A national evaluation of QbTest to support ADHD assessment: a real-world, mixed methods approach.

BACKGROUND: QbTest is a commercially available, computerised test of attention, impulsivity, and activity designed to assist with the diagnosis of attention deficit hyperactivity disorder (ADHD). Health Innovation East Midlands (formerly East Midlands AHSN), led the implementation of the QbTest on behalf of the 15 Health Innovation Networks across Child and Adolescent Mental Health services (CAMHS) and Paediatric sites in England between April 2020 and March 2023. We evaluate the impact of this programme on diagnostic assessment at participating sites. METHODS: A mixed-methods approach was used including: case-note data collected on 10-30 cases per site pre and post QbTest implementation; interviews with healthcare staff working with QbTest; and surveys to explore perspectives of healthcare staff and patients/carers. Case-note data was descriptively analysed to compare time to diagnosis (number of appointments and days) pre/post QbTest implementation. Survey data was analysed descriptively. Qualitative interview data was explored using thematic analysis. RESULTS: Case-note data was provided by 20 sites across England. Comparison of mean values pre- and post-QbTest implementation identified a decrease of 0.37 (11.5%) in number of appointments to reach a diagnostic decision, a 55-day (12.5%) increase in days from initial referral to diagnosis, and a 12-day (10.3%) increase in days to reach a diagnostic decision. Exploratory analyses indicated greater benefit for Paediatric services over CAMHS, in terms of a decrease in days from referral to diagnosis and number of appointments to diagnosis. Interviews with healthcare staff (n=21) revealed that the QbTest was perceived to support a faster, more efficient diagnostic process. Survey data (n=65 healthcare staff, n=22 patients/carers) identified that the QbTest helped patients understand their symptoms and the diagnostic decision.  Although some logistical issues (e.g., room requirements) and patient issues (e.g., sensory sensitivity) were identified, healthcare staff considered that QbTest was easily incorporated into the ADHD assessment pathway. CONCLUSION: The national implementation of QbTest in ADHD clinics resulted in a small reduction in the number of clinical appointments needed to reach a diagnostic decision, with greatest benefit demonstrated in Paediatric sites. Data were impacted by COVID-19 therefore, further evaluation is warranted.

Structural basis of Pseudomonas aeruginosa penicillin binding protein 3 inhibition by the siderophore-antibiotic cefiderocol.

The breakthrough cephalosporin cefiderocol, approved for clinical use in 2019, has activity against many Gram-negative bacteria. The catechol group of cefiderocol enables it to efficiently enter bacterial cells via the iron/siderophore transport system thereby reducing resistance due to porin channel mutations and efflux pump upregulation. Limited information is reported regarding the binding of cefiderocol to its key proposed target, the transpeptidase penicillin binding protein 3 (PBP3). We report studies on the reaction of cefiderocol and the related cephalosporins ceftazidime and cefepime with Pseudomonas aeruginosa PBP3, including inhibition measurements, protein observed mass spectrometry, and X-ray crystallography. The three cephalosporins form analogous 3-exomethylene products with P. aeruginosa PBP3 following elimination of the C3' side chain. pIC50 and k inact/K i measurements with isolated PBP3 imply ceftazidime and cefiderocol react less efficiently than cefepime and, in particular, meropenem with P. aeruginosa PBP3. Crystal structures inform on conserved and different interactions involved in binding of the three cephalosporins and meropenem to P. aeruginosa PBP3. The results will aid development of cephalosporins with improved PBP3 inhibition properties.

Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat.

Prolyl hydroxylase domain-containing proteins 1-3 (PHD1-3) are 2-oxoglutarate (2OG)-dependent oxygenases catalysing C-4 hydroxylation of prolyl residues in α-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF), modifications that promote HIF-α degradation via the ubiquitin-proteasome pathway. Pharmacological inhibition of the PHDs induces HIF-α stabilisation, so promoting HIF target gene transcription. PHD inhibitors are used to treat anaemia caused by chronic kidney disease (CKD) due to their ability to stimulate erythropoietin (EPO) production. We report studies on the effects of the approved PHD inhibitors Desidustat and Enarodustat, and the clinical candidate TP0463518, on activities of a representative set of isolated recombinant human 2OG oxygenases. The three molecules manifest selectivity for PHD inhibition over that of the other 2OG oxygenases evaluated. We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia-inducible factor-α (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1-3. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA-damage repair, and agrochemical resistance.

