Transcriptomic insights into multiple system atrophy from a PLP-α-synuclein transgenic mouse model.

Multiple system atrophy (MSA) is a rare, neurodegenerative disorder with rapid motor and non-motor symptom progression. MSA is characterized by protein aggregations of α-synuclein found in the cytoplasm of oligodendrocytes. Despite this pathological hallmark, there is still little known about the cause of this disease, resulting in poor treatment options and quality of life post-diagnosis. In this study, we investigated differentially expressed genes (DEGs) via RNA-sequencing of brain samples from a validated PLP-α-synuclein transgenic mouse model, identifying a total of 40 DEGs in the PLP group compared to wild-type (WT), with top detected genes being Gm15446, Mcm6, Aldh7a1 and Gm3435. We observed a significant enrichment of immune pathways and endothelial cell genes among the upregulated genes, whereas downregulated genes were significantly enriched for oligodendrocyte and neuronal genes. We then calculated possible overlap of these DEGs with previously profiled human MSA RNA, resulting in the identification of significant downregulation of the Tsr2 gene. Identifying key gene expression profiles specific to MSA patients is crucial to further understanding the cause, and possible prevention, of this rapidly progressive neurodegenerative disorder.

Efficacy and Safety outcomes of a novel model to assess new medical retina referrals in a high-volume medical retina virtual clinic.

BACKGROUND: Ophthalmology outpatient attendances have significantly increased recently with rising pressure from backlogs arising from the pandemic. Medical retina digital surveillance clinics for stable follow-up appointments are well established. We present a model for assessing new referrals and evaluating clinical outcomes and long-term sustainability in a complex high-volume medical retina service. METHODS: Suitable routine new patient referrals were identified from electronic referrals and referred to this new pathway. Structured history, visual acuities, and intraocular pressures were recorded, and widefield colour fundus and optical coherence tomography imaging were performed at a imaging hub for asynchronous consultant-led review. RESULTS: 1458 patients were invited to attend over four months, with a 13.2% did-not-attend (DNA) rate. Common diagnoses included stable diabetic retinopathy (19.9%), early age-related macular degeneration (6.7%), central serous retinopathy (8.8%), and retinal vein occlusion (6.3%). 7 patients (0.05%) required urgent same-day review. 61 (5.0%) required urgent face-to-face (F2F) assessment within two weeks. A total of 727 (59.0%) were either discharged or remained in the virtual pathway following their first visit. CONCLUSION: This study encourages the use of a digital model that efficiently assesses suitable newly referred medical retina patients in both complex and local eye unit settings. This decreased the need for F2F clinics and resources. Further patient satisfaction surveys for digital services are currently being evaluated to guide long-term sustainability of this model.

Links between the organization of the family home environment and child obesity: a systematic review.

Due to increasingly high rates of child overweight and obesity, it is important to identify risk and protective factors that may inform more effective prevention and intervention. The degree of organization in the family home environment is a studied, but not well-specified, factor that may impact child weight. Prior research on household organization has examined an array of constructs, including family routines, limit setting, household chaos, crowding and the broad home environment. This study systematically reviews literature on organization within the family home environment and weight among children ages 2-12. Six hundred thirty-seven studies were reviewed by four coders for eligibility, and 32 studies were included in the final synthesis. Overall, 84% of studies provided evidence for relations between at least one indicator of organization within the family home environment and child weight. Studies provided compelling evidence across several constructs, suggesting that the relevance of household organization to child weight extends beyond a single indicator. Directions for future work include (i) examining the mediating role of health behaviours, (ii) examining the moderating role of socioeconomic factors, (iii) broadening this evidence base across cultures and nationalities and (iv) integrating constructs to develop a comprehensive model of organization within the home environment.

Identification of time point to best define 'sub-optimal response' following intravitreal ranibizumab therapy for diabetic macular edema based on real-life data.

