Telemedicine and home spirometry in cystic fibrosis: A prospective multicenter study.

OBJECTIVES: Telehealth and home spirometry feasibility for children has been established, but their impact on cystic fibrosis (CF) disease progression remains unassessed. We aimed to evaluate the effects of telehealth and home spirometry on CF disease progression and care. METHODS: Children with CF aged 5-17 years from all Swedish CF centers were provided with home spirometers. A minimum of two in-person visits were replaced with telemedicine visits and participants were instructed to conduct home spirometry before visits. Linear mixed-effects models were used to compare annual CF disease trajectories during the intervention period and prepandemic period (1 January 2019 to 28 February 2020). Participants and caregivers completed study questionnaires. RESULTS: A total of 59 individuals completed the study over a mean (SD) period of 6.8 (1.4) months, made 3.1 (1.0) physical visits and 2.2 (0.6) telehealth visits per patient year during the study period. The mean difference (95% CI) between the intervention and prepandemic period progression rate for FEV1%, lung clearance index and BMI were -0.4 (-1.3 to 0.5, p = 0.39), 0.11 (-0.07 to 0.28, p = 0.25) and -0.02 (-0.13 to 0.08, p = 0.70), respectively. There were no major shifts in the incidence of airway pathogens, sputum cultures, or antibiotics use between the periods (p > 0.05). The intervention did not increase stress. Almost all participants and caregivers expressed a desire to continue with home spirometry and telemedicine. CONCLUSION: Combining telehealth and physical visits with access to home spirometry demonstrated comparable effectiveness as exclusively in-person care with enhanced flexibility and personalization of CF care.

Analyses of 1,236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterized by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, FEV1) were collected from 19 countries using the ERN LUNG International PCD Registry. Genetic data were evaluated according to ACMG guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: 1236 individuals carried 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%; 47-100%) and laterality defects (mean 42%; 28-69%) varied widely among the countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). In the group of individuals with CCNO (-3.26), CCDC39 (-2.49), and CCDC40 (-2.96) variants, FEV1 z-scores were significantly lower, while the group of DNAH11 (-0.83) and ODAD1 (-0.85) variant individuals had significantly milder FEV1 z-score reductions compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of genetic epidemiology of PCD and provides prediction of diagnostic and phenotypic features such as the course of lung function.

Exploring the dynamics of COVID-19 in a Greenlandic cohort: Mild acute illness and moderate risk of long COVID.

Objectives: This study aimed to explore how the Greenlandic population experienced the course of both acute and long-term COVID-19. It was motivated by the unique epidemiologic situation in Greenland, with delayed community transmission of SARS-CoV-2 relative to the rest of the world. Methods: In a survey among 310 Greenlandic adults, we assessed the association between previous SARS-CoV-2 infection and overall health outcomes by administering three repeated questionnaires over 12 months after infection, with a response rate of 41% at the 12-month follow-up. The study included 128 individuals with confirmed SARS-CoV-2 infection from January/February 2022 and 182 test-negative controls. Participants were recruited through personal approaches, phone calls, and social media platforms. Results: A total of 53.7% of 162 participants who were test-positive recovered within 4 weeks and 2.5% were hospitalized due to SARS-CoV-2. The most common symptoms were fatigue and signs of mild upper respiratory tract infection. Less than 5% reported sick leave above 2 weeks after infection. Compared with participants who were test-negative, there was an increased risk of reporting fatigue (risk differences 25.4%, 95% confidence interval 8.8-44.0) and mental exhaustion (risk differences 23.4%, 95% confidence interval 4.8-42.2) up to 12 months after a positive test. Conclusions: Our results indicate that during a period dominated by the Omicron variant, Greenlanders experienced a mild acute course of COVID-19, with quick recovery, minimizing the impact on sick leave. Long COVID may be present in Greenlanders, with symptoms persisting up to 12 months after infection. However, it is important to consider the small sample size and modest response rate as limitations when interpreting the results.

Impact of lumacaftor/ivacaftor on the bacterial and fungal respiratory pathogens in cystic fibrosis: a prospective multicenter cohort study in Sweden.

