bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinguishing annular pustular psoriasis from subcorneal pustular dermatosis—A diagnostic dilemma in a 10‐year‐old boy
Authors: Masison Joseph , Adalsteinsson Jonas A. , Chang Mary Wu
Published: February 2023

Subcorneal pustular dermatosis (SPD) and annular pustular psoriasis (APP) are very rare in childhood and difficult to differentiate both clinically and histopathologically. We report the case of a 10‐year‐old male with a 9‐year history of erythematous scaly annular plaques with scattered pustules on the trunk. Although initially diagnosed as SPD, a lack of response to dapsone, presence of spongiosis on histology, and early age of disease onset led to consideration of APP. The patient was subsequently treated with adalimumab 80 mg weekly and completely cleared. This case illustrates the overlapping features of SPD and APP and suggests that the two disorders may represent a spectrum of the same disease.
Identification of adult plant yellow rust resistance QTLs in Jiangsu wheat varieties Ningmai 9 and Yangmai 158
Authors: Jiang Peng , Wu Ling , Ren Yong , Zhang Hua , Wu Lei , He Yi , Li Chang , Zhang Peng , Ma Hongxiang , Zhang Xu
Published: February 2023

Wheat yellow rust (YR) is a most devastating disease in wheat worldwide. In recent years, the epidemic in China has expanded from traditional areas to the middle and lower reaches of the Yangtze River due to the changes in climate and cropping systems. To facilitate YR resistance breeding, it is meaningful to explore resistance loci from local germplasm resources. In this study, a linkage mapping was performed in a recombinant inbred line (RIL) population derived from Ningmai 9 × Yangmai 158 using a high‐density genetic map and phenotypic identification for adult plant resistance (APR) to YR in four environments. Phenotypic analysis showed that Yangmai 158 had better APR than Ningmai 9. Disease severity in different environments was significantly correlated with each other, and it was found that disease severity was significantly influenced by genotype, environment and their interaction. A total of 19 quantitative trait loci (QTLs) were identified, of which four could be detected in multiple environments and four corresponding KASP markers were then developed. Lines with different QTLs from the population including 476 chromosome segment substitution lines (CSSLs) were evaluated for APR. The results revealed that Qyr‐4B.4 and Qyr‐5B.2 could significantly reduce the disease severity, with their combination showing a better effect. The findings of the study can be beneficial for wheat YR resistance breeding in the middle and lower reaches of the Yangtze River.
Techniques on vertical ridge augmentation: Indications and effectiveness
Authors: Urban Istvan A. , Montero Eduardo , Amerio Ettore , Palombo David , Monje Alberto
Published: February 2023

Vertical ridge augmentation techniques have been advocated to enable restoring function and esthetics by means of implant‐supported rehabilitation. There are three major modalities. The first is guided bone regeneration, based on the principle of compartmentalization by means of using a barrier membrane, which has been demonstrated to be technically demanding with regard to soft tissue management. This requisite is also applicable in the case of the second modality of bone block grafts. Nonetheless, space creation and maintenance are provided by the solid nature of the graft. The third modality of distraction osteogenesis is also a valid and faster approach. Nonetheless, owing to this technique's inherent shortcomings, this method is currently deprecated. The purpose of this review is to shed light on the state‐of‐the‐art of the different modalities described for vertical ridge augmentation, including the indications, the step‐by‐step approach, and the effectiveness.
Sedatives and analgesics are major contributors to potentially inappropriate duplicate prescriptions in geriatric psychiatry*
Authors: Schulze Westhoff Martin , Schröder Sebastian , Groh Adrian , Frieling Helge , Bleich Stefan , Koop Felix , Stichtenoth Dirk O. , Krichevsky Benjamin , Heck Johannes
Published: February 2023

Background

This study sought to investigate the frequency and characteristics of duplicate prescriptions (DPs) in elderly psychiatric inpatients using a novel categorisation of DPs that differentiates between appropriate duplicate prescriptions (ADPs) and potentially inappropriate duplicate prescriptions (PIDPs).

Methods

The study was conducted as a monocentric retrospective cross‐sectional pilot study on the gerontopsychiatric ward of the Department of Psychiatry, Social Psychiatry and Psychotherapy of Hannover Medical School, a large university hospital in northern Germany. The outcome measures were the nature and frequency of PIDPs compared with the frequency of ADPs.

