bluuebunny/crossref_metadata_2025 huggingface dataset:
On Being Moved: The Mobility of Inner Landscapes
Authors: Jóhannesdóttir Guðbjörg R.
Published: November 2023

How can we move towards a tourism that focuses on the inner landscape of the guest and the host; on how they are moved from the inside or touched by the tourism experience? What is being moved? Who is being moved? How can both guest and host be moved by the relations created in their encounter? To explore these questions I guide the reader through my own personal journey of being moved by the landscape of Melrakkaslétta, a journey that moved me to think about alternative approaches to tourism where the inner landscapes of guests and hosts are central. The aim of this journey is to highlight how landscapes are not only visual outer phenomena that we look at from a distance but rather whole entanglements of materials, beings, senses and processes that are constantly moving with and being moved by each other.
From Hubble to Bubble
Authors: Kierkla Maciej , Laverda Giorgio , Lewicki Marek , Mantziris Andreas , Piani Matteo , Rubio Javier , Zych Mateusz
Published: November 2023

Abstract

The detection of a stochastic Gravitational Wave (GW) background sourced by a cosmological phase transition would allow us to see the early Universe from a completely new perspective, illuminating aspects of Beyond the Standard Model (BSM) physics and inflationary cosmology. In this study, we investigate whether the evolution of the scalar potential of a minimal SM extension after inflation can lead to a strong first-order phase transition. In particular, we focus on a BSM spectator scalar field that is non-minimally coupled to gravity and has a dynamical double-well potential. As inflation ends, the potential barrier diminishes due to the evolution of the curvature scalar. Therefore, a phase transition can proceed through the nucleation of true-vacuum bubbles that collide as they fill the Universe and produce GWs. We consider high and low scales of inflation, while also taking into account a kination period between inflation and the onset of radiation domination. With this prescription, we showcase a proof-of-concept study of a new triggering mechanism for BSM phase transitions in the early Universe, whose GW signatures could potentially be probed with future detectors.
Achromatic arboricity on complete graphs
Authors: Araujo-Pardo Gabriela , Rubio-Montiel Christian
Published: November 2023

In this paper we study the achromatic arboricity of the complete graph. This parameter arises from the arboricity of a graph as the achromatic index arises from the chromatic index. The achromatic arboricity of a graph G, denoted by $$A_{\alpha }(G)$$

A
α

(
G
)

, is the maximum number of colors that can be used to color the edges of G such that every color class induces a forest but any two color classes contain a cycle. In particular, if G is a complete graph we prove that $$\begin{aligned} \frac{1}{4}n^{\frac{3}{2}}-c_1n \le A_{\alpha }(G)\le \frac{1}{\sqrt{2}}n^{\frac{3}{2}}-c_2n \end{aligned}$$

1
4

n

3
2

-

c
1

n
≤

A
α

(
G
)

≤

1

2

n

3
2

-

c
2

n

where $$c_1$$

c
1

and $$c_2$$

c
2

are constants such that $$0<c_1,c_2<\frac{1}{2}$$

0
<

c
1

,

c
2

<

1
2

.
Quartic surfaces up to volume preserving equivalence
Authors: Ducat Tom
Published: November 2023

We study log Calabi–Yau pairs of the form$$(\mathbb {P}^3,\Delta )$$(P3,Δ), where$$\Delta $$Δis a quartic surface, and classify all such pairs of coregularity less than or equal to one, up to volume preserving equivalence. In particular, if$$(\mathbb {P}^3,\Delta )$$(P3,Δ)is a maximal log Calabi–Yau pair then we show that it has a toric model.
NKLZ 2.0: Die Weiterentwicklung des Nationalen Kompetenzbasierten Lernzielkatalogs Zahnmedizin als Basis für die Ausgestaltung der neuen Approbationsordnung
Authors: Söhnel Andreas , Frankenberger Roland , Kandsperger Lars , Wissing Frank
Published: November 2023

Der Nationale Kompetenzbasierte Lernzielkatalog Zahnmedizin (NKLZ) wurde 2015 verabschiedet und definiert die Lernziele für die zahnmedizinische Ausbildung in Deutschland. Er legt fest, welche Kompetenzen Studierende erwerben sollen, und dient als Grundlage für die curriculare Gestaltung des Studiums, der Prüfungen und der Unterrichtsmaterialien. Der NKLZ fördert eine umfassende Ausbildung, die neben fachlichem Wissen auch klinische Fähigkeiten und Fertigkeiten, professionelles Verhalten und kommunikative Kompetenzen einschließt. Er trägt zur Vorbereitung angehender Zahnmediziner:innen auf ihren Beruf bei und standardisiert die Ausbildung, um Qualität und Vergleichbarkeit sicherzustellen.

Der vorliegende Artikel beschreibt Hintergründe, Geschichte, Aufbau und die Weiterentwicklung des NKLZ. Derzeit wird der NKLZ zur Version 2.0 in einem mehrstufigen Prozess weiterentwickelt. Seine Struktur orientiert sich am NKLM 2.0, dem Nationalen Kompetenzbasierten Lernzielkatalog Medizin. Ziel ist es, die Anforderungen für die Zahnärztliche Approbationsordnung umfassend abzubilden.

