bluuebunny/crossref_metadata_2025 huggingface dataset:
Weight and skeletal muscle loss with cabozantinib in metastatic renal cell carcinoma
Authors: Colomba Emeline , Alves Costa Silva Carolina , Le Teuff Gwénaël , Elmawieh Jamie , Afonso Daniel , Benchimol‐Zouari Axelle , Guida Annalisa , Derosa Lisa , Flippot Ronan , Raynard Bruno , Escudier Bernard , Bidault François , Albiges Laurence
Published: July 2022

Background

Cabozantinib, a standard of care metastatic renal cell carcinoma (mRCC), may be associated with weight and muscle loss. These effects of new generation VEGFR tyrosine kinase inhibitor on muscle mass loss are poorly described.

Methods

All cabozantinib‐treated mRCC patients from January 2014 to February 2019 in our institution were included. Clinical data including weight were collected during therapy. Computed tomography images were centrally reviewed for response assessment, and axial sections at the third lumbar vertebrae were used to measure the total muscle area. Toxicities and cabozantinib outcomes were evaluated. Co‐primary endpoints included skeletal muscle loss and weight loss (WL), longitudinally evaluated during treatment. WL has been classified according to CTCAEv5.0: Grade 1 (loss of 5 to <10% of baseline body weight), Grade 2 (loss of 10% to <20% of baseline body weight), and Grades 3–4 (loss >20% of baseline body weight).

Results

Patients were mostly men (70.3%), median age was 59.2 (range: 22.0–78.0) years, and median baseline body mass index was 25.0 (range: 16.4–49.3) kg/cm2. Prognosis according to International Metastatic RCC Database Consortium score was good, intermediate, and poor for 13 (13.0%), 63 (63.0%), and 24 (24.0%) patients, respectively. Out of a total of 120 patients, 101 patients with a median follow‐up of 22.3 months (range: 4.5–62.2) were eligible for analysis; 85 experienced muscle loss and muscle loss >10% increased during cabozantinib exposition, especially after 6 months of treatment. At cabozantinib baseline, 71 patients (70.3%) had sarcopenia, and 16/30 (53.3%) non‐sarcopenic patients developed sarcopenia during treatment. Baseline sarcopenia was associated with lower response rates (P = 0.031) and higher grades 3–4 toxicities (P = 0.001). Out of 92 patients included in the WL analysis, 44 (47.8%) and 12 (13.0%) experienced grades 2 and 3 WL, respectively.

Conclusions

We report a high incidence of grades 3–4 WL, fourth times higher than reported in prior pivotal trials, and half of the patients developed sarcopenia while on cabozantinib treatment. Weight and muscle mass loss with cabozantinib are underreported and may require further investigations and early management.
Role of sarcopenia in the frailty transitions in older adults: a population‐based cohort study
Authors: Álvarez‐Bustos Alejandro , Carnicero‐Carreño Jose Antonio , Davies Betty , Garcia‐Garcia Francisco Javier , Rodríguez‐Artalejo Fernando , Rodríguez‐Mañas Leocadio , Alonso‐Bouzón Cristina
Published: July 2022

Background

Frailty and sarcopenia are age‐associated syndromes that have been associated with the risk of several adverse events, mainly functional decline and death, that usually coexist. However, the potential role of one of them (sarcopenia) in modulating some of those adverse events associated to the other one (frailty) has not been explored. The aim of this work is to assess the role of sarcopenia within the frailty transitions and mortality in older people.

Methods

Data from the Toledo Study of Healthy Aging (TSHA) were used. TSHA is a cohort of community‐dwelling older adults ≥65. Frailty was assessed according with the Frailty Phenotype (FP) and the Frailty Trait Scale‐5 (FTS5) at baseline and at follow‐up. Basal sarcopenia status was measured with the standardized Foundation for the National Institutes of Health criteria. Fisher's exact test and logistic regression model were used to determine if sarcopenia modified the transition of frailty states (median follow‐up of 2.99 years) and Cox proportional hazard model was used for assessing mortality.

Results

There were 1538 participants (74.73 ± 5.73; 45.51% men) included. Transitions from robustness to prefrailty and frailty according to FP were more frequent in sarcopenic than in non‐sarcopenic participants (32.37% vs. 15.18%, P ≤ 0.001; 5.76% vs. 1.12%; P ≤ 0.001, respectively) and from prefrailty‐to‐frailty (12.68% vs. 4.27%; P = 0.0026). Improvement from prefrail‐to‐robust and remaining robust was more frequent in non‐sarcopenic participants (52.56% vs. 33.80%, P ≤ 0.001; 80.18% vs 61.15%, P ≤ 0.001, respectively). When classified by FTS5, this was also the case for the transition from non‐frail‐to‐frail (25.91% vs. 4.47%, P ≤ 0.001) and for remaining stable as non‐frail (91.25% vs. 70.98%, P ≤ 0.001). Sarcopenia was associated with an increased risk of progression from robustness‐to‐prefrailty [odds ratio (OR) 2.34 (95% confidence interval, CI) (1.51, 3.63); P ≤ 0.001], from prefrailty‐to‐frailty [OR(95% CI) 2.50 (1.08, 5.79); P = 0.033] (FP), and from non‐frail‐to‐frail [OR(95% CI) 4.73 (2.94, 7.62); P‐value ≤ 0.001]. Sarcopenia does not seem to modify the risk of death associated with a poor frailty status (hazard ratios (HR, 95%) P > 0.05).

