Doped GeSe materials for selector applications

We report on the thermal and electrical performance of nitrogen (N) and carbon (C) doped GeSe thin films for selector applications. Doping of GeSe successfully improved its thermal stability to 450 degrees C. N doping led to a decrease in the off-state leakage and an increase in threshold voltage (V-th), while C doping led to an increase in leakage and reduced V-th. Hence, we show an effective method to tune the electrical parameters of GeSe selectors by using N and C as dopants

Influence of soil characteristics and metal(loid)s on antibiotic resistance genes in green stormwater infrastructure in Southern California

The synergetic effects of metal(loid)s and soil characteristics on bacterial antibiotic resistance genes (ARGs) in green stormwater infrastructure (GSI) has been relatively understudied. Surface soil samples from six GSIs in Southern California over three time periods were assessed for selected ARGs, class 1 integron-integrase genes (intI1), 16S rRNA genes, and bioavailable and total concentrations of nine metal(loid)s, to investigate the relationships among ARGs, soil characteristics, and co-occurring metal(loid)s. Significant correlations existed among relative gene abundances (sul1, sul2, tetW, and intI1), total metal(loid)s (arsenic, copper, lead, vanadium, and zinc), and bioavailable metal(loid) (arsenic) (r = 0.29-0.61, padj < 0.05). Additionally, soil texture, organic matter, and nutrients within GSI appeared to be significantly correlated with relative gene abundances of sul1, sul2, and tetW (r = -0.57 to 0.59, padj < 0.05). Multiple regression models significantly improved the estimation of ARGs in GSI when considering multiple effects of soil characteristics and metal(loid)s (r = 0.74, padj < 0.001) compared to correlation results. Total arsenic was a significant (positive) correlate in all the regression models of relative gene abundances. This work provides new insights into co-dependencies between GSI ARGs and co-occurring metal(loid)s, indicating the need for risk assessment of metal(loid)-influenced ARG proliferation

Mechanically assisted electrochemical degradation of alumina-TiC composites

Alumina-TiC composite material is a tough ceramic composite with excellent hardness, wear resistance and oxidation resistance in dry and high-temperature conditions. In aqueous conditions, however, it is likely to be electrochemically active facilitating charge transfer processes due to the conductive nature of TiC. For application as an orthopedic biomaterial, it is crucial to assess the electrochemical behavior of this composite, especially under a combined mechanical and electrochemical environment. In this study, we examined the mechanically assisted electrochemical performance of alumina-TiC composite in an aqueous environment. The spontaneous electrochemical response to brushing abrasion was measured. Changes in the magnitude of electrochemical current with abrasion test conditions and possible causal relationship to the alteration in surface morphology were examined. Results showed that the alumina matrix underwent abrasive wear with evidence of microploughing and grain boundary damage. Chemical analysis revealed TiO2 formation in the abraded region, indicating oxidation of the conductive TiC domain. Furthermore, wear debris from alumina abrasion appeared to affect reaction kinetics at the composite-electrolyte interface. From this work, we established that the composite undergoes abrasion assisted electrochemical degradation even in gentle abrasive conditions and the severity of degradation is related to temperature and conditions of test environment

Recommendations for essential medicines for multiple sclerosis in low-resource settings

Background: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that, when untreated, can lead to significant disability in young adults. Despite the increase in the number of disease-modifying therapies (DMTs), many people living with MS in low-resource settings do not have access to treatment. Objective: The primary aim was to develop recommendations on the minimum essential DMTs for MS that should be available in low-resource settings. Methods: The Multiple Sclerosis International Federation established an independent, international panel including healthcare professionals and people with MS. This panel, in collaboration with the Cochrane MS Group and McMaster GRADE Centre, reviewed evidence for use of MS DMTs following standardized GRADE protocols including consideration of balance of benefits and harms; certainty of evidence; resources required and cost-effectiveness and values, equity, feasibility and availability in low-resource settings. Results: For active and/or worsening forms of relapsing MS, the panel recommends use of ocrelizumab, cladribine, fingolimod, dimethyl fumarate, interferon beta and glatiramer acetate. For active and/or worsening forms of progressive MS, the panel recommends use of rituximab, ocrelizumab, glatiramer acetate, fingolimod and interferon beta. Conclusions: Recommendations for the minimum essential DMTs for MS in low-resource settings were developed based on robust consideration of evidence and relevant context

Women’s, partners’ and healthcare providers’ views and experiences of assisted vaginal birth: a systematic mixed methods review

