Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials.

BACKGROUND: Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late-stage development for adult patients with moderate-to-severe AD. OBJECTIVE: To report pooled safety data for baricitinib in patients with moderate-to-severe AD in the clinical development program including long-term extension (LTE) studies. METHODS: This analysis included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one phase 2 and five phase 3), one double-blinded, randomized, LTE study and one open-label LTE study, reported in three data sets: placebo-controlled, 2-mg - 4-mg extended and All-bari AD. Safety outcomes include treatment-emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. RESULTS: Data were collected for 2531 patients who were given baricitinib for 2247 patient-years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo-controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated patients. Frequency of herpes simplex was higher in the 4-mg group (6.1%) vs. the 2-mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2-mg IR = 9.6; 4-mg IR = 14.5) were lower vs. the placebo-controlled data set (2-mg IR = 12.4; 4-mg IR = 21.3). In the All-bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2-mg group): two venous thrombosis events (4-mg group) and one death. CONCLUSION: This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib.

Efficacy of tildrakizumab by patient demographic and disease characteristics across a phase 2b and 2 phase 3 trials in patients with moderate-to-severe chronic plaque psoriasis.

BACKGROUND: Tildrakizumab is a high-affinity, anti-interleukin-23p19 monoclonal antibody approved for treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: To evaluate the effects of patient demographic and disease characteristics on tildrakizumab efficacy using phase 2b/3 trial data. METHODS: Data from patients who received placebo, or tildrakizumab 100 or 200 mg, in P05495 [NCT01225731], reSURFACE 1 [NCT01722331] and reSURFACE 2 [NCT01729754] were analysed. Patient subgroups were defined by age, sex, race, weight, self-reported psoriatic arthritis, failure of ≥1 traditional systemic treatment and prior biologic use. Percentage of Psoriasis Area and Severity Index (PASI) 75 and 90 responders at Week 12 were compared across treatment arms in each subgroup. Absolute PASI at Weeks 0 and 12 was also determined for each subgroup. RESULTS: Among patients randomized in P05495 (N = 355), reSURFACE 1 (N = 772) and 2 (N = 1090), percentage of PASI 75 and 90 responders were significantly greater for each tildrakizumab dose vs. placebo (P < 0.0001). PASI 75 and 90 responder percentages were numerically greater in patients <65 years of age, bodyweight ≤90 kg, without psoriatic arthritis and with no prior biologic exposure (only PASI 90), vs. their counterparts in corresponding subgroups. There were no clear or consistent differences in efficacy between the other subgroups. Absolute PASI scores were generally similar across subgroups. CONCLUSIONS: Small numerical differences in tildrakizumab efficacy were observed between subgroups defined by patient age and weight, presence of psoriatic arthritis and prior biologic use. These differences were not clinically meaningful; however, analyses of long-term data may be of value. Tildrakizumab efficacy did not differ with respect to patient sex or race, or number of prior failed conventional systemic treatments. Overall, these results suggest tildrakizumab may be appropriate for treatment of moderate-to-severe plaque psoriasis in patients with a range of demographic and disease characteristics.

Number and location of drainage catheter side holes: in vitro evaluation.

AIM: To evaluate the influence of number and location of catheter shaft side holes regarding drainage efficiency in an in vitro model. MATERIALS AND METHODS: Three different drainage catheter models were constructed: open-ended model with no side holes (one catheter), unilateral side hole model (six catheters with one to six unilateral side holes), and bilateral side hole model (six catheters with one to six bilateral side holes). Catheters were inserted into a drainage output-measuring device with a constant-pressure reservoir of water. The volume of water evacuated by each of the catheters at 10-second intervals was measured. A total of five trials were performed for each catheter. Data were analysed using one-way analysis of variance. RESULTS: The open-ended catheter had a mean drainage volume comparable to the unilateral model catheters with three, four, and five side holes. Unilateral model catheters had significant drainage volume increases up to three side holes; unilateral model catheters with more than three side holes had no significant improvement in drainage volume. All bilateral model catheters had significantly higher mean drainage volumes than their unilateral counterparts. There was no significant difference between the mean drainage volume with one, two, or three pairs of bilateral side holes. Further, there was no drainage improvement by adding additional bilateral side holes. CONCLUSION: The present in vitro study suggests that beyond a critical side hole number threshold, adding more distal side holes does not improve catheter drainage efficiency. These results may be used to enhance catheter design towards improving their drainage efficiency.

