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2.  Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues 
Immunology  2015;147(2):141-151.
Summary
Lymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.
doi:10.1111/imm.12554
PMCID: PMC4717241  PMID: 26551738
arthritis; autoimmunity; cancer; infection; lymphoid neogenesis
3.  Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia 
PLoS ONE  2017;12(1):e0169128.
Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and inhibitors of DNA methyltransferase or histone deacetylase (HDAC) enzymes have exhibited activity in preclinical AML models. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have potential beneficial clinical activity in AML, however the toxicity profiles of non-selective HDAC inhibitors in the combination setting limit their clinical utility. In this work, we describe the preclinical development of selective inhibitors of HDAC1 and HDAC2, which are hypothesized to have improved safety profiles, for combination therapy in AML. We demonstrate that selective inhibition of HDAC1 and HDAC2 is sufficient to achieve efficacy both as a single agent and in combination with azacitidine in preclinical models of AML, including established AML cell lines, primary leukemia cells from AML patient bone marrow samples and in vivo xenograft models of human AML. Gene expression profiling of AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the combination of both have identified a list of genes involved in transcription and cell cycle regulation as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients.
doi:10.1371/journal.pone.0169128
PMCID: PMC5218480  PMID: 28060870
4.  CrxRdy Cat: A Large Animal Model for CRX-Associated Leber Congenital Amaurosis 
Purpose
Mutations in the retinal transcription factor cone-rod homeobox (CRX) gene result in severe dominant retinopathies. A large animal model, the Rdy cat, carrying a spontaneous frameshift mutation in Crx, was reported previously. The present study aimed to further understand pathogenesis in this model by thoroughly characterizing the Rdy retina.
Methods
Structural and functional changes were found in a comparison between the retinas of CrxRdy/+ kittens and those of wild-type littermates and were determined at various ages by fundus examination, electroretinography (ERG), optical coherence tomography, and histologic analyses. RNA and protein expression changes of Crx and key target genes were analyzed using quantitative reverse-transcribed PCR, Western blot analysis, and immunohistochemistry. Transcription activity of the mutant Crx was measured by a dual-luciferase transactivation assay.
Results
CrxRdy/+ kittens had no recordable cone ERGs. Rod responses were delayed in development and markedly reduced at young ages and lost by 20 weeks. Photoreceptor outer segment development was incomplete and was followed by progressive outer retinal thinning starting in the cone-rich area centralis. Expression of cone and rod Crx target genes was significantly down-regulated. The mutant Crx allele was overexpressed, leading to high levels of the mutant protein lacking transactivation activity.
Conclusions
The CrxRdy mutation exerts a dominant negative effect on wild-type Crx by overexpressing mutant protein. These findings, consistent with those of studies in a mouse model, support a conserved pathogenic mechanism for CRX frameshift mutations. The similarities between the feline eye and the human eye with the presence of a central region of high cone density makes the CrxRdy/+ cat a valuable model for preclinical testing of therapies for dominant CRX diseases.
doi:10.1167/iovs.16-19444
PMCID: PMC4960999  PMID: 27427859
animal model; cat; CRX; LCA; retinopathy
5.  Assessment of Rod, Cone, and Intrinsically Photosensitive Retinal Ganglion Cell Contributions to the Canine Chromatic Pupillary Response 
Purpose
The purpose of this study was to evaluate a chromatic pupillometry protocol for specific functional assessment of rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) in dogs.
Methods
Chromatic pupillometry was tested and compared in 37 dogs in different stages of primary loss of rod, cone, and combined rod/cone and optic nerve function, and in 5 wild-type (WT) dogs. Eyes were stimulated with 1-s flashes of dim (1 cd/m2) and bright (400 cd/m2) blue light (for scotopic conditions) or bright red (400 cd/m2) light with 25-cd/m2 blue background (for photopic conditions). Canine retinal melanopsin/Opn4 was cloned, and its expression was evaluated using real-time quantitative reverse transcription-PCR and immunohistochemistry.
Results
Mean ± SD percentage of pupil constriction amplitudes induced by scotopic dim blue (scDB), scotopic bright blue (scBB), and photopic bright red (phBR) lights in WT dogs were 21.3% ± 10.6%, 50.0% ± 17.5%, and 19.4% ± 7.4%, respectively. Melanopsin-mediated responses to scBB persisted for several minutes (7.7 ± 4.6 min) after stimulus offset. In dogs with inherited retinal degeneration, loss of rod function resulted in absent scDB responses, followed by decreased phBR responses with disease progression and loss of cone function. Primary loss of cone function abolished phBR responses but preserved those responses to blue light (scDB and scBB). Although melanopsin/Opn4 expression was diminished with retinal degeneration, melanopsin-expressing ipRGCs were identified for the first time in both WT and degenerated canine retinas.
