Search

The lanthanide(III) complexes (Gd, Eu, Dy, and Yb) of DOTA tris(amide) and bis(amide) derivatives (L1 and L2) featuring one redox active TEMPO arm were prepared. Ligand L2 harbours an alkyne fragment for further functionalization. The X-ray crystal structure of ligand L2 in complexation with Na+ was solved. The complexes showed in their CV one oxidation wave (0.26–0. 34 V vs. Fc+/Fc) due to an oxoammonium/nitroxide redox couple and a broad reduction corresponding to the nitroxide/hydroxylamine system. The Eu complexes demonstrated the presence of one water molecule in their coordination sphere. The nitroxide complexes were characterized by EPR spectroscopy, showing the typical 3-line pattern in the high temperature regime, which is quenched upon the addition of ascorbate (reduction into hydroxylamine). In their nitroxide form, the complexes show essentially no CEST peak. Conversely, the reduced complexes demonstrate a 12% CEST peak at 51 ppm, corresponding to the metal bound water molecule. Fast exchange precluded the CEST activity for the amide protons. All the complexes proved to be essentially non-toxic for M21 cells at concentrations up to 50 μM. [ABSTRACT FROM AUTHOR]

The lanthanide complexes EuL3, GdL3, YbL3 and LuL3 of the N,N′-bis(2-hydroxy-di-3,5-tert-butylphenyl)amine were prepared. The X-Ray crystal structures of GdL3 and LuL3 demonstrated a nine-coordinate sphere with three ligand molecules under their anionic diamagnetic form (Cat-N-BQ)−. The complexes showed three oxidation events (E ox11/2 = 0.15–0.16 V, E1/22 = 0.51–55 V, and E1/23 = 0.75–0.78 V vs. Fc+/Fc) via cyclic voltammetry, corresponding to the successive oxidation of the aminophenolate moeities to iminosemiquinone species. The complexes GdL3 and YbL3 were characterized by EPR spectroscopy, allowing for the determination of the zero field splitting (ZFS) parameters in the first case. The monocations (LnL3)+ and monoanions (LnL3)− were electrochemically generated (Ln = Eu, Gd, Yb, Lu), as well as the dications YbL32+ and LuL32+. The spins are antiferromagnetically exchange coupled in the diradical species LuL32+ (‖D‖ = 260 MHz, E = 0). All the complexes (incl. neutral) possess a strong absorption band in the NIR region (730–840 nm, ε > 19 mM−1 cm−1) corresponding to ligand-based transitions. [ABSTRACT FROM AUTHOR]

This study evaluates the pharmacokinetic (PK) and pharmacodynamic (PD) profiles and clinical efficacy of PARP1/2 selective inhibitors, pamiparib and olaparib, in newly-diagnosed or recurrent glioblastoma (GBM) patients in combination with radiotherapy (RT). In this combined phase 0/2 trial presumed newly-diagnosed (Arm A) or recurrent (Arm B) GBM patients received 4 days of pamiparib (60 mg BID) prior to resection either 2-4 or 8-12 hours following the final dose. Arm C enrolled patients with recurrent GBM to 4 days of olaparib (200 mg BID) prior to resection. Enhancing and nonenhancing tumor tissue, cerebrospinal fluid (CSF) and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK 'trigger', defined as unbound drug and gt; 5-fold biochemical IC 50 in nonenhancing tumor, determined eligibility for the therapeutic expansion phase 2. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. Newly-diagnosed MGMT unmethylated GBMs and recurrent GBMs exceeding the PK threshold were eligible for an expansion phase of pamiparib (Arms A and B) or olaparib (Arm C) with concurrent RT followed by maintenance pamiparib or olaparib. RT was 60 Gy in 30 fractions in newly-diagnosed patients and 40 Gy in 15 fractions in recurrent patients, delivered using volumetric-modulated arc therapy (VMAT). A total of 38 patients (Arm A, n = 16; Arm B, n = 16; Arm C, n = 6) were enrolled in the initial phase 0 study. The mean unbound concentrations of pamiparib in nonenhancing tumor region for Arm A and Arm B were 167.3 nM and 109.4 nM respectively, and in Arm C the mean unbound concentration of olaparib was 5.2 nM. All patients in the pamiparib arms (n = 32/32) but only 1 of 6 patients in the olaparib Arm C exceeded the PK threshold. Radiation-induced PAR expression was 2.44-fold in untreated control vs 1.16 in Arm A (p<0.05), 0.85 in Arm B (p<0.01) and 1.11 in Arm C patients, respectively. In Arm A, 11 patients had unmethylated tumors, and of those, 7 patients enrolled in phase 2. In Arm B, 9 of the 16 clinically eligible patients with positive PK results were enrolled in phase 2. At a median follow-up of 8.4 months [range: 1.3-15.7 months], the median progression-free survival (PFS) was 5.4, 6.0, and 3.8 months for Arms A (n = 7), B (n = 9), and C (n = 1), respectively. Grade 3+ toxicities related to pamiparib occurred in 4 patients, with 2 adverse events resulting in treatment discontinuation. No grade 3+ toxicities were documented in the olaparib arm. Pamiparib achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation. The majority of patients with MGMT-unmethylated GBM advanced to the phase 2 portion of the trial, and pamiparib was generally well-tolerated in these patients. [ABSTRACT FROM AUTHOR]

Background A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 ( SPINK5) skin barrier gene have previously been associated with allergic conditions. Objective To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. Method We genotyped 71 'tag' single nucleotide polymorphisms (tag- SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss ( TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value ( PPV) or challenge, corrected for ancestry by principal components. Results SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample ( P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication ( P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis ( P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. Conclusions We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy. [ABSTRACT FROM AUTHOR]

