PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

Reliability of ultrasound imaging of pelvic floor morphology and function among females who have undergone pelvic radiotherapy.

AIMS: To investigate the intra- and inter-rater reliability of two-dimensional (2D) transperineal ultrasound imaging (USI) measures of bladder wall thickness (BWT), urethral length (UL), and parameters related to levator plate length (LP) and transient changes in LP during pelvic floor muscle (PFM) contraction, and on Valsalva in women who received radiation therapy (RT) for treatment of pelvic cancer. METHODS: Twenty women with a history of RT for the treatment of pelvic cancer were assessed independently by two raters on the same day. Five outcomes were assessed for reliability: BWT, UL, and LP at rest (LP-R), during a maximal voluntary contraction of the PFMs (LP-MVC), and during a maximal-effort Valsalva maneuver (LP-MVM). Reliability was determined using intra-class correlation coefficients (ICC) and Bland-Altman analyses. Measurement error was determined using standard error of the measurement (SEM) and minimal detectable difference. RESULTS: Intra-rater reliability was very good for LP-R, LP-MVC, LP-MVM, and UL (ICC: 0.97 [0.93-0.99], 0.95 [0.88-0.98], 0.84 [0.59-0.94], and 0.96 [0.89-0.98], respectively). Inter-rater reliability was very good for LP-R (ICC: 0.82 [0.55-0.93]), and good for LP-MVC, LP-MVM, and UL (ICC: 0.79 [0.46-0.92], 0.79 [0.49-0.92], and 0.75 [0.36-0.90], respectively). BWT had poor intra- and inter-rater reliability. The variability between measurements was the smallest for LP-R, LP-MVC, and UL for intra-rater assessments, and for LP-R and UL for inter-rater assessments. SEM values for intra-rater assessments were LP-R: 1.5 mm, LP-MVC: 1.84 mm, LP-MVM: 4.33 mm, and UL: 1.16 mm. CONCLUSIONS: Although these results support the reliability of 2D-transperineal USI for the evaluation of UL and PFM parameters, they do not support its use for the assessment of BWT.

The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma.

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3ß-hydroxysteroid dehydrogenase-1 (3ß-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3ß-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.

Current Status and Future Opportunities in Lung Precision Medicine Research with a Focus on Biomarkers. An American Thoracic Society/National Heart, Lung, and Blood Institute Research Statement.

BACKGROUND: Thousands of biomarker tests are either available or under development for lung diseases. In many cases, adoption of these tests into clinical practice is outpacing the generation and evaluation of sufficient data to determine clinical utility and ability to improve health outcomes. There is a need for a systematically organized report that provides guidance on how to understand and evaluate use of biomarker tests for lung diseases. METHODS: We assembled a diverse group of clinicians and researchers from the American Thoracic Society and leaders from the National Heart, Lung, and Blood Institute with expertise in various aspects of precision medicine to review the current status of biomarker tests in lung diseases. Experts summarized existing biomarker tests that are available for lung cancer, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, sepsis, acute respiratory distress syndrome, cystic fibrosis, and other rare lung diseases. The group identified knowledge gaps that future research studies can address to efficiently translate biomarker tests into clinical practice, assess their cost-effectiveness, and ensure they apply to diverse, real-life populations. RESULTS: We found that the status of biomarker tests in lung diseases is highly variable depending on the disease. Nevertheless, biomarker tests in lung diseases show great promise in improving clinical care. To efficiently translate biomarkers into tests used widely in clinical practice, researchers need to address specific clinical unmet needs, secure support for biomarker discovery efforts, conduct analytical and clinical validation studies, ensure tests have clinical utility, and facilitate appropriate adoption into routine clinical practice. CONCLUSIONS: Although progress has been made toward implementation of precision medicine for lung diseases in clinical practice in certain settings, additional studies focused on addressing specific unmet clinical needs are required to evaluate the clinical utility of biomarkers; ensure their generalizability to diverse, real-life populations; and determine their cost-effectiveness.

Convergent Aspects of Acoustic Communication in Darters, Sculpins, and Gobies.