Results

For 92 individual patients a total of 339 medication chart reviews were conducted between April 2021 and February 2022. The median age of the study population was 73 years (interquartile range (IQR) 68–82 years); 64.6% were female. Patients' medications comprised a median of eight drugs (IQR 6–11 drugs) and 43.1% of the study population were exposed to at least one PIDP (at least one grade‐1 PIDP: 39.5%; at least one grade‐2 PIDP: 5.0%; at least one grade‐3 PIDP: 1.5%). Sedatives were most frequently responsible for grade‐1 and grade‐2 PIDPs, while grade‐3 PIDPs were elicited exclusively by analgesics. Nearly half of the study population (49.0%) displayed at least one ADP.

Conclusion

Even though the clinical implications of PIDPs are not fully established to date, we recommend that physicians who treat elderly psychiatric patients pay special attention to PIDPs, especially PIDPs elicited by sedatives. Termination of PIDPs may prevent adverse drug reactions and save healthcare expenditures.
Identification of the novel HLA‐B*46:95N allele in a Chinese blood donor
Authors: He Yanmin , You Xuan , Chen Chen , Zhang Wei , Zhu Faming
Published: February 2023

HLA‐B*46:95N shows one nucleotide substitution at position 2 when compared with HLA‐B*46:01:01:01.
Spare Parts
Authors: Sukel Kayt
Published: February 2023

Due to the remarkable advances in biomedical engineering, new technologies like brain-machine interfaces, robotics, tissue engineering, and more, artificial organs are being developed that can replace the function of natural ones. There will soon come a time when we can ask, how much of the human body can be replaced by medical devices?
An Evolutionary Approach of Grasp Synthesis for Sheet Metal Parts With Multitype Grippers
Authors: Tribaldos Jicmat Ali , Sen Chiradeep
Published: February 2023

Robot-mounted grippers are used to position, immobilize, and manipulate parts and assemblies during manufacturing. In the design of these systems, the gripper assembly, comprising the grippers that grasp the part and the frame that holds them together, is customized to each part. Due to the large number of design variables and unique design needs for each gripper, automation of gripper assemblies has been limited, especially where multiple gripper types are used to grasp a part. To this end, this article presents an evolutionary approach that synthesizes and optimizes grasps and gripper assembly layouts using two different gripper types—suction cups and magnets—from the geometric models of sheet metal parts. The method first generates an option space of gripper placement on the suitable faces of the part model. Then, a genetic algorithm generates grasps on this option space by varying both the count and locations of each gripper type. Through generations, these grasps are optimized against five criteria and one constraint: factor of safety, cost, residual moment, deflection, frame weight, and gripper clearance. These criteria are then combined into a single criterion that represents a pareto condition for assessing the grasps. The algorithm is implemented in software code for validation, and the article presents detailed validation of the algorithm using four sheet metal parts. The results show that the algorithm improves the grasp from all six aspects, when started from either program-assigned or user-defined initial grasps. The high agreement between the final grasp designs resulting from multiple runs of the algorithm on a part illustrates the stability and repeatability of the algorithm.
Manufacturing Process Classification Based on Distance Rotationally Invariant Convolutions
Authors: Wang Zhichao , Rosen David
Published: February 2023

Given a part design, the task of manufacturing process classification identifies an appropriate manufacturing process to fabricate it. Our previous research proposed a large dataset for manufacturing process classification and achieved accurate classification results based on a combination of a convolutional neural network (CNN) and the heat kernel signature for triangle meshes. In this paper, we constructed a classification method based on rotation invariant shape descriptors and a neural network, and it achieved better accuracy than all previous methods. This method uses a point cloud part representation, in contrast to the triangle mesh representation used in our previous work. The first step extracted rotation invariant features consisting of a set of distances between points in the point cloud. Then, the extracted shape descriptors were fed into a CNN for the classification of manufacturing processes. In addition, we provide two visualization methods for interpreting the intermediate layers of the neural network. Last, the performance of the method was tested on some ambiguous examples and their performances were consistent with expectations. In this paper, we have considered only shape information, while non-shape information like materials and tolerances were ignored. Additionally, only parts that require one manufacturing process were considered in this research. Our work demonstrates that part shape attributes alone are adequate for discriminating between different manufacturing processes considered.
LA UNIVERSIDAD Y EL DESARROLLO REGIONAL
Authors: Cárdenas Támara Felipe
Published: February 2023