Eine wichtige Voraussetzung für die offizielle Anerkennung des NKLZ als grundlegender Leitfaden für die Ausbildung von Zahnmediziner:innen ist die Verankerung in einer zeitnah zu reformierenden Approbationsordnung Zahnmedizin. Dadurch werden Klarheit und Verbindlichkeit für Lehrende und Studierende geschaffen. Eine solche Verankerung ermöglicht zudem eine bessere Abstimmung zwischen Ausbildungszielen und den Anforderungen der Berufspraxis. Da die Approbationsordnung weniger häufig angepasst wird, bietet die Einbindung des NKLZ die Möglichkeit, Aktualisierungen und Anpassungen des Lernzielkatalogs strukturiert und reguliert vorzunehmen. Dies gewährleistet, dass die Ausbildung den aktuellen Standards und Entwicklungen entspricht.
PCL retained is safe in medial pivot TKA—a prospective randomized trial
Authors: Budhiparama Nicolaas C. , Lumban‐Gaol Imelda , Novito Kiki , Hidayat Hendy , De Meo Federico , Cacciola Giorgio , Cavaliere Pietro
Published: November 2023

Purpose

Medial pivot (MP) designs resemble native knee kinematics and restore the “natural” kinematics of a knee after total knee arthroplasty (TKA). However, whether to preserve or resect the posterior cruciate ligament (PCL) is still under debate. We inquired whether sacrificing the PCL would improve range of motion, functional outcomes, and limb alignment compared to preserving the PCL in TKA using medial pivot implants (MP‐TKA).

Methods

This prospective, double‐blinded, randomized controlled trial consisted of 33 patients (66 knees) undergoing bilateral simultaneous MP‐TKA. In one knee, a PCL preservation technique was performed, and in the contralateral knee, the PCL was resected. The primary outcome was postoperative range of motion (ROM). The secondary outcomes were visual analogue scale (VAS) score for knee pain at walking, Knee Injury and Osteoarthritis Outcome Score for symptoms (KOOS‐S) and quality of life (KOOS‐QoL), Oxford knee score (OKS), and Forgotten Joint Score (FJS), and measurement of the mechanical femoral‐tibial axis (mFTA) on X‐ray images. All patients were followed up for a minimum of 2 years after surgery.

Results

Patients who underwent MP‐TKA with PCL preservation had a similar ROM at 2 years (125.45 ± 7.00 vs. 126.21 ± 6.73, p = 0.65) as those who underwent MP‐TKAs with PCL resection. There was also no difference in VAS score (1.94 ± 0.79 vs. 2.00 ± 0.71, respectively, p = 0.51), OKS (39.97 ± 2.01 vs. 39.67 ± 2.03, respectively, p = 0.52), KOOS‐S (84.41 ± 3.77 vs. 84.19 ± 3.57, respectively, p = 0.92), KOOS‐QoL (82.94 ± 4.76 vs. 82.75 ± 4.70, respectively, p = 0.84), or FJS (72.66 ± 8.99 vs. 72.35 ± 8.64, respectively, p = 0.76) at the 2‐year follow‐up. No difference in the measurement of the mFTA was found between the two groups (180.27 ± 2.25 vs. 181.30 ± 2.13, respectively, p = 0.59).

Conclusion

This study demonstrated that both medial pivot TKA with PCL preservation and PCL resection achieved excellent results. There was no difference at the 2‐year follow‐up in terms of postoperative ROM, patient‐reported outcomes, or radiographic evaluation.

Level of Evidence

Therapeutic study, Level I.
Empagliflozin ameliorates liver fibrosis in NASH rat model via targeting hepatic NF-κB/SOX9/OPN signaling and osteocalcin level
Authors: Elseweidy Mohamed M. , Ali Abd El-Monem , Hassanin Sara M. , Mahmoud Yasmin K.
Published: November 2023

Non-alcoholic steatohepatitis (NASH) may be associated with tissue fibrotic changes and can be treated via different therapeutic tools which may however either initiate weak or long-term side effects that minimize its use. Empagliflozin (EMPA) is an oral anti-diabetic drug which has characteristic effects during hepatic steatosis regarding lipid accumulation and insulin resistance. In this study, we aimed to investigate an additional mechanism through which EMPA can exert and potentiate its anti-inflammatory and anti-fibrotic effects in NASH rat model. Male Wistar albino rats fed on high fat diet (HFD) and 20% fructose in drinking water for 18 weeks and received EMPA (30 mg/kg/day, orally) starting from week 11. Body and liver weights, homeostatic model assessment of insulin resistance (HOMA-IR), lipid profile, liver function tests, other biochemical and histological parameters were determined. HFD joined with fructose intake significantly increased body and liver weights, HOMA-IR value, hepatic inflammatory and fibrotic markers, liver transaminases, hepatic expression of nuclear factor-kappa B (NF-κB), sex determining region Y box 9 (SOX 9), and osteopontin (OPN) with significant decrease in hepatic osteocalcin (OCN). Intense hepatic lesions with severe microsteatosis and deposition of collagen fibers were clearly observed. Effectively, EMPA restored the normal liver functions, downregulated hepatic inflammatory cytokines, NF-κB, SOX 9, OPN, and increased OCN level. These results highlight another pathway illustrated the anti-fibrotic effects of EMPA against liver fibrosis probably through downregulation of NF-κB/SOX 9/OPN signaling along with upregulation of hepatic OCN which may potentiate the valuable anti-inflammatory and anti-fibrotic effects of EMPA.

