bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1
Authors: Shahinozzaman Md , Ahmed Sinthyia , Emran Rashiduzzaman , Tawata Shinkichi 
Published: September 2021

AbstractP21-activated kinases (PAKs) are serine/threonine protein kinase which have six different isoforms (PAK1–6). Of those, PAK1 is overexpressed in many cancers and considered to be a major chemotherapeutic target. Most of the developed PAK1 inhibitor drugs work as pan-PAK inhibitors and show undesirable toxicity due to having untargeted kinase inhibition activities. Selective PAK1 inhibitors are therefore highly desired and oncogenic drug hunters are trying to develop allosteric PAK1 inhibitors. We previously synthesized 1,2,3-triazolyl ester of ketorolac (15K) through click chemistry technique, which exhibits significant anti-cancer effects via inhibiting PAK1. Based on the selective anticancer effects of 15K against PAK1-dependent cancer cells, we hypothesize that it may act as an allosteric PAK1 inhibitor. In this study, computational analysis was done with 15K to explore its quantum chemical and thermodynamic properties, molecular interactions and binding stability with PAK1, physicochemical properties, ADMET, bioactivities, and druglikeness features. Molecular docking analysis demonstrates 15K as a potent allosteric ligand that strongly binds to a novel allosteric site of PAK1 (binding energy ranges – 8.6 to – 9.2 kcal/mol) and does not target other PAK isoforms; even 15K shows better interactions than another synthesized PAK1 inhibitor. Molecular dynamics simulation clearly supports the stable binding properties of 15K with PAK1 crystal. Density functional theory-based calculations reveal that it can be an active drug with high softness and moderate polarity, and ADMET predictions categorize it as a non-toxic drug as evidenced by in vitro studies with brine shrimp and fibroblast cells. Structure–activity relationship clarifies the role of ester bond and triazol moiety of 15K in establishing novel allosteric interactions. Our results summarize that 15K selectively inhibits PAK1 as an allosteric inhibitor and in turn shows anticancer effects without toxicity.
Multi-leader-follower potential games
Authors: Steffensen Sonja 
Published: September 2021

In this paper, we discuss a particular class of Nash games, where the participants of the game (the players) are divided into two groups (leaders and followers) according to their position or influence on the other players. Moreover, we consider the case, when the leaders’ and/or the followers’ game can be described as a potential game. This is a subclass of Nash games that has been introduced by Monderer and Shapley in 1996 and has beneficial properties to reformulate the bilevel Nash game. We develope necessary and sufficient conditions for Nash equilibria and present existence and uniqueness results. Furthermore, we discuss some Examples to illustrate our results.
In this paper, we discussed analytical properties for multi-leader follower potential games, that form a subclass of hierarchical Nash games. The application of these theoretical results to various fields of applications are a future research topic. Moreover, they are meant to serve as a starting point for the developement of efficient numerical solution methods for multi-leader-follower games.
Leveraging American College of Obstetricians and Gynecologists Guidelines for Point-of-Care Decision Support in Obstetrics
Authors: Sanford Brittany H. , Labbad Gabriel , Hersh Alyssa R. , Heshmat Aya , Hasley Steve 
Published: September 2021

Abstract
Background The American College of Obstetricians and Gynecologists (ACOG) provides numerous narrative documents containing formal recommendations and additional narrative guidance within the text. These guidelines are not intended to provide a complete “care pathway” for patient management, but these elements of guidance can be useful for clinical decision support (CDS) in obstetrical and gynecologic care and could be exposed within electronic health records (EHRs). Unfortunately, narrative guidelines do not easily translate into computable CDS guidance.
Objective This study aimed to describe a method of translating ACOG clinical guidance into clear, implementable items associated with specific obstetrical problems for integration into the EHR.
Methods To translate ACOG clinical guidance in Obstetrics into implementable CDS, we followed a set of steps including selection of documents, establishing a problem list, extraction and classification of recommendations, and assigning tasks to those recommendations.
Results Our search through ACOG clinical guidelines produced over 500 unique documents. After exclusions, and counting only sources relevant to obstetrics, we used 245 documents: 38 practice bulletins, 113 committee opinions, 16 endorsed publications, 1 practice advisory, 2 task force and work group reports, 2 patient education, 2 obstetric care consensus, 60 frequently asked questions (FAQ), 1 women's health care guidelines, 1 Prolog series, and 9 others (non-ACOG). Recommendations were classified as actionable (n = 576), informational (n = 493), for in-house summary (n = 124), education/counseling (n = 170), policy/advocacy (n = 33), perioperative care (n = 4), delivery recommendations (n = 50), peripartum care (n = 13), and non-ACOG (n = 25).
Conclusion We described a methodology of translating ACOG narrative into a semi-structured format that can be more easily applied as CDS in the EHR. We believe this work can contribute to developing a library of information within ACOG that can be continually updated and disseminated to EHR systems for the most optimal decision support. We will continue documenting our process in developing executable code for decision support.
Effective Hamiltonians for almost-periodically driven quantum systems*
Authors: Viennot David 
Published: September 2021

