Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis.

Spondyloarthritis encompasses a group of common inflammatory diseases thought to be driven by IL-17A-secreting type-17 lymphocytes. Here we show increased numbers of GM-CSF-producing CD4 and CD8 lymphocytes in the blood and joints of patients with spondyloarthritis, and increased numbers of IL-17A+GM-CSF+ double-producing CD4, CD8, γδ and NK cells. GM-CSF production in CD4 T cells occurs both independently and in combination with classical Th1 and Th17 cytokines. Type 3 innate lymphoid cells producing predominantly GM-CSF are expanded in synovial tissues from patients with spondyloarthritis. GM-CSF+CD4+ cells, isolated using a triple cytokine capture approach, have a specific transcriptional signature. Both GM-CSF+ and IL-17A+GM-CSF+ double-producing CD4 T cells express increased levels of GPR65, a proton-sensing receptor associated with spondyloarthritis in genome-wide association studies and pathogenicity in murine inflammatory disease models. Silencing GPR65 in primary CD4 T cells reduces GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis.

Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients.

INTRODUCTION: Recent discoveries in cancer research have revealed a plethora of clinically actionable mutations that provide therapeutic, prognostic and predictive benefit to patients. The feasibility of screening mutations as part of the routine clinical care of patients remains relatively unexplored as the demonstration of massively parallel sequencing (MPS) of tumours in the general population is required to assess its value towards the health-care system. METHODS: Cancer 2015 study is a large-scale, prospective, multisite cohort of newly diagnosed cancer patients from Victoria, Australia with 1094 patients recruited. MPS was performed using the Illumina TruSeq Amplicon Cancer Panel. RESULTS: Overall, 854 patients were successfully sequenced for 48 common cancer genes. Accurate determination of clinically relevant mutations was possible including in less characterised cancer types; however, technical limitations including formalin-induced sequencing artefacts were uncovered. Applying strict filtering criteria, clinically relevant mutations were identified in 63% of patients, with 26% of patients displaying a mutation with therapeutic implications. A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance. Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents. Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified. CONCLUSIONS: Reliable delivery of a diagnostic assay able to screen for a range of actionable mutations in this cohort was achieved, opening unexpected avenues for investigation and treatment of cancer patients.

Structural, optical and vibrational properties of self-assembled Pbn+1(Ti1-x Fex)nO(3n+1)-δ Ruddlesden-Popper superstructures.

Bulk crystals and thin films of PbTi(1-x)FexO3(-δ) (PTFO) are multiferroic, exhibiting ferroelectricity and ferromagnetism at room temperature. Here we report that the Ruddlesden-Popper phase Pbn+1(Ti(1-x)Fex)nO3(n+1)-δ forms spontaneously during pulsed laser deposition of PTFO on LaAlO3 substrates. High-resolution transmission electron microscopy, x-ray diffraction and x-ray photoemission spectroscopy were utilised to perform a structural and compositional analysis, demonstrating that n ≃ 8 and x ≃ 0.5. The complex dielectric function of the films was determined from far-infrared to ultraviolet energies using a combination of terahertz time-domain spectroscopy, Fourier transform spectroscopy, and spectroscopic ellipsometry. The simultaneous Raman and infrared activity of phonon modes and the observation of second harmonic generation establishes a non-centrosymmetric point group for Pbn+1(Ti0.5Fe0.5)nO3(n+1)-δ, a prerequisite for (but not proof of) ferroelectricity. No evidence of macroscopic ferromagnetism was found in SQUID magnetometry. The ultrafast optical response exhibited coherent magnon oscillations compatible with local magnetic order, and additionally was used to study photocarrier cooling on picosecond timescales. An optical gap smaller than that of BiFeO3 and long photocarrier lifetimes may make this system interesting as a ferroelectric photovoltaic.

High-temperature electromagnons in the magnetically induced multiferroic cupric oxide driven by intersublattice exchange.

