While composting organic waste is increasingly adopted in sustainable agriculture, continued interest in biochar application, dark soils, and compost, showed morphological aspects and functionality of biochar as a challenge to solve the CO 2 aspects related to climatic change, and carbon stability in sustainable soils, as Black carbon presents long chemical permanency due to incomplete combustion of biomass. The objective of this work was to study the characteristics of soil amendments and to review the state of the art of biochar, showing differences in composition and main microorganisms with relevant presence in the soils, such as Arbuscular mycorrhizal spores (S cutellospora sp., Glomus like, Funneliformis geosporus, Glomus crenatum, and Acaulospora excavata, obtained from TPI soil samples. New strategies are highlighted such as nutrient supplementation of compost, which can constitute the basis for improved compost-based biofertilizers in the future. Thus, the most important strategies for carbon (C) sequestration are underlined to diminish substantial organic agro- and municipal waste, increasingly disposed in the fields, landfills or either released by burning or discarding, specially to highlight sustainable technologies to use biochar and compost amendments.

Soil erosion represents a significant environmental challenge, threatening natural resources and diminishing soil productivity and quality. In Nepal, this issue is exacerbated by both natural factors, such as excessive rainfall, weak geology, and earthquakes, and human activities, including deforestation, overgrazing, intensive agriculture, and poorly planned infrastructure construction. This research was conducted in the Manahari Khola Sub-watershed of the Makwanpur district. The primary aim was to evaluate the extent of soil erosion under current Land Use and Land Cover (LULC) conditions. Essential data sets, including LULC parameters, soil properties, rainfall data, and Digital Elevation Models (DEMs), were generated using Landsat images, FAO guideline-based landform maps, data from the Hydrology Department, and Google Earth. The analysis was carried out using ArcGIS 10.8 and ILWIS 3.3 Academic software. The RMMF soil erosion modeling results indicated a range of soil erosion risks, from Very Low to Very High. Forested and bush areas showed lower rates of soil erosion, while barren lands exhibited significantly higher erosion rates. The erosion susceptibility map further demonstrated that forested regions had a very low risk of soil erosion, agricultural areas had low to moderate risk, and barren lands faced moderate to very high susceptibility. The study underscored the necessity for effective conservation measures, particularly in cutting and cliff areas and barren lands, due to their high erosion potential. Recommendations for future action include afforestation of barren areas, implementation of conservation farming practices in agricultural zones, and adoption of appropriate road stabilization measures to mitigate soil erosion risks.

Background: Several bacterial species contaminate the white coats and mobile phones used by students in the examined department. objectives: The aim is to identify and determine the bacterial species that are polluting white coats, students’ mobile phones, and inanimate surfaces at Alsaeeda University, Thamar city, Yemen Methods: We collected a total of 183 swab samples from various inanimate surfaces within the university, including the sleeves of white coats, the keys, interior, posterior, of mobile phones, and the surfaces of chairs, stairs, and door handles. We subjected the samples to microbiological culture and biochemical tests. Results: The study reported that 176 (96.17%) of the 178 samples evaluated tested positive for bacterial contamination . The contamination rate was highest in mobile phones and lowest in lab coats. Based on the kind of isolated bacteria, Staphylococcus aureus has the highest bacterial contamination rate, while Salmonella spp. and Streptococcus pneumoniae have the lowest. The contamination rate was higher in females than in males. According to the department, the laboratory had a higher contamination rate than the pharmacy. The results of antimicrobial susceptibility patterns of organisms isolated from swab samples showed that isolates were resistant to the drugs tested. Penicillin and optochin had the highest resistance rates among gram-positive bacteria. Conclusions: This study concludes that white coats worn by medical college students typically exhibit high levels of microbial contamination. White coats and mobile phones may serve as significant vectors for the transmission of bacterial contamination.

Dynamic Contextual Interpolation (DCI) introduces a novel methodology aimed at enhancing the adaptability and performance of large language models (LLMs) through the dynamic adjustment of contextual embeddings. The proposed approach addresses limitations inherent in static contextual representations, enabling LLMs to process and generate language with improved accuracy and reduced perplexity across diverse datasets. Empirical evaluations demonstrate that DCI effectively mitigates challenges associated with out-of-distribution data and novel linguistic constructs, thereby broadening the applicability of LLMs across various domains. The integration of DCI into existing LLM architectures signifies a significant advancement in natural language processing, promoting the development of more sophisticated and contextually aware language models capable of comprehending and generating human language with greater fidelity.