Graphical abstract
Maximizing Access and Minimizing Barriers to Research in Low- and Middle-Income Countries: Open Access and Health Equity
Authors: Saloojee Haroon , Pettifor John M.
Published: November 2023

Access to published research has always been difficult for researchers and clinicians in low- and middle-income countries, because of the cost of and lack of access to the relevant publications. The dramatic recent increase in electronic research publications has resulted in a marked improvement in reader access to these publications through their mainly Open Access policies, however the costs of processing of submissions and publication have now become the burden of the researchers wishing to publish, rather than the readers. For many researchers working in LMIC, the Article Processing Charges (APC) are prohibitive, hampering the publication of research being conducted in and relevant to these countries. A number of grant funding agencies and international not-for-profit organizations are trying to address these issues by including funding for article publications in their grants, or by supporting publishing entities by subsiding the cost of publication, but more needs to be done by major journal publishers through markedly reducing the APC being charged to researchers in LMIC for open access facilities.
Collaborative Expression: Transcriptomics of Conus virgo Suggests Contribution of Multiple Secretory Glands to Venom Production
Authors: Fedosov Alexander , Tucci Carmen Federica , Kantor Yuri , Farhat Sarah , Puillandre Nicolas
Published: November 2023

Venomous marine gastropods of the family Conidae are among the most diversified predators in marine realm—in large due to their complex venoms. Besides being a valuable source of bioactive neuropeptides conotoxins, cone-snails venoms are an excellent model for molecular evolution studies, addressing origin of key innovations. However, these studies are handicapped by scarce current knowledge on the tissues involved in venom production, as it is generally assumed the sole prerogative of the venom gland (VG). The role of other secretory glands that are present in all Conus species (salivary gland, SG) or only in some species (accessory salivary gland, ASG) remains poorly understood. Here, for the first time, we carry out a detailed analysis of the VG, SG, and ASG transcriptomes in the vermivorous Conus virgo. We detect multiple transcripts clusters in both the SG and ASG, whose annotations imply venom-related functions. Despite the subsets of transcripts highly-expressed in the VG, SG, and ASG being very distinct, SG expresses an L-, and ASG—Cerm08-, and MEFRR- superfamily conotoxins, all previously considered specific for VG. We corroborate our results with the analysis of published SG and VG transcriptomes from unrelated fish-hunting C. geographus, and C. striatus, possibly fish-hunting C. rolani, and worm-hunting Conus quercinus. In spite of low expression levels of conotoxins, some other specific clusters of putative venom-related peptides are present and may be highly expressed in the SG of these species. Further functional studies are necessary to determine the role that these peptides play in envenomation. In the meantime, our results show importance of routine multi-tissue sampling both for accurate interpretation of tissue-specific venom composition in cone-snails, and for better understanding origin and evolution of venom peptides genes.
The evidence-based role of catecholaminergic PET tracers in Neuroblastoma. A systematic review and a head-to-head comparison with mIBG scintigraphy
Authors: Piccardo Arnoldo , Treglia Giorgio , Fiz Francesco , Bar-Sever Zvi , Bottoni Gianluca , Biassoni Lorenzo , Borgwardt Lise , de Keizer Bart , Jehanno Nina , Lopci Egesta , Kurch Lars , Massollo Michela , Nadel Helen , Roca Bielsa Isabel , Shulkin Barry , Vali Reza , De Palma Diego , Cecchin Diego , Santos Ana Isabel , Zucchetta Pietro
Published: November 2023

Background

Molecular imaging is pivotal in staging and response assessment of children with neuroblastoma (NB). [123I]-metaiodobenzylguanidine (mIBG) is the standard imaging method; however, it is characterised by low spatial resolution, time-consuming acquisition procedures and difficult interpretation. Many PET catecholaminergic radiotracers have been proposed as a replacement for [123I]-mIBG, however they have not yet made it into clinical practice. We aimed to review the available literature comparing head-to-head [123I]-mIBG with the most common PET catecholaminergic radiopharmaceuticals.

Methods

We searched the PubMed database for studies performing a head-to-head comparison between [123I]-mIBG and PET radiopharmaceuticals including meta-hydroxyephedrine ([11C]C-HED), 18F-18F-3,4-dihydroxyphenylalanine ([18F]DOPA) [124I]mIBG and Meta-[18F]fluorobenzylguanidine ([18F]mFBG). Review articles, preclinical studies, small case series (< 5 subjects), case reports, and articles not in English were excluded. From each study, the following characteristics were extracted: bibliographic information, technical parameters, and the sensitivity of the procedure according to a patient-based analysis (PBA) and a lesion-based analysis (LBA).

Results

Ten studies were selected: two regarding [11C]C-HED, four [18F]DOPA, one [124I]mIBG, and three [18F]mFBG. These studies included 181 patients (range 5–46). For the PBA, the superiority of the PET method was reported in two out of ten studies (both using [18F]DOPA). For LBA, PET detected significantly more lesions than scintigraphy in seven out of ten studies.