Conclusions

Transitions within frailty status, but not the risk of death associated to frailty, are modulated by the presence of sarcopenia.
Resting‐State Brain Temperature: Dynamic Fluctuations in Brain Temperature and the Brain–Body Temperature Gradient
Authors: Sung Dongsuk , Risk Benjamin B. , Wang Kelly J. , Allen Jason W. , Fleischer Candace C.
Published: July 2022

Background

While fluctuations in healthy brain temperature have been investigated over time periods of weeks to months, dynamics over shorter time periods are less clear.

Purpose

To identify physiological fluctuations in brain temperature in healthy volunteers over time scales of approximately 1 hour.

Study Type

Prospective.

Subjects

A total of 30 healthy volunteers (15 female; 26 ± 4 years old).

Sequence and Field Strength

3 T; T1‐weighted magnetization‐prepared rapid gradient‐echo (MPRAGE) and semi‐localized by adiabatic selective refocusing (sLASER) single‐voxel spectroscopy.

Assessments

Brain temperature was calculated from the chemical shift difference between N‐acetylaspartate and water. To evaluate within‐scan repeatability of brain temperature and the brain–body temperature difference, 128 spectral transients were divided into two sets of 64‐spectra. Between‐scan repeatability was evaluated using two time periods, ~1–1.5 hours apart.

Statistical Tests

A hierarchical linear mixed model was used to calculate within‐scan and between‐scan correlations (Rw and Rb, respectively). Significance was determined at P ≤ .05. Values are reported as the mean ± standard deviation.

Results

A significant difference in brain temperature was observed between scans (−0.4 °C) but body temperature was stable (P = .59). Brain temperature (37.9 ± 0.7 °C) was higher than body temperature (36.5 ± 0.5 °C) for all but one subject. Within‐scan correlation was high for brain temperature (Rw = 0.95) and brain–body temperature differences (Rw = 0.96). Between scans, variability was high for both brain temperature (Rb = 0.30) and brain–body temperature differences (Rb = 0.41).

Data Conclusion

Significant changes in brain temperature over time scales of ~1 hour were observed. High short‐term repeatability suggests temperature changes appear to be due to physiology rather than measurement error.

Evidence Level

2

Technical Efficacy

Stage 1
Neutralizing antibodies to SARS‐CoV‐2 variants of concern including Delta and Omicron in subjects receiving mRNA‐1273, BNT162b2, and Ad26.COV2.S vaccines
Authors: Zhang George Fei , Meng Wen , Chen Luping , Ding Ling , Feng Jian , Perez Joseph , Ali Abid , Sun Shenyu , Liu Zhentao , Huang Yufei , Guo Haitao , Gao Shou‐Jiang
Published: July 2022

SARS‐CoV‐2 vaccines have contributed to the control of COVID‐19 in some parts of the world. However, the constant emergence of variants of concern (VOCs) challenges the effectiveness of SARS‐CoV‐2 vaccines over time. In particular, Omicron contains a high number of mutations in the spike (S) protein gene, on which most vaccines were developed. In this study, we quantitated neutralizing antibodies in vaccine recipients at various times postvaccination using S protein‐based pseudoviruses derived from wild type (WT) SARS‐CoV‐2 and five VOCs including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). We found that two‐dose mRNA‐1273 and BNT162b2 vaccines elicited robust neutralizing antibodies against WT, Alpha, Beta, Gamma, and Delta, but wanned after 6 months with a faster decline observed for BNT162b2. Both mRNA‐1273 and BNT162b2 elicited weak neutralizing antibodies against Omicron. One dose of Ad26.COV2.S vaccine induced weaker neutralizing antibodies against WT and most VOCs than mRNA‐1273 and BNT162b2 did but moderate neutralizing antibodies against Delta and Omicron, which lasted for 6 months. These results support current recommendations of the Centers for Disease Control and Prevention for a booster 5 months after full immunization with an mRNA‐based vaccine and the use of an mRNA‐based vaccine 2 months after Ad26.COV2.S vaccination.
Initial introduction and spread of the SARS‐CoV‐2 AY.4.2.1 Delta variant in Bulgaria, a genomic insight
Authors: Alexiev Ivailo , Giovanetti Marta , Cella Eleonora , Ivanov Ivan , Stoikov Ivan , Donchev Deyan , Grigorova Lubomira , Gancheva Anna , Dimitrova Reneta , Korsun Nelly , Trifonova Ivelina , Philipova Ivva , Dobrinov Veselin , Grigorova Iliana , Kantardjiev Todor , Christova Iva , Ciccozzi Massimo
Published: July 2022

The evolution of the emerging SARS‐CoV‐2 variants carrying mutations in the spike protein raises concerns about the possibility of accelerated transmission in the ever‐evolving COVID‐19 pandemic worldwide. AY.4.2, a sublineage of the Delta variant, was considered a variant under investigation (VUI) and also gained the nickname “Delta Plus,” due to its extra mutations, Y145H and A222V. In this study, using genomic epidemiology, we provide the first insights into the introduction of AY.4.2 in Bulgaria and the AY.4.2.1 sublineage that found larger dissemination only in Bulgaria and the United Kingdom.
Clinical outcome for heart failure hospitalizations in patients with leadless pacemaker
Authors: Katsuki Tomonori , Nagashima Michio , Kono Hiroyuki , Sadohara Yohei , Hirokami Jun , Kuji Rei , Korai Kengo , Fukunaga Masato , Hiroshima Kenichi , Ando Kenji
Published: July 2022

Introduction

The long‐term performance of leadless pacemaker (LPM) has not been well evaluated.

