Pulsed laser ignition of reactive multilayer films

Nanostructured Al/PtAl∕Pt multilayer films were ignited by single pulse irradiation from a Ti:sapphire femtosecond laser system. Critical ignition fluences (0.9–22 J/cm2)(0.9–22J∕cm2) required to initiate a self-propagating reaction were quantified for different multilayer designs. Multilayers with smaller bilayer thickness required relatively lower fluence for ignition. Ignition threshold fluence was also found to be 1.4–3.6 times higher for Al-capped multilayers than for Pt-capped multilayers. Ablation threshold fluences were measured for Al (860±70 mJ/cm2)(860±70mJ∕cm2) and Pt (540±50 mJ/cm2)(540±50mJ∕cm2) and related to the observed difference in ignition fluences for Al- and Pt-capped multilayers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87770/2/144102_1.pd

Human 3D cellular model of hypoxic brain injury of prematurity.

Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain

Changes in presentations with features potentially indicating cancer in primary care during the COVID-19 pandemic:a retrospective cohort study

OBJECTIVES: To investigate how the COVID-19 pandemic affected the number of people aged 50+ years presenting to primary care with features that could potentially indicate cancer, and to explore how reporting differed by patient characteristics and in face-to-face vs remote consultations. DESIGN, SETTING AND PARTICIPANTS: A retrospective cohort study of general practitioner (GP), nurse and paramedic primary care consultations in 21 practices in South-West England covering 123 947 patients. The models compared potential cancer indicators reported in April–July 2019 with April–July 2020. MAIN OUTCOME MEASURES: Potential indicators of cancer were identified using code lists for symptoms, signs, test results and diagnoses listed in the National Institute for Health and Care Excellence suspected cancer referral guidance (NG12). RESULTS: During April–July 2019, 17% of registered patients aged 50+ years reported a potential cancer indicator in a consultation with a GP or nurse. During April–July 2020, this reduced to 11% (incidence rate ratio (IRR) 0.64, 95% CI 0.62 to 0.67, p<0.001). Reductions in potential cancer indicators were stable across age group, sex, ethnicity, index of multiple deprivation quintile and shielding status, but less marked in patients with mental health conditions than without (IRR 0.75, 95% CI 0.72 to 0.79, interaction p<0.001). Proportions of GP consultations with potential indicators of cancer reduced between 2019 and 2020 for face-to-face consultations (IRR 0.84, 95% CI 0.76 to 0.92, p<0.001) and increased for remote consultations (IRR 1.17, 95% CI 1.07 to 1.29, p=0.001), although it remained lower in remote consulting than face-to-face in April–July 2020. This difference was greater for nurse/paramedic consultations (face-to-face: IRR 0.61, 95% CI 0.44 to 0.83, p=0.002; remote: IRR 1.60, 95% CI 1.10 to 2.333, p=0.014). CONCLUSION: The number of patients consulting with presentations that could potentially indicate cancer reduced during the first wave of the COVID-19 pandemic. Patients should be encouraged to continue contacting primary care for persistent signs and symptoms, and GPs and nurses should be encouraged to probe patients for further information during remote consulting, in the absence of non-verbal cues

Physiotherapy for adults with joint hypermobility syndrome: A pilot randomised controlled trial

Background: Joint Hypermobility Syndrome (JHS) is a heritable disorder associated with laxity and pain in multiple joints. Physiotherapy is the mainstay of treatment but there is little research investigating its effectiveness. The aim of this study was therefore to conduct a pilot randomised controlled trial (RCT) to determine the feasibility of conducting a future definitive RCT. Methods: A comprehensive physiotherapy intervention was developed in conjunction with patients and healthcare professionals. It was then piloted and refined on the basis of patient and physiotherapist feedback. A parallel two-arm pilot RCT in two UK secondary care NHS Trusts compared 'Advice' against 'Advice & Physiotherapy'. Inclusion criteria were: >16 years, a diagnosis of JHS, and no other musculoskeletal conditions causing pain. The Advice intervention was a one-off session, supplemented by advice booklets from the Hypermobility Syndromes Association and Arthritis Research UK. All patients could ask questions specific to their circumstances and received tailored advice. Participants were then randomly allocated to 'Advice' (no further advice or physiotherapy) or 'Advice & Physiotherapy' (an additional six 30 minute sessions over 4 months). The Physiotherapy intervention was supported by a patient handbook and delivered on a one-to-one patient-therapist basis. It aimed to increase patients’ physical activity through developing knowledge, understanding and skills to better manage their condition. The primary outcome related to the feasibility of conducting a future definitive RCT. Qualitative interviews with patients and physiotherapists therefore formed a major component of data collection. Secondary outcomes included clinical measures (physical function, pain, global status, self-reported joint count, quality of life, exercise self-efficacy and adverse events); resource use (to estimate cost-effectiveness); and an estimate of the value of information from a future RCT. Outcomes were recorded at baseline, 4 months (at the end of physiotherapy) and 7 months (3 months following physiotherapy). Results: A total of n=29 participants were recruited to the pilot RCT. Recruitment was challenging, primarily due to a perceived lack of equipoise between Advice and Physiotherapy. The qualitative evaluation provided very clear guidance to inform a future RCT, including enhancement of the Advice intervention. Some patients reported that the Advice intervention was useful and the Physiotherapy intervention was evaluated very positively. The rate of return of questionnaires was low within the Advice group but reasonable in the Physiotherapy group. The Physiotherapy intervention showed evidence of promise in terms of primary and secondary clinical outcomes. The Advice arm experienced more adverse events. The value of information estimate indicated the potential for high value from a future RCT. Conclusion: A future definitive RCT of physiotherapy for JHS seems feasible, although the Advice intervention should be made more robust to address perceived equipoise and subsequent attrition

Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin-A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF). The effect of HLA-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients that were exposed to Aa. These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA

Assessing the risk of residues of the toxin indospicine in bovine muscle and liver from north-west Australia

Indospicine is a natural toxin occurring only in Indigofera plant species, including the Australian native species I. linnaei. These perennial legumes are resistant to drought and palatable to grazing livestock including cattle. Indospicine accumulates in the tissues (including muscle) of animals grazing Indigofera and these residues persist for several months after exposure. Dogs are particularly sensitive to indospicine with reports in past decades of hepatotoxicosis and mortalities in dogs after dietary exposure to indospicine-contaminated horse and camel meat. The risk for human consumption is not known, and the current study was undertaken to assess indospicine levels in cattle going to slaughter from divergent regions of Western Australia, and to predict the likelihood of significant residues being present. Muscle and corresponding liver samples from 776 cattle originating from the Kimberley and Pilbara Regions in the tropical north of the state, where I. linnaei is prevalent, and 640 cattle from the South West and South Coast Regions in the temperate south west of the state, where the plant is not known to occur, were collected at abattoirs over four seasons in 2015-2017. Indospicine levels were measured by LC-MS/MS and ranged from below detection to 3.63 mg/kg. No indospicine residues were detected in any of the animals originating from the South West and South Coast Regions. Prevalence of indospicine residues in cattle from the Kimberley Region was as high as 33% in spring and 90% in autumn, with positive animals being present in most consignments and on most properties. The average prevalence of indospicine residues from the Kimberley and Pilbara Regions throughout the survey period was 62%. @Risk best fit probability distributions showed ninety-fifth percentile (P95) indospicine concentrations of 0.54 mg/kg for muscle and 0.77 mg/kg for liver in cattle originating from the Kimberley and Pilbara Regions during the survey period. When considered with average Australian meat consumption data, the estimated consumer exposure from this P95 muscle was 0.32 μg indospicine/kg bw/day, which compared favourably with our calculated provisional tolerable daily intake (PTDI) of 1.3 μg indospicine/kg bw/day. However canine exposure is of potential concern, with active working dog exposure calculated to exceed this PTDI by a factor of 25, based on a P95 indospicine concentration of 0.54 mg/kg in muscle

Cosmetic outcomes and quality of life in children with cardiac implantable electronic devices

BackgroundAxillary implant location is an alternative implant location in patients for cardiac implantable electronic devices (CIEDs) for the purposes of improved cosmetic outcome. The impact from the patient’s perspective is unknown. The purpose of this study was to compare scar perception scores and quality of life (QOL) in pediatric patients with axillary CIED implant location versus the standard infraclavicular approach.MethodsThis is a multicenter prospective study conducted at eight pediatric centers and it includes patients aged from 8 to 18 years with a CIED. Patients with prior sternotomy were excluded. Scar perception and QOL outcomes were compared between the infraclavicular and axillary implant locations.ResultsA total of 141 patients (83 implantable cardioverter defibrillator [ICD]/58 pacemakers) were included, 55 with an axillary device and 86 with an infraclavicular device. Patients with an ICD in the axillary position had better perception of scar appearance and consciousness. Patients in the axillary group reported, on average, a total Pediatric QOL Inventory score that was 6 (1, 11) units higher than the infraclavicular group, after adjusting for sex and race (P = 0.02).ConclusionsQOL is significantly improved in axillary in comparison to the infraclavicular CIED position, regardless of device type. Scar perception is improved in patients with ICD in the axillary position.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147032/1/pace13522.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147032/2/pace13522_am.pd

Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD

Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Peer reviewe

Unfamiliar Territory: Emerging Themes for Ecological Drought Research and Management

Novel forms of drought are emerging globally, due to climate change, shifting teleconnection patterns, expanding human water use, and a history of human influence on the environment that increases the probability of transformational ecological impacts. These costly ecological impacts cascade to human communities, and understanding this changing drought landscape is one of today\u27s grand challenges. By using a modified horizon-scanning approach that integrated scientists, managers, and decision-makers, we identified the emerging issues in ecological drought that represent key challenges to timely and effective responses. Here we review the themes that most urgently need attention, including novel drought conditions, the potential for transformational drought impacts, and the need for anticipatory drought management. This horizon scan and review provides a roadmap to facilitate the research and management innovations that will support forward-looking, co-developed approaches to reduce the risk of drought to our socio-ecological systems during the 21st century. We used a modified horizon-scanning approach that brought together scientists, managers, and decision-makers to identify the emerging issues around the ecological impacts from drought that represent key challenges to effective response. We found three broad themes within ecological drought that need attention, including novel drought conditions, transformational drought impacts, and anticipatory drought management. This horizon scan and integrated review provides a roadmap to inspire the needed research and management innovations to reduce the risk of 21st century droughts