Methods for non-proportional hazards in clinical trials: A systematic review.

For the analysis of time-to-event data, frequently used methods such as the log-rank test or the Cox proportional hazards model are based on the proportional hazards assumption, which is often debatable. Although a wide range of parametric and non-parametric methods for non-proportional hazards has been proposed, there is no consensus on the best approaches. To close this gap, we conducted a systematic literature search to identify statistical methods and software appropriate under non-proportional hazard. Our literature search identified 907 abstracts, out of which we included 211 articles, mostly methodological ones. Review articles and applications were less frequently identified. The articles discuss effect measures, effect estimation and regression approaches, hypothesis tests, and sample size calculation approaches, which are often tailored to specific non-proportional hazard situations. Using a unified notation, we provide an overview of methods available. Furthermore, we derive some guidance from the identified articles.

Time trajectories and within-subject correlations of matrix metalloproteinases 3, 8, 9, 10, 12, and 13 serum levels and their ability to predict mortality in polytraumatized patients: a pilot study.

BACKGROUND: Managing polytrauma victims poses a significant challenge to clinicians since applying the same therapy to patients with similar injury patterns may result in different outcomes. Using serum biomarkers hopefully allows for treating each multiple injured in the best possible individual way. Since matrix metalloproteinases (MMPs) play pivotal roles in various physiological processes, they might be a reliable tool in polytrauma care. METHODS: We evaluated 24 blunt polytrauma survivors and 12 fatalities (mean age, 44.2 years, mean ISS, 45) who were directly admitted to our Level I trauma center and stayed at the intensive care unit for at least one night. We determined their MMP3, MMP8, MMP9, MMP10, MMP12, and MMP13 serum levels at admission (day 0) and on days 1, 3, 5, 7, and 10. RESULTS: Median MMP8, MMP9, and MMP12 levels immediately rose after the polytrauma occurred; however, they significantly decreased from admission to day 1 and significantly increased from day 1 to day 10, showing similar time trajectories and (very) strong correlations between each two of the three enzyme levels assessed at the same measurement point. For a two-day lag, autocorrelations were significant for MMP8 (- 0.512) and MMP9 (- 0.302) and for cross-correlations between MMP8 and MMP9 (- 0.439), MMP8 and MMP12 (- 0.416), and MMP9 and MMP12 (- 0.307). Moreover, median MMP3, MMP10, and MMP13 levels significantly increased from admission to day 3 and significantly decreased from day 3 to day 10, showing similar time trajectories and an (almost) strong association between every 2 levels until day 7. Significant cross-correlations were detected between MMP3 and MMP10 (0.414) and MMP13 and MMP10 (0.362). Finally, the MMP10 day 0 level was identified as a predictor for in-hospital mortality. Any increase of the MMP10 level by 200 pg/mL decreased the odds of dying by 28.5%. CONCLUSIONS: The time trajectories of the highly varying individual MMP levels elucidate the involvement of these enzymes in the endogenous defense response following polytrauma. Similar time courses of MMP levels might indicate similar injury causes, whereas lead-lag effects reveal causative relations between several enzyme pairs. Finally, MMP10 abundantly released into circulation after polytrauma might have a protective effect against dying.

Simultaneous inference procedures for the comparison of multiple characteristics of two survival functions.

Survival time is the primary endpoint of many randomized controlled trials, and a treatment effect is typically quantified by the hazard ratio under the assumption of proportional hazards. Awareness is increasing that in many settings this assumption is a priori violated, for example, due to delayed onset of drug effect. In these cases, interpretation of the hazard ratio estimate is ambiguous and statistical inference for alternative parameters to quantify a treatment effect is warranted. We consider differences or ratios of milestone survival probabilities or quantiles, differences in restricted mean survival times, and an average hazard ratio to be of interest. Typically, more than one such parameter needs to be reported to assess possible treatment benefits, and in confirmatory trials, the according inferential procedures need to be adjusted for multiplicity. A simple Bonferroni adjustment may be too conservative because the different parameters of interest typically show considerable correlation. Hence simultaneous inference procedures that take into account the correlation are warranted. By using the counting process representation of the mentioned parameters, we show that their estimates are asymptotically multivariate normal and we provide an estimate for their covariance matrix. We propose according to the parametric multiple testing procedures and simultaneous confidence intervals. Also, the logrank test may be included in the framework. Finite sample type I error rate and power are studied by simulation. The methods are illustrated with an example from oncology. A software implementation is provided in the R package nph.