Background Food allergies pose a considerable world-wide public health burden with incidence as high as one in ten in 12-month-old infants. Few food allergy genetic risk variants have yet been identified. The Th2 immune gene IL13 is a highly plausible genetic candidate as it is central to the initiation of IgE class switching in B cells. Objective Here, we sought to investigate whether genetic polymorphisms at IL13 are associated with the development of challenge-proven IgE-mediated food allergy. Method We genotyped nine IL13 'tag' single nucleotide polymorphisms (tag SNPs) in 367 challenge-proven food allergic cases, 199 food-sensitized tolerant cases and 156 non-food allergic controls from the HealthNuts study. 12-month-old infants were phenotyped using open oral food challenges. SNPs were tested using Cochran-Mantel-Haenszel test adjusted for ancestry strata. A replication study was conducted in an independent, co-located sample of four paediatric cohorts consisting of 203 food allergic cases and 330 non-food allergic controls. Replication sample phenotypes were defined by clinical history of reactivity, 95% PPV or challenge, and IL13 genotyping was performed. Results IL13 rs1295686 was associated with challenge-proven food allergy in the discovery sample ( P=.003; OR=1.75; CI=1.20-2.53). This association was also detected in the replication sample ( P=.03, OR=1.37, CI=1.03-1.82) and further supported by a meta-analysis ( P=.0006, OR=1.50). However, we cannot rule out an association with food sensitization. Carriage of the rs1295686 variant A allele was also associated with elevated total plasma IgE. Conclusions and Clinical Relavance We show for the first time, in two independent cohorts, that IL13 polymorphism rs1295686 (in complete linkage disequilibrium with functional variant rs20541) is associated with challenge-proven food allergy. [ABSTRACT FROM AUTHOR]

The reversible oxidation of coordinated phenolates into phenoxyl radicals results in a dramatic quenching (＞95%) of the luminescence of the f metal ion. [ABSTRACT FROM AUTHOR]

A suite of three green tea-containing Standard Reference Materials (SRMs) has been issued by the National Institute of Standards and Technology (NIST): SRM 3254 Camellia sinensis (Green Tea) Leaves, SRM 3255 Camellia sinensis (Green Tea) Extract, and SRM 3256 Green Tea-Containing Solid Oral Dosage Form. The materials are characterized for catechins, xanthine alkaloids, theanine, and toxic elements. As many as five methods were used in assigning certified and reference values to the constituents, with measurements carried out at NIST and at collaborating laboratories. The materials are intended for use in the development and validation of new analytical methods, and for use as control materials as a component in the support of claims of metrological traceability. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

A longitudinal analysis of psychiatric severity was conducted with a national sample of recovering substance abusers living in Oxford Houses, which are self-run, self-help settings. Outcomes related to residents’ psychiatric severity were examined at three follow-up intervals over one year. Over time, Oxford House residents with high versus low baseline psychiatric severity reported significantly more days using psychiatric medication, decreased outpatient psychiatric treatment, yet no significant differences for number of days abstinent and time living in an Oxford House. These findings suggest that a high level of psychiatric severity is not an impediment to residing in self-run, self-help settings such as Oxford House among persons with psychiatric comorbid substance use disorders. [ABSTRACT FROM AUTHOR]

Abstract: A reverse line blot hybridization (RLB) one-stage nested PCR (nPCR) for Anaplasma centrale and a nested PCR for Anaplasma marginale were used to detect infected cattle grazing within an endemic region in Israel. A novel set of PCR primers and oligonucleotide probes based on a 16S ribosomal RNA gene was designed for RLB detection of both Anaplasma species, and the performance of the molecular assays compared. The immunofluorescent antibody test (IFA) was used to detect antibodies to both Anaplasma species, whereas, a highly sensitive and specific competitive enzyme-linked immunosorbent assay (cELISA) was used to detect antibodies in A. centrale-vaccinated cattle. The RLB and the nested PCR procedures showed bacteremia with sensitivity of 50 infected erythrocytes per milliliter. Up to 93% of the A. centrale vaccinates carried specific antibodies that were detected by cELISA, and up to 71% of the vaccinated cattle were found to be naturally infected with A. marginale according to the PCR and the RLB assays. Nevertheless, no severe outbreaks of A. marginale infection occurred among vaccinated herds in this endemic region. It appears that both, molecular tools and serology are useful for evaluation of the vaccine efficacy. In the light of wide natural field infection with A. marginale, strong recommendations to continue the A. centrale vaccination program regime will continue until a new generation of non-blood-based vaccine will be developed. [Copyright &y& Elsevier]