Background When certain complications arise during the second stage of labour, assisted vaginal delivery (AVD), a vaginal birth with forceps or vacuum extractor, can effectively improve outcomes by ending prolonged labour or by ensuring rapid birth in response to maternal or fetal compromise. In recent decades, the use of AVD has decreased in many settings in favour of caesarean section (CS). This review aimed to improve understanding of experiences, barriers and facilitators for AVD use. Methods Systematic searches of eight databases using predefined search terms to identify studies reporting views and experiences of maternity service users, their partners, health care providers, policymakers, and funders in relation to AVD. Relevant studies were assessed for methodological quality. Qualitative findings were synthesised using a meta-ethnographic approach. Confidence in review findings was assessed using GRADE CERQual. Findings from quantitative studies were synthesised narratively and assessed using an adaptation of CERQual. Qualitative and quantitative review findings were triangulated using a convergence coding matrix. Results Forty-two studies (published 1985–2019) were included: six qualitative, one mixed-method and 35 quantitative. Thirty-five were from high-income countries, and seven from LMIC settings. Confidence in the findings was moderate or low. Spontaneous vaginal birth was most likely to be associated with positive short and long-term outcomes, and emergency CS least likely. Views and experiences of AVD tended to fall somewhere between these two extremes. Where indicated, AVD can be an effective, acceptable alternative to caesarean section. There was agreement or partial agreement across qualitative studies and surveys that the experience of AVD is impacted by the unexpected nature of events and, particularly in high-income settings, unmet expectations. Positive relationships, good communication, involvement in decision-making, and (believing in) the reason for intervention were important mediators of birth experience. Professional attitudes and skills (development) were simultaneously barriers and facilitators of AVD in quantitative studies. Conclusions Information, positive interaction and communication with providers and respectful care are facilitators for acceptance of AVD. Barriers include lack of training and skills for decision-making and use of instruments

Analysis of NAMCS data for multiple sclerosis, 1998–2004

BACKGROUND: To our knowledge, no study to date has investigated the prescribing patterns of immunomodulatory agents (IMAs) in an outpatient setting in the United States. To address this issue, we performed retrospective data analyses on National Ambulatory Medical Care Survey (NAMCS) data for MS patient visits between 1998 and 2004. METHODS: NAMCS data are a weighted estimate of the nationwide frequency of patients' outpatient clinic visits. We analyzed NAMCS data in the following categories: (1) the proportion of MS patient visits to neurologists, family practitioners or internists, (2) age/gender/race/geographical distribution patterns in patient visits, and (3) the proportion of patients on IMA treatment among established MS patients. RESULTS: There were an estimated 6.7 million multiple sclerosis (MS) patient visits to the clinics between 1998–2004. Neurologists recorded the most patient visits, 50.7%. Patient visits were mostly in the fourth and fifth decade age group (57.9%). The male to female ratio was 1:4. No statistical evidence was observed for a decline or increase in IMA usage. About 62% patients visiting neurologists and 92% seen by family practitioners/internists were not using IMAs. Our results suggest that between the years 1998–2003, the use of interferon-1a tended to decline while the use of interferon-1b and glatiramer acetate, increased. CONCLUSION: Strategies that lead to improved use of IMAs in the management of MS in the outpatient setting are needed

Mitoxantrone Induces Natural Killer Cell Maturation in Patients with Secondary Progressive Multiple Sclerosis

Mitoxantrone is one of the few drugs approved for the treatment of progressive multiple sclerosis (MS). However, the prolonged use of this potent immunosuppressive agent is limited by the appearance of severe side effects. Apart from its general cytotoxic effect, the mode of action of mitoxantrone on the immune system is poorly understood. Thus, to develop safe therapeutic approaches for patients with progressive MS, it is essential to elucidate how mitoxantrone exerts it benefits. Accordingly, we initiated a prospective single-arm open-label study with 19 secondary progressive MS patients. We investigated long-term effects of mitoxantrone on patient peripheral immune subsets using flow cytometry. While we corroborate that mitoxantrone persistently suppresses B cells in vivo, we show for the first time that treatment led to an enrichment of neutrophils and immunomodulatory CD8low T cells. Moreover, sustained mitoxantrone applications promoted not only persistent NK cell enrichment but also NK cell maturation. Importantly, this mitoxantrone-induced NK cell maturation was seen only in patients that showed a clinical response to treatment. Our data emphasize the complex immunomodulatory role of mitoxantrone, which may account for its benefit in MS. In particular, these results highlight the contribution of NK cells to mitoxantrone efficacy in progressive MS

Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis

Atypical imaging features of multiple sclerosis lesions include size >2 cm, mass effect, oedema and/or ring enhancement. This constellation is often referred to as ‘tumefactive multiple sclerosis’. Previous series emphasize their unifocal and clinically isolated nature, however, evolution of these lesions is not well defined. Biopsy may be required for diagnosis. We describe clinical and radiographic features in 168 patients with biopsy confirmed CNS inflammatory demyelinating disease (IDD). Lesions were analysed on pre- and post-biopsy magnetic resonance imaging (MRI) for location, size, mass effect/oedema, enhancement, multifocality and fulfilment of Barkhof criteria. Clinical data were correlated to MRI. Female to male ratio was 1.2 : 1, median age at onset, 37 years, duration between symptom onset and biopsy, 7.1 weeks and total disease duration, 3.9 years. Clinical course prior to biopsy was a first neurological event in 61%, relapsing–remitting in 29% and progressive in 4%. Presentations were typically polysymptomatic, with motor, cognitive and sensory symptoms predominating. Aphasia, agnosia, seizures and visual field defects were observed. At follow-up, 70% developed definite multiple sclerosis, and 14% had an isolated demyelinating syndrome. Median time to second attack was 4.8 years, and median EDSS at follow-up was 3.0. Multiple lesions were present in 70% on pre-biopsy MRI, and in 83% by last MRI, with Barkhof criteria fulfilled in 46% prior to biopsy and 55% by follow-up. Only 17% of cases remained unifocal. Median largest lesion size on T2-weighted images was 4 cm (range 0.5–12), with a discernible size of 2.1 cm (range 0.5–7.5). Biopsied lesions demonstrated mass effect in 45% and oedema in 77%. A strong association was found between lesion size, and presence of mass effect and/or oedema (P < 0.001). Ring enhancement was frequent. Most tumefactive features did not correlate with gender, course or diagnosis. Although lesion size >5 cm was associated with a slightly higher EDSS at last follow-up, long-term prognosis in patients with disease duration >10 years was better (EDSS 1.5) compared with a population-based multiple sclerosis cohort matched for disease duration (EDSS 3.5; P < 0.001). Given the retrospective nature of the study, the precise reason for biopsy could not always be determined. This study underscores the diagnostically challenging nature of CNS IDDs that present with atypical clinical or radiographic features. Most have multifocal disease at onset, and develop RRMS by follow-up. Although increased awareness of this broad spectrum may obviate need for biopsy in many circumstances, an important role for diagnostic brain biopsy may be required in some cases

Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity

BACKGROUND: Processing by gamma-secretase of many type-I membrane protein substrates triggers signaling cascades by releasing intracellular domains (ICDs) that, following nuclear translocation, modulate the transcription of different genes regulating a diverse array of cellular and biological processes. Because the list of gamma-secretase substrates is growing quickly and this enzyme is a cancer and Alzheimer's disease therapeutic target, the mapping of gamma-secretase activity susceptible gene transcription is important for sharpening our view of specific affected genes, molecular functions and biological pathways. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes and molecular functions transcriptionally affected by gamma-secretase activity, the cellular transcriptomes of Chinese hamster ovary (CHO) cells with enhanced and inhibited gamma-secretase activity were analyzed and compared by cDNA microarray. The functional clustering by FatiGO of the 1,981 identified genes revealed over- and under-represented groups with multiple activities and functions. Single genes with the most pronounced transcriptional susceptibility to gamma-secretase activity were evaluated by real-time PCR. Among the 21 validated genes, the strikingly decreased transcription of PTPRG and AMN1 and increased transcription of UPP1 potentially support data on cell cycle disturbances relevant to cancer, stem cell and neurodegenerative diseases' research. The mapping of interactions of proteins encoded by the validated genes exclusively relied on evidence-based data and revealed broad effects on Wnt pathway members, including WNT3A and DVL3. Intriguingly, the transcription of TERA, a gene of unknown function, is affected by gamma-secretase activity and was significantly altered in the analyzed human Alzheimer's disease brain cortices. CONCLUSIONS/SIGNIFICANCE: Investigating the effects of gamma-secretase activity on gene transcription has revealed several affected clusters of molecular functions and, more specifically, 21 genes that hold significant potential for a better understanding of the biology of gamma-secretase and its roles in cancer and Alzheimer's disease pathology