A highly compact packaging concept for ultrasound transducer arrays embedded in neurosurgical needles

State-of-the-art neurosurgery intervention relies heavily on information from tissue imaging taken at a pre-operative stage. However, the data retrieved prior to performing an opening in the patient’s skull may present inconsistencies with respect to the tissue position observed by the surgeon during intervention, due to both the pulsing vasculature and possible displacements of the brain. The consequent uncertainty of the actual tissue position during the insertion of surgical tools has resulted in great interest in real-time guidance techniques. Ultrasound guidance during neurosurgery is a promising method for imaging the tissue while inserting surgical tools, as it may provide high resolution images. Microfabrication techniques have enabled the miniaturisation of ultrasound arrays to fit needle gauges below 2 mm inner diameter. However, the integration of array transducers in surgical needles requires the development of advanced interconnection techniques that can provide an interface between the microscale array elements and the macroscale connectors to the driving electronics. This paper presents progress towards a novel packaging scheme that uses a thin flexible printed circuit board (PCB) wound inside a surgical needle. The flexible PCB is connected to a probe at the tip of the needle by means of magnetically aligned anisotropic conductive paste. This bonding technology offers higher compactness compared to conventional wire bonding, as the individual electrical connections are isolated from one another within the volume of the paste line, and applies a reduced thermal load compared to thermo-compression or eutectic packaging techniques. The reduction in the volume required for the interconnection allows for denser wiring of ultrasound probes within interventional tools. This allows the integration of arrays with higher element counts in confined packages, potentially enabling multi-modality imaging with Raman, OCT, and impediography. Promising experimental results and a prototype needle assembly are presented to demonstrate the viability of the proposed packaging scheme. The progress reported in this work are steps towards the production of fully-functional imaging-enabled needles that can be used as surgical guidance tools

Examining the impact of 11 long-standing health conditions on health-related quality of life using the EQ-5D in a general population sample

Objectives Health-related quality of life (HRQoL) measures have been increasingly used in economic evaluations for policy guidance. We investigate the impact of 11 self-reported long-standing health conditions on HRQoL using the EQ-5D in a UK sample. Methods We used data from 13,955 patients in the South Yorkshire Cohort study collected between 2010 and 2012 containing the EQ-5D, a preference-based measure. Ordinary least squares (OLS), Tobit and two-part regression analyses were undertaken to estimate the impact of 11 long-standing health conditions on HRQoL at the individual level. Results The results varied significantly with the regression models employed. In the OLS and Tobit models, pain had the largest negative impact on HRQoL, followed by depression, osteoarthritis and anxiety/nerves, after controlling for all other conditions and sociodemographic characteristics. The magnitude of coefficients was higher in the Tobit model than in the OLS model. In the two-part model, these four long-standing health conditions were statistically significant, but the magnitude of coefficients decreased significantly compared to that in the OLS and Tobit models and was ranked from pain followed by depression, anxiety/nerves and osteoarthritis. Conclusions Pain, depression, osteoarthritis and anxiety/nerves are associated with the greatest losses of HRQoL in the UK population. The estimates presented in this article should be used to inform economic evaluations when assessing health care interventions, though improvements can be made in terms of diagnostic information and obtaining longitudinal data

Low CCR7-Mediated Migration of Human Monocyte Derived Dendritic Cells in Response to Human Respiratory Syncytial Virus and Human Metapneumovirus

