bluuebunny/crossref_metadata_2025 huggingface dataset:
Achieving Speaking Proficiency For Professionals: Segmental And Suprasegmental Challenges
Authors: Datu Yerly A.
Published: January 2025

Indonesian professionals face significant challenges in achieving English-speaking proficiency due to
phonological hurdles encompassing segmental and suprasegmental aspects. Difficulties with consonant sounds
(/θ/ and /v/), vowel quality, stress patterns, and intonation impede effective communication, impacting clarity,
comprehension, and professionalism. Initial observation shows that there has been an increase of awareness of
professionals to improve their speaking proficiency for professional purposes. Yet, the baseline reveals insufficient
proficiency of their speaking. This study examines common segmental and suprasegmental errors that prevent
professionals from better speaking proficiency. For the purpose, this descriptive qualitative study involves 235
professionals as participants. A set of questionnaires and records of their speaking voice are used as source of
data. For robust analysis, error analysis is also applied for phonological issue encountered by the participants.
Results show that difficulty with /v/ sound, misplacement of word stress, intonation errors, difficulty with /θ/ sound and vowel reduction are still a struggle for them to achieve the expected speaking proficiency
Lactic Acid Production: A Context For Sustainability And Trends
Authors: Valério Pedro Prates , Pereira Margarete Aparecida , Grande Salvador Carlos , Vitor Tamara Gomes , Moreira Wagner Aveino
Published: January 2025

Background: Lactic acid is a significant industrial bioproduct with diverse applications in the food,
pharmaceutical, and cosmetic industries. It is also a key raw material for biodegradable plastics such as
polylactic acid (PLA), offering a sustainable alternative to petrochemical products. This study explores the
production of lactic acid through fermentation, with a specific focus on batch processes, which provide flexibility
and enhanced quality control compared to continuous and semi-continuous methods.
Materials and Methods: The paper examines various fermentation methodologies, comparing batch, continuous,
and semi-continuous variants. Batch fermentation is highlighted for its robustness and suitability in managing
by-product formation, such as acetic acid, formic acid, and succinic acid, which require additional purification
steps. The study also discusses metabolic engineering as a strategy to enhance production efficiency and reduce
unwanted by-products.
Results: The findings emphasize that batch fermentation remains a key industrial technology, providing
advantages in quality control and process adaptability. The role of lactic acid in supporting a circular economy
is underscored, particularly through the use of renewable raw materials. Applications of lactic acid in producing
biodegradable plastics, such as PLA, align with global sustainability goals and demonstrate its potential for
replacing petrochemical-based products.
Conclusion: Batch fermentation is reaffirmed as a crucial industrial process for producing lactic acid. Its
capacity for flexibility, quality control, and alignment with sustainability principles highlights its relevance in industrial applications. The integration of metabolic engineering further enhances its potential, solidifying its role in advancing sustainable industrial practices.
Chemical Parameters, Antioxidants, And Polyphenols In Extra Virgin Olive Oil And Olive Pomace Oil
Authors: Alabdulla Obaidh
Published: January 2025

This study examines two types of olive oil: extra virgin olive oil (EVOO) and olive pomace oil (OPO). EVOO is
known for its high quality and health benefits, while OPO is a by-product obtained through solvent extraction.
We compare their physical and chemical parameters, highlighting differences in quality, nutritional value, and
market demand. EVOO is recommended for health benefits, whereas OPO serves as a cost-effective industrial alternative. Significant differences in polyphenols, carotenoids, and FTIR analysis were found, with a notable difference (143%) at 1720 cm-1 between the two oils
Pharmaceutical Waste And Plasma Pyrolysis: A Review Of Environmental And Public Health Impacts
Authors: Rohit S , Mahalingam Murugappan
Published: January 2025

The pollution caused by the pharmaceutical system is a threat to the environment and human health as chemicals
from the waste that are not handled in the right way contaminates the soil and the water systems; thus, they can
be detrimental to human beings and even nature. Most of the existing disposal practices such as incineration and
dumping on the ground also do not completely destroy the hazardous substances and results to pollution in the
air and water. This paper analyses plasma pyrolysis technology waste treatment as an environmentally friendly
management of pharmaceutical waste and how effective it is to treatment of pollutants, protection of people and
the environment.
A critical appraisal of prevailing modes of waste management and an assessment of the merits of plasma pyrolysis
improves the mode of operation of these methods. In this regard, the process is efficient in the reduction of toxic
wastes as well as the waste management of antibiotic byproducts. However, such approaches have existing
challenges which include cost, energy, and regulatory issues that make such technology unfeasible to many
industries to consider. In endeavoring to aid in developing such practices, this study reviewed the very issues and
prospects surrounding plasma pyrolysis as a new technology for waste management, which required further developments and promotion of the new disposal methods that handle wastes more efficiently and safely
The Status Of Upgraded Elements Through Participatory Approach In Korogocho And Soweto East In Kibera Slums
Authors: Karwitha Njati Doris , Timamy Mohamed Khalil, , Adoyo Laji
Published: January 2025