Abstract
We present an effective Hamiltonian theory available for some quasi-periodically driven quantum systems which does not need the knowledge of the Fourier frequencies of the control signal. It could also be available for some chaotically driven quantum systems. It is based on the Koopman approach which generalizes the Floquet approach used with periodically driven systems. We show the properties of the quasi-energy states (eigenvectors of the effective Hamiltonian) as quasi-recurrent states of the quantum system.
Spectral upper bound for the torsion function of symmetric stable processes
Authors: Panzo Hugo 
Published: September 2021

We prove a spectral upper bound for the torsion function of symmetric stable processes that holds for convex domains in

R

d

\mathbb {R}^d

. Our bound is explicit and captures the correct order of growth in

d
d

, improving upon the existing results of Giorgi and Smits [Indiana Univ. Math. J. 59 (2010), pp. 987–1011] and Biswas and Lőrinczi [J. Differential Equations 267 (2019), pp. 267–306]. Along the way, we make progress towards a torsion analogue of Chen and Song’s [J. Funct. Anal. 226 (2005), pp. 90–113] two-sided eigenvalue estimates for subordinate Brownian motion.
On the homotopy of closed manifolds and finite CW-complexes
Authors: Su Yang , Wu Xiaolei 
Published: September 2021

We study the finite generation of homotopy groups of closed manifolds and finite CW-complexes by relating it to the cohomology of their fundamental groups. Our main theorems are as follows: when

X
X

is a finite CW-complex of dimension

n
n

and

π
1

(
X
)

\pi _1(X)

is virtually a Poincaré duality group of dimension

≥
n
−
1

\geq n-1

, then

π
i

(
X
)

\pi _i(X)

is not finitely generated for some

i
i

unless

X
X

is homotopy equivalent to the Eilenberg–MacLane space

K
(

π
1

(
X
)
,
1
)

K(\pi _1(X),1)

; when

M
M

is an

n
n

-dimensional closed manifold and

π
1

(
M
)

\pi _1(M)

is virtually a Poincaré duality group of dimension

≥
n
−
1

\ge n-1

, then for some

i
≤
[
n

/

2
]

i\leq [n/2]

,

π
i

(
M
)

\pi _i(M)

is not finitely generated, unless

M
M

itself is an aspherical manifold. These generalize theorems of M. Damian [Trans. Amer. Math. Soc. 361 (2009), pp. 1791–1809] from polycyclic groups to any virtually Poincaré duality groups.
Transmembrane channel-like 4 is involved in pH and temperature-dependent modulation of salty taste
Authors: Kasahara Yoichi , Narukawa Masataka , Kanda Shinji , Tominaga Makoto , Abe Keiko , Misaka Takumi , Asakura Tomiko 
Published: September 2021

ABSTRACT
Human susceptibility to NaCl varies depending on temperature and pH, the molecular mechanisms of which remain unclear. The voltage-dependent chloride channel, transmembrane channel-like 4 (TMC4), is activated at approximately 40 °C and is suppressed at pH 5.5. As these are similar in character to human sensory evaluations, human TMC4 may be involved in human salt taste reception.
Magnetic inversion to recover the subsurface block structures based onL1 norm and total variation regularization
Authors: Utsugi Mitsuru 
Published: September 2021

