Leukocyte telomere length is associated with MRI-thigh fat-free muscle volume: data from 16 356 UK Biobank adults.

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 ß (aß) = 0.017, 95% CI 0.009 to 0.026, P < 0.001, per SD increase in LTL), with stronger associations in men (aß = 0.022, 95% CI 0.010 to 0.034, P < 0.001) than in women (aß = 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.

Accelerated aging mediates the associations of unhealthy lifestyles with cardiovascular disease, cancer, and mortality.

BACKGROUND: With two well-validated aging measures capturing mortality and morbidity risk, this study examined whether and to what extent aging mediates the associations of unhealthy lifestyles with adverse health outcomes. METHODS: Data were from 405,944 adults (40-69 years) from UK Biobank (UKB) and 9972 adults (20-84 years) from the US National Health and Nutrition Examination Survey (NHANES). An unhealthy lifestyles score (range: 0-5) was constructed based on five factors (smoking, drinking, physical inactivity, unhealthy body mass index, and unhealthy diet). Two aging measures, Phenotypic Age Acceleration (PhenoAgeAccel) and Biological Age Acceleration (BioAgeAccel) were calculated using nine and seven blood biomarkers, respectively, with a higher value indicating the acceleration of aging. The outcomes included incident cardiovascular disease (CVD), incident cancer, and all-cause mortality in UKB; CVD mortality, cancer mortality, and all-cause mortality in NHANES. A general linear regression model, Cox proportional hazards model, and formal mediation analysis were performed. RESULTS: The unhealthy lifestyles score was positively associated with PhenoAgeAccel (UKB: ß = 0.741; NHANES: ß = 0.874, all p < 0.001). We further confirmed the respective associations of PhenoAgeAccel and unhealthy lifestyles with the outcomes in UKB and NHANES. The mediation proportion of PhenoAgeAccel in associations of unhealthy lifestyles with incident CVD, incident cancer, and all-cause mortality were 20.0%, 17.8%, and 26.6% (all p < 0.001) in UKB, respectively. Similar results were found in NHANES. The findings were robust when using another aging measure-BioAgeAccel. CONCLUSIONS: Accelerated aging partially mediated the associations of lifestyles with CVD, cancer, and mortality in UK and US populations. The findings reveal a novel pathway and the potential of geroprotective programs in mitigating health inequality in late life beyond lifestyle interventions.

Prevalence of likely retro-odontoid pseudotumor in patients receiving dental CBCT examinations.

OBJECTIVES: We calculated the prevalence of unsuspected retro-odontoid pseudotumor (ROP) as detected in cone beam computed tomography (CBCT) examinations. Additionally, we examined patient age, sex, and presence and severity of cervical osteoarthritis (OA) as potential risk factors for ROP. STUDY DESIGN: We retrospectively analyzed de-identified CBCT scans of 455 patients from the Division of Oral and Maxillofacial Radiology at the University of Connecticut School of Dental Medicine. Identification of likely ROP was completed through a likelihood scoring scale (1-4) due to the lack of magnetic resonance images. Severity of cervical OA was determined using 5 osteoarthritic features. An ordinal logistic regression model was used to link potential risk factors to ROP. RESULTS: In total, 18 patients (3.9%) were classified with probable (11 patients [2.4%]) or definite (7 patients [1.5%]) likely ROP. Older age and the presence and severity of OA were significantly associated with higher ROP scores (P < .001). There was no significant association of ROP likelihood and patient sex (P = .637). An increase of 1 year of age increased the chance of a patient having a higher ROP likelihood score (P < .001). The age-adjusted chance of having a more severe ROP increased with moderate to severe OA (P ≤ .017). CONCLUSIONS: Prevalence of likely ROP increases with age and OA but is not associated with sex. Individuals with moderate or severe OA are more likely to have ROP.

Very Low and High Levels of Vitamin D Are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants.