Serum levels of matrix metalloproteinases 1, 2, and 7, and their tissue inhibitors 1, 2, 3, and 4 in polytraumatized patients: Time trajectories, correlations, and their ability to predict mortality.

There has been limited research on assessing metalloproteinases (MMPs) 1, 2, and 7, as well as their tissue inhibitors (TIMPs) 1, 2, 3, and 4 in the context of polytrauma. These proteins play crucial roles in various physiological and pathological processes and could be a reliable tool in polytrauma care. We aimed to determine their clinical relevance. We assessed 24 blunt polytrauma survivors and 12 fatalities (mean age, 44.2 years, mean ISS, 45) who were directly admitted to our Level I trauma center and spent at least one night in the intensive care unit. We measured serum levels of the selected proteins on admission (day 0) and days 1, 3, 5, 7, and 10. The serum levels of the seven proteins varied considerably among individuals, resulting in similar median trend curves for TIMP1 and TIMP4 and for MMP1, MMP2, TIMP2, and TIMP3. We also found a significant interrelationship between the MMP2, TIMP2, and TIMP3 levels at the same measurement points. Furthermore, we calculated significant cross-correlations between MMP7 and MMP1, TIMP1 and MMP7, TIMP3 and MMP1, TIMP3 and MMP2, and TIMP4 and TIMP3 and an almost significant correlation between MMP7 and TIMP1 for a two-day-lag. The autocorrelation coefficient reached statistical significance for MMP1 and TIMP3. Finally, lower TIMP1 serum levels were associated with in-hospital mortality upon admission. The causal effects and interrelationships between selected proteins might provide new insights into the interactions of MMPs and TIMPs. Identifying the underlying causes might help develop personalized therapies for patients with multiple injuries. Administering recombinant TIMP1 or increasing endogenous production could improve outcomes for those with multiple injuries. However, before justifying further investigations into basic research and clinical relevance, our findings must be validated in a multicenter study using independent cohorts to account for clinical and biological variability.

The type of suture material affects transverse aortic constriction-induced heart failure development in mice: a repeated measures correlation analysis.

Introduction: Transverse-aortic constriction (TAC) operation is a widely used animal model to induce hypertrophy and heart failure through left-ventricular pressure overload. In mice, the cardiac response to TAC exhibits considerable variability influenced by factors such as strain, sub-strain, age, sex and vendor. Methods: To investigate the impact of suture material (silk versus prolene) and size (6-0 versus 7-0) on the TAC-induced phenotype, we performed surgeries on male C57BL6/N mice at 9 weeks of age defining the aortic constriction by a 27G needle, thereby employing most frequently used methodological settings. The mice were randomly assigned into four separate groups, 6-0 silk, 7-0 silk, 6-0 prolene and 7-0 prolene (10 mice per group). Echocardiography was conducted before TAC and every 4 weeks thereafter to monitor the development of heart failure. Repeated measures correlation analysis was employed to compare disease progression among the different groups. Results: Our findings reveal a significant influence of the chosen suture material on TAC outcomes. Mice operated with prolene showed increased mortality, slower body weight gain, faster left-ventricular mass increase, and a faster decline in left-ventricular ejection fraction, fractional shortening and aortic pressure gradient compared to silk-operated mice. Moreover, despite non significant, using thinner suture threads (7-0) tended to result in a more severe phenotype compared to thicker threads (6-0) across all tested parameters. Discussion: Collectively, our results highlight the importance of suture material selection in determining the cardiac phenotype induced by TAC and emphasize the need to consider this factor when comparing data across different research laboratories.