SUMMARYThis paper presents a new sparse inversion method based on L1 norm regularization for 3-D magnetic data. In isolation, L1 norm regularization yields model elements which are unconstrained by the input data to be exactly zero, leading to a sparse model with compact and focused structure. Here, we complement the L1 norm with a penalty minimizing total variation, the L1 norm of the model gradients; it is expected that the sharp boundaries of the subsurface structure are not compromised by incorporating this penalty. Although this penalty is widely used in the geophysical inversion studies, it is often replaced by an alternative quadratic penalty to ease solution of the penalized inversion problem; in this study, the original definition of the total variation, that is form of the L1 norm of the model gradients, is used. To solve the problem with this combined penalty of L1 norm and total variation, this study introduces alternative direction method of multipliers, which is a primal-dual optimization algorithm that solves convex penalized problems based on the optimization of an augmented Lagrange function. To improve the computational efficiency of the algorithm to make this method applicable to large-scale magnetic inverse problems, this study applies matrix compression using the wavelet transform and the preconditioned conjugate gradient method. The inversion method is applied to both synthetic tests and real data, the synthetic tests demonstrate that, when subsurface structure is blocky, it can be reproduced almost perfectly.
Abuse of dominance (1): non-pricing practices
Authors: Whish Richard , Bailey David 
Published: September 2021

Abstract
This chapter considers abusive non-pricing practices under Article 102 TFEU and the Chapter II prohibition in the Competition Act 1998. It deals in turn with exclusive dealing agreements; tying; refusals to supply; abusive non-pricing practices that are harmful to the single market; and miscellaneous other non-pricing practices which might infringe Article 102 or the Chapter II prohibition. Reference is made to the case-law of the Court of Justice and the Commission’s Guidance on the Commission’s Enforcement Priorities in Applying Article [102 TFEU] to Abusive Exclusionary Conduct by Dominant Undertakings
Widespread translational control regulates retinal development in mouse
Authors: Chen Kaining , Chen Congying , Li Huihui , Yang Jiaqi , Xiang Mengqing , Wang Hongwei , Xie Zhi 
Published: September 2021

Abstract
Retinal development is tightly regulated to ensure the generation of appropriate cell types and the assembly of functional neuronal circuitry. Despite remarkable advances have been made in understanding regulation of gene expression during retinal development, how translational regulation guides retinogenesis is less understood. Here, we conduct a comprehensive translatome and transcriptome survey to the mouse retinogenesis from the embryonic to the adult stages. We discover thousands of genes that have dynamic changes at the translational level and pervasive translational regulation in a developmental stage-specific manner with specific biological functions. We further identify genes whose translational efficiencies are frequently controlled by changing usage in upstream open reading frame during retinal development. These genes are enriched for biological functions highly important to neurons, such as neuron projection organization and microtubule-based protein transport. Surprisingly, we discover hundreds of previously uncharacterized micropeptides, translated from putative long non-coding RNAs and circular RNAs. We validate their protein products in vitro and in vivo and demonstrate their potentials in regulating retinal development. Together, our study presents a rich and complex landscape of translational regulation and provides novel insights into their roles during retinogenesis.
Opioid-Free Anesthesia for Craniotomy
Authors: McCullough Ian L. , Shteamer Jack W. , Erwood Andrew M. , Spektor Boris , Boorman David W. , Sharifpour Milad , Olson Jeffery J. , Papangelou Alexander 
Published: September 2021

Background:
Perioperative opioids are problematic following craniotomy as they can impede neurological examination because of excessive sedation and mask surgical complications. Multimodal anesthetic techniques including nerve blocks have been used successfully to deliver opioid-free anesthesia in other surgical populations; however, no clinical data evaluating opioid-free anesthesia for craniotomy exists within the current body of literature.

Materials and Methods:
Six prospectively identified patients underwent supratentorial craniotomy at Emory University Hospital using a multimodal opioid-free anesthetic (OFA) technique consisting of preoperative scalp block, dexmedetomidine and intravenous acetaminophen. These opioid-free patients were matched by age, sex, incision length, and incision location to 18 retrospectively identified control patients who underwent craniotomy using conventional, opioid-based anesthetic techniques. Postoperative opioid consumption and pain scores were compared and analyzed for noninferiority.

Results:
Noninferiority of the OFA technique was demonstrated for opioid consumption at all measured intervals from postanesthesia care unit arrival to 24 hours postoperatively. Noninferiority was also demonstrated with respect to average postoperative pain scores from 0 to 12 hours, 0 to 24 hours, as well as length of postanesthesia care unit stay. Noninferiority was not shown for time to first rescue opioid postoperatively, pain scores for the 12 to 24 hours postoperative period, or time to emergence from anesthesia.

