Use of smartphone-based remote assessments of multiple sclerosis in Floodlight Open, a global, prospective, open-access study.

Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a 'bring-your-own-device' solution that remotely measures a user's mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input ('active tests'). Levels of mobility of study participants ('life-space measurement') were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.

Evaluation of a national database of completed investigations into radiology service complaints in New Zealand: What can the radiologist, and radiology service providers, learn?

INTRODUCTION: The Health and Disability Commissioner (HDC) is responsible for dealing with most complaints from service users resulting from their interactions with a healthcare service provider in New Zealand. We analysed all published reports involving a radiologist or radiology service in order to gain insights that might promote safer working across the radiology community. METHODS: We searched the entire HDC online report database choosing a limit of 'radiologist' as occupation. RESULTS: Twenty-seven investigations were included, published between 1999 and 2021. Seventeen (63%) involved private radiology providers and 10 (37%) involved public providers. Ultrasound featured in 12 cases (44%), x-ray 6 (22%), CT 5 (19%), mammography 2 (7%), MRI 1 (4%) and interventional 1 (4%). Obstetric ultrasound accounted for 9 (75%) of the ultrasound cases. In 24 (89%) cases, the HDC felt an error had been made. Of the 34 radiologists investigated, 21 (62%) were found in breach of the HDC code, with adverse comment made regarding 4 (12%). A total of 46 incidences of different error types were identified including: communication 14 (30%), perceptual 11 (24%), technical 8 (17%) and interpretative 7 (15%). Forty-five incidences of contributing factors were identified, including organizational 9 (20%) and clinical information provided 7 (16%). CONCLUSION: Errors in radiology practice, leading to complaints, are often multifactorial and systemic. Reflection on the myriad of error types and contributing factors (including 'human factors') is imperative to reduce errors. Multifaceted strategies are likely required for radiologists to enhance their systems and practice.

Smartphone- and Smartwatch-Based Remote Characterisation of Ambulation in Multiple Sclerosis During the Two-Minute Walk Test.

Leveraging consumer technology such as smartphone and smartwatch devices to objectively assess people with multiple sclerosis (PwMS) remotely could capture unique aspects of disease progression. This study explores the feasibility of assessing PwMS and Healthy Control's (HC) physical function by characterising gait-related features, which can be modelled using machine learning (ML) techniques to correctly distinguish subgroups of PwMS from healthy controls. A total of 97 subjects (24 HC subjects, 52 mildly disabled (PwMSmild, EDSS [0-3]) and 21 moderately disabled (PwMSmod, EDSS [3.5-5.5]) contributed data which was recorded from a Two-Minute Walk Test (2MWT) performed out-of-clinic and daily over a 24-week period. Signal-based features relating to movement were extracted from sensors in smartphone and smartwatch devices. A large number of features (n = 156) showed fair-to-strong (R 0.3) correlations with clinical outcomes. LASSO feature selection was applied to select and rank subsets of features used for dichotomous classification between subject groups, which were compared using Logistic Regression (LR), Support Vector Machines (SVM) and Random Forest (RF) models. Classifications of subject types were compared using data obtained from smartphone, smartwatch and the fusion of features from both devices. Models built on smartphone features alone achieved the highest classification performance, indicating that accurate and remote measurement of the ambulatory characteristics of HC and PwMS can be achieved with only one device. It was observed however that smartphone-based performance was affected by inconsistent placement location (running belt versus pocket). Results show that PwMSmod could be distinguished from HC subjects (Acc. 82.2 ± 2.9%, Sen. 80.1 ± 3.9%, Spec. 87.2 ± 4.2%, F 1 84.3 ± 3.8), and PwMSmild (Acc. 82.3 ± 1.9%, Sen. 71.6 ± 4.2%, Spec. 87.0 ± 3.2%, F 1 75.1 ± 2.2) using an SVM classifier with a Radial Basis Function (RBF). PwMSmild were shown to exhibit HC-like behaviour and were thus less distinguishable from HC (Acc. 66.4 ± 4.5%, Sen. 67.5 ± 5.7%, Spec. 60.3 ± 6.7%, F 1 58.6 ± 5.8). Finally, it was observed that subjects in this study demonstrated low intra- and high inter-subject variability which was representative of subject-specific gait characteristics.