PurposeTo determine the average time-point at which it is best to define 'sub-optimal response' after ranibizumab treatment for diabetic macular edema (DME) based on the data obtained from real-life clinical practice.MethodsIn this retrospective observational study, 322 consecutive treatment naïve eyes with DME were treated with three loading doses of intravitreal ranibizumab followed by re-treatment based on decision of the treating physician on a case-by-case basis. The demographic data, clinic-based visual acuity measurements and central subfield thickness (CST) assessed on spectral domain optical coherence tomography (OCT) were evaluated at baseline (month 0), 1, 2, 3, 6, and 12 months.ResultsOn an average, the improvement in visual acuity and CST was first seen after the loading dose. However, the maximal response in terms of proportion of patients with improvement in visual acuity and/ or CST in this cohort was observed at 12 months. Patients who presented with low visual acuity at baseline (<37 ETDRS letters) were unlikely to attain driving vision with ranibizumab therapy.ConclusionsOn an average, a 'sub-optimal response' after ranibizumab therapy is best defined at month 12 as patients may continue to improve with treatment.

Influence of baseline diabetic retinopathy status on initial anatomical response of intravitreal ranibizumab therapy for diabetic macular oedema.

PurposeIntraocular vascular endothelial growth factor (VEGF) levels increases with the severity of diabetic retinopathy. Response of diabetic macular oedema (DMO) to ranibizumab is driven by VEGF suppression. We hypothesised that the initial reduction of central macular thickness by ranibizumab should be maximum in severe diabetic retinopathy until the levels of VEGF decreases to the levels observed in eyes with mild retinopathy.MethodsConsecutive patients with centre-involving DMO (central subfield thickness (CSFT)>300 µm) who had three consecutive monthly ranibizumab injections followed by as needed therapy were included. Retinopathy status was graded as mild non-proliferative diabetic retinopathy (NPDR) (G1), moderate to severe NPDR with no prior panretinal photocoagulation (G2), and treated PDR (G3).ResultsTwo hundred and thirty-nine eyes from 204 patients with a mean age of 64.9 years were included. The distribution was 31.4 G1, 32.2 G2, and 36.4% G3. Mean baseline CSFT for all eyes was 458.5±110.8 µm. Baseline CSFT for G1, G2, and G3, respectively, were 437.6±90.9, 472.3±109.8, and 464.7±124.9 µm (P=0.2155). Mean change in CSFT after three consecutive injections was 128.5±116.6 µm. The mean changes were 95.8±101.4 µm for G1, 137.2±112.9 µm for G2, and 148.9±126.9 µm for G3. The changes in CSFT between groups adjusted for baseline CSFT were statistically significant (P=0.0473). At 6 and 12 months after a mean of 4.5 and 7.7 injections, the changes between groups were no longer significant, P=0.4783 and P=0.8271, respectively.ConclusionsThe initial anatomical response of DMO with intravitreal ranibizumab injections was maximum in eyes with treated PDR, suggesting that the higher the VEGF levels, the better the response with ranibizumab.

Differences in mortality characteristics in neonates with Down's syndrome.