¿Tienen o cuentan las universidades con modelos de desarrollo regional estructurados de orden transversal a todos sus procesos de servicio, investigación educación y extensión universitaria que les permita potencial y maximizar su misión? Considero que la pregunta no es banal, especialmente para un país como Colombia, y desde mi experiencia como antropólogo colombiano desarrollaré algunas ideas que considero que son pertinentes también para muchos países del mundo donde la universidad es el puente que integra, genera y difunde conocimientos, particularmente en naciones con inmensas diversidades regionales y subregionales de orden territorial, ambiental y cultural. Cada rector y su equipo tendrá que dar respuesta afirmativa o negativa al anterior interrogante. (...)
Fabrication of plasmonic Au nanostructures on dielectric supports using 10 keV electron beam lithography and tests for SERS biodetection
Authors: Ahmed Haseeb , Wu Min , Stepanova Maria
Published: February 2023

Plasmonic nanostructures have received an increasing attention due to their unique ability to mediate conversion of energy of light into different useful forms. This opens pathways for numerous applications from ultrasensitive surface-enhanced Raman scattering (SERS) characterization of materials to heterogeneous photocatalysis and green energy harvesting. However, plasmonic nanostructures should meet a number of requirements for their potential could be realized. In addition to nanoscale dimensions, a high uniformity and compatibility with existing microelectronic settings are required. Electron beam lithography (EBL) offers an unmatched control over nanoscale geometries and also a flexibility to allow for various designs. However, careful co-optimization of EBL exposure and development is required to fabricate periodic patterns with deep nanoscale dimensions. The usage of dielectric substrates is particularly challenging due to the accumulation of charge during EBL exposures. In this work, we have optimized a 10 keV EBL process to fabricate periodic arrays of 50 nm pitch dots on fused silica (FS) supports. To avoid distortions due to charging, a layer of conductive polymer was applied on the surface of the EBL resist, PMMA. In addition, we have investigated the impact of the conductive layer on the PMMA’s exposure by numerical modeling. Despite the predicted significant broadening of the 10 keV electron beam that reaches PMMA after traveling through the conductive layer, quality arrays of dots were successfully fabricated. We used the patterned PMMA as a mask to fabricate 50 nm pitch arrays of Au dots on FS. In order to verify the performance of these Au/FS structures, we used them for SERS biodetection. For this purpose, the samples were biofunctionalized with thiolated DNA aptamers that bind specifically to an important biomarker, protein interleukin 6 (IL-6). The samples were loaded with IL-6 from a solution and characterized by SERS. The results suggest that the fabricated Au/FS plasmonic nanostructures produce an efficient SERS effect. Anticipated multifunctional applications of the plasmonic nanostructures beyond the demonstrated SERS biodetection are discussed.
In vacuo cluster tool for studying reaction mechanisms in atomic layer deposition and atomic layer etching processes
Authors: Nieminen Heta-Elisa , Chundak Mykhailo , Heikkilä Mikko J. , Kärkkäinen Paloma Ruiz , Vehkamäki Marko , Putkonen Matti , Ritala Mikko
Published: February 2023

In this paper, we introduce a vacuum cluster tool designed specifically for studying reaction mechanisms in atomic layer deposition (ALD) and atomic layer etching (ALE) processes. In the tool, a commercial flow-type ALD reactor is in vacuo connected to a set of UHV chambers so that versatile surface characterization is possible without breaking the vacuum environment. This way the surface composition and reaction intermediates formed during the precursor or etchant pulses can be studied in very close to true ALD and ALE processing conditions. Measurements done at each step of the deposition or etching cycle add important insights about the overall reaction mechanisms. Herein, we describe the tool and its working principles in detail and verify the equipment by presenting results on the well-known trimethyl aluminum–water process for depositing Al2O3.
Ultra high vacuum beam pipe of the Einstein Telescope project: Challenges and perspectives
Authors: Grado Aniello , Tofani Emanuele , Angelucci Marco , Cimino Roberto , Gargiulo Julien , Getman Fedor , Liedl Andrea , Limatola Luca , Mennella Vito , Pasqualetti Antonio , Ricci Fulvio , Sentenac Daniel , Spallino Luisa
Published: February 2023

The Einstein Telescope (ET) is a project aiming to realize a facility to host a gravitational wave (GW) detector of the third generation. The new instrument will change our vision of the Universe by observing millions of GW signals emitted during the coalescence of stellar and intermediate-mass black hole binary systems. It will permit to shed light on the first phase of the Universe formation and it will contribute to solving the dark matter enigma. The new GW detector is conceived as a series of six nested Michelson interferometers forming a triangle of 10 km side. The laser light biasing the interferometers must propagate in large ultra-high vacuum (UHV) tubes in order to reduce the noise induced by the residual gas pressure fluctuations, setting a requirement on the residual pressure in the 10−10 mbar range. The vacuum system will be made of a pipe with a 1 m diameter and an overall length of 120 km, making ET one of the largest UHV systems ever made. The giant UHV project asks for attentive optimization of material choice, manufacturing processes, post-processing treatments of the tubes, and pumping systems in order to find a cost-effective solution. In this article, we shortly review the vacuum solution adopted in the case of the second generation of GW detectors. After a general description of the main elements that constitute the ET vacuum system, the detailed design being the subject of the next 3 years of work, we will present a refined calculation of the noise due to residual-gas pressure fluctuations in the ET beam pipe.
Effects of depth in semi-controlled artificial incubation on egg hatching success of Crocodylus acutus (Cuvier, 1807) and hatchlings biometry
Authors: Larreal Junior T. , Quintero-Torres Enrique , Barros Tito R.
Published: February 2023

