Specific Baseline Characteristics Research Articles

Baseline characteristics of SARS-CoV-2 vaccine non-responders in a large population-based sample.

Studies indicate that individuals with chronic conditions and specific baseline characteristics may not mount a robust humoral antibody response to SARS-CoV-2 vaccines. In this paper, we used data from the Texas Coronavirus Antibody REsponse Survey (Texas CARES), a longitudinal state-wide seroprevalence program that has enrolled more than 90,000 participants, to evaluate the role of chronic diseases as the potential risk factors of non-response to SARS-CoV-2 vaccines in a large epidemiologic cohort. A participant needed to complete an online survey and a blood draw to test for SARS-CoV-2 circulating plasma antibodies at four-time points spaced at least three months apart. Chronic disease predictors of vaccine non-response are evaluated using logistic regression with non-response as the outcome and each chronic disease + age as the predictors. As of April 24, 2023, 18,240 participants met the inclusion criteria; 0.58% (N = 105) of these are non-responders. Adjusting for age, our results show that participants with self-reported immunocompromised status, kidney disease, cancer, and "other" non-specified comorbidity were 15.43, 5.11, 2.59, and 3.13 times more likely to fail to mount a complete response to a vaccine, respectively. Furthermore, having two or more chronic diseases doubled the prevalence of non-response. Consistent with smaller targeted studies, a large epidemiologic cohort bears the same conclusion and demonstrates immunocompromised, cancer, kidney disease, and the number of diseases are associated with vaccine non-response. This study suggests that those individuals, with chronic diseases with the potential to affect their immune system response, may need increased doses or repeated doses of COVID-19 vaccines to develop a protective antibody level.

Non-stenotic fibro-calcific aortic valve as a predictor of myocardial infarction recurrence.

Patients with acute myocardial infarction (AMI) are at increased risk of recurrent cardiovascular events. Non-stenotic aortic valve fibro-calcific remodeling (AVSc), reflecting systemic damage, may serve as a new marker of risk. To stratify subgroups of AMI patients with specific probabilities of recurrent AMI and to evaluate the importance of AVSc in this setting. Consecutive AMI patients (n = 2530) were admitted at Centro Cardiologico Monzino (2010-2019) and followed up for 5 years. Patients were divided into study (n = 1070) and test (n = 966) cohorts. Topological data analysis (TDA) was used to stratify patient subgroups, while Kaplan-Meier and Cox regressions analyses were used to evaluate the significance of baseline characteristics. TDA identified 11 subgroups of AMI patients with specific baseline characteristics. Two subgroups showed the highest rate of reinfarction after 5 years from the indexed AMI with a combined hazard ratio (HR) of 3.8 (95%CI: 2.7-5.4) compared to the other subgroups. This was confirmed in the test cohort (HR = 3.1; 95%CI: 2.2-4.3). These two subgroups were mostly men, with hypertension and dyslipidemia, who exhibit higher prevalence of AVSc, higher levels of high-sensitive c-reactive protein and creatinine. In the year-by-year analysis, AVSc, adjusted for all confounders, showed an independent association with the increased risk of reinfarction (odds ratio of ∼2 at all time-points), in both the study and the test cohorts (all p < 0.01). AVSc is a crucial variable for identifying AMI patients at high risk of recurrent AMI and its presence should be considered when assessing the management of AMI patients. The inclusion of AVSc in risk stratification models may improve the accuracy of predicting the likelihood of recurrent AMI, leading to more personalized treatment decisions.

Individualized Dosing of Ropeginterferon Alfa-2b Ensures Optimal Response in Patients with Low-Risk Polycythemia Vera (PV)

