Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle.

Robot-actuated mechanical loading (ML)-based therapies ("mechanotherapies") can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.

Changes in fecal microbiota with CFTR modulator therapy: A pilot study.

Studies have demonstrated that people with CF with pancreatic insufficiency (PI) have fecal dysbioses. Evidence suggests the causes of these dysbioses are multifactorial, and that important drivers include antibiotic exposure, dietary intake, and CF gastrointestinal tract dysfunction, including nutrient malabsorption. In this pilot study, we tested whether initiation of the CFTR modulator treatments ivacaftor (in a cohort of pancreatic sufficient (PS) people with CF and an R117H CFTR variant) or lumacaftor/ivacaftor (in a cohort of PI people with CF and an F508del variant) changed fecal measures of malabsorption or fecal microbiomes. While we identified no statistically significant fecal changes with either treatment, we detected trends in the PI cohort when initiating lumacaftor/ivacaftor towards decreased fecal fat content and towards fecal microbiomes that more closely resembled the fecal microbiota of people without PI. While these findings support a model in which nutrient malabsorption resulting from CF-induced PI drives fecal dysbiosis, they must be validated in future, larger studies of fecal microbiome and malabsorption outcomes with highly effective CFTR modulator therapies.

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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Initial development and pilot testing of observer-reported outcomes (ObsROs) for children with cystic fibrosis ages 0-11years.

PURPOSE: Patient-reported outcomes are important clinical trial endpoints. Young children may not be able to reliably report on how they feel or function, so observer-reported outcomes (ObsROs) may be more appropriate for them. The purpose of this study was to develop and pilot field test electronic parent-reported observational instruments for children with cystic fibrosis (CF) 0-6 and 7-11years of age. METHODS: We performed concept elicitation interviews with parents of children with CF ≤11years of age to elicit the respiratory signs they could observe at baseline and during an acute respiratory illness. The resulting instruments were refined based on interviews with parents and clinicians. We conducted a pilot field test to evaluate test-retest reliability and the ability of items to distinguish well and sick periods. RESULTS: The instruments consist of 17 items assessing respiratory signs and observable CF-related impacts. Test-retest reliability was acceptable for both age groups but discrimination was low for ages 7-11, likely reflecting less direct observation of older children by their parents. CONCLUSIONS: An ObsRO for children with CF ages 0-6 appears promising, while self-report may be more appropriate for children >6years of age. Next steps for the 0-6year old instrument will be utilizing it as an exploratory endpoint in clinical trials to enable item reduction, scale development, and further reliability and validity testing. Ultimately, this ObsRO could be a promising endpoint for early intervention trials in young children with CF.

Pregabalin Abuse amongst Opioid Substitution Treatment Patients.

Pregabalin (Lyrica®) is used in treating epilepsy, nerve pain and anxiety. Pregabalin was initially thought to have a low misuse potential however there are emerging reports of Pregabalin being abused. A study was commenced at the National Drug Treatment Centre's (NDTC) Drug Analysis Laboratory to determine the level of usage of Pregabalin within the addiction services population in Ireland. A total of 498 urine samples representing samples from 440 individual opioid substitution patients, initially screened by immunoassay for drugs of abuse, were subjected to further analysis for Pregabalin by Liquid Chromatography/Mass Spectrometry (LC/MS). Of 440 patients tested, 39 tested positive for Pregabalin (9.2%). Only 10 patients from this group were prescribed this drug to our knowledge thus giving an estimated rate of misuse of 7.0%. Other drugs detected in the Pregabalin positive patients were Opiates (31.8%), Cocaine (11.4%), Benzodiazepines (79.5%) and Cannabis (77.8%). Our study confirms that Pregabalin abuse is taking place amongst the addiction services population. We believe that misuse of this prescription drug is a serious emerging issue which should be monitored carefully.

Symptoms and medication management in the end of life phase of high-grade glioma patients.