Conclusions
Pupil responses elicited by light stimuli of different colors and intensities allowed differential functional assessment of canine rods, cones, and ipRGCs. Chromatic pupillometry offers an effective tool for diagnosing retinal and optic nerve diseases.
doi:10.1167/iovs.16-19865
PMCID: PMC5231906  PMID: 28061512
canine; chromatic pupillometry; intrinsically photosensitive retinal ganglion cells; melanopsin; retinal dystrophy
6.  Enzyme replacement therapy prior to haematopoietic stem cell transplantation in Mucopolysaccharidosis Type I: 10 year combined experience of 2 centres 
Molecular genetics and metabolism  2016;117(3):373-377.
Haematopoietic stem cell transplantation is the treatment of choice for the severe form of Mucopolysaccharidosis Type I, or Hurler syndrome. In many centres standard practice is to deliver enzyme replacement therapy alongside haematopoietic stem cell transplantation to improve the condition of the patient prior to transplant. We report the combined 10 year experience of this approach in two paediatric metabolic and transplant centres. Of 81 patients who underwent a first transplant procedure for Hurler, 88% (71/81) survived and 81% (66/81) were alive and engrafted at a median follow-up of 46 months (range 3–124 months). The incidence of grade II–IV acute and any chronic graft versus host disease was 17% and 11% respectively. Urinary glycosaminoglycans were significantly reduced after a period of enzyme replacement therapy, and further reductions were seen at 13–24 months and 25+ months after transplantation. In several individuals with decreased cardiac contractility, an improvement of their condition during enzyme replacement therapy enabled them to undergo transplantation, with one individual receiving full intensity conditioning.
doi:10.1016/j.ymgme.2016.01.011
PMCID: PMC5177791  PMID: 26832957
Mucopolysaccharidosis Type I; Hurler syndrome; Enzyme replacement therapy; Haematopoietic stem cell transplantation; Outcome
7.  Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence 
PLoS Pathogens  2016;12(12):e1006050.
CD4+ T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4+ T cells from systemic and mucosal tissues of hosts infected with the β-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10+CD4+ T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10+CD4+ T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10+ T cell responses were ICOS-dependent. Infected Il27rα-deficient mice with reduced peripheral IL-10+CD4+ T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that β-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity.
Author Summary
Viruses including the pathogenic β-herpesvirus human cytomegalovirus (HCMV) can replicate within and disseminate from mucosal tissues. Understanding how to improve antiviral immune responses to restrict virus replication in the mucosa could help counter virus transmission. Studies in the murine cytomegalovirus (MCMV) model have demonstrated the importance of the CD4+ T cells in control of mucosal MCMV replication. However, this process is inefficient, allowing virus persistence. Herein, we reveal that production by CD4+ T cells of the immune-suppressive soluble protein, or cytokine, interleukin (IL)-10 facilitates virus persistence in mucosal tissue. Mice deficient in T cell-derived IL-10 mounted heightened T cell responses and reduced virus replication in the salivary glands and shedding in the saliva. The cytokine IL-27 induced IL-10-producing CD4+ T cells in the periphery whereas a cell surface-expressed protein, ICOS, promoted mucosal IL-10+ T cell responses. IL-27 acted in the initial stages of infection to impinge on T cell responses and antiviral control. In turn, IL-27 production in response to viral infection was triggered by type-I interferon, a prototypic antiviral cytokine. Thus, our data suggest that herpesviruses may exploit immune-suppressive properties of this early antiviral cytokine response to facilitate persistence within and shedding from mucosal tissue.
doi:10.1371/journal.ppat.1006050
PMCID: PMC5142785  PMID: 27926930
8.  Impact of Information Technology–Based Interventions for Type 2 Diabetes Mellitus on Glycemic Control: A Systematic Review and Meta-Analysis 
Background
Information technology–based interventions are increasingly being used to manage health care. However, there is conflicting evidence regarding whether these interventions improve outcomes in people with type 2 diabetes.
Objective
The objective of this study was to conduct a systematic review and meta-analysis of clinical trials, assessing the impact of information technology on changes in the levels of hemoglobin A1c (HbA1c) and mapping the interventions with chronic care model (CCM) elements.