OBJECTIVE: Neonates with Down's syndrome (nDS) may have multiple medical issues that place them at increased risk for mortality during the newborn period. Goal of this study was to determine if there are differences in baseline characteristics, medical complications or procedures performed during hospitalization between nDS who survived versus those who died during initial hospitalization. STUDY DESIGN: Data from 2000 to 2014 were reviewed using the Pediatric Health Information Systems (PHIS) database on all DS patients admitted to the hospital <30 days postnatal life. Baseline demographics, medical complications, procedures performed and mortality were recorded. Patients were divided into nDS patients who were discharged alive (nDS-a) versus nDS patients who died (nDS-d). Multivariate logistic analysis with odds ratios was performed to determine significant predictors of death. A P<0.05 was considered significant. RESULTS: A total of 5737 nDS were evaluated. Overall mortality was 7.5% (431/5737). nDS-d were more likely than nDS-a to have a lower birth weight (1.0 (0.9 to 1.0)), presence of a diaphragmatic hernia (6.9 (1.9 to 25.1), or a cardiac diagnosis of a pulmonary venous abnormality (6.8 (1.9 to 24.4)), Ebstein's anomaly (3.2 (1.2 to 8.5)) or left-sided obstructive lesion (2.0 (1.3 to 3.0). nDS-d were more likely to develop hydrops (5.7 (3.5 to 9.5)) and necrotizing enterocolitis (1.7 (1.2 to 2.6)). In addition, nDS-d had significantly higher odds of requiring mechanical ventilation (20.7 (9.9 to 43.1)) or extracorporeal membrane oxygenation (8.7 (4.7 to 16.1)). CONCLUSIONS: A number of characteristics, specifically certain cardiac diagnosis, place nDS at increased risk for mortality. Furthermore, development of specific medical complications or need for particular procedures increases the odds for mortality in nDS. Caregivers should be cognizant that they are taking care of a high-risk population nDS with an increased risk for mortality if these variables are present.

Generalized Hyperalgesia in Children and Adults Diagnosed With Hypermobility Syndrome and Ehlers-Danlos Syndrome Hypermobility Type: A Discriminative Analysis.

OBJECTIVE: Lowered pressure-pain thresholds have been demonstrated in adults with Ehlers-Danlos syndrome hypermobility type (EDS-HT), but whether these findings are also present in children is unclear. Therefore, the objectives of the study were to determine whether generalized hyperalgesia is present in children with hypermobility syndrome (HMS)/EDS-HT, explore potential differences in pressure-pain thresholds between children and adults with HMS/EDS-HT, and determine the discriminative value of generalized hyperalgesia. METHODS: Patients were classified in 1 of 3 groups: HMS/EDS-HT, hypermobile (Beighton score ≥4 of 9), and healthy controls. Descriptive data of age, sex, body mass index, Beighton score, skin laxity, and medication usage were collected. Generalized hyperalgesia was quantified by the average pressure-pain thresholds collected from 12 locations. Confounders collected were pain locations/intensity, fatigue, and psychological distress. Comparisons between children with HMS/EDS-HT and normative values, between children and adults with HMS/EDS-HT, and corrected confounders were analyzed with multivariate analysis of covariance. The discriminative value of generalized hyperalgesia employed to differentiate between HMS/EDS-HT, hypermobility, and controls was quantified with logistic regression. RESULTS: Significantly lower pressure-pain thresholds were found in children with HMS/EDS-HT compared to normative values (range -22.0% to -59.0%; P ≤ 0.05). When applying a threshold of 30.8 N/cm2 for males and 29.0 N/cm2 for females, the presence of generalized hyperalgesia discriminated between individuals with HMS/EDS-HT, hypermobility, and healthy controls (odds ratio 6.0). CONCLUSION: Children and adults with HMS/EDS-HT are characterized by hypermobility, chronic pain, and generalized hyperalgesia. The presence of generalized hyperalgesia may indicate involvement of the central nervous system in the development of chronic pain.

The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis.

Macrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A2 (Lp-PLA2), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a result of macrophage activation; hence inhibition of Lp-PLA2 may limit macrophage activation and protect the tissue. Utilising Lp-PLA2 gene-deficient (KO) mice and a pharmacological inhibitor of Lp-PLA2 (SB-435495) we aimed to determine the effect of Lp-PLA2 suppression in mediating retinal protection in a model of autoimmune retinal inflammation, experimental autoimmune uveoretinitis (EAU). Following immunisation with RBP-3 (IRBP) 1-20 or 161-180 peptides, clinical disease was monitored and severity assessed, infiltrating leukocytes were enumerated by flow cytometry and tissue destruction quantified by histology. Despite ablation of Lp-PLA2 enzyme activity in Lp-PLA2 KO mice or wild-type mice treated with SB-435495, the number of infiltrating CD45+ cells in the retina was equivalent to control EAU animals, and there was no reduction in disease severity. Thus, despite the reported beneficial effects of therapeutic Lp-PLA2 depletion in a variety of vascular inflammatory conditions, we were unable to attenuate disease, show delayed disease onset or prevent progression of EAU in Lp-PLA2 KO mice. Although EAU exhibits inflammatory vasculopathy there is no overt defect in lipid metabolism and given the lack of effect following Lp-PLA2 suppression, these data support the hypothesis that sub-acute autoimmune inflammatory disease progresses independently of Lp-PLA2 activity.