Conclusions

PET/CT using catecholaminergic tracers shows superior diagnostic performance than mIBG scintigraphy. However, it is still unknown if such superiority can influence clinical decision-making. Nonetheless, the PET examination appears promising for clinical practice as it offers faster image acquisition, less need for sedation, and a single-day examination.
Coronary no-reflow and adverse events in patients with acute myocardial infarction after percutaneous coronary intervention with current drug-eluting stents and third-generation P2Y12 inhibitors
Authors: Ndrepepa Gjin , Cassese Salvatore , Xhepa Erion , Joner Michael , Sager Hendrik B. , Kufner Sebastian , Laugwitz Karl-Ludwig , Schunkert Heribert , Kastrati Adnan
Published: November 2023

Background

The frequency and prognostic value of coronary no-reflow (CNR) was investigated in studies that have used an outdated reperfusion therapy in terms of stent technology and antithrombotic drugs. We assessed the association of CNR with adverse outcomes in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and newer antithrombotic drugs, ticagrelor or prasugrel.

Methods

This study included 3100 patients with AMI who underwent PCI with current DES and third-generation P2Y12 inhibitors. CNR was defined as Thrombolysis in Myocardial Infarction (TIMI) blood flow grade ≤ 2 at the end of PCI. The primary end point was 1-year incidence of net adverse clinical and cerebral events—a composite end point of death of any cause, myocardial infarction, stroke or major bleeding.

Results

CNR was diagnosed in 130 patients (4.2%). The primary end point occurred in 28 patients in the CNR group and 354 patients in the reflow group (cumulative incidence 23.2% and 12.8%; adjusted hazard ratio = 1.53, 95% confidence interval 1.01–2.33; P = 0.049). The 1-year incidences of death or myocardial infarction (14.6% vs. 7.6%; P = 0.003), myocardial infarction (8.8% vs. 3.9%; P = 0.007) and major bleeding (10.9% vs. 5.6%; P = 0.008) were significantly higher in patients with CNR than patients with reflow. The risk of adverse events in patients with CNR was highest within the first 30 days after PCI.

Conclusion

In patients with AMI undergoing PCI with current DES and third generation P2Y12 receptor inhibitors, CNR was associated with a higher risk of adverse outcomes at 1 year.

Graphical abstract
Marked intestinal trans-differentiation by autoimmune gastritis along with ectopic pancreatic and pulmonary trans-differentiation
Authors: Takeuchi Chihiro , Sato Junichi , Yamamichi Nobutake , Kageyama-Yahara Natsuko , Sasaki Akiko , Akahane Takemi , Aoki Rika , Nakajima Shigemi , Ito Masayoshi , Yamamichi Mitsue , Liu Yu-Yu , Sakuma Nobuyuki , Takahashi Yu , Sakaguchi Yoshiki , Tsuji Yosuke , Sakurai Kouhei , Tomida Shuta , Niimi Keiko , Ushijima Toshikazu , Fujishiro Mitsuhiro
Published: November 2023

Background

Autoimmune gastritis (AIG) is a prevalent chronic inflammatory disease with oncogenic potential that causes destruction of parietal cells and severe mucosal atrophy. We aimed to explore the distinctive gene expression profiles, activated signaling pathways, and their underlying mechanisms.

Methods

A comprehensive gene expression analysis was conducted using biopsy specimens from AIG, Helicobacter pylori-associated gastritis (HPG), and non-inflammatory normal stomachs. Gastric cancer cell lines were cultured under acidic (pH 6.5) conditions to evaluate changes in gene expression.

Results

Gastric mucosa with AIG had a unique gene expression profile compared with that with HPG and normal mucosa, such as extensively low expression of ATP4A and high expression of GAST and PAPPA2, which are involved in neuroendocrine tumorigenesis. Additionally, the mucosa with AIG and HPG showed the downregulation of stomach-specific genes and upregulation of small intestine-specific genes; however, intestinal trans-differentiation was much more prominent in AIG samples, likely in a CDX-dependent manner. Furthermore, AIG induced ectopic expression of pancreatic digestion-related genes, PNLIP, CEL, CTRB1, and CTRC; and a master regulator gene of the lung, NKX2-1/TTF1 with alveolar fluid secretion-related genes, SFTPB and SFTPC. Mechanistically, acidic conditions led to the downregulation of master regulator and stemness control genes of small intestine, suggesting that increased environmental pH may cause abnormal intestinal differentiation in the stomach.

Conclusions

AIG induces diverse trans-differentiation in the gastric mucosa, characterized by the transactivation of genes specific to the small intestine, pancreas, and lung. Increased environmental pH owing to AIG may cause abnormal differentiation of the gastric mucosa.
Evaluating a cutting-edge augmented reality-supported navigation system for spinal instrumentation
Authors: Schwendner Maximilian , Ille Sebastian , Wostrack Maria , Meyer Bernhard
Published: November 2023

Objective

Dorsal instrumentation using pedicle screws is a standard treatment for multiple spinal pathologies, such as trauma, infection, or degenerative indications. Intraoperative three-dimensional (3D) imaging and navigated pedicle screw placement are used at multiple centers. For the present study, we evaluated a new navigation system enabling augmented reality (AR)-supported pedicle screw placement while integrating navigation cameras into the reference array and drill guide. The present study aimed to evaluate its clinical application regarding safety, efficacy, and accuracy.