To compare lighting levels in care facilities with local recommendations and determine their cross-sectional association with fall rate, we recruited residents ( n = 126) from 12 long-term care facilities (mean ± SD age 85.1 ± 7.9 years; 64.3% female). Lighting levels were measured at different times in various areas within facilities, according to each resident's movements and habitual use of light. Lighting fell short of focused activity recommendations in 57.7% of bedrooms and 68.5% of bathrooms (bathing and toileting areas); 22.8% and 41.9%, respectively, were also below general activity recommendations. Lower bedroom and overall lighting correlated with higher fall rates (all p < .05). Covariate-adjusted negative binomial models showed lighting in dining rooms (incidence rate ratio [IRR] = 0.92 (95% CI 0.87-0.98; p = .005) for 100 lux increase), bathrooms (IRR = 0.87 [0.78-0.98]; p = .016), and overall (IRR = 0.91 [0.83-1.00]; p = .03-.04) predicted lower fall rates. Areas used by care facility residents commonly have lower than recommended lighting levels, which increases fall risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Medical tubing, particularly cardiovascular tubing, is a critical area of research where continuous improvements are necessary to advance medical devices and improve patient care. While polymers are fundamental for these applications, on their own they present several limitations such as insufficient X-ray contrasting capabilities. As such, polymer composites utilizing radiopaque fillers are a necessity for this application. For medical tubing in vivo, radiopacity is a crucial parameter that virgin polymers alone fall short in achieving due to limited X-ray absorption. To address this shortcoming, inorganic radiopaque fillers such as barium sulphate (BaSO 4 ) and bismuth oxychloride (BiOCl) are incorporated into polymer matrices to increase the X-ray contrast of the manufactured tubing. It is also known, however, that the incorporation of these fillers can affect the mechanical, physical, and thermal properties of the finished product. This research evaluated the impact of incorporating the two aforementioned fillers into Pebax ® 6333 SA01 MED at three different loading levels (10, 20, and 30 wt.%) on the physical, thermal, and mechanical properties of the composite. Composites were prepared by twin screw extrusion and injection molding followed by characterization of the mechanical (tensile, impact, and flexural), thermal (DSC), rheological (MFI), and physical (density and ash content) properties. The performed analysis shows that BiOCl enhanced the aesthetic properties, increased stiffness, and maintained flexibility while having minimal impact on the tensile and impact properties. When comparing BiOCl to BaSO 4 -filled composites, it was clear that depending on the application of the polymer composite, BiOCl may provide more desirable properties. The study highlights the importance of optimizing filler concentration and processing conditions to achieve desired composite properties for specific medical applications.

Background: Acute otitis media with discharge (AOMd) results from a tympanic membrane perforation secondary to a middle ear infection. Currently, the impact of AOMd on children and young people (CYP) and their families is not well understood. There is also a need to explore the experience of healthcare professionals in treating AOMd. Interviews with CYP and their parents, and focus groups with medical professionals, were conducted to explore these objectives., Methods: A total of 26 parents of CYP (age range: 7 months to 15 years) with a history of AOMd (within the last year) and 28 medical professionals were recruited across the UK between August 2023 and March 2024. Healthcare professionals were from primary care (n=17), ear, nose and throat (ENT) (n=7) and emergency medicine (n=4) backgrounds. Thematic analysis was performed independently by three reviewers., Results: The majority of CYP (n=25/26) (96.2%) had suffered from multiple episodes of AOMd. AOMd has a physical, psychological, educational, financial and social impact on CYP and their parents. Parents found accessing healthcare services and information difficult, which increased parental anxiety. Antibiotic overuse was also a concern among parents. The majority of general practitioners and emergency care staff described using oral amoxicillin, compared with ENT doctors who predominantly prescribed topical antibiotics., Conclusions: AOMd has a significant impact on CYP and their parent's daily lives. Need for clear, easily accessible patient information was identified as a priority by the parents of CYP with AOMd. Evidence-based management guidelines should be developed once high-quality evidence is available., Trial Registration Number: ISCTRN43760., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

In 2021, two US military hospitals, Landstuhl Regional Medical Center in Landstuhl, Germany, and Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland, USA, observed a high prevalence of multidrug-resistant bacteria among refugees evacuated from Afghanistan during Operation Allies Refuge. Multidrug-resistant isolates collected from 80 patients carried an array of antimicrobial resistance genes, including carbapenemases (bla NDM-1 , bla NDM-5 , and bla OXA-23 ) and 16S methyltransferases (rmtC and rmtF). Considering the rising transmission of antimicrobial resistance and unprecedented population displacement globally, these data are a reminder of the need for robust infection control measures and surveillance.

Objectives: Nurse practitioner-led MET calls have been shown to improve clinical outcomes versus ICU registrar-led MET calls. However, the cost implications of a nurse practitioner-led MET call system is not known. We conducted cost analysis from the healthcare service perspective to compare the costs of nurse practitioner- and ICU registrar-led MET calls., Research Methodology: A retrospective study of MET calls between 1 June 2016 and 9 March 2018 including patients with first MET call during their hospital admission. The cost analysis compared MET calls attended by nurse practitioners against those attended by ICU registrars., Main Outcome Measures: Inpatient costs for nurse practitioner- and ICU registrar-led MET calls., Results: 1,343 MET calls were included in the full dataset with a mean cost per ICU registrar-led MET calls and nurse practitioner led MET calls of AU$19,836 (95 % CI: AU$15,778 - AU$23,895) versus AU$16,404 (95 % CI: AU$14,988 - AU$17,820) respectively and a difference of AU$3,432 (95 % CI: -AU$38 - AU$6,903, p = 0.053). In the propensity-score matched analysis, the mean cost per ICU registrar-led MET calls and nurse practitioner led MET calls was AU$19,009 (95 % CI: AU$15,439 - AU$22,578) and AU$13,937 (95 % CI: AU$12,038 - AU$15,835) respectively, with a difference of AU$5,072 (95 % CI: AU$1,061 - AU$9,082, p = 0.013). A 24-hour nurse practitioners-led MET call service would break even at 101 MET calls leading to ICU admissions per year., Conclusion: Nurse practitioners-led MET calls saved significant costs compared to ICU registrar-led MET calls. Assuming that the difference in costs is due to shorter ICU length of stay, a health service that receives more than 101 MET calls leading to ICU admissions per year can save costs with a 24-hour nurse practitioner-led MET call service., Implications for Clinical Practice: This study helps in identifying the healthcare services where nurse practitioners -led MET systems could be implemented to be cost saving from health service perspective., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background Paediatric otorrhoea (PO) is a symptom-based diagnosis encompassing acute and chronic ear infections which cause otorrhoea in children and young people (CYP). Aim To understand the burden of PO on primary care services. Design and Setting A longitudinal population study in UK primary care. Methods Data from the Clinical Practice Research Datalink (CPRD Aurum), January 2005 to December 2019, was analysed. CYP under 17 years of age with otorrhoea were included. Standardised annual incidence and presentation rates were estimated. Poisson regression modelling was used to determine risk ratios comparing sex, age and IMD. A probabilistic simulation scaled-up estimates for the UK population. Results The cohort included 6,605,193 CYP, observed over 32,942,594 person-years. There were 80,454 incident cases and 106,318 presentations of PO during the 15-year period, equating to standardised annual incidence and presentation rates per 1000 patient-years of 2.42 (95% CI: 2.40-2.44) and 3.15 (3.13-3.17) respectively. In the UK this equates to 41,141 primary care appointments per year. Incidence was higher in males, those aged 0-2 years, and those living in the least deprived quintile. Treatment involved oral antibiotics (57.1%), no prescription (28.1%), topical antibiotics (9.7%), or combination (4.9%). The cost to NHS primary care is estimated at £1.97 million per year. Conclusions This is the first longitudinal population-based study investigating PO which demonstrates the burden on primary care. Antimicrobial prescribing predominantly follows NICE guidelines using oral amoxicillin. Aminoglycosides are the most frequently prescribed topical antibiotic despite the concern of ototoxicity., (Copyright © 2024, The Authors.)