Conclusions:
This pilot study demonstrates the feasibility of an OFA technique for patients undergoing supratentorial craniotomy and suggests that larger prospective randomized controlled trials are indicated to examine the role of multimodal anesthetic techniques for craniotomy.
What’s New in Pain Management for Pediatric Orthopaedic Surgery
Authors: Johnson Mitchell A. , Andras Lindsay M. , Andras Lydia E. , Ellington Matthew D. , Upasani Vidyadhar V. , Shah Apurva S. 
Published: September 2021

Background:
Improving pain control and decreasing opioid prescription and usage continue to be emphasized across both pediatric and adult populations. The purpose of this review is to provide a comprehensive assessment of recent literature and highlight new advancements pertaining to pain control in pediatric orthopaedic surgery.

Methods:
An electronic search of the PubMed database was performed for keywords relating to perioperative pain management of pediatric orthopaedic surgery. Search results were filtered by publication date for articles published between January 1, 2015 and December 1, 2020 and yielded 404 papers.

Results:
A total of 32 papers were selected for review based upon new findings and significant contributions in the following categories: risk factors for increased opioid usage, opioid overprescribing and disposal, nonpharmacologic interventions, nonsteroidal anti-inflammatory drugs, peripheral nerve blocks, spine surgery specific considerations, surgical pathway modifications, and future directions.

Conclusions:
There have been many advances in pain management for pediatric patients following orthopaedic surgery. Rapid recovery surgical care pathways are associated with shorter length of stay and improved pain control in pediatric spine surgery. Opioid overprescribing continues to be common and information regarding safe opioid disposal practices should be routinely provided for pediatric patients undergoing surgery.

Level of Evidence:
Level IV—literature review.
Rates of Upstaging, Between Diagnosis and Surgery, and Clinical Management of Metastatic Cutaneous Squamous Cell Carcinoma: A Case–Control Study
Authors: Costello Collin M. , Cumsky Helen J. L. , Severson Kevin J. , Mi Lanyu , DiCaudo David J. , Ochoa Shari A. , Baum Christian L. , Mangold Aaron R. 
Published: September 2021

BACKGROUND
Cutaneous squamous cell carcinomas (cSCC) have upstage rates of approximately 10.3% to 11.1%. Data are currently limited on the rate of upstaging for metastatic cSCC.

OBJECTIVE
The aim of this study was to determine the rates of upstaging, between diagnosis and surgery, and differences in management for metastatic and non-metastatic high-risk cSCC.

MATERIALS AND METHODS
This was a retrospective, case–control, single institution, multi-center study. Univariate analysis was used.

RESULTS
Sixty-eight subjects (34 metastatic & 34 non-metastatic) with 69 tumors were included. The overall rate of upstaging was 46.4%. The most common reasons for upstage were undocumented tumor size and under-diagnosis of poor differentiation. There were no differences in rates of upstaging. Preoperative imaging was performed in 43.6% of wide local excisions (WLE) versus 3.3% of Mohs micrographic surgery (MMS; p < .001). The median days from surgery to sentinel lymph node biopsy (SLNB), or nodal dissection was shorter for WLE versus MMS (0 vs 221 days, p < .001).

CONCLUSION
Improved clinical documentation, including documenting tumor size, and the identification of pathologic risk factors, including poor differentiation and depth of invasion, are needed for proper staging. Preoperative imaging and discussion of SLNB may be beneficial for high-risk T2b and T3 tumors.
Drug–Drug Interactions With Over-The-Counter Medicines: Mind the Unprescribed
Authors: Scherf-Clavel Oliver 
Published: September 2021

Background:
This review provides a summary of the currently available clinical data on drug–drug interactions (DDIs) involving over-the-counter (OTC) medicines. It aims to educate and increase awareness among health care providers and to support decisions in daily practice.

Methods:
An extensive literature search was performed using bibliographic databases available through PubMed.gov. An initial structured search was performed using the keywords “drug-drug-interaction AND (over-the-counter OR OTC),” without further restrictions except for the language. The initial results were screened for all described DDIs involving OTC drugs, and further information was gathered specifically on these drugs using dedicated database searches and references found in the bibliography from the initial hits.