Methods

A total of 20 patients were operated on between 06/2021 and 01/2022 using the new technique for intraoperative navigation. Intraoperative data with a focus on accuracy and patient safety, including patient outcome, were analyzed. The accuracy of pedicle screw placement was evaluated by intraoperative CT imaging.

Results

A median of 8 (4–18) pedicle screws were placed in each case. Percutaneous instrumentation was performed in 14 patients (70%). The duration of pedicle screw placement (duration scan–scan) was 56 ± 26 (30–107) min. Intraoperative screw revision was necessary for 3 of 180 pedicle screws (1.7%). Intraoperatively, no major complications occurred—one case of delay due to software issues and one case of difficult screw placement were reported.

Conclusion

The current study's results could confirm the use of the present AR-supported system for navigated pedicle screw placement for dorsal instrumentation in clinical routine. It provides a reliable and safe tool for 3D imaging-based pedicle screw placement, only requires a minimal intraoperative setup, and provides new opportunities by integrating AR.
The changing pattern of common respiratory viruses among children from 2018 to 2021 in Wuhan, China
Authors: Wan Lu , Li Liangyu , Zhang Haiyue , Liu Chan , Li Ruiyun , Wu Xiaojun , Chen Jianjun
Published: November 2023

Background

Acute respiratory infections in children are a global public health challenge. Owing to the coronavirus disease (COVID-19) pandemic, non-pharmaceutical interventions, including patient isolation, social distancing, hand washing, and mask wearing, have been widely implemented, impacting the transmission of common respiratory viruses. The aim of this study was to clarify the epidemiological features of respiratory viruses in children less than 14 years of age in Wuhan before and after COVID-19.

Methods

Respiratory specimens were collected from patients aged < 14 years at two hospitals in Wuhan, China, from January 2018 to December 2021. Seven respiratory viruses were identified using an immunofluorescence assay. Pathogen profiles and seasonality were analysed.

Results

The number of visits and virus detection rate decreased dramatically after February 2020. The respiratory virus detection rate peaked in January and December and decreased dramatically in February and August. The detection rate was lower in 2021 than in 2018 and 2019. Respiratory syncytial virus (RSV) was identified as the leading pathogen in children aged < 1 year and 1–4 years before and after the COVID-19 pandemic. In children aged 5–14 years, influenza virus was detected at the highest rate before, and RSV after, the COVID-19 pandemic. RSV was the most common virus in coinfections.

Conclusions

This study revealed the epidemiological patterns of common respiratory viruses from 2018 to 2021. The spectrum of pathogens involved in paediatric respiratory infections had partly changed. Non-pharmaceutical interventions resulted in fewer opportunities for the spread of common viruses but also in an “immunity debt” that could have negative consequences when the pandemic is under control in Wuhan.
Rigorous engineering of collective adaptive systems – 2nd special section
Authors: Wirsing Martin , Jähnichen Stefan , De Nicola Rocco
Published: November 2023

An adaptive system is able to adapt at runtime to dynamically changing environments and to new requirements. Adaptive systems can be single adaptive entities or collective ones that consist of several collaborating entities. Rigorous engineering requires appropriate methods and tools that help guaranteeing that an adaptive system lives up to its intended purpose. This paper introduces the special section on “Rigorous Engineering of Collective Adaptive Systems.” It presents the 11 contributions of the section categorizing them into five distinct research lines: correctness by design and synthesis, computing with bio-inspired communication, new system models, machine learning, and programming and analyzing ensembles.
Constructing hermeneutical relations: a postphenomenological inquiry into immersive VR memory palaces
Authors: Vindenes Joakim , Wasson Barbara
Published: November 2023

While VR adaptations of the mnemonic Method of Loci (or the ‘Memory Palace’ technique) show promising results in increasing mnemonic capabilities, little to no research has explored the use and integration of Virtual Memory Palaces over time in a context of self-initiated studying. To explore the use of Virtual Memory Palaces (VMPs) contextually, we conducted an in-the-wild study where we gave ten participants a VR Head-Mounted Display through which they could access and furnish their VMP over eight weeks. We conducted go-along interviews in our participants’ VMPs at various intervals throughout the eight-week study, exploring their creations and querying them about their experience. Based on our findings, this article discusses individual and contextual factors that come into play when a VMP is approached as a personal project in the midst of an already-established study routine. We frame our study as a postphenomenological inquiry into the mediating effects of VMPs, where our primary interest lies in what relationship the students developed to the VMP.
Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy
Authors: Michaeli Daniel Tobias , Michaeli Thomas , Albers Sebastian , Boch Tobias , Michaeli Julia Caroline
Published: November 2023

Background

Over the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

Objectives

This study reviews the FDA’s five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price.

Methods

We conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview.

Results

Expedited approval reduces new drugs’ time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as “breakthroughs”, are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US.