Background: Shorter leukocyte telomere length (LTL) is observed in multiple age-related diseases, which are also associated with vitamin D deficiency (i.e., osteosarcopenia, neurocognitive disorders, cancer, osteoarthritis, etc.), suggesting a close association between vitamin D and LTL. In this study, we examined the relationship between vitamin D levels and LTL in older participants of the UK Biobank. Methods: Data were collected from the UK Biobank. Participants aged 60 and older (n = 148,321) were included. Baseline LTL was measured using a multiplex qPCR technique and expressed as the ratio of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Serum 25-hydroxyvitamin D (25OHD) was stratified by z score and linked to LTL in a linear regression model adjusting for covariates. Results: Compared to the medium level, a low (in the range of 16.6 nmol/L, 29.7 nmol/L) or extremely low (≤16.6 nmol/L) level of serum 25OHD was associated with shorter LTL: 0.018 SD (standardized ß = -0.018, 95% CI -0.033 to -0.003, p = 0.022) and 0.048 SD (standardized ß = -0.048, 95% CI -0.083 to -0.014, p = 0.006), respectively. Additionally, the high serum 25OHD groups (>95.9 nmol/L) had 0.038 SD (standardized ß = -0.038, 95% CI -0.072 to -0.004, p = 0.030) shorter mean LTL than the group with medium 25OHD levels. The associations above were adjusted for multiple variables. Conclusions: In this population-based study, we identified an inverted U-shape relationship between LTL and vitamin D status. Our findings could be affected by unmeasured confounders. Whether high or low vitamin D-associated shorter LTL is mechanistically related to age-related conditions remains to be elucidated.

Assessment of the occlusal outcomes in patients treated with orthognathic surgery and clear aligners.

OBJECTIVE: This retrospective two-centre study aimed to evaluate the occlusal outcomes in patients undergoing orthognathic surgery with clear aligners. METHODS: A retrospective chart review and occlusal outcomes for 15 patients (10 females and five males) with different types of dentofacial deformities in the anteroposterior, vertical and transverse dimensions, who underwent orthognathic surgery in conjunction with clear aligners were evaluated. Weighed Peer Assessment Rating (PAR) index scores of the pre-treatment and post-treatment digital models were used to assess initial complexity, final occlusal outcomes and degree of improvement with surgery and clear aligners. RESULTS: The mean post-treatment PAR score was 3.5 ± 2.54, which was a statistically significant improvement from the pre-treatment PAR score of 27.63 ± 12.09, an 87% improvement was achieved. All subcategories of the PAR index showed statistically significant improvement except for midline assessment component. CONCLUSIONS: Occlusal outcomes with aligners showed great improvement as indicated with the PAR index scores. Orthognathic surgical cases can be treated efficiently with aligners and future studies should compare occlusal outcomes between orthognathic surgical patients treated with clear aligners and those treated with fixed appliances.

Comparable Skeletal and Dental Movements Achieved Using Conventional and Surgery-First Techniques in Class III Patients.

PURPOSE: The surgery-first (SF) approach to orthognathic surgery has been proposed as a more efficient method to correct the dentofacial deformity. This study aimed to evaluate if the magnitude of skeletal and dental changes achieved in Class III patients treated with either conventional orthognathic surgery (COS) or SF techniques differ. METHODS: A retrospective cohort study of Class III orthognathic surgery patients between January 2006 and May 2020 with available pre- and post-treatment lateral cephalograms was conducted at an academic institution. The primary predictor variable was surgery technique: COS or SF. Assessed outcome variables included cephalometric skeletal parameters: SNA, SNB, ANB, Wits Appraisal, Sn-GoGn, and FMA; and dental parameters: U1-SN, U1-NA (°), U1-NA (mm), L1-NB (°), L1-NB (mm), and overjet. Within-group posttreatment parameters were analyzed with paired t tests. Pretreatment, posttreatment, and between-group parameter changes were analyzed by 2-sided 2-sample independent t tests. Potential covariates, including gender, surgical procedure, previous conventional treatment, extractions (excluding 3rd molars), crowding, and midline discrepancy, were analyzed using Fisher exact tests. RESULTS: Thirty-nine subjects were included in this study: 1) 21 COS (age: 20.9 ± 8.7 years) and 2) 18 SF (age: 19.6 ± 5.0 years). Cohorts were comparable (P > .05) for all analyzed covariates. COS showed statistically significant increases in L1-GoGn (3.31 ± 6.23°; P = .024), overjet (4.26 ± 3.99 mm; P < .001), ANB (3.5 ± 2.79°; P < .001), SNA (3.5 ± 1.85°; P < .001), and Wits Appraisal (3.78 ± 4.97 mm; P = .002). SF showed statistically significant increases in L1-GoGn (4.19 ± 4.85°; P = .002), L1-NB (3.08 ± 4.13°; P = .006), L1-NB (0.79 ± 1.35 mm; P = .023), overjet (5.82 ± 2.96 mm; P < .001), ANB (5.51 ± 3°; P < .001), SNA (4.13 ± 2.38°; P < .001), and Wits Appraisal (5.92 ± 3.42 mm; P < .001) and statistically significant decreases in U1-NA (-3.69 ± 7.35°; P = .048) and SNB (-1.38 ± 2.14°; P = .014). There were no statistically significant differences in skeletal or dental parameters between groups when adjusted for pretreatment levels of that parameter. The mean treatment duration was 38 months (standard deviation = 12.7) in COS and 17.6 months (standard deviation = 5.2) in SF. CONCLUSIONS: The results show that skeletal and dental changes between groups were not statistically different, despite an average 20-month difference in treatment duration. This suggests that either technique can be used to achieve comparable degrees of skeletal and dental movement in Class III patients.