Semi-controlled artificial incubation methods of crocodile eggs use low technology devices where one or more parameters cannot be controlled, but with the advantage that they are less expensive and logistically more feasible. This study evaluated the effect of different artificial incubation depths on the hatching success of eggs of Crocodylus acutus, under semi-controlled conditions, and analyzed biometric data of the hatchlings. The crocodile nests were collected from sandbanks of the two rivers (Río Negro and Río Santa Rosa), both located at Machiques de Perijá, Zulia state, Venezuela. The results showed a significant and positive effect on hatching success when the eggs were buried at 2 cm depth, compared to those at 10 cm and 20 cm. The hatching success at 2 cm depth was 82.43%. Also, we found that the size and weight of the hatchlings, as well as the relationships between these biometric variables, depend on the place of origin of the nests. The highest hatching percentage obtained at 2 cm was probably due to the effect of optimal incubation temperatures at this depth. The isolation and controlled heating system of the incubation room would prevent extreme fluctuations in temperature, favoring greater hatching at 2 cm depth. Differences in the biometric aspects of the hatchlings could be associated with differences in the size and the physiological status of the females from both sites.
Herpetology in Spain: a current overview through doctoral theses
Authors: Marín-Capuz Gisela , Menéndez-Blázquez Javier
Published: February 2023

This study summarizes the temporal variation, the relative contribution of each university, the research topics addressed, the taxonomic groups studied and the differences in author and its advisors’ gender in the 303 PhD theses on herpetology defended in Spain and gathered in Teseo© and Dialnet© between 1977 and 2020. The number of theses defended per year is around 7 with an upward trend. Complutense and Autonomous University of Madrid universities hosted the highest number of theses, followed by Barcelona and Valencia universities. The most addressed topic was morphology, biometry and anatomy, followed by physiology and histology, genetics and habitat selection. The most studied herpetofauna orders were Squamata and Anura and the families most tackled were Lacertidae, followed by Ranidae and Salamandridae. The most addressed species were native to Spain and without protection status, as opposed to those that were non-native or with protection status. The study of invasive species is very poorly represented. The number of PhD theses defended by men is higher compared to those by women (1.43:1), however, both genders show an upward trend in the number of theses. The results represent an approximation of the development, trends and interests pursued by herpetological research in Spain.
Direct, wave-equation-based modeling of Marchenko-type focusing functions
Authors: Diekmann Leon , Vasconcelos Ivan
Published: February 2023

Focusing functions are wavefields that focus at a single point when injected into a source-free volume from its boundary. Focusing functions that are related to the Marchenko equation can be injected from an open part of the boundary only, while vanishing on the remaining boundary. Building on this property, a method for direct, wave-equation-based modeling of Marchenko-type focusing functions in arbitrarily complex media is presented. The method naturally extends conventional frequency-domain modeling. While the numerical examples are for one dimension, a similar concept should, in principle, be applicable to the general three-dimensional case.
The career and research contributions of Richard R. Fay
Authors: Fay Richard R. , Coombs Sheryl , Popper Arthur N.
Published: February 2023

For over 50 years, Richard R. (Dick) Fay made major contributions to our understanding of vertebrate hearing. Much of Dick's work focused on hearing in fishes and, particularly, goldfish, as well as a few other species, in a substantial body of work on sound localization mechanisms. However, Dick's focus was always on using his studies to try and understand bigger issues of vertebrate hearing and its evolution. This article is slightly adapted from an article that Dick wrote in 2010 on the closure of the Parmly Hearing Institute at Loyola University Chicago. Except for small modifications and minor updates, the words and ideas herein are those of Dick.
On minimal focal distance of a focused ultrasound probe for neuromodulation
Authors: Chu Ya-Cherng , Ho Chien-Ying , Chuo Yue , Wu Hao-Hsuan , Wang Jaw-Lin
Published: February 2023