Methods
Electronic databases PubMed and EMBASE were searched to identify relevant studies that were published up until July 2016, a method that was supplemented by identifying articles from the references of the articles already selected using the electronic search tools. The study search and selection were performed by independent reviewers. Of the 1082 articles retrieved, 32 trials (focusing on a total of 40,454 patients) were included. A random-effects model was applied to estimate the pooled results.
Results
Information technology–based interventions were associated with a statistically significant reduction in HbA1c levels (mean difference −0.33%, 95% CI −0.40 to −0.26, P<.001). Studies focusing on electronic self-management systems demonstrated the largest reduction in HbA1c (0.50%), followed by those with electronic medical records (0.17%), an electronic decision support system (0.15%), and a diabetes registry (0.05%). In addition, the more CCM-incorporated the information technology–based interventions were, the more improvements there were in HbA1c levels.
Conclusions
Information technology strategies combined with the other elements of chronic care models are associated with improved glycemic control in people with diabetes. No clinically relevant impact was observed on low-density lipoprotein levels and blood pressure, but there was evidence that the cost of care was lower.
doi:10.2196/jmir.5778
PMCID: PMC5148808  PMID: 27888169
diabetes mellitus; medical informatics applications; technology
9.  11β‐Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation 
The Journal of Pathology  2016;240(4):472-483.
Abstract
Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is a bidirectional GC‐activating enzyme that is potently upregulated by inflammation within mesenchymal‐derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11β‐HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF‐Tg) driven by overexpression of tumour necrosis factor (TNF)‐α within tissues, including muscle. The inflammatory regulation and functional consequences of 11β‐HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11β‐HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF‐Tg mouse on an 11β‐HSD1 null background. 11β‐HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF‐Tg mice. In human and murine primary myotubes, 11β‐HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF‐α (mRNA, 7.6‐fold, p < 0.005; activity, 4.1‐fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11β‐HSD1 suppressed proinflammatory cytokine output (interkeukin‐6, TNF‐α, and interferon‐γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF‐Tg mice on an 11β‐11β‐HSD1 knockout background developed greater muscle wasting than their TNF‐Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF‐Tg mice with normal 11β‐HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11β‐HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF‐α‐driven model, local endogenous GC activation appears to be an important anti‐inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
doi:10.1002/path.4806
PMCID: PMC5111591  PMID: 27578244
muscle wasting; glucocorticoids; chronic inflammation; 11β‐HSD1; animal models
10.  The Cost-Effectiveness of Antibiotic Prophylaxis for Patients at Risk of Infective Endocarditis 
Circulation  2016;134(20):1568-1578.
Supplemental Digital Content is available in the text.
Background:
In March 2008, the National Institute for Health and Care Excellence recommended stopping antibiotic prophylaxis (AP) for those at risk of infective endocarditis (IE) undergoing dental procedures in the United Kingdom, citing a lack of evidence of efficacy and cost-effectiveness. We have performed a new economic evaluation of AP on the basis of contemporary estimates of efficacy, adverse events, and resource implications.
Methods:
A decision analytic cost-effectiveness model was used. Health service costs and benefits (measured as quality-adjusted life-years) were estimated. Rates of IE before and after the National Institute for Health and Care Excellence guidance were available to estimate prophylactic efficacy. AP adverse event rates were derived from recent UK data, and resource implications were based on English Hospital Episode Statistics.
Results:
AP was less costly and more effective than no AP for all patients at risk of IE. The results are sensitive to AP efficacy, but efficacy would have to be substantially lower for AP not to be cost-effective. AP was even more cost-effective in patients at high risk of IE. Only a marginal reduction in annual IE rates (1.44 cases in high-risk and 33 cases in all at-risk patients) would be required for AP to be considered cost-effective at £20 000 ($26 600) per quality-adjusted life-year. Annual cost savings of £5.5 to £8.2 million ($7.3–$10.9 million) and health gains >2600 quality-adjusted life-years could be achieved from reinstating AP in England.
Conclusions:
AP is cost-effective for preventing IE, particularly in those at high risk. These findings support the cost-effectiveness of guidelines recommending AP use in high-risk individuals.
doi:10.1161/CIRCULATIONAHA.116.022047
PMCID: PMC5106088  PMID: 27840334
antibiotic prophylaxis; cost-benefit analysis; endocarditis; prevention
11.  Man versus Machine: Software Training for Surgeons—An Objective Evaluation of Human and Computer-Based Training Tools for Cataract Surgical Performance 
Journal of Ophthalmology  2016;2016:3548039.
