A de novo mutation in CACNA1A is associated with autosomal dominant bovine familial convulsions and ataxia in Angus cattle.

Bovine familial convulsions and ataxia (BFCA) is considered an autosomal dominant syndrome with incomplete penetrance. Nine Angus calves from the same herd were diagnosed with BFCA within days of birth. Necropsy revealed cerebellar and spinal cord lesions associated with the condition. Parentage testing confirmed that all affected calves had a common sire. The sire was then bred to 36 cows across two herds using artificial insemination, producing an additional 14 affected calves. The objective of this investigation was to identify hypothesized dominant genetic variation underlying the condition. Whole-genome sequencing was performed on the sire, six affected and seven unaffected paternal half-sibling calves and combined with data from 135 unrelated controls. The sire and five of the six affected calves were heterozygous for a nonsense variant (Chr7 g.12367906C>T, c.5073C>T, p.Arg1681*) in CACNA1A. The other affected calves (N = 8) were heterozygous for the variant but it was absent in the other unaffected calves (N = 7) and parents of the sire. This variant was also absent in sequence data from over 6500 other cattle obtained via public repositories and collaborator projects. The variant in CACNA1A is expressed in the cerebellum of the ataxic calves as detected in the transcriptome and was not differentially expressed compared with controls. The CACNA1A protein is part of a highly expressed cerebellar calcium voltage gated channel. The nonsense variant is proposed to cause haploinsufficiency, preventing proper transmission of neuronal signals through the channel and resulting in BFCA.

Nonsteroidal anti-inflammatory drug-sparing effect of secukinumab in patients with radiographic axial spondyloarthritis: 4-year results from the MEASURE 2, 3 and 4 phase III trials.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain and inflammation, and are considered the cornerstone of pharmacological intervention in patients with radiographic axial spondyloarthritis (r-axSpA); however, the long-term use of NSAIDs is debatable due to their restricted therapeutic potential and the risk of side effects and complications. Therefore, reduction in NSAID intake is desirable in r-axSpA patients. Here, we report the long-term NSAID-sparing effect of secukinumab over 4 years in patients with r-axSpA. This post hoc analysis pooled data from 3 secukinumab trials (MEASURE 2-4) for each secukinumab maintenance dose of 150 and 300 mg, regardless of the loading dose regimen being i.v. or s.c. NSAID intake was evaluated prospectively using the Assessment of SpondyloArthritis International Society (ASAS)-NSAID score. Patients with an ASAS-NSAID score > 0 at baseline were analysed. NSAID-sparing endpoints included the mean change in the ASAS-NSAID score, the proportion of patients achieving 50% reduction, and the proportion of patients with an ASAS-NSAID score < 10. Percentages of patients who achieved BASDAI ≤ 2 were also assessed. Overall, 562 patients were included in this pooled analysis (secukinumab: 150 mg, N = 467; 300 mg, N = 95). The mean ASAS-NSAID score decreased with time in both the secukinumab 150 mg and 300 mg dose groups. The proportion of patients who achieved 50% reduction in the ASAS-NSAID score and clinically meaningful reduction of ASAS-NSAID score < 10 increased with time in both dose groups and in both low and high NSAID intake patients. The percentage of patients with a clinically relevant improvement (BASDAI ≤ 2) was consistently higher in patients with an ASAS-NSAID score < 10 than in patients with an ASAS-NSAID score ≥ 10. Secukinumab provided sustained, long-term NSAID-sparing effects in patients with r-axSpA for up to 4 years of treatment, as measured using the ASAS-NSAID score. Trial registered at clinicaltrials.gov: NCT01649375 ( https://clinicaltrials.gov/ct2/show/NCT01649375 ); NCT02008916 ( https://clinicaltrials.gov/ct2/show/NCT02008916 ); NCT02159053 ( https://clinicaltrials.gov/ct2/show/NCT02159053 ).

Pathologic characterization of canine multiple system degeneration in the Ibizan hound.