BACKGROUND: A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden. OBJECTIVES: The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden. DESIGN: The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor. METHODS: Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed. RESULTS: Lung function measured as ppFEV1 (p < 0.001), body mass index (BMI) in adults (p < 0.001), and BMI z-score in children (p = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of Streptococcus pneumoniae (p = 0.007) and Stenotrophomonas maltophilia (p < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for Candida albicans (p = 0.009), Penicillium spp (p = 0.026), and Scedosporium apiospermum (p < 0.001) shifted from negative to positive. CONCLUSION: The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for Pseudomonas aeruginosa, Staphylococcus aureus, or Aspergillus fumigatus, key pathogens in the CF context.

SARS-CoV-2 Antibodies in Breastmilk Three and Six Months Postpartum in Relation to the Trimester of Maternal SARS-CoV-2 Infection-An Exploratory Study.

The immune system of neonates is immature and therefore knowledge of possible early-life protection against SARS-CoV-2 infection, such as breastfeeding, is of great importance. Few studies have investigated the presence and duration of SARS-CoV-2 antibodies in breastmilk in relation to the trimester of maternal infection during pregnancy, and none with successful participation from all three trimesters. This study has dual objectives (1) in relation to the trimester of infection to examine the frequency, concentration and duration of IgA and IgG antibodies in breastmilk and blood serum in the third and sixth month post-partum in former SARS-CoV-2-infected mothers and (2) to examine the association in pediatric emergency admission of children within the first six months of life compared to children of non-SARS-CoV-2-infected women. The first objective is based on a prospective cohort and the second is based on a nested case-control design. The study participants are women with a former SARS-CoV-2 infection during pregnancy, whose serology IgG tests at delivery were still positive. Maternal blood and breastmilk samples were collected at three and six months postpartum. Serum IgA frequency three months pp was 72.7% (50%, 90% and 60% in the first, second and third trimester) and 82% six months pp (67%, 91% and 82% in the first, second and third trimester). Breastmilk IgA frequency three months pp was 27% (16.6%, 36% and 20% in first, second and third trimester) and 28% six months pp (0%, 38% and 28% in the first, second and third trimester). The highest IgA concentration in breastmilk was found six months post-partum with infection in the third trimester. Serum IgA was detectable more than 400 days post infection, and serum IgG above threshold was found 430 days after date of infection. We found no correlation between serum IgA and breastmilk IgA, nor between serum IgG and breastmilk IgA regardless of the trimester of infection.

Phased Correction of a Worn Dentition With a Severe Occlusal Cant Using a Systematic Management System.

In cases of extreme worn dentition, being able to complete treatment over a series of phases can not only allow patients to move forward with treatment that fits into their budgetary and time constraints, but may also enable them to consider more comprehensive treatment options. In the case presented, the patient at presentation was well aware of his dental problems but overwhelmed by the scope and potential cost of comprehensive treatment. This case report illustrates the correction of the patient's severe occlusal cant and restoration of his worn dentition using phased digital treatment planning and a step-by-step management system. Among the challenges of the case, which was carried out over the course of five phases, was establishing an appropriate occlusal cant and incisal edge position while maintaining function.

The impact of acute SARS-CoV-2 on testicular function including insulin-like factor 3 (INSL3) in men with mild COVID-19: A longitudinal study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect the male reproductive system as it uses angiotensin-converting enzyme (ACE)2, which is expressed in testicular tissue, as an entry point into the cell. Few studies have evaluated the long-term effects of mild coronavirus disease 2019 (COVID-19) on testicular function, and insulin-like factor 3 (INSL3) levels have not previously been assessed during acute SARS-CoV-2 infection. OBJECTIVES: The aim of the study was to assess the impact of acute SARS-CoV-2 infection on testicular function including INSL3 and the presence of SARS-CoV-2 RNA in semen in non-hospitalised men with mild COVID-19. MATERIALS AND METHODS: This longitudinal study included 36 non-hospitalised SARS-CoV-2-positive men (median age 29 years). Inclusion was within seven days following a positive SARS-CoV-2 reverse-transcription polymerase chain reaction test. Reproductive hormone levels, semen parameters, and the presence of SARS-CoV-2 RNA in oropharyngeal and semen samples were assessed during acute SARS-CoV-2 infection (baseline) and at three- and six-month follow-up. Wilcoxon matched-pair signed-rank (two samples) test was used to assess time-related alterations in reproductive hormone levels and semen parameters. RESULTS: Lower plasma testosterone (T) (total and calculated free (c-fT)) and higher luteinising hormone (LH) concentrations were observed during acute SARS-CoV-2 infection (baseline) compared to three- and six-month follow-up. Consequently, ratios of c-fT/LH were lower at baseline compared to three- and six-month follow-up (p < 0.001 and p = 0.003, respectively). Concomitantly, lower INSL3 concentrations were observed at baseline compared to three-month follow-up (p = 0.01). The total number of motile spermatozoa was also lower at baseline compared to six-month follow-up (p = 0.02). The alterations were detected irrespective of whether the men had experienced SARS-CoV-2-related fever episodes or not. No SARS-CoV-2 RNA was detected in semen at any time point. DISCUSSION AND CONCLUSION: This study showed a reduction in testicular function, which was for the first time confirmed by INSL3, in men mildly affected by SARS-CoV-2 infection. The risk of transmission of SARS-CoV-2 RNA via semen seems to be low. Febrile episodes may impact testicular function, but a direct effect of SARS-CoV-2 cannot be excluded.