As a result of technological advancements, functional capacity assessments, such as the 6-minute walk test, can be performed remotely, at home and in the community. Current studies, however, tend to overlook the crucial aspect of data quality, often limiting their focus to idealised scenarios. Challenging conditions may arise when performing a test given the risk of collecting poor-quality GNSS signal, which can undermine the reliability of the results. This work shows the impact of applying filtering rules to avoid noisy samples in common algorithms that compute the walked distance from positioning data. Then, based on signal features, we assess the reliability of the distance estimation using logistic regression from the following two perspectives: error-based analysis, which relates to the estimated distance error, and user-based analysis, which distinguishes conventional from unconventional tests based on users' previous annotations. We highlight the impact of features associated with walked path irregularity and direction changes to establish data quality. We evaluate features within a binary classification task and reach an F1-score of 0.93 and an area under the curve of 0.97 for the user-based classification. Identifying unreliable tests is helpful to clinicians, who receive the recorded test results accompanied by quality assessments, and to patients, who can be given the opportunity to repeat tests classified as not following the instructions.

Background: Hip resurfacing arthroplasty (HRA) provides an attractive alternative to total hip arthroplasty (THA) for the management of osteoarthritis in younger, more active patients; however, concerns persist over complications specific to HRA. The aims of this systematic review were to assess the documented long-term survival rates of the metal-on-metal BIRMINGHAM HIP Resurfacing System at a follow-up of at least 10 years and to analyze the functional outcomes and cause of failures., Methods: A systematic review was undertaken of all published cohort studies available in the MEDLINE, Cochrane, Embase, and PubMed research databases up to December 2021, as recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data extraction was focused on survival rates, causes of failure, and functional outcomes. Survival estimates at 10 years were pooled in a meta-analysis, with each series weighted by its variance. Causes of failure were presented as a percentage of the pooled revisions., Results: A total of 11 studies were identified, encompassing 3,129 cases. Across the 9 studies that had reported a mean follow-up, the mean follow-up was 11.7 years (range, 9.55 to 13.7 years). We found a pooled 10-year survival rate of 95.5% (95% confidence interval, 93.4% to 97.1%). There were 149 revisions among the studies (range, 4 to 38 revisions per study), a rate of 4.8% of the total procedures performed. The 2 main causes of revision were aseptic loosening (20.1% of revisions) and adverse reactions to metal debris (20.1%). There were no revisions for dislocation. Of the studies that reported preoperative functional scores, all reported significant improvement in mean scores postoperatively except for 1 study in which the mean Tegner activity score did not significantly improve., Conclusions: When performed for appropriate indications, patients undergoing an HRA with use of the BIRMINGHAM HIP Resurfacing System can expect good implant survivorship at 10 years with acceptable functional results and low rates of dislocation and infection. This systematic review, however, confirms concerns regarding adverse reactions to metal debris as a leading cause of revision., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: No external funding was received for this study. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A609)., (Copyright © 2024 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Introduction: Paediatric otorrhoea (PO) describes a middle ear infection that results in a perforation of the tympanic membrane and ear discharge, in children and young people (CYP). Prolonged infection may be associated with hearing loss and developmental delay. The current management of paediatric otorrhoea is variable, including non-invasive treatments (conservative, oral antibiotics, topical antibiotics) and surgery, reflecting the lack of a sufficiently strong evidence base. Outcome reporting is fundamental to producing reliable and meaningful evidence to inform best practice., Objectives: Primary objective: to determine which outcome measures are currently used to evaluate treatment success in studies of non-surgical treatments for paediatric otorrhoea., Secondary Objectives: to identify outcome measurement instruments used in the literature and assess their applicability for use in clinical trials of PO., Methods: This systematic review was registered with PROSPERO (CRD42023407976). Database searches of EMBASE, MEDLINE and Cochrane was performed on June 6, 2023, covering from Jan 1995 to May 2023. Randomised controlled trials or study protocols involving CYP with PO were included following PRISMA guidelines. Risk of bias was assessed with Cochrane's tool., Results: Of the 377 papers identified, six were included in the systematic review. The primary outcome of five of the studies related to otorrhoea cessation; both time to cessation and proportion recovered at various time points were used as measures. Two measurement instruments were identified: Otitis Media-6 Questionnaire and the Institute for Medical Technology Assessment Productivity Cost Questionnaire. Both were shown to be applicable measurement instruments when used in clinical trials of PO., Conclusions: To promote homogeneity and facilitate meaningful comparison and combination of studies, we propose that time to cessation of otorrhoea from onset of otorrhoea should be used as the primary outcome in future studies. Further research is needed to establish if this is the most important outcome to children and their caregivers., Competing Interests: Declaration of competing interest No completing interests declared for all authors., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Chronic suppurative otitis media (CSOM) is defined as persistent discharge through a tympanic membrane perforation for greater than 2 weeks. It is associated with a significant disease burden, including hearing loss, and reducing its incidence could significantly improve short- and long-term health. We aimed to identify risk factors associated with the development of CSOM in children., Design and Setting: Systematic review and meta-analysis of studies set in community, primary and secondary care settings, identified from Medline, Embase and Cochrane databases from 2000 to 2022., Participants: Children 16 years old and below., Main Outcome Measures: Clinical diagnosis of CSOM., Results: In total, 739 papers were screened, with 12 deemed eligible for inclusion in the systematic review, of which, 10 were included in the meta-analysis. Risk factors examined included perinatal, patient, dietary, environmental and parental factors. Meta-analysis results indicate that atopy (RR = 1.18, 95% CI [1.01-1.37], p = .04, 2 studies); and birth weight <2500 g (RR = 1.79 [1.27-2.50], p < .01, 2 studies) are associated with an increased risk of CSOM development. Factors not associated were male sex (RR = 0.96 [0.82-1.13], p = .62, 8 studies); exposure to passive smoking (RR = 1.27 [0.81-2.01], p = .30, 3 studies); and parental history of otitis media (RR = 1.14 [0.59-2.20], p = .69, 2 studies)., Conclusion: Optimal management of risk factors associated with CSOM development will help reduce the burden of disease and prevent disease progression or recurrence. The current quality of evidence in the literature is variable and heterogeneous. Future studies should aim to use standardised classification systems to define risk factors to allow meta-analysis., (© 2023 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