Methods

Between September 2017 and January 2021, 929 consecutive patients who underwent pacemaker implantation were grouped according to the types of pacemakers: LPM (LPM group, n = 368) and conventional pacemaker (PM group, n = 561).

Results

The median follow‐up duration was 1.7 years (interquartile range 0.8–2.6 years). Hospitalization rate for heart failure in the LPM group was 9.3%, 15.6%, and 21.6% at 1, 2, 3 years, respectively. The LPM group had a significantly higher adjusted heart failure hospitalization risk than the PM group [hazard ratio (HR) 1.70, 95% confidence interval (CI) 1.09–2.64, p = .01]. More patients with symptomatic bradycardia caused by sinus node dysfunction (SND) in the LPM group (n = 150) were admitted to the hospital for heart failure compared to those in the PM group (n = 219) (HR 2.02, 95%CI 1.04–3.90, p = .03), whereas no significant difference was observed between the two groups in the patients with bradycardia caused by atrial fibrillation (LPM group, n = 71; PM group, n = 18) or atrioventricular block (LPM group, n = 147; PM group, n = 324).

Conclusions

Patients who received LPM implantation had greater hospitalization risk for heart failure, compared to those who received conventional pacemaker implantation. The increased risk was mainly attributed to patients with SND.
Economic Viability of Penicillin Allergy Testing to Avoid Improper Clindamycin Surgical Prophylaxis
Authors: Liu Matthew Y. , Challa Megana , McCoul Edward D. , Chen Philip G.
Published: July 2022

Objective

Patients mislabeled with a penicillin allergy are often unnecessarily given prophylactic clindamycin. Thus, otolaryngologists may cause harm due to clindamycin's associated risk of Clostridioides difficile infections (CDI) and surgical site infections (SSI). The objective of this study was to determine the economic feasibility of penicillin allergy testing in preventing unnecessary clindamycin use among patients with an unconfirmed penicillin allergy prior to otolaryngologic surgery.

Methods

A break‐even analysis was performed using the average cost of penicillin allergy testing and a CDI/SSI to calculate the absolute risk reduction (ARR) in baseline CDI/SSI rate due to clindamycin required for penicillin testing to be economically sustainable. The binomial distribution was used to calculate the probability that current penicillin testing can achieve this study's ARR.

Results

Preoperative penicillin testing was found to be economically sustainable if it could decrease the baseline CDI rate by an ARR of 1.06% or decrease the baseline SSI rate by an ARR of 1.34%. The probability of penicillin testing achieving these ARRs depended on the baseline CDI and SSI rates. When the CDI rate was at least 5% or the SSI rate was at least 7%, penicillin allergy testing was guaranteed to achieve economic sustainability.

Conclusion

In patients mislabeled with a penicillin allergy, preoperative penicillin allergy testing may be an economically sustainable option to prevent the unnecessary use of prophylactic clindamycin during otolaryngologic surgery. Current practice guidelines should be modified to recommend penicillin allergy testing in patients with an unconfirmed allergy prior to surgery.

Level of Evidence

NA Laryngoscope, 133:1086–1091, 2023
Cryogenic freezing: A reliable preservation method of samples for seawater nutrient analysis
Authors: Rho TaeKeun , Son Purena , Choi Sang‐Hwa , Kang Dong‐Jin
Published: July 2022

Freezing is a strongly recommended preservation method of samples for seawater nutrient analysis when onboard analysis is not available. Previous studies on the effects of freezing methods have explored issues including freezing period, prefiltration, and freezing speed. In this study, the effects of various freezing and storage temperatures on seawater nutrient analysis were examined using a domestic freezer (−18°C), scientific freezer (−23°C), and cryogenic freezer (−80°C). The results showed no difference between the fresh and frozen samples stored in the cryogenic freezer. The observed differences between samples from the domestic freezer and those from the scientific freezers can be attributed to the freezer auto‐defrost function. Transferring samples between the scientific and cryogenic freezers maintained their condition during freezing and storage when a scientific freezer without an auto‐defrost function was used. Silicate concentrations in frozen samples in the cryogenic freezer were similar to those of the fresh samples, even when the frozen samples were analyzed several hours after thawing. Therefore, a cryogenic freezer is highly recommended for freezing and storing seawater nutrient samples because of its stability and independence from silicate polymer formation.
Preparation of CO2‐Based Cationic Polycarbonate/Polyacrylonitrile Nanofibers with an Optimal Fibrous Microstructure for Antibacterial Applications
Authors: Lin Zheng‐Ian , Tsai Han‐Lin , Liu Guan‐Lin , Lu Xie‐Hong , Cheng Pei‐Wen , Chi Pei‐Ling , Wang Chih‐Kuang , Tsai Tzu‐Hsien , Wang Chih‐Chia , Yang Jason Hsiao Chun , Ko Bao‐Tsan , Chen Chih‐Kuang
Published: July 2022

Utilizing CO2 as one of the monomer resources, poly(vinylcyclohexene carbonates) (PVCHCs) are used as the precursor for preparing cationic PVCHCs (CPVCHCs) via thiol‐ene click functionalization. Through the functionalization, CPVCHC‐43 with a tertiary amine density of 43% relative to the backbone is able to display a significantly antibacterial ability against Staphylococcus aureus (S. aureus). Blending CPVCHC‐43 with polyacrylonitrile (PAN), CPVCHC/PAN nanofiber meshes (NFMs) have been successfully prepared by electrospinning. More importantly, two crucial fibrous structural factors including CPVCHC/PAN weight ratio and fiber diameter have been systematically investigated for the effects on the antibacterial performance of the NFMs. Sequentially, a quaternization treatment has been employed on the NFMs with an optimal fibrous structure to enhance the antibacterial ability. The resulting quaternized NFMs have demonstrated the great biocidal effects against Gram‐positive and Gram‐negative bacteria. Moreover, the excellent biocompatibility of the quaternized NFMs have also been thoroughly evaluated and verified.
Photo‐Rewritable Glaring Patterns Composed of Stripe Domains in Nematic Elastomers
Authors: Ohzono Takuya , Koyama Emiko
Published: July 2022

