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Background and Aims: 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., Methods: 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., Results: 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., Conclusions: 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Conflict of interest: H-M. Pan has received funding support from the National Institutes of Health (T32HL007891). R.L. McClelland has received full-time-equivalent salary support via a subcontract from the University of Pennsylvania. J.S. Fritz has had grants or contracts from United Therapeutics as monies paid to the institution for the conduct of multicentre pulmonary arterial hypertension drug trials. J.H. Holmes has received funding support from the Cardiovascular Medical Research and Education Fund; has received grants or contracts from the National Institutes of Health, University of Florida Juvenile Diabetes Research Foundation and the University of Pavia; has served as a participant on the Clinical Data to Health External Advisory Board and COACH T2D (Columbia University); and has served unpaid leadership or fiduciary roles for the American College of Medical Informatics, American College of Epidemiology and the Artificial Intelligence Society. J. Minhas has received funding support from the National Institutes of Health (T32HL007891) and the American Thoracic Society Early Career Investigator Award. H.I. Palevsky has participated on a data safety monitoring board for studies for pulmonary arterial hypertension sponsored by United Therapeutics. S.M. Kawut has received funding support from the National Institutes of Health (K24HL103844) and the Cardiovascular Medical Research and Education Fund; received consulting fees from Janssen, Morphic and Regeneron; received payment or honoraria from Janssen; contributed to continuing medical education courses through Accredo, Actelion, Aerovate, Bayer, Inari Medical, Merck, United Therapeutics, Janssen, Liquidia and Pfizer; received support for attending meetings from Aerovate; participated in data safety monitoring boards or advisory boards for United Therapeutics, Acceleron, Vivus and Aerovate; participated in leadership or fiduciary roles for the editorial board of the European Respiratory Journal (ended 2022); received stock or stock options from Verve Therapeutics; and received remote monitory equipment from PhysIQ. N. Al-Naamani has received funding support from the National Institutes of Health (K23HL141584) and from the Cardiovascular Medical Research and Education Fund. The remaining authors disclose no potential conflicts of interest., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: 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. Objectives: We aimed to determine the minimal clinically important difference in the 6MWD. Methods: 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. Measurements and Main Results: 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. Conclusions: 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.

Rationale: Sex-based differences in pulmonary arterial hypertension (PAH) are known, but the contribution to disease measures is understudied. Objectives: We examined whether sex was associated with baseline 6-minute-walk distance (6MWD), hemodynamics, and functional class. Methods: 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. Results: 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 2 . Among 1,436 males, the mean age was 49.7 years, and the mean BMI was 26.4 kg/m 2 . The most common etiology of PAH was idiopathic. Females had shorter 6MWD. For every 1 kg/m 2 increase in BMI for females, 6MWD decreased 2.3 (1.6-3.0) meters ( P  < 0.001), whereas 6MWD did not significantly change with BMI in males (0.31 m [-0.30 to 0.92]; P  = 0.32). Females had lower right atrial pressure (RAP) and mean pulmonary artery pressure, and higher cardiac index than males (all P  < 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]; P  < 0.001), but not in females (0.13 [-0.03 to 0.28]; P  = 0.10). There was a significant decrease in pulmonary vascular resistance (PVR) with increasing age regardless of sex ( P  < 0.001). For every 1 kg/m 2 increase in BMI, there was a 3% decrease in PVR for males ( P  < 0.001), compared with a 2% decrease in PVR in females ( P  < 0.001). Conclusions: 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.