Preventable Patient Harm: a Multidisciplinary, Bundled Approach to Reducing Clostridium difficile Infections While Using a Glutamate Dehydrogenase/Toxin Immunochromatographic Assay/Nucleic Acid Amplification Test Diagnostic Algorithm.

Health care facility-onset Clostridium difficile infections (HO-CDI) are an important national problem, causing increased morbidity and mortality. HO-CDI is an important metric for the Center for Medicare and Medicaid Service's (CMS) performance measures. Hospitals that fall into the worst-performing quartile in preventing hospital-acquired infections, including HO-CDI, may lose millions of dollars in reimbursement. Under pressure to reduce CDI and without a clear optimal method for C. difficile detection, health care facilities are questioning how best to use highly sensitive nucleic acid amplification tests (NAATs) to aid in the diagnosis of CDI. Our institution has used a two-step glutamate dehydrogenase (GDH)/toxin immunochromatographic assay/NAAT algorithm since 2009. In 2016, our institution set an organizational goal to reduce our CDI rates by 10% by July 2017. We achieved a statistically significant reduction of 42.7% in our HO-CDI rate by forming a multidisciplinary group to implement and monitor eight key categories of infection prevention interventions over a period of 13 months. Notably, we achieved this reduction without modifying our laboratory algorithm. Significant reductions in CDI rates can be achieved without altering sensitive laboratory testing methods.

Highly-Integrated Hydraulic Smart Actuators and Smart Manifolds for High-Bandwidth Force Control.

Hydraulic actuation is the most widely used alternative to electric motors for legged robots and manipulators. It is often selected for its high power density, robustness and high-bandwidth control performance that allows the implementation of force/impedance control. Force control is crucial for robots that are in contact with the environment, since it enables the implementation of active impedance and whole body control that can lead to a better performance in known and unknown environments. This paper presents the hydraulic Integrated Smart Actuator (ISA) developed by Moog in collaboration with IIT, as well as smart manifolds for rotary hydraulic actuators. The ISA consists of an additive-manufactured body containing a hydraulic cylinder, servo valve, pressure/position/load/temperature sensing, overload protection and electronics for control and communication. The ISA v2 and ISA v5 have been specifically designed to fit into the legs of IIT's hydraulic quadruped robots HyQ and HyQ-REAL, respectively. The key features of these components tackle 3 of today's main challenges of hydraulic actuation for legged robots through: (1) built-in controllers running inside integrated electronics for high-performance control, (2) low-leakage servo valves for reduced energy losses, and (3) compactness thanks to metal additive manufacturing. The main contributions of this paper are the derivation of the representative dynamic models of these highly integrated hydraulic servo actuators, a control architecture that allows for high-bandwidth force control and their experimental validation with application-specific trajectories and tests. We believe that this is the first work that presents additive-manufactured, highly integrated hydraulic smart actuators for robotics.

MicroRNA regulation of bovine monocyte inflammatory and metabolic networks in an in vivo infection model.

Bovine mastitis is an inflammation-driven disease of the bovine mammary gland that costs the global dairy industry several billion dollars per year. Because disease susceptibility is a multifactorial complex phenotype, an integrative biology approach is required to dissect the molecular networks involved. Here, we report such an approach using next-generation sequencing combined with advanced network and pathway biology methods to simultaneously profile mRNA and miRNA expression at multiple time points (0, 12, 24, 36 and 48 hr) in milk and blood FACS-isolated CD14(+) monocytes from animals infected in vivo with Streptococcus uberis. More than 3700 differentially expressed (DE) genes were identified in milk-isolated monocytes (MIMs), a key immune cell recruited to the site of infection during mastitis. Upregulated genes were significantly enriched for inflammatory pathways, whereas downregulated genes were enriched for nonglycolytic metabolic pathways. Monocyte transcriptional changes in the blood, however, were more subtle but highlighted the impact of this infection systemically. Genes upregulated in blood-isolated monocytes (BIMs) showed a significant association with interferon and chemokine signaling. Furthermore, 26 miRNAs were DE in MIMs and three were DE in BIMs. Pathway analysis revealed that predicted targets of downregulated miRNAs were highly enriched for roles in innate immunity (FDR < 3.4E-8), particularly TLR signaling, whereas upregulated miRNAs preferentially targeted genes involved in metabolism. We conclude that during S. uberis infection miRNAs are key amplifiers of monocyte inflammatory response networks and repressors of several metabolic pathways.

