bluuebunny/crossref_metadata_2025 huggingface dataset:
A Study on Converging-Diverging Nozzle Design for Supersonic Spraying of Liquid Droplets Toward Nanocoating Applications
Authors: Akin Semih , Wu Puyuan , Nath Chandra , Chen Jun , Jun Martin Byung-Guk
Published: April 2023

Supersonic cold spray (CS) of functional nanomaterials from atomized droplets has attracted significant attention in advanced thin-film coating as it enables particle deposition with high-adhesion strength. In CS, optimum design of the supersonic nozzle (i.e., converging-diverging nozzle) is essential for accelerating particles to desired velocities. However, research on the nozzle design for supersonically spraying of “liquid droplets” for nanocoating applications is limited. To this end, we investigate the effect of nozzle geometrical parameters, including throat diameter, exit diameter, and divergent length on droplets impact velocity by numerical modeling and experimental validation, followed by a case study on nanocoating. The discrete-phase modeling was employed to study droplets’ flow behavior in continuous gas flow for various nozzle geometries. The results reveal that the nozzle expansion ratio, defined as a function of throat and exit diameters, has a significant influence on droplet velocity, followed by divergent length. Noteworthy, to correctly accelerate “low-inertia liquid microdroplets,” it was found that the optimum nozzle expansion ratio for axisymmetric convergent-divergent nozzles should be in a range of 1.5–2.5, which is different and way smaller than the recommended expansion ratio (i.e., 5–9) for CS of conventional micron-scale “metal” powders. Based on the simulation results, an optimum design of supersonic nozzle is established and prototyped for the experimental studies. Particle image velocimetry (PIV) was used to experimentally investigate the spray flow field and to validate the numerical modeling results. Moreover, coating experiments using the optimized nozzle confirmed the effective supersonic spraying of droplets containing nanoparticles, thereby showing the potential for advanced nanocoating applications.
Implementing the Analytical Reachable Body Workspace for Calculating the Obstacle-Crossing Ability of a Hexapod Robot
Authors: Qi Chenkun , Li Huayang , Gao Feng , Chen Xianbao , Zhao Yue , Chen Zhijun
Published: April 2023

Calculating the maximum obstacle-crossing ability accurately at the mechanism design stage can better ensure that the manufactured robot prototype meets the predefined indices. The obstacle-crossing task of the legged robot is achieved by the collaborative movement of the leg and body. The reachable workspace constrains the spatial movement boundary of the foot tip and the robot body. The reachable workspace of the foot tip is invariant, while the shape and volume of the reachable body workspace vary with the supporting footholds. In this study, the body movement is modeled as a six-bar mechanism, and the reachable body workspace means the reachable region of the specified target point located on the moving platform of the six-bar mechanism. Unlike the previous work, the analytical method of calculating the reachable workspace for the target point outside the moving platform, named the external target point, is further studied. The influence of supporting footholds and shank-ground interference on the reachable body workspace is considered. The selection of supporting footholds, the collaborative motion sequences of the robot body and legs, and the determination of the maximum ability for crossing a ditch and climbing a step are demonstrated as cases of implementing the analytical reachable body workspace for the internal target point and the external target point, respectively. Finally, simulations verify the correctness of the theoretical analysis.
Association of Time-of-Day Physical Activity With Incident Cardiovascular Disease: The UK Biobank Study
Authors: Ma Tongyu , Sirard John R. , Jennings Lydia
Published: April 2023

Introduction: Early morning is characterized by an increased risk of cardiovascular events, a sudden rise in blood pressure, impaired endothelial function, and exacerbated hemodynamic changes during physical activity. The study aims to examine whether the time of day of physical activity is associated with incident cardiovascular disease (CVD). Methods: We prospectively analyzed 83,053 participants in the UK Biobank with objectively measured physical activity and initially free of CVD. Based on the diurnal patterns of physical activity, participants were categorized into 4 groups: early morning (n = 15,908), late morning (n = 22,371), midday (n = 24,764), and evening (n = 20,010). Incident CVD was defined as the first diagnosis of coronary heart disease or stroke. Results: During 197.4 million person-years of follow-up, we identified 3454 CVD cases. After adjusting for the overall acceleration average, the hazard ratios and 95% confidence intervals were 0.95 (0.86–1.07) for late morning, 1.15 (1.03–1.27) for midday, and 1.03 (0.92–1.15) for evening, as compared with the early morning group. In the joint analyses, higher levels of physical activity were associated with a lower risk of incident CVD in a similar manner across the early morning, late morning, and evening groups. However, the beneficial association was attenuated in the midday group. Conclusion: In conclusion, early morning, late morning, and evening are all favorable times of day to engage in physical activity for the primary prevention of CVD, while midday physical activity is associated with an increased risk of CVD compared with early morning physical activity after controlling for the levels of physical activity.
A snapshot of the long-term evolution of a distributed tectonic plate boundary
Authors: Dalaison Manon , Jolivet Romain , Le Pourhiet Laetitia
Published: April 2023