Verification of the prognostic precision of the new 2023 FIGO staging system in endometrial cancer patients - An international pooled analysis of three ESGO accredited centres.

BACKGROUND: Recently, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer (EC) critically integrating new pathological and molecular features was published. The present study evaluated the clinical impact of the new 2023 FIGO staging system by comparing it to the previous 2009 system. METHODS: This is an international, pooled retrospective study of 519 EC patients who underwent primary treatment (and molecular characterisation) at three European Society of Gynaecological Oncology (ESGO) accredited centres in Austria/Italy. Patients were categorised according to the 2009 and the 2023 FIGO staging systems. Stage shifts were analysed and (sub)stage specific 5-year progression-free (PFS) and overall survival (OS) rates were calculated and compared. Different statistical tests were applied to evaluate the prognostic precision of the two FIGO staging systems and to compare them to each other. RESULTS: (Sub)stage shifts occurred in 143/519 (27.6%) patients: 123 upshifts (23.7%) and 20 (3.9%) downshifts. 2023 FIGO staging system identified a stage I cohort with a notably higher 5-year PFS rate compared to 2009 (93.0% versus 87.4%, respectively). For stage II disease, the 5-year PFS rate was similar in the 2023 and the 2009 FIGO staging systems (70.2% versus 71.2%, respectively). The two new molecularly defined 2023 FIGO substages IAmPOLEmut and IICmp53abn displayed distinct, particularly favourable and adverse oncologic outcomes within early stage disease, respectively. A remarkably lower 5-year PFS rate for stage III patients was revealed in the 2023 FIGO staging system compared to 2009 (44.4% versus 54.1%, respectively). All applied statistical tests confirmed a more accurate prediction of PFS and OS by the 2023 FIGO staging system compared to 2009. CONCLUSION: The new 2023 FIGO stating system led to a substantial stage shift in about one quarter of patients leading to a higher prognostic precision. In early stage disease, the new substages added further prognostic granularity and identified treatment relevant subgroups.

Rate of Involved Endocervical Margins According to High-Risk Human Papillomavirus Subtype and Transformation Zone Type in Specimens with Cone Length ≤ 10 mm versus > 10 mm-A Retrospective Analysis.

The aim of this study was to evaluate the endocervical margin status according to transformation zone (TZ) and high-risk HPV (hr-HPV) subtype in specimens with cone length ≤ 10 mm versus > 10 mm to provide data for informed decision making and patients counseling especially for women wishing to conceive. In this retrospective cohort study, 854 patients who underwent large loop excision of the transformation zone during a nine-year period (2013-2021) for cervical disease were analyzed. The main outcome parameters were excision length, histological result, TZ type, HPV subtype and endocervical margin status. A subgroup analysis was performed according to excision length, with a cut-off value of 10 mm. A two-step surgical procedure was performed in case of an excision length of > 10 mm. The overall rate of positive endocervical margins irrespective of excision length was 17.2%, with 19.3% in specimens with ≤ 10 mm and 15.0% with > 10 mm excision length. Overall, 41.2% of women with a visible TZ and HPV 16/hr infection and 27.0% of women with HPV 18 received an excisional treatment of > 10 mm length without further oncological benefit, respectively. In contrast, assuming that only an excision of ≤ 10 mm length had been performed in women with visible TZ, the rate of clear endocervical margins would have been 63.7% for HPV 16/hr infections and 49.3% for HPV 18 infections. In conclusion, the decision about excision length should be discussed with the patient in terms of oncological safety and the risk of adverse pregnancy events. An excision length > 10 mm increases the number of cases with cervical tissue removed without further oncological benefit, which needs to be taken into account in order to provide an individual therapeutic approach. Furthermore, HPV 18 positivity is related to a higher rate of positive endocervical margins irrespective of TZ.