The Government of Kenya in its national slum policy seeks to encourage, facilitate and secure community and
stakeholder participation, transparency, and accountability in integrated approaches of slum upgrading and
prevention, redevelopment, rehabilitation, and improvement programmes. The study conducted the assessment
of elements upgraded through participatory approach in Korogocho and Soweto East in Kibera slums. The
study established the economic activities, residents’ length of stay and status of elements that were upgraded
through a participatory approach in Korogocho and Soweto East in Kibera slums. The capabilities approach
theory that views people as active participants during the process of development and not mere cogs as passive
onlookers guided the study. The study adopted a descriptive design approach to establish the elements
upgraded through participatory approach in Korogocho and Soweto East in Kibera slums in Nairobi.
Multistage and systematic random sampling while employing the use of Taro Yamane’s table of samples was
employed in sampling the households and respondents within the households. This yielded 199 and 201 totaling
to 400 respondents from Soweto East in Kibera and Korogocho slums respectively. Questionnaires, interview
schedule, observation guide and focus group discussions (FGD) were used during field inquiries. The study
found out that basic elements of housing units, cabro and tarmac roads, and perimeter wall and storm water
drainage were erected at Soweto East in Kibera slum. The tarmac road, foot bridge, multipurpose hall and
primary school; gate, perimeter fence, common hall and playground were upgraded in Korogocho slums. The
study concluded that at Korogocho and Soweto East Zone A in Kibera slums a substantial number of facilities
were upgraded into permanent structures through manipulations and tokenism level of participation. Finally,
the study concluded that the use of direct resident participation on slum upgrading processes was significant
and instrumental in influencing the sustainability of the upgraded slum facilities at Soweto East Zone A in
Kibera slum. It was recommended that upgrading agencies should transpose community participation from nonparticipation and tokenism to citizen empowerment to involve the community to be part of the project and hence work towards its sustainability.
Online Classroom Attendance System With Multiple Face Recognition
Authors: D Mr. Venugopala Gowda , Y J Mrs. Shashirekha , R Mrs. Sowmya
Published: January 2025

In this digital world automation is most effective and essential in all aspects. Getting and maintaining classroom
attendance for every hour in a day at school or college by calling names and marking on book is very hectic and
time-consuming, there are some chances of proxy attendance. There are many automated human identification
techniques such as biometrics, RFID, voice recognition still those techniques some issues systems are vulnerable
to proxies. But we are implementing the multiple face recognition technique to get all candidate in single or
multiple frames to get attendance conformation. The algorithms are implemented using a series of signal
processing methods including Harr-cascade classifier, Local Binary Pattern (LBP), Haar-like feature, facial
image pre-processing and Principal Component Analysis (PCA). The Ada Boost algorithm is implemented in a
cascade classifier to train the face and eye detectors with robust detection accuracy. Faces are detected and recognized from live streaming video of the classroom. Attendance will be updated student details with date and time to online database
Cost Benefit Analysis Of Rice Production Systems In The Varying Ecologies Of Sierra Leone
Authors: Mahmood Nazir Ahmed , Gorie Moses , Kanu Adam Sheka
Published: January 2025

Global demand for rice has increased significantly and its production requires careful consideration to ensure
farmers benefit from their production activities.
In Sierra Leone, rice is cultivated in five growing ecologies. The understanding on the cost-Benefit for
cultivating rice in these different ecologies is still relatively poor. As a result there is the need to investigate and
provide information on the cost and returns of rice production in the different rice ecologies. The study was
done in four districts each representing a rice ecological zone. Data on farmers’ practices were collected using
structured questionnaires. Farmers’ cost and returns were then compared to cost and returns using Rokupr
Agricultural Research Center (RARC) recommended technologies. Gross revenue, net operating profit returns
to management and return to person day were calculated for the study ecologies. The marginal rate of returns MRR) was determined to ascertain the financial reliability of adopting RARC technologies. Result of the study showed that adopting RARC technologies have huge financial benefit.
Impact Of Organisational Culture AndLeadership Model On Employees Performance In The Financial Services Sector
Authors: Abdullahi Hassan
Published: January 2025

Background: Leadership and organisational culture are significant factors that influence individual and
organisational results. Several studies have examined the relationship between organisational culture types and
employee performance in various organisations. Their conclusions, however, are conflicting and have
conflicting outcomes. Whether organisational culture enhances or detracts from employee performance, their
arguments show inconsistent findings.This study investigated how organisational culture and leadership models
impact employee performance in the financial services sector.
Materials and Methods: Employee performance was used as the dependent variable with organisational
culture and leadership model as the independent variable. To determine the connection between organisational
culture and leadership model and employee performance, structured questionnaires were administered to
junior staff, senior staff, and managers. The factors tested were organisational culture, leadership, workplace
environment, rewards and recognition, training, and Promotion. One hundred (100) sample respondents were
selected using a convenient sampling method. Descriptive and multivariate analyses were used to analyse the
collected data.
Results: bBased on the responses from the respondents, the results show that staff training has a mean of 4.42;
workplace environment has a mean of 3.71; organisational culture has a mean of 3.56; and Leadership has a
mean of 3.24. The result further shows that the junior staff respondents indicated that training (55.7) and a
good workplace environment (53.6) are influencing factors forinfluencetheir performance. The senior staff
respondents show that organisational culture (53.3) is an influencing factor for their performance. The
respondents who are managers show that rewards and recognition (73.9), promotion (73.2), and organisational
culture (72.6) are factors that influence their performance. The test result further revealed that the calculated
Chi-Square values for the degree of freedom two (2) are found significant for Organisational culture (15.968),
Promotion (13.872), Rewards and Recognition (18.232), and Training (7.275). The p values are less than 0.01.
Conclusion:Employers can improve employee performance by providing the necessary resources and support
to help employees overcome challenges and achieve their goals. To improve Employees' Performance through Leadership, leaders should cultivate an innovative Organizational Culture. In addition, leaders should address employee behaviour deviations and reward their staff's performance.
Trends in the Use of Gabapentinoids and Opioids in the Postoperative Period Among Older Adults
Authors: Bongiovanni Tasce , Gan Siqi , Finlayson Emily , Ross Joseph S. , Harrison James D. , Boscardin W. John , Steinman Michael A.
Published: June 2023