Introduction: Ropeginterferon alfa-2b at a fixed dose of 100 µg/2 weeks was efficacious in patients with low-risk polycythemia vera (PV) in the Low-PV trial, but the response rate was lower in a group of patients who switched to ropeginterferon alfa-2b after failing to respond to phlebotomy alone (Barbui et al., 2023). The finding that this group had a higher proportion of males and higher baseline values for body-mass index, phlebotomy demand, blood counts and JAK2V617F allele burden suggests that these characteristics might predict a higher dose requirement of ropeginterferon alfa-2b. We analyzed low-risk PV patients from the PROUD-PV/CONTINUATION-PV (NCT01949805/NCT02218047) cohort to examine the impact of baseline characteristics and individually optimized dose levels of ropeginterferon alfa-2b on response status at 12, 24 and 72 months. Methods: Patients diagnosed with PV (WHO 2008 criteria) were randomized 1:1 and received ropeginterferon alfa-2b or standard care for a total of ≥6 years during the 12-month PROUD-PV study and its extension CONTINUATION-PV. Low-risk patients (aged ≤60 years with no history of thrombosis) allocated to the ropeginterferon alfa-2b arm were analyzed. Ropeginterferon alfa-2b was started at a dose of 100 µg/2 weeks (50 µg if transitioning from hydroxyurea) and escalated by 50 µg/2 weeks until blood counts normalized to a maximum of 500 µg/2 weeks. Grade 2-3 drug-related toxicity mandated dose reduction/interruption. During maintenance treatment the dosing interval could be extended to 3-4 weeks. Complete hematologic response (CHR) defined by modified ELN criteria (without the spleen criterion) and safety data at 12, 24 and 72 months were assessed. Results: In the setting of individualized dosing, 33/56 (58.9%) low-risk PV patients allocated to ropeginterferon alfa-2b in PROUD-PV achieved a CHR at month 12. Response rates increased with longer treatment duration; of the 46 low-risk patients enrolled in CONTINUATION-PV; 80.4% and 73.2% of patients with available data achieved a CHR at months 24 and 72, respectively. Baseline characteristics by response status at month 12 indicated that males were overrepresented among non-responders (15/23 non-responders [65.2%] were male vs 11/33 responders [33.3%] [p=0.0291]), and baseline median JAK2V617F allele burden was non-significantly higher in non-responders at 12 months (45.6% vs 35.5%: p=0.1860). However, no significant differences in these baseline parameters were observed by long-term response status (24 months or 72 months), nor were there consistent differences in baseline body mass index or blood counts according to response status at any time point evaluated. The most frequent reason for non-response was failure to meet the CHR criterion hematocrit &amp;lt;45% without phlebotomy in the past 3 months, accounting for the majority of non-responders at months 12, 24 and 72 (13/23 [56.5%], 6/9 [66.7%], and 6/11 [54.5%], respectively), followed by discontinuation for any reason, which accounted for 30.4% of non-responders at month 12 and 36.4% at month 72. Only one low-risk patient discontinued due to ropeginterferon alfa-2b-related toxicity. Despite response-driven dosing, the median 4-weekly derived dose of ropeginterferon alfa-2b in the first year was only somewhat higher in non-responders compared with responders (809 µg [range: 209-898] vs 717 µg [188-898]; p=0.6954); 10/23 of non-responders at month 12 did not escalate the dose immediately according to protocol on ≥1 occasion during the first year, e.g. due to responses already observed for leukocyte or platelet counts. In the second year, the median 4-weekly doses were 997 µg (range: 211-997) vs 690 µg (88-1036) respectively (p=0.2024), indicating that non-responders received and tolerated the maximum dose (500 µg/2 weeks). Conclusions: High long-term response rates (80.4% at 24 months; 73.2% at 72 months) were achieved with ropeginterferon alfa-2b treatment in the low-risk PV population when the dose was optimized on an individual basis. No specific baseline characteristics among low-risk PV patients appear to be associated with long-term response to ropeginterferon alfa-2b. However, the PROUD-PV/CONTINUATION-PV studies show that - as hypothesized based on the Low-PV trial data - some low-risk patients require and can tolerate high doses, and that the optimal dose of ropeginterferon alfa-2b varies substantially between patients.

Albumin administration in septic shock-Protocol for post-hoc analyses of data from a multicentre RCT.

Intravenous (IV) albumin is suggested for patients with septic shock who have received large amounts of IV crystalloids; a conditional recommendation based on moderate certainty of evidence. Clinical variation in the administration of IV albumin in septic shock may exist according to patient characteristics and location. This is a protocol and statistical analysis plan for a post-hoc secondary study of the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) RCT of 1554 adult ICU patients with septic shock. We will assess if specific baseline characteristics or trial site are associated with the administration of IV albumin during ICU stay using Cox models with competing events. All models will be adjusted for the treatment allocation in CLASSIC (restrictive vs. standard IV fluid), and all analyses will consider competing events (death, ICU discharge and loss-to-follow-up). We will present results as hazard ratios with 95% confidence intervals and p-values for the associations of baseline characteristics or site with IV albumin administration. Between-group differences (interactions) will be assessed using p-values from likelihood ratio tests. All results will be considered exploratory only. This secondary study of the CLASSIC RCT may yield important insight into potential practice variation in the administration of albumin in septic shock.

Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases

To evaluate the clinical features, laboratory and imaging results, treatment and outcomes of eosinophilic fasciitis (EF) and assess the value of ultrasound in the diagnosis of EF. We retrospectively analyzed the clinical data of 45 patients with EF treated in our center from January 1, 2006 to February 28, 2022. The consistency between the diagnoses of EF based on ultrasound and MRI findings was assessed. In the 45 EF patients (male/female ratio 3.5:1), the age of onset ranged from 16 to 64 years with a mean disease course of 22.6 months. The average time from symptom onset to diagnosis was 16 months. The most common possible trigger of the disease was vigorous exercise (10/45), causing symmetrical lesions in the limbs, most commonly in the forearms (86.7%) and lower legs (80%). Clinical features of EF included subcutaneous swelling and induration (95.6%), arthralgia and arthritis (55.6%), groove sign (42.2%), hand joint contractures (42.2%), skin pigmentation (37.8%), and peau d'orange appearance (13.3%). Eosinophilia was found in 31 patients (68.9%). Hypergammaglobulinemia was seen in 23/44 (52.3%) and positive antinuclear antibodies in 9 (20%) of the patients. Twentyone of the patients were treated with high-dose methylprednisolone (≥200 mg daily for 3 to 5 consecutive days), and compared with the patients who did not receive this treatment, these patients more frequently experienced relapse before admission, had more extensive involvement, and had a higher rate of hypergammaglobulinemia without fever, but these differences were not statistically significant. Of the 31 patients (68.9%) with follow-up data (for a median of 3.2 years [range 0.2-15.9]), complete remission was achieved in 12 (38.7%) patients, and the accumulative complete remission rate was 44.1% at 5.5 years. No specific baseline characteristics or immunosuppressants were found to correlate with the treatment response. A total of 26 patients underwent both ultrasound and MRI examination, and the Kappa value of the diagnostic results between ultrasound and MRI was 0.91. EF is characterized by symmetrical subcutaneous swelling and induration in the limbs, accompanied by eosinophilia and hypergammaglobulinemia. Glucocorticoid is effective for treating EF. Ultrasound examination can identify thickening of subcutaneous fascia for an early diagnosis of EF.