Focal distance is a key parameter for a focused ultrasound probe, especially in mouse brain stimulation where targets are right below the skull. A closed-form solution for the minimal focal distance with a given transducer size was derived in this study to facilitate precise focal spot alignment with targets in the mouse brain. The spherical profile corresponding to the minimal focal distance does not produce accurate focusing. An iterative algorithm based on Snell’s law was introduced for lens profile calculation. With a suitable step size, an accurate lens profile can be obtained for the minimal focal distance.
Observed correlations between the sediment grain size and the high-frequency backscattering strength
Authors: Wendelboe Gorm , Hefner Todd , Ivakin Anatoliy
Published: February 2023

In March 2019, Teledyne RESON and the Applied Physics Laboratory at the University of Washington conducted surveys with a calibrated multibeam echosounder at ten sites in Sequim Bay, a shallow sheltered bay in Washington State, USA. For each site, the mean grain size was obtained from a diver core sample, and estimates of the backscattering strength at frequencies ranging between 200 and 350 kHz were calculated. The correlation between the backscattering strength and the normalized grain size have been investigated for the grazing angles 45° and 75°. For 45°, a correlation consistent with previous results has been found. It demonstrates the potential for simple seabed classification.
“An Occupational Hazard”: Former Elite Male Professional Players’ Experiences of On-Field Violence in Australian Football (1970 to 1995)
Authors: Kerr John H.
Published: February 2023

This oral history research explores the experience of ten retired elite Australian football players during their careers in the period from 1970 to 1995. The ex-players were interviewed about their careers by sports journalist, Mike Sheahan, in the long-running Australia Fox Sports Open Mike television series. The particular focus of this historical research is ex-players’ experience of on-field violence. Findings indicated that ex-players were willing to break the Australian football rules and engage in on-field violence either as intimidation or retaliation against opponents. When ex-players did engage in violent intimidatory behavior, they were cool and callous, and anger rarely played a role. Violent retaliation to opposition player transgressions was either immediate or delayed until a future opportunity presented itself. For one Indigenous ex-player, violent responses during games were often sparked by opponents’ verbal racial abuse. In retrospect, he considered this a form of intimidation aimed at putting him off his game that was just part of Australian football at the time. Some ex-players did feel remorse about their violent acts, but others were adamant that they had no regrets about their behavior. Violence was almost expected as an everyday aspect of their football experience and was accepted as an occupational hazard.
Decoding geobiological evolution from microbiomes
Authors: Orsi William D. , Inagaki Fumio
Published: February 2023

Genomic records of genetic recombination and mutation rates indicate that freshwater ammonia-oxidizing archaea have evolved through paleoclimate and geohydrological history.
Immune Literacy: a Call to Action for a System-Level Change
Authors: Mixter Philip F. , Kleinschmit Adam J. , Lal Archana , Vanniasinkam Thiru , Condry Danielle L. J. , Taylor Rebekah T. , Justement Louis B. , Pandey Sumali
Published: February 2023

Immune literacy—the ability to hear, learn, read, write, explain, and discuss immunological content with varied audiences—has become critically important in recent years. Yet, with its complex terminology and discipline-specific concepts, educating individuals about the immune system and its role in health and disease may seem daunting.
Growth Arrest of Staphylococcus aureus Induces Daptomycin Tolerance via Cell Wall Remodelling
Authors: Ledger Elizabeth V. K. , Edwards Andrew M.
Published: February 2023

Understanding why antibiotics sometimes fail to cure infections is fundamental to improving treatment outcomes. This is a major challenge when it comes to
Staphylococcus aureus
because this pathogen causes several different chronic or recurrent infections.
Beyond Costs: Pragmatic Considerations for Pooling of SARS-CoV-2 Test Samples for Nursing Home Surveillance
Authors: Gussin Gabrielle M. , Singh Raveena D. , Tifrea Delia F. , Tjoa Thomas , Bittencourt Cassiana E. , Edwards Robert A. , Monuki Edwin S. , Huang Susan S.
Published: February 2023

This study highlights the pragmatic considerations surrounding SARS-CoV-2 sample pooling beyond accuracy and costs. We performed a cost analysis to determine the percent positivity at which pooling would reduce costs versus single testing.
Supplemental Material: Evidence for Caribbean plate subduction in southern Costa Rica
Authors: Bourke James , al. et
Published: February 2023

Methods, Figures S1–S6, and Table S1. 
Are we levelling the playing field? A qualitative case study of the awareness, uptake and relevance of the IOC consensus statements in two countries
Authors: Fortington Lauren V , Badenhorst Marelise , Bolling Caroline , Derman Wayne , Emery Carolyn A , Pasanen Kati , Schwellnus Martin , Verhagen Evert , Finch AO Caroline F
Published: February 2023

Objectives

Research evidence is commonly compiled into expert-informed consensus guidelines intended to consolidate and distribute sports medicine knowledge. Between 2003 and 2018, 27 International Olympic Committee (IOC) consensus statements were produced. This study explored the policy and practice impact of the IOC Statements on athlete health and medical team management in two economically and contextually diverse countries.

