Optimal treatment allocation for placebo‐treatment comparisons in trials with discrete‐time survival endpoints

In many randomized controlled trials, treatment groups are of equal size, but this is not necessarily the best choice. This paper provides a methodology to calculate optimal treatment allocations for longitudinal trials when we wish to compare multiple treatment groups with a placebo group, and the comparisons may have unequal importance. The focus is on trials with a survival endpoint measured in discrete time. We assume the underlying survival process is Weibull and show that values for the parameters in the Weibull distribution have an impact on the optimal treatment allocation scheme in an interesting way. Additionally, we incorporate different cost considerations at the subject and measurement levels and determine the optimal number of time periods. We also show that when many events occur at the beginning of the trial, fewer time periods are more efficient. As an application, we revisit a risperidone maintenance treatment trial in schizophrenia and use our proposed methodology to redesign it and compare merits of our optimal design. Copyright © 2015 John Wiley & Sons, Ltd.     

Feasibility and diagnostic performance of hybrid PET/MRI compared with PET/CT for gynecological malignancies: a prospective pilot study

Purpose

The purpose of the study was to assess the feasibility and diagnostic performance of FDG-PET/MR imaging compared to PET/CT for staging of patients with a gynecological malignancy.

Methods

25 patients with a gynecological malignancy were prospectively enrolled into this pilot study. Patients underwent sequential full-body PET/CT and PET/MR of the abdomen and pelvis after administration of a single dose of F-18 FDG. PET/MRI and PET/CT images were independently reviewed by two expert radiologists. Readers were blinded to the results of the other imaging procedures. Clinical and pathologic information was abstracted from medical charts.

Results

18 patients were included in the final analysis with a median age of 62 years (range 31–88). 61% of patients (11/18) had cervical cancer, while the remaining patients had endometrial cancer. PET/MRI as compared to PET/CT detected all primary tumors, 7/7 patients with regional lymph nodes, and 1/1 patient with an abdominal metastasis. Two patients had additional lymph nodes outside of the abdominopelvic cavity detected on PET/CT that were not seen on PET/MRI, whereas 6 patients had parametrial invasion and one patient had invasion of the bladder seen on PET/MRI not detected on PET/CT. Five cervical cancer patients had discordant clinical vs. radiographic staging based on PET/MRI detection of soft tissue involvement. Management changed for two patients who had clinical stage IB1 and radiographic stage IIB cervical cancer.

Conclusions

PET/MRI is feasible and has at least comparable diagnostic ability to PET/CT for identification of primary cervical and endometrial tumors and regional metastases. PET/MRI may be superior to PET/CT for initial radiographic assessment of cervical cancers.

     

Increased PUFA Content and 5-Lipoxygenase Pathway Expression Are Associated with Subcutaneous Adipose Tissue Inflammation in Obese Women with Type 2 Diabetes

Obese women with type 2 diabetes mellitus (T2DM) have more inflammation in their subcutaneous white adipose tissue (sWAT) than age-and-BMI similar obese women with normal glucose tolerance (NGT). We aimed to investigate whether WAT fatty acids and/or oxylipins are associated with the enhanced inflammatory state in WAT of the T2DM women. Fatty acid profiles were measured in both subcutaneous and visceral adipose tissue (vWAT) of 19 obese women with NGT and 16 age-and-BMI similar women with T2DM. Oxylipin levels were measured in sWAT of all women. Arachidonic acid (AA) and docosahexaenoic acid (DHA) percentages were higher in sWAT, but not vWAT of the T2DM women, and AA correlated positively to the gene expression of macrophage marker CD68. We found tendencies for higher oxylipin concentrations of the 5-LOX leukotrienes in sWAT of T2DM women. Gene expression of the 5-LOX leukotriene biosynthesis pathway was significantly higher in sWAT of T2DM women. In conclusion, AA and DHA content were higher in sWAT of T2DM women and AA correlated to the increased inflammatory state in sWAT. Increased AA content was accompanied by an upregulation of the 5-LOX pathway and seems to have led to an increase in the conversion of AA into proinflammatory leukotrienes in sWAT.     

The effect of glucose dynamics on plasma copeptin levels upon glucagon,arginine, and macimorelin stimulation in healthy adults

Pituitary - Non-osmotic stimulation tests using glucagon, arginine, or macimorelin were recently evaluated for their ability to assess posterior pituitary function. Glucagon and arginine, but not...     

Pituitary Society Delphi Survey: An international perspective on endocrine management of patients undergoing transsphenoidal surgery for pituitary adenomas

Pituitary - In adults and children, transsphenoidal surgery (TSS) represents the cornerstone of management for most large or functioning sellar lesions with the exception of prolactinomas....     