Canine multiple system degeneration (CMSD) is a progressive hereditary neurodegenerative disorder commonly characterized by neuronal degeneration and loss in the cerebellum, olivary nuclei, substantia nigra, and caudate nuclei. In this article, we describe 3 cases of CMSD in Ibizan hounds. All patients exhibited marked cerebellar ataxia and had cerebellar atrophy on magnetic resonance imaging. At necropsy, all cases showed varying degrees of cerebellar atrophy, and 2 cases had gross cavitation of the caudate nuclei. Histologic findings included severe degeneration and loss of all layers of the cerebellum and neuronal loss and degeneration within the olivary nuclei, substantia nigra, and caudate nuclei. Pedigree analysis indicated an autosomal recessive mode of inheritance, but the causative gene in this breed is yet to be identified. CMSD resembles human multiple system atrophy and warrants further investigation.

Canine Gliomatosis Cerebri: Morphologic and Immunohistochemical Characterization Is Supportive of Glial Histogenesis.

Gliomatosis cerebri (GC) is a glioma subtype with diffuse neuroparenchymal infiltration without architectural distortion. GC was first used in human neuropathology and remained controversial until its elimination from the diagnostic lexicon in 2016. GC is currently defined as a diffuse growth pattern of glioma rather than a distinct entity. In this article, we characterize 24 cases of canine GC and classify these neoplasms as diffuse gliomas. Selected cases of canine GC were reviewed and immunolabeled for oligodendrocyte lineage transcription factor 2 (Olig2), glial fibrillary acidic protein (GFAP), and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase). The mean age of affected dogs was 7 years, and 9 were brachycephalic. Gross lesions (8 cases) consisted mainly of parenchymal swelling. Histologically, of the 24 cases, there was widespread infiltration of neoplastic cells with astrocytic (12 cases), oligodendroglial (8 cases), or mixed morphology (4 cases) in the brain (18 cases), spinal cord (4 cases), or both (2 cases). Secondary structures occurred across different tumor grades and were not restricted to high-grade neoplasms. Astrocytic neoplasms had moderate nuclear immunolabeling for Olig2 and robust cytoplasmic immunolabeling for GFAP. Oligodendroglial neoplasms had robust nuclear immunolabeling for Olig2, moderate or absent cytoplasmic immunolabeling for GFAP, and moderate cytoplasmic immunolabeling for CNPase. Tumors with mixed morphology had robust nuclear immunolabeling for Olig2 and variable cytoplasmic immunolabeling for GFAP and CNPase. Morphologic and immunohistochemical features confirmed a glial histogenesis for all tumors and allowed for their classification as diffuse, low- or high-grade astrocytoma; oligodendroglioma; or undefined glioma. Further research is needed to confirm or refute the hypothesis that canine GC represents an infiltrative growth pattern of canine glioma.

Effects of secukinumab on bone mineral density and bone turnover biomarkers in patients with ankylosing spondylitis: 2-year data from a phase 3 study, MEASURE 1.