Performance of clinical risk scores and prediction models to identify pathogenic germline variants in patients with advanced prostate cancer.

PURPOSE: Determining the frequency and distribution of pathogenic germline variants (PGVs) in Austrian prostate cancer (PCa) patients and to assess the accuracy of different clinical risk scores to correctly predict PGVs. METHODS: This cross-sectional study included 313 men with advanced PCa. A comprehensive personal and family history was obtained based on predefined questionnaires. Germline DNA sequencing was performed between 2019 and 2021 irrespective of family history, metastatic or castration status or age at diagnosis. Clinical risk scores for hereditary cancer syndromes were evaluated and a PCa-specific score was developed to assess the presence of PGVs. RESULTS: PGV presence was associated with metastasis (p = 0.047) and castration resistance (p = 0.011), but not with personal cancer history or with relatives with any type of cancer. Clinical risk scores (Manchester score, PREMM5 score, Amsterdam II criteria or Johns Hopkins criteria) showed low sensitivities (3.3-20%) for assessing the probability of PGV presence. A score specifically designed for PCa patients stratifying patients into low- or high-risk regarding PGV probability, correctly classified all PGV carriers as high-risk, whereas a third of PCa patients without PGVs was classified as low risk of the presence of PGVs. CONCLUSION: Application of common clinical risk scores based on family history are not suitable to identify PCa patients with high PGV probabilities. A PCa-specific score stratified PCa patients into low- or high-risk of PGV presence with sufficient accuracy, and germline DNA sequencing may be omitted in patients with a low score. Further studies are needed to evaluate the score.

Nasal IL-13 production identifies patients with late-phase allergic responses.

BACKGROUND: There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regard to the "late allergic response," which occurs in approximately 40% to 50% of patients with allergy. OBJECTIVE: We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response. METHODS: In this randomized, double-blind, placebo-controlled trial, birch pollen-allergic participants were challenged with birch pollen extract (n = 20) or placebo (n = 10) on 3 consecutive days. On days 1 and 3, nasal secretions were collected at selected time points over a 24-hour time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. RESULTS: Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and the soluble IL-33 receptor serum stimulation 2 (sST2) in nasal secretions within minutes compared with the placebo group. Eight of 20 provoked participants displayed high IL-13 levels 2 to 8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction, which significantly differed from IL-13 nonresponders after 6 hours. CONCLUSIONS: IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

Comparing maximum diameter and volume when assessing the growth of small abdominal aortic aneurysms using longitudinal CTA data: cohort study.

BACKGROUND: Monitoring of abdominal aortic aneurysms (AAAs) is currently based on serial measurements of maximum aortic diameter. Additional assessment of aneurysm volume has previously been proposed to possibly improve growth prediction and treatment decisions. To evaluate the use of supplementing volume measurements, the authors aimed to characterise the growth distribution of AAA volume and to compare the growth rates of the maximum diameter and volume at the patient level. METHODS: Maximum diameter and volume were monitored every 6 months in 84 patients with small AAAs, with a total of 331 computed tomographic angiographies (with initial maximum diameters of 30-68 mm). A previously developed statistical growth model for AAAs was applied to assess the growth distribution of volume and to compare individual growth rates for volume and for maximum diameter. RESULTS: The median (25-75% quantile) expansion in volume was 13.4 (6.5-24.7) % per year. Cube root transformed volume and maximum diameter showed a closely linear association with a within-subject correlation of 0.77. At the surgery threshold maximum diameter of 55 mm, the median (25-75% quantile) volume was 132 (103-167) ml. In 39% of subjects, growth rates for volume and maximum diameter were equivalent, in 33% growth was faster in volume and in 27% growth was faster in maximum diameter. CONCLUSION: At the population level, volume and maximum diameter show a substantial association such that the average volume is approximately proportional to the average maximum diameter raised to a power of three. At the individual level, however, in the majority of patient's AAAs grow at different pace in different dimensions. Hence, closer monitoring of aneurysms with sub-critical diameter but suspicious morphology may benefit from complementing maximum diameter by volume or related measurements.