Short-term exposure to zinc- and copper-containing welding fumes: Effects on pulmonary function in humans.

Zinc- and copper-containing welding fumes typically induce a systemic inflammation indicated by increase in C-reactive protein (CRP) levels, also known as welding fume fever. It typically includes symptoms like fever, myalgia or headaches, but only a quarter of patients experience respiratory symptoms, e.g. coughing. This retrospective analysis of data of three studies with either control (filtered air) or zinc- and copper-containing welding fume exposure aims to identify and characterize the effect of the welding fumes on lung function. Spirometry and body plethysmography data of male healthy volunteers were analyzed and comparisons between different timepoints after a 6 h exposure were conducted. For controls no significant changes in spirometry were observed between baseline and 6 h, 24 h and 1 week after exposure. For volunteers exposed to zinc- and copper-containing welding fumes no significant reductions in forced expiratory volume in 1 s (FEV1) and minimal reductions in vital capacity (VC) (52 ml, 0.9%) were detected after 6 h. After 24 h significant reductions in FEV1 (147 ml, 3.2%) and VC (162 ml, 2.9%) could be observed. 1 week after exposure FEV1 was still significantly reduced (102 ml, 2.1%) and airway resistance were increased while no differences in VC were detected. The reduction of FEV1% after 24 week significantly correlated with increases in CRP levels. In conclusion, a single exposure to zinc- and copper-containing welding fumes leads not only to a systemic inflammation but could also induce slight sustained airway constrictions after 24 h and 1 week. The observed slight airway constriction is not caused by immediate effects but possibly inflammatory processes. Although welding fume fever does not necessarily present respiratory symptoms, welders exposed to zinc- and copper-containing welding fumes should be monitored for respiratory symptoms and obstructive ventilation pattern.

Frequent body position changes and physical activity as effective as standard care for infants hospitalised with acute respiratory infections - a randomised controlled trial.

Background: No definite consensus has been reached yet on the best treatment strategy for the large group of infants hospitalised with bronchiolitis or pneumonia. Minimal handling is often recommended, although not evaluated scientifically. There is a need to evaluate the management, as the infants often are critically affected, and the costs for society are high. The aim of this RCT was to evaluate the most common physiotherapy intervention in Sweden for this patient group, including frequent changes in body position and stimulation of physical activity, compared to standard care. Methods: Infants 0-24 months old, without previous cardiac or respiratory diagnoses and born in gestational week 35+, were recruited in two Swedish hospitals. The participants (n=109) were randomised to either interventions in addition to standard care (intervention group) or to standard care alone (control group). The primary outcome measure was time to improvement. The secondary outcomes were immediate changes in oxygen saturation, heart rate and respiratory rate, time to improved general condition (parents' assessment), and lung complications. Results: The median time to improvement was 6 hours in both groups (p=0.54). The result was similar when we adjusted for age in months, sex, tobacco smoke exposure, heredity for asthma/atopic disease, and early stage of the infection (for those with RSV), p=0.69. Analyses of the immediate changes showed no significant differences either (p=0.49-0.89). Time to improved general condition was median 3 hours in the intervention group and 6 hours in the control group, p=0.76. No lung complications occurred. Conclusions: No statistically significant differences in outcomes were detected between the intervention group and the control group. Both strategies were found to be equally effective and safe, indicating that the current recommendation of minimal handling for these infants should be reconsidered. Furthermore, the findings suggest that this treatment can be safely continued.