Background: 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., Research Question: Does BMI modify treatment effectiveness in PAH?, Study Design and Methods: 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., Results: A total of 5,440 participants from 17 trials were included. Patients with overweight and obesity had lower baseline 6MWD and were more likely to be WHO functional class III or IV. Treatment was associated with a 27.01-m 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 2 increase in BMI, 6MWD was reduced by 0.66 m (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 2 increase in BMI increased odds of worse WHO functional class by 3% (OR, 1.03; P for interaction = .06)., Interpretation: Patients with overweight and obesity had lower baseline 6MWD and worse WHO functional class than patients with normal weight 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., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: The population of patients with pulmonary arterial hypertension (PAH) has evolved over time from predominantly young White women to an older, more racially diverse and obese population. Whether these changes are reflected in clinical trials is not known. Objectives: To determine secular and regional trends among PAH trial participants. Methods: We performed a pooled cohort analysis using harmonized data from phase III clinical trials of PAH therapies submitted to the U.S. Food and Drug Administration. We used mixed-effects linear and logistic regression to assess regional differences in participant age, sex, body habitus, and hemodynamics over time. Results: A total of 6,599 participants were enrolled in 18 trials between 1998 and 2013; 78% were female. The mean age of participants in North America, Europe, and Latin America at the time of study start increased by 2.09 (95% confidence interval [CI], 0.67-3.51), 1.62 (95% CI, 0.24-3.00), and 4.75 (95% CI, 2.29-7.21) years per 5 years, respectively ( P  = 0.01). Body mass index at the time of study start increased by 0.72 kg/m 2 per 5 years (95% CI, 0.44-0.99; P  < 0.001) across all regions. Eighty-five percent of participants in early studies were non-Hispanic White, but this decreased over time to 70%. Ninety-seven percent of Asians and 74% of Hispanics in the sample were recruited from Asia and Latin America. Conclusions: Patients enrolled in more recent PAH therapy trials are older and more obese, mirroring the changing epidemiology of observational cohorts. However, these trends varied by geographic region. PAH cohorts remain predominantly female, presenting challenges for generalizability to male patients. Although the proportion of non-White participants increased over time, this was primarily through recruitment in Asia and Latin America.

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: Women with prior ectopic pregnancy (EP) have an increased failure rate when treated with single-dose methotrexate (MTX) for subsequent EP. We sought to determine whether previous EP remained a risk factor for failure when using the two-dose MTX protocol., Study Design: Retrospective cohort study of women managed with two-dose MTX. Risk factors for MTX failure were evaluated in univariable analysis and multivariable regression modeling., Results: A total of 234 women with EP between 1999 and 2009 were studied. Of those, 37 (15.8%) had a prior EP. In univariable analysis, prior EP was associated with a greater than twofold increased risk of MTX failure (RR 2.67, 95% CI 1.20-3.77). Higher hCG levels and ultrasound visualization of EP also increased the risk of MTX failure. In multivariable analysis hCG level remained associated with MTX failure, while prior EP did not (adjusted RR 0.97, 95% CI 0.33-2.82)., Conclusion: Prior EP is not independently associated with MTX failure in women receiving two-dose MTX therapy after controlling for known risk factors.

An understanding of the anatomic distributions of major neurodegenerative disease lesions is important to appreciate the differential clinical profiles of these disorders and to serve as neuropathological standards for emerging molecular neuroimaging methods. To address these issues, here we present a comparative survey of the topographical distribution of the defining molecular neuropathological lesions among 10 neurodegenerative diseases from a large and uniformly assessed brain collection. Ratings of pathological severity in 16 brain regions from 671 cases with diverse neurodegenerative diseases are summarized and analyzed. These include: 1) amyloid-β and tau lesions in Alzheimer's disease; 2) tau lesions in three other tauopathies including Pick's disease, progressive supranuclear palsy and corticobasal degeneration; 3) α-synuclein inclusion ratings in four synucleinopathies including Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, and multiple system atrophy; and 4) TDP-43 lesions in two TDP-43 proteinopathies, including frontotemporal lobar degeneration associated with TDP-43 and amyotrophic lateral sclerosis. The data presented graphically and topographically confirm and extend previous pathological anatomic descriptions and statistical comparisons highlight the lesion distributions that either overlap or distinguish the diseases in each molecular disease category., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: A critical and as-yet unmet need in Alzheimer disease (AD) research is the development of novel markers that can identify individuals at risk for cognitive decline due to AD. This would aid intervention trials designed to slow the progression of AD by increasing diagnostic certainty, and provide new pathophysiologic clues and potential drug targets., Results: We used two metabolomics platforms (gas chromatography-time of flight mass spectrometry [GC-TOF] and liquid chromatography LC-ECA array [LC-ECA]) to measure a number of metabolites in cerebrospinal fluid (CSF) from patients with AD dementia and from cognitively normal controls. We used stepwise logistic regression models with cross-validation to assess the ability of metabolite markers to discriminate between clinically diagnosed AD participants and cognitively normal controls and we compared these data with traditional CSF Luminex immunoassay amyloid-β and tau biomarkers. Aβ and tau biomarkers had high accuracy to discriminate cases and controls (testing area under the curve: 0.92). The accuracy of GC-TOF metabolites and LC-ECA metabolites by themselves to discriminate clinical AD participants from controls was high (testing area under the curve: 0.70 and 0.96, respectively)., Conclusions: Our study identified several CSF small-molecule metabolites that discriminated especially well between clinically diagnosed AD and control groups. They appear to be suitable for further confirmatory and validation studies, and show the potential to provide predictive performance for AD.