Polyunsaturated Fatty Acid Intake during Complementary Feeding and Neurodevelopmental Outcome in Very Low Birth Weight Infants.

Polyunsaturated fatty acids (PUFAs) are vital for brain development, yet limited knowledge exists regarding PUFA intake during complementary feeding (CF) and its impact on neurodevelopmental outcomes in very low birth weight (VLBW) infants. This secondary analysis of a randomized intervention trial, aimed to investigate the association between dietary intake of total PUFAs, arachidonic acid (AA), and docosahexaenoic acid (DHA) during CF and neurodevelopmental outcomes at 12 and 24 months of corrected age (CA). Dietary intakes were assessed using monthly 3 day dietary protocols from 3 to 12 months CA. Neurodevelopmental outcome was evaluated using the Bayley Scales of Infant Development-III. Among the 177 randomized patients, PUFA intake and neurodevelopmental outcomes were evaluated in 140 (79%) infants. Higher total PUFA and DHA intakes significantly correlated with improved cognitive and motor function at 12 months CA, while increased AA intake notably enhanced motor scores at 12 months CA. However, median dietary intakes of AA and DHA (AA: 53.50-84.25 mg/d; DHA: 51.47-76.23 mg/d) fell short of recommended levels (AA: 140 mg/d; DHA: 100 mg/d) at any of the investigated timepoints. These findings emphasize the need to enhance total PUFA, DHA and AA intakes during CF, ensuring adherence to guidelines and unlocking the potential to improve neurodevelopmental outcomes in VLBW infants.

Effects of early introduction of solid foods on nutrient intake in preterm infants during their 1st year of life: a secondary outcome analysis of a prospective, randomized intervention study.

Very low birth weight (VLBW) infants have higher nutritional needs even after hospital discharge. However, data concerning current nutrient intakes at different time points after the introduction of solid foods and whether dietary reference values are being met are scarce. To adress this issue, this secondary analysis of a prospective, two-arm interventional study in 177 VLBW infants 21 investigates dietary intake comparing early and late (early: 10-12 weeks corrected for gestational age, late: 16-18 weeks corrected for gestational age) introduction of standardized complementary food during the first year of life. Nutritional intake was assessed using self-reported monthly 3-day dietary records from 3 until 12 months, corrected for gestational age. The time point of the introduction of solid foods did not influence nutrient intake, but the early introduction of solids tended toward a higher proportional intake of protein and carbohydrates and a lower intake of fat as a percentage of total energy) during the 1st year of life, corrected for gestational age. The results of this study indicate that this standardized feeding concept was sufficient for zinc, calcium, and phosphorus intake. However, dietary iron and vitamin D intakes did not meet the recommendations. Thus, prolonged iron supplementation should be considered beyond the introduction of meat and vitamin D supplementation at least until 12 months, corrected for gestational age. Trial registration number: ClinicalTrials.gov: NCT01809548.

Incidence and outcomes of AKI in postoperative patients admitted to ICU using full KDIGO criteria - a cohort study.

