Anti-Ro52/TRIM21 is independently associated with pulmonary arterial hypertension and mortality in a cohort of systemic sclerosis patients.

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement.Method: The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses.Results: Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications.Conclusion: Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

Factors affecting the growth of infants diagnosed with cystic fibrosis by newborn screening.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) improves nutritional outcomes. Despite early dietetic intervention some children fail to grow optimally. We report growth from birth to 2 years in a cohort of children diagnosed with CF by NBS and identify the variables that influence future growth. METHODS: One hundred forty-four children were diagnosed with CF by the West Midlands Regional NBS laboratory between November 2007 and October 2014. All anthropometric measurements and microbiology results from the first 2 years were collated as was demographic and CF screening data. Classification modelling was used to identify the key variables in determining future growth. RESULTS: Complete data were available on 129 children. 113 (88%) were pancreatic insufficient (PI) and 16 (12%) pancreatic sufficient (PS). Mean birth weight (z score) was 3.17 kg (- 0.32). There was no significant difference in birth weight (z score) between PI and PS babies: 3.15 kg (- 0.36) vs 3.28 kg (- 0.05); p = 0.33. By the first clinic visit the difference was significant: 3.42 kg (- 1.39) vs 4.60 kg (- 0.48); p < 0.0001. Weight and height remained lower in PI infants in the first year of life. In the first 2 years of life, 18 (14%) infants failed to regain their birth weight z score. The median time to achieve a weight z score of - 2, - 1 and 0 was 18, 33 and 65 weeks respectively. The median times to reach the same z scores for height were 30, 51 and 90 weeks. Birth weight z score, change in weight z score from birth to first clinic, faecal elastase, isolation of Pseudomonas aeruginosa, isolation of Staphylococcus aureus and sweat chloride were the variables identified by the classification models to predict weight and height in the first and second year of life. CONCLUSIONS: Babies with CF have a lower birth weight than the healthy population. For those diagnosed with CF by NBS, the weight difference between PI and PS babies was not significantly different at birth but became so by the first clinic visit. The presence of certain factors, most already identifiable at the first clinic visit can be used to identify infant at increased risk of poor growth.

Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: a pilot study.

OBJECTIVES: The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented. METHODS: HIV-infected subjects ≥ 55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography-ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration-time curve over 24 h (AUC0-24h ) and maximal concentration (Cmax )]. These parameters were compared with historical values from the general HIV-infected population. RESULTS: Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8-13% decreased TFV AUC0-24h and Cmax , and 19-78% increased FTC and RTV AUC0-24h and Cmax . Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax . Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects. CONCLUSIONS: This study demonstrates that the PK of these ARVs are altered by 5-78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients.

Adapting lean methodology towards surgical tray rationalisation in inguinoscrotal day case surgery in the republic of Ireland.

INTRODUCTION: Lean methodologies have been used successfully in both industry and healthcare to reduce waste. The operating room (OR) and central supplies department (CSD) are areas associated with high hospital costs. The aim of this study was to employ Lean methodologies to support the rationalisation of surgical trays in paediatric inguinoscrotal surgery in order to reduce instrument wastage, processing times and overall costs in a European setting. METHODS: This was a prospective, pilot observation and implementation study using Lean methodology including DMAIC (Define, Measure, Analyse, Improve and Control) cycles. Relevant tray set-up included trays for boys ≥12 months age undergoing open elective inguinoscrotal surgery. A comparative analysis of two phases, pre and post-standardization was then carried out with respect to operating times, instrument set-up times, tray weights, and costs. Instruments that were used <40% of the time were eliminated from the surgical tray. RESULTS: Rationalization of the inguinoscrotal tray led to a 34.7% reduction in tray size, with a concomitant time-reduction of >2 min per case. The average overall instrument utilisation rate increased from 56% to 80% across users. Cost savings were projected at €5380.40 per annum based on current changes. There were no differences in operative time, or adverse outcomes. DISCUSSION: At the hospital level, the reduction in variation, and rationalisation of this single surgical tray could lead to both operational (Tray assembly process; Operating rooms; Ergonomic functionality) as well as economic (Sterilisation; Instrument repair; Purchases) financial and ergonomic improvements for the healthcare system. The reduction in time taken to count and sterilise instruments can lead to a potential manpower saving involving a redistribution of activities to other areas which may require them. CONCLUSION: Surgical tray rationalisation is emerging Lean concept with overlap across a number of specialities, and represents a technique by which to manage costs, and improve supply chain efficiency without any adverse effect in patient healthcare outcomes.

Survival in scleroderma: results from the population-based South Australian Register.