Importance

In response to the opioid epidemic, recommendations from some pain societies have encouraged surgeons to embrace multimodal pain regimens with the intent of reducing opioid use in the postoperative period, including by prescribing gabapentinoids.

Objective

To describe trends in postoperative prescribing of both gabapentinoids and opioids after a variety of surgical procedures by examining nationally representative Medicare data and further understand variation by procedure.

Design, Setting, and Participants

This serial cross-sectional study of gabapentinoid prescribing from January 1, 2013, through December 31, 2018, used a 20% US Medicare sample. Gabapentinoid-naive patients 66 years or older undergoing 1 of 14 common noncataract surgical procedures performed in older adults were included. Data were analyzed from April 2022 to April 2023.

Exposure

One of 14 common surgical procedures in older adults.

Main Outcomes and Measures

Rate of postoperative prescribing of gabapentinoids and opioids, defined as a prescription filled between 7 days before the procedure and 7 days after discharge from surgery. Additionally, concomitant prescribing of gabapentinoids and opioids in the postoperative period was assessed.

Results

The total study cohort included 494 922 patients with a mean (SD) age of 73.7 (5.9) years, 53.9% of whom were women and 86.0% of whom were White. A total of 18 095 patients (3.7%) received a new gabapentinoid prescription in the postoperative period. Of those receiving a new gabapentinoid prescription, 10 956 (60.5%) were women and 15 529 (85.8%) were White. After adjusting for age, sex, race and ethnicity, and procedure type in each year, the rate of new postoperative gabapentinoid prescribing increased from 2.3% (95% CI, 2.2%-2.4%) in 2014 to 5.2% (95% CI, 5.0%-5.4%) in 2018 (P < .001). While there was variation between procedure types, almost all procedures saw an increase in both gabapentinoid and opioid prescribing. In this same period, opioid prescribing increased from 56% (95% CI, 55%-56%) to 59% (95% CI, 58%-60%) (P < .001). Concomitant prescribing also increased from 1.6% (95% CI, 1.5%-1.7%) in 2014 to 4.1% (95% CI, 4.0%-4.3%) in 2018 (P < .001).

Conclusions and Relevance

The findings of this cross-sectional study of Medicare beneficiaries suggest that new postoperative gabapentinoid prescribing increased without a subsequent downward trend in the proportion of patients receiving postoperative opioids and a near tripling of concurrent prescribing. Closer attention needs to be paid to postoperative prescribing for older adults, especially when using multiple types of medications, which can have adverse drug events.
Comparison of Female Ovarian Reserve Before vs After COVID-19 Vaccination
Authors: Yang Liubin , Neal Samantha , Lee Tiffany , Chou Andrew , Schutt Amy K. , Gibbons William
Published: June 2023

This cohort study examines the association of COVID-19 vaccination with levels of anti-Mullerian hormone and antral follicle count in women seeking fertility treatment.
Recent Advancements in Design Optimization of Lattice‐Structured Materials
Authors: Almesmari Abdulla , Alagha Ali N. , Naji Mohammed M. , Sheikh-Ahmad Jamal , Jarrar Firas
Published: June 2023

Metamaterials, also known as lattice‐structured materials, imitate the multifunctionality of natural architects as tailoring their physical properties is associated with manipulating their microstructure. As the recent evolution of additive manufacturing enables the creation of intricate geometries with minimal material wastage, improving the design to manufacturing cycle of lattice structured materials has become one of the trending research areas. Triply periodic minimal surface (TPMS) and plate lattice materials are renowned for their exceptional mechanical behavior in lightweight applications. Apparently, several types of design optimization strategies are explored to maximize their performance for better biocompatibility and mechanical loading resistance. Some of these strategies include functional gradation and multimorphology hybridization that are comprehensively described in this review. Their benefits and drawbacks are highlighted with a focus on TPMS and plate lattice materials. The review anticipates the utilization of automated design exploration methods (i.e., topology optimization and data‐driven methods) to further enhance the design optimization procedure of lattice structured materials.
3D Printing‐Assisted Nanoimprint Lithography of Polymers
Authors: Martínez-García Patricia , Rebollar Esther , Nogales Aurora , García-Gutiérrez Mari Cruz , Sena-Fernández Jose , Ezquerra Tiberio A.
Published: June 2023