Conclusion

Special FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.
Robots for inclusive classrooms: a scoping review
Authors: Díaz-Boladeras Marta , Claver i Díaz Ada , García-Sánchez Marta
Published: November 2023

Robot-based activities have been proven to be a valuable tool for children with learning and developmental disabilities. However, their feasibility in general educational environments needs further exploration. This scoping review provides a critical examination of robot-based learning experiences involving children with disabilities, implemented either in mainstream schools or in specialized centers in order to gain insight into their potential to support inclusion. For this purpose, a search was conducted in the multidisciplinary Scopus and WoS databases, completed with Dialnet database. Based on PRISMA guidelines for literature reviews, we limited the systematic analysis to 33 papers published after 2009 that contain information on the instructional design and details of how the activities were implemented. On the other hand, studies reporting interventions with robots for clinical purposes were excluded as well as papers focused exclusively on technical developments. Content analysis shows that most experiences lead to improvements in terms of educational goals and/or stakeholders’ satisfaction. However, the analysis also reported issues that may hinder the adoption of these practices in general classrooms and integrated education services. The reported difficulties include the lack of stability and autonomy of the robots used, the need for aids and adaptations to enable children with sensory and physical impairments to interact easily with the robots, and the requirement of technical support with system’s setup, implementation and maintenance. We conclude that robots and robotics are a powerful tool to address the needs of diverse learners who are included in mainstream classrooms. This review aims at presenting evidences of good practices and recommendations for successful implementation.
On maximal partial Latin hypercubes
Authors: Donovan Diane M. , Grannell Mike J. , Yazıcı Emine Şule
Published: November 2023

A lower bound is presented for the minimal number of filled cells in a maximal partial Latin hypercube of dimension d and order n. The result generalises and extends previous results for $$d=2$$

d
=
2

(Latin squares) and $$d=3$$

d
=
3

(Latin cubes). Explicit constructions show that this bound is near-optimal for large $$n> d$$

n
>
d

. For $$d>n$$

d
>
n

, a connection with Hamming codes shows that this lower bound gives a related upper bound for the same quantity. The results can be interpreted in terms of independent dominating sets in certain graphs, and in terms of codes that have covering radius 1 and minimum distance at least 2.
A Fully Privacy-Preserving Solution for Anomaly Detection in IoT using Federated Learning and Homomorphic Encryption
Authors: Arazzi Marco , Nicolazzo Serena , Nocera Antonino
Published: November 2023

Anomaly detection for the Internet of Things (IoT) is a very important topic in the context of cyber-security. Indeed, as the pervasiveness of this technology is increasing, so is the number of threats and attacks targeting smart objects and their interactions. Behavioral fingerprinting has gained attention from researchers in this domain as it represents a novel strategy to model object interactions and assess their correctness and honesty. Still, there exist challenges in terms of the performance of such AI-based solutions. The main reasons can be alleged to scalability, privacy, and limitations on adopted Machine Learning algorithms. Indeed, in classical distributed fingerprinting approaches, an object models the behavior of a target contact by exploiting only the information coming from the direct interaction with it, which represents a very limited view of the target because it does not consider services and messages exchanged with other neighbors. On the other hand, building a global model of a target node behavior leveraging the information coming from the interactions with its neighbors, may lead to critical privacy concerns. To face this issue, the strategy proposed in this paper exploits Federated Learning to compute a global behavioral fingerprinting model for a target object, by analyzing its interactions with different peers in the network. Our solution allows the training of such models in a distributed way by relying also on a secure delegation strategy to involve less capable nodes in IoT. Moreover, through homomorphic encryption and Blockchain technology, our approach guarantees the privacy of both the target object and the different workers, as well as the robustness of the strategy in the presence of attacks. All these features lead to a secure fully privacy-preserving solution whose robustness, correctness, and performance are evaluated in this paper using a detailed security analysis and an extensive experimental campaign. Finally, the performance of our model is very satisfactory, as it consistently discriminates between normal and anomalous behaviors across all evaluated test sets, achieving an average accuracy value of 0.85.
Augmented ant colony algorithm for virtual drug discovery
Authors: Donati Luca , Fackeldey Konstantin , Weber Marcus
Published: November 2023

Docking is a fundamental problem in computational biology and drug discovery that seeks to predict a ligand’s binding mode and affinity to a target protein. However, the large search space size and the complexity of the underlying physical interactions make docking a challenging task. Here, we review a docking method, based on the ant colony optimization algorithm, that ranks a set of candidate ligands by solving a minimization problem for each ligand individually. In addition, we propose an augmented version that takes into account all energy functions collectively, allowing only one minimization problem to be solved. The results show that our modification outperforms in accuracy and efficiency.
ISO/TS 21564:2019- based Evaluation of a Semantic Map between Variables in the ISARIC Freestanding Follow Up Survey and ORCHESTRA Studies
Authors: Rinaldi Eugenia , Thun Sylvia , Stellmach Caroline
Published: November 2023