During the end of life (EOL) phase of high-grade glioma (HGG) patients, care is primarily aimed at reducing symptom burden while maintaining quality of life as long as possible. In this study, we evaluated the prevalence of symptoms and medication management in HGG patients during the EOL phase. We analyzed disease-specific symptoms, general EOL symptoms, symptom frequency, and medication use at 3 months and 1 week before death in a cohort of 178 HGG patients, based on questionnaires completed by physicians responsible for EOL care. In addition, information on patient's perceived quality of care (QOC) was derived from 87 questionnaires completed by patient's relatives. Somnolence, focal neurological deficits and cognitive disturbances were the most prevalent symptoms during the EOL phase. Overall, disease-specific symptoms occurred more often than general EOL symptoms at both 3 months and 1 week before death. Somnolence and/or dysphagia were present in 81 % of patients whose medication was withdrawn and 96 % of patients in whom antiepileptic drugs (AEDs) were withdrawn. One week before death, 65.9 % of patients with high symptom frequency experienced good QOC, compared to 87.5 % of patients with low symptom frequency (p = 0.032). Disease-specific symptoms are the main concern in EOL care for HGG patients. Somnolence and dysphagia may hamper the regular oral administration of drugs, and particularly AEDs, during the EOL phase. High symptom frequency at 1 week before death negatively affects patient's perceived QOC.

End of life care in high-grade glioma patients in three European countries: a comparative study.

Exploring cross-national differences is useful to evaluate whether different patterns of end of life (EOL) care meet patient's specific needs. This study aimed to (1) compare EOL care processes for high-grade glioma (HGG) patients in three European countries, (2) explore differences in perceived quality of care (QOC), and (3) identify aspects of good QOC in the EOL phase. We analyzed 207 questionnaires from relatives of deceased HGG patients, using a similar retrospective study design in three countries [The Netherlands (n = 83), Austria (n = 72) and the UK (n = 52)], and examined four subthemes: (1) organization of EOL care, (2) treatment preferences, (3) experiences with EOL care, (4) perceived QOC. Three months before death 75 % of patients were at home. In all countries, on average, 50 % were transferred to a hospital at least once and received effective symptom treatment during the last 3 months. In The Netherlands, Austria and UK, respectively, patients most often died at home (60 %), in a hospital (41 %) or hospice (41 %) (p < 0.001). Advance directives were present in 46 % of Dutch, 36 % of British and 6 % of Austrian patients (p < 0.001). Fifty-three percent of patients experienced good QOC, irrespective of country. Dying at the preferred place, satisfaction with information provided and effective symptom treatment were independently associated with good QOC. There are various cross-national differences in organization and experiences with EOL care for HGG, but patient's perceived QOC is similar in the three countries. As symptom treatment was considered effective in only half of HGG patients, and independently predicted good QOC, this particularly needs further improvement in all countries.

Resting-state connectivity deficits associated with impaired inhibitory control in non-treatment-seeking adolescents with psychotic symptoms.

OBJECTIVE: Psychotic symptoms are common in the population and index risk for a range of severe psychopathological outcomes. We wished to investigate functional connectivity in a community sample of adolescents who reported psychotic symptoms (the extended psychosis phenotype). METHOD: This study investigated intrinsic functional connectivity (iFC) during resting-state functional magnetic resonance imaging (fMRI; rs-fMRI). Following screening in schools, 11 non-treatment seeking, youth with psychotic symptoms (aged 11-13) and 14 community controls participated in the study. Seed regions of interest comprised brain regions previously shown to exhibit aberrant activation during inhibitory control in adolescents with psychotic symptoms. RESULTS: Relative to controls, adolescents with psychotic symptoms exhibited reduced iFC between regions supporting inhibitory control. Specifically, they showed weaker iFC between the right inferior frontal gyrus (IFG) and the cingulate, IFG and the striatum, anterior cingulate and claustrum, and precuneus and supramarginal gyrus. Conversely, the psychotic symptoms group exhibited stronger iFC between the superior frontal gyrus and claustrum and IFG and lingual gyrus. CONCLUSION: The present findings are the first to reveal aberrant functional connectivity in resting-state networks in a community sample of adolescents with psychotic symptoms and suggest that disruption in integration between distributed neural networks (particularly between prefrontal, cingulate and striatal brain regions) may be a key neurobiological feature of the extended psychosis phenotype.

Infection rate and colonization with antibiotic-resistant organisms in skilled nursing facility residents with indwelling devices.