Thrombotic Events in Covid-19: Incidence and their Association with Lab Parameters, Vaccination Status and Mortality

Background &amp; Objectives: Major arterial or venous thrombotic complications occur frequently with COVID-19. This risk seems to be present despite no known underlying thrombophilia and even adequate anticoagulation does not diminish its risk. Whilst pulmonary embolism may seem to be the most common thrombotic complication, others may also occur. A vaccination link to thrombotic events in COVID-19 has not been studied to the best of our knowledge. Methods: In this retrospective cross-sectional study we determined the incidence of total thrombotic events, individual Venous Thromboembolisms (VTE) and Arterial Thromboembolisms (ATE) that occurred in patients requiring ICU admission for COVID-19 in one of Bahrain’s main COVID ICU facilities for a period of 6 months. We also aim to determine mortality rate in this group of patients, links with specific baseline characteristics, laboratory parameters and patient vaccination status. Results: We studied 1597 patients over 6 months, 6% of patients were found to have VTE or ATE with a cumulative incidence of 6.5% thrombotic events. Elevated D dimer &gt;1 was associated with an increased risk of thrombosis and an increased risk of mortality. There was a higher risk of thrombotic events in unvaccinated individuals. All-cause mortality in COVID-19 patients complicated with thrombosis and mortality solely secondary to thrombotic event were both significantly higher in unvaccinated individuals. Conclusions: Based on the findings of this study, unvaccinated individuals are at significantly higher risk of developing thrombotic events. This will assist in enabling physicians to lower their threshold of diagnosing such events. The urgency of lab parameters the swift management of other risk factors and the importance of vaccination against COVID-19 can be further studied. Keywords: COVID-19, Venous Thromboembolisms, Arterial Thromboembolisms, Mortality, D dimer, Vaccination status

Predictive Biomarkers of Age-Related Macular Degeneration Response to Anti-VEGF Treatment.

Age-related macular degeneration (AMD) is an incurable disease associated with aging that destroys sharp and central vision. Increasing evidence implicates both systemic and local inflammation in the pathogenesis of AMD. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is currently the first-line therapy for choroidal neovascularization in AMD patients. However, a high number of patients do not show satisfactory responses to anti-VEGF treatment after three injections. Predictive treatment response models are one of the most powerful tools for personalized medicine. Therefore, the application of these models is very helpful to predict the optimal treatment for an early application on each patient. We analyzed the transcriptome of peripheral blood mononuclear cells (PBMCs) from AMD patients before treatment to identify biomarkers of response to ranibizumab. A classification model comprised of four mRNAs and one miRNA isolated from PBMCs was able to predict the response to ranibizumab with high accuracy (Area Under the Curve of the Receiver Operating Characteristic curve = 0.968), before treatment. We consider that our classification model, based on mRNA and miRNA from PBMCs allows a robust prediction of patients with insufficient response to anti-VEGF treatment. In addition, it could be used in combination with other methods, such as specific baseline characteristics, to identify patients with poor response to anti-VEGF treatment to establish patient-specific treatment plans at the first visit.

Predicting the treatment response of certolizumab for individual adult patients with rheumatoid arthritis: protocol for an individual participant data meta-analysis

BackgroundA model that can predict treatment response for a patient with specific baseline characteristics would help decision-making in personalized medicine. The aim of the study is to develop such a model in the treatment of rheumatoid arthritis (RA) patients who receive certolizumab (CTZ) plus methotrexate (MTX) therapy, using individual participant data meta-analysis (IPD-MA).MethodsWe will search Cochrane CENTRAL, PubMed, and Scopus as well as clinical trial registries, drug regulatory agency reports, and the pharmaceutical company websites from their inception onwards to obtain randomized controlled trials (RCTs) investigating CTZ plus MTX compared with MTX alone in treating RA. We will request the individual-level data of these trials from an independent platform (http://vivli.org). The primary outcome is efficacy defined as achieving either remission (based on ACR-EULAR Boolean or index-based remission definition) or low disease activity (based on either of the validated composite disease activity measures). The secondary outcomes include ACR50 (50% improvement based on ACR core set variables) and adverse events. We will use a two-stage approach to develop the prediction model. First, we will construct a risk model for the outcomes via logistic regression to estimate the baseline risk scores. We will include baseline demographic, clinical, and biochemical features as covariates for this model. Next, we will develop a meta-regression model for treatment effects, in which the stage 1 risk score will be used both as a prognostic factor and as an effect modifier. We will calculate the probability of having the outcome for a new patient based on the model, which will allow estimation of the absolute and relative treatment effect. We will use R for our analyses, except for the second stage which will be performed in a Bayesian setting using R2Jags.DiscussionThis is a study protocol for developing a model to predict treatment response for RA patients receiving CTZ plus MTX in comparison with MTX alone, using a two-stage approach based on IPD-MA. The study will use a new modeling approach, which aims at retaining the statistical power. The model may help clinicians individualize treatment for particular patients.Systematic review registrationPROSPERO registration number pending (ID#157595).