BACKGROUND: Axial spondyloarthritis including ankylosing spondylitis (AS) is characterized by chronic inflammation and new bone formation in the axial skeleton. On the other hand, bone loss, osteoporosis and an increased risk of vertebral fractures is known to frequently occur in AS. In the MEASURE 1 study, the clinically efficacious interleukin-17A inhibitor secukinumab was shown to have limited radiographic progression through 4 years in patients with active AS. Here we present a post hoc analysis to evaluate the effect of secukinumab on bone mineral density (BMD) and bone turnover biomarkers over 2 years in this study. METHODS: BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine, total hip, and femoral neck. Spinal radiographs performed at baseline and Week 104 were assessed by modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and analyzed in relation to BMD change, considering baseline syndesmophytes. Bone turnover biomarkers were assessed at baseline and at Weeks 52 or 104. RESULTS: Among 104 patients included in this analysis, 66% were male, with a mean (SD) age of 40.4 (12.3) years. In postmenopausal women and men ≥50 years of age (T-score), the proportion of patients having normal BMD at baseline and Week 104 were 54.5%/54.5% (lumbar spine), 31.6%/55.6% (total hip), and 42.1%/44.4% (femoral neck). Similarly, at baseline, the proportion of patients with osteopenia/osteoporosis was 31.8%/13.6% (lumbar spine), 57.9%/10.5% (total hip), 42.1%/15.8% (femoral neck), and 36.4%/9.1% (lumbar spine), 44.4%/0% (total hip) and 55.6%/0% (femoral neck) at Week 104, respectively. In premenopausal women and men < 50 years of age (Z-score), the proportion of patients having BMD below the expected range for age at baseline and Week 104 were 25.0%/21.2% (lumbar spine), 11.3%/17.8% (total hip), and 9.9%/8.9% (femoral neck). In relation to mSASSS change scores ≥2 over 2 years, the increase in lumbar spine BMD was not related to radiographic progression and syndesmophyte formation. No significant changes were observed in the bone turnover markers over time. CONCLUSION: The high proportion of AS patients with diminished BMD was confirmed in this study. An increase of BMD in the lumbar spine after 2 years of secukinumab treatment in patients with AS was found that was probably unrelated to radiographic progression. No relevant effects of secukinumab on bone turnover biomarkers were documented. TRIAL REGISTRATION: MEASURE 1 (post hoc analysis) Clinicaltrials.gov, NCT01358175 ; Registered, 23 May 2011.

Uveal Malignant Melanoma in a Hybrid Macaw Parrot (Ara chloropterus × Ara militaris).

An adult male green-winged (Ara chloropterus) × military (Ara militaris) hybrid macaw of unknown age was presented to the Texas A&M Veterinary Medical Teaching Hospital for evaluation of left periocular swelling, blepharospasm, and ocular discharge. Complete ophthalmic examination and B mode ocular ultrasonography were performed to evaluate the affected eye. Ocular examination revealed a blind left globe with exophthalmos, periocular swelling, diffuse corneal edema, and severe anterior fibrinous uveitis obscuring visualization of the intraocular structures. An ultrasound examination revealed a hyperechoic mass that filled the posterior segment of the globe. Focal discontinuity of the posterior sclera suggested scleral rupture. Enucleation with histopathology was recommended and performed 1.5 months later. Intraoperatively, a heavily pigmented and friable soft tissue mass extruded through the posterior sclera and extended into the orbit. Histologically, the mass was consistent with a malignant melanoma. The patient died 18 hours after the surgical procedure because of unknown complications. Postmortem examination did not identify evidence of metastasis. This study described the clinical appearance and histopathologic findings of a rare ocular neoplasm with extrascleral extension in a hybrid macaw. Although uncommon in psittacine birds, primary ocular melanocytic neoplasms may display features of malignancy with scleral or orbital invasion, or both.

Patients' Experiences with Telecare for Chronic Pain and Mood Symptoms: A Qualitative Study.

OBJECTIVE: Pain, anxiety, and depression commonly co-occur, can have reciprocal effects, and are associated with substantial disability and health care costs. However, few interventions target treatment of pain and mood disorders as a whole. The Comprehensive vs. Assisted Management of Mood and Pain Symptoms (CAMMPS) trial was a randomized trial comparing two pragmatic telecare interventions, a high- vs low-resource approach to pain and anxiety/depression treatment. The purpose of the current study is to better understand patients' perspectives on both intervention approaches, including intervention components, delivery, patient experiences, and patient outcomes. DESIGN: Qualitative, semistructured interviews. SETTING: A Veterans Affairs Medical Center. SUBJECTS: Twenty-five patients were purposefully sampled from both study arms. METHODS: Patients were interviewed about their experiences with pain and mood treatment, perceived benefits and changes, and experiences with the intervention model to which they were randomized. The constant comparison method guided analysis. RESULTS: Pain was more important than mood for most participants. Participants described developing increased awareness of their symptoms, including connecting pain and mood, which enabled better management. Participants in the high-resource intervention described the added value of the study nurse in their symptom management. CONCLUSIONS: Patients in a telecare intervention for chronic pain and mood symptoms learned to connect pain and mood and be more aware of their symptoms, enabling more effective symptom management. Patients in the high-resource intervention described the added benefits of a nurse who provided informational and motivational support. Implications for tradeoffs between resource intensity and patient outcomes are discussed.

