured during the imaging visit (2014–2018). Regression models were used to model LTL against a muscle or bone outcome, unadjusted and adjusted for covariates. Results A total of 16 356 adults (mean age: 62.8 ± 7.5 years, 50.5% women) were included. In the fully adjusted model, thigh fat‐free muscle volume was associated with LTL in the overall sample (adjusted standardized β (aβ) = 0.017, 95% CI 0.009 to 0.026, P < 0.001, per SD increase in LTL), with stronger associations in men (aβ = 0.022, 95% CI 0.010 to 0.034, P < 0.001) than in women (aβ = 0.013, 95% CI 0.000 to 0.025, P = 0.041) (sex‐LTL P = 0.028). The adjusted odds ratio (aOR) for low thigh fat‐free muscle volume (body mass index‐adjusted, sex‐specific bottom 20%) was 0.93 per SD increase in LTL (95% CI 0.89 to 0.96, P < 0.001) in the overall sample, with stronger associations in men (aOR = 0.92, 95% CI 0.87 to 0.99, P = 0.008) than women (aOR = 0.93, 95% CI 0.88 to 0.98, P = 0.009), although the sex difference was not statistically significant in this model (sex‐LTL P = 0.37). LTL was not associated with bone mineral density, trabecular bone score, or muscle fat infiltration in the overall or subgroup analyses (P > 0.05). Conclusions LTL was consistently associated with thigh fat‐free muscle volume in men and women. Future research should investigate moderating effects of lifestyle factors (e.g., physical activity, nutrition, or chronic diseases) in the association between LTL and muscle volume.

Sporadic, solitary parathyroid adenoma is the most common cause of primary hyperparathyroidism (PHPT). Apart from germline variants in certain cyclin-dependent kinase inhibitor genes and occasionally in MEN1, CASR, or CDC73, little is known about possible genetic variants in the population that may confer increased risk for development of typical sporadic adenoma. Transcriptionally activating germline variants, especially within in the C-terminal conserved inhibitory domain (CCID) of glial cells missing 2 (GCM2), encoding a transcription factor required for parathyroid gland development, have recently been reported in association with familial and sporadic PHPT. To evaluate the potential role of specific GCM2 activating variants in sporadic parathyroid adenoma. Regions encoding hyperparathyroidism-associated, activating GCM2 variants were PCR amplified and sequenced in genomic DNA from 396, otherwise unselected, cases of sporadic parathyroid adenoma. Activating GCM2 CCID variants (p.V382M and p.Y394S) were identified in six of 396 adenomas (1.52%), and a hyperparathyroidism-associated GCM2 non-CCID activating variant (p.Y282D) was found in 20 adenomas (5.05%). The overall frequency of tested activating GCM2 variants in this study was 6.57%, approximately threefold greater than their frequency in the general population. The examined, rare CCID variants in GCM2 were enriched in our cohort of patients and appear to confer a moderately increased risk of developing sporadic solitary parathyroid adenoma compared with the general population. However, penetrance of these variants is low, suggesting that the large majority of individuals with such variants will not develop a sporadic parathyroid adenoma.

Pediatric providers play an important role in parental and youth smoking cessation. The goal of this study was to understand smoking cessation attitudes of parents and the behaviors, confidence and self-efficacy of pediatricians related to providing smoking cessation counseling to parents and youth. A mixed methods study was conducted in a convenience sample of families (n = 1,549) and pediatric primary care clinicians (n = 95) in Connecticut using surveys and focus groups from April, 2016 to January, 2017. The smoking rate (cigarettes or electronic cigarettes) among all households surveyed was 21%. Interest in quitting smoking was high (71%) and did not differ based on smoking amount, duration, type of community of residence (urban, rural, etc), or race/ethnicity. For example, compared to participants who smoked for <10 years, those who smoked ≥20 years had a similar interest in quitting (OR = 1.12; 95% CI: 0.85-1.48). Ninety percent of clinicians surveyed asked parents about their smoking behavior at least annually but 36% offered no smoking cessation counseling services or referral. Clinicians almost always reported counseling youth about the dangers of nicotine and tobacco use (99%), were more confident about counseling youth than parents (p<0.01) and reported low self-efficacy about smoking cessation and prevention counseling of parents and youth. Ninety-three percent of clinicians opined that electronic cigarettes were equally or more dangerous than cigarettes but 34% never counseled youth about the dangers of electronic cigarettes. Clinicians frequently screen parents about their smoking behaviors, but rarely provide smoking cessation counseling and express low confidence in this activity. Clinicians are more confident counseling youth than parents. Clinicians also recognize the dangers of electronic cigarettes, yet they infrequently counsel youth about these dangers.

Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers. A large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%, <50 year olds, 28.4%). RDW was associated with 194 independent genetic signals; 71 are known for conditions including autoimmune disease, certain cancers, BMI, Alzheimer's disease, longevity, age at menopause, bone density, myositis, Parkinson's disease, and age-related macular degeneration. Exclusion of anemic participants did not affect the overall findings. Pathways analysis showed enrichment for telomere maintenance, ribosomal RNA, and apoptosis. The majority of RDW-associated signals were intronic (119 of 194), including SNP rs6602909 located in an intron of oncogene GAS6, an eQTL in whole blood. Although increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks, and a RDW genetic score was not predictive of incident disease. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.