STUDY OBJECTIVE: Acute kidney injury (AKI) is a serious complication in postoperative ICU patients. The incidence of AKI varies substantially based on the type of surgery and definition used. This study focuses on the incidence of AKI in postoperative ICU patients using full KDIGO criteria and related outcomes regarding to different types of surgery. DESIGN: Retrospective cohort study. SETTING: Tertiary level university hospital, eight anaesthesiological/surgical ICUs, between 2016 and 2018. PATIENTS: 6261 adult patients. MEASUREMENTS: Primary outcome was 28-day all-cause mortality in different stages of AKI according to complete KDIGO criteria. MAIN RESULTS: We found 3497 (55.9%) postoperative ICU patients with AKI. The severity distribution of AKI stage 1 to 3 was 19.7%, 28.4% and 7.8%, respectively, and 235 (4%) patients received RRT. The 28-day mortality was 3% (n = 205). Increasing AKI severity was associated with increased 28-day mortality when adjusted for other variables (AKI 2°: OR 2.81; 95% CI 1.55 to 5.24; p < 0.001 and AKI 3°: OR 11.37.; 95% CI 5.91 to 22.55; p < 0.001). Besides AKI stages 2 and 3, age (OR 1.02; 95% CI 1.01 to 1.04, p < 0.001), NYHA IV (OR 2.23; 95% CI 1.03 to 4.43, p = 0.042), need for surgical reintervention within 48 h (OR 2.92; 95% CI 1.76 to 4.72, p = 0.001), urgent surgery (OR 1.78; 95% CI 1.15 to 2.71, p = 0.01), emergency surgery (OR 2.63; 95% CI 1.58 to 4.31, p = 0.001), vascular surgery (OR 2.01; 95% CI 1.06 to 3.98, p = 0.033), and orthopedic and trauma surgery (OR 3.79; 95% CI 1.98 to 7.09, p < 0.001) versus cardiac surgery was significantly associated with increased risk for 28-days mortality in multivariate analysis. CONCLUSION: AKI based on full KDIGO criteria is very common in postoperative ICU patients and it is associated with stepwise increase in 28-days mortality.

Association between reactogenicity and immunogenicity after BNT162b2 booster vaccination: a secondary analysis of a prospective cohort study.

OBJECTIVES: A weak correlation between symptom severity and antibody levels after primary immunization against COVID-19 has already been shown. This study aimed to describe the association between reactogenicity and immunogenicity after booster vaccination. METHODS: This secondary analysis of a prospective cohort study included 484 healthcare workers who received a booster vaccination with BNT162b2. Anti-receptor binding domain (RBD) antibodies were assessed at baseline and 28 days after booster vaccination. Side effects were graded (none, mild, moderate, or severe) and reported daily for 7 days after booster vaccination. Spearman correlation coefficient (rho) was used to determine the correlations between the severity of each symptom and anti-RBD levels before vaccination and 28 days after. The Bonferroni method was used to adjust p values for multiple comparisons. RESULTS: Most of the 484 participants reported at least one local (451 [93.2%]) or systemic (437 [90.3%]) post-booster symptom. No correlations between the severity of local symptoms and antibody levels were found. Except for nausea, systemic symptoms showed weak but statistically significant correlations with 28-day anti-RBD levels (fatigue [rho = 0.23, p < 0.01], fever [rho = 22, p < 0.01], headache [rho = 0.15, p 0.03], arthralgia [rho = 0.2, p < 0.01], myalgia [rho = 0.17, p < 0.01]). There was no association between post-booster symptoms and pre-booster antibody levels. DISCUSSION: This study showed only a weak correlation between the severity of systemic post-booster symptoms and anti-SARS-CoV-2 antibody levels at 28 days. Therefore, self-reported symptom severity cannot be used to predict immunogenicity after booster vaccination.

Effect of Regular Electrotherapy on Spinal Flexibility and Pain Sensitivity in Patients with Chronic Non-Specific Neck Pain and Low Back Pain: A Randomized Controlled Double-Blinded Pilot Trial.