The Pathology of Cetacean Morbillivirus Infection and Comorbidities in Guiana Dolphins During an Unusual Mortality Event (Brazil, 2017-2018).

Cetacean morbillivirus (CeMV; Paramyxoviridae) is the most significant pathogen of cetaceans worldwide. The novel "multi-host" Guiana dolphin (Sotalia guianensis; GD)-CeMV strain is reported in South American waters and infects Guiana dolphins and southern right whales (Eubalaena australis). This study aimed to describe the pathologic findings, GD-CeMV viral antigen distribution and detection by RT-PCR (reverse transcriptase polymerase chain reaction), and infectious comorbidities in 29 Guiana dolphins that succumbed during an unusual mass-mortality event in Rio de Janeiro state, Brazil, between November 2017 and March 2018. The main gross findings were lack of ingesta, pulmonary edema, ascites, icterus, hepatic lipidosis, multicentric lymphadenomegaly, as well as pneumonia, polyserositis, and multiorgan vasculitis caused by Halocercus brasiliensis. Microscopically, the primary lesions were bronchointerstitial pneumonia and multicentric lymphoid depletion. The severity and extent of the lesions paralleled the distribution and intensity of morbilliviral antigen. For the first time in cetaceans, morbilliviral antigen was detected in salivary gland, optic nerve, heart, diaphragm, parietal and visceral epithelium of glomeruli, vulva, and thyroid gland. Viral antigen within circulating leukocytes suggested this as a mechanism of dissemination within the host. Comorbidities included disseminated toxoplasmosis, mycosis, ciliated protozoosis, and bacterial disease including brucellosis. These results provide strong evidence for GD-CeMV as the main cause of this unusual mass-mortality event.

Efficacy and safety of secukinumab in Japanese patients with active ankylosing spondylitis: 24-week results from an open-label phase 3 study (MEASURE 2-J).

Objective: Secukinumab, a fully human monoclonal antibody that neutralizes interleukin-17A, improved the signs and symptoms of ankylosing spondylitis (AS) in three Phase 3 global studies (MEASURE 1, 2, and 3). Here, we describe the efficacy and safety results through Week 24 of a study of secukinumab in Japanese patients with active AS.Methods: In this multicenter, open-label, single arm, 52-week study, 30 AS patients self-administered secukinumab 150 mg subcutaneously at baseline, Weeks 1, 2, 3, and 4, and every 4 weeks thereafter. The primary efficacy endpoint was ASAS 20 response at Week 16. Overall safety and tolerability were assessed beyond Week 24 up to the data reporting cut-off date.Results: The ASAS 20 response rate was 70% (21/30) at Week 16, which was sustained to Week 24. Secukinumab was effective in various clinical outcomes including patient's global assessment of disease activity, spinal pain, nocturnal pain, physical function, spinal mobility, and CRP level. Comparable ASAS 20 and 40 responses were observed regardless of previous anti-TNF therapy. Secukinumab was well-tolerated with a safety profile consistent with previous reports.Conclusion: Secukinumab 150 mg provided sustained improvement in the signs and symptoms of Japanese AS patients through 24 weeks, with no new or unexpected safety signals.

Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials.

OBJECTIVES: Here, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials. METHODS: Data from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)). RESULTS: A total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients with PsA, there were 3 cases of UC, 3 cases of CD and 2 cases of IBDU (EAIRs 0.08, 0.08 and 0.05); 7 of these represented new-onset cases. Among 794 patients with AS, there were 4 cases of UC, 8 cases of CD and 1 case of IBDU (EAIRs 0.2, 0.4 and 0.1); 9 were new-onset cases. In the per year analysis, the EAIRs for each indication did not increase over time with secukinumab treatment. CONCLUSIONS: In this pooled secukinumab safety analysis of 7355 patients across 21 clinical trials, cases of IBD events (including CD, UC and IBDU) were uncommon.

