DIGIPREDICT: physiological, behavioural and environmental predictors of asthma attacks-a prospective observational study using digital markers and artificial intelligence-study protocol.

INTRODUCTION: Asthma attacks are a leading cause of morbidity and mortality but are preventable in most if detected and treated promptly. However, the changes that occur physiologically and behaviourally in the days and weeks preceding an attack are not always recognised, highlighting a potential role for technology. The aim of this study 'DIGIPREDICT' is to identify early digital markers of asthma attacks using sensors embedded in smart devices including watches and inhalers, and leverage health and environmental datasets and artificial intelligence, to develop a risk prediction model to provide an early, personalised warning of asthma attacks. METHODS AND ANALYSIS: A prospective sample of 300 people, 12 years or older, with a history of a moderate or severe asthma attack in the last 12 months will be recruited in New Zealand. Each participant will be given a smart watch (to assess physiological measures such as heart and respiratory rate), peak flow meter, smart inhaler (to assess adherence and inhalation) and a cough monitoring application to use regularly over 6 months with fortnightly questionnaires on asthma control and well-being. Data on sociodemographics, asthma control, lung function, dietary intake, medical history and technology acceptance will be collected at baseline and at 6 months. Asthma attacks will be measured by self-report and confirmed with clinical records. The collected data, along with environmental data on weather and air quality, will be analysed using machine learning to develop a risk prediction model for asthma attacks. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the New Zealand Health and Disability Ethics Committee (2023 FULL 13541). Enrolment began in August 2023. Results will be presented at local, national and international meetings, including dissemination via community groups, and submission for publication to peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12623000764639; Australian New Zealand Clinical Trials Registry.

A framework for leveraging network course-based undergraduate research experience (CURE) faculty to develop, validate, and administer an assessment instrument.

Over the last several years, nationally disseminated course-based undergraduate research experiences (CUREs) have emerged as an alternative to developing a novel CURE from scratch, but objective assessment of these multi-institution (network) CUREs across institutions is challenging due to differences in student populations, instructors, and fidelity of implementation. The time, money, and skills required to develop and validate a CURE-specific assessment instrument can be prohibitive. Here, we describe a co-design process for assessing a network CURE [the Prevalence of Antibiotic Resistance in the Environment (PARE)] that did not require support through external funding, was a relatively low time commitment for participating instructors, and resulted in a validated instrument that is usable across diverse PARE network institution types and implementation styles. Data collection efforts have involved over two dozen unique institutions, 42 course offerings, and over 1,300 pre-/post-matched assessment record data points. We demonstrated significant student learning gains but with small effect size in both content and science process skills after participation in the two laboratory sessions associated with the core PARE module. These results show promise for the efficacy of short-duration CUREs, an educational research area ripe for further investigation, and may support efforts to lower barriers for instructor adoption by leveraging a CURE network for developing and validating assessment tools.

Epigenetic associations in HPA axis genes related to bronchopulmonary dysplasia and antenatal steroids.

BACKGROUND: Bronchopulmonary dysplasia (BPD), a common morbidity among very preterm infants, is associated with chronic disease and neurodevelopmental impairments. A hypothesized mechanism for these outcomes lies in altered glucocorticoid (GC) activity. We hypothesized that BPD and its treatments may result in epigenetic differences in the hypothalamic-pituitary-adrenal (HPA) axis, which is modulated by GC, and could be ascertained using an established GC risk score and DNA methylation (DNAm) of HPA axis genes. METHODS: DNAm was quantified from buccal tissue (ECHO-NOVI) and from neonatal blood spots (ELGAN ECHO) via the EPIC microarray. Prenatal maternal characteristics, pregnancy complication, and neonatal medical complication data were collected from medical record review and maternal interviews. RESULTS: The GC score was not associated with steroid exposure or BPD. However, six HPA genes involved in stress response regulation demonstrated differential methylation with antenatal steroid exposure; two CpGs within FKBP5 and POMC were differentially methylated with BPD severity. These findings were sex-specific in both cohorts; males had greater magnitude of differential methylation within these genes. CONCLUSIONS: These findings suggest that BPD severity and antenatal steroids are associated with DNAm at some HPA genes in very preterm infants and the effects appear to be sex-, tissue-, and age-specific. IMPACT: This study addresses bronchopulmonary dysplasia (BPD), an important health outcome among preterm neonates, and interrogates a commonly studied pathway, the hypothalamic-pituitary-adrenal (HPA) axis. The combination of BPD, the HPA axis, and epigenetic markers has not been previously reported. In this study, we found that BPD itself was not associated with epigenetic responses in the HPA axis in infants born very preterm; however, antenatal treatment with steroids was associated with epigenetic responses.

