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.

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.

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.

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.

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.

Origin of substituent effects in the absorption spectra of peroxy radicals: time dependent density functional theory calculations.

We investigate the assignment of electronic transitions in alkyl peroxy radicals. Past experimental work has shown that the phenyl peroxy radical exhibits a transition in the visible region; however, previous high level calculations have not reproduced this observed absorption. We use time dependent density functional theory (TDDFT) to characterize the electronic excitations of the phenyl peroxy radical as well as other hydrocarbon substituted peroxy radicals. TDDFT calculations of the phenyl peroxy radical support an excitation in the visible spectrum. Further, we investigate the nature of this visible absorption using electron attachment/detachment density diagrams of the peroxy radicals and present a qualitative picture of the origin of the visible absorption based on molecular orbital perturbations. The peroxy radical substituent is also compared against isoelectronic radical groups. The visible absorption is determined to be dependent on mixing of the alkyl and radical substituent orbitals.

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.

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.

Mood recognition across the ages.

A cross-sectional study was conducted in which level of mood recognition was assessed from early childhood through old age. Asymptotic performance was obtained on facial affect recognitions tasks from ages 3-34 yrs. There was a progressive decline in facial affect recognitions beginning at age 45, with the principal problem that of recognizing angry faces. With respect to auditory prosody, there was an improvement in recognition level from ages 3-12 yrs. Performance remained asymptotic through age 43 and then began to decline increasingly beyond age 45.

Frequencies of MMPI-168 code types among asymptomatic and symptomatic HIV-1 seropositive gay men.

Welsh codes of Minnesota Multiphasic Personality Inventory-168 (MMPI-168) profiles were calculated for 151 HIV-1 seropositive gay men and 27 gay seronegative controls. Although 99% of seropositives' profiles were clinically elevated, the profile configurations among subjects were varied. These data document the presence of considerable emotional distress among HIV-infected individuals, yet the heterogeneity of codes encountered argues against generalizations of seropositive subjects based upon mean MMPI profiles.

Facial affect recognition in singly diagnosed mentally retarded people and normal young children: a methodological comparison.

Facial affect recognition was studied in groups of mildly retarded subjects, moderately retarded subjects, and nonretarded children. Subjects were tested under five conditions. In Condition 1, they were presented with happy, sad and angry faces simultaneously in each of 18 trials and were prompted with short commands to point to one of the affective faces. Conditions 2 and 3 were the same as the first, except that subjects were prompted with short affective vignettes. In Condition 2, the vignettes were followed by tag lines identifying the moods of the vignettes. There were no tag lines in Condition 3. Conditions 4 and 5 were identical to Conditions 2 and 3, except that the vignettes were longer. The error data were analyzed and results showed that the groups did not differ in response to short commands and vignette prompts produced more errors than short commands. Also, long vignettes gave rise to more mistakes than short vignettes, and vignettes without tag lines resulted in more errors than those with tag lines. Group differences emerged when vignettes were presented, with more errors made as level of retardation and length of vignettes increased. It was concluded that mental retardation is not associated with a disturbance in facial affect recognition.

Depressed mood and its relationship to neuropsychological test performance in HIV-1 seropositive individuals.

The relationship between depression and neuropsychological test performance in HIV-1 seropositive individuals is unclear. The present study was conducted to determine whether different patterns of neuropsychological test performance would be present in depressed vs. nondepressed individuals infected by the Human Immunodeficiency Virus (HIV-1). It was hypothesized that subjects evidencing depressed mood would demonstrate greater difficulty on measures of neuropsychological function. The subjects were 54 mostly symptomatic HIV-1 seropositive homosexual/bisexual males aged 20 to 60. A neuropsychological test battery together with the Beck Depression Inventory (BDI) was administered to all subjects. Stepwise multiple regression analysis revealed a significant relationship only between scores on the BDI and the Grooved Pegboard test and Trial 6 of the RAVLT. Subjects were then dichotomized using the BDI into high-BDI (M = 28.9) and low-BDI (M = 6.3) groups. Analysis of variance failed to reveal significant group differences between the depressed vs. the non-depressed groups on the neuropsychological measures despite their marked separation on the BDI. Similarly, examination of individual neuropsychological outliers again failed to demonstrate an increased number of outliers in the high- and low-BDI groups. These results suggest that the presence of clinically significant levels of depression in a non-elderly HIV-1 seropositive sample does not necessarily lead to significant neuropsychological dysfunction.

Neuroretinitis: an unusual presentation of ocular toxoplasmosis.

Neuroretinitis is a clinical condition usually seen in young healthy adults that is characterized by rapid profound unilateral loss of vision. Funduscopic findings include swollen disc, splinter hemorrhages, and macular star. Catscratch fever and leptospirosis have been suggested as possible etiologies in this condition. We report a case of a patient with neuroretinitis whose only laboratory abnormality was an elevated enzyme-linked immunosorbent assay immunoglobulin G Toxoplasma titer. The patient responded favorably to treatment with clindamycin, triple sulfa, and systemic corticosteroids. We recommended toxoplasmic serology be added to the workup of patients with neuroretinitis.