New 2019 ESC Guidelines for Diagnosis and Management of Chronic Coronary Syndromes (review)

Chronic stable angina (CCS) is the most prevalent symptom of ischaemic heart disease and its management is a priority. CCS are defined by the different evolutionary phases of CAD, excluding situations in which an acute coronary artery thrombosis dominates the clinical presentation (i.e ACS). The most frequently encountered clinical scenarios in patients with suspected or established CCS are: 1) CAD patients with suspected CAD and ''stable'' anginal symptoms, and/or dyspnoea; 2) patients with new onset of heart failure or left ventricular dysfunction and suspected CAD;3) asymptomatic and symptomatic patients with stabilized symptoms &lt;1 year after ASC or patients with recent revascularization;4) asymptomatic and symptomatic patients &gt; 1 year after initial diagnosis or revascularization; 5) patients with angina and suspected vasospastic or microvascular disease; 6) and asymptomatic subjects in whom CAD is screening. Т h е new technologies improve the results of treatment of these patients. Authors used determinants of the clinical likelihood of obstructive coronary artery disease and suggested stepwise strategy for long-term anti-ischemic drug therapy in patients with CCS and specific baseline characteristics. Current guidelines recommend pharmacological therapy with drugs classified as being first line (beta blockers, calcium channel blockers, short acting nitrates) or second line (long-acting nitrate, ivabradine, nicorandil, ranolazine and trimetazidine). Second line drugs are indicated for patients who have contraindications to first line agents, do not tolerante them or remain symptomatic. Patients with angina pectoris due coronary artery disease should also detreated with low dose aspirin and a statin. The demonstrated effect of the drugs include disease clinical manifestation, reduction and decrease of cardiovascular incidence and mortality rates.

Secukinumab Efficacy in Psoriatic Arthritis: Machine Learning and Meta-analysis of Four Phase 3 Trials.

Using a machine learning approach, the study investigated if specific baseline characteristics could predict which psoriatic arthritis (PsA) patients may gain additional benefit from a starting dose of secukinumab 300 mg over 150 mg. We also report results from individual patient efficacy meta-analysis (IPEM) in 2049 PsA patients from the FUTURE 2 to 5 studies to evaluate the efficacy of secukinumab 300 mg, 150 mg with and without loading regimen versus placebo at week 16 on achievement of several clinically relevant difficult-to-achieve (higher hurdle) endpoints. Machine learning employed Bayesian elastic net to analyze baseline data of 2148 PsA patients investigating 275 predictors. For IPEM, results were presented as difference in response rates versus placebo at week 16. Machine learning showed secukinumab 300 mg has additional benefits in patients who are anti-tumor necrosis factor-naive, treated with 1 prior anti-tumor necrosis factor agent, not receiving methotrexate, with enthesitis at baseline, and with shorter PsA disease duration. For IPEM, at week 16, all secukinumab doses had greater treatment effect (%) versus placebo for higher hurdle endpoints in the overall population and in all subgroups; 300-mg dose had greater treatment effect than 150 mg for all endpoints in overall population and most subgroups. Machine learning identified predictors for additional benefit of secukinumab 300 mg compared with 150 mg dose. Individual patient efficacy meta-analysis showed that secukinumab 300 mg provided greater improvements compared with 150 mg in higher hurdle efficacy endpoints in patients with active PsA in the overall population and most subgroups with various levels of baseline disease activity and psoriasis.

Sex/gender differences in the association of environmental noise exposure and cardiovascular health - systematic review and meta-analysis

TPS 781: Health effects of noise, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Epidemiological studies have demonstrated cardiovascular health effects of environmental noise exposure with some showing different effect estimates for males and females. However, results are far from being consistent. There is a need to disentangle the impact of biological sex and gender including social role or cultural norms and the interplay of both. Our objective is to evaluate the current state of integrating sex/gender into environmental noise epidemiology and to quantify the sex/gender specific effects of noise from different sources on cardiovascular health outcomes. We conducted a systematic literature search using the electronic databases PubMed and Web of Science (WoS). Publications in English or German between 2000 and 2019 which provide sex/gender specific effect estimates for short- and long-term associations between noise and ischemic heart disease (IHD) as well as blood pressure and hypertension were screened. We will review the studies concerning conceptualization and operationalization of sex/gender, report male and female specific baseline characteristics, exposure and health data as well as discuss the sex/gender specific results. After study quality rating sex/gender specific effects will be quantified by applying meta-analytic tools. Of 247 and 194 identified articles in Pubmed and WoS, respectively, 33 studies met our inclusion criteria, of which 12 studies deal with IHD, 19 studies with hypertension and 8 studies with blood pressure. The studies cover noise from road (N=24), aircraft (N=8) and railway traffic (N= 4) as well as community noise (N=6). Preliminary results show that studies generally used a dichotomous category “male/female”, did not contain information on a clear conceptualization and missed a gainful discussion of their sex-specific results. In the next steps we will continue with the extraction of necessary information and preparation of meta-analysis where possible.