Modified stoke ankylosing spondylitis spinal score as an outcome measure to assess the impact of treatment on structural progression in ankylosing spondylitis.

In ankylosing spondylitis (AS), structural damage that occurs as a result of syndesmophyte formation and ankylosis of the vertebral column is irreversible. Structural damage is currently assessed by conventional radiography and scoring systems that reliably assess radiographic structural damage are needed to capture the differential effects of drugs on structural damage progression. The validity of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) as a primary outcome measure in evaluating the effect of AS treatments on radiographic progression rates was assessed in this review. The mSASSS has not been used, to date, as a primary outcome measure in a prospective randomized controlled clinical trial of biologic therapy in AS. This review of the medical literature confirmed that the mSASSS is the most validated and widely used method for assessing radiographic progression in AS, correlating with worsening measures of disease signs and symptoms, spinal mobility and physical function, with a 2-year interval being required to ensure sufficient sensitivity to change.

Secukinumab shows sustained efficacy and low structural progression in ankylosing spondylitis: 4-year results from the MEASURE 1 study.

OBJECTIVE: To evaluate the effect of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, on efficacy, imaging outcomes, and safety through 4 years (208 weeks) in patients with ankylosing spondylitis. METHODS: Patients opting to enrol had completed 2 years' treatment in the MEASURE 1 core study with subcutaneous secukinumab 150 or 75 mg every 4 weeks (q4Wk), following intravenous loading to Week (Wk) 4, or placebo treatment to Wk16/24. Up-titration from secukinumab 75-150 mg q4Wk was permitted following a protocol amendment. Efficacy is reported for patients originally randomized to secukinumab. Radiographic changes were assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and changes in MRI measures of inflammation using the Berlin scoring method. Safety and tolerability were evaluated. RESULTS: Among 274 extension study participants, 89.7% (78/87) and 93.0% (93/100) originally randomized to secukinumab 150 and 75 mg, respectively, completed 208Wk. Through Wk208, Assessment of Spondyloarthritis International Society 20/40 (observed) were 79.7%/60.8% (150 mg), 71.0%/43.5% (75 mg) and 80.0%/76% (up-titrators; n = 25). Mean (s.d.) changes in mSASSS were 1.2 (3.91) (150 mg), 1.8 (4.32) (75 mg) and 1.6 (5.67) (up-titrators). No radiographic progression (mSASSS change from Baseline < 2) was observed in 79% of patients receiving either secukinumab dose. Exposure-adjusted incidence rates per 100 patient-years were: serious infections (1.0), Candida infections (0.4), Crohn's disease (0.6), ulcerative colitis (0.2), and malignant/unspecified tumours (0.5), with no new safety signals. CONCLUSION: Through 4 years, secukinumab provided sustained efficacy on signs and symptoms, and MRI outcomes, a low rate of radiographic progression and a consistent safety profile. TRIAL REGISTRATION: NCT01863732.

Automated Self-management (ASM) vs. ASM-Enhanced Collaborative Care for Chronic Pain and Mood Symptoms: the CAMMPS Randomized Clinical Trial.