Epigenetic landscape of 5-hydroxymethylcytosine and associations with gene expression in placenta.

5-hydroxymethylcystosine (5hmC), is an intermediate product in the DNA demethylation pathway, but may act as a functional epigenetic modification. We have conducted the largest study of site-specific 5hmC in placenta to date using parallel bisulphite and oxidative bisulphite modification with array-based assessment. Incorporating parallel RNA-sequencing data allowed us to assess associations between 5hmC and gene expression, using expression quantitative trait hydroxymethylation (eQTHM) analysis. We identified ~ 47,000 loci with consistently elevated (systematic) 5hmC proportions. Systematic 5hmC was significantly depleted (p < 0.0001) at CpG islands (CGI), and enriched (p < 0.0001) in 'open sea' regions (CpG >4 kb from CGI). 5hmC was most and least abundant at CpGs in enhancers and active transcription start sites (TSS), respectively (p < 0.05). We identified 499 significant (empirical-p <0.05) eQTHMs within 1 MB of the assayed gene. At most (75.4%) eQTHMs, the proportion of 5hmC was positively correlated with transcript abundance. eQTHMs were significantly enriched among enhancer CpGs and depleted among CpGs in active TSS (p < 0.05 for both). Finally, we identified 107 differentially hydroxymethylated regions (DHMRs, p < 0.05) across 100 genes. Our study provides insight into placental distribution of 5hmC, and sheds light on the functional capacity of this epigenetic modification in placenta.

The Power of Mindfulness: Examining Power Imbalances, Mindfulness, and Couples' Relational and Sexual Well-Being.

Perceptions of power imbalance are common in relationships. We used the relational model of mindfulness to examine links between marital perceptions of power, relational and sexual well-being and to evaluate whether trait mindfulness and sexual mindfulness moderate these associations. Using a nationally representative sample (N = 1,519 couples at Wave III) of mixed-sex newlywed couples, an actor-partner-interdependence model indicated that trait mindfulness and state sexually mindful awareness buffered the link between men's and women's own perceived power imbalance and relational well-being. Sexually mindful non-judgment, however, accentuated the negative association between perceived power imbalance and sexual well-being for men. We discuss the need for therapists to consider the need to encourage mindful awareness to attenuate perceptions of power imbalances and to evaluate how sexually mindful non-judgment influences men's feelings of sexual well-being. Therapeutic implications of these findings are also discussed.

Low Cancer Occurrence Rate following Prophylactic Nipple-Sparing Mastectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) has become widely available for breast cancer prophylaxis. There are limited data on its long-term oncologic safety. The objective of this study was to determine the incidence of breast cancer in patients who underwent prophylactic NSM. METHODS: All patients undergoing prophylactic NSM at a single institution from 2006 through 2019 were retrospectively reviewed. Patient demographic factors, genetic predispositions, mastectomy specimen pathology, and oncologic occurrences at follow-up were recorded. Descriptive statistics were performed where necessary to classify demographic factors and oncologic characteristics. RESULTS: A total of 871 prophylactic NSMs were performed on 641 patients, with median follow-up of 82.0 months (standard error 1.24). A total of 94.4% of patients ( n = 605) underwent bilateral NSMs, although only the prophylactic mastectomy was considered. The majority of mastectomy specimens (69.6%) had no identifiable pathology. A total of 38 specimens (4.4%) had cancer identified in mastectomy specimens, with ductal carcinoma in situ being the most common (92.1%; n = 35). Multifocal or multicentric disease was observed in seven cases (18.4%) and lymphovascular invasion was identified in two (5.3%). One patient (0.16%), who was a BRCA2 variant carrier, was found to have breast cancer 6.5 years after prophylactic mastectomy. CONCLUSIONS: Overall primary oncologic occurrence rates are very low in high-risk patients undergoing prophylactic NSM. In addition to reducing the risk of oncologic occurrence, prophylactic surgery itself may be therapeutic in a small proportion of patients. Continued surveillance for these patients remains important to assess at longer follow-up intervals. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.

Patient preferences for disposable and reusable vaginal specula and their willingness to compromise in the era of climate change: A cross-sectional study.