DNA-methylation and immunological response in medication overuse headache.

OBJECTIVE: To investigate whether medication-overuse headache patients have differential DNA-methylation pattern. METHODS: We collected blood samples from 120 medication-overuse headache-patients, 57 controls (29 episodic migraine patients and 28 healthy controls) in a hypothesis-generating cross-sectional case-control pilot study; 100 of the medication-overuse headache-patients were followed for six months and samples were collected at two and six months for the longitudinal methylation analyses. Blood cell proportions of leucocytes (neutrophils, NK-cells, monocytes, CD8+ and CD4+ T-cells, and B-cells) and the neutrophile-lymphocyte ratio were estimated using methylation data as a measure for immunological analysis and a cell type-specific epigenome wide association study was conducted between medication-overuse headache-patients and controls, and longitudinally for reduction in headache days/month among medication-overuse headache-patients. RESULTS: We found a higher neutrophile-lymphocyte ratio in medication-overuse headache-patients compared to controls, indicating a higher immunological response in medication-overuse headache-patients (false discovery rate (adjusted p-value)<0.001). Reduction in headache days/month (9.8; 95% CI 8.1-11.5) was associated with lower neutrophile-lymphocyte ratio (false discovery rate adjusted p-value = 0.041).Three genes (CORIN, CCKBR and CLDN9) were hypermethylated in specific cell types in medication-overuse headache-patients compared to controls. No methylation differences were associated with reduction in headache days in medication-overuse headache-patients after six months. CONCLUSION: This pilot study was consistent with higher immunological response in medication-overuse headache-patients which decreased with a reduction in headache days in longitudinal analysis. medication-overuse headache-patients exhibited differential methylation in innate immune cells but did not exhibit longitudinal differences with alterations in headache days. Our study creates hypotheses for further biomarker searches.ClinicalTrials.gov Identifier: NCT02993289.

Cognitive-behavioural therapy reduces psychological distress in younger patients with cardiac disease: a randomized trial.

AIMS: To test whether usual outpatient cardiac rehabilitation (CR) supplemented by a cognitive-behavioural therapy (CBT) intervention may reduce anxiety and depression compared with usual CR. METHODS AND RESULTS: In this multicentre randomized controlled trial, 147 cardiac patients (67% men, mean age 54 years, 92% with coronary artery disease) with psychological distress defined as a hospital anxiety and depression scale (HADS) anxiety or depression score ≥8 were randomized to five sessions of group CBT plus usual CR (intervention, n = 74) or CR alone (control, n = 73). Patients with severe distress or a psychiatric diagnosis were excluded. The intervention was delivered by cardiac nurses with CBT training and supervised by a psychologist. A reference, non-randomized group (background, n = 41) of consecutive patients without psychological distress receiving usual CR was included to explore the effect of time on HADS score. The primary outcome, total HADS score after 3 months, improved more in the intervention than in the control group [the mean total HADS score improved by 8.0 (standard deviation 5.6) vs. 4.1 (standard deviation 7.8), P < 0.001]. Significant between-group differences were maintained after 6 months. Compared with the control group, the intervention group also had greater adherence to CR (P = 0.003), more improvement in the heart-related quality of life (HeartQoL) at 6 months (P < 0.01), and a significant reduction in cardiac readmissions at 12 months (P < 0.01). The background group had no significant change in HADS score over time. CONCLUSION: Brief CBT provided by cardiac nurses in relation to CR reduced anxiety and depression scores, improved HeartQoL and adherence to CR, and reduced cardiovascular readmissions. The programme is simple and may be implemented by CR nurses.

Methylation microarray-based detection of clinical copy-number aberrations in CLL benchmarked to standard FISH analysis.

Copy-number aberrations (CNAs) are assessed using FISH analysis in diagnostics of chronic lymphocytic leukemia (CLL), but CNAs can also be extrapolated from Illumina BeadChips developed for genome-wide methylation microarray screening. Increasing numbers of microarray data-sets are available from diagnostic samples, making it useful to assess the potential in CNA diagnostics. We benchmarked the limitations of CNA testing from two Illumina BeadChips (EPIC and 450k) and using two common packages for analysis (conumee and ChAMP) to FISH-based assessment of 11q, 13q, and 17p deletions in 202 CLL samples. Overall, the two packages predicted CNAs with similar accuracy regardless of the microarray type, but lower than FISH-based assessment. We showed that the bioinformatics analysis needs to be adjusted to the specific CNA, as no general settings were identified. Altogether, we were able to predict CNAs using methylation microarray data, however, with limited accuracy, making FISH-based assessment of deletions the superior diagnostic choice.