Along a plate boundary, why deformation and seismic hazard distributes across multiple active faults or along a single major structure remains unknown. The transpressive Chaman plate boundary (CPB) is a wide faulted region of distributed deformation and seismicity that accommodates the differential motion between India and Eurasia at 30 mm/year. However, main identified faults, including the Chaman fault, only accommodate 12 to 18 mm/year of relative motion and large earthquakes (
M
w
> 7) occurred east of them. We use Interferometric Synthetic Aperture Radar to locate the missing strain and identify active structures. The current displacement is partitioned between the Chaman fault, Ghazaband fault and a recent, immature but fast fault zone to the east. Such partitioning matches known seismic ruptures and results in the ongoing widening of the plate boundary, potentially controlled by the depth of the brittle-ductile transition. The CPB illustrates the impact of geological time scale deformation on today’s seismic activity.
Local brain oscillations and interregional connectivity differentially serve sensory and expectation effects on pain
Authors: Bott Felix S. , Nickel Moritz M. , Hohn Vanessa D. , May Elisabeth S. , Gil Ávila Cristina , Tiemann Laura , Gross Joachim , Ploner Markus
Published: April 2023

Pain emerges from the integration of sensory information about threats and contextual information such as an individual’s expectations. However, how sensory and contextual effects on pain are served by the brain is not fully understood so far. To address this question, we applied brief painful stimuli to 40 healthy human participants and independently varied stimulus intensity and expectations. Concurrently, we recorded electroencephalography. We assessed local oscillatory brain activity and interregional functional connectivity in a network of six brain regions playing key roles in the processing of pain. We found that sensory information predominantly influenced local brain oscillations. In contrast, expectations exclusively influenced interregional connectivity. Specifically, expectations altered connectivity at alpha (8 to 12 hertz) frequencies from prefrontal to somatosensory cortex. Moreover, discrepancies between sensory information and expectations, i.e., prediction errors, influenced connectivity at gamma (60 to 100 hertz) frequencies. These findings reveal how fundamentally different brain mechanisms serve sensory and contextual effects on pain.
Conformability of flexible sheets on spherical surfaces
Authors: Liu Siyi , He Jinlong , Rao Yifan , Dai Zhaohe , Ye Huilin , Tanir John C. , Li Ying , Lu Nanshu
Published: April 2023

Three-dimensional surface-conformable electronics is a burgeoning technology with potential applications in curved displays, bioelectronics, and biomimetics. Flexible electronics are notoriously difficult to fully conform to nondevelopable surfaces such as spheres. Although stretchable electronics can well conform to nondevelopable surfaces, they need to sacrifice pixel density for stretchability. Various empirical designs have been explored to improve the conformability of flexible electronics on spherical surfaces. However, no rational design guidelines exist. This study uses a combination of experimental, analytical, and numerical approaches to systematically investigate the conformability of both intact and partially cut circular sheets on spherical surfaces. Through the analysis of thin film buckling on curved surfaces, we identify a scaling law that predicts the conformability of flexible sheets on spherical surfaces. We also quantify the effects of radial slits on enhancing conformability and provide a practical guideline for using these slits to improve conformability from 40% to more than 90%.
RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription
Authors: Blatter Markus , Meylan Charlotte , Cléry Antoine , Giambruno Roberto , Nikolaev Yaroslav , Heidecker Michel , Solanki Jessica Arvindbhai , Diaz Manuel O. , Gabellini Davide , Allain Frédéric H.-T.
Published: April 2023

Mixed-lineage leukemia 1 (MLL1) is a transcription activator of the HOX family, which binds to specific epigenetic marks on histone H3 through its third plant homeodomain (PHD3) domain. Through an unknown mechanism, MLL1 activity is repressed by cyclophilin 33 (Cyp33), which binds to MLL1 PHD3. We determined solution structures of Cyp33 RNA recognition motif (RRM) free, bound to RNA, to MLL1 PHD3, and to both MLL1 and the histone H3 lysine N6-trimethylated. We found that a conserved α helix, amino-terminal to the RRM domain, adopts three different positions facilitating a cascade of binding events. These conformational changes are triggered by Cyp33 RNA binding and ultimately lead to MLL1 release from the histone mark. Together, our mechanistic findings rationalize how Cyp33 binding to MLL1 can switch chromatin to a transcriptional repressive state triggered by RNA binding as a negative feedback loop.
Asymmetric redox benzylation of enals enabled by NHC/Ru cooperative catalysis
Authors: Li Shuai , Wen Yu-Hua , Song Jin , Gong Liu-Zhu
Published: April 2023

The development of general methods for asymmetric benzylation of prochiral carbon nucleophiles remains a challenge in organic synthesis. The merging of ruthenium catalysis and N-heterocyclic carbene (NHC) catalysis for asymmetric redox benzylation of enals has been achieved, which opens up strategic opportunities for the asymmetric benzylation reactions. A wide range of 3,3′-disubstituted oxindoles with a stereogenic quaternary carbon center widely existing in natural products and biologically interesting molecules is successfully obtained with excellent enantioselectivities [up to 99% enantiomeric excess (ee)]. The generality of this catalytic strategy was further highlighted by its successful application in the late-stage functionalization of oxindole skeletons. Furthermore, the linear correlation between ee values of NHC precatalyst and the product elucidated the independent catalytic cycle of either the NHC catalyst or the ruthenium complex.
Resistless EUV lithography: Photon-induced oxide patterning on silicon
Authors: Tseng Li-Ting , Karadan Prajith , Kazazis Dimitrios , Constantinou Procopios C. , Stock Taylor J. Z. , Curson Neil J. , Schofield Steven R. , Muntwiler Matthias , Aeppli Gabriel , Ekinci Yasin
Published: April 2023