The objective of this prospective surveillance study was to quantify colonization with antimicrobial-resistant organisms (AROs) and infections attributable to indwelling devices in skilled nursing facility (SNF) residents. The study was conducted in 15 SNFs in Southeast Michigan. Residents with (n=90) and without (n=88) an indwelling device were enrolled and followed for 907 resident-months. Residents were cultured monthly from multiple anatomic sites and data on infections were obtained. The device-attributable rate was calculated by subtracting the infection rate in the device group from the infection rate in the non-device group. A total of 197 new infections occurred during the study period; 87 in the device group (incidence rate [IR] =331/1,000 resident-months) and 110 infections in the non-device group (IR=171/1,000 resident-months), with a relative risk of 1.9 (95% confidence interval [CI]: 1.4-2.6). The attributable rate of excess infections among residents in the device group was 160/1,000 resident-months, with an attributable fraction of 48% (95% CI: 31-61%). Prevalence rates for all AROs were higher in the device group compared with the no-device group. The prevalence of the number of AROs per 1,000 residents cultured increased from no-device to those with only feeding tubes, followed by those with only urinary catheters and both these devices. In conclusion, the presence of indwelling devices is associated with higher incidence rates for infections and prevalence rates for AROs. Our study quantifies this risk and shows that approximately half of all infections in SNF residents with indwelling devices can be eliminated with device removal. Effective strategies to reduce infections and AROs in these residents are warranted.

Trends in classification, referral and treatment and the effect on outcome of patients with glioma: a 20 year cohort.

This retrospective audit was conducted to examine the changes in patient characteristics, referral, treatment and outcome over a 20-year period in a large regional neuro-oncology centre, focusing on the impact of the changes in pathological classification of gliomas. Using the Edinburgh Cancer Centre (ECC) database all cases of glioma were identified and patient, tumour and treatment characteristics noted. Survival was calculated from date of surgery or, if no operation was performed, the date of referral. Comparison was made between four periods 1988-1992 (c1), 1993-1997(c2), 1998-2002(c3) and 2003-2007 (c4). During the 20 years, 1175 patients with a glioma were referred to ECC. The median age increased from 53 years to 57 years (p < 0.001) but the proportion without pathology remained unchanged (10%). The distribution of pathological grades changed over time Grade I-II: 24, 6, 6, and 6%, Grade III: 42, 27, 17, and 13% and Grade IV: 24, 61, 68, and 68% in c1, c2, c3 and c4, respectively (p < 0.001). Immediate RT was given to 68% (c1), 70% (c2), 78% (c3) and 79% (c4). Median interval from resection to RT reduced from 43 days (c1) to 36 days (c4) (p < 0.001). 5-year overall survival for patients with Grade III lesions increased: 21% (c1), 35% (c2), 37% (c3), 33% (c4) as did 1-year overall survival for Grade IV lesions: 18% (c1), 26% (c2), 29% (c3), 27% (c4)). This improvement probably reflects the change in pathological classification rather than a change in management. Proportional hazards analysis of grade IV 1993-2007 only (to reduce pathological variation) showed that younger age, frontal lesions, excision, higher RT dose had reduced hazard of death. Interval from surgery to RT had no impact on survival in this series.

Carriage of Clostridium difficile and other enteric pathogens among a 4-H avocational cohort.

Clostridium difficile (CD), Salmonella, Campylobacter and enterohemorrhagic Escherichia coli (EHEC) are major causes of morbidity in a variety of enteric diseases in humans and animals, but subclinical carriage in both is probably more common than are clinical cases. Little is known regarding the prevalence of these pathogens in animals raised for exhibit at Michigan county fairs or the frequency with which Michigan citizens raising these animals may have been subclinically colonized. To address these issues, 361 fecal specimens from 158 humans and 203 of their farm animals were cultured for CD, Salmonella and Campylobacter. Additionally, 50 people and their cattle were tested for EHEC. No EHEC, Salmonella or Campylobacter were detected. However, 16 specimens (4.4%) were positive for CD: 13 humans, two horses and one pig. None of the farm animal specimens submitted by any of the 13 CD-positive humans were positive for CD. Strain characterization [toxinotype, pulsed-field gel electrophoresis (PFGE)] demonstrated that the human CD isolates were similar to what has been reported previously in the general US population. We conclude that horses and farm animals (cattle, sheep, goats and swine) at 1-2 months before market weight showed no evidence of wide-spread carriage of the common enteric pathogens, including the recently reported CD toxinotype V. These results provide no support to the hypothesis that 4-H members or others visiting county fair animal husbandry projects in these counties may be at increased risk for acquisition of CD, Salmonella, Campylobacter or EHEC from animals.

Head shop compound abuse amongst attendees of the Drug Treatment Centre Board.

The use of "Head Shop" compounds has received much media attention lately. There is very little research in the current literature with regard to the extent of the usage of these substances amongst the drug using population in Ireland. We conducted a study to examine the extent of the usage of Mephedrone, Methylone and BZP amongst attendees of Methadone maintenance programs at the DTCB. Two hundred and nine samples in total were tested. The results showed significant usage of these compounds amongst this cohort of drug users, with 29 (13.9%) of samples tested being positive for Mephedrone, 7 (3.3%) positive for Methylone and 1 (0.5%) positive for BZP.