Associations between leukocyte telomere length and osteosarcopenia in 20,400 adults aged 60 years and over: Data from the UK Biobank.

PURPOSE: Two mechanisms implicated in telomere shortening are oxidative stress and inflammation, both of which are linked to bone and muscle loss suggesting a pathological link between telomere attrition and osteosarcopenia. Using older adults aged 60 years and over in the UK Biobank, we examined the association between leukocyte telomere length and osteosarcopenia. METHODS: Baseline leukocyte telomere length was measured using a multiplex qPCR technique and expressed as the amount of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Osteosarcopenia data was from the first imaging visit and defined by WHO criteria (femoral neck bone density T score ≤ -1) for osteopenia/osteoporosis plus either the EWGSOP2 (low appendicular lean mass/height2 and low grip strength) or SDOC (low grip strength and slow walking pace) criteria for sarcopenia. Binary or multinomial logistic regression models were used to associate telomere length and osteosarcopenia or its components, adjusting for the covariates: age, sex, race, education, Townsend deprivation index, alcohol, smoking, BMI/weight, physical activity levels. RESULTS: Among 20,400 older adults (mean age: 67.79 ± 4.9 years, 53% men), the prevalence of osteosarcopenia by EWGSOP2 (n = 96, 0.47%) or SDOC (n = 205, 1%) criteria was low at the first imaging visit (mean 8.82 years after baseline). Baseline telomere length was not associated with osteosarcopenia by EWGSOP2 (Relative Risk (RR): 1.00, 95% CI: 0.82-1.23 comparing osteosarcopenia to normal (non-osteopenic, non-osteoporotic, and non-sarcopenic) per Standard Deviation (SD) increase in telomere length) or SDOC (RR: 0.95, 95% CI: 0.83-1.09) criteria. Longer telomere length was associated with a lower risk of slow walking pace (Odds Ratio: 0.92, 95% CI: 0.87-0.99 per SD increase in telomere length, p = 0.021). Telomere length, however, was not associated with low grip strength, low bone density or low appendicular lean mass/height2 (p > 0.05). CONCLUSIONS: In this population-based study, telomere length was not associated with osteosarcopenia; however, slow walking pace was. Further studies are needed to reexamine this relationship, including a greater number of the oldest-old (≥75 years) where osteosarcopenia is more prevalent.

Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: Long-term outcomes in women and men.

OBJECTIVE: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. METHODS AND ANALYSIS: This study comprised 69 185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40-79 years at first prescription, treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5 mmol/L) at baseline, plus treatment discontinuation. RESULTS: A total of 48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol vs 41.7% of those with functioning SLCO1B1 (odds ratio 1.31, 95% confidence interval [CI] 1.1-1.55, P = .001). Fewer males had high cholesterol and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (hazard ratio [HR] 1.19, 95% CI 1.03-1.37, P = .01), amounting to five discontinuations per 100 statin-years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3, 95% CI 1.08-1.56, P = .006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year. CONCLUSIONS: In this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve the effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype-guided statin selection.

GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism.

CONTEXT: Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism and sporadic PHPT. However, as these previously reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. OBJECTIVE: Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. DESIGN AND PATIENTS: DNA-encoding PHPT-associated GCM2 germline variants were polymerase chain reaction-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. RESULTS: GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and 3 (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease, but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33% and 1.04%, respectively). CONCLUSIONS: Observed in vitro-activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared to the general population, yet penetrance values are very low; that is, most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.

Antidiabetic Effects of the Senolytic Agent Dasatinib.