This study aimed to address two queries: firstly, the relationship between two cataract surgical feedback tools for training, one human and one software based, and, secondly, evaluating microscope control during phacoemulsification using the software. Videos of surgeons with varying experience were enrolled and independently scored with the validated PhacoTrack motion capture software and the Objective Structured Assessment of Cataract Surgical Skill (OSACCS) human scoring tool. Microscope centration and path length travelled were also evaluated with the PhacoTrack software. Twenty-two videos correlated PhacoTrack motion capture with OSACCS. The PhacoTrack path length, number of movements, and total procedure time were found to have high levels of Spearman's rank correlation of −0.6792619 (p = 0.001), −0.6652021 (p = 0.002), and −0.771529 (p = 0001), respectively, with OSACCS. Sixty-two videos evaluated microscope camera control. Novice surgeons had their camera off the pupil centre at a far greater mean distance (SD) of 6.9 (3.3) mm, compared with experts of 3.6 (1.6) mm (p ≪ 0.05). The expert surgeons maintained good microscope camera control and limited total pupil path length travelled 2512 (1031) mm compared with novices of 4049 (2709) mm (p ≪ 0.05). Good agreement between human and machine quantified measurements of surgical skill exists. Our results demonstrate that surrogate markers for camera control are predictors of surgical skills.
doi:10.1155/2016/3548039
PMCID: PMC5102740  PMID: 27867658
12.  Dual targeting of protein degradation pathways with the selective HDAC6 inhibitor, ACY-1215, and bortezomib is synergistic in lymphoma 
Purpose
Pan-class histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform selective HDAC inhibitors are emerging as potentially more targeted agents. HDAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for degradation. We investigated the mechanism and therapeutic impact of the selective HDAC6 inhibitor ACY-1215 alone and in combination with bortezomib in preclinical models of lymphoma.
Experimental Design
Concentration : effect relationships were defined for ACY-1215 across 16 lymphoma cell lines and for synergy with bortezomib. Mechanism was interrogated by immunoblot and flow cytometry. An in vivo xenograft model of DLBCL was utilized to confirm in vitro findings. A collection of primary lymphoma samples were surveyed for markers of the UPR.
Results
Concentration : effect relationships defined maximal cytotoxicity at 48 hours with IC50 values ranging from 0.9—4.7 μM. Strong synergy was observed in combination with bortezomib. Treatment with ACY-1215 led to inhibition of the aggresome evidenced by acetylated α-tubulin and accumulated poly-ubiquitinated proteins, and up-regulation of the UPR. All pharmacodynamic effects were enhanced with the addition of bortezomib. Findings were validated in vivo where mice treated with the combination demonstrated significant tumor growth delay and prolonged overall survival. Evaluation of a collection of primary lymphoma samples for markers of the UPR revealed increased HDAC6, GRP78 and XBP-1 expression as compared to reactive lymphoid tissue.
Conclusion
These data are the first results to demonstrate that dual targeting of protein degradation pathways represents an innovative and rational approach for the treatment of lymphoma.
doi:10.1158/1078-0432.CCR-14-3068
PMCID: PMC4609274  PMID: 26116270
13.  Maternal mosaicism for IDUA deletion clarifies recurrence risk in MPS I 
Human Genome Variation  2016;3:16031-.
Mucopolysaccharidosis I (MPS I) is a rare autosomal recessive multisystem lysosomal storage disorder. It is caused by biallelic loss-of-function variants in IDUA, encoding alpha-l iduronidase. Here, we describe an individual affected by MPS I due to a paternally inherited deletion of IDUA exons 1 and 2, c.(?_-88)_(299+1_300-1)del and a whole-gene deletion of IDUA (?_-88?)_(*136?)del secondary to maternal somatic mosaicism. We define a previously unreported mutational mechanism for this disorder.