Risk factors for obstetric anal sphincter injuries at vaginal birth after caesarean: a retrospective cohort study

Introduction and hypothesisVaginal birth after caesarean (VBAC) is associated with an increased risk of obstetric anal sphincter injuries (OASIS). However, specific factors that influence the risk of OASIS at VBAC have not been studied, particularly whether there are specific baseline characteristics of the first delivery which affect the subsequent perineal outcomes.MethodsRetrospective analysis of prospectively collected data from University of Southampton NHS Foundation Trusts’ maternity database. This included secundiparous women with a previous caesarean delivery (CS) who achieved a singleton, term, cephalic vaginal delivery from 2004 to 2014. Univariate analysis compared maternal, intrapartum and neonatal factors of those who suffered OASIS at VBAC with those who did not. A binary logistic regression model calculated the adjusted, independent odds ratio (OR) of OASIS.ResultsA total of 1375 women met the inclusion criteria. The OASIS rate was 8.1%, a 1.4-fold increase compared with primiparous women [difference 2.4% (95% CI 1.1, 3.6)]. Those sustaining OASIS at VBAC were older (p = 0.011) and had infants of greater birth weight at initial caesarean (p < 0.001) and VBAC (p = 0.04). Analysis of odds ratios revealed that mediolateral episiotomy (MLE) at VBAC halved the risk of OASIS [37.5% VBAC with OASIS vs. 52.2% VBAC without OASIS (OR 0.51, 95% CI 0.32–0.81)], whereas an urgent CS at initial delivery doubled the risk [52.3% VBAC with OASIS vs. 34.9% VBAC without OASIS (OR 2.05, 95% CI 1.31–3.21)].ConclusionsAdvanced maternal age, increased infant birth weight and an urgent category of initial CS increase the risk of OASIS at VBAC, whereas MLE is protective.

Patient characteristics associated with benefits from weight loss to prevent progression of knee osteoarthritis: data from the osteoarthritis initiative

Purpose: The effect of weight loss on knee osteoarthritis (OA) development and severity has been subject to a number of previous studies that found significantly less progression of cartilage degeneration in subjects with weight loss compared to those with stable weight or weight gain. However, little is known about the extent to which subgroups with certain demographic characteristics and imaging findings benefit from weight loss, and if some groups could benefit more from weight loss compared to others. Since OA and overweight are both frequent disorders with a rising prevalence, identifying those that would particularly benefit from weight loss would be highly useful in clinical practice. Our aim was therefore to assess how different baseline subject characteristics influence the protective effect of weight loss on morphological knee joint degeneration over 4 years. Methods: In this study, 592 subjects (age 62.2 ± 8.9 years, sex: 39.5% females, BMI: 30.1 ± 3.6 kg/m2) from the Osteoarthritis Initiative (OAI) were included who were overweight or obese (BMI ≥ 25 kg/m2) and showed either weight loss or stable weight over 4 years. Weight loss was defined as ≥ 5% decrease in BMI over 4 years (n = 367), while stable weight was defined as a weight change of < 3% in BMI over 4 years (n = 225). Morphological knee abnormalities were assessed on 3T MRIs at baseline and 4 year follow-up in the right knee using the Whole-Organ Magnetic Resonance Imaging Score (WORMS). In addition Kellgren-Lawrence (KL) scores were assessed from weight bearing fixed flexion radiographs. Cartilage composition was obtained by measuring T2 relaxation time using 3T MRI and available in a subset of 370 knees. To identify the characteristics of subjects who would benefit most from weight loss, in a multivariable linear regression model we tested for the interaction of baseline demographics (age, sex, BMI), baseline radiographic findings (KL scores), and cartilage T2 with weight loss in predicting WORMS sum score changes over 4 years. Results: Our data showed that progression of WORMS sum scores over 4 years was significantly associated with weight loss (effect size -1.09; 95% confidence interval (CI) -2.00, - 0.18; p = 0.019) and KL scores at baseline (effect size 0.79; 95% CI 0.37, 1.2; p < 0.001). However, no significant interaction with weight loss was found for any of the subject demographics (age, sex, BMI), baseline radiographic imaging findings (KL score), and cartilage T2 at baseline (p>0.05 for all interaction terms). Overall, we could not identify a subcohort with specific baseline subject characteristics that were associated with significantly more benefits from weight loss as measured by progression of WORMS scores. Conclusions: Our findings highlight the importance of weight loss for the overweight and obese population to prevent progression of morphological knee joint degeneration as measured by WORMS. Moreover, our results suggest that weight loss is beneficial for all individuals suffering from obesity or overweight. We could not identify specific baseline characteristics that significantly influenced the protective effect of weight loss on morphologic knee joint degeneration over 4 years.