OBJECTIVE: To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients with type 2 diabetes mellitus. METHODS: This retrospective cohort study included enterprise-wide Mayo Clinic patients using Informatics for Integrating Biology at the Bedside from January 1994 through December 2019. The antidiabetic outcomes (change in hemoglobin A1c value, serum glucose concentration, and diabetic medications) after 1 year of a strongly senolytic tyrosine kinase inhibitor, dasatinib (n=16), was compared with a weakly senolytic tyrosine kinase inhibitor, imatinib (n=32). RESULTS: Relative to imatinib, patients treated with dasatinib had a mean reduction of 43.7 mg/dL (P=.005) in serum glucose concentration (to convert glucose values to mmol/L, multiply by 0.0555) and required 28.8 fewer total daily insulin units (P=.08) in the setting of a 4.8-kg relative weight loss (5.3% of total body weight; P=.045). Linear regression analysis suggests that the relative difference in weight accounts for 8.4 mg/dL of the 43.7 mg/dL blood glucose value decrease, or 19.2%. Relative to imatinib, patients treated with dasatinib had a mean 0.80 absolute point (P=.05) reduction in hemoglobin A1c and required 18.2 fewer total daily insulin units (P=.16) in the setting of a 5.9-kg relative weight loss (6.3% of total body weight; P=.06). CONCLUSION: Dasatinib may have antidiabetic effects comparable to contemporary diabetic treatments and may be considered for use as a novel diabetic therapy. Future studies are needed to determine whether these results are translatable to patients with type 2 diabetes mellitus without underlying malignant diseases and to determine whether the antidiabetic effects of dasatinib are due to its senolytic properties.

Examining the Development of Operative Autonomy in Vascular Surgery Training and When Trainees and Program Directors Agree and Disagree.

BACKGROUND: Lack of autonomy in the operating room (OR) during general surgery residency is a major contributing factor to low confidence operating independently after graduation. Although attempts to address decreased autonomy and development of entrustment in the OR are being made in general surgery programs, this issue has not been examined thoroughly in vascular surgery. We sought to determine barriers and opportunities for developing operative autonomy during vascular surgery training by surveying program directors (PDs) and trainees (integrated residents and fellows) in U.S. vascular surgery training programs. METHODS: An anonymous electronic survey was sent via email to all PDs (n = 155) and trainees (n = 516) in United States vascular surgery training programs. Demographics, academic characteristics, and responses regarding factors impacting the development of entrustment were collected. RESULTS: Thirty-five PDs and 100 trainees completed the survey (22.5% and 19.4% response rate, respectively). Sixty percent of trainees were integrated residents and 40% were fellows. Twenty percent of PDs and 33% of trainees were female, and 5% of all PDs and trainees were from underrepresented minorities. The single most positive factor affecting the development of autonomy according to trainees and PDs is familiarity of the faculty with the trainee. Both PDs and trainees thought the trainee's preparation for the case positively affected development of autonomy; however, more PDs believed that involvement with preoperative preparation in particular (marking the patient, consenting the patient, filling out a history and physical, prepping and draping the patient) was important (P < 0.05). PDs believed that duty-hour limitations negatively affected the trainee's ability to develop autonomy in the OR, whereas more trainees believed that hospital or OR efficiency policies played a negative role (P < 0.05). Finally, compared with trainees, PDs believed that the appropriate amount of time for safe struggle before the attending should take over the case was when OR efficiency was compromised or at any moment the trainee is unsure of themselves (P < 0.05); trainees believed that the attending should take over the case after the limit of their skill set or troubleshooting ability was reached (P < 0.05). CONCLUSIONS: Familiarity of the attending physician with the trainee is an important positive factor for development of entrustment and autonomy in vascular surgery trainees. Duty-hour limitations and belief of the need for hospital efficiency may negatively impact operative independence of trainees. An open discussion about balancing OR efficiency and trainees' safe struggle is essential to address the growth of independent operative skills in vascular surgery trainees.

Smoking cessation and counseling: A mixed methods study of pediatricians and parents.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort.

BACKGROUND: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. OBJECTIVE: To estimate p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. METHODS: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2* measures (lower values indicating more iron). RESULTS: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2* measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. CONCLUSION: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy.