AIM: To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR). METHODS: The SASR is a population-based register, which was commenced in 1993 and has actively sought to recruit all scleroderma patients diagnosed in SA over a 15-year period. Clinical and serological details have been accessed from questionnaires or from clinical and laboratory files. Standardized mortality ratio (SMR) was calculated and survival analyses performed on all living and deceased patients listed on this SASR (n = 786). RESULTS: Patients with scleroderma had increased mortality compared with the general SA population (SMR 1.46 (95% confidence interval (CI) 1.28-1.69)). Factors that adversely altered survival included older age at onset, male gender, diffuse skin involvement, presence of scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer and anti-topoisomerase (Scl-70) and anti-U1 RNP antibodies, while a trend was observed with increased nailfold capillary dropout. Mean age of death for patients with limited scleroderma was 74.1 years (95% CI 72.5-75.7), diffuse scleroderma 62.9 years (95% CI 59.4-66.4) and overlap disease 57.8 years (95% CI 48.7-66.9). Survival improved over the 15-year study period. CONCLUSIONS: Scleroderma substantially reduces life expectancy. Survival is influenced by age at onset, gender, diffuse involvement of skin fibrosis, visceral involvement, development of cancer, extent of microvascular capillary damage and by the presence of scleroderma-associated antibodies, Scl-70 and RNP. Scleroderma renal crisis continues to carry high mortality. Survival improved over the 15-year study period.

Microbial community changes in a female rat model of Rett syndrome.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is predominantly caused by alterations of the methyl-CpG-binding protein 2 (MECP2) gene. Disease severity and the presence of comorbidities such as gastrointestinal distress vary widely across affected individuals. The gut microbiome has been implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) as a regulator of disease severity and gastrointestinal comorbidities. Although the gut microbiome has been previously characterized in humans with RTT compared to healthy controls, the impact of MECP2 mutation on the composition of the gut microbiome in animal models where the host and diet can be experimentally controlled remains to be elucidated. By evaluating the microbial community across postnatal development as behavioral symptoms appear and progress, we have identified microbial taxa that are differentially abundant across developmental timepoints in a zinc-finger nuclease rat model of RTT compared to WT. We have additionally identified p105 as a key translational timepoint. Lastly, we have demonstrated that fecal SCFA levels are not altered in RTT rats compared to WT rats across development. Overall, these results represent an important step in translational RTT research.

Adjuvant therapy used in conjunction with combination therapy for chronic hepatitis C improves sustained virus response rates in genotype 1 patients.

Combination treatment with pegylated interferon (Peg-IFN) and ribavirin remains the gold standard in the treatment of chronic hepatitis C. This therapy is limited by many side-effects including anaemia, neutropenia and reduced quality of life. The use of adjuvant agents to reduce the frequency of dose reductions because of haematological side-effects has been proven to be effective but there are few reports of what effect the use of these adjuvant therapies is having on sustained virological response (SVR). The aim of the study was to assess the clinical impact on sustained virological response of adjuvant therapies during combination therapy with Peg-IFN and ribavirin for chronic hepatitis C. A total of 132 patients, 96 males, were included in the study. The overall SVR was 66.7%, with 50% of genotype 1/4/6 (n = 27/54) patients achieving SVR and 78.2% of genotypes 2/3. The overall SVR of the treatment naïve patients (83/121) was 68.6%. Fifty-one of these patients were genotype 1 with 49.0% (25/51) of this group achieving SVR. The genotype 2/3 group of treatment naïve patients reached an SVR of 82.9% (58/70). Adjuvant therapy was used in 57 patients (43.8%). With the use of supportive adjuvant therapy, we achieved an overall SVR of 66.7% and in treatment naïve patients 68.6%. In genotype 1 patients, SVR rates of up to 46% have been reported in previous studies without the use of erythropoietin and granulocyte colony stimulating factor. We have demonstrated the SVR for genotype 1 can be improved to 50% overall.

Vitamin D content and variability in fluid milks from a US Department of Agriculture nationwide sampling to update values in the National Nutrient Database for Standard Reference.

This study determined the vitamin D(3) content and variability of retail milk in the United States having a declared fortification level of 400 IU (10 µg) per quart (qt; 1 qt=946.4 mL), which is 25% daily value per 8 fluid ounce (236.6 mL) serving. In 2007, vitamin D(3) fortified milk (skim, 1%, 2%, whole, and 1% fat chocolate milk) was collected from 24 statistically selected supermarkets in the United States. Additionally, 2% milk samples from an earlier 2001 USDA nationwide collection were reanalyzed. Vitamin D(3) was determined using a specifically validated method involving HPLC with UV spectroscopic detection and vitamin D(2) as an internal standard. Quality control materials were analyzed with the samples. Of the 120 milk samples procured in 2007, 49% had vitamin D(3) within 100 to 125% of 400 IU (10 µg)/qt (label value), 28% had 501 to 600 IU (12.5-15 µg)/qt, 16% had a level below the label amount, and 7% had greater than 600 IU (15 µg)/qt (>150% of label). Even though the mean vitamin D(3) content did not differ statistically between milk types, a wide range in values was found among individual samples, from nondetectable [<20 IU (0.5 µg)/qt] for one sample to almost 800 IU (20 µg)/qt, with a trend toward more samples of whole milk having greater than 150% of the labeled content. On average, vitamin D(3) in 2% milk was higher in 2007 compared with in 2001 [473 vs. 426 IU (11.8 vs. 10.6 µg)/qt].