Dynamic ordered micropatterns in polymeric materials provide an effective approach for the on‐demand tuning of optical properties toward a smart optical material. In this study, it is shown that glaring patterns exhibiting strong anisotropic light diffusion can be developed at specific locations in nematic liquid‐crystal elastomers with light‐sensitive azobenzene units. Glaring originates from the stripe domains of the nematic directors that self‐organize in light‐irradiated regions after a simple uniaxial stretching and releasing process without any complicated lithographic technique. The nematic order transiently reduced by the photo‐induced cis azobenzene isomers unlocks entropic elasticity, which induces local uniaxial shrinkage that causes buckling of the directors forming stripe domains. The written pattern on the film is tangibly visible with the backlight owing to the difference in anisotropic light diffusion. Furthermore, this pattern can be erased by light irradiation or thermal annealing. These films can be applied to optical elements for achieving augmented luminaries, security labeling, and sign‐sheeting applications.
Conformational Effects of Mutations and Spherical Confinement in Small Peptides through Hybrid Multi‐Population Genetic Algorithms
Authors: Gonzalez‐Olvera Marcos A , Olivares‐Quiroz Luis
Published: July 2022

In this work the role of spherical confinement combined with single and block mutations in small peptides on the onset of specific conformational states is analyzed. An intramolecular potential for the polypeptide chain, composed by a bending term plus a Lennard‐Jones type long range potential is proposed. For the intermolecular interaction with the sphere an integrated Lennard‐Jones (LJ) type potential is used between monomers and the sphere surface. To compute the set of minima values for the total intra and intermolecular potential a combination of a multi‐population genetic algorithm and an hybridized Nelder—Mead simplex algorithm are used, that yield to a larger degree of precision in the prediction of the set of minima potential energy values. To characterize the conformational states of the peptides the gyration tensor, radius of gyration, the asphericity, and the linear anisotropy are computed, and the influence of single‐point and block mutations on the most energetically stable conformations are assed. Results suggest that the spherical confinement does have a significant influence of the polymer conformations; and single‐point mutations introduced along the chain also have a prominent role on peptide's folded states. This opens up the possibility to targeted‐designed peptides with particular and desired properties upon folding.
Recent progress in 3D printing degradable polylactic acid‐based bone repair scaffold for the application of cancellous bone defect
Authors: Hu Xulin , Lin Zhidong , He Jian , Zhou Minchang , Yang Shuhao , Wang Yao , Li Kainan
Published: July 2022

Large size bone defects have become a growing clinical challenge. Cancellous bone, which has the highest volume ratio, the fastest replacement rate, and interconnected porous structure, plays a major role in bone repairing. Considering the structure and composition of cancellous bone, building a bionic 3D scaffold via customized‐3D printing technology is the key to solving the problem. As the earliest degradable medical polymer material approved by Food and Drug Administration, polylactic acid has been proved to have excellent biosafety and can be copolymerized or blended with other synthetic polymers, natural polymers, and inorganic materials to improve its performance to better meet clinical applications. A series of biodegradable bone repair scaffolds based on polylactic acid composites and 3D printing technology are developed to achieve large bone defects. Here, we review the composition and structure of cancellous bone, highlighting the relationship to the requirements of bone repair scaffolds. The different types of polylactic‐acid‐based materials applied in 3D printing technology are described, emphasizing the connection between materials, preparation methods, and applications.
Advocates call for expanded authority at US Labor Department to enforce parity
Authors: Enos Gary
Published: July 2022

Seeing insufficient protection for consumers against insurer violations of the federal mental health parity law, mental health advocates are calling on Congress to strengthen the U.S. Department of Labor's authority to impose penalties for failure to comply.
Yale study finds one‐half of counties lack CIT service access
Authors: Canady Valerie A.
Published: July 2022

More than two weeks after the country has transitioned to a 988 suicide and mental health crisis lifeline, Yale School of Public Health researchers — based on a study conducted in 2020 — have found that nearly half of all U.S. counties lack access to a facility providing community crisis intervention team (CIT) services.
Foundation awards grants to address youth MH initiatives
Authors: Canady Valerie A.
Published: July 2022

Seeking to dramatically reduce the number of children with mental illness and lessen the severity of its impact on youth, a relatively new foundation has awarded multimillion grants to three organizations that officials say “create systemic change in the youth and mental health arena.”
Mental Health Weekly wins APEX Award for Publication Excellence
Authors: Canady Valerie A.
Published: July 2022

Mental Health Weekly has won an Award of Excellence in the Newsletters – Print (Entire Issue – Content & Design) category in the APEX 2022 Awards — the 34th annual awards program recognizing excellence in publishing by professional communicators. The APEX 2022 Award recognizes publishing editor Valerie A. Canady, contributing editor Gary Enos, production editor Douglas Devaux, and copy editor James Sigman. APEX Awards are based on excellence in editorial content, graphic design and the ability to achieve overall communications excellence. The full list of winners can be viewed at https://apexawards.com.
Standing on the parent's shoulder or in its shadow? Alliance partner overlap between employee spinouts and their parents
Authors: Gaonkar Shweta , Moeen Mahka
Published: July 2022

Research Summary

Employee spinouts, defined as startups founded by prior employees of an industry firm, play a critical role in firm creation and knowledge transfer. Their superior performance often arises from resources and knowledge accrued during employment in parent firms. An understudied question is whether prior employment in parent firms affects an employee spinout's alliance formation, given that alliances are critical to startups' survival and commercial success. This article examines when an employee spinout's alliance partners overlap with the parent's partners. Drawing on alliance formation patterns of U.S. medical device spinouts founded between 1990 and 2013, we find that spinouts building on their parents' technologies tend to have a greater partner overlap with their parents, whereas product market overlap leads to fewer overlapping partners.