OBJECTIVE: To evaluate patient satisfaction on gynaecological examination with metal, plastic and biobased plastic vaginal specula, and to investigate whether patients are willing to compromise on comfort for a more sustainable healthcare system. DESIGN: Cross-sectional study: population-based survey. SETTING: Gynaecological outpatient clinics in five Dutch hospitals. POPULATION: Patients during general gynaecology consultation hours. METHODS: A survey containing two questions about patient demographics, four about comfort and five about sustainability and healthcare was distributed. MAIN OUTCOME MEASURES: Comfort score (scale 1-10). SECONDARY OUTCOMES: (1) temperature, size and ease of insertion, (2) willingness to compromise for a more sustainable healthcare system. RESULTS: In all, 196 patients completed the survey. Biobased plastic vaginal specula scored significantly higher on comfort than the metal ones (mean 8.03 ± 1.65 versus 7.26 ± 1.51 respectively; P < 0.001). The biobased plastic vaginal speculum is significantly the most comfortable on temperature, whereas the metal speculum is the least comfortable (P < 0.007). Most patients are willing to compromise on comfort or are open to the reuse of disposables to contribute to a more sustainable healthcare. The majority of patients (77%) urge healthcare organisations to combat climate change. CONCLUSIONS: There is a small but statistically significant difference in favour of a biobased plastic speculum regarding comfort score, although it might be questioned whether this is clinically relevant. Furthermore, patients are willing to compromise on comfort for a more sustainable healthcare, which should be a contributing factor in speculum selection.

Cultural competency of GP trainees and GP trainers: a cross-sectional survey study.

OBJECTIVE: To assess the cultural competence (CC) of GP trainees and GP trainers.Design and setting: A cross-sectional survey study was conducted at the GP Training Institute of Amsterdam UMC. SUBJECTS: We included 92 GP trainees and 186 GP trainers. MAIN OUTCOME MEASURES: We measured the three domains of cultural competency: 1) knowledge, 2) culturally competent attitudes and 3) culturally competent skills. Regression models were used to identify factors associated with levels of CC. Participants rated their self-perceived CC at the beginning and end of the survey, and the correlation between self-perceived and measured CC was assessed. RESULTS: Approximately 94% of the GP trainees and 81% of the GP trainers scored low on knowledge; 45% and 42%, respectively, scored low on culturally competent attitudes. The level of culturally competent skills was moderate (54.3%) or low (48.4%) for most GP trainees and GP trainers. The year of residency and the GP training institute were significantly associated with one or more (sub-)domains of CC in GP trainees. Having >10% migrant patients and experience as a GP trainer were positively associated with one or more (sub-) domains of cultural competence in GP trainers. The correlation between measured and self-perceived CC was positive overall but very weak (Spearman correlation coefficient ranging from -0.1-0.3). CONCLUSION: The level of cultural competence was low in both groups, especially in the knowledge scores. Cultural competence increased with experience and exposure to an ethnically diverse patient population. Our study highlights the need for cultural competence training in the GP training curricula.

General practitioner (GP) trainees find cross-cultural consultations stressful due to a self-perceived lack of cultural competence (CC). The level of CC in general practice is as yet unknown.On average, the level of CC was low for the majority of GP trainees and GP trainers, especially for the scores on knowledge.CC increased with experience and exposure to an ethnically diverse patient population.GP trainees and trainers perceived a lack of covered education on various topics related to the care of migrants.Our study highlights the need for cultural competence training in the GP training curricula.

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

Prospective Clinical Prognostication of Endometrial Carcinomas Based on Next-Generation Sequencing and Immunohistochemistry-Real-World Implementation and Results at a Tertiary Care Center.

Based on findings from The Cancer Genome Atlas and the Proactive Molecular Risk Classifier for Endometrial Cancer algorithm, endometrial carcinoma can now be stratified into 4 prognostically distinct subgroups based on molecular alterations and immunohistochemical (IHC) aberrations. In this study, we describe the de novo adoption and clinical reporting of prognostic subgroup classification based on next-generation sequencing (NGS) and IHC analyses of all endometrial carcinoma resections at a single institution, framed by the Exploration, Preparation, Implementation, and Sustainment model. Results from the first 13 months show 188 tumors underwent analysis by a combination of IHC and a medium-sized (56 analyzed genes) NGS-based assay. All cases were assigned as either POLE (POLE-mutated) (5.3%), mismatch repair deficient (27.7%), no specific molecular profile (45.7%), or p53 abnormal (21.3%) inclusive of multiple-classifier cases. NGS-based analysis revealed additional distinctions among the subgroups, including reduced levels of PI3K pathway activation in the p53 abnormal subgroup, an increased rate of CTNNB1 activating mutation in the no specific molecular profile subgroup, and lower TP53 mutation variant allele frequencies in POLE and mismatch repair deficient subgroups compared with the p53 abnormal subgroup. Overall, we describe the testing protocol, reporting, and results of a combination of NGS and IHC to prospectively prognosticate endometrial carcinomas at a single tertiary care center.