Investigating the Feasibility and Performance of Hybrid Overmolded UHMWPE 3D-Printed PEEK Structural Composites for Orthopedic Implant Applications: A Pilot Study.

Ultra-high-molecular-weight polyethylene (UHMWPE) components for orthopedic implants have historically been integrated into metal backings by direct-compression molding (DCM). However, metal backings are costly, stiffer than cortical bone, and may be associated with medical imaging distortion and metal release. Hybrid-manufactured DCM UHMWPE overmolded additively manufactured polyetheretherketone (PEEK) structural components could offer an alternative solution, but are yet to be explored. In this study, five different porous topologies (grid, triangular, honeycomb, octahedral, and gyroid) and three surface feature sizes (low, medium, and high) were implemented into the top surface of digital cylindrical specimens prior to being 3D printed in PEEK and then overmolded with UHMWPE. Separation forces were recorded as 1.97-3.86 kN, therefore matching and bettering the historical industry values (2-3 kN) recorded for DCM UHMWPE metal components. Infill topology affected failure mechanism (Type 1 or 2) and obtained separation forces, with shapes having greater sidewall numbers (honeycomb-60%) and interconnectivity (gyroid-30%) through their builds, tolerating higher transmitted forces. Surface feature size also had an impact on applied load, whereby those with low infill-%s generally recorded lower levels of performance vs. medium and high infill strategies. These preliminary findings suggest that hybrid-manufactured structural composites could replace metal backings and produce orthopedic implants with high-performing polymer-polymer interfaces.

A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.

A BIOCOMPATIBLE GLASS-ENCAPSULATED TRIAXIAL FORCE SENSOR FOR IMPLANTABLE TACTILE SENSING APPLICATIONS.

This paper reports a microfabricated triaxial capacitive force sensor. The sensor is fully encapsulated with inert and biocompatible glass (fused silica) material. The sensor comprises two glass plates, on which four capacitors are located. The sensor is intended for subdermal implantation in fingertips and palms and providing tactile sensing capabilities for patients with paralyzed hands. Additional electronic components, such as passives and IC chips, can also be integrated with the sensor in a hermetic glass package to achieve an implantable tactile sensing system. Through attachment to a human palm, the sensor has been shown to respond appropriately to typical hand actions, such as squeezing or picking up a bottle.

Frequency tunable magnetostatic wave filters with zero static power magnetic biasing circuitry.

A single tunable filter simplifies complexity, reduces insertion loss, and minimizes size compared to frequency switchable filter banks commonly used for radio frequency (RF) band selection. Magnetostatic wave (MSW) filters stand out for their wide, continuous frequency tuning and high-quality factor. However, MSW filters employing electromagnets for tuning consume excessive power and space, unsuitable for consumer wireless applications. Here, we demonstrate miniature and high selectivity MSW tunable filters with zero static power consumption, occupying less than 2 cc. The center frequency is continuously tunable from 3.4 GHz to 11.1 GHz via current pulses of sub-millisecond duration applied to a small and nonvolatile magnetic bias assembly. This assembly is limited in the area over which it can achieve a large and uniform magnetic field, necessitating filters realized from small resonant cavities micromachined in thin films of Yttrium Iron Garnet. Filter insertion loss of 3.2 dB to 5.1 dB and out-of-band third order input intercept point greater than 41 dBm are achieved. The filter's broad frequency range, compact size, low insertion loss, high out-of-band linearity, and zero static power consumption are essential for protecting RF transceivers from interference, thus facilitating their use in mobile applications like IoT and 6 G networks.

Optimal bilayer composites for temperature-tracking wireless electronics.

Modern silicone-based epidermal electronics engineered for body temperature sensing represent a pivotal development in the quest for advancing preventive medicine and enhancing post-surgical monitoring. While these compact and highly flexible electronics empower real-time monitoring in dynamic environments, a noteworthy limitation is the challenge in regulating the infiltration or obstruction of heat from the external environment into the surface layers of these electronics. The study presents a cost-effective temperature sensing solution by embedding wireless electronics in a multi-layered elastomeric composite to meet the dual needs of enhanced thermal insulation for encapsulation in contact with air and improved thermal conductivity for the substrate in contact with the skin. The encapsulating composite benefits from the inclusion of hollow silica microspheres, which reduce the thermal conductivity by 40%, while non-spherical aluminum nitride enhances the thermal conductivity of the substrate by 370%. The addition of particles to the respective composites inevitably leads to an increase in modulus. Two composite elements are engineered to coexist while maintaining a matching low modulus of 3.4 MPa and a stretchability exceeding 30%, all without compromising the optimized thermal properties. Consecutive thermal, electrical, and mechanical characterization confirms the sensor's capacity for precise body temperature monitoring during a single day's lifespan, while also assessing the influence of behavioral factors on body temperature.

