Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus ...metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2–4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.
The 6-minute-walk distance (6MWD) is an important clinical and research metric in pulmonary arterial hypertension (PAH); however, there is no consensus about what minimal change in 6MWD is clinically ...significant.
We aimed to determine the minimal clinically important difference in the 6MWD.
We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for PAH submitted to the U.S. Food and Drug Administration to derive minimal clinically important differences in the 6MWD. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in 6MWD to the change in the Medical Outcomes Survey Short Form physical component score.
The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with PAH, respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years, and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27-38), which was almost identical to that in the validation sample (36 m 95% confidence interval, 29-43). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class.
We estimated a 6MWD minimal clinically important difference of approximately 33 meters for adults with PAH. Our findings can be applied to the design of clinical trials of therapies for PAH.
Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the ...effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity.
A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways.
The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {β: 43.7 m 95% confidence interval (CI): 32.9, 54.4}, nitric oxide pathway β: 29.4 m (95% CI: 22.6, 36.3), endothelin pathway β: 25.3 m (95% CI: 19.8, 30.8), and prostacyclin pathway oral/inhaled β: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous β: 24.4 m (95% CI: 15.1, 33.7) significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease.
Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.
It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction ...algorithms, modified response to therapy in randomised clinical trials in PAH.
We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening.
Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86-19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms.
We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.
Obesity is increasingly prevalent in pulmonary arterial hypertension (PAH) but is associated with improved survival, creating an "obesity paradox" in PAH. It is unknown if the improved outcomes could ...be attributable to obese patients deriving a greater benefit from PAH therapies.
Does BMI modify treatment effectiveness in PAH?
Using individual participant data, a meta-analysis was conducted of phase III, randomized, placebo-controlled trials of treatments for PAH submitted for approval to the U.S. Food and Drug Administration from 2000 to 2015. Primary outcomes were change in 6-min walk distance (6MWD) and World Health Organization (WHO) functional class.
A total of 5,440 participants from 17 trials were included. Overweight and obese patients had lower baseline 6MWD and were more likely to be WHO functional class III or IV. Treatment was associated with a 27.01-meter increase in 6MWD (95% CI, 21.58-32.45; P < .001) and lower odds of worse WHO functional class (OR, 0.58; 95% CI, 0.48-0.70; P < .001). For every 1 kg/m
increase in BMI, 6MWD was reduced by 0.66 meter (P = .07); there was no significant effect modification of treatment response in 6MWD according to BMI (P for interaction = .34). Higher BMI was not associated with odds of WHO functional class at end of follow-up; however, higher BMI attenuated the treatment response such that every 1 kg/m
increase in BMI increased odds of worse WHO functional class by 3% (OR, 1.03; P for interaction = .06).
Overweight and obese patients had lower baseline 6MWD and worse WHO functional class than normal weight patients with PAH. Higher BMI did not modify the treatment response for change in 6MWD, but it attenuated the treatment response for WHO functional class. PAH trials should include participants representative of all weight groups to allow for assessment of treatment heterogeneity and mechanisms.
Sex-based differences in pulmonary arterial hypertension (PAH) are known, but the contribution to disease measures is understudied.
We examined whether sex was associated with baseline 6-minute-walk ...distance (6MWD), hemodynamics, and functional class.
We conducted a secondary analysis of participant-level data from randomized clinical trials of investigational PAH therapies conducted between 1998 and 2014 and provided by the U.S. Food and Drug Administration. Outcomes were modeled as a function of an interaction between sex and age or sex and body mass index (BMI), respectively, with generalized mixed modeling.
We included a total of 6,633 participants from 18 randomized clinical trials. A total of 5,197 (78%) were female, with a mean age of 49.1 years and a mean BMI of 27.0 kg/m
. Among 1,436 males, the mean age was 49.7 years, and the mean BMI was 26.4 kg/m
. The most common etiology of PAH was idiopathic. Females had shorter 6MWD. For every 1 kg/m
increase in BMI for females, 6MWD decreased 2.3 (1.6-3.0) meters (
< 0.001), whereas 6MWD did not significantly change with BMI in males (0.31 m -0.30 to 0.92;
= 0.32). Females had lower right atrial pressure (RAP) and mean pulmonary artery pressure, and higher cardiac index than males (all
< 0.03). Age significantly modified the sex by RAP and mean pulmonary artery pressure relationships. For every 10-year increase in age, RAP was lower in males (0.5 mm Hg 0.3-0.7;
< 0.001), but not in females (0.13 -0.03 to 0.28;
= 0.10). There was a significant decrease in pulmonary vascular resistance (PVR) with increasing age regardless of sex (
< 0.001). For every 1 kg/m
increase in BMI, there was a 3% decrease in PVR for males (
< 0.001), compared with a 2% decrease in PVR in females (
< 0.001).