Satellite cells say NO to radiation.

Skeletal muscles are commonly exposed to radiation for diagnostic procedures and the treatment of cancers and heterotopic bone formation. Few studies have considered the impact of clinical doses of radiation on the ability of satellite cells (myogenic stem cells) to proliferate, differentiate and contribute to recovering/maintaining muscle mass. The primary objective of this study was to determine whether the proliferation of irradiated satellite cells could be rescued by manipulating NO levels via pharmacological approaches and mechanical stretch (which is known to increase NO levels). We used both SNP (NO donor) and PTIO (NO scavenger) to manipulate NO levels in satellite cells. We observed that SNP was highly effective in rescuing the proliferation of irradiated satellite cells, especially at doses less than 5 Gy. The potential importance of NO was further illustrated by the effects of PTIO, which completely inhibited the rescue effect of SNP. Mechanical cyclic stretch was found to produce significant increases in NO levels of irradiated satellite cells, and this was associated with a robust increase in satellite cell proliferation. The effects of both radiation and NO on two key myogenic regulatory factors (MyoD and myogenin) were also explored. Irradiation of satellite cells produced a significant increase in both MyoD and myogenin, effects that were mitigated by manipulating NO levels via SNP. Given the central role of myogenic regulatory factors in the proliferation and differentiation of satellite cells, the findings of the current study underscore the need to more fully understand the relationship between radiation, NO and the functionality of satellite cells.

The radiosensitivity of satellite cells: cell cycle regulation, apoptosis and oxidative stress.

Skeletal muscles are the organ of movement, and their growth, regeneration and maintenance are dependent in large part on a population of myogenic stem cells known as satellite cells. Skeletal muscles and these resident myogenic stem cells (i.e., satellite cells) are commonly exposed to significant doses of radiation during diagnostic procedures and/or during the radiotherapeutic management of cancer. The main objective of this study was to examine the effects of clinically relevant doses of γ radiation on satellite cell survival and proliferation, cell cycle regulation, apoptosis, DNA double-strand break repair, oxidative stress and NO production. Overall, our findings demonstrate that doses of γ radiation ≥5 Gy reduced satellite cell numbers by at least 70% due in part to elevated apoptosis and the inhibition of cell cycle progression. Radiation was also found to cause a significant and persistent increase in the level of reactive oxygen and nitrogen species. Interestingly, and within this backdrop of elevated oxidative stress, similar doses were found to produce substantial reductions in the levels of nitric oxide (NO). Proliferation of satellite cells has been shown to depend in part on the production of NO, and our findings give rise to the possibility that radiation-induced reductions in NO levels may provide a mechanism for the inhibition of satellite cell proliferation in vitro and possibly the regrowth of skeletal muscle exposed during clinical irradiation procedures.

Paternal cranial irradiation induces distant bystander DNA damage in the germline and leads to epigenetic alterations in the offspring.

It is now well accepted that parental whole body irradiation causes transgenerational genome and epigenome instability in the offspring. The majority of human exposures to radiation, such as therapeutic and diagnostic irradiation, are localized and focused. The potential of localized body-part exposures to affect the germline and thus induce deleterious changes in the progeny has not been studied. To investigate whether or not the paternal cranial irradiation can exert deleterious changes in the protected germline, we studied the accumulation of DNA damage in the shielded testes tissue. Here we report that the localized paternal cranial irradiation results in a significant accumulation of unrepaired DNA lesions in sperm cells and leads to a profound epigenetic dysregulation in the unexposed progeny conceived a week after paternal exposure.

Radiation-induced molecular changes in rat mammary tissue: possible implications for radiation-induced carcinogenesis.