Managerial Summary

A rich context for entrepreneurs to identify new opportunities is through their employment in existing industry firms. When employees leave their job and create a spinout, their employment experience often provides them superior knowledge and expertise. Our study of medical device startups uncovers another distinctive feature of employee spinouts, that is, access to their employer's alliance partners. However, for such opportunities to come to fruition, entrepreneurs need to pay attention to their technical and product market positioning relative to their past employers. When spinouts build on their employer's technologies without challenging them in the product space, they can leverage connections to their employer's partners. This alliance strategy may free spinouts from the alliance formation struggles faced by resource‐deficient startups.
Light‐Harvesting Artificial Cells Containing Cyanobacteria for CO2 Fixation and Further Metabolism Mimicking
Authors: Yang Boyu , Li Shubin , Mu Wei , Wang Zhao , Han Xiaojun
Published: July 2022

The bottom‐up constructed artificial cells help to understand the cell working mechanism and provide the evolution clues for organisms. The energy supply and metabolism mimicry are the key issues in the field of artificial cells. Herein, an artificial cell containing cyanobacteria capable of light harvesting and carbon dioxide fixation is demonstrated to produce glucose molecules by converting light energy into chemical energy. Two downstream “metabolic” pathways starting from glucose molecules are investigated. One involves enzyme cascade reaction to produce H2O2 (assisted by glucose oxidase) first, followed by converting Amplex red to resorufin (assisted by horseradish peroxidase). The other pathway is more biologically relevant. Glucose molecules are dehydrogenated to transfer hydrogens to nicotinamide adenine dinucleotide (NAD+) for the production of nicotinamide adenine dinucleotide hydride (NADH) molecules in the presence of glucose dehydrogenase. Further, NADH molecules are oxidized into NAD+ by pyruvate catalyzed by lactate dehydrogenase, meanwhile, lactate is obtained. Therefore, the cascade cycling of NADH/NAD+ is built. The artificial cells built here pave the way for investigating more complicated energy‐supplied metabolism inside artificial cells.
X‐Ray Photon Correlation Spectroscopy Towards Measuring Nanoparticle Diameters in Biological Environments Allowing for the In Situ Analysis of their Bio‐Nano Interface
Authors: Otto Ferdinand , Sun Xing , Schulz Florian , Sanchez‐Cano Carlos , Feliu Neus , Westermeier Fabian , Parak Wolfgang J.
Published: July 2022

X‐ray photon correlation spectroscopy (XPCS), a synchrotron source‐based technique to measure sample dynamics, is used to determine hydrodynamic diameters of gold nanoparticles (Au NPs) of different sizes in biological environments. In situ determined hydrodynamic diameters are benchmarked with values obtained by dynamic light scattering. The technique is then applied to analyze the behavior of the Au NPs in a biological environment. First, a concentration‐dependent agglomeration in the presence of NaCl is determined. Second, concentration‐dependent increase in hydrodynamic diameter of the Au NPs upon the presence of proteins is determined. As X‐rays in the used energy range are barely scattered by biological matter, dynamics of the Au NPs can be also detected in situ in complex biological environments, such as blood. These measurements demonstrate the possibility of XPCS for in situ analytics of nanoparticles (NPs) in biological environments where similar detection techniques based on visible light would severely suffer from scattering, absorption, and reflection effects.
Statistical Methods for the Quantitative Genetic Analysis of High-Throughput Phenotyping Data
Authors: Morota Gota , Jarquin Diego , Campbell Malachy T. , Iwata Hiroyoshi
Published: July 2022

The advent of plant phenomics, coupled with the wealth of genotypic data generated by next-generation sequencing technologies, provides exciting new resources for investigations into and improvement of complex traits. However, these new technologies also bring new challenges in quantitative genetics, namely, a need for the development of robust frameworks that can accommodate these high-dimensional data. In this chapter, we describe methods for the statistical analysis of high-throughput phenotyping (HTP) data with the goal of enhancing the prediction accuracy of genomic selection (GS). Following the Introduction in Sec. 1, Sec. 2 discusses field-based HTP, including the use of unoccupied aerial vehicles and light detection and ranging, as well as how we can achieve increased genetic gain by utilizing image data derived from HTP. Section 3 considers extending commonly used GS models to integrate HTP data as covariates associated with the principal trait response, such as yield. Particular focus is placed on single-trait, multi-trait, and genotype by environment interaction models. One unique aspect of HTP data is that phenomics platforms often produce large-scale data with high spatial and temporal resolution for capturing dynamic growth, development, and stress responses. Section 4 discusses the utility of a random regression model for performing longitudinal modeling. The chapter concludes with a discussion of some standing issues.
The Dyadic Representation Theorem Using Smooth Wavelets with Compact Support
Authors: Hytönen Tuomas , Lappas Stefanos
Published: July 2022