In this work, we show the feasibility of extreme ultraviolet (EUV) patterning on an HF-treated silicon (100) surface in the absence of a photoresist. EUV lithography is the leading lithography technique in semiconductor manufacturing due to its high resolution and throughput, but future progress in resolution can be hampered because of the inherent limitations of the resists. We show that EUV photons can induce surface reactions on a partially hydrogen-terminated silicon surface and assist the growth of an oxide layer, which serves as an etch mask. This mechanism is different from the hydrogen desorption in scanning tunneling microscopy–based lithography. We achieve silicon dioxide/silicon gratings with 75-nanometer half-pitch and 31-nanometer height, demonstrating the efficacy of the method and the feasibility of patterning with EUV lithography without the use of a photoresist. Further development of the resistless EUV lithography method can be a viable approach to nanometer-scale lithography by overcoming the inherent resolution and roughness limitations of photoresist materials.
Unveiling the secret of ancient Maya masons: Biomimetic lime plasters with plant extracts
Authors: Rodriguez-Navarro Carlos , Monasterio-Guillot Luis , Burgos-Ruiz Miguel , Ruiz-Agudo Encarnación , Elert Kerstin
Published: April 2023

Ancient Maya produced some of the most durable lime plasters on Earth, yet how this was achieved remains a secret. Here, we show that ancient Maya plasters from Copan (Honduras) include organics and have a calcite cement with meso-to-nanostructural features matching those of calcite biominerals (e.g., shells). To test the hypothesis that the organics could play a similar toughening role as (bio)macromolecules in calcium carbonate biominerals, we prepared plaster replicas adding polysaccharide-rich bark extracts from Copan’s local trees following an ancient Maya building tradition. We show that the replicas display similar features as the organics-containing ancient Maya plasters and demonstrate that, as in biominerals, in both cases, their calcite cement includes inter- and intracrystalline organics that impart a marked plastic behavior and enhanced toughness while increasing weathering resistance. Apparently, the lime technology developed by ancient Maya, and likely other ancient civilizations that used natural organic additives to prepare lime plasters, fortuitously exploited a biomimetic route for improving carbonate binders performance.
Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused immune stimulation
Authors: Bhagchandani Sachin H. , Vohidov Farrukh , Milling Lauren E. , Tong Evelyn Yuzhou , Brown Christopher M. , Ramseier Michelle L. , Liu Bin , Fessenden Timothy B. , Nguyen Hung V.-T. , Kiel Gavin R. , Won Lori , Langer Robert S. , Spranger Stefani , Shalek Alex K. , Irvine Darrell J. , Johnson Jeremiah A.
Published: April 2023

Imidazoquinolines (IMDs), such as resiquimod (R848), are of great interest as potential cancer immunotherapies because of their ability to activate Toll-like receptor 7 (TLR7) and/or TLR8 on innate immune cells. Nevertheless, intravenous administration of IMDs causes severe immune-related toxicities, and attempts to improve their tissue-selective exposure while minimizing acute systemic inflammation have proven difficult. Here, using a library of R848 “bottlebrush prodrugs” (BPDs) that differ only by their R848 release kinetics, we explore how the timing of R848 exposure affects immune stimulation in vitro and in vivo. These studies led to the discovery of R848-BPDs that exhibit optimal activation kinetics to achieve potent stimulation of myeloid cells in tumors and substantial reductions in tumor growth following systemic administration in mouse syngeneic tumor models without any observable systemic toxicity. These results suggest that release kinetics can be tuned at the molecular level to provide safe yet effective systemically administered immunostimulant prodrugs for next-generation cancer immunotherapies.
Sunlight-powered self-excited oscillators for sustainable autonomous soft robotics
Authors: Zhao Yusen , Li Qiaofeng , Liu Zixiao , Alsaid Yousif , Shi Pengju , Khalid Jawed Mohammad , He Ximin
Published: April 2023

As the field of soft robotics advances, full autonomy becomes highly sought after, especially if robot motion can be powered by environmental energy. This would present a self-sustained approach in terms of both energy supply and motion control. Now, autonomous movement can be realized by leveraging out-of-equilibrium oscillatory motion of stimuli-responsive polymers under a constant light source. It would be more advantageous if environmental energy could be scavenged to power robots. However, generating oscillation becomes challenging under the limited power density of available environmental energy sources. Here, we developed fully autonomous soft robots with self-sustainability based on self-excited oscillation. Aided by modeling, we have successfully reduced the required input power density to around one-Sun level through a liquid crystal elastomer (LCE)–based bilayer structure. The autonomous motion of the low-intensity LCE/elastomer bilayer oscillator “LiLBot” under low energy supply was achieved by high photothermal conversion, low modulus, and high material responsiveness simultaneously. The LiLBot features tunable peak-to-peak amplitudes from 4 to 72 degrees and frequencies from 0.3 to 11 hertz. The oscillation approach offers a strategy for designing autonomous, untethered, and sustainable small-scale soft robots, such as a sailboat, walker, roller, and synchronized flapping wings.
Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer’s disease
Authors: Huang Wen-Chin , Peng Zhuyu , Murdock Mitchell H. , Liu Liwang , Mathys Hansruedi , Davila-Velderrain Jose , Jiang Xueqiao , Chen Maggie , Ng Ayesha P. , Kim TaeHyun , Abdurrob Fatema , Gao Fan , Bennett David A. , Kellis Manolis , Tsai Li-Huei
Published: April 2023