Fused filament fabrication, commonly referred to as 3D printing, is an additive manufacturing method finding plenty of applications nowadays. In contrast, polymer nanopatterning by nanolithographic techniques plays an important role in obtaining functional surfaces and coatings for applications in different fields including micro‐ and nanoelectronics. In spite of their relevance, additive manufacturing and polymer nanolithography have not found yet a common niche to be developed. Although both approaches are oriented to achieve different types of objects, it is shown that the confluence of both technologies can be desirable and potentially convenient. Herein, it is demonstrated that by employing conventional 3D printing, it is possible to fabricate nanostructured polymer surfaces in a relatively simple way by using similar approaches as those used in nanoimprint lithography but without the need for clean room conditions. To do that, a printed‐assisted nanoimprint lithography concept (3DPrANIL) has been tested for different types of polymer and silicon templates. It is demonstrated that a polymeric nanostructured hydrophilic template can be replicated accurately on another polymer rendering a nanostructured surface with enhanced hydrophobicity. The results support 3DPrANIL as novel method to obtain micro‐ and nanostructured surfaces with different functionalities like iridescence and hydrophobicity.
Grain Distribution for Optimal Strength in Homogeneous and Gradient Nano‐Grained Coppers
Authors: Qiang Wanzhi , Wu Qi , Long Lianchun
Published: June 2023

The distribution of grains plays a crucial role in determining the strength of polycrystalline copper when the grain size is constant. Herein, the mechanical properties of homogeneous nano‐grained (HNG) and gradient nano‐grained (GNG) coppers with different grain distributions are examined using molecular dynamics (MD) simulations. The HNG‐ordered structure has all triple junctions (TJs), whereas the random structure contains many quadruple and quintuple junctions. When grain size is below the critical size in the inverse Hall–Petch relationship, the high‐density TJs in the HNG‐ordered structure effectively inhibit grain boundary (GB) softening compared with the random structure, leading to higher strength. However, when grain size is above the critical size, subgrains are produced inside the large grains due to dislocation slip. In addition, disordered atoms in HNG‐random structure are stacked in the quadruple and quintuple junctions, resulting in thicker GBs. This triggers grain boundary migration, and forms more subgrains at GBs. Subsequently, grain boundary sliding and grain rotation of subgrains induce partial recrystallization in the structure. This consecutively triggered deformation mechanism leads to extra strengthening in the random structure. Further research indicates that combining small‐grained ordered and large‐grained random structures can be a new approach to effectively strengthen GNG materials.
A Cellular Membrane‐Confined Concatenate DNA Circuit for Non‐Invasive Cell Modulation with High Accuracy and Efficiency
Authors: Wang Hong , Wang Yushi , Wan Yeqing , Shang Jinhua , Wang Qing , Jiang Yuqian , Liu Xiaoqing , Wang Fuan
Published: June 2023

Non‐invasive cell regulation represents a promising approach for on‐site cell modulation, but is confronted with inaccuracy or poor cell selectivity. Herein, by virtue of the interfacial‐activated concatenate DNA circuit, an activated recombination‐to‐modulation (ARM) machinery is developed to achieve accurate membrane imaging and effective cell modulation. Bioorthogonal signal transduction through the catalytic hairpin assembly circuit can continuously regenerate triggers for activating the subsequent circuit, with no activator consumption and occupation. The ARM strategy utilizes the amplified hybridization chain reaction to sensitively rearrange membrane receptors for blocking the related signaling pathways and indirectly modulating cell behaviors. Based on these two membrane receptor inputs, the controllably‐activated ARM strategy enables the identification of target cells among similar interfering cells with high accuracy and sensitivity. This machinery has demonstrated good performance in the efficient inhibition of tumor metastasis via the disruption of HGF/c‐Met‐signaling pathway. The modular‐designed ARM machinery provides a general platform for non‐invasive and specific cell modulation, suggesting a broad opportunity for advanced exploration of cellular metabolism behaviors.
Designing Anti‐Swelling Nanocellulose Separators with Stable and Fast Ion Transport Channels for Efficient Aqueous Zinc‐Ion Batteries
Authors: Yang Shanchen , Zhang YaXin , Zhang Ying , Deng Jie , Chen Ningxin , Xie Sida , Ma Yue , Wang Zhaohui
Published: June 2023

Separators swelling in aqueous electrolytes can cause inhomogeneous ion flux and unregulated dendrite propagation, yet the corresponding phenomenon and mitigation strategy are rarely studied. This article deals with the issue of pore structure variation caused by separator swelling in aqueous zinc‐ion batteries (AZBs) by employing nanocellulose separator as a representative example. A multifunctional separator composed of Zr4+‐hydrolysate‐coated nanocellulose (Zr‐CNF) is developed by in situ hydrolysis of Zr4+, which demonstrates excellent swelling resistance, pore‐structure stability, and percolating porosity due to cross‐linking and hydrogen bond shielding effect. Consequently, the homogeneous Zn‐ion flux, high ionic conductivity, and Zn2+ transfer number are maintained upon cycling. Moreover, the amorphous ZrO containing coating induces a homogeneous directional electric field around the interface, accelerating the Zn2+ influx, reducing the nucleation overpotential, and promoting homogeneous nucleation for Zn deposition. The Zr‐CNF separator enable dendrite‐free Zn anode with high Coulombic efficiency (99.7%) and exceptional cyclability for 680 h under 5 mA cm−2/5 mAh cm−2. The feasibility of the Zr‐CNF separator is verified in PANI/V2O5‐based AZBs and activated carbon‐based Zn‐ion capacitors. This study provides a facile approach to address separator swelling issue, enlightening novel insights into the efficient and sustainable aqueous battery technologies in the future.
Effective Modulation of Inflammation and Oxidative Stress for Enhanced Regeneration of Intervertebral Discs Using 3D Porous Hybrid Protein Nanoscaffold
Authors: Yang Letao , Bhujel Basanta , Hou Yannan , Luo Jeffrey , An Seong Bae , Han Inbo , Lee Ki‐Bum
Published: June 2023