doi:10.1038/hgv.2016.31
PMCID: PMC5052355  PMID: 27766162
14.  Clearance of Hepatic Sphingomyelin by Olipudase Alfa Is Associated With Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency 
Acid sphingomyelinase deficiency (ASMD; Niemann-Pick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation. Prominent liver involvement results in hepatomegaly, fibrosis/cirrhosis, abnormal liver chemistries, and a proatherogenic lipid profile. Olipudase alfa (recombinant human ASM) is in clinical development as an investigational enzyme replacement therapy for the non-neurological manifestations of ASMD. In a phase 1b study conducted to evaluate the safety and tolerability of within-patient dose escalation with olipudase alfa, measurement of SM levels in liver biopsies was used as a pharmacodynamic biomarker of substrate burden. Five adult patients with non neuronopathic ASMD received escalating doses of olipudase alfa every 2 weeks for 26 weeks. Liver biopsies obtained at baseline and 26 weeks after treatment were evaluated for SM storage by histomorphometric analysis, biochemistry, and electron microscopy. Biopsies were also assessed for inflammation and fibrosis, and for the association of SM levels with liver volume, liver function tests, and lipid profiles. At baseline, SM storage present in Kupffer cells and hepatocytes ranged from 9.8% to 53.8% of the microscopic field. After 26 weeks of treatment, statistically significant reductions in SM (P<0.0001) measured by morphometry were seen in 4 patients with evaluable liver biopsies. The 26-week biopsy of the fifth patient was insufficient for morphometric quantitation. Posttreatment SM levels ranged from 1.2% to 9.5% of the microscopic field, corresponding to an 84% to 92% relative reduction from baseline. Improvements in liver volume, liver function tests, and lipid profiles were also observed. This study illustrates the utility of SM assessment by liver biopsy as a pharmacodynamic biomarker of disease burden in these patients.
doi:10.1097/PAS.0000000000000659
PMCID: PMC4987207  PMID: 27340749
enzyme replacement therapy; Niemann-Pick disease type B; lysosomal storage disease; liver pathology; hyperlipidemia
15.  Editorial: Hallucinations: New Interventions Supporting People with Distressing Voices and/or Visions 
Frontiers in Psychology  2016;7:1418.
doi:10.3389/fpsyg.2016.01418
PMCID: PMC5030884  PMID: 27708604
psychosis; schizophrenia; post-traumatic stress disorder; cognitive behavioral therapy; traumatology
16.  IL‐10 differentially controls the infiltration of inflammatory macrophages and antigen‐presenting cells during inflammation 
European Journal of Immunology  2016;46(9):2222-2232.
The inflammatory activation and recruitment of defined myeloid populations is essential for controlling the bridge between innate and adaptive immunity and shaping the immune response to microbial challenge. However, these cells exhibit significant functional heterogeneity and the inflammatory signals that differentially influence their effector characteristics are poorly characterized. In this study, we defined the phenotype of discrete subsets of effective antigen‐presenting cells (APCs) in the peritoneal cavity during peritonitis. When the functional properties of these cells were compared to inflammatory monocyte‐derived macrophages we noted differential responses to the immune‐modulatory cytokine IL‐10. In contrast to the suppressive actions of IL‐10 on inflammatory macrophages, the recruitment of APCs was relatively refractory and we found no evidence for selective inhibition of APC differentiation. This differential response of myeloid cell subsets to IL‐10 may thus have limited impact on development of potentially tissue‐damaging adaptive immune responses, while restricting the magnitude of the inflammatory response. These findings may have clinical relevance in the context of peritoneal dialysis patients, where recurrent infections are associated with immune‐mediated membrane dysfunction, treatment failure, and increased morbidity.
doi:10.1002/eji.201646528
PMCID: PMC5026061  PMID: 27378515
Antigen presenting; Antigen processing; Dendritic cells; Fate‐mapping; Inflammation; Macrophages; Monocytes
17.  Successful Within-patient Dose Escalation of Olipudase Alfa in Acid Sphingomyelinase Deficiency 
Background
Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy.
Methods
Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks.
Results
All patients successfully reached 3.0 mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4 hours across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed.
Conclusions
This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD.
doi:10.1016/j.ymgme.2015.05.013
PMCID: PMC4561589  PMID: 26049896
olipudase alfa; recombinant human acid sphingomyelinase; dose escalation; nonneuronopathic ASMD; Niemann-Pick disease type B
18.  Physician Associate and General Practitioner Consultations: A Comparative Observational Video Study 
PLoS ONE  2016;11(8):e0160902.
Background
Physician associates, known internationally as physician assistants, are a mid-level practitioner, well established in the United States of America but new to the United Kingdom. A small number work in primary care under the supervision of general practitioners, where they most commonly see patients requesting same day appointments for new problems. As an adjunct to larger study, we investigated the quality of the patient consultation of physician associates in comparison to that of general practitioners.