OUTCOMES FOLLOWING ACL RECONSTRUCTION USING PATELLAR TENDON VERSUS HAMSTRING TENDON AUTOGRAFT IN ADOLESCENT ATHLETES: AN AGE-MATCH, SEX-MATCHED, AND BODY MASS INDEX-MATCHED COHORT STUDY

Background: Anterior cruciate ligament reconstruction (ACLR) remains one of the most commonly performed orthopaedic surgeries in adolescents and young adults. However, selection of the optimal graft for the individual patient remains controversial, considering multiple graft options, subtle technique differences, and wide-ranging bodies of evidence for each graft option in largely adult populations. However, multiple epidemiologic studies clearly demonstrate adolescents as the most greatly affected age-based sub-population, with the highest rates of re-tear and global morbidity, due to psychological and physical effects of long absences from athletic activity. Nevertheless, methodologically rigorous comparative studies specific to the adolescent athlete are largely absent from the literature. The purpose of the current study is to therefore investigate the outcomes of ACLR in adolescents receiving either patellar tendon/bone-tendon-bone (BTB) autograft (ACLR-BTB) or hamstring tendon autograft (ACLR-HS), using retrospective propensity score matching techniques to generate comparable cohorts. Methods: The study was designed as a retrospective chart review, with collection of cross-sectional data from a single pediatric tertiary care center over a thirteen year period (2003-2015). An initial cohort of patients, aged 13-19 years at time of primary ACLR-BTB or primary ACLR-HS by one of 5 surgeons, was identified through a comprehensive electronic medical record database query. Propensity score matching of ACLR-BTB and ACLR-HS subjects through a logistic regression model, with caliper restriction of 0.1 standard deviations, was then applied, based upon specific baseline characteristics that are frequently used by some surgeons to guide graft selection: age, sex, and body mass index (BMI). The resultant cohort of patients obtained a 1:2 (ACLR-BTB: ACLR-HS, 83 patients:186 patients) match. A chart review was performed to identify patient demographics, surgical data, and post-operative outcomes including graft rupture/re-tear and length of clinical follow-up. Patients were additionally contacted to obtain longer term sport participation and re-injury data that may have been investigated or addressed at outside institutions, as well as to obtain functional outcomes using region-specific questionnaires (Pedi-IKDC and HSS-Pedi FABS), which are validated for both this younger population and adult populations. Due to previous literature-based reports on greater anterior knee pain following ACLR-BTB, compared to ACL-HS, scores from the questions specific to knee pain or kneeling pain were extracted from the Pedi-IKDC results and analyzed to assess the potential influence of anterior knee pain on overall scores within this adolescent population. Results: At time of ACLR, the mean age and BMI of the matched ACLR-BTB patients were 17.1 years (sd: +/-1.14 years) and 25.8 (sd: +/-5.04), compared to 16.9 years (sd: +/- 1.38, p: 0.18) and 24.9 (sd: +/- 5.01, p: 0.18) for matched ACLR-HS patients, with similar male preponderance (ACLR-BTB: 77%, ACLR-HS: 72%, p: 0.47) and mean length of follow-up (ACLR-BTB: 42.9 months; ACLR-HS: 43.3 months). While mean Pedi-IKDC scores were slightly higher in the ACLR-BTB group (88.8; sd: +/-10.2, range: 56.5-100) than the ACLR-HS group (85.2; sd: +/- 16.1, range: 23.9-100), this difference was not statistically different (p: 0.50). When scores on questions regarding knee pain and kneeling difficulty were analyzed, no differences were seen between graft cohorts (ACLR-BTB: median knee pain score: 4, ACLR-HS: 4 p: 0.73; ACLR-BTB median kneeling difficulty score: 4, ACLR-HS: 4, p: 0.21). Activity level, based on the HSS-Pedi FABS score, was also similar (ACLR-BTB: 16, range: 3-29 vs. ACLR-HS: 17, range: 0-30; p: 0.96). Rates of ACL graft re-tear were not significantly different between groups, both when calculated based all possible follow-up methods (ACLR-BTB: 11%, ACLR-HS: 11%, p: 0.91), or when those patients responding to long-term follow up questionnaires were isolated (ACLR-BTB: 15%, ACLR-HS: 16%, p: 0.85). Conclusion/Significance: Despite previous studies, including large, multi-country registry-based analyses, demonstrating lower re-tear rates following ACLR-BTB than ACLR-HS, the current study, focused exclusively on adolescent cohorts matched for age, sex, and BMI, showed no difference in graft re-tear rates between the two cohorts at medium-term follow-up. Moreover, activity scores and functional knee outcome scores appear to be equivalent between these younger graft-based populations. In contrast to previous studies associating BTB autograft with greater long term anterior knee pain, adolescents appear to have equal degrees of knee pain or kneeling pain, regardless of graft choice, which may stem from greater healing and biologic remodeling capacity at graft harvest sites than adults or more modern techniques of patellar bone grafting and paratenon closure. Given the consistently high adolescent ACL re-tear rates in this and other studies, continued focus on ACL prevention programs and optimizing the timing and safety of return to play remains critical.

Efficacy and safety of omalizumab for the treatment of refractory chronic spontaneous urticaria in Japanese patients: Subgroup analysis of the phase 3 POLARIS study