Degeneration of fibrocartilaginous tissues is often associated with complex pro‐inflammatory factors. These include reactive oxygen species (ROS), cell‐free nucleic acids (cf‐NAs), and epigenetic changes in immune cells. To effectively control this complex inflammatory signaling, it developed an all‐in‐one nanoscaffold‐based 3D porous hybrid protein (3D‐PHP) self‐therapeutic strategy for treating intervertebral disc (IVD) degeneration. The 3D‐PHP nanoscaffold is synthesized by introducing a novel nanomaterial‐templated protein assembly (NTPA) strategy. 3D‐PHP nanoscaffolds that avoid covalent modification of proteins demonstrate inflammatory stimuli‐responsive drug release, disc‐mimetic stiffness, and excellent biodegradability. Enzyme‐like 2D nanosheets incorporated into nanoscaffolds further enabled robust scavenging of ROS and cf‐NAs, reducing inflammation and enhancing the survival of disc cells under inflammatory stress in vitro. Implantation of 3D‐PHP nanoscaffolds loaded with bromodomain extraterminal inhibitor (BETi) into a rat nucleotomy disc injury model effectively suppressed inflammation in vivo, thus promoting restoration of the extracellular matrix (ECM). The resulting regeneration of disc tissue facilitated long‐term pain reduction. Therefore, self‐therapeutic and epigenetic modulator‐encapsulated hybrid protein nanoscaffold shows great promise as a novel approach to restore dysregulated inflammatory signaling and treat degenerative fibrocartilaginous diseases, including disc injuries, providing hope and relief to patients worldwide.
Identifying the essential roles of light and sonication in dual‐stimuli regulated bulk atom transfer radical polymerization by multiscale simulation
Authors: Li Shen , Bian Chao , Liu Zhong‐Xin , Zhou Yin‐Ning , Luo Zheng‐Hong
Published: June 2023

More and more attention has been paid to the important roles of external fields in controlled radical polymerization (CRP). However, their essential roles have not been studied thoroughly yet, which hinders the in‐depth understanding of the mechanism and kinetics. Herein, a strategy combining quantum chemical calculations (QCC) and kinetic modeling was adopted to identify the essential roles of light and ultrasonication in the dual‐stimuli regulated bulk atom transfer radical polymerization (ATRP). At the molecular level, the impact of light on Cu‐catalyzed ATRP was investigated. The CuIIBr/Me6TREN has high absorbance at an experimental wavelength of 365 nm (main excitation S0 → D7 accounts for 84.93%). Electron transfer reactions involving Me6TREN are more favorable paths for photochemical reactions, and the mechanism of the copper activation/deactivation pathway is inner sphere electron transfer. At the micro‐scale, a kinetic model based on the method of moment was established with a “series” encounter pair model to consider the influence of ultrasound on diffusional limitation. Simulation results show that the changes of the reaction rate coefficients ka, kda, and kt at high conversion reflect the degree of diffusional limitation by ultrasound. The multiscale modeling strategy applied in this study identifies the essential roles of photo and ultrasonication in dual‐stimuli regulated model systems, which can be extended to other external‐field regulated CRP to improve the mechanistic understanding.
The association between allostatic load, Alzheimer biomarkers and cognition among patients at the memory clinic: A longitudinal study
Authors: Adedeji Dickson O. , Holleman Jasper , Juster Robert‐Paul , Udeh‐Momoh Chi T. , Kåreholt Ingemar , Hagman Göran , Aspö Malin , Håkansson Krister , Solomon Alina , Kivipelto Miia , Sindi Shireen ,   Cortisol and Stress in Alzheimer’s Disease (Co‐STAR)
Published: June 2023

Background

Various lifestyle and physiological dementia risk factors have been identified. However, little is still known about the role of stress‐related risk factors. Chronic psychological stress affects several systems, such as the immune and cardiovascular systems, and increases the risk for physical, behavioral and mental disorders and reduced cognitive function. The goal of this study is to assess whether allostatic load (AL), a composite biomarker measure of chronic stress, is associated with AD biomarkers and cognitive function among memory clinic patients.

Methods

Data were derived from the Co‐STAR study at Karolinska University Hospital Memory Clinic, Sweden. Participants underwent baseline assessments including blood tests for AL measures, and cerebrospinal fluid sampling for AD biomarkers (Ab1‐42, total Tau (T‐tau), phosphorylated Tau (P‐tau)), a neuropsychological test battery was performed with measures for the following cognitive domains: general cognition, memory, working memory, processing speed and perceptual reasoning. Multiple linear regressions were conducted, adjusting for age, sex and education. P‐value <0.05 was used to identify significant associations.