The neural circuits governing the induction and progression of neurodegeneration and memory impairment in Alzheimer’s disease (AD) are incompletely understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in the MB correlates with pathological diagnosis of AD in human postmortem brain tissue. Whether and how MB neuronal circuitry contributes to neurodegeneration and memory deficits in AD are unknown. Using 5xFAD mice and postmortem MB samples from individuals with varying degrees of AD pathology, we identified two neuronal cell types in the MB harboring distinct electrophysiological properties and long-range projections: lateral neurons and medial neurons. lateral MB neurons harbored aberrant hyperactivity and exhibited early neurodegeneration in 5xFAD mice compared with lateral MB neurons in wild-type littermates. Inducing hyperactivity in lateral MB neurons in wild-type mice impaired performance on memory tasks, whereas attenuating aberrant hyperactivity in lateral MB neurons ameliorated memory deficits in 5xFAD mice. Our findings suggest that neurodegeneration may be a result of genetically distinct, projection-specific cellular dysfunction and that dysregulated lateral MB neurons may be causally linked to memory deficits in AD.
Rescue of glutaric aciduria type I in mice by liver-directed therapies
Authors: Barzi Mercedes , Johnson Collin G. , Chen Tong , Rodriguiz Ramona M. , Hemmingsen Madeline , Gonzalez Trevor J. , Rosales Alan , Beasley James , Peck Cheryl K. , Ma Yunhan , Stiles Ashlee R. , Wood Timothy C. , Maeso-Diaz Raquel , Diehl Anna Mae , Young Sarah P. , Everitt Jeffrey I. , Wetsel William C. , Lagor William R. , Bissig-Choisat Beatrice , Asokan Aravind , El-Gharbawy Areeg , Bissig Karl-Dimiter
Published: April 2023

Glutaric aciduria type I (GA-1) is an inborn error of metabolism with a severe neurological phenotype caused by the deficiency of glutaryl–coenzyme A dehydrogenase (GCDH), the last enzyme of lysine catabolism. Current literature suggests that toxic catabolites in the brain are produced locally and do not cross the blood-brain barrier. In a series of experiments using knockout mice of the lysine catabolic pathway and liver cell transplantation, we uncovered that toxic GA-1 catabolites in the brain originated from the liver. Moreover, the characteristic brain and lethal phenotype of the GA-1 mouse model was rescued by two different liver-directed gene therapy approaches: Using an adeno-associated virus, we replaced the defective
Gcdh
gene or we prevented flux through the lysine degradation pathway by CRISPR deletion of the aminoadipate-semialdehyde synthase (
Aass
) gene. Our findings question the current pathophysiological understanding of GA-1 and reveal a targeted therapy for this devastating disorder.
Metabolic Consequences of Polyphosphate Synthesis and Imminent Phosphate Limitation
Authors: Kim Geun-Don , Qiu Danye , Jessen Henning Jacob , Mayer Andreas
Published: April 2023

Cells must strike a delicate balance between the high demand of inorganic phosphate (P
i
) for synthesizing nucleic acids and phospholipids and its detrimental bioenergetic effects by reducing the free energy of nucleotide hydrolysis. The latter may stall metabolism.
Generation and Functional Analysis of Defective Viral Genomes during SARS-CoV-2 Infection
Authors: Zhou Terry , Gilliam Nora J. , Li Sizhen , Spandau Simone , Osborn Raven M. , Connor Sarah , Anderson Christopher S. , Mariani Thomas J. , Thakar Juilee , Dewhurst Stephen , Mathews David H. , Huang Liang , Sun Yan
Published: April 2023

Defective viral genomes (DVGs) are generated ubiquitously in many RNA viruses, including SARS-CoV-2. Their interference activity to full-length viruses and IFN stimulation provide the potential for them to be used in novel antiviral therapies and vaccine development.
Mycoplasma genitalium Protein of Adhesion Suppresses T Cell Activation via CypA-CaN-NFAT Pathway
Authors: Luo Dan , Luo Haodang , Yan Xiaoliang , Lei Aihua , He Jun , Liao Yating , Peng Kailan , Li Xia , Ye Youyuan , Chen Li , Zeng Zhuo , Xiao Hua , Zeng Yanhua
Published: April 2023

Mycoplasma genitalium
is a sexually transmitted bacterium that can co-infect with other infections and causes nongonococcal urethritis in males, cervicitis, pelvic inflammatory disease, premature birth, and ectopic pregnancy in women. The adhesion protein of
M. genitalium
(MgPa) is the primary virulence factor in the complicated pathogenicity of
M. genitalium
.
Collateral Changes in Cell Physiology Associated with ADC-7 β-Lactamase Expression in Acinetobacter baumannii
Authors: Colquhoun Jennifer M. , Farokhyfar Marjan , Anderson Alexander C. , Bethel Christopher R. , Bonomo Robert A. , Clarke Anthony J. , Rather Philip N.
Published: April 2023