Mixed functional characteristics correlating with TCR‐ligand koff‐rate of MHC‐tetramer reactive T cells within the naive T‐cell repertoire

The low frequency of antigen‐specific naïve T cells has challenged numerous laboratories to develop various techniques to study the naïve T‐cell repertoire. Here, we combine the generation of naïve repertoire‐derived antigen‐specific T‐cell lines based on MHC‐tetramer staining and magnetic‐bead enrichment with in‐depth functional assessment of the isolated T cells. Cytomegalovirus (CMV) specific T‐cell lines were generated from seronegative individuals. Generated T‐cell lines consisted of a variety of immunodominant CMV‐epitope‐specific oligoclonal T‐cell populations restricted to various HLA‐molecules (HLA‐A1, A2, B7, B8, and B40), and the functional and structural avidity of the CMV‐specific T cells was studied. Although all CMV‐specific T cells were isolated based on their reactivity toward a specific peptide‐MHC complex, we observed a large variation in the functional avidity of the MHC‐tetramer positive T‐cell populations, which correlated with the structural avidity measured by the recently developed Streptamer k_off‐rate assay. Our data demonstrate that MHC‐tetramer staining is not always predictive for specific T‐cell reactivity, and challenge the sole use of MHC‐tetramers as an indication of the peripheral T‐cell repertoire, independent of the analysis of functional activity or structural avidity parameters.     

Effect of pitch–space correspondence on sound-induced visual motion perception

The brain tends to associate specific features of stimuli across sensory modalities. The pitch of a sound is for example associated with spatial elevation such that higher-pitched sounds are felt as being “up” in space and lower-pitched sounds as being “down.” Here we investigated whether changes in the pitch of sounds could be effective for visual motion perception similar to those in the location of sounds. We demonstrated that only sounds that alternate in up/down location induced illusory vertical motion of a static visual stimulus, while sounds that alternate in higher/lower pitch did not induce this illusion. The pitch of a sound did not even modulate the visual motion perception induced by sounds alternating in up/down location. Interestingly, though, sounds alternating in higher/lower pitch could become a driver for visual motion if they were paired in a previous exposure phase with vertical visual apparent motion. Thus, only after prolonged exposure, the pitch of a sound became an inducer for upper/lower visual motion. This occurred even if during exposure the pitch and location of the sounds were paired in an incongruent fashion. These findings indicate that pitch–space correspondence is not so strong to drive or modulate visual motion perception. However, associative exposure could increase the saliency of pitch–space relationships and then the pitch could induce visual motion perception by itself.     

Risk factors for calcification of the vertebrobasilar arteries in cardiovascular patients referred for a head CT,the SMART study

Background and purposeVertebrobasilar artery calcification (VBAC) has been associated with increased stroke occurrence. Little is known on VBAC risk factors, especially for patients with cardiovascular disease. We aimed to assess risk factors associated with VBAC in a cohort of cardiovascular patients referred for a head computed tomography (CT) scan.Materials and methodsAll patients who underwent a clinically indicated, unenhanced, thin slice head CT 6 months before or after inclusion in the SMART study were included. CTs were assessed for presence of VBAC (dichotomously). Relative risks of the associations of age, sex, diabetes mellitus (DM), obesity, body mass index, estimated glomerular filtration rate, hypertension, hyperlipidemia, use of lipid lowering medication, smoking status, high sensitivity C-reactive protein, ankle-brachial index (ABI; ≤ 0.90, ≥ 1.30, continuous), internal carotid artery stenosis ≥ 70%, and carotid intima-media thickness (IMT) with VBAC were estimated using Poisson regression analysis with robust standard errors, adjusted for age and sex.ResultsOf the 471 patients included (57% male, median age 58 [interquartile range 47–63]), 117 (24.8%) showed VBAC. Presence of VBAC was associated with older age (RR per 10 years = 1.70 [95%CI 1.46–1.99]), DM (RR = 1.45 [95%CI 1.03–2.06]), obesity (RR = 1.53 [95%CI 1.10–2.12]), ABI ≤ 0.90 (RR = 1.57 [95%CI 1.02–2.41]), and an increased carotid IMT (RR = 2.60 per mm [95%CI 1.20–5.62]). Other measurements were not associated with VBAC.ConclusionsWe identified several markers associated with VBAC in patients with cardiovascular disease referred for a head CT. Future investigation into the relationship between VBAC and stroke is warranted to determine the potential of VBAC in stroke prevention.     

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: –0.23 to –0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: –0.29 to –0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.