Results

Higher AL was associated with lower CSF Ab1‐42 level (β = ‐0.175, p = 0.025) reflecting higher brain levels of Ab1‐42. Analyses stratified by sex showed that these associations were only present for women, but not for men. AL was not significantly associated with T‐tau level and P‐tau level. Multiple regression analyses showed that there were no significant association between AL and general cognitive functioning, processing speed, working memory, memory, and perceptual reasoning. AL modified the association between Ab1‐42 and perceptual reasoning; the non‐significant association was significant when additionally adjusted for AL (β = 0.157, p< 0.05).

Conclusion

This study identified a significant negative association between AL and Ab1‐42 among women, and AL modified the association between Ab1‐42 and perceptual reasoning. This suggests that AL may play a role in dementia pathophysiology. Further evidence is needed on whether specific subgroups in memory clinic samples are particularly vulnerable to the effects of high AL burden.
Identifying Protein Quantitative Trait Loci in the Cerebrospinal Fluid Proteome
Authors: Reus Lianne M. , Teunissen Charlotte E. , Gobom Johan , Vos Stephanie J. B. , Blennow Kaj , Zetterberg Henrik , Bertram Lars , Visser Pieter Jelle , Tijms Betty M. ,   the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF‐AD MBD) study group
Published: June 2023

Background

Genome‐wide association studies (GWAS) on dementia have successfully identified variants conferring risk to disease. Still, how such variants impact exact biological mechanisms underlying disease remains largely unclear. Protein quantitative trait loci (pQTLs) measured in cerebrospinal fluid (CSF) may provide insight into these neurobiological mechanisms, since CSF protein levels can reflect ongoing processes in the brain and have been related to genetic variants. We used a CSF pQTL approach in individuals along the Alzheimer’s disease (AD) spectrum to reveal intermediate molecular pathways by which genetic variance influences neurobiological processes. Improving the functional interpretation of genetic variants in a matrix relevant to neurological disease helps deciphering biological mechanisms underlying neurological traits.

Method

We selected 243 subjects (106 controls/67 mild cognitive impairment/70 AD‐dementia, age 66.8±8.1 years, 53.9%female) from the EMIF‐AD MBD study, who had genetic data and CSF data (n = 1,351 proteins, tandem mass tag (TMT) mass spectrometry) available. Association signals between genetic variants and CSF proteins were tested using linear regression, adjusted for principal components (PC1‐3), age and sex using the genome‐wide significance threshold (P<5.0e−8). CSF pQTLs were identified as novel if the association has not been previously reported in Yang et al., (2021), Sasayama et al., (2017) or Kauwe et al., (2014).

Results

Twenty‐four out of 1,351 CSF proteins (1.78%) showed genome‐wide significant associations with in total 147 SNPs (Table 1; Figure 1). We identified 25 CSF pQTLs, representing three cis‐acting (IGH, LTF and ADAMTS8) and 22 trans‐acting pQTLs. Results included mostly novel CSF pQTL associations, exception for the cis association of LTF with LTF protein levels. Two novel cis‐acting pQTLs were previously reported in a study on human lymphocytes (IGH on IGHV2‐70D) (Theusch et al., 2020) and prefrontal cortex brain data (ADAMTS8 on ADAMTS8) (Ng et al., 2017).

Conclusions

These results contribute to the functional interpretation of genetic variance on neurobiological processes, by pinpointing inflammation and tissue remodeling as potential contributing mechanisms in AD.
12‐weeks of caloric restriction diet improves cortical cerebral blood flow in healthy middle‐age adults
Authors: Rahmani Farzaneh , Piccio Laura , Wang Yong , Benzinger Tammie L.S. , Tosti Valeria , Ghezzi Laura , Raji Cyrus A.
Published: June 2023

Background

Caloric restriction (CR) improves neuronal stress resistance in animals and improves cognitive performance in older adults (1‐3). Neuroinflammation is an increasingly recognized mechanism relevant to Alzheimer disease (AD). We investigated the effect of a 12‐week CR diet on imaging markers of dementia and neuroinflammation in midlife individuals with multiple sclerosis (MS), a prototype neuroinflammatory disease.

Methods

In a single‐blind randomized controlled trial, 10 participants with MS (8 women and 2 men, age: 45.5±10.67 and education: 16.4±2.5 years) were recruited from the Washington University John L. Trotter MS Center and randomly assigned to participate in either a 12‐week CR or control group on their regular diet. Participants fasted 2 days a week and during those days eating no more than 500 calories. Participants underwent MRI scanning at the time of recruitment and at the end of the 12‐week program. Volumetric analyses were conducted through FreeSurfer 7.1.1 (4), relative regional cerebral blood flow (rCBF) was obtained through ASL‐MRICloud (5), and hindered and restricted diffusion fractions (HF and RF) were calculated through the diffusion basis spectrum imaging (DBSI), representing tissue edema and inflammatory cell infiltration respectively

Results

Six participants were obese, two were overweight and two had normal weight with an average BMI of 30.3±5.48 kg/m2 across participants. Following 12‐weeks of CR, participants showed an increase in normalized hippocampal volume (p:0.02) compared to those on regular diet. CR also resulted in improved cortical thickness in the bilateral medial orbitofrontal cortices compared to the control group (p:0.014). An average increase in relative perfusion (rCBF) in the bilateral inferior temporal gyri (p:0.02, & p:0.004) and bilateral fusiform gyri (p:0.008 & p:0.002) was observed in participants undergoing CR compared to those on a regular diet at the end of 12‐weeks (Figure 1 and 2). Being on a CR diet was associated with reduced HF and RF in the bilateral inferior longitudinal fasciculi (p:0.04 & p:0.002) indicating reduced edema and cellularity (6).