Acinetobacter baumannii
has become resistant to all classes of antibiotics, with β-lactam resistance responsible for the majority of treatment failures. New classes of antimicrobials are needed to treat this high-priority pathogen. This study had uncovered a new genetic vulnerability in β-lactamase-expressing
A. baumannii
, where reduced carbonic anhydrase activity becomes lethal. Inhibitors of carbonic anhydrase could represent a new method for treating
A. baumannii
infections.
To sink, or not to sink: The thermal and density structure of the modern northern Andean arc constrained by xenolith petrology
Authors: Zieman Lisa , Ibañez-Mejia Mauricio , Rooney Alan D. , Bloch Elias , Pardo Natalia , Schoene Blair , Szymanowski Dawid
Published: April 2023

The thermal and compositional structure of arcs influence magmatic differentiation and lower-crustal foundering, two key processes impacting the evolution of the continental crust. Although many studies have proposed time scales of lithospheric recycling based on convective downwelling calculations, these models depend on the composition, density (ρ), and thermal structure of the lower crust and mantle, which are difficult to quantify in active continental arcs. Here, we constrained these properties for the Andean Northern Volcanic Zone using direct petrologic observations from a unique suite of lower-crust and mantle xenoliths from Mercaderes, Colombia. Chemical abrasion–isotope dilution–thermal ionization mass spectrometry (CA-ID-TIMS) U-Pb dates for zircons within the host tuff indicate the xenoliths erupted no earlier than 238 (±19) ka and thus capture a recent snapshot of the arc and subarc mantle. Equilibrium pressure-temperature (P-T) estimates for 81 xenoliths define three distinct thermal domains, interpreted as (1) a steep conductive geothermal gradient in the lower arc crust; (2) a convecting mantle wedge; and (3) cooled mantle in proximity to the subducting slab. Our results indicate the presence of an ~10–14-km-thick, high-density lithospheric root that is ~0.1 g/cm3 denser than the underlying mantle. Unlike records from exhumed paleoarcs, Rayleigh-Taylor instability calculations using our P-T-ρ constraints are unrealistically short for the northern Andes. We suggest the presence of partial melts in this hot arc root as a potential source of buoyancy preventing or significantly slowing down foundering.
Supplemental Material: Precise U-Pb dating of incremental calcite slickenfiber growth: Evidence for far-field Eocene fold reactivation in Ireland
Authors: Monchal Vincent , al. et
Published: April 2023

Details on the EBSD analyses, analytical setup and LA-ICP-MS operating conditions. Analytical data are provided in tables S1 to S5 (U-Pb LA-ICP-MS) and S6 and S7 (EBSD).  
Supplemental Material: The source of tungsten-associated magmas in the northern Cordillera and implications for the basement
Authors: Rasmussen Kirsten L. , al. et
Published: April 2023

Appendix S1 (methods); Data Set S1 (sample summary, analytical conditions, new U-Pb data, compiled U-Pb data, new Sm-Nd data, compiled Sm-Nd data); Data Set S2 (results of cross-correlation statistical analysis).  
P27 The accuracy of tablet splitting to provide appropriate paediatric enalapril doses
Authors: Conquest Amy , Ames Matt , Shaw Helen
Published: April 2023

Aim

The angiotensin-converting enzyme inhibitor, enalapril, is considered a first-line treatment for chronic heart failure in children. However, there is a lack of an age-appropriate formulation and tablet splitting, although not recommended, is common, in an attempt, to provide suitable doses for paediatric use. An analysis of currently available UK brands explored the accuracy of splitting low-dose tablets of enalapril.

Method

Four different commercially available enalapril tablets were evaluated: Innovace® enalapril 2.5 mg and 5 mg, (both Organon Pharma UK), generic enalapril 5 mg (Ria Generics Ltd) and generic enalapril 2.5 mg (Dexcel Pharma Ltd). Five tablets from each brand/dose were split manually where possible. For unscored tablets, a sharp knife or metal spatula was used to replicate the home environment. Tablet fragments were weighed. Using high-performance liquid chromatography, the percentage of the theoretical 1.25 mg or 2.5 mg dose contained within the half-tablet fragments was analysed (percentage label claim [%LC]) and the uniformity of dosage units was calculated (acceptance value [AV]), where an AV of ≤15 is considered to meet the acceptance criteria.

Results

Manual splitting proved relatively easy only with the deep-scoring of the Innovace 5 mg tablets; 0.007 to 0.483 mg of material was lost across the five replicates, the mean%LC (SD) was 97.5% (4.3) and the AV was 11.3. The unscored Innovace 2.5 mg tablets split less easily; 0.113 to 0.627 mg of material was lost, mean%LC (SD) was 99.9% (10.7) and the AV was 25.7. The soft 5 mg Ria Generics tablets split with high variability: 0.609 to 13.488 mg of material was lost, mean%LC (SD) was 96.0% (17.9) and AV was 45.5. Dose variation was also high with 2.5 mg Dexcel tablets, with 1.097 to 13.801 mg of material lost, mean%LC (SD) of 95.9% (11.7) and an AV of 30.7.