The diterpenoid paclitaxel (Taxol) is a chemotherapy medication widely used as a first-line treatment against several types of solid cancers. The supply of paclitaxel from natural sources is limited. However, missing knowledge about the genes involved in several specific metabolic steps of paclitaxel biosynthesis has rendered it difficult to engineer the full pathway. In this study, we used a combination of transcriptomics, cell biology, metabolomics, and pathway reconstitution to identify the complete gene set required for the heterologous production of paclitaxel. We identified the missing steps from the current model of paclitaxel biosynthesis and confirmed the activity of most of the missing enzymes via heterologous expression in Nicotiana benthamiana. Notably, we identified a new C4β-C20 epoxidase that could overcome the first bottleneck of metabolic engineering. We used both previously characterized and newly identified oxomutases/epoxidases, taxane 1β-hydroxylase, taxane 9α-hydroxylase, taxane 9α-dioxygenase, and phenylalanine-CoA ligase, to successfully biosynthesize the key intermediate baccatin III and to convert baccatin III into paclitaxel in N. benthamiana. In combination, these approaches establish a metabolic route to taxoid biosynthesis and provide insights into the unique chemistry that plants use to generate complex bioactive metabolites., (Copyright © 2023 The Author. Published by Elsevier Inc. All rights reserved.)

Introduction: Paediatric otorrhoea (PO) refers to the leakage of fluid through a perforation in the ear drum, resulting from an infection of the middle ear of a child or young person (CYP). PO frequently results in hearing loss which may lead to developmental delay, restricted communication and reduced educational attainment.Epidemiological information for PO is largely derived from low-income countries. The aim of this study will be to establish the incidence of PO within the UK and to understand the impact of PO on CYP and their families' everyday lives. It will build the foundations for a randomised controlled trial investigating the best antibiotic treatment for PO., Methods and Analysis: The study will consist of two work packages. (1) Data from the Clinical Practice Research Datalink (CPRD), January 2005 to July 2021, will be used to determine the incidence of patient presentations with PO to primary care in the UK. It will also explore the current antimicrobial prescribing practice for PO in primary care. (2) Thirty semi-structured interviews will be conducted from 13 July to 31 October 2023 with CYP and their parents/carers to help identify the impact of PO on everyday life, the patient journey and how service users define treatment success. Three medical professional focus groups will be used to understand the current management practice, how treatment success is measured and acceptability to randomise patients. Thematic analysis will be used., Ethics and Dissemination: The Health Research Authority, The Health and Social Care Research Ethics Committee (23/NI/0082) and the CPRD's research data governance panel (22&#95;002508) reviewed this study. Results will be disseminated at medical conferences, in peer-reviewed journals and via social media. The study will cocreate a webpage on healthtalk.org, with the Dipex Charity, about PO to ensure members of the public can learn more about the condition., Trial Registration Number: ISRCTN46071200., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The mechanisms underlying the protective effect of older siblings on allergic disease remain unclear but may relate to the infant gut microbiota., Objective: We sought to investigate whether having older siblings decreases the risk of IgE-mediated food allergy by accelerating the maturation of the infant gut microbiota., Methods: In a birth cohort assembled using an unselected antenatal sampling frame (n = 1074), fecal samples were collected at 1 month, 6 months, and 1 year, and food allergy status at 1 year was determined by skin prick test and in-hospital food challenge. We used 16S rRNA gene amplicon sequencing to derive amplicon sequence variants. Among a random subcohort (n = 323), microbiota-by-age z scores at each time point were calculated using fecal amplicon sequence variants to represent the gut microbiota maturation over the first year of life., Results: A greater number of siblings was associated with a higher microbiota-by-age z score at age 1 year (β  = 0.15 per an additional sibling; 95% CI, 0.05-0.24; P = .003), which was in turn associated with decreased odds of food allergy (odds ratio, 0.45; 95% CI, 0.33-0.61; P < .001). Microbiota-by-age z scores mediated 63% of the protective effect of siblings. Analogous associations were not observed at younger ages., Conclusions: The protective effect of older siblings on the risk of developing IgE-mediated food allergy during infancy is substantially mediated by advanced maturation of the gut microbiota at age 1 year., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