Darters (Perciformes, Percidae), sculpins (Perciformes, Cottidae), and gobioids (Gobiiformes, Gobioidei) exhibit convergent life history traits, including a benthic lifestyle and a cavity nesting spawning mode. Soniferous species within these taxa produce pulsed and/or tonal sounds with peak frequencies below 200 Hz (with some exceptions), primarily in agonistic and/or reproductive contexts. The reduced or absent swim bladders found in these taxa limit or prevent both hearing enhancement via pressure sensitivity and acoustic amplification of the contracting sonic muscles, which are associated with the skull and pectoral girdle. While such anatomies constrain communication to low frequency channels, optimization of the S/N (signal-to-noise) ratio in low frequency channels is evident for some gobies, as measured by habitat soundscape frequency windows, nest cavity sound amplification, and audiograms. Similar S/N considerations are applicable to many darter and sculpin systems. This chapter reviews the currently documented diversity of sound production in darters, sculpins, and gobioids within a phylogenetic context, examines the efficacy of signal transmission from senders to receivers (sound production mechanisms, audiograms, and masking challenges), and evaluates the potential functional significance of sound attributes in relation to territorial and reproductive behaviours.

Future Research Directions in Asthma. An NHLBI Working Group Report.

Asthma is a common chronic disease without cure. Our understanding of asthma onset, pathobiology, classification, and management has evolved substantially over the past decade; however, significant asthma-related morbidity and excess healthcare use and costs persist. To address this important clinical condition, the NHLBI convened a group of extramural investigators for an Asthma Research Strategic Planning workshop on September 18-19, 2014, to accelerate discoveries and their translation to patients. The workshop focused on (1) in utero and early-life origins of asthma, (2) the use of phenotypes and endotypes to classify disease, (3) defining disease modification, (4) disease management, and (5) implementation research. This report summarizes the workshop and produces recommendations to guide future research in asthma.

Uterine arteriovenous malformations following gestational trophoblastic neoplasia: a systematic review.

Uterine arteriovenous malformation (AVM) following gestational trophoblastic neoplasia (GTN) is a rare condition. It can be associated with chronic vaginal bleeding or life-threatening heavy bleeding, even after complete resolution of the tumor following chemotherapy. This analysis aimed to perform an extensive systematic review highlighting clinical symptoms, imaging, management and prognosis of this rare complication of GTN. We also describe an additional case of uterine AVM following GTN. We conducted a literature search using Medline, Embase and Cochrane library to analyze the clinical data of 49 published cases of uterine AVM following GTN. Median age of the women diagnosed with AVM was 29 years (range 15-49). Median gravidity was 2 (range 1-8) and 50% of women were nulligravida. Complete molar pregnancy was the most common initial gestational trophoblastic diagnosis (48%). Overall, 44 patients (88%) were symptomatic and presented with chronic or acute abnormal vaginal bleeding. Only 3 patients had an undetectable HCG level at the time of uterine AVM diagnosis. Hypo-echoic space in the myometrium is the most relevant finding on ultrasonography but the gold standard for the definitive diagnosis of AVMs is angiographic examination. Uterine artery embolization was the most common treatment option performed in 82% of the patients and was successful in controlling the bleeding in 85% of cases. We identified 20 pregnancies after successful embolization of uterine AVM following a GTN and 90% of them were successful. Because of the risk of life-threatening heavy bleeding, the diagnosis of uterine AVM should always be considered in patients with a history of recurrent unexplained vaginal bleeding after gestational trophoblastic neoplasia. Angiographic embolization is successful in the majority of cases and does not appear to compromise future pregnancy.

Early cervical carcinoma and fertility-sparing treatment options: MR imaging as a tool in patient selection and a follow-up modality.

Because of the widespread use of cytologic screening programs in industrialized nations, cervical carcinoma is being diagnosed in younger patients and at an earlier stage. The traditional therapy for early-stage disease is radical hysterectomy with pelvic lymphadenectomy, which leads to infertility. In the past 20 years, fertility-sparing therapies, such as cervical conization and radical trachelectomy, have emerged and show good oncologic and obstetric outcomes. The selection criteria for vaginal radical trachelectomy include stages IA2 and IB1, a tumor that is smaller than 2 cm, distance from the internal os of at least 1 cm, limited stromal invasion, and no nodal or extracervical extension. Magnetic resonance (MR) imaging accurately depicts these criteria and is a necessary tool in the preoperative evaluation of patients with cervical carcinoma who are eligible for fertility-sparing surgery. The MR imaging report must provide the following pieces of information for adequate surgical planning: tridimensional diameters of the lesion, uterine and cervical lengths, the degree of stromal invasion, distance from the internal os, and the presence of extracervical or nodal involvement. Because patients also undergo follow-up MR imaging, radiologists must be familiar with the postoperative imaging appearance of the cervix. After trachelectomy, the uterovaginal anastomosis may appear end-to-end or with a neoposterior vaginal fornix. Vaginal wall thickening, hematomas, lymphoceles, and hematometra secondary to isthmic stenosis may be seen. The normal postoperative appearance must be differentiated from recurrent disease, which is seen as a mass with intermediate to high signal intensity in the vaginal vault or parametrium on T2-weighted images. Functional imaging, including diffusion-weighted and dynamic contrast-enhanced imaging, may help characterize recurrence.

Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop.

Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts.

Simple vaginal trachelectomy in early-stage low-risk cervical cancer: a pilot study of 16 cases and review of the literature.

OBJECTIVE: This study aimed to evaluate the feasibility of simple vaginal trachelectomy and node assessment in patients with low-risk early-stage cervical cancer (<2 cm). METHODS: From May 2007 to November 2012, 16 women with low-risk small-volume cervical cancer underwent a simple vaginal trachelectomy preceded by laparoscopic sentinel node mapping plus or minus pelvic node dissection. Data were collected prospectively in a computerized database. Descriptive statistics and Kaplan-Meyer estimate were used for analysis. RESULTS: Patients' median age was 30 years and 12 (75%) were nulliparous. Six had a diagnostic cone, 6 had a loop electrocautery excision procedure, 3 had cervical biopsies, and 1 had polyp excision. All patients underwent a preoperative pelvic magnetic resonance imaging. Four patients had stage IA1 with lymph vascular space invasion (LSVI), 6 IA2, and 6 IB1. Ten (62.5%) had squamous lesions, 7 had adenocarcinoma. LVSI was present in 4 cases, suspicious in 2, and absent in 10. There were 2 surgical complications: a trocar site hematoma and a vaginal laceration. The median OR time was 150 minutes (range, 120-180 minutes) and median blood loss was 50 mL (range, 50-150 mL). On final pathology, lymph nodes were negative in all patients. Thirteen (81%) patients had either no residual disease (6) or residual dysplasia only (7) in the trachelectomy specimen. Margins were negative in all cases. With a median follow-up of 27 months (range, 1-65 months), there have been no recurrences. The recurrence-free survival at 24 months is 100%. Eight patients have conceived: 3 were term deliveries and 4 are ongoing. CONCLUSIONS: Simple trachelectomy and nodes seems to be a safe alternative in well-selected patients with early-stage low-risk cervical cancer. Our data will need to be confirmed in larger series.

Optimizing cine MRI for uterine peristalsis: a comparison of three different single shot fast spin echo techniques.

PURPOSE: To determine the optimal single shot fast spin echo (SSFSE) technique by varying interval between image acquisitions for cine MRI of uterine peristalsis. MATERIALS AND METHODS: MRI was performed in 13 premenopausal women (4 normal and 9 with benign pelvic pathology) in various phases of their menstrual cycle. Midsagittal uterus was scanned using a multiphasic SSFSE technique at 2-, 3-, and 4-s intervals over 2 min. Three readers independently and randomly evaluated for peristaltic frequency/2 min, longitudinal direction and intensity of peristalsis in three imaging parameters. Contrast-to-noise ratios (CNRs) were also obtained. RESULTS: Peristaltic frequency for the 2, 3, and 4 s was 2.2 ± 2.3, 3.3 ± 1.5, and 3.6 ± 1.3 waves/2 min, respectively. It increased by 1.5 (95% confidence interval [CI]: 0.31-2.64) waves/2 min with 4 s compared with 2 s. Direction was detected for the 2, 3, and 4 s in 5/13(38%), 9/13(69%) and 12/13(92%) women. Compared with 2 s, intensity of peristalsis in endometrial movement (P = 0.04), signal change of the JZ (P = 0.03), and spread into outer myometrium (P = 0.02), CNRendometrium-JZ by 57% (P < 0.001), and CNRouter myometrium-JZ by 45% (P < 0.01) increased with 4 s. CONCLUSION: Cine MRI with SSFSE sequence for uterine peristaltism is best performed using a 4-s scan interval.