Conclusion

In general, splitting low-dose tablets of enalapril for paediatric use results in inaccurate dosing. Acceptable dosing was only achieved with the scored 5 mg tablets. Accurate doses below 2.5 mg were not achieved. An age-appropriate dosage formulation of enalapril to provide dosing below 2.5 mg is needed.
P10 Initiation of bisoprolol in paediatric patients – experience from a specialist paediatric cardiac centre
Authors: Bueno Gomez Andrea , Healy Mary , Delle Donne Grazia , Bentley Sian , Makhecha Sukeshi , Daubeney Piers , Naqvi Nitha , Till Jan , Wong Leonie
Published: April 2023

Aim

Given the lack of published dosing information to guide the use of bisoprolol in our paediatric cardiology patients, we assessed the safety and tolerability of initiation and maintenance doses of bisoprolol in a cohort of children with congenital structural heart disease, cardiomyopathy, or structural normal heart, to treat heart failure, arrhythmias or hypertension, and prevention of arrhythmias in channelopathies.

Method

A retrospective review of hospital records of all children who received bisoprolol between May 2014 and August 2019 in a tertiary paediatric referral centre. Patients were identified via pharmacy records and clinical informatic systems were used to identify the indication, dose at initiation (mg/kg), up-titration dose, and any documented side effects.

Results

157 children (mean 11.6 years; range 2 months – 17.8 years) were identified. 56 children (36%) had a cardiomyopathy, 23 (15%) had structural heart disease and 78 (50%) were receiving bisoprolol with a structural normal heart for the prevention or treatment of arrhythmias. 149 children had a weight documented. The starting dose of bisoprolol ranged from 0.02 mg/kg/day to 0.19 mg/kg/day (mean 0.06 mg/kg/day); independent of the indication. The dose was up titrated in 90 (57%) of children. The weight was documented in 77 of these patients and up-titrated doses in these patients ranged from 0.02 mg/kg/day to 0.4 mg/kg/day (mean 0.14 mg/kg/day). A total of 24 (15%) of children had documented adverse events attributed to bisoprolol. Fatigue or dizziness were the most common reported adverse events, with 67% of the total events. In total, 5 children (3%) stopped bisoprolol due to adverse events; 4 due to fatigue or dizziness and 1 because of wheeze in a known asthmatic. HR was documented before and after initiation of bisoprolol in 89 patients (57%). The mean change was a decrease of 8 beats per minute (bpm) and all were within normal limits. Systolic blood pressure (BP) was documented before and after initiation of bisoprolol in 61 patients (39%). The mean change was a reduction of 4.2 millimeters of mercury (mmHg) and all were within normal limits.

Conclusion

Our experience shows that initiating bisoprolol in paediatric cardiology patients with a cardiomyopathy, structural heart disease and normal structural heart, to treat arrhythmias, heart failure, outflow tract obstruction and systemic hypertension at a dose of 0.06 mg/kg once a day, up to a maintenance dose of 0.14 mg/kg/day was safe. However, this is limited by the sample size and retrospective nature of the study. Further studies are needed to be able to comment on the efficacy in this cohort of patients.
Rapid reviews methods series: Guidance on assessing the certainty of evidence
Authors: Gartlehner Gerald , Nussbaumer-Streit Barbara , Devane Declan , Kahwati Leila , Viswanathan Meera , King Valerie J , Qaseem Amir , Akl Elie , Schuenemann Holger J
Published: April 2023

This paper is part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group. Rapid reviews (RRs) use modified systematic review methods to accelerate the review process while maintaining systematic, transparent and reproducible methods. This paper addresses considerations for rating the certainty of evidence (COE) in RRs. We recommend the full implementation of GRADE (Grading of Recommendations, Assessment, Development and Evaluation) for Cochrane RRs if time and resources allow.

If time or other resources do not permit the full implementation of GRADE, the following recommendations can be considered: (1) limit rating COE to the main intervention and comparator and limit the number of outcomes to critical benefits and harms; (2) if a literature review or a Delphi approach to rate the importance of outcomes is not feasible, rely on informal judgements of knowledge users, topic experts or team members; (3) replace independent rating of the COE by two reviewers with single-reviewer rating and verification by a second reviewer and (4) if effect estimates of a well-conducted systematic review are incorporated into an RR, use existing COE grades from such a review. We advise against changing the definition of COE or the domains considered part of the GRADE approach for RRs.
Rapid reviews methods series: Guidance on team considerations, study selection, data extraction and risk of bias assessment
Authors: Nussbaumer-Streit Barbara , Sommer Isolde , Hamel Candyce , Devane Declan , Noel-Storr Anna , Puljak Livia , Trivella Marialena , Gartlehner Gerald
Published: April 2023

This paper is part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group (RRMG). Rapid reviews (RRs) use modified systematic review (SR) methods to accelerate the review process while maintaining systematic, transparent and reproducible methods to ensure integrity. This paper addresses considerations around the acceleration of study selection, data extraction and risk of bias (RoB) assessment in RRs. If a RR is being undertaken, review teams should consider using one or more of the following methodological shortcuts: screen a proportion (eg, 20%) of records dually at the title/abstract level until sufficient reviewer agreement is achieved, then proceed with single-reviewer screening; use the same approach for full-text screening; conduct single-data extraction only on the most relevant data points and conduct single-RoB assessment on the most important outcomes, with a second person verifying the data extraction and RoB assessment for completeness and correctness. Where available, extract data and RoB assessments from an existing SR that meets the eligibility criteria.
Sensitivity and specificity of CRP and symptom screening as tuberculosis screening tools among HIV-positive and negative outpatients at a primary healthcare facility in Lusaka, Zambia: a prospective cross-sectional study
Authors: Kagujje Mary , Mwanza Winnie , Somwe Paul , Chilukutu Lophina , Creswell Jacob , Muyoyeta Monde
Published: April 2023

Objectives

To evaluate the performance of point-of-care C-reactive protein (CRP) as a screening tool for tuberculosis (TB) using a threshold of 10 mg/L in both people living with HIV (PLHIV) and HIV-negative individuals and compare it to symptom screening using a composite reference for bacteriological confirmation of TB.