Background: Congenital cytomegalovirus infections (cCMV) are an important cause of childhood neurodevelopmental deficits. Most cCMV are the result of maternal non-primary infections during pregnancy, which can be due to reactivation or reinfection. Objective: To identify the rate of CMV reinfection during pregnancy and its risk factors. Study Design: We performed a secondary analysis of CMV seropositive participants from two prospective cohort studies in Quebec, Canada. Antibody responses to four strain-specific CMV epitopes located in glycoproteins B and H were measured by enzyme-linked immunosorbent assay. CMV reinfection was defined as the appearance of an antibody response to a new epitope in the third compared to the first trimester. Risk factors for reinfection were assessed. Results: Among 1614 participants, CMV reinfection was identified in 2.7% of participants, representing an incidence of 54.99 per 1000 person-years at risk (95% confidence interval 39.95-73.82). Age, marital status, household income, continent of birth or ethnicity were not associated with reinfection during pregnancy. Conclusions: The incidence of CMV reinfection during pregnancy is like what has been reported for primary infection in Quebec. A greater understanding of the patterns of reinfection is needed to inform strategies to reduce the burden of disease from cCMV.

Meditation is one of the most widely used psychological tools worldwide, with a plethora of scientific articles documenting its effectiveness and making it an evidence-based practice and method of choice for a variety of mental health problems. However, there are several ambiguities in its approach, noting confusion and alternative use of the terms meditation, mindfulness and transcendence, while the mechanisms and processes of its operation remain unclear. The present research project is a quantitative study that investigated the effects of frequency, duration, total duration and regularity of meditative practices on mindfulness, transcendence and psychological well-being. Overall, the findings highlight the role of meditative experience, particularly stronger engagement in meditative practices. Meditative experience was found to be related to increased levels of mindfulness and associated with all dimensions of mindfulness: increased levels of observability, descriptiveness and action with awareness and lower levels of criticality and reactivity. From the structural equation model tested, psychological well-being is predicted by the application of meditative practices mediated by mindfulness and transcendence. Mindfulness mediates the path from meditative experience to psychological well-being and emerges as a catalyst for the meditative experience in promoting mindfulness and psychological well-being.

Meditation and mindfulness have gathered increasing research attention worldwide, with millions of people adopting these practices. Despite being one of the most extensively studied psychological tools with global reach and recognition as a research-based psychotherapeutic practice, there remains ambiguity surrounding its approach. Research on meditation has predominantly taken quantitative approach, with minimal exploration of its cross-cultural dimensions in the international literature. This study aimed to address this gap by focusing on the cross-cultural examination of the social representation of meditation among Greek and Indian participants, both with and without meditation experience. Qualitative research methods, including interviews and thematic analysis were employed. Four main themes emerged from the analysis: meditation meaning-making, meditation teachers, meditation outcomes, and meditation mechanisms. Interestingly, the findings revealed more similarities than differences in the social representations of meditation across cultures. This suggests the presence of universal elements, possibly reflecting fundamental aspects of human functioning that transcend cultural boundaries.

Vehicle counting plays an important role in traffic management and surveillance systems. Counting the vehicles is challenging due to various factors, such as lighting variations, occlusions, and diverse vehicle types. Existing methods for vehicle counting often relied on manual or semi-automated methods, which are both labor intensive and are also bound to have some human error. Automating the counting process using deep learning algorithms can provide a more efficient and accurate solution. This work aims to detect and count vehicles in real-time video streams for which real-time recorded video datasets are used. A centroid-based tracking algorithm has been implemented to track the vehicles across consecutive frames, the algorithm associates the center points of vehicles over time, thereby enabling the tracking of individual vehicles as they move throughout the video. The evaluation demonstrates YOLOv8's high accuracy in detecting and counting vehicles in comparison with YOLOv5, which makes it suitable for diverse real-world applications such as traffic flow analysis, congestion management, and the system's real-time processing capabilities which further enhance its practical utility in surveillance systems.