State-of-the-art solid-state electrolytes (SSEs) are limited in their energy density and processability based on thick, brittle pellets, which are generally hot pressed in vacuum over the course of several hours. We report on a high-throughput, open-air process for printable thin-film ceramic SSEs in a remarkable one-minute time frame using a lithium lanthanum titanium oxide (LLTO)-based SSE that we refer to as robust LLTO (R-LLTO). Powder XRD analysis revealed that the main phase of R-LLTO is polycrystalline LLTO, accompanied by selectively retained crystalline precursor phases. R-LLTO is highly dense and closely matched to the stoichiometry of LLTO with some heterogeneity throughout the film. A minimal presence of lithium carbonate is identified despite processing fully in ambient conditions. The LLTO films exhibit remarkable mechanical properties, demonstrating both flexibility with a low modulus of ∼35 GPa and a high fracture toughness of >2.0 . We attribute this mechanical robustness to several factors, including grain boundary strengthening, the presence of precursor crystalline phases, and a decrease in crystallinity or ordering caused by ultrafast processing. The creation of R-LLTO-a ceramic material with elastic properties that are closer to polymers with higher fracture toughness-enables new possibilities for the design of robust solid-state batteries., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

We study the effect of the COVID-19 pandemic and the associated government measures on individual mobility choices in Switzerland. Our data is based on over 1,600 people for which we observe all trips during eight weeks before the pandemic and until May 2021. We find an overall reduction of travel distances by 60 percent, followed by a gradual recovery during the subsequent re-opening of the economy. Whereas driving distances have almost completely recovered, public transport re-mains under-used. The introduction of a requirement to wear a mask in public transport had no measurable impact on ridership. The individual travel response to the pandemic varies along socio-economic dimensions such as education and house-hold size, with mobility tool ownership, and with personal values and lifestyles. We find no evidence for a significant substitution of leisure travel to compensate for the reduction in work-related travel., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Programming is a powerful and ubiquitous problem-solving tool. Systems that can assist programmers or even generate programs themselves could make programming more productive and accessible. Recent transformer-based neural network models show impressive code generation abilities yet still perform poorly on more complex tasks requiring problem-solving skills, such as competitive programming problems. Here, we introduce AlphaCode, a system for code generation that achieved an average ranking in the top 54.3% in simulated evaluations on recent programming competitions on the Codeforces platform. AlphaCode solves problems by generating millions of diverse programs using specially trained transformer-based networks and then filtering and clustering those programs to a maximum of just 10 submissions. This result marks the first time an artificial intelligence system has performed competitively in programming competitions.

Sustainable aviation fuel (SAF) can reduce aviation's CO 2 and non-CO 2 impacts. We quantify the change in contrail properties and climate forcing in the North Atlantic resulting from different blending ratios of SAF and demonstrate that intelligently allocating the limited SAF supply could multiply its overall climate benefit by factors of 9-15. A fleetwide adoption of 100% SAF increases contrail occurrence (+5%), but lower nonvolatile particle emissions (-52%) reduce the annual mean contrail net radiative forcing (-44%), adding to climate gains from reduced life cycle CO 2 emissions. However, in the short term, SAF supply will be constrained. SAF blended at a 1% ratio and uniformly distributed to all transatlantic flights would reduce both the annual contrail energy forcing (EF contrail ) and the total energy forcing (EF total , contrails + change in CO 2 life cycle emissions) by ∼0.6%. Instead, targeting the same quantity of SAF at a 50% blend ratio to ∼2% of flights responsible for the most highly warming contrails reduces EF contrail and EF total by ∼10 and ∼6%, respectively. Acknowledging forecasting uncertainties, SAF blended at lower ratios (10%) and distributed to more flights (∼9%) still reduces EF contrail (∼5%) and EF total (∼3%). Both strategies deploy SAF on flights with engine particle emissions exceeding 10 12 m -1 , at night-time, and in winter.

This article presents the MOBIS dataset and underlying survey methods used in its collection. The MOBIS study was a nation-wide randomised controlled trial (RCT) of transport pricing in Switzerland, utilising a combination of postal recruitment, online surveys, and GPS tracking. 21,571 persons completed the first online survey, and 3680 persons completed 8 weeks of GPS tracking. Many continued tracking for over a year after the study was completed. In the field experiment, participants participated through the use of a GPS tracking app, Catch-my-Day, which logged their daily travel on different transport modes and imputed the trip segments and modes. The experiment lasted 8 weeks, bookended by two online surveys. After the first 4-week control phase, participants were split into two different treatment groups and a continued control group. An analysis of the survey participation shows that the technology is capable of supporting such an experiment on both Android and iOS, the two main mobile platforms. Significant differences in the engagement and attrition were observed between iOS and Android participants over the 8-week period. Finally, the attrition rate did not vary between treatment groups. This paper also reports on the wealth of data that are being made available for further research, which includes over 3 million trip stages and activities, labelled with transport mode and purpose respectively., Supplementary Information: The online version contains supplementary material available at 10.1007/s11116-022-10299-4., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2022.)