The COVID-19 pandemic has led to tremendous investment in clinical studies to generate much-needed knowledge on the prevention, diagnosis, treatment and long-term effects of the disease. Case report forms, comprised of questions and answers (variables), are commonly used to collect data in clinical trials. Maximizing the value of study data depends on data quality and on the ability to easily pool and share data from several sources. ISARIC, in collaboration with the WHO, has created a case report form that is available for use by the scientific community to collect COVID-19 trial data. One of such research initiatives collecting and analyzing multi-country and multi-cohort COVID-19 study data is the Horizon 2020 project ORCHESTRA. Following the ISO/TS 21564:2019 standard, a mapping between five ORCHESTRA studies’ variables and the ISARIC Freestanding Follow-Up Survey elements was created. Measures of correspondence of shared semantic domain of 0 (perfect match), 1 (fully inclusive match), 2 (partial match), 4 (transformation required) or 4* (not present in ORCHESTRA) as compared to the target code system, ORCHESTRA study variables, were assigned to each of the elements in the ISARIC FUP case report form (CRF) which was considered the source code system. Of the ISARIC FUP CRF’s variables, around 34% were found to show an exact match with corresponding variables in ORCHESTRA studies and about 33% showed a non-inclusive overlap. Matching variables provided information on patient demographics, COVID-19 testing, hospital admission and symptoms. More in-depth details are covered in ORCHESTRA variables with regards to treatment and comorbidities. ORCHESTRA’s Long-Term Sequelae and Fragile population studies’ CRFs include 32 and 27 variables respectively which were evaluated as a perfect match to variables in the ISARIC FUP CRF. Our study serves as an example of the kind of maps between case report form variables from different research projects needed to link ongoing COVID-19 research efforts and facilitate collaboration and data sharing. To enable data aggregation across two data systems, the information they contain needs to be connected through a map to determine compatibility and transformation needs. Combining data from various clinical studies can increase the power of analytical insights.
Evaluating Standard of Care and Obstetrical Outcomes in a Reduced Contact Prenatal Care Model in the COVID-19 Pandemic
Authors: Mei Jenny Y. , Bernstein Megan E. , Patton Eden , Duong Hai-Lang , Negi Masaru
Published: November 2023

Introduction

We aimed to investigate the impact of reduced contact prenatal care necessitated by the COVID-19 pandemic on meeting standards of care and perinatal outcomes.

Methods

This was a retrospective case-control study of patients in low-risk obstetrics clinic at a tertiary care county facility serving solely publicly insured patients comparing reduced in-person prenatal care (R) over 12 weeks with a control group (C) receiving traditional prenatal care who delivered prior.

Results

Total 90 patients in reduced contact (R) cohort were matched with controls (C). There were similar rates of standard prenatal care metrics between groups. Gestational age (GA) of anatomy ultrasound was later in R (p = 0.017). Triage visits and missed appointments were similar, though total number of visits (in-person and telehealth) was higher in R (p = 0.043). R group had higher GA at delivery (p = 0.001). Composite neonatal morbidity and length of stay were lower in R (p = 0.017, p = 0.048). Maternal and neonatal outcomes did not otherwise differ between groups. Using Kotelchuck Adequacy of Prenatal Care Utilization index, R had higher rates of adequate prenatal care (45.6% R vs. 24.4% C, p = 0.005).

Discussion

Our study demonstrates the non-inferiority of a hybrid, reduced schedule prenatal schedule to traditional prenatal scheduling. In a reduced contact prenatal care model, more patients met criteria for adequate prenatal care, likely due to higher attendance of telehealth visits. These findings raise the question of revising the prenatal care model to mitigate disparities in disadvantaged populations.
Time-Based and Event-Based Prospective Memory in Mild Cognitive Impairment and Alzheimer’s Disease Patients: A Systematic Review and Meta-analysis
Authors: Román-Caballero Rafael , Mioni Giovanna
Published: November 2023

Prospective memory (PM) is the ability to remember to perform planned actions in a future moment and it is of fundamental importance for an independent and autonomous lifestyle from development to late adulthood. Deficits in episodic memory and executive functions, which are involved in PM are characteristic features of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Considering that the number of older adults is drastically increasing over the next decades, it is of great interest to understand how PM decline in healthy older adults and patients with different degree of cognitive decline. The present meta-analysis included 46 studies investigating PM performance in AD patients (17 studies) and people with MCI (24 studies); 5 studies included both clinical conditions in the same article. The 46 studies contributed a total of 63 independent samples and 129 effect sizes from 4668 participants (2115 patients and 2553 controls). Unlike previous reviews of the literature, our results with a larger and updated sample of studies confirmed lower PM abilities in AD compared to MCI and controls, although we did not observe conclusive differences between event-based and time-based PM in patients. Surprisingly, PM deficits shown by MCI and AD patients have decreased across years, in parallel to a reduction of the evidence of publication bias and an increase in the number of observations per task. We propose the use of more reliable research designs as one plausible explanation for the reduction of PM impairments.
Tribo-Electric Analysis of Multi-Cycle Wear in Asymmetric Laser-Structured Cu-Sn Connectors
Authors: Schütz Silas , Suarez Sebastian , Mücklich Frank
Published: November 2023