Driver drowsiness is a critical factor contributing to road accidents worldwide. The accidents can be prevented if warning is provided on time to the drowsy driver. This research proposes a deep learning based approach for detection of drowsiness in drivers. The system leverages computer vision techniques, specifically the calculation of Eye Aspect Ratio (EAR), to monitor and detect signs of drowsiness by analysing facial landmarks. EAR is computed to determine eye closure patterns indicative of drowsiness. To enhance accuracy, a method for detecting sunglasses is integrated in the proposed system by utilizing Hue, Saturation and Value (HSV) color space and color masks to identify regions obstructing the eyes. Upon detecting drowsiness, the system triggers visual and auditory alerts to notify the driver, promoting timely intervention for safer driving. Experimental results demonstrate the system's effectiveness in various lighting conditions and validate its ability to differentiate between drowsy and alert states with high accuracy. The proposed approach not only addresses the challenge of detecting drowsiness in diverse conditions but also contributes to mitigating road accidents caused by driver fatigue, thereby enhancing overall road safety.

In this paper, A 7.2 GHz dual-core H-shaped-inductor based voltage-controlled oscillator (VCO) with single-mode oscillation is presented. The VCO utilizes a novel 6-port H-shaped structure formed by coupling two single-turn inductors, which effectively suppresses unwanted oscillation modes and enhances the quality factor (Q) of the desired mode. Furthermore, a noise compensation technique is proposed, which employs varactors to mitigate thermal noise induced by bias resistors, thereby improving the VCO’s overall performance. Implemented in a 110 nm CMOS process, the VCO consumes 39.6 mW and achieves a phase noise of -128.9 dBc/Hz at a 1 MHz frequency offset from a 7.2 GHz carrier frequency, with a corresponding figure of merit (FoM) of 190.1 dBc/Hz.

Tyre pressure plays a vital role in dynamic control over the vehicle and enhancing overall fuel efficiency by lowering rolling resistance and, as a result, tractive effort. Excessive speeding causes traction loss, which is a primary cause of accidents. Wet roads make driving more perilous, hence the majority of accidents occur during the rainy season. As the world's crude oil sources deplete and the electric car industry expands, it is critical that we extend the range of currently existing automobiles by improving their fuel efficiency. In order to find a solution to the above problems, authors investigated the impact of tyre pressure on the coefficient of rolling resistance and friction and designed and developed a tyre pressure regulating system that uses an infrared rpm sensor to track the rate at which a tire's rotational speed decreases as a function of time, and it then uses that information to calculate the ideal tyre pressure based on the current environmental conditions and data from various accelerometers. This unique system automatically changes tyre pressure to provide the best combination of fuel efficiency and driver safety based on data from sensors detecting tyre slip and lateral acceleration, regardless of road surface conditions.

The nuclear steroid hormone receptor Progesterone Receptor (PGR) is expressed in granulosa cells in the ovarian follicle in a tightly regulated pattern in response to the surge of Luteinizing Hormone (LH) that stimulates ovulation. PGR plays a critical role in mediating ovulation in response to LH, however the mechanism for this is still unknown. We performed immunoprecipitation-mass spectrometry using the KGN human granulosa cell line expressing the primary PGR isoforms PGR-A or PGR-B, to identify novel interacting proteins that regulate PGR function in these ovary-specific target cells. Proteomic analysis revealed protein interactions with both PGR isoforms that were gained (e.g. transcriptional coactivators) or lost (e.g. chaperone proteins) in response to the PGR agonist R5020. Additionally, isoform-specific interactions, including different families of transcriptional regulators, were identified. Comparison with published datasets of PGR interacting proteins in human breast cancer cell lines and decidualised endometrial stromal cells demonstrated a remarkable number of tissue-specific interactions, shedding light on how PGR can maintain diverse functions in different tissues. In conclusion, we provide a comprehensive novel dataset of the PGR interactome in previously unstudied ovarian cells and offer new insights into ovary-specific PGR transcriptional mechanisms.