Method
We conducted a comparative observational study using video recordings of consultations by volunteer physician associates and general practitioners with consenting patients in single surgery sessions. Recordings were assessed by experienced general practitioners, blinded to the type of the consulting practitioner, using the Leicester Assessment Package. Assessors were asked to comment on the safety of the recorded consultations and to attempt to identify the type of practitioner. Ratings were compared across practitioner type, alongside the number of presenting complaints discussed in each consultation and the number of these which were acute, minor, or regarding a chronic condition.
Results
We assessed 62 consultations (41 general practitioner and 21 physician associates) from five general practitioners and four physician associates. All consultations were assessed as safe; but general practitioners were rated higher than PAs in all elements of consultation. The general practitioners were more likely than physician associates to see people with multiple presenting complaints (p<0.0001) and with chronic disease related complaints (p = 0.008). Assessors correctly identified general practitioner consultations but not physician associates. The Leicester Assessment Package had limited inter-rater and intra-rater reliability.
Conclusions
The physician associate consultations were with a less complex patient group. They were judged as competent and safe, although general practitioner consultations, unsurprisingly, were rated as more competent. Physician associates offer a complementary addition to the medical workforce in general practice.
doi:10.1371/journal.pone.0160902
PMCID: PMC4999215  PMID: 27560179
19.  Examining the influence of country-level and health system factors on nursing and physician personnel production 
Background
A key component to achieving good patient outcomes is having the right type and number of healthcare professionals with the right resources. Lack of investment in infrastructure required for producing and retaining adequate numbers of health professionals is one reason, and contextual factors related to socioeconomic development may further explain the trend. Therefore, this study sought to explore the relationships between country-level contextual factors and healthcare human resource production (defined as worker-to-population ratio) across 184 countries.
Methods
This exploratory observational study is grounded in complexity theory as a guiding framework. Variables were selected through a process that attempted to choose macro-level indicators identified by the interdisciplinary literature as known or likely to affect the number of healthcare workers in a country. The combination of these variables attempts to account for the gender- and class-sensitive identities of physicians and nurses. The analysis consisted of 1 year of publicly available data, using the most recently available year for each country where multiple regressions assessed how context may influence health worker production. Missing data were imputed using the ICE technique in STATA and the analyses rerun in R as an additional validity and rigor check.
Results
The models explained 63 % of the nurse/midwife-to-population ratio (pseudo R2 = 0.627, p = 0.0000) and 73 % of the physician-to-population ratio (pseudo R2 = 0.729, p = 0.0000). Average years of school in a country’s population, emigration rates, beds-per-1000 population, and low-income country statuses were consistently statistically significant predictors of production, with percentage of public and private sector financing of healthcare showing mixed effects.
Conclusions
Our study demonstrates that the strength of political, social, and economic institutions does impact human resources for health production and lays a foundation for studying how macro-level contextual factors influence physician and nurse workforce supply. In particular, the results suggest that public and private investments in the education sector would provide the greatest rate of return to countries. The study offers a foundation from which longitudinal analyses can be conducted and identifies additional data that may help enhance the robustness of the models.
Electronic supplementary material
The online version of this article (doi:10.1186/s12960-016-0145-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12960-016-0145-4
PMCID: PMC4983794  PMID: 27523185
Human resources for health; Socioeconomic development; Policy; Global health; Complexity theory; Nurse-to-population ratio; Physician-to-population ratio
20.  Abnormal white matter microstructure and increased extracellular free-water in the cingulum bundle associated with delusions in chronic schizophrenia 
NeuroImage : Clinical  2016;12:405-414.
Background
There is growing evidence to suggest that delusions associated with schizophrenia arise from altered structural brain connectivity. The present study investigated whether structural changes in three major fasciculi that interconnect the limbic system – the cingulum bundle, uncinate fasciculus and fornix – are associated with delusions in chronic schizophrenia patients.
Methods
Free-water corrected Diffusion Tensor Imaging was used to investigate the association between delusions and both microstructural changes within these three fasciculi and extracellular changes in the surrounding free-water. Clinical data and diffusion MRI scans were obtained from 28 healthy controls and 86 schizophrenia patients, of whom 34 had present state delusions, 35 had a lifetime history but currently remitted delusions, and 17 had never experienced delusions.
Results
While present state and remitted delusions were found to be associated with reduced free-water corrected fractional anisotropy (FAT) and increased free-water corrected radial diffusivity (RDT) in the cingulum bundle bilaterally, extracellular free-water (FW) in the left cingulum bundle was found to be specifically associated with present state delusions in chronic schizophrenia. No changes were observed in the remaining tracts.