Importance: Hereditary hemochromatosis is predominantly caused by the HFE p.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping. Objective: To estimate the incidence of primary hepatic carcinoma and death by HFE variant status. Design, Setting, and Participants: Cohort study of 451 186 UK Biobank participants of European ancestry (aged 40-70 years), followed up from baseline assessment (2006-2010) until January 2018. Exposures: Men and women with HFE p.C282Y and p.H63D genotypes compared with those with neither HFE variants. Main Outcomes and Measures: Two linked co-primary outcomes (incident primary liver carcinoma and death from any cause) were ascertained from follow-up via hospital inpatient records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data were available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetics substructure. Kaplan-Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75 years by HFE genotype and sex. Results: A total of 451 186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% women) were followed up for a median (interquartile range) of 8.9 (8.3-9.5) years. Among the 1294 male p.C282Y homozygotes, there were 21 incident hepatic malignancies, 10 of which were in participants without a diagnosis of hemochromatosis at baseline. p.C282Y homozygous men had a higher risk of hepatic malignancies (hazard ratio [HR], 10.5 [95% CI, 6.6-16.7]; P < .001) and all-cause mortality (n = 88; HR, 1.2 [95% CI, 1.0-1.5]; P = .046) compared with men with neither HFE variant. In lifetables projections for male p.C282Y homozygotes to age 75 years, the risk of primary hepatic malignancy was 7.2% (95% CI, 3.9%-13.1%), compared with 0.6% (95% CI, 0.4%-0.7%) for men with neither variant, and the risk of death was 19.5% (95% CI, 15.8%-24.0%), compared with 15.1% (95% CI, 14.7%-15.5%) among men with neither variant. Among female p.C282Y homozygotes (n = 1596), there were 3 incident hepatic malignancies and 60 deaths, but the associations between homozygosity and hepatic malignancy (HR, 2.1 [95% CI, 0.7-6.5]; P = .22) and death (HR, 1.2 [95% CI, 0.9-1.5]; P = .20) were not statistically significant. Conclusions and Relevance: Among men with HFE p.C282Y homozygosity, there was a significantly increased risk of incident primary hepatic malignancy and death compared with men without p.C282Y or p.H63D variants; there was not a significant association for women. Further research is needed to understand the effects of early diagnosis and treatment.

Utility of Smartphone Telemedical Consultations for Peritonsillar Abscess Diagnosis and Triage.

Importance: Telemedicine is rapidly gaining traction as a way to reduce costs and connect patients with medical experts outside their local communities. Peritonsillar abscess (PTA) is a logical pathologic condition to evaluate for effectiveness of remote diagnosis given its prevalence and the paucity of on-site otolaryngologists at many institutions. Objective: To explore the potential of otolaryngology telemedical consultation in triaging and diagnosing patients with suspected PTA. Design, Setting, and Participants: A comparative effectiveness research study was conducted from January 1 to June 30, 2018, at 3 tertiary care hospitals among 31 consecutive patients aged 18 to 85 years for whom the otolaryngology department was consulted to assess for PTA. Statistical analysis was conducted from July 1 to September 30, 2018. Interventions: Telemedical evaluation of suspected PTA by 5 attending otolaryngologists blinded to patients' history aside from the chief report of odynophagia. Otolaryngologists rated each patient video on whether they believed the patient had a PTA and whether the case warranted prompt evaluation by an otolaryngologist. Predictions were compared with the criterion standard of drainage or negative needle aspiration. Otolaryngologists additionally assessed video quality. Main Outcomes and Measures: Rates of accurate diagnosis and triage of PTA based on otolaryngologists' review of oropharyngeal examinations recorded using standard smartphone cameras, as well as percentage of videos of oropharyngeal examinations using standard smartphone cameras deemed of sufficiently high quality for clinical decision-making. Results: A total of 31 patients (16 women [51.6%]; mean age, 31.9 years [range, 18-62 years]) were recruited, and 16 patients (51.6%) had a PTA. Comparing otolaryngologists' predictions with PTA status by the criterion standard, the prediction was consistent with that of the criterion standard 81% of the time averaged across otolaryngologists (mean diagnostic accuracy, 0.81). Similarly, the mean diagnostic accuracy was 0.83 when comparing the otolaryngologist's suggestion for a prompt in-person evaluation with actual PTA status by the criterion standard. Comparing patients who were deemed to require prompt otolaryngology evaluation and those with PTA by the criterion standard, mean sensitivity was 90%. Videos were rated as of sufficiently high quality to make a diagnosis in 154 of 155 videos (99.4%). Conclusions and Relevance: This study suggests that telemedical consultation is a viable, cost-conscious, efficient, and safe approach to PTA management. Despite having some difficulty diagnosing PTAs based on "history concerning for PTA" and oropharyngeal video alone, otolaryngologists are able to determine, with high sensitivity, which patients require prompt otolaryngology evaluation. The recording of consistently high-quality video using a standard smartphone camera is achievable without formal training.