Understanding the roles of activation threshold and infections in the dynamics of autoimmune disease.

Onset and development of autoimmunity have been attributed to a number of factors, including genetic predisposition, age and different environmental factors. In this paper we discuss mathematical models of autoimmunity with an emphasis on two particular aspects of immune dynamics: breakdown of immune tolerance in response to an infection with a pathogen, and interactions between T cells with different activation thresholds. We illustrate how the explicit account of T cells with different activation thresholds provides a viable model of immune dynamics able to reproduce several types of immune behaviour, including normal clearance of infection, emergence of a chronic state, and development of a recurrent infection with autoimmunity. We discuss a number of open research problems that can be addressed within the same modelling framework.

The relationship between area deprivation and contact with community intellectual disability psychiatry.

BACKGROUND: People with intellectual disabilities (ID) have high rates of psychiatric illness and are known to live in more deprived areas than the general population. This study investigated the relationship between area deprivation and contact with ID psychiatry. METHOD: Psychiatric case notes and electronic records were used to identify all patients who had face-to-face contact with community ID psychiatric services over 1 year in the North East Community Health Partnership of Greater Glasgow and Clyde (estimated population 177,867). The Scottish Index of Multiple Deprivation (SIMD) were determined for the patient sample and for the general population living in the same area. RESULTS: Between 1 June 2012 and 1 June 2013, 184 patients were seen by ID psychiatry over a total of 553 contacts, with valid SIMD data for 179 patients and 543 contacts. Fifty-two per cent of patients (n = 93) lived in the most deprived SIMD decile, and 90.5% (n = 152) in the lowest 5 deciles. Compared with the general population, there were significantly more patients than expected living in the most deprived decile (Fisher's Exact test, P = 0.009) and in the most deprived 5 deciles (Fisher's Exact test, P = 0.001). The median number of contacts was 2 (interquartile range = 1-3). There was no significant association between the number of contacts and SIMD decile. Forty-eight point one per cent (n = 261) of all contacts were with patients living in the most deprived decile and 88.6% (n = 481) in the most deprived 5 deciles. This was significantly more than expected compared with general population data (Fisher's Exact test, P = 0.008 and Fisher's Exact test, P ≤ 0.001). CONCLUSIONS: In the area under study, contact with ID psychiatry was greater in more deprived areas. Given the high psychiatric morbidity of people with ID, if services do not adjust for deprivation, this may lead to further discrimination in an already disadvantaged population.

Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel.

These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non-hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non-cancer settings. The guidelines are only applicable to parenterally administered agents.

Connexin hemichannel blockade is neuroprotective after, but not during, global cerebral ischemia in near-term fetal sheep.