Development of the next-generation functional neuro-cognitive imaging protocol - Part 1: A 3D sliding-window convolutional neural net for automated brain parcellation.

Functional MRI has emerged as a powerful tool to assess the severity of Post-concussion syndrome (PCS) and to provide guidance for neuro-cognitive therapists during treatment. The next-generation functional neuro-cognitive imaging protocol (fNCI2) has been developed to provide this assessment. This paper covers the first step in the analysis process, the development of a rapidly re-trainable, machine-learning, brain parcellation tool. The use of a sufficiently deep U-Net architecture encompassing a small (39 × 39 × 39 voxel input, 27 × 27 × 27 voxel output) sliding window to sample the entirety of the 3D image allows for the prediction of the entire image using only a single trained network. A large number of training, validating, and testing windows are thus generated from the 101 manually-labeled Mindboggle images, and full-image prediction is provided via a voxel-vote method using overlapping windows. Our method produces parcellated images that are highly consistent with standard atlas-based methods in under 3 min on a modern GPU, and the single network architecture allows for rapid retraining (<36 hr) as needed.

An implantable, wireless, battery-free system for tactile pressure sensing.

The sense of touch is critical to dexterous use of the hands and thus an essential component of efforts to restore hand function after amputation or paralysis. Prosthetic systems have addressed this goal with wearable tactile sensors. However, such wearable sensors are suboptimal for neuroprosthetic systems designed to reanimate a patient's own paralyzed hand. Here, we developed an implantable tactile sensing system intended for subdermal placement. The system is composed of a microfabricated capacitive pressure sensor, a custom integrated circuit supporting wireless powering and data transmission, and a laser-fused hermetic silica package. The miniature device was validated through simulations, benchtop assessment, and testing in a primate hand. The sensor implanted in the fingertip accurately measured applied skin forces with a resolution of 4.3 mN. The output from this novel sensor could be encoded in the brain with microstimulation to provide tactile feedback. More broadly, the materials, system design, and fabrication approach establish new foundational capabilities for various applications of implantable sensing systems.

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

Parent personality traits and problem behavior in adolescence: The mediating role of adolescent personality.

INTRODUCTION: Parental personality traits are predicted to influence offspring outcomes through parenting behavior and offspring personality traits. This study explored whether mother and father personality traits relate to offspring behavior problems in mid-late adolescence METHOD: In total, 3089 Australian adolescents (1576 boys, 1513 girls; Mage = 16.46 ± 0.50 years) and their parents completed questionnaires assessing personality, conduct problems, emotional and social functioning, antisocial and criminal behavior, cigarette smoking and drug use, at a single time-point. RESULTS: After controlling for sociodemographic factors, results showed that problem behaviors in adolescence were most consistently related to mothers' scores on neuroticism and conscientiousness, and fathers' scores on neuroticism. Father personality traits were most important for antisocial and criminal behavior, whereas mother personality traits were most important for social and emotional functioning. Moderation analysis showed that associations between fathers' personality traits and some adolescent outcomes (cigarette smoking and drug use) were stronger for adolescent boys than for adolescent girls. Mediation models further demonstrated that adolescent personality traits mediated associations between parent personality and adolescent outcomes in almost all cases. Indirect effects expressed as a percentage showed that between 1.4% and 33.3% of the variance in the association between parent personality and adolescent outcomes was shared with the corresponding adolescent personality trait. CONCLUSIONS: Overall, the findings of this study provide evidence that traits inherited (directly or indirectly) from parents might have an important role in shaping problem behavior in adolescence.

Rational Design of a Bifunctional Peptide Exhibiting Lithium Titanate Oxide and Carbon Nanotube Affinities for Lithium-Ion Battery Applications.