Cell-free systems for gene expression have gained attention as platforms for the facile study of genetic circuits and as highly effective tools for teaching. Despite recent progress, the technology remains inaccessible for many in low- and middle-income countries due to the expensive reagents required for its manufacturing, as well as specialized equipment required for distribution and storage. To address these challenges, we deconstructed processes required for cell-free mixture preparation and developed a set of alternative low-cost strategies for easy production and sharing of extracts. First, we explored the stability of cell-free reactions dried through a low-cost device based on silica beads, as an alternative to commercial automated freeze dryers. Second, we report the positive effect of lactose as an additive for increasing protein synthesis in maltodextrin-based cell-free reactions using either circular or linear DNA templates. The modifications were used to produce active amounts of two high-value reagents: the isothermal polymerase Bst and the restriction enzyme Bsa I. Third, we demonstrated the endogenous regeneration of nucleoside triphosphates and synthesis of pyruvate in cell-free systems (CFSs) based on phosphoenol pyruvate (PEP) and maltodextrin (MDX). We exploited this novel finding to demonstrate the use of a cell-free mixture completely free of any exogenous nucleotide triphosphates (NTPs) to generate high yields of sfGFP expression. Together, these modifications can produce desiccated extracts that are 203-424-fold cheaper than commercial versions. These improvements will facilitate wider use of CFS for research and education purposes.

Protein reagents are indispensable for most molecular and synthetic biology procedures. Most conventional protocols rely on highly purified protein reagents that require considerable expertise, time, and infrastructure to produce. In consequence, most proteins are acquired from commercial sources, reagent expense is often high, and accessibility may be hampered by shipping delays, customs barriers, geopolitical constraints, and the need for a constant cold chain. Such limitations to the widespread availability of protein reagents, in turn, limit the expansion and adoption of molecular biology methods in research, education, and technology development and application. Here, we describe protocols for producing a low-resource and locally sustainable reagent delivery system, termed "cellular reagents," in which bacteria engineered to overexpress proteins of interest are dried and can then be used directly as reagent packets in numerous molecular biology reactions, without the need for protein purification or a constant cold chain. As an example of their application, we describe the execution of polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) using cellular reagents, detailing how to replace pure protein reagents with optimal amounts of rehydrated cellular reagents. We additionally describe a do-it-yourself fluorescence visualization device for using these cellular reagents in common molecular biology applications. The methods presented in this article can be used for low-cost, on-site production of commonly used molecular biology reagents (including DNA and RNA polymerases, reverse transcriptases, and ligases) with minimal instrumentation and expertise, and without the need for protein purification. Consequently, these methods should generally make molecular biology reagents more affordable and accessible. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation of cellular reagents Alternate Protocol 1: Preparation of lyophilized cellular reagents Alternate Protocol 2: Evaluation of bacterial culture growth via comparison to McFarland turbidity standards Support Protocol 1: SDS-PAGE for protein expression analysis of cellular reagents Basic Protocol 2: Using Taq DNA polymerase cellular reagents for PCR Basic Protocol 3: Using Br512 DNA polymerase cellular reagents for loop-mediated isothermal amplification (LAMP) Support Protocol 2: Building a fluorescence visualization device., (© 2022 Wiley Periodicals LLC.)

Competing Interests: Competing interests: None declared.

Reverse transcription-loop-mediated isothermal amplification (RT-LAMP) has gained popularity for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The high specificity, sensitivity, simple protocols, and potential to deliver results without the use of expensive equipment has made it an attractive alternative to RT-PCR. However, the high cost per reaction, the centralized manufacturing of required reagents, and their distribution under cold chain shipping limit RT-LAMP's applicability in low-income settings. The preparation of assays using homebrew enzymes and buffers has emerged worldwide as a response to these limitations and potential shortages. Here, we describe the production of Moloney murine leukemia virus reverse transcriptase and BstLF DNA polymerase for the local implementation of RT-LAMP reactions at low cost. These reagents compared favorably to commercial kits, and optimum concentrations were defined in order to reduce time to threshold, increase ON/OFF range, and minimize enzyme quantities per reaction. As a validation, we tested the performance of these reagents in the detection of SARS-CoV-2 from RNA extracted from clinical nasopharyngeal samples, obtaining high agreement between RT-LAMP and RT-PCR clinical results. The in-house preparation of these reactions results in an order of magnitude reduction in costs; thus, we provide protocols and DNA to enable the replication of these tests at other locations. These results contribute to the global effort of developing open and low-cost diagnostics that enable technological autonomy and distributed capacities in viral surveillance., (© 2021 ABRF.)

As the second year of the COVID-19 pandemic begins, it remains clear that a massive increase in the ability to test for SARS-CoV-2 infections in a myriad of settings is critical to controlling the pandemic and to preparing for future outbreaks. The current gold standard for molecular diagnostics is the polymerase chain reaction (PCR), but the extraordinary and unmet demand for testing in a variety of environments means that both complementary and supplementary testing solutions are still needed. This review highlights the role that loop-mediated isothermal amplification (LAMP) has had in filling this global testing need, providing a faster and easier means of testing, and what it can do for future applications, pathogens, and the preparation for future outbreaks. This review describes the current state of the art for research of LAMP-based SARS-CoV-2 testing, as well as its implications for other pathogens and testing. The authors represent the global LAMP (gLAMP) Consortium, an international research collective, which has regularly met to share their experiences on LAMP deployment and best practices; sections are devoted to all aspects of LAMP testing, including preanalytic sample processing, target amplification, and amplicon detection, then the hardware and software required for deployment are discussed, and finally, a summary of the current regulatory landscape is provided. Included as well are a series of first-person accounts of LAMP method development and deployment. The final discussion section provides the reader with a distillation of the most validated testing methods and their paths to implementation. This review also aims to provide practical information and insight for a range of audiences: for a research audience, to help accelerate research through sharing of best practices; for an implementation audience, to help get testing up and running quickly; and for a public health, clinical, and policy audience, to help convey the breadth of the effect that LAMP methods have to offer., (© 2021 ABRF.)