Human respiratory syncytial virus (HRSV) and, to a lesser extent, human metapneumovirus (HMPV) and human parainfluenza virus type 3 (HPIV3), can re-infect symptomatically throughout life without significant antigenic change, suggestive of incomplete or short-lived immunity. In contrast, re-infection by influenza A virus (IAV) largely depends on antigenic change, suggestive of more complete immunity. Antigen presentation by dendritic cells (DC) is critical in initiating the adaptive immune response. Antigen uptake by DC induces maturational changes that include decreased expression of the chemokine receptors CCR1, CCR2, and CCR5 that maintain DC residence in peripheral tissues, and increased expression of CCR7 that mediates the migration of antigen-bearing DC to lymphatic tissue. We stimulated human monocyte-derived DC (MDDC) with virus and found that, in contrast to HPIV3 and IAV, HMPV and HRSV did not efficiently decrease CCR1, 2, and 5 expression, and did not efficiently increase CCR7 expression. Consistent with the differences in CCR7 mRNA and protein expression, MDDC stimulated with HRSV or HMPV migrated less efficiently to the CCR7 ligand CCL19 than did IAV-stimulated MDDC. Using GFP-expressing recombinant virus, we showed that the subpopulation of MDDC that was robustly infected with HRSV was particularly inefficient in chemokine receptor modulation. HMPV- or HRSV-stimulated MDDC responded to secondary stimulation with bacterial lipopolysaccharide or with a cocktail of proinflammatory cytokines by increasing CCR7 and decreasing CCR1, 2 and 5 expression, and by more efficient migration to CCL19, suggesting that HMPV and HRSV suboptimally stimulate rather than irreversibly inhibit MDDC migration. This also suggests that the low concentration of proinflammatory cytokines released from HRSV- and HMPV-stimulated MDDC is partly responsible for the low CCR7-mediated migration. We propose that inefficient migration of HRSV- and HMPV-stimulated DC to lymphatic tissue contributes to reduced adaptive responses to these viruses

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Studies of beta-sheet rearrangements in antichymotrypsin

A hallmark of serpin function is the massive $\beta$-sheet rearrangement involving the insertion of the cleaved reactive loop into $\beta$-sheet A as strand s4A. Although the structures of intact and cleaved serpins are known, structural details of what happens during the transition have eluded researchers. Furthermore, the extent of strand insertion involved in the inhibition process is widely debated. Substitutions in the serpin reactive loop can affect specificity and/or function. I have determined the structure of cleaved antichymotrypsin-P3P3\sp\prime, which has conservative substitutions in the six residues directly surrounding the scissile bond, altering the specificity of the serpin. Although this structure is nearly identical to that of the native protein, it nevertheless represents the cleaved counterpart to the structure of intact ACT-P3P3\sp\prime and highlights the differences between native and recombinant proteins. Small hydrophobic residues in the hinge region (around P14) of s4A facilitate strand insertion, since they eventually pack in the hydrophobic core. The substitution of bulky, charged residues at the P14 and P12 positions is postulated to change a serpin from inhibitor to substrate by slowing the rate of strand insertion. I support this theory with the structures of four cleaved s4A arginine variants of antichymotrypsin, demonstrating that strand insertion is not prevented by such substitutions. In cleaved A347R-ACT (P12), strand s4A is fully inserted with normal $\beta$-sheet geometry; the R347 side chain is buried in the hydrophobic protein core. In cleaved T345R-ACT (P14), strand s4A is mostly inserted, but R345 twists in order to remain solvent exposed. Both of these variants are chymotrypsin substrates. The structure of cleaved A349R-ACT (P10) reveals full strand insertion and the burial of R349 with a salt-linked acetate counterion. A349R-ACT has a stoichiometry of inhibition of $\sim$5. Finally, the structure of cleaved A350R-ACT (P9) shows accommodation of the arginine on the other side of the s4A. In this inhibitory variant, full strand insertion is observed, but the adjacent surface loop becomes disordered

