Sample size re-estimation for clinical trials with longitudinal negative binomial counts including time trends

In some diseases, such as multiple sclerosis, lesion counts obtained from magnetic resonance imaging (MRI) are used as markers of disease progression. This leads to longitudinal, and typically overdispersed, count data outcomes in clinical trials. Models for such data invariably include a number of nuisance parameters, which can be difficult to specify at the planning stage, leading to considerable uncertainty in sample size specification. Consequently, blinded sample size re-estimation procedures are used, allowing for an adjustment of the sample size within an ongoing trial by estimating relevant nuisance parameters at an interim point, without compromising trial integrity. To date, the methods available for re-estimation have required an assumption that the mean count is time-constant within patients. We propose a new modeling approach that maintains the advantages of established procedures but allows for general underlying and treatment-specific time trends in the mean response. A simulation study is conducted to assess the effectiveness of blinded sample size re-estimation methods over fixed designs. Sample sizes attained through blinded sample size re-estimation procedures are shown to maintain the desired study power without inflating the Type I error rate and the procedure is demonstrated on MRI data from a recent study in multiple sclerosis.     

Evaluation of two-dimensional lateral cephalogram and three-dimensional cone beam computed tomography superimpositions: a comparative study

Superimposition of radiographic imaging is used to evaluate patient growth and the effects of surgical and/or orthodontic treatment. The purpose of this study was to compare the outcomes of superimposition between two-dimensional (2D) and three-dimensional (3D) superimpositions. 2D lateral cephalograms were generated from the initial and final cone beam computed tomography scans (CBCT) of 18 patients and superimposed. Both 3D CBCT and 2D CBCT generated lateral cephalograms were oriented to the Frankfort horizontal plane and superimposed according to the American Board of Orthodontics recommendations. Changes in landmark position were quantified from the resulting superimposition outcomes via linear measurements made with Dolphin software. Differences between the two methods were analyzed using paired t-tests. Measurements were repeated twice for 10 randomly selected scans to assess reliability by intra-class correlation coefficient (ICC) analysis. Intra-examiner reliability was high for all measurements (ICC > 0.84). Agreement between 2D and 3D superimposition outcomes, as measured by P-values, was low for ANS (P = 0.026), B-point (P < 0.001), ST Upper lip (P = 0.019), U1 tip (P = 0.010), and U1 apex (P = 0.026). 2D measurements were significantly higher than 3D measurements for ANS, B-point, ST Upper lip, U1 tip, and U1 apex. Findings indicated that both methods of superimposition (2D and 3D) are highly reliable. Statistical differences between 2D and 3D superimposition outcomes were below the threshold of clinical significance.     

Reston virus causes severe respiratory disease in young domestic pigs

Reston virus (RESTV), an ebolavirus, causes clinical disease in macaques but has yet only been associated with rare asymptomatic infections in humans. Its 2008 emergence in pigs in the Philippines raised concerns about food safety, pathogenicity, and zoonotic potential, questions that are still unanswered. Until today, the virulence of RESTV for pigs has remained elusive, with unclear pathogenicity in naturally infected animals and only one experimental study demonstrating susceptibility and evidence for shedding but no disease. Here we show that combined oropharyngeal and nasal infection of young (3- to 7-wk-old) Yorkshire cross pigs with RESTV resulted in severe respiratory disease, with most animals reaching humane endpoint within a week. RESTV-infected pigs developed severe cyanosis, tachypnea, and acute interstitial pneumonia, with RESTV shedding from oronasal mucosal membranes. Our studies indicate that RESTV should be considered a livestock pathogen with zoonotic potential.