Background and Objectives: Chronic neck pain and low back pain are common conditions in high-income countries leading to social and medical problems such as invalidity and decreased quality of life. The aim of this study was to investigate the effect of supra-threshold electrotherapy on pain level, subjective feeling of disability, and spinal mobility in patients with chronic pain in the spinal cord. Materials and Methods: 11 men and 24 women with a mean age of 49 years were randomly divided into three groups: group 1, "therapy": supra-threshold electrotherapy was applied on the whole back after electrical calibration; group 2, "control": electrical calibration without successive electrotherapy; group 3, "control of control": no stimulation. Sessions were performed once a week and six times in total, each lasting 30 min. The numeric pain rating scale (NRS), cervical and lumbar range of motion (ROM), as well as disability in daily live were investigated before and after the sessions using questionnaires (Neck Disability Index, Roland Morris Questionnaire, Short-form Mc Gill Pain Questionnaire (SF-MPQ)). Results: Spinal mobility improved significantly in the lumbar anteflexion (baseline mean, 20.34 ± SD 1.46; post session mean, 21.43 ± SD 1.95; p = 0.003) and retroflexion (baseline mean, 13.68 ± SD 1.46; post session mean, 12.05 ± SD 1.37; p = 0.006) in the group receiving electrotherapy. Pain levels measured by the NRS and disability-questionnaire scores did not differ significantly before and after treatment in any of the groups. Conclusions: Our data indicate that regular supra-threshold electrotherapy for six times has a positive effect on lumbar flexibility in chronic neck pain and low back pain patients, whereas pain sensation or subjective feeling of disability remained unchanged.

Associations between nailfold capillary aberrations and autoantibodies in children and adults with Raynaud's phenomenon.

OBJECTIVE: To characterise associations between individual nailfold capillary aberrations with autoantibodies in a cross-sectional study on children and adults with Raynaud's phenomenon (RP). METHODS: Consecutive children and adults with RP and without previously known connective tissue disease (CTD) systemically underwent nailfold capillaroscopy and laboratory tests for the presence of antinuclear antibodies (ANA). The prevalence of individual nailfold capillary aberrations and ANA was assessed, and the associations between individual nailfold capillary aberrations and ANA were analysed separately in children and adolescents. RESULTS: In total, 113 children (median age 15 years) and 2858 adults (median age 48 years) with RP and without previously known CTD were assessed. At least one nailfold capillary aberration was detected in 72 (64%) of included children and in 2154 (75%) of included adults with RP (children vs adults p<0.05). An ANA titre ≥1:80, ≥1:160 or≥1:320 was observed in 29%, 21% or 16% of included children, and in 37%, 27% or 24% of screened adults, respectively. While the occurrence of individual nailfold capillary aberrations was related to the presence of an ANA titre of ≥1:80 in adults (reduced capillary density, avascular fields, haemorrhages, oedema, ramifications, dilations and giant capillaries: each p<0.001), no comparable association between nailfold capillary aberrations and ANA was observed in children with RP without previously known CTD. CONCLUSION: In contrast to adults, the association between nailfold capillary aberrations and ANA might be less pronounced in children. Further studies are warranted to validate these observations in children with RP.

Patient adherence to fully reimbursed proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) treatment.

AIMS: Proprotein convertase subtilisin/kexin-type 9 inhibitor (PCSK9i) treatment reduces cardiovascular events when taken over a long time for secondary prevention. Data on treatment adherence are scarce and maybe affected by co-payment of patients. The aim of this study was to elucidate PCSK9i treatment adherence in a setting of full cost coverage as it is the case in a number of European countries. METHODS AND RESULTS: Baseline data and prescription patterns of all 7302 patients with PCSK9i prescriptions dispensed on the account of Austrian Social Insurances between September 2015 and December 2020 were retrieved and analyzed. A gap of ≥ 60 days between prescriptions was defined as treatment discontinuation. Patient adherence was evaluated as the proportion of days covered (PDC) over the observation period and treatment discontinuation rates were investigated by the Kaplan-Meier method. The mean PDC was 81.8% and was significantly lower in female patients. A PDC of ≥ 80% indicating adequate adherence was found in 73.8%. Of the study population 27.4% discontinued PCSK9i treatment and 49.2% thereof re-initiated treatment during the observation period. Most of the patients who discontinued treatment did so within the first year. Male patients and patients under 64 years showed significantly lower discontinuation and higher re-initiation rates. CONCLUSION: Considering the high PDC and low discontinuation rates, the majority of patients adhere to PCSK9i treatment. Hence, in a system where PCSK9i treatment is made available at virtually no costs for patients this highly effective treatment is well-accepted as a long-term treatment.