Using the multiphase optimization strategy to adapt cognitive processing therapy (CPT MOST): study protocol for a randomized controlled factorial experiment.

BACKGROUND: Approximately ten percent of US military veterans suffer from posttraumatic stress disorder (PTSD). Cognitive processing therapy (CPT) is a highly effective, evidence-based, first-line treatment for PTSD that has been widely adopted by the Department of Veterans Affairs (VA). CPT consists of discrete therapeutic components delivered across 12 sessions, but most veterans (up to 70%) never reach completion, and those who discontinue therapy receive only four sessions on average. Unfortunately, veterans who drop out prematurely may never receive the most effective components of CPT. Thus, there is an urgent need to use empirical approaches to identify the most effective components of CPT so CPT can be adapted into a briefer format. METHODS: The multiphase optimization strategy (MOST) is an innovative, engineering-inspired framework that uses an optimization trial to assess the performance of individual intervention components within a multicomponent intervention such as CPT. Here we use a fractional factorial optimization trial to identify and retain the most effective intervention components to form a refined, abbreviated CPT intervention package. Specifically, we used a 16-condition fractional factorial experiment with 270 veterans (N = 270) at three VA Medical Centers to test the effectiveness of each of the five CPT components and each two-way interaction between components. This factorial design will identify which CPT components contribute meaningfully to a reduction in PTSD symptoms, as measured by PTSD symptom reduction on the Clinician-Administered PTSD Scale for DSM-5, across 6 months of follow-up. It will also identify mediators and moderators of component effectiveness. DISCUSSION: There is an urgent need to adapt CPT into a briefer format using empirical approaches to identify its most effective components. A brief format of CPT may reduce attrition and improve efficiency, enabling providers to treat more patients with PTSD. The refined intervention package will be evaluated in a future large-scale, fully-powered effectiveness trial. Pending demonstration of effectiveness, the refined intervention can be disseminated through the VA CPT training program. TRIAL REGISTRATION: ClinicalTrials.gov NCT05220137. Registration date: January 21, 2022.

Polymorphonuclear myeloid-derived suppressor cells and phosphatidylinositol-3 kinase gamma are critical to tobacco-mimicking oral carcinogenesis in mice.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC. METHODS: Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation. RESULTS: In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner. CONCLUSIONS: Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.

Electronic monitoring with a digital smart spacer to support personalized inhaler use education in patients with asthma: The randomized controlled OUTERSPACE trial.

BACKGROUND: Poor adherence to inhaled medication has been associated with poor outcomes. Smart spacers can monitor inhaler use and technique, yet their feasibility in adults with asthma and their potential benefits are unknown. OBJECTIVE: Assessing the feasibility of undertaking a definitive randomized controlled trial (RCT) of smart spacer-based inhaler education and explore potential clinical benefits in adults with asthma. METHODS: Two-month randomized controlled feasibility OUtcomes following Tailored Education and Retraining: Studying Performance and AdherenCE (OUTERSPACE) trial comparing personalized smart spacer-based inhaler education versus usual care. Patients were recruited in four Dutch primary care centres. Outcomes were feasibility (inclusion speed, patient acceptance), medication adherence, inhaler technique, clinical effects (lung function, ACQ, FeNO) and usability (System Usability Scale [SUS]). RESULTS: 42 patients were randomized and all completed the study. The feasibility of performing a larger trial focusing on asthma patient education using a smart spacer was demonstrated with all patients included in four months and a participation rate of 86%. In the intervention group, inhalation errors per day decreased by 26.2% while in the usual care group inhalation errors increased by 14.6% (p = 0.021). Adherence decreased slightly in the intervention group as opposed to improvement in the control group (difference 12%, p = 0.028). No changes in lung function, ACQ or FeNO were observed. Usability was deemed high (SUS patients 71, nurses 89). CONCLUSION: This RCT showed that smart spacer-driven education in patients with asthma is feasible and in this short-term study reduced inhaler errors. Longer-term and larger studies are required to assess clinical effects.

No Cancer Occurrences in 10-year Follow-up after Prophylactic Nipple-sparing Mastectomy.