Mining real-world high dimensional structured data in medicine and its use in decision support. Some different perspectives on unknowns, interdependency, and distinguishability.

There are many difficulties in extracting and using knowledge for medical analytic and predictive purposes from Real-World Data, even when the data is already well structured in the manner of a large spreadsheet. Preparative curation and standardization or "normalization" of such data involves a variety of chores but underlying them is an interrelated set of fundamental problems that can in part be dealt with automatically during the datamining and inference processes. These fundamental problems are reviewed here and illustrated and investigated with examples. They concern the treatment of unknowns, the need to avoid independency assumptions, and the appearance of entries that may not be fully distinguished from each other. Unknowns include errors detected as implausible (e.g., out of range) values that are subsequently converted to unknowns. These problems are further impacted by high dimensionality and problems of sparse data that inevitably arise from high-dimensional datamining even if the data is extensive. All these considerations are different aspects of incomplete information, though they also relate to problems that arise if care is not taken to avoid or ameliorate consequences of including the same information twice or more, or if misleading or inconsistent information is combined. This paper addresses these aspects from a slightly different perspective using the Q-UEL language and inference methods based on it by borrowing some ideas from the mathematics of quantum mechanics and information theory. It takes the view that detection and correction of probabilistic elements of knowledge subsequently used in inference need only involve testing and correction so that they satisfy certain extended notions of coherence between probabilities. This is by no means the only possible view, and it is explored here and later compared with a related notion of consistency.

Massive Muscular Infection by a Sarcocystis Species in a South American Rattlesnake (Crotalus durissus terrificus).

Massive numbers of sarcocysts of a previously undescribed species of Sarcocystis were observed in the skeletal muscles throughout the body of an adult, female South American rattlesnake (Crotalus durissus terrificus). Examination of tissue sections by light microscopy demonstrated that sarcocysts were present in 20 to 40% of muscle fibers from 5 sampled locations. Sarcocysts were not present in cardiac muscle, smooth muscle, or other organs. Sarcocysts were 0.05-0.15 mm wide, had variable length depending on the viewed orientation and size of the muscle fiber, and had a sarcocyst wall less than 1-µm thick. Sarcocysts were subdivided by septa and had central degeneration in older sarcocysts. Host induced secondary encapsulation or an inflammatory response was not present. By transmission electron microscopy (TEM), the sarcocyst wall was Type I, with a parasitophorous membrane of approximately 100 nanometers in width arranged in an undulating pattern and intermittently folded inward in a branching pattern. The sarcocysts contained metrocytes in different stages of development and mature bradyzoites. The nucleic acid sequence from a section of the 18S small subunit rRNA gene was most closely related to S. mucosa that uses marsupials as intermediate hosts and has an unknown definitive host. This is apparently the third report of muscular Sarcocystis infection in snakes and is the first to describe the ultrastructure of the sarcocysts and use sequencing methods to aid in identification.

Sequential inferior vena cava filter insertion and peripherally inserted central catheter placement through upper extremity veins.

PURPOSE: To report the sequential placement of inferior vena cava filter (IVCF) and peripherally inserted central catheter (PICC) using the same upper extremity venous access. MATERIAL AND METHODS: This is a retrospective study that reviewed the medical records of 379 consecutive patients who underwent IVCF insertion during a 39-month period at our center. Of these 379 patients, 28 patients had sequential insertion of an IVCF and a PICC through the same upper extremity venous access. The same vein entry site was used for placement of the IVCF followed by PICC insertion. Data collected included: indication and duration of IVCF and PICC placement, access site location, complications, and the type of IVCF. RESULTS: IVCFs were placed for prophylactic purposes in 15 patients (53.6%) and therapeutic purposes in 13 patients (46.4%). Right upper extremity veins were used for venous access in 27 patients (96.4%): brachial (n=16), basilic (n=9), and cephalic (n=2). The left basilic vein was used in one patient (3.6%). IVCFs were temporary in 20 patients (71.4%) and permanent in 8 patients (28.6%). There were no procedural complications. The OptEase filter was used in 23 patients (82.1%) and the TrapEase filter was used in 5 patients (17.9%). CONCLUSION: Simultaneous IVCF and PICC insertion using the same upper extremity venous access was feasible and safe in our series. This combined technique provides the patient with central venous access for repeated blood collections and intravenous therapy.