Results:
From more than 1200 initial hits (1972–June 2021), 408 relevant publications were screened for DDIs involving OTC drugs, leading to 2 major findings: first, certain types of drug regimens are more prone to DDIs or have more serious DDI-related consequences, such as antiretroviral, anti-infective, and oral anticancer therapies. Second, although most DDIs involve OTC drugs as the perpetrators, some prescription drugs (statins or phosphodiesterase-5 inhibitors) that currently have OTC status can be identified as the victims in DDIs. The following groups were identified to be frequently involved in DDIs: nonsteroidal anti-inflammatory drugs, food supplements, antacids, proton-pump inhibitors, H2 antihistamines, laxatives, antidiarrheal drugs, and herbal drugs.

Conclusions:
The most significant finding was the lack of high-quality evidence for commonly acknowledged interactions. High-quality interaction studies involving different phenotypes in drug metabolism (cytochrome P450) and distribution (transporters) are urgently needed. This should include modern and critical drugs, such as oral anticancer medications and direct oral anticoagulants.
IMMEDIATE SUBRETINAL FLUID DISPLACEMENT FROM THE BUOYANT FORCE OF A SMALL GAS BUBBLE IN PNEUMATIC RETINOPEXY: INSIGHTS INTO THE POTENTIAL MECHANISM OF RETINAL DISPLACEMENT AFTER RETINAL DETACHMENT REPAIR
Authors: Lee Wei Wei , Ramachandran Arun , Hamli Hesham , Escaf Luis C. , Bansal Aditya , Muni Rajeev H. 
Published: September 2021

Purpose:
To demonstrate how a small gas bubble injected into the vitreous cavity in pneumatic retinopexy for rhegmatogenous retinal detachment causes immediate displacement of subretinal fluid and to gain insights into the potential mechanism of retinal displacement.

Methods:
Three patients with rhegmatogenous retinal detachment who underwent pneumatic retinopexy were enrolled and prospectively followed. All patients underwent ultra-widefield fundus photography at baseline and at 1 to 2 minutes after intravitreal gas injection.

Results:
In all cases, the ultra-widefield fundus photograph demonstrated immediate displacement of subretinal fluid, suggesting that the buoyant force applied to the retina by the bubble was responsible for the displacement of subretinal fluid. The results were extrapolated to determine the buoyant force applied by a small and large gas bubble as in pneumatic retinopexy and pars plana vitrectomy. We determined that the buoyant force applied with a larger bubble in pars plana vitrectomy was substantially greater, and this may lead to retinal displacement.

Conclusion:
Intravitreal gas applies significant buoyant force to the detached retina and subretinal fluid that leads to substantial and rapid displacement of subretinal fluid. Understanding the affect of the buoyant force of the gas bubble on the detached retina can provide insight into possible mechanisms of retinal displacement.
Improving smoking cessation education and documentation
Authors: Gennette Ryan L. 
Published: September 2021

ABSTRACT

Background:
New lung cancer cases and annual deaths caused by lung cancers are significantly associated with tobacco smoking. Continued, routine smoking cessation prevention education has been linked with a decrease in lung cancer prevalence, resulting in a decline in new lung cancer diagnoses annually and ultimately less lung cancer–associated deaths in the United States.

Local problem:
An independent review of core measures revealed inadequate smoking cessation education documentation and no established system-based monitoring protocols, including formal education of health care providers. The lack of education and understanding contributed to a low compliance rate of 25% in core measure documentation.

Methods:
An educational program was designed to increase smoking cessation documentation core measures adherence. A preimplementation and postimplementation design was used to compare smoking cessation documentation compliance rates.

Intervention:
The program included education in the form of guided handouts, practical demonstrations, and one-on-one teaching sessions. Compliance, under guidance set forth by the Quality Oncology Practice Initiative, was calculated over a quarterly period including all practice providers.

Results:
Results revealed a smoking cessation documentation compliance rate of 25% preimplementation and 77% postimplementation, reflecting a 52% increase in rate of smoking cessation documentation adherence over a 6-month project period.

Conclusion: :
Z-test analysis showed statistical significance determining the interventions are a successful method to help increase smoking cessation core measure compliance. The smoking cessation education program led to better understanding of core measures, improved documentation, increased revenue, and increased level of patient smoking cessation.