Methods

A qualitative case study design was adopted. Fourteen face-to-face interviews were conducted with purposively selected interviewees, seven participants from Australia (higher economic equality) and seven from South Africa (lower economic equality), representing their national medical commissions (doctors and physiotherapists of Olympic, Paralympic and Youth teams). A framework method was used to analyse interview transcripts and identify key themes.

Results

Differences across resource settings were found, particularly in the perceived usefulness of the IOC Statements and their accessibility. Both settings were unsure about the purpose of the IOC Statements and their intended audience. However, both valued the existence of evidence-informed guidelines. In the Australian setting, there was less reliance on the resources developed by the IOC, preferring to use locally contextualised documents that are readily available.

Conclusion

The IOC Statements are valuable evidence-informed resources that support translation of knowledge into clinical sports medicine practice. However, to be fully effective, they must be perceived as useful and relevant and should reach their target audiences with ready access. This study showed different contexts require different resources, levels of support and dissemination approaches. Future development and dissemination of IOC Statements should consider the perspectives and the diversity of contexts they are intended for.
Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus
Authors: Wong Charis , Gregory Jenna M , Liao Jing , Egan Kieren , Vesterinen Hanna M , Ahmad Khan Aimal , Anwar Maarij , Beagan Caitlin , Brown Fraser S , Cafferkey John , Cardinali Alessandra , Chiam Jane Yi , Chiang Claire , Collins Victoria , Dormido Joyce , Elliott Elizabeth , Foley Peter , Foo Yu Cheng , Fulton-Humble Lily , Gane Angus B , Glasmacher Stella A , Heffernan Áine , Jayaprakash Kiran , Jayasuriya Nimesh , Kaddouri Amina , Kiernan Jamie , Langlands Gavin , Leighton D , Liu Jiaming , Lyon James , Mehta Arpan R , Meng Alyssa , Nguyen Vivienne , Park Na Hyun , Quigley Suzanne , Rashid Yousuf , Salzinger Andrea , Shiell Bethany , Singh Ankur , Soane Tim , Thompson Alexandra , Tomala Olaf , Waldron Fergal M , Selvaraj Bhuvaneish T , Chataway Jeremy , Swingler Robert , Connick Peter , Pal Suvankar , Chandran Siddharthan , Macleod Malcolm
Published: February 2023

Objectives

Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART:NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.

Methods

We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.

Results

From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.

Discussion

For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.
Safety and efficacy of an artificial intelligence-enabled decision tool for treatment decisions in neovascular age-related macular degeneration and an exploration of clinical pathway integration and implementation: protocol for a multi-methods validation study
Authors: Hogg Henry David Jeffry , Brittain Katie , Teare Dawn , Talks James , Balaskas Konstantinos , Keane Pearse , Maniatopoulos Gregory
Published: February 2023

Introduction

Neovascular age-related macular degeneration (nAMD) management is one of the largest single-disease contributors to hospital outpatient appointments. Partial automation of nAMD treatment decisions could reduce demands on clinician time. Established artificial intelligence (AI)-enabled retinal imaging analysis tools, could be applied to this use-case, but are not yet validated for it. A primary qualitative investigation of stakeholder perceptions of such an AI-enabled decision tool is also absent. This multi-methods study aims to establish the safety and efficacy of an AI-enabled decision tool for nAMD treatment decisions and understand where on the clinical pathway it could sit and what factors are likely to influence its implementation.

Methods and analysis

Single-centre retrospective imaging and clinical data will be collected from nAMD clinic visits at a National Health Service (NHS) teaching hospital ophthalmology service, including judgements of nAMD disease stability or activity made in real-world consultant-led-care. Dataset size will be set by a power calculation using the first 127 randomly sampled eligible clinic visits. An AI-enabled retinal segmentation tool and a rule-based decision tree will independently analyse imaging data to report nAMD stability or activity for each of these clinic visits. Independently, an external reading centre will receive both clinical and imaging data to generate an enhanced reference standard for each clinic visit. The non-inferiority of the relative negative predictive value of AI-enabled reports on disease activity relative to consultant-led-care judgements will then be tested. In parallel, approximately 40 semi-structured interviews will be conducted with key nAMD service stakeholders, including patients. Transcripts will be coded using a theoretical framework and thematic analysis will follow.