One of the key objectives of the connector industry for the past years has been to reduce the insertion friction forces of detachable electrical connections, where the majority of approaches combine a particular connector design with the usage of lubricants. The necessity for a solution that uses less contact force to maintain a lasting electrically conductive connection without sacrificing the mechanical robustness of the connection during use is a significant challenge in this situation. The approach in this work is to create surfaces supporting asymmetric friction, meaning lower insertion than removal forces. By Direct Laser Interference Patterning (DLIP), asymmetric saw-tooth structures with different structural inclinations and periodicities were generated on Sn-coated Cu plates. It is determined that topographical interlocking is the primary operating mechanism providing the required anisotropy. Multiple insertion/removal cycles were simulated on the tailored surfaces to tribologically characterize them and to determine the evolution of the electrical contact resistance at the end of each insertion motion. The vast majority of the generated structures showed an improvement compared to the reference state, with lower insertion and higher removal forces while the electrical behavior is not significantly impacted.
Rock typing and uncertainty assessment in geological and petrophysical properties by integrating electrofacies, hydraulic flow units, and geostatistical techniques in the Kangan gas field, Zagros basin
Authors: Bakhtiyari Mohammad , Qajar Jafar , Karimian Torghabeh Amir , Dehghan Abnavi Ali
Published: November 2023

The structural complexities of hydrocarbon reservoirs make it difficult to correlate geological and petrophysical properties. A successful field development depends on accurately mapping the spatial distributions of reservoir key parameters. In this study, we present results on rock type analysis, estimation, and uncertainty evaluation of geological and petrophysical data of 33 wells in one of the south Iranian gas fields. This paper is divided into two parts. In the first part, we used a reservoir rock classification theme based on identifying electrofacies (EFs) and hydraulic flow units by analyzing both log and core data. In the second part of the paper, we performed estimation, uncertainty evaluation, and assessment of the porosity–thickness relationship of the high-quality EFs using geostatistical techniques. We used sequential simulation schemes to map the spatial distributions of porosity and thickness of the high-quality EFs across the field. Using probabilistic approaches, the generated multiple realizations were used to quantify the local and spatial uncertainties. Variogram analysis showed that property distributions had a higher continuity and minimum variance in the NW–SE direction. Based on spatial uncertainty analysis, we found that the indicator-based sequential simulated maps exhibited less spatial uncertainty. Furthermore, the obtained probability maps indicated that the SE part of the study area is more suitable for drilling and production scenarios.
Trust-based health decision-making recruits the neural interoceptive saliency network which relates to temporal trajectories of Hemoglobin A1C in Diabetes Type 1
Authors: Jorge Helena , Duarte Isabel C. , Melo Miguel , Relvas Ana Paula , Castelo-Branco Miguel
Published: November 2023

Experimental approaches in neuroeconomics generally involve monetary utility. Utility in the health domain is relevant in diabetes because constant daily life decisions are critical for self-consequential long-term outcomes. We used fMRI to investigate self-consequent decision-making in the health and economic domains in Type 1 Diabetes Mellitus and controls (N = 50). We focused on two critical phases of decision-making: Investment and Feedback (Positive or Negative). Patients showed larger BOLD activation of limbic, and reward/dopaminergic regions in particular in the health trust game. Importantly, the worse the trajectory of metabolic control (increasing HbA1C), the higher the BOLD activity in regions of the interoceptive saliency network. This was manifested by positive correlations between brain activity during investment in anterior cingulate cortex and insula and HbA1c blood level progression. We conclude that the neural correlates of health-consequent decision-making domain involve limbic and reward related dopaminergic regions in Type 1 Diabetes Mellitus. Furthermore, the temporal trajectory of HbA1C blood levels is correlated with neural risk processing in the saliency network. Evidence for differential risk processing in the health versus the neuroeconomic context, and the discovery of a role for the saliency interoceptive network in metabolic control trajectories suggests a new perspective on the development of personalized interventions.
Determine the Optimal Parameters for Biogas Production from Common Reed (Phragmites australis)
Authors: Al-Iraqi Ahmed R. , Gandhi Bhushan P. , Folkard Andrew M. , Barker Philip A. , Semple Kirk T.
Published: November 2023

A series of batch assays have been conducted to investigate the optimal factors that can be adopted to improve the anaerobic digestion (AD) performance of Phragmites australis and increase biogas production. The assays were carried out using 125 mL microcosm reactors with a working volume of 80 mL and incubated at mesophilic conditions (37 ± 1ºC). The effect of particle size (10, 5, 2, and < 1 mm) and alkaline pre-treatment of P. australis using various concentrations of sodium hydroxide (0.5, 1, 2, and 4%) on biogas production was examined. Furthermore, the best pre-treatment incubation time (12, 24, 48, 72, 96, and 120 h) and the optimal inoculum to substrate ratio (ISR: 4:1, 2:1, 1:1, 1:2 and 1:4) were also assessed. The results revealed that the highest biogas production from P. australis was achieved at particle size < 1 mm (27.97 ± 0.07 and 16.67 ± 0.09 mL/g VS added, for pre-treated and untreated P. australis respectively); 2% and 4% NaOH concentration for pre-treatment (70.01 ± 3.75 and 76.14 ± 2.62 mL/g VS added, respectively); pre-treatment incubation time of 72, 96, and 120 h (71.18 ± 1.79, 72.46 ± 1.08, and 73.78 ± 1.87 mL/g VS added, respectively); and ISR of 1:2 for pre-treated P. australis (78.21 ± 0.36 mL/g VS added) and ISR 1:4 for untreated P. australis (28.93 ± 1.55 mL/g VS added). Determining optimal parameters in this work would guide further development of process configurations, such as continuous AD systems.