Cell-free gene expression systems have emerged as a promising platform for field-deployed biosensing and diagnostics. When combined with programmable toehold switch-based RNA sensors, these systems can be used to detect arbitrary RNAs and freeze-dried for room temperature transport to the point-of-need. These sensors, however, have been mainly implemented using reconstituted PURE cell-free protein expression systems that are difficult to source in the Global South due to their high commercial cost and cold-chain shipping requirements. Based on preliminary demonstrations of toehold sensors working on lysates, we describe the fast prototyping of RNA toehold switch-based sensors that can be produced locally and reduce the cost of sensors by two orders of magnitude. We demonstrate that these in-house cell lysates provide sensor performance comparable to commercial PURE cell-free systems. We further optimize these lysates with a CRISPRi strategy to enhance the stability of linear DNAs by knocking-down genes responsible for linear DNA degradation. This enables the direct use of PCR products for fast screening of new designs. As a proof-of-concept, we develop novel toehold sensors for the plant pathogen Potato Virus Y (PVY), which dramatically reduces the yield of this important staple crop. The local implementation of low-cost cell-free toehold sensors could enable biosensing capacity at the regional level and lead to more decentralized models for global surveillance of infectious disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Arce, Guzman Chavez, Gandini, Puig, Matute, Haseloff, Dalchau, Molloy, Pardee and Federici.)

We recently developed 'cellular' reagents-lyophilized bacteria overexpressing proteins of interest-that can replace commercial pure enzymes in typical diagnostic and molecular biology reactions. To make cellular reagent technology widely accessible and amenable to local production with minimal instrumentation, we now report a significantly simplified method for preparing cellular reagents that requires only a common bacterial incubator to grow and subsequently dry enzyme-expressing bacteria at 37°C with the aid of inexpensive chemical desiccants. We demonstrate application of such dried cellular reagents in common molecular and synthetic biology processes, such as PCR, qPCR, reverse transcription, isothermal amplification, and Golden Gate DNA assembly, in building easy-to-use testing kits, and in rapid reagent production for meeting extraordinary diagnostic demands such as those being faced in the ongoing SARS-CoV-2 pandemic. Furthermore, we demonstrate feasibility of local production by successfully implementing this minimized procedure and preparing cellular reagents in several countries, including the United Kingdom, Cameroon, and Ghana. Our results demonstrate possibilities for readily scalable local and distributed reagent production, and further instantiate the opportunities available via synthetic biology in general., Competing Interests: HA is affiliated with Kumasi Hive, a Ghanaian not-for-profit social enterprise. SF is Executive Director of Mboalab, a Cameroonian registered company. JM is an unpaid Executive Director of Beneficial Bio Ltd, a UK not-for-profit company limited by guarantee and a volunteer board member of the Gathering for Open Science Hardware Inc, a US 501c3 nonprofit. ADE and SB are named inventors on pending US patent application S20200399679A1 covering cellular reagents, assigned to the University of Texas System. These competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

In Switzerland, strict measures as a response to the Covid-19 pandemic were imposed on March 16, 2020, before being gradually relaxed from May 11 onwards. We report the impact of these measures on mobility behaviour based on a GPS tracking panel of 1439 Swiss residents. The participants were also exposed to online questionnaires. The impact of both the lockdown and the relaxation of the measures up until the middle of August 2020 are presented. Reductions of around 60% in the average daily distance were observed, with decreases of over 90% for public transport. Cycling increased in mode share drastically. Behavioural shifts can even be observed in response to the announcement of the measures and relaxation, a week before they came in to place. Long-term implications for policy are discussed, in particular the increased preference for cycling as a result of the pandemic., (© 2021 The Author(s).)

Objective: Medical emergency teams (MET) are mostly led by physicians. Some hospitals are currently using nurse practitioners (NP) to lead MET calls. These are no studies comparing clinical outcomes between these two care models. To determine whether NP-led MET calls are associated with lower risk of acute patient deterioration, when compared to intensive care (ICU) registrar (ICUR)-led MET calls., Methods: The composite primary outcome included recurrence of MET call, occurrence of code blue or ICU admission within 24 h. Secondary outcomes were mortality within 24 h of MET call, length of hospital stay, hospital mortality and proportion of patients discharged home. Propensity score matching was used to reduce selection bias from confounding factors between the ICUR and NP group., Results: A total of 1343 MET calls were included (1070 NP, 273 ICUR led). On Univariable analysis, the incidence of the primary outcome was higher in ICUR-led MET calls (26.7% vs. 20.6%, p = 0.03). Of the secondary outcome measures, mortality within 24 h (3.4% vs. 7.7%, p = 0.002) and hospital mortality (12.7% vs. 20.5%, p = 0.001) were higher in ICUR-led MET calls. Propensity score-matched analysis of 263 pairs revealed the composite primary outcome was comparable between both groups, but NP-led group was associated with reduced risk of hospital mortality (OR 0.57, 95% CI 0.35-0.91, p = 0.02) and higher likelihood of discharge home (OR 1.55, 95% CI 1.09-2.2, p = 0.015)., Conclusion: Acute patient deterioration was comparable between ICUR- and NP-led MET calls. NP-led MET calls were associated with lower hospital mortality and higher likelihood of discharge home.