Ethics and dissemination

NHS Research Ethics Committee and UK Health Research Authority approvals are in place (21/NW/0138). Informed consent is planned for interview participants only. Written and oral dissemination is planned to public, clinical, academic and commercial stakeholders.
Time trends in caesarean section rates and associations with perinatal and neonatal health: a population-based cohort study of 1 153 789 births in Norway
Authors: Laine Katariina , Pay Aase Devold , Yli Branka M
Published: February 2023

Objectives

To study caesarean section (CS) rates and associations with perinatal and neonatal health in Norway during 1999–2018.

Design

Population-based cohort study.

Setting

Medical Birth Registry of Norway.

Participants

1 153 789 births and 1 174 066 newborns.

Methods

CS, intrapartum, perinatal and neonatal mortality rates expressed as percentages (%) or per mille (‰) with 95% CIs.

Primary and secondary outcome measures

CS rates in the Robson Ten-Group Classification System; intrapartum, perinatal and neonatal mortality rates.

Results

The overall CS rate increased from 12.9% in 1999 to 16.7% in 2008 (p<0.001), and then reduced to 15.8% in 2018 (p<0.001). The largest reductions were observed in Robson groups 2 and 4. In Robson group 2, the planned CS rate decreased from 9.6% in 2007–2008 to 4.6% in 2017–2018, the intrapartum CS rate decreased from 26.6% in 2007–2008 to 22.3% in 2017–2018. In Robson group 4, the planned CS rate decreased from 16.1% in 2007–2008 to 7.6% in 2017–2018, and the intrapartum CS rate decreased from 7.8% in 2007–2008 to 5.2% in 2017–2018.

The intrapartum fetal mortality rate decreased from 0.51 per 1000 (‰) in 1999–2000 to 0.14‰ in 2017–2018. Neonatal mortality decreased from 2.52‰ to 1.58‰.

Conclusions

CS rates in Norway increased between 1999 and 2008, followed by a significant reduction between 2008 and 2018. At the same time, fetal and neonatal mortality rates decreased. Norwegian obstetricians and midwives have contributed to maintaining a low CS rate under 17%. These findings indicate that restricting the use of CS is a safe option for perinatal health.
Observational prospective study of social media, smartphone use and self-harm in a clinical sample of young people: study protocol
Authors: Bye Amanda , Carter Ben , Leightley Daniel , Trevillion Kylee , Liakata Maria , Branthonne-Foster Stella , Williamson Grace , Zenasni Zohra , Dutta Rina
Published: February 2023

Introduction

Young people are the most frequent users of social media and smartphones and there has been an increasing speculation about the potential negative impacts of their use on mental health. This has coincided with a sharp increase in the levels of self-harm in young people. To date, studies researching this potential association are predominantly cross-sectional and reliant on self-report data, which precludes the ability to objectively analyse behaviour over time. This study is one of the first attempts to explore temporal patterns of real-world usage prior to self-harm, to identify whether there are usage patterns associated with an increased risk.

Methods and analysis

To study the mechanisms by which social media and smartphone use underpin self-harm in a clinical sample of young people, the Social media, Smartphone use and Self-harm in Young People (3S-YP) study uses a prospective, observational study design. Up to 600 young people aged 13–25 years old from secondary mental health services will be recruited and followed for up to 6 months. Primary analysis will compare real-world data in the 7 days leading up to a participant or clinician recorded self-harm episode, to categorise patterns of problematic usage. Secondary analyses will explore potential mediating effects of anxiety, depression, sleep disturbance, loneliness and bullying.

Ethics and dissemination

This study was approved by the National Research Ethics Service, London - Riverside, as well as by the Joint Research and Development Office of the Institute of Psychiatry, Psychology and Neuroscience and South London and Maudsley NHS Foundation Trust (SLaM), and the SLaM Clinical Research Interactive Search (CRIS) Oversight Committee. The findings from this study will be disseminated through peer-reviewed scientific journals, conferences, websites, social media and stakeholder engagement activities.

Trial registration number

NCT04601220.
Factor analysis of community-ranked built environment factors contributing to pedestrian injury risk in Kampala city, Uganda
Authors: Bayiga-Zziwa Esther , Nsubuga Rogers , Mutto Milton
Published: February 2023

Background

Examining community perspective on an issue is not only a key consideration in research on road safety but also on other topics. There is substantial theoretical and empirical knowledge on built environment factors that contribute to pedestrian injury but how the community views these factors is least studied and constitutes the focus of this study. Our study investigated how respondents ranked the relative importance of selected built environment factors that contribute to pedestrian injury risk in Kampala city, Uganda and examined the underlying pattern behind the rankings.