BACKGROUND: Chronic musculoskeletal pain is often accompanied by depression or anxiety wherein co-occurring pain and mood symptoms can be more difficult to treat than either alone. However, few clinical trials have examined interventions that simultaneously target both pain and mood conditions. OBJECTIVE: To determine the comparative effectiveness of automated self-management (ASM) vs. ASM-enhanced collaborative care. DESIGN: Randomized clinical trial conducted in six primary care clinics in a VA medical center. PARTICIPANTS: Two hundred ninety-four patients with chronic musculoskeletal pain of at least moderate intensity and clinically significant depressive and/or anxiety symptoms. INTERVENTION: ASM consisted of automated monitoring and 9 web-based self-management modules. Comprehensive symptom management (CSM) combined ASM with collaborative care management by a nurse-physician team. Both interventions were delivered for 12 months. MAIN MEASURES: Primary outcome was a composite pain-anxiety-depression (PAD) z-score consisting of the mean of the BPI, PHQ-9, and GAD-7 z-scores: 0.2, 0.5, and 0.8 represent potentially small, moderate, and large clinical differences. Secondary outcomes included global improvement, health-related quality of life, treatment satisfaction, and health services use. KEY RESULTS: Both CSM and ASM groups had moderate PAD score improvement at 12 months (z = - 0.65 and - 0.52, respectively). Compared to the ASM group, the CSM group had a - 0.23 (95% CI, - 0.38 to - 0.08; overall P = .003) greater decline in composite PAD z-score over 12 months. CSM patients were also more likely to report global improvement and less likely to report worsening at 6 (P = .004) and 12 months (P = .013). CONCLUSIONS: Two intervention models relying heavily on telecare delivery but differing in resource intensity both produced moderate improvements in pain and mood symptoms. However, the model combining collaborative care led by a nurse-physician team with web-based self-management was superior to self-management alone. TRIAL REGISTRATION: ClinicalTrials.gov : NCT0175730.

Secukinumab provides rapid and persistent relief in pain and fatigue symptoms in patients with ankylosing spondylitis irrespective of baseline C-reactive protein levels or prior tumour necrosis factor inhibitor therapy: 2-year data from the MEASURE 2 study.

OBJECTIVES: To evaluate improvement in pain and fatigue in ankylosing spondylitis (AS) patients treated with secukinumab over 2 years (MEASURE 2 study). METHODS: Patients with active AS were randomised to receive secukinumab 150 mg, 75 mg, or placebo weekly until Week 4, and every 4 weeks thereafter. This post hoc analysis included assessment of spinal and nocturnal back pain, FACIT-Fatigue, and association between pain and either FACIT-Fatigue or ASQoL item 5 (sleep quality) for the approved secukinumab 150 mg dose in the overall population, and stratified by baseline high-sensitivity C-reactive protein (hsCRP) levels (normal [<5 mg/L] or elevated [≥5 mg/L]) or prior TNF inhibitor therapy status (TNFi-naïve or inadequate response [TNFi-IR]). RESULTS: Secukinumab-treated patients reported rapid improvement in pain and fatigue scores in overall population by Weeks 1 and 4, respectively; this trend of improvement was also observed irrespective of baseline hsCRP levels or prior TNFi therapy. Mean change at Week 16 in spinal/nocturnal pain (secukinumab vs. placebo) for the subgroups were -34.6/-30.2 vs. -16.6/-10.0, p<0.05/0.01 (normal hsCRP); -26.7/-31.6 vs. -7.8/-9.3, p<0.001/0.0001 (elevated hsCRP); -33.2/-35.4 vs. -13.2/-14.9, both p<0.0001 (TNFi-naïve); and -22.5/-22.8 vs. -9.4/-4.0, p=0.06/p<0.01 (TNFi-IR). FACIT-Fatigue was 7.1 vs. 3.3, p=0.15 (normal hsCRP); 8.7 vs. 3.6, p<0.05 (elevated hsCRP); 10.0 vs. 5.2, p<0.05 (TNFi-naïve); and 5.7 vs. 0.5, p=0.06 (TNFi-IR). These improvements were sustained or further improved through Week 104. CONCLUSIONS: Secukinumab provides rapid and sustained relief of pain and fatigue over 2 years in patients with AS regardless of baseline hsCRP levels and prior TNFi therapy.

Canine Ependymoma: Diagnostic Criteria and Common Pitfalls.