Sexual dimorphism in subjects enrolled in clinical trials extends to 6MWD and hemodynamics; these relationships are modified by age and BMI. Sex, age, and body size should be considered in the evaluation and interpretation of surrogate outcomes in PAH.
Objective We sought to determine utility of uterine evacuation for diagnosis of nonviable pregnancy of unknown location (PUL). Study Design We conducted a cohort study to assess the prevalence of ...ectopic pregnancy (EP), overall, and stratified by presenting signs and symptoms in women with a nonviable PUL. Results Of the 173 women, 66 (38%) had miscarriage (spontaneous abortion SAB) and 107 (62%) had EP. When initial human chorionic gonadotropin (hCG) was <2000 mIU/mL, the odds of an EP were greater (odds ratio, 4.32; 95% confidence interval, 2.04–9.12). Demographic factors, obstetric history, and clinical presentation were not useful in distinguishing between EP and SAB. Pre-evacuation hCG increase had strong trend association with EP (odds ratio, 2.14; 95% confidence interval, 0.98–4.68). A >30% fall in postcurettage hCG was suggestive, but was not a diagnostic indicator of SAB. Conclusion Uterine evacuation is a useful diagnostic aid for women with nonviable PUL. Nondiagnostic ultrasound findings and absolute and serial hCG values are associated with, but do not accurately predict final diagnosis.
Objective We determined whether an environmental exposure to bacterial vaginosis (BV) modified genetic susceptibilities for spontaneous preterm delivery within genes that regulate the inflammatory ...response. Study Design Maternal DNA samples and vaginal smears for Gram staining were collected from 743 women (68 preterm births). We used a 1536–single nucleotide polymorphism (SNP) custom chip to study associations between genotype distributions and preterm birth. Results For 8 SNPs in 3 genes (protein kinase C alpha, fms-like tyrosine kinase 1, and interleukin 6), the odds ratios for preterm birth ranged from 1.9–4.0 among women with susceptible genotypes who were BV positive. The odds ratios for preterm birth were 2.0-5.0 times greater among women who were BV positive than among women who were BV negative. The significance of these differences was demonstrated by logistic regression analyses for genotype/BV interaction. Conclusion These results demonstrate that the risk of preterm delivery that is associated with tag SNPs in genes that regulate the inflammatory response is modified by an environmental exposure such as bacterial vaginosis.
Rationale
Reports of cognitive decline, particularly in the domains of executive functions (EFs), are common among menopausal women.
Objective
This study aims to determine the impact of the ...psychostimulant lisdexamfetamine (LDX) on subjective and objective cognitive function among menopausal women who report new-onset EF complaints.
Methods
Thirty-two healthy perimenopausal and early postmenopausal women experiencing mid-life-onset executive function difficulties as measured using the Brown Attention Deficit Disorder Scale (BADDS) were administered LDX 40–60 mg/day for 4 weeks in this double-blind, placebo-controlled, cross-over study. Diagnosis of lifetime ADHD was exclusionary. BADDS total and subscale scores and performance on verbal memory and working memory tasks were outcomes of interest.
Results
Analyses revealed a significant effect of LDX treatment over placebo for total BADDS scores (
p
= 0.0001) and for four out of the five BADDS subscales (all
p
< 0.004). LDX treatment also resulted in significant improvement in delayed paragraph recall (
p
= 0.018), but there was no significant effect of treatment on other cognitive measures. Systolic blood pressure (
p
= 0.017) and heart rate increased significantly (
p
= 0.006) when women were on LDX but remained, on average, within the normal range.
Conclusions
LDX 40–60 mg/day was well tolerated and improved the subjective measures of executive function as well as objective measures of delayed verbal recall in this sample of healthy menopausal women.
Objective The purpose of this study was to test whether treating periodontal disease (PD) in pregnancy will reduce the incidence of spontaneous preterm delivery (SPTD) at ≤35 weeks of gestation. ...Study Design A multicenter, randomized clinical trial was performed. Subjects with PD were randomized to scaling and root planing (active) or tooth polishing (control). The primary outcome was the occurrence of SPTD at <35 weeks of gestation. Results We screened 3563 subjects for PD; the prevalence of PD was 50%. Seven hundred fifty-seven subjects were assigned randomly; 378 subjects were assigned to the active group, and 379 subjects were assigned to the placebo group. Active treatment did not reduce the risk of SPTD at <35 weeks of gestation (relative risk, 1.19; 95% confidence interval CI, 0.62–2.28) or composite neonatal morbidity (relative risk, 1.30; 95% CI, 0.83–2.04). There was a suggestion of an increase in the risk of indicated SPTD at <35 weeks of gestation in those subjects who received active treatment (relative risk, 3.01; 95% CI, 0.95–4.24). Conclusion Treating periodontal disease does not reduce the incidence of SPTD.
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