Methods

Prospective cross-sectional study.

Setting

A primary healthcare facility in Lusaka, Zambia.

Participants

Consecutive adults (≥18 years) presenting for routine outpatient healthcare were enrolled. Of the 816 individuals approached to participate in the study, 804 eligible consenting adults were enrolled into the study, of which 783 were included in the analysis.

Primary outcome measures

Sensitivity, specificity, positive predictive value and negative predictive value (NPV) of CRP and symptom screening.

Results

Overall, sensitivity of WHO-recommended four-symptom screen (W4SS) and CRP were 87.2% (80.0–92.5) and 86.6% (79.6–91.8) while specificity was 30.3% (26.7–34.1) and 34.8% (31.2–38.6), respectively. Among PLHIV, sensitivity of W4SS and CRP was 92.2% (81.1–97.8) and 94.8% (85.6–98.9) while specificity was 37.0% (31.3–43.0) and 27.5% (22.4–33.1), respectively. Among those with CD4≥350, the NPV for CRP was 100% (92.9–100). In the HIV negative, sensitivity of W4SS and CRP was 83.8% (73.4–91.3) and 80.3% (69.5–88.5) while specificity was 25.4% (20.9–30.2) and 40.5% (35.3–45.6), respectively. Parallel use of CRP and W4SS yielded a sensitivity and NPV of 100% (93.8–100) and 100% (91.6–100) among PLHIV and 93.3% (85.1–97.8) and 90.0% (78.2–96.7) among the HIV negatives, respectively.

Conclusion

Sensitivity and specificity of CRP were similar to symptom screening in HIV-positive outpatients. Independent use of CRP offered limited additional benefit in the HIV negative. CRP can independently accurately rule out TB in PLHIV with CD4≥350. Parallel use of CRP and W4SS improves sensitivity irrespective of HIV status and can accurately rule out TB in PLHIV, irrespective of CD4 count.
Assessing the impact of digital patient monitoring on health outcomes and healthcare resource usage in addition to the feasibility of its combination with at-home treatment, in participants receiving systemic anticancer treatment in clinical practice: protocol for an interventional, open-label, multicountry platform study (ORIGAMA)
Authors: Iivanainen Sanna , Baird Anne-Marie , Balas Bogdana , Bustillos Alberto , Castro Sanchez Amparo Yovanna , Eicher Manuela , Golding Sophie , Mueller-Ohldach Mathis , Reig Maria , Welslau Manfred , Ammann Johannes
Published: April 2023

Introduction

Digital patient monitoring (DPM) tools can enable more effective clinical care and improved patient outcomes in cancer. However, their broad adoption requires ease of use and demonstration of real-world clinical utility/impact. ORIGAMA (MO42720) is an interventional, open-label, multicountry platform study investigating the clinical utility of DPM tools and specific treatments. ORIGAMA will begin with two cohorts that aim to assess the impact of the atezolizumab-specific Roche DPM Module (hosted on the Kaiku Health DPM platform (Helsinki, Finland)) on health outcomes and healthcare resource usage, and its feasibility to support at-home treatment administration, in participants receiving systemic anticancer treatment. Other digital health solutions may be added to future cohorts.

Methods and analysis

In Cohort A, participants with metastatic non-small cell lung cancer (NSCLC), extensive-stage SCLC or Child Pugh A unresectable hepatocellular carcinoma will be randomised to a locally approved anticancer regimen containing intravenous atezolizumab (TECENTRIQ, F. Hoffmann-La Roche Ltd/Genentech) and local standard-of-care support, with/without the Roche DPM Module. Cohort B will assess the feasibility of the Roche DPM Module in supporting administration of three cycles of subcutaneous atezolizumab (1875 mg; Day 1 of each 21-day cycle) in the hospital, followed by 13 cycles at home by a healthcare professional (ie, flexible care), in participants with programmed cell-death ligand 1-positive, early-stage NSCLC. The primary endpoints are the mean difference in change of the participant-reported Total Symptom Interference Score at Week 12 from baseline (Cohort A) and flexible care adoption rate at Cycle 6 (Cohort B).

Ethics and dissemination

This study will be conducted according to the Declaration of Helsinki, and/or the applicable laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study received its first Ethics Committee approval in Spain in October 2022. Participants will provide written informed consent in a face-to-face setting. The results of this study will be presented at national and/or international congresses and disseminated via publication in peer-reviewed journals.

Trial registration number

NCT05694013.
Cost-utility analysis of a multispecialty interprofessional team dementia care model in Ontario, Canada
Authors: Wong William W L , Lee Linda , Walker Sasha , Lee Catherine , Patel Tejal , Hillier Loretta M , Costa Andrew P , Sinha Samir K
Published: April 2023

Objectives

To examine the cost-effectiveness of Multi-specialty INterprofessional Team (MINT) Memory Clinic care in comparison to the provision of usual care.