Conclusion

CR is associated with alterations in brain’s structure and function in terms of improved volumetric measurements, regional perfusion and reduced tissue inflammation, and hence implicated as a neuroprotective intervention in midlife persons.
The cross‐sectional association between peripheral TNF‐∝, white matter hyperintensities, and cognitive outcomes in the HABS‐HD study
Authors: Vintimilla Raul , Hall James , Johnson Leigh , O'Bryant Sid E. ,   HABS‐HD Study Team
Published: June 2023

Background

Low‐grade inflammation appears with advance age, with the end result of an increase ratio of pro to anti‐inflammatory cytokines. Inflammatory cytokines are considered cerebrovascular disease markers, but the association of cytokine levels with poorer cognition is not conclusive. TNFα, a pro‐inflammatory cytokine, may have a role on neurodegenerative diseases, such as Alzheimer’s disease. The effect of peripheral TNFα on brain structure and cognitive outcomes in cognitively normal older adults is not well understood. A few studies have described this relationship in White cohorts, but there is a lack of research in minorities like Mexican Americans.

Method

We studied 510 cognitively normal Mexican Americans from the Health and Aging Brain Study (HABS‐HD) with signed consent, fasting blood samples, 3T MRI, clinical evaluation, and cognitive testing. TNFα was assayed via a multiple‐plex biomarker assay platform using electrochemiluminescence. White matter hyperintensities (WMH) volume was measured from FLAIR using the Statistical Parametric Mapping Lesion Segmentation Tool. Pearson correlations were used to assess the association between TNFα with WMH, global cognition (MMSE), memory (SEVLT), executive function and attention (Trails B and digit symbol substitution) measures. Linear regression was used to predict the effect of TNF‐α on WMH volume and cognitive measures. APOE4 status was assessed, and age, sex, systolic blood pressure and education were entered as covariates in the models.

Result

Seventy percent of the sample were female. Sample means were 62.84 years of age, 9.94 years of education, and 137.33 for systolic blood pressure (SBP). There was not significant difference in TNFα and WMH values between APOE4 carriers and non‐carriers. TNFα had a positive significant correlation with age, education, SBP, WMH volume, and digit symbol substitution scores. Linear regression showed no association between TNFα value and WMH volume nor cognitive measures, with the exception of digit symbol substitution (B = ‐2.62; t = ‐2.03; p = 0.04).

Conclusion

These results suggest TNFα peripheral values are not related to WMH volume, but were related to executive‐attention measures. Prospective studies are necessary to evaluate the use of TNFα as a potential biomarker of brain health in Mexican Americans.
Variations in rest‐activity cycle length and peak timing during Alzheimer’s progression
Authors: Gao Chenlu , Gao Lei , Gaykova Nicole , Yu Lei , Yang Jingyun , Bennett David A , Buchman Aron S , Hu Kun , Li Peng
Published: June 2023

Background

Rest‐activity rhythm is commonly used to assess the circadian regulation and its changes with aging and Alzheimer’s disease (AD). Traditional rhythmicity analyses such as Cosinor analysis assume a rhythm of a constant waveform while ignoring the variations in the length and peak timing between different cycles/days. We introduced a novel rhythmicity analysis based on the uniform phase empirical mode decomposition (UPMEMD) that can provide detailed information of each individual cycle in rest‐activity rhythm. We tested whether variations in rest‐activity cycles change during aging and at different stages of AD.

Method

Participants were 1,065 older adults (baseline age = 80.9±7.3[SD], 807 females) from the Rush Memory and Aging Project. Actigraphy (∼10‐day) was performed annually for up to 13 years. For each recording, the UPMEMD was used to extract the rhythm of ∼24‐h; the length and peak timing were obtained from each cycle; and standard deviations (SD) of cycle lengths and peak timings were computed for each participant. Linear mixed effects models were performed to quantify the within‐subject changes over time in SD of cycle lengths, and separately, SD of peak timings, with adjustments of age, sex, and education years. Change points at diagnoses of mild cognitive impairment (MCI) and Alzheimer’s dementia were considered in the mixed models to examine whether the rates of changes were altered after the diagnoses.

Result

SD of cycle length increased by 0.04 hours/year when participants were cognitively intact (95%CI: 0.02‐0.05, p<0.001); the rate increased by an additional 0.04 hours/year after the onset of MCI (95%CI: 0.02‐0.06, p<0.001) and increased further by 0.18 hours/year (95%CI: 0.12‐0.24, p<0.001) after the onset of AD. Moreover, SD of peak timing increased by 0.04 hours/year when the participants were cognitively intact (95%CI: 0.02‐0.05, p<0.001); the rate was accelerated by 0.06 hours/year after the onset of MCI (95%CI: 0.03‐0.08, p<0.001) and further accelerated by 0.26 hours/year (95%CI: 0.20‐0.32, p<0.001) after the onset of AD.