Magnetically induced ferroelectric multiferroics present an exciting new paradigm in the design of multifunctional materials, by intimately coupling magnetic and polar order. Magnetoelectricity creates a novel quasiparticle excitation--the electromagnon--at terahertz frequencies, with spectral signatures that unveil important spin interactions. To date, electromagnons have been discovered at low temperature (<70 K) and predominantly in rare-earth compounds such as RMnO3. Here we demonstrate using terahertz time-domain spectroscopy that intersublattice exchange in the improper multiferroic cupric oxide (CuO) creates electromagnons at substantially elevated temperatures (213-230 K). Dynamic magnetoelectric coupling can therefore be achieved in materials, such as CuO, that exhibit minimal static cross-coupling. The electromagnon strength and energy track the static polarization, highlighting the importance of the underlying cycloidal spin structure. Polarized neutron scattering and terahertz spectroscopy identify a magnon in the antiferromagnetic ground state, with a temperature dependence that suggests a significant role for biquadratic exchange.

Modifying the polarization state of terahertz radiation using anisotropic twin-domains in LaAlO3.

Polarization-resolved terahertz (THz) time-domain spectroscopy was utilized to examine the complex refractive index of lanthanum aluminate (LaAlO3), a rhombohedrally distorted perovskite that exhibits crystallographic twin domains. The uniaxial anisotropy of the refractive index was quantified. The ellipticity of THz radiation pulses after transmission through single domains indicated that LaAlO3 can be used as a quarter- or half-wave plate. The effective anisotropy of [001]-oriented LaAlO3 was found to be reduced when the material exhibited multiple, narrow twin domains.

Referrals for movement disorder surgery: under-representation of females and reasons for refusal.

OBJECTIVE: Referral of movement disorder patients for deep brain stimulation surgery was examined to determine whether referred patients were representative of gender proportions in our population, and reasons why patients do not proceed to surgery. METHODS: Demographic information on referrals to the surgical program was retrospectively reviewed from our database and from a detailed chart review. RESULTS: Although almost equal numbers of movement disorder patients are male and female, of the 91 patients referred for surgery, only 31% were female. Sixty-one percent of referred patients did not undergo surgery. Of these, the majority were denied for medical reasons, including cognitive decline (21%), psychiatric concerns (5%) and neurological reasons (42%). CONCLUSIONS: Almost one-third of patients referred for movement disorder surgery were denied for medical reasons. This underscores the importance of evaluation of all potential patients by a multidisiplinary team to fully assess suitablity for stereotactic surgery. Interestingly, women were under-represented in those referred. In order that all appropriate patients have the opportunity to consider surgery, education of both physicians and patients, and different strategies to approach females regarding surgery may allow more patients to benefit from this treatment.

CLT and CLS job responsibilities: current distinctions and updates.

OBJECTIVE: This study was undertaken to address the following questions: 1. What tasks distinguish the job of a clinical laboratory scientist (CLS) from that of a clinical laboratory technician (CLT)? 2. What changes in role distinctions, have occurred for entry-level CLS and CLT practitioners over the five-year period 1993-98? 3. What tasks have been deleted from the CLT and CLS content outlines because they were not frequently performed or not considered entry-level? 4. What changes in practice are reflected in the current job analyses? DESIGN: A national job analysis of tasks constituting the job of clinical laboratory scientists (CLSs) and clinical laboratory technicians (CLTs) was conducted in 1998-99 as part of a standard setting process for the certifying examinations of the National Credentialing Agency for Laboratory Personnel (NCA). The job analyses relied upon mail surveys to 1200 individuals for each job level asking respondents to identify tasks significant to effective practice at job entry. The task lists resulting from statistical analysis of those surveys were examined to answer the study questions. PARTICIPANTS: The sample for each survey included 1200 practitioners, educators and laboratory managers selected at random from membership in professional organizations or from NCA certificant lists. Sampling was stratified to insure adequate practitioner representation. MAIN OUTCOME MEASURES: The mean rating on a four point scale for each item on the surveys was evaluated for overall significance as well as significance across geographic regions. The tasks meeting specified criteria were retained in the final task lists. Tasks were counted and their content evaluated to compare CLS and CLT job tasks. RESULTS: The response rates to the surveys were 33% for CLT and 21% for CLS. Reliability was judged based on average intraclass correlation coefficients of .86 and .82 for the CLT and CLS surveys, respectively. There were 952 tasks retained on the CLS content outline and 725 retained on the CLT content outline of the 1151 tasks on the original survey. Seven hundred and twenty two tasks were found on content outlines of both job levels, representing a 76% overlap. Tasks found only on the CLS outline included advanced technical tasks, a few management tasks, and more communication tasks. CONCLUSIONS: The jobs of CLS and CLT practitioners are distinct at job entry level with CLSs performing a broader array of technical and communication tasks as well as some management tasks. Though CLS staff uses few management skills at job entry, those tasks are performed by CLS staff in the laboratory and curricula must help prepare graduates for these tasks expected of experienced staff. CLTs perform tasks requiring problem solving and high level reasoning. CLT curricula must address the need for CLTs to perform these tasks.