The representation of a general Calderón–Zygmund operator in terms of dyadic Haar shift operators first appeared as a tool to prove the $$A_2$$

A
2

theorem, and it has found a number of other applications. In this paper we prove a new dyadic representation theorem by using smooth compactly supported wavelets in place of Haar functions. A key advantage of this is that we achieve a faster decay of the expansion when the kernel of the general Calderón–Zygmund operator has additional smoothness.
Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomisation study
Authors: Zheng Jie , Xu Min , Walker Venexia , Yuan Jinqiu , Korologou-Linden Roxanna , Robinson Jamie , Huang Peiyuan , Burgess Stephen , Au Yeung Shiu Lun , Luo Shan , Holmes Michael V. , Davey Smith George , Ning Guang , Wang Weiqing , Gaunt Tom R. , Bi Yufang
Published: July 2022

Aims/hypothesis

Metformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer’s disease and potential causal mechanisms in the brain linking the two.

Methods

Genetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA1c level (N=344,182) and expression level of the corresponding gene (N≤31,684). The cognitive outcomes were derived from genome-wide association studies comprising 527,138 middle-aged Europeans, including 71,880 with Alzheimer’s disease or Alzheimer’s disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer’s disease and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6601 donors) on Alzheimer’s disease was further estimated.

Results

Genetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA1c, was associated with 4% lower odds of Alzheimer’s disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10−4) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer’s disease (OR 0.88, p=4.73×10−4) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer’s disease risk (OR 0.95, p=4.64×10−4) and favourable cognitive function.

Conclusions/interpretation

Metformin use may cause reduced Alzheimer’s disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection.

Graphical abstract
Sirolimus-Coated Balloon Angioplasty of Infra-popliteal Lesions for the Treatment of Chronic Limb-Threatening Ischemia: Study Protocol for the Randomized Controlled LIMES Study
Authors: Teichgräber Ulf , Platzer Stephanie , Lehmann Thomas , Ingwersen Maja , Aschenbach René , Beschorner Ulrich , Scheinert Dierk , Zeller Thomas
Published: July 2022

Purpose

Evidence on efficacy and long-term safety of paclitaxel-coated devices is still conflicting. Therefore, this study aims to assess whether sirolimus-coated balloon angioplasty is safe and effective for the treatment of infra-popliteal occlusions in patients with chronic limb-threatening ischemia (CLTI).

Study design

The randomized controlled, single-blinded, multicentre, investigator-initiated study aims to enrol 230 participants with CLTI and infra-popliteal occlusions at up to 25 centres. Patients will be randomized in a 1:1 ratio to either sirolimus-coated balloon angioplasty or to plain old balloon angioplasty (POBA). Bailout stenting in case of flow-limiting dissection or ≥ 50% residual diameter stenosis is permitted.

Outcome measures

Primary outcome is the Kaplan–Meier estimate of primary patency at 6 months, defined as the absence of target lesion occlusion with restoration of in-line flow to the ankle. Key secondary outcome is non-inferiority in the proportionate occurrence of major adverse limb events and perioperative all-cause death at 30 days. Overall, participants will be followed for 36 months to assess further secondary efficacy and safety outcomes.

Assumed gain of knowledge

If sirolimus-coated balloon angioplasty turns out to be superior to uncoated-balloon angioplasty regarding patency of infra-popliteal lesions without safety signals, it could become a welcome treatment option for patients with CLTI.

Trial Registration ClinicalTrial.gov Identifier: NCT04772300, German Clinical Trials Register: DRKS00024629.

Level of Evidence Level 2a, randomized controlled trial.
HLA-G as a prognostic marker in stage II/III colorectal cancer: not quite there yet
Authors: Gambella Alessandro , Scabini Stefano , Zoppoli Gabriele , De Silvestri Annalisa , Pigozzi Simona , Paudice Michele , Campora Michela , Fiocca Roberto , Grillo Federica , Mastracci Luca
Published: July 2022

Identifying innovative molecules involved in the tumor immune escape process could help refine the survival stratification of colorectal cancer (CRC) patients. HLA-G, a non-classical HLA molecule, physiologically involved in tolerogenic mechanisms, has recently emerged as a relevant prognostic marker in other tumor types, but ambiguous data are reported in the CRC setting. This study aims to evaluate the HLA-G expression and prognostic potential in a series of stage II/III CRCs. HLA-G expression was evaluated in 100 pT3 CRC cases by means of immunohistochemistry using the 4H84 and MEM-G/2 monoclonal antibodies. We observed heterogeneous expression of HLA-G showing different ranges: 4H84 expression ranged from > 1 to 40%—median 7%; MEM-G/2 expression ranged from 20 to 90%—median 50%. HLA-G positivity (any intensity > 1%) varied according to the antibody employed, identifying: 8 4H84 positive, 34 MEM-G/2 positive, 6 double-positive and 52 negative cases. Correlation with clinico-pathologic data showed a significant association with a poor tumor differentiation in stage III right-sided CRC subgroup (p = 0.043), while no other pathologic variable was significantly associated. Survival analysis revealed a reduced disease-free survival rate (HR 4.304613; p = 0.031) in the subgroup of CRC-related death cases, while no correlations were observed considering the whole series and the overall survival. In conclusion, HLA-G is a promising CRC prognostic marker however much work is still required regarding technical aspects and evaluation of expression.
Perioperative functional imaging after extracranial carotid endarterectomy for the detection of cerebral hyperperfusion syndrome
Authors: Hoffmann-Wieker Carola Marie , Ronellenfitsch U. , Rengier F. , Otani K. , Stepina E. , Böckler D.
Published: July 2022

Introduction

SyngoDynaPBVNeuro® is a tool to perform cerebral blood volume (CBV) measurements intraoperatively by functional imaging producing CT-like images. Aim of this prospective study was to analyze the clinical relevance and benefit of CBV measurement with regard to neurological complications like cerebral hyperfusion syndrome (CHS).