Physiotherapy interventions encouraging frequent changes of the body position and physical activity for infants hospitalised with bronchiolitis: an internal feasibility study of a randomised control trial.

BACKGROUND: The effect of a treatment that includes frequent changes of the body position for infants with bronchiolitis has not been evaluated, although it is often used in Swedish hospitals. Because of this, a randomised control trial (RCT) has begun with the aim to evaluate this treatment, comparing the effect of an individualised physiotherapy intervention, a non-individualised intervention, and standard care in a control group. The objective of this internal pilot study was to address uncertainties concerning the ongoing RCT and to determine whether the trial is feasible or not, possibly with adjustments to the protocol. METHODS: Descriptive analyses of the recruitment, retention, data supply for the primary end point, and the usability of the primary outcome measure in the full RCT were performed. A safety analysis was conducted by an independent analysis group. RESULTS: Ninety-one infants were included, 33 (36.3%), 28 (30.8%), and 30 (33.0%) in the respective allocation groups. Fifty-nine (64.8%) were boys. The median age was 2.5 (min-max 0.2-23.7) months. They remained in the study for a median of 46 hours (min-max 2-159). The recruitment rate was 19%. The data supply for the primary end point and for the primary outcome measure was lower than anticipated in the original sample size calculation. Difficulties concerning utilising the primary outcome measure were identified. The safety analysis detected no risks of harm related to participation in the study. CONCLUSIONS: It is feasible to continue the RCT with modifications of the analysis plan. Participation in the study was not associated with any safety risks. TRIAL REGISTRATION: ClinicalTrials.gov NCT03575091 . Registered 2 July 2018. Retrospectively registered.

The Evaluation of a Social Media Campaign to Increase COVID-19 Testing in Migrant Groups: Cluster Randomized Trial.

BACKGROUND: A low test positivity rate is key to keeping the COVID-19 pandemic under control. Throughout the pandemic, several migrant groups in Norway have seen higher rates of confirmed COVID-19 and related hospitalizations, while test positivity has remained high in the same groups. The Norwegian government has used several platforms for communication, and targeted social media advertisements have in particular been an important part of the communication strategy to reach these groups. OBJECTIVE: In this study, we aimed to investigate whether such a targeted Facebook campaign increased the rate of COVID-19 tests performed in certain migrant groups. METHODS: We randomly assigned 386 Norwegian municipalities and city districts to intervention or control groups. Individuals born in Eritrea, Iraq, Pakistan, Poland, Russia, Somalia, Syria, and Turkey residing in intervention areas were targeted with a social media campaign aiming at increasing the COVID-19 test rate. The campaign message was in a simple language and conveyed in the users' main language or in English. RESULTS: During the 2-week follow-up period, the predicted probability of having a COVID-19 test taken was 4.82% (95% CI 4.47%-5.18%) in the control group, and 5.58% (95% CI 5.20%-5.99%) in the intervention group (P=.004). CONCLUSIONS: Our targeted social media intervention led to a modest increase in test rates among certain migrant groups in Norway. TRIAL REGISTRATION: ClinicalTrials.gov NCT04866589; https://clinicaltrials.gov/ct2/show/NCT04866589.

IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load.

Currently, no molecular biomarker indices are used in standard care to make treatment decisions at diagnosis of chronic lymphocytic leukemia (CLL). We used Infinium MethylationEPIC array data from diagnostic blood samples of 114 CLL patients and developed a procedure to stratify patients based on methylation signatures associated with mutation load of the IGHV gene. This procedure allowed us to predict the time to treatment with a hazard ratio (HR) of 8.34 (95% confidence interval [CI]: 4.54-15.30), as opposed to a HR of 4.35 (95% CI: 2.60-7.28) using IGHV mutation status. Detailed evaluation of 17 cases for which the two classification procedures gave discrepant results showed that these cases were incorrectly classified using IGHV status. Moreover, methylation-based classification stratified patients with different overall survival (HR=1.82; 95% CI: 1.07-3.09), which was not possible using IGHV status. Furthermore, we assessed the performance of the developed classification procedure using published HumanMethylation450 array data for 159 patients for whom information on time to treatment, overall survival and relapse was available. Despite 450K array methylation data not containing all the biomarkers used in our classification procedure, methylation signatures again stratified patients with significantly better accuracy than did IGHV mutation load regarding all available clinical outcomes. Thus, stratification using IGHV-associated methylation signatures may provide better prognostic power than IGHV mutation status.