"I remember it as if it were yesterday": memory for recent events in patients with semantic dementia.

Patients with semantic dementia (SD), who have an incontrovertible deficit in semantic memory, are reported to show good day-to-day memory for recent events; but experimental evidence on their anterograde episodic memory/new learning is somewhat sparse and does not always tell a consistent story. We describe the performance of five SD patients, relative to controls, on (a) a range of semantic memory measures that predictably revealed substantial impairment, and (b) a newly designed naturalistic and incidental episodic task, which included information regarding the items and context of the semantic tasks. As a group, the patients' episodic memory for these natural events was good, even after a 24-h delay, although case-by-case analysis revealed some heterogeneity in performance. These findings are discussed with regard to the neural substrate of episodic memory and psychological models of long-term memory.

Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery.

BACKGROUND: Post-operative cognitive dysfunction (POCD) commonly occurs after cardiac surgery. Ketamine exerts neuroprotective effects after cerebral ischemia by anti-excitotoxic and anti-inflammatory mechanisms. We hypothesized that ketamine attenuates POCD in patients undergoing cardiac surgery concomitant with an anti-inflammatory effect. METHODS: Patients randomly received placebo (0.9% saline; n=26) or an i.v. bolus of ketamine (0.5 mg/kg; n=26) during anesthetic induction. Anesthesia was maintained with isoflurane and fentanyl. A nonsurgical group (n=26) was also included as control. Recent verbal and nonverbal memory and executive functions were assessed before and 1 week after surgery or a 1-week waiting period for the nonsurgical controls. Serum C-reactive protein (CRP) concentrations were determined before surgery and on the first post-operative day. RESULTS: Baseline neurocognitive and depression scores were similar in the placebo, ketamine, and nonsurgical control groups. Cognitive performance after surgery decreased by at least 2 SDs (z-score of 1.96) in 21 patients in the placebo group and only in seven patients in the ketamine group compared with the nonsurgical controls (P<0.001, Fisher's exact test). Cognitive performance was also significantly different between the placebo- and the ketamine-treated groups based on all z-scores (P<0.001, Mann-Whitney U-test). Pre-operative CRP concentrations were similar (P<0.33, Mann-Whitney U-test) in the placebo- and ketamine-treated groups. The post-operative CRP concentration was significantly (P<0.01, Mann-Whitney U-test) lower in the ketamine-treated than in the placebo-treated group. CONCLUSIONS: Ketamine attenuates POCD 1 week after cardiac surgery and this effect may be related to the anti-inflammatory action of the drug.

Can We Accurately Predict Cost Effectiveness Without Access to Overall Survival Data? The Case Study of Nivolumab in Combination with Ipilimumab for the Treatment of Patients with Advanced Melanoma in England.

BACKGROUND: Nivolumab with ipilimumab (the Regimen) is the first immuno-oncology combination treatment to demonstrate long-term clinical benefit for advanced melanoma patients. We evaluated the cost effectiveness of the Regimen in this population, with and without the availability of overall survival (OS) data. METHODS: A partitioned survival model and a Markov state-transition model were developed to estimate the lifetime costs and benefits of the Regimen versus ipilimumab. These models were built with and without the availability of OS data, as only progression-free survival data were available from the head-to-head, phase III trial against ipilimumab at the time of the National Institute for Health and Care Excellence (NICE) submission. Patient utilities and resource use data were sourced from trial data or the literature. RESULTS: Incremental cost-effectiveness ratios (ICERs) and absolute costs were similar between the models with and without OS data, but the model with OS data generated more than 1 additional quality-adjusted life-year (QALY) across both treatment arms. In both models, based on list prices, the Regimen was the most cost-effective treatment. CONCLUSIONS: The analyses show that the Regimen is a cost-effective treatment for advanced melanoma patients in England, and methods to overcome the lack of OS can give reasonable estimates of QALYs gained and ICERs.

Correction to: Can We Accurately Predict Cost Effectiveness Without Access to Overall Survival Data? The Case Study of Nivolumab in Combination with Ipilimumab for the Treatment of Patients with Advanced Melanoma in England.

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Focal cortical presentations of Alzheimer's disease.