Conclusion

Interdaily variability in rest‐activity rhythm increased with aging, and the ageing‐related circadian disturbance was accelerated as AD progressed. The markers of rest‐activity rhythm based on proposed rhythmicity analysis may facilitate identification of AD and monitoring of its progression.
Apathy and dysfunction early in the course of behavioral variant frontotemporal dementia
Authors: Zhu Carolyn W , Grossman Hillel , Sano Mary
Published: June 2023

Background

Apathy is highly prevalent in frontotemporal dementia (FTLD) but its impact on function is less understood. This study (1) examined the natural history of apathy in a large, national sample of well‐characterized patients clinically diagnosed with FTLD who had regular assessments over time, and (2) estimated the impact of apathy on function longitudinally across spectrum of disease severity.

Method

Sample includes individuals enrolled in the National Alzheimer’s Coordinating Center Uniform Data Set (NACC‐UDS, 9/2005‐12/2019) who had a primary clinical diagnosis of FTLD at baseline with suspected underlying etiology of behavioral variant of FTLD (bvFTLD) with at least one follow‐up visit (N = 888). Apathy was identified using clinician judgment. Prevalence, incidence, and persistence of apathy at each visit and cumulatively over time were assessed. Participants’ function was measured using the Functional Assessment Questionnaire (FAQ). Dementia severity as measured by baseline CDR. Linear mixed model (LMM) was used to estimate relationships between apathy, baseline CDR, and function over time.

Result

Average age of the sample = 63.4±9.1, 61% male, 92% non‐Hispanic white, average education = 15.4±3.1. Average MMSE = 23.0±6.7, GDS = 3.2±3.1 NPIQ = 8.4±5.9, CDR Sum of Boxes = 5.6±4.2, FAQ = 14.5±9.4. Presence of apathy fluctuated between 52‐65% for those with baseline CDR = 0.5, 73‐83% for CDR = 1, and 82‐87% for CDR = 2. Cumulative prevalence of apathy, i.e., proportion of participants with an endorsement of apathy in at least one visit over participant’s entire follow‐up, was 81.4% in CDR = 0.5, 93% in CDR = 1, and 94% in CDR≥2. LMM estimation results showed that independent of dementia severity and other participant characteristics, FAQ was 3.3±0.8 points higher at baseline in participants with persistent apathy and 2.1±0.8 points higher in those who always had apathy compared to (those without apathy or with intermittent apathy. Interaction terms between apathy and time were not statistically significant.

Conclusion

Results confirm apathy is highly prevalent across the range of dementia severity in bvFTLD. Independent of dementia severity, more persistent apathy was strongly associated with worse function. However, apathy was not associated with the rate of decline in function over time, likely because function was already highly impaired by CDR = 1. Interventions to support function may be needed early in the course of bvFTLD.
Integrated actigraphy‐based biomarker for Alzheimer’s dementia progression
Authors: Yang Hui‐Wen , Li Peng , Sun Haoqi , Lim Andrew , Bennett David A , Yu Lei , Buchman Aron S , Hu Kun
Published: June 2023

Background

Actigraphy derived measures including amplitude, regularity, and variability of daily rhythm, have been shown to predict incident Alzheimer’s dementia. Here we developed an integrated actigraphy biomarker (IAB) for Alzheimer’ risk and investigated whether the IAB predicted the conversion from mild cognitive impairment (MCI) to Alzheimer’ dementia.

Method

We studied 1195 participants (age 80.8±7.2yrs [SD]) from the Rush Memory and Aging Project who had finished baseline actigraphy assessment (∼10 days), were free from Alzheimer’s dementia at actigraphy baseline and had been followed for up to 15 years with annual cognitive assessment and clinical diagnoses. Ten sleep/circadian related features were derived from baseline actigraphy recordings and were fed into a random forest survival model for prediction of time and incident Alzheimer’s dementia. IAB was derived from the model as the relative risk. Cox proportional hazards and logistic regression models were used to evaluate the performance of IAB in predicting incident Alzheimer’s dementia (all 1195 participants) or MCI (858 without MCI at baseline) and predicting the conversion from MCI to Alzheimer’s dementia. Demographic variables including age, sex, and education were controlled in all Cox and logistic regression models.

Result

Total 287 participants developed Alzheimer’s dementia during the follow‐up. The derived IAB was 0.6 SD larger in the participants developed Alzheimer’s dementia as compared with the controls. Larger IAB was associated with increased risk of AD with a hazard ratio (HR) = 1.63 (95% CI = 1.46‐1.81, P<0.0001) for 1‐SD increase in IAB. IAB did not predict incident MCI (P = 0.8). Within participants with MCI (337 at baseline and 308 developed), larger IAB was associated with a higher risk for AD, i.e., HR = 1.34 for 1 SD increase (95% CI = 1.18‐1.51, P<0.0001). The logistic model using the cutoff of 3 years for the MCI‐Alzheimer’s dementia conversion gives the odd ratio = 1.56 for 1 SD increase of IAB, and results in AUC = 0.68, with a sensitivity = 0.68 and specificity = 0.61.

Conclusion

Derived actigraphy biomarker was predictive of Alzheimer’s risk at preclinical stages, and the conversion from MCI. Actigraphy provides useful information for early prediction and detection of AD thought its performance needs to be improved.