Studies of beta-sheet rearrangements in antichymotrypsin

A hallmark of serpin function is the massive $\beta$-sheet rearrangement involving the insertion of the cleaved reactive loop into $\beta$-sheet A as strand s4A. Although the structures of intact and cleaved serpins are known, structural details of what happens during the transition have eluded researchers. Furthermore, the extent of strand insertion involved in the inhibition process is widely debated. Substitutions in the serpin reactive loop can affect specificity and/or function. I have determined the structure of cleaved antichymotrypsin-P3P3\sp\prime, which has conservative substitutions in the six residues directly surrounding the scissile bond, altering the specificity of the serpin. Although this structure is nearly identical to that of the native protein, it nevertheless represents the cleaved counterpart to the structure of intact ACT-P3P3\sp\prime and highlights the differences between native and recombinant proteins. Small hydrophobic residues in the hinge region (around P14) of s4A facilitate strand insertion, since they eventually pack in the hydrophobic core. The substitution of bulky, charged residues at the P14 and P12 positions is postulated to change a serpin from inhibitor to substrate by slowing the rate of strand insertion. I support this theory with the structures of four cleaved s4A arginine variants of antichymotrypsin, demonstrating that strand insertion is not prevented by such substitutions. In cleaved A347R-ACT (P12), strand s4A is fully inserted with normal $\beta$-sheet geometry; the R347 side chain is buried in the hydrophobic protein core. In cleaved T345R-ACT (P14), strand s4A is mostly inserted, but R345 twists in order to remain solvent exposed. Both of these variants are chymotrypsin substrates. The structure of cleaved A349R-ACT (P10) reveals full strand insertion and the burial of R349 with a salt-linked acetate counterion. A349R-ACT has a stoichiometry of inhibition of $\sim$5. Finally, the structure of cleaved A350R-ACT (P9) shows accommodation of the arginine on the other side of the s4A. In this inhibitory variant, full strand insertion is observed, but the adjacent surface loop becomes disordered

Systematic literature review and meta-analysis on the epidemiology of propionic acidemia

Abstract Propionic acidemia (PA, OMIM #606054) is a serious, life-threatening, inherited, metabolic disorder caused by the deficiency of the mitochondrial enzyme propionyl-coenzyme A (CoA) carboxylase (EC 6.4.1.3). The primary objective of this study was to conduct a systematic literature review and meta-analysis on the epidemiology of PA. The literature search was performed covering Medline, Embase, Cochrane Database of Systematic Reviews, CRD Database, Academic Search Complete, CINAHL and PROSPERO databases. Websites of rare disease organizations were also searched for eligible studies. Of the 2338 identified records, 188 articles were assessed for eligibility in full text, 43 articles reported on disease epidemiology, and 31 studies were included into the quantitative synthesis. Due to the rarity of PA, broadly targeted population-based prevalence studies are not available. Nonetheless, implementation of newborn screening programs has allowed the estimation of the birth prevalence data of PA across multiple geographic regions. The pooled point estimates indicated detection rates of 0.29; 0.33; 0.33 and 4.24 in the Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, respectively. Our systematic literature review and meta-analysis confirm that PA is an ultra-rare disorder, with similar detection rates across all regions with the exception of the MENA region where the disease, similar to other inherited metabolic disorders, is more frequent

Systematic literature review and meta-analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl-CoA mutase (mut) deficiency

Abstract Methylmalonic acidemia/aciduria (MMA) is a genetically heterogeneous group of inherited metabolic disorders biochemically characterized by the accumulation of methylmalonic acid. Isolated MMA is primarily caused by the deficiency of methylmalonyl-CoA mutase (MMA mut; EC 5.4.99.2). A systematic literature review and a meta-analysis were undertaken to assess and compile published epidemiological data on MMA with a focus on the MMA mut subtype (OMIM #251000). Of the 1114 identified records, 227 papers were assessed for eligibility in full text, 48 articles reported on disease epidemiology, and 39 articles were included into the quantitative synthesis. Implementation of newborn screening in various countries has allowed for the estimation of birth prevalence of MMA and its isolated form. Meta-analysis pooled point estimates of MMA (all types) detection rates were 0.79, 1.12, 1.22 and 6.04 per 100,000 newborns in Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, respectively. The detection rate of isolated MMA was < 1 per 100,000 newborns in all regions with the exception of MENA where it approached 6 per 100,000 newborns. Few studies published data on the epidemiology of MMA mut, therefore no meta-analysis could have been performed on this subtype. Most of the identified papers reported birth prevalence estimates below 1 per 100,000 newborns for MMA mut. The systematic literature review clearly demonstrates that MMA and its subtypes are ultra-rare disorders