Orbital inflammation and optic neuropathies associated with chronic sinusitis of intranasal cocaine abuse. Possible role of contiguous inflammation.

Three cases of long-standing intranasal cocaine abuse were associated with orbitopathy or optic neuropathy. All three cases were characterized by chronic sinusitis. Histopathologic examination of involved sinus and orbital tissues revealed chronic and acute nonspecific inflammation, with no evidence of unusual infections or of idiopathic midline destructive disease. In two of the cases, there was radiographic evidence of contiguous orbital inflammation associated with sinusitis. The inflammatory orbital process in these two cases was steroid responsive, but in one case recurrent inflammation occurred in response to steroid tapering. One patient suffered a complete loss of vision in the involved eye due to fulminant orbital inflammation and optic nerve dysfunction.

Reversible visual loss caused by fibrous dysplasia.

Fibrous dysplasia is a developmental anomaly of bone, often affecting the facial bones. We treated a patient who had fibrous dysplasia involving the right maxillary and sphenoid bones. The patient had a sudden loss of visual acuity to R.E.: counting fingers. Visual fields demonstrated a central scotoma, and retrobulbar neuritis was diagnosed. When vision failed to improve spontaneously, however, radiologic studies were performed. These showed compromise of the optic canal by bony proliferation and an apparent mucocele at the orbital apex. Surgical exploration disclosed fibrous dysplastic bone and a cystic structure overlying the optic nerve. Successful surgical excision of the cyst and debulking of the fibrous dysplasia resulted in visual acuity returning to R.E.: 20/25.

Nonhypercalcemic analogs of vitamin D stimulate creatine kinase B activity in osteoblast-like ROS 17/2.8 cells and up-regulate their responsiveness to estrogens.

We have reported that pretreatment with 1 alpha, 25(OH)2D3(1, 25) up-regulates responsiveness and sensitivity to 17 beta estradiol (E2) in osteoblast-like cells, as measured by parallel stimulation of [3H]thymidine incorporation into DNA and the specific activity of creatine kinase BB (CK). Increased responsiveness was correlated with increased E2 receptor concentration. In this study, we have extended these observations to new nonhypercalcemic analogs of 1,25. We compared the analogs hexafluoro vitamin D3 (FL), and the side chain modified derivatives: EB 1089 (EB), CB 1093 (CB) and MC 1288 (MC) with 1,25 and 25 (OH)D3(25 D3). Treatment with 30 nM E2 for 4 h stimulated CK activity in ROS 17/2-8 cells by 40%; there was no further increase after 3 daily additions of E2. Treatment by 3 daily additions, at 1 nM, of all analogs except 25 D3 caused a 2-3-fold increase in CK specific activity. This schedule of treatment also upregulated the response to 4 h exposure to 30 nM E2 by 30-70% above the response to vitamin D analogs alone, and by up to 2 fold compared to E2 without pretreatment. At 1 pM, the analogs doubled CK activity, and, except for 1,25, upregulated the response to E2 to levels characteristic of each analog. Pretreatment with vitamin D analogs also increased the sensitivity to E2 by lowering the dose for a comparable response to E2 by one or two orders of magnitude. Stimulation of specific activity of CK by the analogs was paralleled by increases in the steady state level of mRNA for CKB, but not in its half life. Whereas pretreatment by vehicle followed by E2 for 2 h was unable to increase CKB mRNA, pretreatment with the analogs made possible detection of mRNA responsiveness to E2. These results add to the evidence for the interaction of estrogens and antiestrogens with vitamin D metabolites in regulation of bone growth in vitro. They also strengthen the potential for treatment of bone loss, as occurs in postmenopausal osteoporosis, by a combination of nonhypercalcemic vitamin D analogs and estrogens.

[The radiological diagnosis of recurrent subluxations of the shoulder (author's transl)]. / Zur Röntgendiagnostik der habituellen Luxation des Oberarmgelenks

Contrast arrhrography has shown that this is a neccessary investigation in all cases of recurrent dislocation of the shoulder, in order to show the changes in the shoulder joint. The examination can be carried out in the early or late stages after trauma. The method is also indicated before carrying out reconstructive operations on the joint.

[Normal and post-traumatic radiographic morphology of the subtalar joint]. / Normale und posttraumatische Röntgenmorphologie der Articulatio subtalaris.