BackgroundOmalizumab, a humanized anti-IgE monoclonal antibody, proved efficacious and well tolerated in patients with chronic spontaneous urticaria (CSU) refractory to H1 antihistamines (H1AH) in the POLARIS study (NCT02329223), a randomized, double-blind, placebo-controlled trial in East Asian patients. However, data in Japanese patients, who have specific baseline characteristics (e.g., low angioedema incidence, different background medications) that may impact clinical outcomes, are lacking. This pre-specified analysis presents additional patient-level data over time, pharmacokinetic and pharmacodynamics data for omalizumab and IgE, and efficacy and safety data for omalizumab in Japanese patients. MethodsJapanese patients (N = 105) were randomized 1:1:1 to omalizumab 300 mg, 150 mg, or placebo by subcutaneous injection every 4 weeks. Efficacy and safety were assessed primarily based on changes from baseline to Week 12 in weekly itch-severity scores (ISS7) and weekly urticaria activity scores (UAS7), and incidence of adverse events (AEs), respectively. Patient-level UAS7 data over time were also reviewed. ResultsAt Week 12, least squares mean (LSM) changes from baseline in ISS7 were greater with omalizumab vs. placebo (−9.54 and −7.29 for omalizumab 300 mg and 150 mg, respectively, vs. placebo [−5.17]). Corresponding LSM changes from baseline in UAS7 were −21.61 and −15.59 (vs. placebo [−10.88]). Most responders in the omalizumab 300 mg group displayed improvement of disease activity within 2–4 weeks and had well-controlled symptoms during the treatment period. Overall AE incidence was similar across treatment arms. ConclusionsThis subgroup analysis demonstrated that omalizumab is a well-tolerated, beneficial option for treatment of CSU in H1AH-refractory Japanese patients.

Changes in Eating Behaviors of Children with Obesity in Response to Carbohydrate-Modified and Portion-Controlled Diets.

This study's objective was to determine whether two distinct carbohydrate (CHO)-modified diets and a standard portion-controlled (PC) diet differentially impacted children's eating behaviors and whether eating behavior scores predicted lower BMI among children with obesity. Children (n = 102) aged 7-12 years with obesity were randomly assigned to a 12-month intervention of a low-carbohydrate (LC), reduced glycemic load (RGL), or standard PC diet. The Three-Factor Eating Questionnaire (TFEQ) was completed at baseline, 3, 6, and 12 months by parents to characterize their child's hunger (H), disinhibition (D), and cognitive restraint (CR). Baseline and follow-up TFEQ scores by diet were evaluated relative to BMI status over time. All diet groups showed increased CR and decreased H and D from baseline to 3 months, with differences from baseline remaining at 12 months for CR and H. Lower BMI status during study follow-up was associated with different TFEQ scores by diet group (LC and RGL: higher CR; PC: lower H), adjusting for sex, age, and race. Higher CR at follow-up was predicted by race and higher baseline CR; only lower H at baseline predicted lower H at follow-up. Eating behaviors improved significantly with all diets during the initial 3 months; higher CR and lower H were sustained at treatment's end. BMI outcomes were associated with different eating behaviors in CHO-modified diet groups compared with PC diets. Targeting diets of children with obesity with specific baseline characteristics may lead to improved outcomes.

Baseline predictors of treatment gains in peak propulsive force in individuals poststroke.

BackgroundCurrent rehabilitation for individuals poststroke focuses on increasing walking speed because it is an indicator of community walking ability and quality of life. Propulsive force generated from the paretic limb is critical to walking speed and may reflect actual neural recovery that restores the affected neural systems. A wide variation across individuals in the improvements in paretic propulsive force was observed following an intervention that targeted paretic propulsive force. This study aimed to determine if specific baseline characteristics can be used to predict patients who would respond to the intervention.MethodsParticipants (N = 19) with chronic poststroke hemiparesis walked at their self-selected and maximal walking speeds on a treadmill before and after a 12-week gait training program. Propulsive forces from the paretic limb were analyzed. Pearson correlation coefficient was used to determine the relationships between (1) treatment gains in walking speed and propulsive force following intervention, and (2) treatment gains in propulsive force and baseline propulsive forces.ResultsTreatment gains in self-selected walking speed were correlated to treatment gains in paretic propulsive force following intervention. In addition, changes in paretic propulsive force between self-selected and maximal walking speeds at baseline were strongly correlated to treatment gains in paretic propulsive force.ConclusionsThe capacity to modulate paretic propulsive force, rather than the absolute propulsive force during self-selected or maximal walking speed, predicted treatment gains in propulsive force following the intervention. Findings from this research could help to inform clinicians and researchers to target the appropriate patient population for rehabilitation interventions.

Poor ESA Responders As Defined By Week 4 Hemoglobin Response Have Greater ESA Dosing but Worse Cardiovascular Outcomes in Patients with Anemia of Chronic Kidney Disease (CKD) Not on Dialysis