There is increasing evidence that connexin hemichannels, the half gap junctions that sit unopposed in the cell membrane, can open during ischemia and that blockade of connexin43 hemichannels after cerebral ischemia can improve neural outcomes. However, it is unclear whether connexin blockade during ischemia is protective. In the present study global cerebral ischemia was induced by 30 min of bilateral carotid artery occlusion in near-term (128 ± 1 day gestation age) fetal sheep. A specific mimetic peptide that blocks connexin43 hemichannels was infused into the lateral ventricle for either 1h before and during ischemia (intra-ischemia group, n=6) or for 25 h starting 90 min after the end of ischemia (post-ischemia group, n=7). The vehicle was infused in the ischemia-vehicle group (n=6) and sham-controls received sham occlusion plus vehicle (n=10). The post-ischemia group showed enhanced recovery of EEG power from day five until the end of the experiment (-5 ± 1.6 dB) compared to ischemia-vehicle (-13 ± 1.9 dB, p<0.05) and intra-ischemia infusion (-14.4 ± 3.6 dB, p<0.05). Post-ischemic infusion was associated with higher neuronal counts compared to ischemia-vehicle and intra-ischemia in the cortex (p<0.05) but not the CA1 and CA3 regions of the hippocampus. Oligodendrocyte cell counts in the intragyral and periventricular white matter were significantly higher in the post-ischemia group compared to ischemia-vehicle and intra-ischemia infusion (p<0.05). These large animal data support the hypothesis that connexin hemichannel opening after, but not during, ischemia contributes to the spread of white and gray matter injury of the developing brain.

Intestinal location of necrotizing enterocolitis among infants with congenital heart disease.

OBJECTIVE: To determine whether differences exist in the location of necrotizing enterocolitis (NEC) in infants with congenital heart disease (CHD) versus those without CHD. STUDY DESIGN: Retrospective cohort study utilizing 11 years of patient data. Inclusion criterion was surgical exploration for NEC. Presence or absence of CHD was determined. Surgical and/or pathology reports were reviewed to identify the location of NEC. Data were analyzed by t-tests and χ(2) analyses. RESULT: One hundred and sixty-seven patients met the inclusion criteria. CHD infants had a higher percentage of mortality. There was no difference in the location of NEC between non-CHD and CHD patients, with the predominant location being the small intestine in both. In addition, there was no difference in the location of NEC between preterm non-CHD patients and full-term CHD patients with the small intestine again being the primary site. CONCLUSION: Despite differences in gestational age between non-CHD and CHD patients, the location of NEC in these infants did not differ.

Social exclusion and people with intellectual disabilities: a rural-urban comparison.

BACKGROUND: Research suggests that social exclusion is a problem both for people with intellectual disabilities (ID) and for people living in rural areas. This may give rise to a double disadvantage for people with ID living in rural areas. Conversely, aspects of rural life such as community spirit and social support may protect against social exclusion in this population. This study was designed to compare a number of measures of social exclusion in adults with ID living in rural and urban areas, with the aim of identifying whether a double disadvantage exists. METHOD: Adults with ID were recruited from a rural and an urban area in Scotland. Participants participated in a face-to-face interview and their medical notes were accessed. Social exclusion was investigated using a number of measures comprising: daytime opportunities and physical access to community facilities (using part of the British Institute of Learning Disabilities questionnaire), recent contact with others and the quality of personal relationships (using a modified Interview Measure of Social Relationships questionnaire) and area deprivation by postcode (using the Scottish Index of Multiple Deprivation). The data were analysed using a series of binary logistic regression models that adjusted for variables including age, gender, level of ID, mental illhealth and common physical co-morbidities. RESULTS: A representative sample of adults with ID from rural (n = 39) and urban (n = 633) areas participated. Participants from rural areas were significantly more likely to have any regular daytime opportunity [odds ratio (OR) = 10.8, 95% CI = 2.3-51.5] including employment (OR = 22.1, 95% CI = 5.7-85.5) and attending resource centres (OR = 6.7, 95% CI = 2.6-17.2) than were participants from urban areas. They were also more likely to have been on holiday (OR = 17.8, 95% CI = 4.9-60.1); however, were less likely to use community facilities on a regular basis. Participants from urban and rural areas had a similar number of contacts with other people in a wide range of situations, but the quality of relationships may have been less close in rural areas. Finally, participants lived in significantly less deprived areas when in rural compared with urban areas (Mann-Whitney U = 7826, Z = -3.675, P ≤ 0.001). CONCLUSIONS: These results suggest that adults with ID living in rural areas have better opportunities and live in less deprived areas than adults with ID living in urban areas. However, they may not hold such positive or close relationships, and this may be important when considering the subjective experience of social exclusion.