Phage display is employed as a method for identifying polypeptides that bind to lithium-ion battery materials, specifically lithium titanate oxide (LTO) and multiwalled carbon nanotubes (MWCNTs). Output/input assays are used as a quantitative measure to narrow down the strongest binding polypeptides from several peptides selected through biopanning. Negatively stained transmission electron microscopy is used to verify that a phage presenting a particular LTO or MWCNT binding peptide sequence colocalizes with the respective material. Heterologous expression allows for ample polypeptides to be grown and purified using a peptide expression vector. Isothermal titration calorimetry in conjunction with alanine scanning enables determination of the pertinent residues involved in LTO binding and yields a dissociation constant of 3.41 µM. A rationally designed bifunctional peptide exhibiting LTO and MWCNT binding domains is subsequently validated to exhibit both LTO and MWCNT affinities and is incorporated as a binding agent in LTO coin-type electrochemical cells where the bifunctional peptide demonstrates stability at high cycle rates and potential as an alternative to non-specific binding agents for aqueous slurry processing of lithium-ion battery electrodes.

An implantable wireless tactile sensing system.

The sense of touch is critical to dexterous use of the hands and thus an essential component to efforts to restore hand function after amputation or paralysis. Prosthetic systems have focused on wearable tactile sensors. But wearable sensors are suboptimal for neuroprosthetic systems designed to reanimate a patient's own paralyzed hand. Here, we developed an implantable tactile sensing system intended for subdermal placement. The system is composed of a microfabricated capacitive force sensor, a custom integrated circuit supporting wireless powering and data transmission, and a laser-fused hermetic silica package. The miniature device was validated through simulations, benchtop testing, and ex vivo testing in a primate hand. The sensor implanted in the fingertip accurately measured skin forces with a resolution of 4.3 mN. The output from this novel sensor could be encoded in the brain with microstimulation to provide tactile feedback. More broadly, the materials, system design, and fabrication approach establish new foundational capabilities for various applications of implantable sensing systems.

Concentration-Dependent Inhibition of Mesophilic PETases on Poly(ethylene terephthalate) Can Be Eliminated by Enzyme Engineering.

Enzyme-based depolymerization is a viable approach for recycling of poly(ethylene terephthalate) (PET). PETase from Ideonella sakaiensis (IsPETase) is capable of PET hydrolysis under mild conditions but suffers from concentration-dependent inhibition. In this study, this inhibition is found to be dependent on incubation time, the solution conditions, and PET surface area. Furthermore, this inhibition is evident in other mesophilic PET-degrading enzymes to varying degrees, independent of the level of PET depolymerization activity. The inhibition has no clear structural basis, but moderately thermostable IsPETase variants exhibit reduced inhibition, and the property is completely absent in the highly thermostable HotPETase, previously engineered by directed evolution, which simulations suggest results from reduced flexibility around the active site. This work highlights a limitation in applying natural mesophilic hydrolases for PET hydrolysis and reveals an unexpected positive outcome of engineering these enzymes for enhanced thermostability.

High-Energy-Density Zinc-Air Microbatteries with Lean PVA-KOH-K2CO3 Gel Electrolytes.

Small-scale, primary electrochemical energy storage devices ("microbatteries") are critical power sources for microelectromechanical system (MEMS)-based sensors and actuators. However, the achievable volumetric and gravimetric energy densities of microbatteries are typically insufficient for intermediate-term applications of MEMS-enabled distributed internet-connected devices. Further, in the increasing subset of Internet of Things (IoT) nodes, where actuation is desired, the peak power density of the microbattery must be simultaneously considered. Metal-air approaches to achieving microbatteries are attractive, as the anode and cathode are amenable to miniaturization; however, further improvements in energy density can be obtained by minimizing the electrolyte volume. To investigate these potential improvements, this work studied very lean hydrogel electrolytes based on poly(vinyl alcohol) (PVA). Integration of high potassium hydroxide (KOH) loading into the PVA hydrogel improved electrolyte performance. The addition of potassium carbonate (K2CO3) to the KOH-PVA gel decreased the carbonation consumption rate of KOH in the gel electrolyte by 23.8% compared to PVA-KOH gel alone. To assess gel performance, a microbattery was formed from a zinc (Zn) anode layer, a gel electrolyte layer, and a carbon-platinum (C-Pt) air cathode layer. Volumetric energy densities of approximately 1400 Wh L-1 and areal peak power densities of 139 mW cm-2 were achieved with a PVA-KOH-K2CO3 electrolyte. Further structural optimization, including using multilayer gel electrolytes and thinning the air cathode, resulted in volumetric and gravimetric energy densities of 1576 Wh L-1 and 420 Wh kg-1, respectively. The batteries described in this work are manufactured in an open environment and fabricated using a straightforward layer-by-layer method, enabling the potential for high fabrication throughput in a MEMS-compatible fashion.