Erythropoiesis-stimulating agents (ESAs) reduce transfusion use in patients with anemia of CKD (A-CKD) but ESA use is associated with worse cardiovascular outcomes in all trials to date. Several studies indicate that patients with A-CKD who have initial poor responses to ESAs have even worse cardiovascular outcomes than others. No specific baseline characteristics identify poor ESA responders. If these patients could be identified early in their therapy, their anemia management might be altered to reduce their known greater risks of major adverse cardiovascular events (MACE). A standardized and early definition of poor ESA responders is desirable but has not been established.We analyzed three groups of patients with anemia of CKD not on dialysis (A-CKD-NOD), for their initial response to ESA therapy, ESA dosing over time, and subsequent MACE outcomes. One group consisted of all patients in the TREAT trial receiving darbepoetin alfa (n=1981; New Engl J Med 2009 and 2010). The other two groups consisted of all patients in the phase 3 trials of the ESA peginesatide for A-CKD-NOD (New Engl J Med 2013), based on the ESA to which they were randomized. Patients receiving peginesatide (n=600) comprised one group, and the control group receiving darbepoetin alfa therapy (n=304) comprised the third group (for this group, events are too few for further analysis). In all patients, peginesatide was given once monthly and darbepoetin was given every two weeks, initially at a prespecified dose and then titrated to achieve and maintain target hemoglobin (Hgb) levels of 11-12 g/dL. All analyses used the patient populations with both baseline and week 4-5 Hgb values. Peginesatide was non-inferior to darbepoetin in raising Hgb in the trials. Our analyses compared early Hgb responses at week 4-5 for each patient with later Hgb levels, cumulative ESA dosage, and with primary outcomes of MACE (time to first event of stroke, myocardial infarction, or death) for each group. Patient level data was available for all patients, and all data has been reported publically. All outcomes were assessed by blinded independent review. The relationships between MACE outcomes and the hemoglobin response were assessed using three methods: Kaplan-Meier analysis with log-rank test, adjusted Cox model with model selection, and bootstrap simulations.Results: In all groups, patients’ baseline Hgb was 10-10.5 g/dL. No individual or composite baseline characteristics were predictive for defining a poor responder group. “Poor responders” for each group, identified by week 4-5 Hgb values, remained poor responders at week 12. The average Hgb level after 12 weeks remained marginally lower in the poor responder group. Over time, the poor responder group received more ESA dose yet achieved lower Hgb increments and sustained more MACE events. TableStudy groupsCKD not on dialysisNPoor responder: Hgb increment from baselinen (%)Relative Risk for MACE for poor vs better responderPeginesatide6000.3 g/dL or less112 (19)2.56Darbepoetin (TREAT trial)19810.1 g/dL or less451 (23)1.22In exploratory analyses, patients with little or no increment in Hgb at 4 weeks on ESA therapy, defined by having 0.3 g/dL Hgb increment with peginesatide or 0.1 g/dL or less Hgb increment with darbepoetin, have the greatest risk for MACE outcomes and should be studied prospectively for alternatives to continuing or escalating usual ESA therapy, to determine if the poor responder findings are prognostic or predictive (or both). The risk of a MACE outcome is less common but not eliminated among better responders. In sensitivity analyses, by using additional adverse outcomes (such as onset of heart failure or of hospitalization) in composite models, more events are identified and allow for greater precision for risk estimates but may not be as reliable clinically as are MACE events.This work is independent and does not represent views of any government agency. DisclosuresNo relevant conflicts of interest to declare.

A Phase 2, Randomized, Double-Blind, Efficacy and Safety Study of Oxybutynin Vaginal Ring for Alleviation of Overactive Bladder Symptoms in Women

We evaluated the efficacy and safety of a once monthly oxybutynin vaginal ring in women with overactive bladder. This randomized, multicenter, double-blind, 12-week phase 2 study compared oxybutynin vaginal ring (4 or 6 mg daily) to a placebo vaginal ring in women with well-defined overactive bladder symptoms. The primary efficacy variable was the change from baseline to week 12 in the total weekly number of incontinence episodes (stress and urge). Safety was measured in terms of treatment emergent adverse events, laboratory, physical, gynecologic examinations, electrocardiogram and vital signs. After a 3-week post-randomization placebo run-in phase (sample size 720) 445 women entered the treatment phase (safety population). Of these women 323 met all 3 overactive bladder specific baseline characteristics of 10 or more urinary urge incontinence episodes weekly, urinary frequency 8 or more voids per 24 hours and voided volume 3 L or less per 24 hours) (analysis population). Women treated with 4 and 6 mg daily oxybutynin vaginal ring had significantly fewer incontinence episodes weekly (p = 0.036 and p = 0.018, respectively), lower daily urinary frequency (p = 0.014, p = 0.002) and a higher proportion had no incontinence episodes at week 12 (p = 0.026, p = 0.027) compared with placebo. The change in severity of urgency and voided volume was similar for all groups (p >0.05). Except for a higher incidence of dry mouth and urinary tract infections that were not always culture confirmed, the oxybutynin vaginal ring was well tolerated and had a safety profile similar to that of the placebo vaginal ring. The oxybutynin vaginal ring appears to be an effective and safe once monthly treatment option for women with overactive bladder characterized primarily by urinary urge incontinence that merits further evaluation in a phase 3 study.

Initial Outcomes Following Intravitreal Ocriplasmin for Treatment of Symptomatic Vitreomacular Adhesion

When delivered via a single intravitreal injection, ocriplasmin can effect proteolytic resolution of symptomatic vitreomacular adhesion (VMA). The authors describe their initial clinical experience with ocriplasmin at a large academic center. Retrospective review of all patients with symptomatic VMA treated with ocriplasmin from January 2013 through May 2013 at a single center. Nineteen patients with symptomatic VMA received intravitreal ocriplasmin. Eight patients (42%) exhibited resolution of VMA. Macular holes in three of six patients (50%) closed after injection. A higher proportion of VMA resolution was observed in patients with the following baseline characteristics: age less than 65 years, focal adhesions less than or equal to 1,500 μm, presence of macular hole, phakic status, and absence of epiretinal membrane. Initial clinical outcomes using ocriplasmin in this study are consistent with those reported in the phase 3 clinical trials. Improved clinical results can be achieved with careful case selection based on specific baseline characteristics.