Prophylactic nipple-sparing mastectomies (NSM) have become increasingly common, although there is little long-term data on its efficacy in prevention of breast cancer. The objective of this study was to assess the incidence of breast cancer in a cohort of patients undergoing prophylactic NSM with a median follow-up of 10 years. Methods: Patients receiving prophylactic NSM at a single institution from 2006 to 2019 were included in a retrospective nature. Patient demographics, genetic mutations, operative details, and specimen pathology were recorded, and all postoperative patient visits and documentation were screened for cancer occurrence. Descriptive statics were performed where appropriate. Results: Two hundred eighty-four prophylactic NSMs were performed on 228 patients with a median follow-up of 120.5 ± 15.7 months. Roughly, a third of patients had a known genetic mutation, with 21% BRCA1 and 12% BRCA2. The majority (73%) of prophylactic specimens had no abnormal pathology. The most commonly observed pathologies were atypical lobular hyperplasia (10%) and ductal carcinoma in situ (7%). Cancer was identified in 10% of specimens, with only one case of lymphovascular invasion. Thus far, there have been no incidences of locoregional breast cancer occurrence in this cohort. Conclusions: The long-term breast cancer occurrence rate in this cohort of prophylactic NSM patients at the time of this study is negligible. Despite this, continued surveillance of these patients is necessary until lifetime risk of occurrence following NSM has been established.

Changes in Breast Cancer Presentation during COVID-19: Experience in an Urban Academic Center.

The COVID-19 pandemic strained healthcare systems worldwide, delaying breast cancer screening and surgery. In 2019, approximately 80% of breast cancers in the U.S. were diagnosed on screening examinations, with 76.4% of eligible Medicare patients undergoing screening at least every two years. Since the start of the pandemic, many women have been reluctant to seek elective screening mammography, even with the lifting of pandemic-related restrictions in access to routine healthcare. We describe the effect of the COVID-19 pandemic on breast cancer presentation at a tertiary academic medical center greatly impacted by the pandemic.

Asp179 in the class A ß-lactamase from Mycobacterium tuberculosis is a conserved yet not essential residue due to epistasis.

Conserved residues are often considered essential for function, and substitutions in such residues are expected to have a negative influence on the properties of a protein. However, mutations in a few highly conserved residues of the ß-lactamase from Mycobacterium tuberculosis, BlaC, were shown to have no or only limited negative effect on the enzyme. One such mutant, D179N, even conveyed increased ceftazidime resistance upon bacterial cells, while displaying good activity against penicillins. The crystal structures of BlaC D179N in resting state and in complex with sulbactam reveal subtle structural changes in the Ω-loop as compared to the structure of wild-type BlaC. Introducing this mutation in four other ß-lactamases, CTX-M-14, KPC-2, NMC-A and TEM-1, resulted in decreased antibiotic resistance for penicillins and meropenem. The results demonstrate that the Asp in position 179 is generally essential for class A ß-lactamases but not for BlaC, which can be explained by the importance of the interaction with the side chain of Arg164 that is absent in BlaC. It is concluded that Asp179 though conserved is not essential in BlaC, as a consequence of epistasis.

Prolongation of the QTc interval is associated with an increased risk of cardiovascular diseases: The Hoorn study.

BACKGROUND/OBJECTIVE: Prolonged heart rate-corrected QT interval (QTc) on the electrocardiogram (ECG) is maybe associated with the occurrence of cardiovascular diseases (CVD), but the evidence is inconsistent. Therefore, we investigated whether baseline prolongation of the QTc interval is associated with CVD morbidity and mortality and its subtypes and whether glucose tolerance modifies this association in a population-based cohort study with a mean follow-up of 10.8 years. METHODS: We analyzed a glucose tolerance stratified sample (N = 487) from the longitudinal population-based Hoorn Study cohort (age 64 ± 7 years, 48% female). Cox regression was used to investigate the association between sex-specific baseline QTc quartiles and CVD morbidity and mortality. The risk was also estimated per 10 ms increase in QTc. All analyses were adjusted for age, sex, smoking status, systolic blood pressure, prevalent CVD, glucose tolerance status, hypertension and total cholesterol. In addition, stratified analyses were conducted for glucose tolerance status. RESULTS: During a mean follow-up of 10.8 years, 351 CVD events were observed. The adjusted hazard ratios (95% CI) for each 10 ms increase in QTc interval were 1.06 (95% CI: 1.02-1.10) for CVD, 1.06 (95% CI: 0.97-1.15) for acute myocardial infarction, 1.07 (95% CI: 1.01-1.13) for stroke, 1.12 (95% CI: 1.06-1.19) for heart failure, 1.04 (95% CI: 0.96-1.12) for peripheral arterial disease and 1.01 (95% CI:0.95-1.08) for coronary heart disease. Glucose tolerance status did not modify the association (P > 0.2). CONCLUSION/INTERPRETATION: Prolongation of the QTc interval is associated with morbidity and mortality due to general CVD. Glucose tolerance status did not modify these associations.

Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque: Individual Participant Data Meta-Analysis of 20 Prospective Studies.

Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.