Gapless Electrocardiogram-Monitoring in stroke at high risk of atrial fibrillation.

BACKGROUND AND PURPOSE: Previous studies investigating prolonged electrocardiogram (ECG)-monitoring after ischemic stroke had significant gaps between the index event and the beginning of long-term monitoring. Atrial fibrillation (AF) detection might be higher if prolonged cardiac rhythm documentation is performed with a gapless approach without any interruption of monitoring time. METHODS: This investigator-initiated, prospective study included patients with acute ischemic stroke or transient ischemic attack at three study centers. Participants received gapless ECG-monitoring via telemetry during stroke-unit admission until implantation of an insertable cardiac monitor (ICM) within the first days after the index event. Patients acted as their own controls and also received standard 24-72-h Holter ECG. RESULTS: A total of 110 patients were included, of whom 86 (78.2%) had an embolic stroke of unknown source, 14 (12.7%) had small-vessel disease, and 10 (9.1%) had large-artery disease. AF was newly diagnosed in 17 (15.5%) patients via ICM monitoring, compared to one (0.9%) patient via Holter ECG during 6 months of follow-up (p < 0.001). The detection rate of AF within the first 30 days was 10.0%, which accounted for 64% of all new AF diagnoses. The median duration of the detected episodes was 1.7 (interquartile range = 0.2-4.7) h. All patients with new onset AF were treated with oral anticoagulation. CONCLUSIONS: Gapless ECG-monitoring is an effective strategy to significantly increase the detection rate of AF after ischemic stroke. This finding supports the use of long-term ECG-monitoring with a gapless approach without any interruption in monitoring time as the gold standard for clinical practice.

Longitudinal Assessment of Serum 25-Hydroxyvitamin D Levels during Pregnancy and Postpartum-Are the Current Recommendations for Supplementation Sufficient?

(1) Background: Pregnant women are at risk of vitamin D deficiency. Data on pregnancy outcomes in women with vitamin D deficiency during pregnancy are controversial, and prospective longitudinal data on vitamin D deficiency with consistent definitions in pregnant women are scarce. (2) Methods: The aim of this prospective longitudinal cohort study was to investigate 25-hydroxyvitamin D levels over the course of pregnancy and postpartum in singleton and twin pregnancies with regard to dietary and supplemental vitamin D intake and environmental factors influencing vitamin D levels, evaluated by a standardized food frequency questionnaire. (3) Results: We included 198 healthy singleton and 51 twin pregnancies for analysis. A total of 967 study visits were performed over a 3-year period. Overall, 59.5% of pregnant women were classified as vitamin D deficient in the first trimester, 54.8% in the second trimester, 58.5% in the third trimester, 66.9% at birth, and 60% 12 weeks postpartum, even though 66.4% of the study population reported daily pregnancy vitamin intake containing vitamin D. Dietary vitamin D intake did not affect vitamin D levels significantly. (4) Conclusions: The majority of pregnant women evaluated in this study were vitamin D deficient, despite administration of pregnancy vitamins containing vitamin D. Individualized vitamin D assessment during pregnancy should be considered to ensure adequate supplementation and prevention of hypovitaminosis D.

Risk Factors for Local Failure Following Chemoradiation and Magnetic Resonance Image-Guided Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study. MATERIALS AND METHODS: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis. RESULTS: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTVHR), maximum tumor dimension, CTVHR > 45 cm3, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTVHR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology. CONCLUSION: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.