The normal and post-traumatic appearances of the sub-talar joints are illustrated by means of a number of arthrograms. Special projections were used in order to demonstrate various parts of the joints. The mobility of the articulating bones and its relationship to the trabecular structure has been demonstrated. The mechanism of typical injuries in normal limbs, and in the presence of pes planus, is described. Radiological features of capsular injuries of the sub-talar joint have been studied by arthrography.

Urethral T-cell lymphoma as the initial manifestation of the acquired immune deficiency syndrome.

We report the first case (to our knowledge) of a primary urethral T-cell lymphoma as the initial manifestation of the acquired immune deficiency syndrome. A 36-year-old white homosexual man with antibodies to human immunodeficiency virus type 1 was evaluated for a hemorrhagic urethral discharge. A 2-cm fleshy, polypoid mass in the bulbous urethra was removed, and the diagnosis of small non-cleaved cell (non-Burkitt's) lymphoma was made. Immunohistochemical analysis confirmed that the tumor was of T-cell lineage. Patients with the acquired immunodeficiency syndrome have an increased incidence of lymphomas, particularly extranodal high-grade non-Hodgkin's lymphomas. Primary urethral lymphomas are extremely rare, with only a handful of cases reported in the literature. This rare form and site of lymphoma should be considered in patients with the acquired immunodeficiency syndrome who have genitourinary symptoms.

Isolation of Yersinia (Pasteurella) pseudotuberculosis from the Palm dove (Streptopelia senegalensis).

Yersinia pseudotuberculosis was isolated from a sick Palm dove (Streptopelia senegalensis) picked up near a turkey farm in Nir-Banim, Israel. Clean birds and a guinea pig inoculated with the isolate died of the infection, or were killed in extremis. Y. pseudotuberculosis showing the same cultural characteristics as the original isolate was recovered from these animals. This is the first reported case of this infection from Israel.

Virus-neutralization versus agar-gel precipitin tests for detecting serological response to infectious bursal disease virus.

The virus-neutralization (VN) test was found much more sensitive than the agar-gel precipitin (AGP) test for detecting prior exposure to infectious bursal disease (IBD). Many sera that were negative in the AGP test were found to have VN antibodies, and virtually all sera in a commercial flock were free of precipitin but had VN titers. VN titers varied widely on a flock basis, and revaccination of an 8-month-old flock through the drinking water did not alter the antibody titers. Inoculation of maternally immune chicks at 7 days of age with IBD virus resulted in a good serologic response by both the AGP and VN tests.

Infectious bursal disease virus infection attempts in turkeys and Coturnix quail.

Attempts failed to infect Coturnix quail with infectious bursal disease (IBD) virus by exposure at 7, 14, 21, and 31 days old. There were no clinical signs or gross and microscopic changes in the bursa of Fabricius, and serologic tests and virus isolation attempts from cloacal swabs were negative. Turkeys of two breeds exposed to IBD virus at 6 or 8 weeks old showed no clinical signs or lesions in the bursa of Fabricius, and the virus could not be isolated from cloacal swabs. They did respond serologically, however, by developing both precipitin and virus-neutralizing antibodies.

Electronic spectra and ionization potentials of a stable class of closed shell polycyclic aromatic hydrocarbon cations.

Due to their stability, closed shell polycyclic aromatic hydrocarbon (PAH) cations are possible candidates as carriers for some of the diffuse interstellar bands (DIBs). The electronic absorption spectra and ionization potentials of several closed shell PAH cations are determined in this study. We use density functional theory (DFT) at the BLYP/6-31G* level to determine the ionization potentials and thus confirm the stability of the PAH cations of interest. We use time-dependent density functional theory (TDDFT), again at the BLYP/6-31G* level, to calculate the vertical excitation energies and oscillator strengths of the PAH cations. We observe dominant single absorptions within the DIB spectral region of interest in all of the PAH cation spectra except for the smallest member of the series.

Comparing three head-pointing systems using a single subject design.

The keyboard is the most commonly used input method for interfacing with computers. When using a keyboard is not possible, alternative computer input methods are needed. Three methods using head control are: Head Master by Prentke Romich, Free Wheel by Pointer Systems, and LROP by Words+. The purpose of this study was to compare these three methods for speed and accuracy using a single subject design for nine individuals with disabilities. Visual inspection of the data revealed that subjects obtained higher scores when using Head Master and LROP than Free Wheel. As a follow-up test, an analysis of variance test for repeated measures showed no difference between using Head Master and LROP but did show a significant difference between Head Master and Free Wheel, and LROP and Free Wheel.