Methods

Eight hundred and fifty-one pedestrians selected from 14 different road sections in Kampala city were asked to rank each of the 27 built environment variables on a 4-point Likert scale. Point score analysis was used to calculate scores for the different built environment variables and rank them in order of perceived contribution while factor analysis was used to determine the pattern underlying the responses.

Results

Factor analysis isolated two factors that explained 92% of the variation in respondents’ rankings: ‘road adjacent trip generators and attractors’ and ‘structure of traffic flows’. This finding implies that pedestrians in Kampala city perceived trip generators and attractors adjacent to the road and the structure of traffic flows as major explanations of the influence of the built environment on pedestrian injury risk.

Conclusion

While these rankings and factors identified may not necessarily equate to actual risk, they are important in providing an understanding of pedestrian injury risk from the perspective of the community.
First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817
Authors: Ready Neal E , Audigier-Valette Clarisse , Goldman Jonathan W , Felip Enriqueta , Ciuleanu Tudor-Eliade , Rosario García Campelo María , Jao Kevin , Barlesi Fabrice , Bordenave Stéphanie , Rijavec Erika , Urban Laszlo , Aucoin Jean-Sébastien , Zannori Cristina , Vermaelen Karim , Arén Frontera Osvaldo , Curioni Fontecedro Alessandra , Sánchez-Gastaldo Amparo , Juan-Vidal Oscar , Linardou Helena , Poddubskaya Elena , Spigel David R , Ahmed Samreen , Maio Michele , Li Sunney , Chang Han , Fiore Joseph , Acevedo Angelic , Paz-Ares Luis
Published: February 2023

Background

CheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0–1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection).

Methods

Cohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3–4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory.

Results

The most common grade 3–4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3–4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively.

Conclusions

Flat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0–1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate.

Trial registration number

NCT02869789.
Gene–environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures
Authors: Nasr Zahra , Schoeps Vinicius Andreoli , Ziaei Amin , Virupakshaiah Akash , Adams Cameron , Casper T Charles , Waltz Michael , Rose John , Rodriguez Moses , Tillema Jan-Mendelt , Chitnis Tanuja , Graves Jennifer S , Benson Leslie , Rensel Mary , Krupp Lauren , Waldman Amy T , Weinstock-Guttman Bianca , Lotze Tim , Greenberg Benjamin , Aaen Gregory , Mar Soe , Schreiner Teri , Hart Janace , Simpson-Yap Steve , Mesaros Clementina , Barcellos Lisa F , Waubant Emmanuelle
Published: February 2023

Background

We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis.

Methods

Using a case–control paediatric multiple sclerosis study, gene–environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.

Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence ofDRB1*15and the absence ofA*02,and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, includingIL-6(rs2069852),BCL-2(rs2187163) andNFKB1(rs7665090).

Results

490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products andNFKB1SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence ofHLA-A*02(AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products andNFKB1SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found withIL-6andBCL-2SNP GG genotypes.

Conclusions

The presence of gene–environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.
Macroeconomic impact of tobacco taxation in Indonesia
Authors: Bella Adrianna , Swarnata Arya , Vulovic Violeta , Nugroho Dhanie , Meilissa Yurdhina , Usman Usman , Dartanto Teguh
Published: February 2023

Background

A significant tobacco tax increase has long been advocated to reduce Indonesia’s high smoking prevalence. However, implementing such a policy remains challenging due to the tobacco industry’s argument that it would negatively impact the economy.

Objective

This study aims to provide a comprehensive estimate of the net impact of tobacco taxation on Indonesia’s economy.

Method

The impact of the tax hike on the economy is simulated through a change in cigarette demand and reallocation of household’s budget and allocation government spending from additional tobacco tax revenue. Input-output analysis is employed to estimate the net effect of the tobacco tax rise on the total economic output, income and employment in Indonesia.

Finding

Increasing the tobacco tax would generate a net positive impact on the economy as it would increase economic output, household income and employment. The positive impact is mainly driven by government spending from additional revenue from increased tobacco taxes. Spending tax revenue using the current structure of government spending has the potential to generate the optimal economic effect. Increasing tobacco tax by 45% from the 2019 tax level would increase economic output, household income and employment by Rp84.2 trillion, Rp24.1 trillion and 400.3 thousand jobs, respectively.