Recruitment to intellectual disability research: a qualitative study.

BACKGROUND: Difficulties in the recruitment of adults with intellectual disability (ID) to research studies are well described but little studied. The aim of this study was to investigate the difficulties in recruiting to a specific research project, in order to inform future recruitment to ID research. METHODS: Individual semi-structured interviews were held between September 2009 and May 2010 with people who had been involved as intermediaries in recruitment to the research project. These were transcribed verbatim and were independently analysed by two researchers using the Framework approach, who then agreed upon the key emerging themes. RESULTS: Ten interviews were analysed. A number of themes arose, including participant factors (interview anxiety, difficulties in understanding the concept of research, worry about negative feedback), the importance of the researcher (using a personal approach, meeting potential participants prior to recruitment) and motivators [enjoyment of the research interview (participant), obtaining a medical assessment (carer)]. The themes were then used to generate strategies to improve recruitment to ID research: these include the research team applying a more personal approach, developing the recruitment process to allow for multiple meetings with potential participants, and considering motivators for both participants and carers. CONCLUSIONS: This study has used the experiences of intermediaries to identify strategies for improving recruitment to future ID research. This has implications in terms of both time and money. However, successful recruitment is essential to ID research, and we hope that the study will be used by ID researchers to review and improve their recruitment processes.

Therapy-induced clearance of HCV core antigen from plasma predicts an end of treatment viral response.

During viral assembly, viral proteins are released into plasma and can be used to infer viral load. The Architect hepatitis C virus (HCV) core antigen (Ag) assay is a potential alternative to HCV RNA quantification for measuring response to therapy and predicting an end of treatment viral response (EOTR). The HCVp22Ag assay was used to infer viral load in 68 window RNA-containing samples and in 284 samples from baseline to week 14 of ribavirin/interferon treatment in 23 patients with EOTR including three who relapsed, 20 not achieving EOTR and 11 controls. HCV Ag and RNA correlated well (r = 0.86) with linear dose responses on dilution. In patients on therapy and control patients, plasma HCV antigen was detected in 51 of 54 with an interpolated LOD cut off between 10(3) and 10(4) RNA IU/mL. Plasma HCV antigenaemia and plasma RNA levels were significantly different in EOTR from non-EOTR patients at 3 days after treatment start and all times thereafter. Positive and negative EOTR predictive values for HCV RNA >2 log drop and HCV Ag loss at 12 weeks were 70% and 74%, 85% and 93% respectively. HCV Ag reactivity has a linear dose response independent of genotype and correlates well with HCV RNA. The failure to clear HCV Ag is as accurate as the failure to clear HCV RNA at twelve weeks into therapy in predicting the likelihood of failure to achieve EOTR. HCV Ag potentially offers a convenient alternative to RNA measurement for defining a futility flag in HCV therapy.

The role of tunable activation thresholds in the dynamics of autoimmunity.

It has been known for some time that human autoimmune diseases can be triggered by viral infections. Several possible mechanisms of interactions between a virus and immune system have been analysed, with a prevailing opinion being that the onset of autoimmunity can in many cases be attributed to "molecular mimicry", where linear peptide epitopes, processed from viral proteins, mimic normal host self-proteins, thus leading to a cross-reaction of immune response against virus with host cells. In this paper we present a mathematical model for the dynamics of an immune response to a viral infection and autoimmunity, which takes into account T cells with different activation thresholds. We show how the infection can be cleared by the immune system, as well as how it can lead to a chronic infection or recurrent infection with relapses and remissions. Numerical simulations of the model are performed to illustrate various dynamical regimes, as well as to analyse the potential impact of treatment of autoimmune disease in the chronic and recurrent states. The results provide good qualitative agreement with available data on immune responses to viral infections and progression of autoimmune diseases.