PURPOSE: Ionizing radiation is a potent mammary gland carcinogen, yet the exact molecular etiology of radiation-induced breast cancer remains unknown. MATERIALS AND METHODS: Our study utilized a rat model of breast carcinogenesis to analyse the molecular and epigenetic changes induced in mammary gland tissue upon exposure to ionizing radiation (IR). Using a methylation-sensitive cytosine extension assay we studied the IR-induced changes in DNA methylation. In parallel, we analysed the expression of proteins involved in DNA methylation, DNA repair and cell proliferation control. Molecular changes were related to cellular proliferation and apoptosis. RESULTS: We found that IR led to a loss of genomic cytosine methylation in the exposed mammary tissue. Global DNA hypomethylation was paralleled by reduction in the levels of maintenance (DNMT1) and de novo (DNMT3a and 3b) DNA methyltransferases and methyl-binding protein MeCP2. The observed DNA hypomethylation was linked, at least in part, to activation of DNA repair processes. Concurrently, we observed increased levels of phosphorylated extracellular signal-regulated kinase (p-ERK1/2), phosphorylated AKT kinase (p-AKT), cyclin D1 and proliferating cells nuclear antigen (PCNA) proteins, suggesting IR alters intra-cellular signaling and cell cycle control mechanisms in mammary tissue. We also noted a significant induction of apoptosis in the exposed tissue 6 hours after irradiation. The observed apoptosis levels were paralleled by the slight elevation of cellular proliferation. CONCLUSIONS: We have demonstrated that a single exposure to 5 Gy of X rays leads to noticeable epigenetic changes in the rat mammary gland that occurred in the context of activation of DNA damage repair and alterations in the pro-survival growth-stimulatory cellular signaling pathways. The possible cellular repercussions of the observed changes in relationship to breast carcinogenesis are discussed.

Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo.

PURPOSE: Although modern cancer radiation therapy has led to increased patient survival rates, the risk of radiation treatment-related complications is becoming a growing problem. Among various complications, radiation also poses a threat to the progeny of exposed parents. It causes transgenerational genome instability that is linked to transgenerational carcinogenesis. Although the occurrence of transgenerational genome instability, which manifests as elevated delayed and nontargeted mutation, has been well documented, the mechanisms by which it arises remain obscure. We hypothesized that epigenetic alterations may play a pivotal role in the molecular etiology of transgenerational genome instability. METHODS AND MATERIALS: We studied the levels of cytosine DNA methylation in somatic tissues of unexposed offspring upon maternal, paternal, or combined parental exposure. RESULTS: We observed a significant loss of global cytosine DNA methylation in the thymus tissue of the offspring upon combined parental exposure. The loss of DNA methylation was paralleled by a significant decrease in the levels of maintenance (DNMT1) and de novo methyltransferases DNMT3a and 3b and methyl-CpG-binding protein MeCP2. Along with profound changes in DNA methylation, we noted a significant accumulation of DNA strand breaks in thymus, which is a radiation carcinogenesis target organ. CONCLUSIONS: The observed changes were indicative of a profound epigenetic dysregulation in the offspring, which in turn could lead to genome destabilization and possibly could serve as precursor for transgenerational carcinogenesis. Future studies are clearly needed to address the cellular and carcinogenic repercussions of those changes.

Novel retinoblastoma binding protein RBBP9 modulates sex-specific radiation responses in vivo.

Retinoblastoma (RB) tumor suppressor is a key regulator of apoptosis, a central mediator of the proliferative block induced by ionizing radiation (IR) and a binding target for a variety of proteins that regulate its activity. One of the recently discovered and the least investigated of these is the novel Rb-binding protein RBBP9/BOG. We studied the effects of acute and chronic low dose radiation (LDR) exposure on the induction of RBBP9 and RB signaling pathway in vivo in mouse spleen and found that RBBP9 played a pivotal role in IR responses in vivo. We observed that chronic LDR exposure led to a significant increase of RBBP9 expression in males and a significant decrease in females. Elevated RBBP9 expression in males was paralleled by a pronounced dephosphorylation of RB and a significant drop of PCNA and cyclin A expression. On the contrary, chronic exposure in females led to decreased levels of RBBP9 and increased levels of hyperphosphorylated RB (ppRB) in spleen. Decreased levels of ppRB in spleen of chronically exposed males were correlated with strongly elevated apoptotic rates. In females, the radiation-induced increase of apoptotic index was much less pronounced. Quite surprisingly, the observed sex-specific signaling changes did not result in the sex-specificity of cellular proliferation. The molecular mechanisms and possible repercussions of the radiation-induced sex differences in cellular proliferation and apoptosis are discussed.