Background: Several node staging schemes have been proposed for gastric cancer. The optimal system remains controversial., Methods: Patients with gastric cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database, and a Chinese patient cohort was used for independent validation. The prognostic performance of three node staging schemes was compared, involving a number-based scheme (pN), ratio-based scheme (rN) and log odds of positive lymph nodes scheme (LODDS)., Results: There were 12 443 patients in the SEER database and 866 in the Chinese cohort. LODDS provided better discriminatory capacity and higher predictive accuracy than either pN or rN, for patients with gastric cancer in both the SEER database and the Chinese cohort. The multivariable model using the LODDS classification was significantly more predictive than the pN classification. LODDS suffered much less from stage migration and was able efficiently to discriminate the heterogeneity for patients with no nodes involved or all nodes involved, whereas the pN and rN schemes could not., Conclusion: LODDS showed a clear prognostic superiority over both pN and rN schemes. It could serve as an important reference for the tumour node metastasis (TNM) node classification., (Copyright © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

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., (Copyright © 2011. Published by Mosby, Inc.)

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., (Copyright 2010 Mosby, Inc. All rights reserved.)

The use of computerized interdepartmental transfer records to identify lost drug charges and a program to capture those charges are described. All charges for medications ordered on floor-stock requisitions for the operating room and various intensive-care units in a 400-bed hospital were entered into the pharmacy's computer. Medications ordered on requisitions that were not stamped with a specific patient's name were charged to the patient-care unit using the computer's interdepartmental transfer program. Computer reports itemizing these charges indicated that over $5100 per month was being lost, approximately half of which originated from the operating room. To reduce lost charges, an improved method of drug-inventory control was implemented in the operating room, and two nurses were hired to coordinate the drug-distribution system in this area. In addition, nurses in other intensive-care units were informed about the liabilities associated with failure to charge for medications, and incentive programs were developed to improve compliance with these procedures. During the first six months after implementation of these measures, monthly lost charges were reduced by a mean of 86%. The use of computerized interdepartmental transfer records to identify lost pharmacy charges may help to justify the cost of computer systems.

Quinidine pharmacokinetics are known to be altered by a number of drugs. We present a case where dose-related increases in quinidine serum concentrations were significantly suppressed by concurrent nifedipine therapy. Clinicians should be alert to the possibility of an alteration in quinidine serum concentrations when instituting or discontinuing nifedipine in patients receiving quinidine.

We have described the use of low-dose local infusion of streptokinase to treat subclavian vein thrombosis in a 30-year-old woman. Streptokinase was infused at 5,000 units per hour for three days, resulting in complete resolution of the thrombus.

We studied the effect of peritoneal dialysis solution (PDS) on the antibacterial activity of seven cephalosporins, gentamicin, tobramycin and amikacin. The six bacterial species employed in the study survived in a wide range of concentrations of PDS, however, Staphylococcus aureus did not survive beyond 24 h in PDS. There were no physical incompatibilities between any of the antibiotics and PDS. None of the cephalosporins was bactericidal in PDS, whereas, the bactericidal concentrations of the aminoglycosides in PDS approximated those of aminoglycosides in broth. We conclude from these in vitro data that cephalosporins may not be ideal agents for intraperitoneal therapy when they are administered in PDS.