Reports of canine ependymoma are generally restricted to single case reports with tumor incidence estimated at 2% to 3% of primary central nervous system (CNS) tumors. While most commonly reported in the lateral ventricle, tumors can occur anywhere in the ventricular system and in extraventricular locations. Rosettes and pseudorosettes are a common histologic feature; however, these features can be mimicked by other CNS neoplasms. Thirty-seven potential ependymoma cases were identified in a retrospective database search of 8 institutions, and a histologic review of all cases was conducted. Of 37 cases, 22 candidate cases were further subjected to a consensus histologic and immunohistochemical review, and only 5 of 37 (13.5%) were conclusively identified as ependymoma. The neuroanatomic locations were the lateral ventricle (3/5), third ventricle (1/5), and mesencephalic aqueduct (1/5). Subtypes were papillary (4/5) and tanycytic (1/5). Histologic features included rosettes (5/5), pseudorosettes (5/5), ependymal canals (2/5), tanycytic differentiation (1/5), blepharoplasts (1/5), ciliated cells (1/5), and high nuclear to cytoplasmic ratio (5/5). Immunolabeling for GFAP (4/4) and CKAE1/3 (3/4) was found in pseudorosettes, rosettes, and scattered individual neoplastic cells. Diffuse but variably intense cytoplasmic S100 immunolabeling was detected in 3 of 4 cases. Olig2 intranuclear immunolabeling was observed in less than 1% of the neoplastic cells (3/3). Tumors that had pseudorosettes and mimicked ependymoma included oligodendroglioma, choroid plexus tumor, pituitary corticotroph adenoma, papillary meningioma, and suprasellar germ cell tumor. These findings indicate that canine ependymoma is an extremely rare neoplasm with histomorphologic features that overlap with other primary CNS neoplasms.

Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis.

BACKGROUND: Secukinumab is an anti-interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial. We conducted two phase 3 trials of secukinumab in patients with active ankylosing spondylitis. METHODS: In two double-blind trials, we randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16. RESULTS: In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P=0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients. CONCLUSIONS: Secukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16. Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT01358175 and NCT01649375.).

Administration of interleukin-7 increases CD4 T cells in idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphopenia (ICL) is a rare syndrome defined by low CD4 T-cell counts (<300/µL) without evidence of HIV infection or other known cause of immunodeficiency. ICL confers an increased risk of opportunistic infections and has no established treatment. Interleukin-7 (IL-7) is fundamental for thymopoiesis, T-cell homeostasis, and survival of mature T cells, which provides a rationale for its potential use as an immunotherapeutic agent for ICL. We performed an open-label phase 1/2A dose-escalation trial of 3 subcutaneous doses of recombinant human IL-7 (rhIL-7) per week in patients with ICL who were at risk of disease progression. The primary objectives of the study were to assess safety and the immunomodulatory effects of rhIL-7 in ICL patients. Injection site reactions were the most frequently reported adverse events. One patient experienced a hypersensitivity reaction and developed non-neutralizing anti-IL-7 antibodies. Patients with autoimmune diseases that required systemic therapy at screening were excluded from the study; however, 1 participant developed systemic lupus erythematosus while on study and was excluded from further rhIL-7 dosing. Quantitatively, rhIL-7 led to an increase in the number of circulating CD4 and CD8 T cells and tissue-resident CD3 T cells in the gut mucosa and bone marrow. Functionally, these T cells were capable of producing cytokines after mitogenic stimulation. rhIL-7 was well tolerated at biologically active doses and may represent a promising therapeutic intervention in ICL. This trial was registered at www.clinicaltrials.gov as #NCT00839436.

Long-term effects of interleukin-17A inhibition with secukinumab in active ankylosing spondylitis: 3-year efficacy and safety results from an extension of the Phase 3 MEASURE 1 trial.