To determine the frequency of Alzheimer's disease (AD) pathology in patients presenting with progressive focal cortical syndromes, notably posterior cortical atrophy (PCA), corticobasal syndrome (CBS), behavioural variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) (or a mixed aphasia) and semantic dementia (SD); and to compare the age of onset, evolution and prognosis in patients with focal cortical presentations of AD versus more typical AD and those with non AD pathology. From a total of 200 patients with comprehensive prospective clinical and pathological data we selected 120 : 100 consecutive cases with focal cortical syndromes and 20 with clinically typical AD. Clinical files were reviewed blind to pathological diagnosis. Of the 100 patients with focal syndromes, 34 had AD as the primary pathological diagnosis with the following distribution across clinical subtypes: all 7 of the PCA (100%); 6 of 12 with CBS (50%); 2 of 28 with bvFTD (7.1%); 12 of 26 with PNFA (44.1%); 5 of 7 with mixed aphasia (71.4%) and 2 of 20 with SD (10%). Of 20 with clinically typical AD, 19 had pathological AD. Age at both onset and death was greater in the atypical AD cases than those with non-AD pathology, although survival was equivalent. AD is a much commoner cause of focal cortical syndromes than previously recognised, particularly in PCA, PNFA and CBS, but rarely causes SD or bvFTD. The focal syndrome may remain pure for many years. Patients with atypical AD tend to be older than those with non-AD pathology.

Hyperammonaemic encephalopathy associated with rituximab-containing chemotherapy.

Abstract Hyperammonaemic encephalopathy has been infrequently reported after both standard and high-dose chemotherapy for solid and haematological malignancies. It is important to consider this diagnosis for patients with unexplained behaviour changes or encephalopathy and this case report emphasizes this condition and the importance of early diagnosis and is the first reported in association with rituximab-containing chemotherapy.

Semantic dementia and fluent primary progressive aphasia: two sides of the same coin?

Considerable controversy exists regarding the relationship between semantic dementia (SD) and progressive aphasia. SD patients present with anomia and impaired word comprehension. The widely used consensus criteria also include the need for patients to exhibit associative agnosia and/or prosopagnosia: many authors have used the label SD for patients with non-verbal, as well as verbal, semantic deficits on formal testing even if they recognize the objects and people encountered in everyday life; others interpret the criterion of agnosia to require pervasive recognition impairments affecting daily life. According to this latter view, SD patients have pathology that disrupts both a bilateral ventrotemporal-fusiform network (resulting in agnosia) and the left hemisphere language network (resulting in profound aphasia). These authors suggest that this profile is different to that seen in the fluent form of primary progressive aphasia (fPPA), a neurodegenerative disease primarily affecting language function. We present data on seven patients who met the diagnostic criteria for fPPA. All seven showed deficits relative to matched controls on both verbal and non-verbal measures of semantic memory, and these deficits were modulated by degree of anomia, concept familiarity and item typicality. Voxel-based morphometry revealed reduced grey matter density in the temporal lobes bilaterally (more widespread on the left), with the severity of atrophy in the left inferior temporal lobe being significantly related to performance on both the verbal and non-verbal measures. Together these findings suggest that patients who meet the diagnostic criteria for fPPA, can also meet the diagnostic criteria for early-stage SD provided that the impact of concept familiarity and typicality is taken into account. In addition, these findings support a claim that the patients' deficits on both verbal and non-verbal tasks reflect progressive deterioration of an amodal integrative semantic memory system critically involving the rostral temporal lobes, rather than a combination of atrophy in the left language network and a separate bilateral ventrotemporal-fusiform network.

Nutrient composition and retention in whole turkeys with and without added solution.

Whole turkeys sold in retail outlets are typically processed with added solutions to improve their taste and tenderness. The purpose of this study was to evaluate the nutrient composition of whole turkeys with and without added solution, and to update the nutrient profile of turkey for the USDA National Nutrient Database for Standard Reference. Eleven pairs of turkeys with added solution were obtained from statistically representative retail outlets using a nationwide sampling plan developed for USDA's National Food and Nutrient Analysis Program; 4 pairs of turkeys without added solution were purchased from local food outlets. Turkeys were roasted to an internal temperature of 165°F (74°C). Values of selected nutrients in light and dark meat, including skin, were determined by USDA approved laboratories using quality assurance protocols. Both raw and cooked turkeys, with and without added solution, were compared by one-way and 2-way factorial ANOVA. The results showed a significant interaction for fat (P < 0.0001) and zinc (P = 0.0070) between turkeys that were raw and cooked and those prepared with or without added solution. Fat was higher in raw turkeys with added solution compared to without added solution. Similarly, sodium, phosphorus, and calcium values were significantly higher in turkeys with added solution (P < 0.05) than in turkeys without added solution. Data from this study will be useful for developing strategies to address sodium-related health issues, nutrition monitoring, consumption surveys, and policy development.

Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV-Infected Subjects With Aging Biomarkers.

Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m2 . No alterations in drug clearance or unbound fraction with age, frailty, or p16INK4a expression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.