A comparison of characteristics of periodic surface micro/nano structures generated via single laser beam direct writing and particle lens array parallel beam processing

Abstract Changing material surface micro/nanostructures using laser beam texturing is a valuable approach in wide applications such as control of cell/bacterial adhesion and proliferation, solar cells and optical metamaterials. Here, we report a comparison of the characteristics of surface micro/nanostructures produced using single beam laser direct writing and particle lens array parallel laser beam patterning. A Nd:YVO4 nanosecond pulsed laser at the wavelength of 532 nm was used in the laser direct writing method to texture the stainless steel surface submerged in water and in air with different scanning patterns. Changes in surface morphology, wettability, surface chemistry, and optical reflectivity were analyzed. In the particle lens array method, an excimer nanosecond laser at 248 nm wavelength was adopted to produce surface patterns on GeSbTe (GST) film coated on a polycarbonate substrate by splitting and focusing a single laser beam into millions of parallel breams. Single beam laser direct writing shows that the surface of high roughness and oxygen percentage content presented high wettability and low reflectivity characteristics. However, the controllability of the type of surface micro/nanopatterns is limited. The parallel laser beam processing using particle lens array allows rapid production of user designed periodic surface patterns at nanoscale overcoming the optical diffraction limit with a high degree of controllability. Controlling the uniformity of the particle lens array is a challenge

The influence of picosecond laser generated periodic structures on bacterial behaviour

The formation of a biofilm is preceded by bacterial retention and proliferation on a surface. Biofilm development on surfaces can cause numerous issues in terms of fouling and bacterial transmission and contamination. The design and fabrication of surfaces that prevent bacterial retention and biofilm formation may provide a potential solution to reduce bacterial fouling of surfaces. An EdgeWave, Nd:YVO4 picosecond laser was used to generate two periodic surface topographies on 316L stainless steel surfaces with and without fluoroalkylsilane (FAS) treatment. These were characterised using Optical Laser Microscopy (OLM), Scanning Electron Microscopy (SEM), contact angle measurements, and Energy Dispersive X-ray Spectroscopy (EDX). The surface wettability and retention of Escherichia coli bacteria on the laser generated surfaces were analysed over one month. Without chemical treatment, and with increasing the time to one month, the results showed that the wettability of laser treated surfaces was decreased as was subsequent bacterial retention. However, the control surface recorded the lowest number of adhered bacteria. After reducing the surface tension, the number of bacteria retention was decreased on all surfaces and one of laser generated surfaces which presented higher contact angle and lower surface tension components (CA = 132°, ΔGiwi = −85.26, γs = 13.81, γsLW = 13.37, and γs− = 0.13) recorded the minimal number of bacteria retention. The results showed that reducing the surface tension played an important role which reduced bacterial fouling

Expanding the genetic heterogeneity of intellectual disability

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

An investigation of the strength and stiffness of weight-saving sandwich beams with CFRP face sheets and seven 3D printed cores

Although sandwich panels are widely used in the industry, the limitations in the cores’ structure designs and materials restrain their use in stiffness- or strength-critical applications without increasing the sandwich beams’ dimensions. The use of additive manufacturing over conventional fabrication methods enabled us to tune the cores’ design according to the stiffness and strength requirements without increasing the beams’ overall dimensions. Seven core structures were 3D printed of Nylon PA12 using powder bed fusion and were tested for their strength and stiffness using three-point bending test. The novel 3D printed core structures were combined, for the first time in the literature, with thin CFRP face sheets. The small Re-entrant and Gyroid structures achieved the highest strength and stiffness values respectively, while the 3D printed conventional honeycomb structures performed the poorest among all other core structures. The stiffness and strength values were normalised using the samples weights and the gyroid structure recorded the highest specific stiffness and strength, making it ideal for supporting weight-critical applications such as motorsport and aerospace

Notch1 in cancer therapy: possible clinical implications and challenges

The Notch family consists of four highly conserved transmembrane receptors, the release of the active intracellular domain requires the enzymatic activity of gamma secretase. Notch is involved in embryonic development and in many physiological processes of normal cells where it regulates growth, apoptosis and differentiation. Notch 1, a member of the Notch family, is implicated in many types of cancer, including breast cancer (especially triple negative breast cancer), leukemias, brain tumors, and many others. Notch 1 is tightly connected to many signaling pathways that are therapeutically involved in tumorigenesis. Together, they impact apoptosis, proliferation, chemosensitivity, immune-response and the population of cancer stem cells. Notch 1 inhibition can be achieved through various and diverse methods, among the most common are the gamma secretase inhibitors which produce a pan-Notch inhibition, or the use of Notch 1 siRNA or Notch 1 monoclonal antibodies (mAb) which produce a more specific blockade. Downregulation of Notch 1 can be used alone or in combination with chemotherapy where a synergistic effect and a decrease in chemoresistance can be achieved. Targeting Notch1 in cancers that harbor high expression levels of Notch 1 offers an addition to therapeutic strategies recruited for managing cancer. Considering available evidence, Notch 1 offers a legitimate target that might be incorporated in future strategies for combating cancer. In this review, the possible clinical applications of Notch 1 inhibition and the obstacles that hinder its clinical application are discussed. SIGNIFICANCE STATEMENT: Notch 1 plays an important role in different types of cancer. Numerous approaches of Notch 1 inhibition possess potential benefits in the management of various clinical aspects of cancer. The application of different Notch 1 inhibition modalities faces many challenges