EWAS of Monozygotic Twins Implicate a Role of mTOR Pathway in Pathogenesis of Tic Spectrum Disorder.

Tic spectrum disorder (TSD) is an umbrella term which includes Gilles de la Tourette syndrome (GTS) and chronic tic disorder (CTD). They are considered highly heritable, yet the genetic components remain largely unknown. In this study we aimed to investigate disease-associated DNA methylation differences to identify genes and pathways which may be implicated in TSD aetiology. For this purpose, we performed an exploratory analysis of the genome-wide DNA methylation patterns in whole blood samples of 16 monozygotic twin pairs, of which eight were discordant and six concordant for TSD, while two pairs were asymptomatic. Although no sites reached genome-wide significance, we identified several sites and regions with a suggestive significance, which were located within or in the vicinity of genes with biological functions associated with neuropsychiatric disorders. The two top genes identified (TSC1 and CRYZ/TYW3) and the enriched pathways and components (phosphoinosides and PTEN pathways, and insulin receptor substrate binding) are related to, or have been associated with, the PI3K/AKT/mTOR pathway. Genes in this pathway have previously been associated with GTS, and mTOR signalling has been implicated in a range of neuropsychiatric disorders. It is thus possible that altered mTOR signalling plays a role in the complex pathogenesis of TSD.

Idiopathic early ovarian aging: is there a relation with premenopausal accelerated biological aging in young women with diminished response to ART?

PURPOSE: To evaluate whether young women with idiopathic early ovarian aging, as defined by producing fewer oocytes than expected for a given age over multiple in vitro fertilization (IVF) cycles, have changes in telomere length and epigenetic age indicating accelerated biological aging (i.e., increased risk of morbidity and mortality). METHODS: A prospective cohort study was conducted at two Danish public fertility clinics. A total of 55 young women (≤ 37 years) with at least two IVF cycles with ≤ 5 harvested oocytes despite sufficient stimulation with follicle-stimulating hormone (FSH) were included in the early ovarian aging group. As controls, 52 young women (≤ 37 years) with normal ovarian function, defined by at least eight harvested oocytes, were included. Relative telomere length (rTL) and epigenetic age acceleration (AgeAccel) were measured in white blood cells as markers of premenopausal accelerated biological aging. RESULTS: rTL was comparable with a mean of 0.46 (± SD 0.12) in the early ovarian aging group and 0.47 (0.14) in the normal ovarian aging group. The AgeAccel of the early ovarian aging group was, insignificantly, 0.5 years older, but this difference disappeared when adjusting for chronological age. Sub-analysis using Anti-Müllerian hormone (AMH) as selection criterion for the two groups did not change the results. CONCLUSION: We did not find any indications of accelerated aging in whole blood from young women with idiopathic early ovarian aging. Further investigations in a similar cohort of premenopausal women or other tissues are needed to fully elucidate the potential relationship between premenopausal accelerated biological aging and early ovarian aging.

Genetic regulation of spermine oxidase activity and cancer risk: a Mendelian randomization study.

Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 × 10-49) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10-28) and adults (P = 2.748 × 10-8) explaining 37% and 6% of the variance, respectively. Genetically determined SMOX activity was not associated with neuroblastoma, gastric, lung, breast, prostate nor colorectal cancer (P > 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. These results may inform studies of SMOX inhibition as a target for chemoprevention.

Comprehensive, Phased Restoration of Worn Dentition Utilizing Digital Analysis and Diagnostic Protocols.

In this case of a comprehensive dental restoration, a predictable course of treatment is demonstrated in which dental risk was stabilized and definitive treatment was provided in a phased approach to accommodate financial limitations of the patient. Utilizing digital photographic analysis, facial reference glasses, and intraoral scanning, the clinician implemented a treatment plan that was aimed at minimizing and managing the patient's biomechanical and functional risks and resolving his concerns about past failing dental work and an unattractive smile. The phased rehabilitation plan included opening of the vertical dimension of occlusion to accommodate restorative space, appropriate incisal edge position, and function.