The Child Development Inventory: A developmental outcome measure for follow-up of the high-risk infant.

OBJECTIVE: To examine the validity of the Child Development Inventory (CDI) compared with other commonly used measures of developmental outcomes in high-risk infants. STUDY DESIGN: Primary caregivers of 63 toddlers and preschoolers enrolled at a routine neonatal high-risk follow-up clinic completed a CDI describing their children. Only those with successfully completed CDIs were included in the analysis (n = 43). The CDI General Development Developmental Quotient was compared with the Clinical Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS) and the Bayley Scales of Infant Development, 2nd Edition (BSID-II). RESULTS: Significant correlations were found between the CDI, the CAT/CLAMS (r =.87, P <.001), and the BSID-II (r =.86, P <.001). There were no significant correlations between the CDI and parent education and income. Findings revealed high sensitivity (80% to 100%) and specificity (94% to 96%) for the CDI. CONCLUSION: The CDI appears to be a useful and cost-effective screening measure for determining developmental outcomes among high-risk infants.

Teaching of pathology in United States medical schools, 1996/1997 survey.

A variety of pressures to change curriculum have resulted in revision of pathology teaching in most medical schools in the United States. Responses obtained from 71% of schools on a recent survey of pathology teaching indicate the following: There are wide variations in the extent of use of various teaching modalities with resulting emergence of different teaching formats which can be categorized as "traditional," "enhanced traditional," predominantly "problem based" or "case oriented," entirely "problem based," or some form of "hybrid" of traditional and problem based. The traditional lecture and laboratory continue to be the primary modes of teaching in the vast majority (74%) of schools, however, 53% also use other approaches, eg, small group discussion, case studies, or conferences to enhance instruction. The lecture remains an important component of instruction in all major models. The form and extent of the laboratory use varies remarkably from minimal to large number of hours of instruction. The laboratory material is incorporated into small group discussion or conferences in many schools. The use of small group discussions (presently, by 79% of schools) has increased since the last survey conducted in 1986. The mean curricular time (presently 188 hours) has dropped, however, it is not easy to quantify pathology teaching in many schools with increasing integration. Instruction is entirely integrated, multidisciplinary in 28% of schools. Computer-aided instruction is used in some form to varying extents in 66% of schools, with the majority using it as a supplementary tool. There are persistent concerns about faculty time, and high student-faculty ratio.

The value of noncognitive factors in predicting students' first-year academic probation.

PURPOSE: To test the value of Sedlacek's Noncognitive Questionnaire (NQ) in predicting the risk of academic probation for first-year students at the College of Human Medicine at Michigan State University. METHOD: Ninety-six of 106 students completed the NQ during their first week of medical school. The NQ assesses the students in eight noncognitive domains such as academic positive self-concept and realistic self-appraisal. Using a previously derived grade-point average (GPA) and Medical College Admission Test (MCAT)-based risk-prediction equation, students were classified as high- or low-risk for first-year academic probation. At the end of their first year, students actually on probation were identified. RESULTS: High-risk students scored significantly higher than did low-risk students in both academic positive self-concept and realistic self-appraisal. The NQ factors alone predicted risk at a 70% accuracy rate, slightly lower than when the previously derived risk equation was used (74%). CONCLUSION: Sedlacek's noncognitive factors did not improve upon a prediction of academic probation based on GPA and MCAT scores. Sedlacek's NQ may lack the sensitivity required for use with medical students. Further research may identify more appropriate noncognitive factors.