A 16-Year Study on Incidence and Progression of Diseased Sphenoethmoidal (Onodi) Cell.

Traumatic operative injury of the optic nerve in an endoscopic sinus surgery may cause immediate or delayed blindness. It should be cautioned when operating in a sphenoethmoidal cell, or known as Onodi cell, with contact or bulge of the optic canal. It remains unclear how frequent progression to visual loss occurs and how long it progresses to visual loss because of a diseased sphenoethmoidal cell. Research to discuss these questions is expected to help decision making to treat diseased sphenoethmoidal cells. From July 2001 to June 2017, 216 patients received conservative endoscopic sinus surgery without opening a diseased sphenoethmoidal cell. We used their computed tomography images of paranasal sinuses to identify diseased sphenoethmoidal cells that could be associated with progression to visual loss. Among the 216 patients, 52.3% had at least one sphenoethmoidal cell, and 14.8% developed at least one diseased sphenoethmoidal cell. One patient developed acute visual loss 4412 days after the first computed tomography. Our results show that over half of the patients have a sphenoethmoidal cell but suggest a rare incidence of a diseased sphenoethmoidal cell progressing to visual loss during the follow-up period.

GRK2 enforces androgen receptor dependence in the prostate and prostate tumors.

Metastatic tumors that have become resistant to androgen deprivation therapy represent the major challenge in treating prostate cancer. Although these recurrent tumors typically remain dependent on the androgen receptor (AR), non-AR-driven tumors that also emerge are particularly deadly and becoming more prevalent. Here, we present a new genetically engineered mouse model for non-AR-driven prostate cancer that centers on a negative regulator of G protein-coupled receptors that is downregulated in aggressive human prostate tumors. Thus, prostate-specific expression of a dominant-negative G protein-coupled receptor kinase 2 (GRK2-DN) transgene diminishes AR and AR target gene expression in the prostate, and confers resistance to castration-induced involution. Further, the GRK2-DN transgene dramatically accelerates oncogene-initiated prostate tumorigenesis by increasing primary tumor size, potentiating visceral organ metastasis, suppressing AR, and inducing neuroendocrine marker mRNAs. In summary, GRK2 enforces AR-dependence in the prostate, and the loss of GRK2 function in prostate tumors accelerates disease progression toward the deadliest stage.

Interaction Between Vitamin D and Interleukin 6 on Slow Gait Speed: 6-Year Follow-up Data of Older Adults From InCHIANTI.

BACKGROUND: Whereas the independent effects of biomarkers, including 25-hydroxy vitamin D (25(OH)D), insulin-like growth factor 1, C-reactive protein, and interleukin 6 (IL-6), on gait speed in older adults have been evaluated, their joint effects on gait speed are not well understood. METHODS: Study subjects aged at least 65 at baseline (N = 970) were enrolled in the population-based Invecchiare in Chianti (InCHIANTI) study from 1998 to 2000 and were followed up at 3 and 6 years. All above biomarkers and gait speed data were measured at each of the three time points. Using a generalized estimating equation approach, we determined if slow gait speed (<0.8 m/s) was associated with the biomarkers. Further investigation was conducted for interactions between high IL-6 (≥.87 pg/mL) and other biomarkers focusing on low 25(OH)D (<20 ng/mL). RESULTS: After controlling for other biomarkers and potential confounders, IL-6 emerged as the only biomarker independently associated with gait speed. The association between high IL-6 and slow gait speed was enhanced by low 25(OH)D, with significant interaction between high IL-6 and low 25(OH)D (p = .038). The odds ratio of slow gait speed for low 25(OH)D and high IL-6 was 1.63 (95% confidence interval [CI]: 1.15, 2.32) compared with the reference groups with both biomarker levels at the other ends. CONCLUSION: The association of low vitamin D with slow gait speed statistically interacts with high IL-6. Coexisting vitamin D insufficiency and inflammation may provide a better biomarker for identifying those at risk of developing impairments in gait speed than either factor alone.