Targeting PKC delta-mediated topoisomerase II beta overexpression subverts the differentiation block in a retinoic acid-resistant APL cell line.

Retinoic acid (RA) relieves the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. However, RA treatment alone invariably results in RA resistance, both in vivo and in vitro. RA-resistant cell lines have been shown to serve as useful models for elucidation of mechanisms of resistance. Previously, we identified topoisomerase II beta (TOP2B) as a novel mediator of RA-resistance in APL cell lines. In this study, we show that both TOP2B protein stability and activity are regulated by a member of the protein kinase C (PRKC) family, PRKC delta (PRKCD). Co-treatment with a pharmacologic inhibitor of PRKCD and RA resulted in the induction of an RA responsive reporter construct, as well as the endogenous RA target genes, CEBPE, CYP26A1 and RIG-I. Furthermore, the co-treatment overcame the differentiation block in RA-resistant cells, as assessed by morphological analysis, restoration of promyelocytic leukemia nuclear bodies, induction of CD11c cell surface expression and an increase in nitro-blue-tetrazolium reduction. Cumulatively, our data suggest a model whereby inhibition of PRKCD decreases TOP2B protein levels, leading to a loss of TOP2B-mediated repressive effects on RA-induced transcription and granulocytic differentiation.

Sediment transport in the saltation regime.

We present a study of sediment transport in the creeping and saltation regimes. In our model, a bed of particles is simulated with the conventional event-driven method. The particles are considered as hard disks in a two-dimensional domain with periodic boundary conditions in the horizontal direction. The flow of the fluid over this bed of particles is modeled by imposing a force on each particle that depends on the velocity of the fluid at its height above the bed. We consider two velocity profiles for the fluid, parabolic and logarithmic. The first one models laminar flow and the second corresponds to turbulent flow. For each case we investigate the behavior of the saturated flux. We find that for the logarithmic profile, the saturated flux shows a quadratic increase with the strength of the flow, and for parabolic profile, a cubic increase. The velocity distribution functions are used to interpret the results.

Microscopic origin of granular ratcheting.

Numerical simulations of assemblies of grains under cyclic loading exhibit "granular ratcheting:" a small net deformation occurs with each cycle, leading to a linear accumulation of deformation with cycle number. We show that this is due to a curious property of the most frequently used models of the particle-particle interaction: namely, that the potential energy stored in contacts is path dependent. There exist closed paths that change the stored energy, even if the particles remain in contact and do not slide. An alternative method for calculating the tangential force removes granular ratcheting.

Relationships among milk production, energy balance, plasma analytes, and reproduction in Holstein-Friesian cows.

Associations were examined between components and indicators of early lactation energy balance (EB) and measures of fertility in Holstein cows. Milk production, dry matter intake (DMI), body condition score (BCS), and endocrine and metabolite data from 96 cows were analyzed using multivariate logistic regression and survival analysis. Fertility variables investigated were interval to commencement of luteal activity (C-LA), calving to conception interval (CCI), and conception rate to first service (CON1). Mean daily EB, milk protein content, and DMI during the first 28 d in milk were associated positively with CON1. Cows having poorer BCS (< or =2.25) at first service had a lower CON1. Positive associations were identified among EB, milk protein content, DMI, and the likelihood of a shorter interval to C-LA. Cows having greater DMI and a more positive EB had an increased likelihood of a shorter CCI, whereas a lower nadir BCS was associated with an increased likelihood of a longer CCI. Milk yield was not associated with any of the fertility variables investigated. A greater plasma concentration of insulin-like growth factor I (IGF-I) during the first 2 wk of lactation was associated with a greater CON1 and an increased likelihood of a shorter interval to C-LA. In conclusion, we identified DMI as the principal component of EB influencing subsequent fertility. Furthermore, results indicate that milk protein content and plasma IGF-I concentration in early lactation may be useful indicators of reproductive efficiency.

Shearing behavior of polydisperse media.

We study the shearing of polydisperse and bidisperse media with a size ratio of 10. Simulations are performed with a two-dimensional shear cell using contact dynamics. With a truncated power law for the polydisperse media we find that they show a stronger dilatancy and greater resistance to shearing than bidisperse mixtures. To model additives used to control viscosity we introduce so-called "point-like particles". Even changing the kinematic behavior very little, the point-like particles reduce the force necessary to maintain a fixed shearing velocity.