Methods

Forty-five patients undergoing endarterectomy (CEA) of the internal carotid artery were included; functional imaging with CBV measurement was performed before and after CEA. To evaluate and analyze CBV, six regions of interest (ROI) were identified for all patients with an additional ROI in patients with symptomatic ICA stenosis and previous stroke. The primary endpoint of the study was a perioperative change in CBV measurements. Secondary outcomes were incidence of stroke, TIA, CHS, and perioperative morbidity and mortality.

Results

Thirty-day stroke incidence and thirty-day mortality were 0%. Thirty-day morbidity was 6.7%. Two patients from the asymptomatic group suffered from transient neurological symptoms without signs of intracerebral infarction in CT or MR scan, meeting diagnostic criteria for CHS. In 83.3% of ROIs in these patients, an increase of blood volume was detected. Overall, 26.7% patients suffered from unilateral headache as expression of potential CHS. A total of 69.4% of ROIs in patients with postoperative unilateral headache showed an increase when comparing pre- and postoperative CBV measurements.

Conclusion

The results show that increased CBV measured by functional imaging is a possible surrogate marker of neurological complications like CHS after CEA. By using intraoperative CBV measurement, the risk of CHS can be estimated early and appropriate therapeutic measures can be applied.
Risk of all-cause mortality according to the European Society of Cardiology risk categories in individuals with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study
Authors: Orsi Emanuela , Solini Anna , Bonora Enzo , Vitale Martina , Garofolo Monia , Fondelli Cecilia , Trevisan Roberto , Vedovato Monica , Cavalot Franco , Laviola Luigi , Morano Susanna , Pugliese Giuseppe ,   for the Renal Insufficiency And Cardiovascular Events (RIACE) Study Group
Published: July 2022

Aims

The 2019 and 2021 European Society of Cardiology (ESC) classifications stratified patients with type 2 diabetes into three categories according to the 10-year risk of death from atherosclerotic cardiovascular disease (ASCVD). The very high-risk category included individuals with established ASCVD, target organ damage (TOD), and/or, in the 2019 classification only, ≥ 3 additional ASCVD risk factors. We assessed risk of all-cause mortality according to the two ESC classifications in the Renal Insufficiency And Cardiovascular Events cohort.

Methods

Participants (n = 15,773) were stratified based on the presence of ASCVD, TOD, and ASCVD risk factors at baseline (2006–2008). Vital status was retrieved in 2015.

Results

Less than 1% of participants fell in the moderate-risk category. According to the 2019 classification, ~ 1/3 fell in the high-risk and ~ 2/3 in the very high-risk category, whereas the opposite occurred with the 2021 classification. Mortality risk increased across categories according to both classifications. Among very high-risk patients, mortality was much lower in those with ≥ 3 additional ASCVD risk factors and almost equal in those with TOD and ASCVD ± TOD, using the 2019 classification, whereas it was much higher in those with ASCVD + TOD and, to a lesser extent, TOD only than in those with ASCVD only, using the 2021 classification.

Conclusions

The negligible number of moderate-risk patients suggests that these classifications might overestimate risk of ASCVD death. Downgrading patients with ≥ 3 additional ASCVD risk factors to the high-risk category is consistent with mortality data. Risk of death is very high in the presence of TOD irrespective of established ASCVD.

Trial registration: ClinicalTrials.gov, NCT00715481.
Heart rate thresholds for cardiovascular risk and sympathetic activation in the metabolic syndrome
Authors: Seravalle Gino , Vanoli Jennifer , Molisano Concetta , Merati Valeria , Grassi Guido
Published: July 2022

Aims

We examined whether to what extent resting heart rate (HR) values are capable to reflect in the metabolic syndrome (MS) a different degree of sympathetic activation. We also thought to determine at which HR cutoff values the sympathetic nervous system becomes more activated in the MS.

Methods

In 70 MS patients aged 55.5 ± 1.8 (mean ± SEM) years we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the study population in three different subgroups according to resting clinic and 24-h HR values (< 70, 70–79 and ≥ 80 beats/min).

Results

MS patients with clinic HR values ≥ 80 beats/min displayed MSNA and NE values significantly increased when compared to those found in MS with HR between 70 and 79 beats/min or below 70 beats/min (MSNA: 55.2 ± 0.9 vs 44.6 ± 0.6 and 39.2 ± 0.6 bursts/min, P < 0.01, NE: 403.9 ± 6.9 vs 330.1 ± 4.3 and 258.3 ± 6.8 pg/ml, respectively, P < 0.01). A similar behavior was observed for 24-h HR. In the group as a whole both MSNA and plasma NE showed highly significant direct relationships with clinic HR, the correlation being similar for MSNA and NE (r = 0.89 and r = 0.91, P < 0.01 for both) Similar significant relationships were also found between 24-h HR values and MSNA or NE.