Conclusions
These findings suggest that state and trait delusions in chronic schizophrenia are associated with microstructural processes, such as myelin abnormalities (as indicated by decreased FAT and increased RDT) in the cingulum bundle and that state delusions are additionally associated with extracellular processes such as neuroinflammation or atrophy (as indicated by increased FW) in the left cingulum bundle.
Highlights
•Free-water imaging was used to differentiate microstructural and extracellular processes.•Patients with delusions showed increased RDT and FW in the cingulum bundle.•Myelin abnormalities and neuroinflammation may be involved in the manifestation of delusions.
doi:10.1016/j.nicl.2016.08.004
PMCID: PMC5008040  PMID: 27622137
Free-water imaging; Schizophrenia; Delusions; Limbic system; Diffusion Tensor Imaging
21.  Incidence and nature of adverse reactions to antibiotics used as endocarditis prophylaxis 
Objectives
Antibiotic prophylaxis (AP) administration prior to invasive dental procedures has been a leading focus of infective endocarditis prevention. However, there have been long-standing concerns about the risk of adverse drug reactions as a result of this practice. The objective of this study was to identify the incidence and nature of adverse reactions to amoxicillin and clindamycin prophylaxis to prevent infective endocarditis.
Methods
We obtained AP prescribing data for England from January 2004 to March 2014 from the NHS Business Services Authority, and adverse drug reaction data from the Medicines and Healthcare Products Regulatory Agency's Yellow Card reporting scheme for prescriptions of the standard AP protocol of a single 3 g oral dose of amoxicillin or a single 600 mg oral dose of clindamycin for those allergic to penicillin.
Results
The reported adverse drug reaction rate for amoxicillin AP was 0 fatal reactions/million prescriptions (in fact 0 fatal reactions for nearly 3 million prescriptions) and 22.62 non-fatal reactions/million prescriptions. For clindamycin, it was 13 fatal and 149 non-fatal reactions/million prescriptions. Most clindamycin adverse drug reactions were Clostridium difficile infections.
Conclusions
AP adverse drug reaction reporting rates in England were low, particularly for amoxicillin, and lower than previous estimates. This suggests that amoxicillin AP is comparatively safe for patients without a history of amoxicillin allergy. The use of clindamycin AP was, however, associated with significant rates of fatal and non-fatal adverse drug reactions associated with C. difficile infections. These were higher than expected and similar to those for other doses, durations and routes of clindamycin administration.
doi:10.1093/jac/dkv115
PMCID: PMC4580535  PMID: 25925595
adverse drug reactions; amoxicillin; clindamycin; dental
22.  Predicting Falls and When to Intervene in Older People: A Multilevel Logistical Regression Model and Cost Analysis 
PLoS ONE  2016;11(7):e0159365.
Introduction
Falls are the leading cause of injury in older people. Reducing falls could reduce financial pressures on health services. We carried out this research to develop a falls risk model, using routine primary care and hospital data to identify those at risk of falls, and apply a cost analysis to enable commissioners of health services to identify those in whom savings can be made through referral to a falls prevention service.
Methods
Multilevel logistical regression was performed on routinely collected general practice and hospital data from 74751 over 65’s, to produce a risk model for falls. Validation measures were carried out. A cost-analysis was performed to identify at which level of risk it would be cost-effective to refer patients to a falls prevention service. 95% confidence intervals were calculated using a Monte Carlo Model (MCM), allowing us to adjust for uncertainty in the estimates of these variables.
Results
A risk model for falls was produced with an area under the curve of the receiver operating characteristics curve of 0.87. The risk cut-off with the highest combination of sensitivity and specificity was at p = 0.07 (sensitivity of 81% and specificity of 78%). The risk cut-off at which savings outweigh costs was p = 0.27 and the risk cut-off with the maximum savings was p = 0.53, which would result in referral of 1.8% and 0.45% of the over 65’s population respectively. Above a risk cut-off of p = 0.27, costs do not exceed savings.
Conclusions
This model is the best performing falls predictive tool developed to date; it has been developed on a large UK city population; can be readily run from routine data; and can be implemented in a way that optimises the use of health service resources. Commissioners of health services should use this model to flag and refer patients at risk to their falls service and save resources.
doi:10.1371/journal.pone.0159365
PMCID: PMC4957756  PMID: 27448280
23.  Long Intergenic Noncoding RNAs Mediate the Human Chondrocyte Inflammatory Response and Are Differentially Expressed in Osteoarthritis Cartilage 
Objective
To identify long noncoding RNAs (lncRNAs), including long intergenic noncoding RNAs (lincRNAs), antisense RNAs, and pseudogenes, associated with the inflammatory response in human primary osteoarthritis (OA) chondrocytes and to explore their expression and function in OA.