Reston virus (RESTV) was discovered in 1989/1990 in macaques imported into the United States from the Philippines for research purposes (1). Since then, there have been several episodes of disease caused by RESTV in macaques and rare asymptomatic infections in humans (2, 3). Unexpectedly, in 2008, RESTV emerged in pigs in the Philippines, and, shortly thereafter, RESTV sequences were detected in Chinese swine, raising zoonotic and food safety concerns (4, 5). RESTV constitutes a separate species in the genus Ebolavirus, family Filoviridae, and is generally thought of as the human apathogenic filovirus (6). Aside from humans (2, 3), RESTV has been shown to naturally and experimentally infect macaques, swine, ferrets, bats, and several rodent species (4, 5, 7–13). Upon experimental infection, macaques and ferrets, as well as immunocompromised rodents, such as STAT-1 knockout mice, develop severe disease with lethal outcome, whereas immunocompetent rodents generally do not (9–12). Whether RESTV itself causes disease in naturally infected domestic pigs remains unknown, since the RESTV-infected pigs from the Philippines were coinfected with the virulent arterivirus porcine reproductive and respiratory syndrome virus (PRRSV; now Betaarterivirus suid 1). In an initial experimental study, domestic pigs infected with RESTV only exhibited subclinical infections with evidence for virus shedding (7). We studied RESTV infection in young (3- to 7-wk-old) Yorkshire cross pigs, a swine breed used frequently in commercial pig production systems around the world. The main objective was to determine an age-dependent susceptibility to infection.     

Syringocystadenocarcinoma papilliferum associated with atypical stroma: A hitherto undocumented variant of sarcomatoid carcinoma

Carcinosarcomas are biphasic tumors composed of admixed malignant epithelial and mesenchymal components. Numerous terms have been used to name such neoplasms; therefore, terminological confusion is frequent. Most examples of carcinosarcomas are encountered in non‐cutaneous sites, with approximately 100 cases of cutaneous carcinosarcomas reported so far in the English literature. Although different theories have been suggested to explain the occurrence of these peculiar neoplasms, histogenetic mechanisms should be better hypothesized depending on each individual case. Even though prognosis tends to be related to the specific components of the lesion, especially the epithelial one, it seems that cases of cutaneous localization usually have a better outcome. We report an exceedingly rare case of syringocystadenocarcinoma papilliferum which showed an atypical stroma with sarcomatoid appearance, and highlight that the terminology used for this spectrum of lesions is disorganized and confusing.     

Plasmacytic cutaneous pathology: A review

We review the spectrum of cutaneous disorders associated with inflammatory and neoplastic plasmacytic pathology. Because plasma cells are derived from B‐lymphocytes our overview includes discussion of certain lymphoplasmacytic proliferations. It is structured along histopathological lines, addressing conditions characterized by (a) cutaneous plasma cell infiltrates, (b) deposits of plasma cell products or their derivatives in the skin and (c) miscellaneous, poorly understood cutaneous complications of plasmacytic disorders. Lesions arising primarily in the skin and those due to cutaneous involvement by multisystem disorders are addressed. The range includes a spectrum of tumefactive and circulatory manifestations. We highlight key clinical and pathological features of the different conditions and outline recent advances in our understanding of these entities. By emphasizing the dermatopathological characteristics of this spectrum of disorders we hope to hone the diagnostic accuracy of practitioners in the field.     

The awareness of the scared - context dependent influence of oxytocin on brain function

Brain Imaging and Behavior - Oxytocin is both a hormone and a neurotransmitter and has been originally recognized for its role in childbirth and lactation. Later, it became widely known as a...     

Superficial dermal melanocytosis of the elderly: An exceptional occurrence?

The development of flat pigmented lesions on chronically sun-damaged (CSD) skin of the face may represent the clinical manifestation of a wide variety of hyperplastic/neoplastic melanocytic proliferations. We report the exceptional case of an acquired pigmented patch occurring on CSD skin, histopathologically characterized by diffuse hyperplasia of dendritic/spindled melanocytes in the superficial dermis within a widened band of actinic elastosis. This lesion was associated with a small focus of early invasive lentigo maligna melanoma (LMM). We show the melanocytic nature of the population of dermal pigmented cells by means of single and double immunohistochemical staining for melanocytic and histiocytic markers. The biologic significance of the focus of LMM within the hyperpigmented lesion (whether random collision phenomenon or causally related occurrence), as well as the pathogenesis of the whole dermal lesion are difficult to elucidate. Our case emphasizes the need for a better understanding of the pathophysiology of so-called dermal melanocytes.