Conclusions

In the MS HR values ≥ 80 beats/min are associated with an increased sympathetic activation, both when assessed by direct recording of MSNA and when evaluated as plasma NE. The sympathetic overdrive parallels for magnitude the HR elevations, this being the case for both clinic and 24-h HR.
Prognostic value of lymph node involvement in oral squamous cell carcinoma
Authors: Voss Jan Oliver , Freund Lea , Neumann Felix , Mrosk Friedrich , Rubarth Kerstin , Kreutzer Kilian , Doll Christian , Heiland Max , Koerdt Steffen
Published: July 2022

Objectives

Different parameters have been identified in patients with oral squamous cell carcinomas (OSCC) that have a serious impact on survival, including residual tumour and extracapsular spread. Moreover, other factors, including the lymph node ratio (LNR) and lymph node yield (LNY), have been suggested as prognostic markers.

Material and methods

This retrospective study included patients diagnosed with OSCC and cervical lymph node metastases during the years 2010–2020. Patients’ records were evaluated regarding lymph node status, final therapy regime, tumour recurrence, time to death, tumour association with death, disease-free survival (DSF), and overall survival (OS).

Results

In 242 patients with a mean age of 63.57 ± 11.24 years, treated either by selective neck dissection (SND; n = 70) or by modified radical neck dissection (MRND; n = 172), 5772 lymph nodes were detected. The LNR and LNY were identified as independent risk factors in OS and DFS. The optimal cut-off point for the LNY was ≥ 17 lymph nodes in the SND and ≥ 27 lymph nodes in the MRND group.

The metastatic lymph node clearance (MLNC) was established as a score to relate the LNR and LNY to the extent of lymph node removal. Survival analysis showed statistically significant differences among score levels.

Conclusions

As information about the extent of nodal dissection is excluded from LNR and LNY, we propose the use of a new scoring system comprising individual cut-off values for LNY and LNR with regard to the extent of neck dissection.

Clinical Relevance

MLNC might help to identify high-risk OSCC patients with metastatic lymph nodes.
Association of periodontal therapy, with inflammatory biomarkers and complications in COVID-19 patients: a case control study
Authors: Said Khalid N. , Al-Momani Ahmed M. , Almaseeh Jassim A. , Marouf Nadya , Shatta Amer , Al-Abdulla Jassim , Alaji Sahar , Daas Hanin , Tharupeedikayil Shailaja S. , Chinta Venkateswara Rao , Hssain Ali Ait , Abusamak Mohammad , Salih Shiraz , Barhom Noha , Cai Wenji , Sanz Mariano , Tamimi Faleh
Published: July 2022

Background

In previous studies, COVID-19 complications were reported to be associated with periodontitis. Accordingly, this study was designed to test the hypothesis that a history of periodontal therapy could be associated with lower risk of COVID-19 complications.

Methods

A case–control study was performed using the medical health records of COVID-19 patients in the State of Qatar between March 2020 and February 2021 and dental records between January 2017 and December 2021. Cases were defined as COVID-19 patients who suffered complications (death, ICU admissions and/or mechanical ventilation); controls were COVID-19 patients who recovered without major complications. Associations between a history of periodontal therapy and COVID-19 complications were analysed using logistic regression models adjusted for demographic and medical factors. Blood parameters were compared using Kruskal–Wallis test.

Results

In total, 1,325 patients were included. Adjusted odds ratio (AOR) analysis revealed that non-treated periodontitis was associated with significant risk of need for mechanical ventilation (AOR = 3.91, 95% CI 1.21–12.57, p = 0.022) compared to periodontally healthy patients, while treated periodontitis was not (AOR = 1.28, 95% CI 0.25–6.58, p = 0.768). Blood analyses revealed that periodontitis patients with a history of periodontal therapy had significantly lower levels of D-dimer and Ferritin than non-treated periodontitis patients.

Conclusion

Among COVID-19 patients with periodontal bone loss, only those that have not received periodontal therapy had higher risk of need for assisted ventilation. COVID-19 patients with a history of periodontal therapy were associated with significantly lower D-dimer levels than those without recent records of periodontal therapy.

Clinical relevance

The fact that patients with treated periodontitis were less likely to suffer COVID-19 complications than non-treated ones further strengthen the hypothesis linking periodontitis to COVID-19 complications and suggests that managing periodontitis could help reduce the risk for COVID-19 complications, although future research is needed to verify this.
The role of threat anticipation in the development of psychopathology in adolescence: findings from the SIGMA Study
Authors: Paetzold Isabell , Gugel Jessica , Schick Anita , Kirtley Olivia J. , Achterhof Robin , Hagemann Noemi , Hermans Karlijn S. F. M. , Hiekkaranta Anu P. , Lecei Aleksandra , Myin-Germeys Inez , Reininghaus Ulrich
Published: July 2022

Childhood adversity is associated with psychopathology. First evidence in adults suggests that threat anticipation, i.e., an enhanced anticipation of unpleasant events creating an enduring sense of threat, may be a putative mechanism linking childhood adversity to psychopathology. This study aimed to test the indirect effect of childhood adversity on psychopathology via threat anticipation in a large community sample of adolescents. We measured childhood trauma and bullying victimization (as indicators of childhood adversity), threat anticipation, general psychopathology and prodromal psychotic symptoms in adolescents aged 12–16 years (full sample size N = 1682; minimum sample size in the complete case sample N = 449) in wave I of the SIGMA study. We found strong evidence that childhood adversity (e.g. childhood trauma, adj. β (aβ) = 0.54, p < .001) and threat anticipation (e.g. aβ = 0.36, p < .001) were associated with general psychopathology and prodromal psychotic symptoms. Moreover, there was evidence that the association between childhood adversity, general psychopathology and prodromal psychotic symptoms is mediated via pathways through threat anticipation (e.g. childhood trauma, aβindirect effect = 0.13, p < .001). Threat anticipation may be a potential mechanism linking childhood adversity and psychopathology in adolescents.