Methods
OA cartilage was obtained from patients with hip or knee OA following joint replacement surgery. Non‐OA cartilage was obtained from postmortem donors and patients with fracture of the neck of the femur. Primary OA chondrocytes were isolated by collagenase digestion. LncRNA expression analysis was performed by RNA sequencing (RNAseq) and quantitative reverse transcriptase–polymerase chain reaction. Modulation of lncRNA chondrocyte expression was achieved using LNA longRNA GapmeRs (Exiqon). Cytokine production was measured with Luminex.
Results
RNAseq identified 983 lncRNAs in primary human hip OA chondrocytes, 183 of which had not previously been identified. Following interleukin‐1β (IL‐1β) stimulation, we identified 125 lincRNAs that were differentially expressed. The lincRNA p50‐associated cyclooxygenase 2–extragenic RNA (PACER) and 2 novel chondrocyte inflammation–associated lincRNAs (CILinc01 and CILinc02) were differentially expressed in both knee and hip OA cartilage compared to non‐OA cartilage. In primary OA chondrocytes, these lincRNAs were rapidly and transiently induced in response to multiple proinflammatory cytokines. Knockdown of CILinc01 and CILinc02 expression in human chondrocytes significantly enhanced the IL‐1–stimulated secretion of proinflammatory cytokines.
Conclusion
The inflammatory response in human OA chondrocytes is associated with widespread changes in the profile of lncRNAs, including PACER, CILinc01, and CILinc02. Differential expression of CILinc01 and CIinc02 in hip and knee OA cartilage, and their role in modulating cytokine production during the chondrocyte inflammatory response, suggest that they may play an important role in mediating inflammation‐driven cartilage degeneration in OA.
doi:10.1002/art.39520
PMCID: PMC4950001  PMID: 27023358
24.  Sex-biased gene expression and sequence conservation in Atlantic and Pacific salmon lice (Lepeophtheirus salmonis) 
BMC Genomics  2016;17:483.
Background
Salmon lice, Lepeophtheirus salmonis (Copepoda: Caligidae), are highly important ectoparasites of farmed and wild salmonids, and cause multi-million dollar losses to the salmon aquaculture industry annually. Salmon lice display extensive sexual dimorphism in ontogeny, morphology, physiology, behavior, and more. Therefore, the identification of transcripts with differential expression between males and females (sex-biased transcripts) may help elucidate the relationship between sexual selection and sexually dimorphic characteristics.
Results
Sex-biased transcripts were identified from transcriptome analyses of three L. salmonis populations, including both Atlantic and Pacific subspecies. A total of 35-43 % of all quality-filtered transcripts were sex-biased in L. salmonis, with male-biased transcripts exhibiting higher fold change than female-biased transcripts. For Gene Ontology and functional analyses, a consensus-based approach was used to identify concordantly differentially expressed sex-biased transcripts across the three populations. A total of 127 male-specific transcripts (i.e. those without detectable expression in any female) were identified, and were enriched with reproductive functions (e.g. seminal fluid and male accessory gland proteins). Other sex-biased transcripts involved in morphogenesis, feeding, energy generation, and sensory and immune system development and function were also identified. Interestingly, as observed in model systems, male-biased L. salmonis transcripts were more frequently without annotation compared to female-biased or unbiased transcripts, suggesting higher rates of sequence divergence in male-biased transcripts.
Conclusions
Transcriptome differences between male and female L. salmonis described here provide key insights into the molecular mechanisms controlling sexual dimorphism in L. salmonis. This analysis offers targets for parasite control and provides a foundation for further analyses exploring critical topics such as the interaction between sex and drug resistance, sex-specific factors in host-parasite relationships, and reproductive roles within L. salmonis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-2835-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-016-2835-7
PMCID: PMC4932673  PMID: 27377915
Copepoda; Evolution; Lepeophtheirus salmonis; Reproduction; Sea lice; Sex-bias; Sexual dimorphism; Transcriptomics
25.  Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease 
Neuropsychopharmacology  2016;41(8):2171-2177.
Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest (‘task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems.
doi:10.1038/npp.2016.18
PMCID: PMC4856878  PMID: 26837463

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