Preoperative Type and Screen Before General Thoracic Surgery: A Nomogram to Reduce Unnecessary Tests.

BACKGROUND: A preoperative type and screen (T&S) is traditionally routinely obtained before noncardiac thoracic surgery; however an intraoperative blood transfusion is rare. This practice is overly cautious and expensive. METHODS: We included adult patients undergoing major thoracic surgery at the Mayo Clinic from 2007 to 2016. Patients receiving a T&S blood test ≤72 hours of surgery was the main exposure. We randomly split the cohort into derivation and validation datasets. We used multiple logistic regression to create a parsimonious nomogram predicting the need for a T&S in relation to the likelihood of intraoperative blood transfusion. We validated the nomogram in terms of discrimination, calibration, and negative predictive value. RESULTS: Of 6280 patients 46.1% had a preoperative T&S, but only 7.1% received intraoperative transfusions. The derivation dataset had 4196 patients. Patients who had a T&S were more likely to have baseline hemoglobin level <10 g/dL (7.9% vs 3.6%, P < .001) and less likely to have minimally invasive operations (36.1% vs 43.5%, P < .001) but were otherwise similar in baseline age and comorbidities. A transfusion threshold of 5% was selected a priori. The nomogram included age, planned operation, approach, body mass index, and preoperative hemoglobin. The nomogram was validated with a c-statistic of 86% and a negative predictive value of 97.9%. Patients who needed a blood transfusion but who did not have a preoperative T&S did not have a higher rate of mortality (P = .121). CONCLUSIONS: An intraoperative blood transfusion during major thoracic surgery is a rare event. Patient who required transfusion but did not have a T&S did not have worse outcomes. A simple nomogram can aid in the selective use of T&S orders preoperatively.

Neratinib in advanced HER2-positive breast cancer: experience from the royal Marsden hospital.

PURPOSE: To describe the tolerability and efficacy of neratinib as a monotherapy and in combination with capecitabine in advanced HER2-positive breast cancer in a real-world setting. METHODS: Patients who received neratinib for advanced HER2-positive at the Royal Marsden Hospital NHS Trust between August 2016 and May 2020 were identified from electronic patient records and baseline characteristics, previous treatment and response to treatment were recorded. The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. RESULTS: Seventy-two patients were eligible for the analysis. Forty-five patients received neratinib in combination with capecitabine and 27 patients received monotherapy. After a median duration of follow-up of 38.5 months, the median PFS for all patients was 5.9 months (95% confidence interval (CI) 4.9-7.4 months) and median OS was 15.0 months (95% Cl 10.4-22.2 months). Amongst the 52.7% (38/72) patients with confirmed brain metastases at baseline, median PFS was 5.7 months (95% CI 2.9-7.4 months) and median OS was 12.5 months (95% CI 7.7-21.4 months). Despite anti-diarrhoeal prophylaxis, diarrhoea was the most frequent adverse event, reported in 64% of patients which was grade 3 in 10%. There were no grade 4 or 5 toxicities. Seven patients discontinued neratinib due to toxicity. CONCLUSIONS: Neratinib monotherapy or in combination with capecitabine is a useful treatment for patients with and without brain metastases. PFS and OS were found to be similar as previous trial data. Routine anti-diarrhoeal prophylaxis allows this combination to be safely delivered to patients in a real-world setting.

Hydrological control of river and seawater lithium isotopes.

Seawater lithium isotopes (δ7Li) record changes over Earth history, including a ∼9‰ increase during the Cenozoic interpreted as reflecting either a change in continental silicate weathering rate or weathering feedback strength, associated with tectonic uplift. However, mechanisms controlling the dissolved δ7Li remain debated. Here we report time-series δ7Li measurements from Tibetan and Pamir rivers, and combine them with published seasonal data, covering small (<102 km2) to large rivers (>106 km2). We find seasonal changes in δ7Li across all latitudes: dry seasons consistently have higher δ7Li than wet seasons, by -0.3‰ to 16.4‰ (mean 5.0 ± 2.5‰). A globally negative correlation between δ7Li and annual runoff reflects the hydrological intensity operating in catchments, regulating water residence time and δ7Li values. This hydrological control on δ7Li is consistent across climate events back to ~445 Ma. We propose that hydrological changes result in shifts in river δ7Li and urge reconsideration of its use to examine past weathering intensity and flux, opening a new window to reconstruct hydrological conditions.