OBJECTIVES: Secukinumab, a fully human anti-IL-17A monoclonal antibody, provided rapid and sustained improvements in signs and symptoms of ankylosing spondylitis (AS) over 2 years in the Phase 3 MEASURE 1 trial. Here, we report efficacy and safety after 3 years of treatment. METHODS: AS subjects completing 2 years of treatment every 4 weeks with subcutaneous secukinumab 150 or 75 mg (following intravenous loading or initial placebo treatment to 16/24 weeks) entered a separate 3-year extension study (NCT01863732). Assessments included ASAS20/40, ASAS5/6, BASDAI, BASDAI 50, BASFI, BASMI, SF-36 physical component summary, ASAS partial remission and ASDAS-CRP. Results were also analysed by prior anti-TNF treatment status. RESULTS: Among 290 subjects completing the core trial, 274 entered the extension study, with 260 subjects (94.9%) completing 156 weeks of treatment. ASAS20/40 response (observed) was 80.2%/61.6% in the IV→150 mg group and 75.5%/50.0% in the IV→75 mg group after 156 weeks. Sustained improvements were also seen in BASDAI, BASFI, BASMI and across all other endpoints regardless of previous exposure to anti-TNF agents. Mean secukinumab exposure was 964.3 days (137.8 weeks). Discontinuation rates were low, and secukinumab had a favourable safety profile, consistent with previous reports. Exposure-adjusted incidence rates for serious infections, Candida infections, Crohn's disease, ulcerative colitis, malignant/unspecified tumours, and adjudicated major adverse cardiac events were 1.1, 0.4, 0.5, 0.1, 0.5 and 0.7 per 100 subject-years, respectively. CONCLUSIONS: Secukinumab provided sustained efficacy in signs, symptoms and physical function in subjects with AS over 3 years. No new safety signals were observed.

Usability evaluation of a medication reconciliation tool: Embedding safety probes to assess users' detection of medication discrepancies.

OBJECTIVE: An electronic medication reconciliation tool was previously developed by another research team to aid provider-patient communication for medication reconciliation. To evaluate the usability of this tool, we integrated artificial safety probes into standard usability methods. The objective of this article is to describe this method of using safety probes, which enabled us to evaluate how well the tool supports users' detection of medication discrepancies. MATERIALS AND METHODS: We completed a mixed-method usability evaluation in a simulated setting with 30 participants: 20 healthcare professionals (HCPs) and 10 patients. We used factual scenarios but embedded three artificial safety probes: (1) a missing medication (i.e., omission); (2) an extraneous medication (i.e., commission); and (3) an inaccurate dose (i.e., dose discrepancy). We measured users' detection of each probe to estimate the probability that a HCP or patient would detect these discrepancies. Additionally, we recorded participants' detection of naturally occurring discrepancies. RESULTS: Each safety probe was detected by ≤50% of HCPs. Patients' detection rates were generally higher. Estimates indicate that a HCP and patient, together, would detect 44.8% of these medication discrepancies. Additionally, HCPs and patients detected 25 and 45 naturally-occurring discrepancies, respectively. DISCUSSION: Overall, detection of medication discrepancies was low. Findings indicate that more advanced interface designs are warranted. Future research is needed on how technologies can be designed to better aid HCPs' and patients' detection of medication discrepancies. CONCLUSION: This is one of the first studies to evaluate the usability of a collaborative medication reconciliation tool and assess HCPs' and patients' detection of medication discrepancies. Results demonstrate that embedded safety probes can enhance standard usability methods by measuring additional, clinically-focused usability outcomes. The novel safety probes we used may serve as an initial, standard set for future medication reconciliation research. More prevalent use of safety probes could strengthen usability research for a variety of health information technologies.

Identification of a Candidate Mutation in the COL1A2 Gene of a Chow Chow With Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic disease that occurs in humans and animals. Individuals with OI exhibit signs of extreme bone fragility and osteopenia with frequent fractures and perinatal lethality in severe cases. In this study, we report the clinical diagnosis of OI in a dog and the use of targeted next-generation sequencing to identify a candidate autosomal dominant mutation in the COL1A2 gene. A 5-month-old male Chow Chow was examined with a fractured left humerus and resolving, bilateral femoral fractures. Radiographs revealed generalized osteopenia and bilateral humeral, radial, and femoral fractures. Targeted next-generation sequencing of genes associated with OI in humans (COL1A1, COL1A2, LEPRE1, SERPINH1, and CRTAP) revealed a G>A heterozygous mutation in the splice donor site of exon 18 of the COL1A2 gene (c.936 + 1G>A). The splice donor mutation was not detected among 91 control dogs representing 21 breeds. A comparative analysis of exon 18 and the exon-intron junction further showed that the mutated splice donor site is conserved among vertebrates. Altogether, these findings reveal a candidate autosomal splice donor site mutation causing OI in an individual Chow Chow.