Design

Using a Markov-based state transition model, we performed a cost-utility (costs and quality-adjusted life years, QALY) analysis of MINT Memory Clinic care and usual care not involving MINT Memory Clinics.

Setting

A primary care-based Memory Clinic in Ontario, Canada.

Participants

The analysis included data from a sample of 229 patients assessed in the MINT Memory Clinic between January 2019 and January 2021.

Primary outcome measures

Effectiveness as measured in QALY, costs (in Canadian dollars) and the incremental cost-effectiveness ratio calculated as the incremental cost per QALY gained between MINT Memory Clinics versus usual care.

Results

MINT Memory Clinics were found to be less expensive ($C51 496 (95% Crl $C4806 to $C119 367) while slightly improving quality of life (+0.43 (95 Crl 0.01 to 1.24) QALY) compared with usual care. The probabilistic analysis showed that MINT Memory Clinics were the superior treatment compared with usual care 98% of the time. Variation in age was found to have the greatest impact on cost-effectiveness as patients may benefit from the MINT Memory Clinics more if they receive care beginning at a younger age.

Conclusion

Multispecialty interprofessional memory clinic care is less costly and more effective compared with usual care and early access to care significantly reduces care costs over time. The results of this economic evaluation can inform decision-making and improvements to health system design, resource allocation and care experience for persons living with dementia. Specifically, widespread scaling of MINT Memory Clinics into existing primary care systems may assist with improving quality and access to memory care services while decreasing the growing economic and social burden of dementia.
Parents’ experience of children with acquired brain injury undergoing neuro-rehabilitation: thematic synthesis protocol
Authors: Fernandes Marta , Rathinam Chandrasekar , Topping Anne Elizabeth
Published: April 2023

Introduction

Children with moderate to severe acquired brain injury frequently require a period of demanding medical and rehabilitative care to optimise their long-term capabilities and quality of life. Usually, the initial acute care is provided in tertiary centres and can last up to 12 months following the original injury. Parents of children with acquired brain injury share that experience with their child and face many different challenges encountered as their child’s long-term needs become apparent. Parents are essential partners in care, hence there is a need to better understand their experiences to support them as they face those challenges and adapt to the needs of their child. We aim to synthesise the qualitative evidence exploring parents’ experiences of children undergoing neuro-rehabilitative care.

Methods and analysis

The Enhancing Transparency in Reporting the Synthesis of Qualitative Research guideline was used in the design of this protocol. The Population, Exposure and Outcome model was used to define inclusion and exclusion criteria and refine search terms. The databases Ovid Embase, Ovid MEDLINE, CINAHL, Scopus and PsychINFO will be searched from 2009 to 2022. Two independent reviewers will review studies, assess quality using the Critical Appraisal Skills Programme and scrutinise and extract the data. Disagreements will be resolved after discussion with the third reviewer. Thematic synthesis using Thomas and Harden’s approach will be undertaken to provide the evidence to develop a model for parental support during the first year of their child’s neuro-rehabilitation.

Ethics and dissemination

Ethical committee approval will not be required as no new data will be collected. The findings will be disseminated through presentations at professional conferences, publications in peer-reviewed journals and shared with the public through relevant charities and local family support groups and networks.

PROSPERO registration number

CRD42022333182.
Integrating post-fracture care into the primary care setting (interFRACT): Protocol for a mixed-methods study to co-design a care program to improve rates of osteoporosis and fracture treatment
Authors: Talevski Jason , Beauchamp Alison , Bird Stefanie , Daly Robin M
Published: April 2023

Introduction

Despite evidence showing that timely diagnosis and appropriate pharmacological treatment of osteoporosis reduces subsequent fracture rates, osteoporosis remains significantly underdiagnosed and undertreated. The large and ongoing treatment gap for osteoporosis and associated fragility fractures could be addressed by considering systematic approaches for post-fracture care in the primary care setting. This study will develop the Integrating Post-Fracture Care into Primary Care (interFRACT) care program that aims to enhance diagnosis and treatment of osteoporosis and improve initiation and adherence to fracture prevention strategies for older adults in the primary care setting.

Methods and analysis

This mixed-methods study will follow an established co-design approach that involves six steps; the first three aim to gain an understanding of the consumer experience and needs, while the latter three focus on how to improve that experience through design and action. This will include: development of a Stakeholder Advisory Committee to provide guidance on all aspects of study design, including implementation, evaluation and dissemination; interviews with primary care physicians to explore beliefs and attitudes towards osteoporosis and fracture treatment; interviews with consumers (older adults with a diagnosis of osteoporosis and/or fragility fracture) to identify current needs for osteoporosis treatment and fracture prevention; a series of co-design workshops to develop the components of the interFRACT care program based on published guidance and findings from interviews; and a feasibility study with primary care physicians to determine the usability and acceptability of the interFRACT care program.

Ethics and dissemination

Ethical approval was obtained from Deakin University Human Research Ethics Committee (approval number: HEAG-H 56_2022). Study results will be published in peer-reviewed journals, presented at national and international conferences, and collated in reports for participating primary care practices.