ABSTRACT Objective: This study aimed to investigate the effects of moxibustion on the expression of kisspeptin-related proteins and its association with the ALK/JNK/NLRP3 pyroptosis signaling pathway in rats with chemotherapy-induced Premature ovarian insufficiency (POI) induced by cyclophosphamide (Cy). We sought to evaluate the therapeutic potential of moxibustion and its protective effects against Cy-induced POI. Methods: A POI model was established. Moxibustion treatment was administered at acupoints SP6 and bilateral CV4. Following the intervention, we compared the morphological characteristics of ovarian and uterine tissues, as well as the number and morphological changes of ovarian follicles. Pathological examination of ovarian tissue slices was performed. Serum levels of FSH, LH, E2, AMH, IL-1β, and IL-18 were quantified using enzyme-linked immunosorbent assay. Differences in ER mRNA levels were assessed using quantitative reverse transcription q-PCR. Western blotting was conducted to detect the expression of pyroptosis-related proteins NLRP3 and GSDMD, as well as NLRP3 inflammatory activation-related proteins ALK and JNK. The expression of kisspeptin, P450Arom, and FSHR proteins was also analyzed. Estrous cycle changes were statistically evaluated, and the increment in body weight along with changes in ovarian and other visceral mass indices were calculated. Results: The POI group exhibited significantly elevated levels of FSH, LH, IL-1β, and IL-18 following Cy intervention, along with upregulation of ALK,JNK,NLRP3,GSDMD proteins. In comparison to the control group, the POI group showed a decrease in ovarian follicle count, E2, AMH, Moxibustion altered the expression of kisspeptin, P450Arom, and FSHR, as well as the aforementioned proteins, alleviating biochemical abnormalities and delaying the progression of POI. Significance: These findings support the hypothesis that moxibustion may improve Cy-induced POI by mitigating NLRP3 inflammatory activation and modulating the expression of proteins such as kisspeptin. Targeting kisspeptin and inhibiting NLRP3 inflammatory activation and granulosa cell pyroptosis may represent a novel therapeutic strategy for POI

Significant advances have been achieved in the biofortification of common beans to increase bioavailable Zinc (Zn) and iron (Fe) but the mechanisms involved remain poorly understood. We explored relationships between phosphate (Pi) nutrition and Zn and Fe accumulation in four bean genotypes (Edar, Nizok, Colorado and Chimbolos) that nominally show differences in seed Fe and Zn accumulation. Edar seeds had the lowest phytic acid-to-iron molar ratios, which is a measure of iron bioavailability, under full nutrient conditions. Phosphate limitation impaired plant metabolism and yield, decreasing seed Pi and phytate levels but with no effect on seed Fe and Zn accumulation. Edar plants had a higher seed yield under low Pi than the other lines. Analysis of the seed proteome also revealed that Edgar was highly resistant to Pi deficiency. The phytic acid-to-iron molar ratios in Edgar seeds under Pi deficiency was about twice that of low phytic acid ( lpa) beans that have a 90% lower phytic acid content compared to conventional beans. Proteome analysis revealed that primary metabolism is shifted in the lpa beans, particularly regarding carbohydrate metabolism. We conclude that the ability to maintain Pi cycling and transport pathways is important in controlling seed phytic acid-to-iron molar ratios.

The increasing sophistication of cyber threats targeting critical digital infrastructures demands innovative approaches to detection and mitigation. A novel framework, Dynamic Anomaly Pattern Reconstruction (DAPR), was developed to address the limitations of traditional and AI-based methods in identifying and responding to malicious activities. Leveraging adaptive mechanisms and advanced feature extraction techniques, DAPR demonstrated a detection accuracy of 97.5%, outperforming existing methodologies in precision and robustness. Its scalability and efficient resource utilization make it suitable for deployment in varied operational contexts, while its ability to detect previously unseen variants highlights its adaptability to evolving threats. Through a combination of quantitative performance metrics and comparative analysis, the study establishes the framework's significant contributions to the field of cybersecurity. The findings emphasize the importance of real-time, adaptive detection systems in mitigating risks posed by increasingly dynamic and evasive malicious activities.

Human action recognition has emerged as a pivotal area of contemporary research, due to its immense potential across various fields.Yet, traditional machine learning methods struggle with complex recognition tasks amidst rapid advancements in sensor technology and deep learning. To resolve this challenge, our research introduces MHCAGE, a novel dual-stream neural network model with a multi-head attention mechanism based on the CAGE model. This model seamlessly integrates accelerometer and gyroscope signal characteristics, boosting recognition accuracy and robustness. Furthermore, to further enhance the feature extraction module, we append a batch normalization layer subsequent to each convolutional layer’s output, aiming to bolster the model’s stability and reliability during training.Experiments on UCI_HAR and mHealth datasets confirm MHCAGE’s superior recognition performance, validating our method’s efficacy and feasibility.

We aim to investigate changes in objective measures of physical activity (PA) and sleep patterns one month before and during Ramadan among healthy fasting individuals. Twenty-two healthy individuals (Mean age= 23.09 ±7.95 years and mean BMI 24.92 ±4.42, and 50% of females) voluntarily participated in this observational study. Participants wore the ActiGraph activity monitor wGT3X-BT on the right hip for seven consecutive days (24 hrs./day), expect for bathing and swimming activities, during a month before and during the month of Ramadan. During the time of wearing, each participant completed sleep diary to subjectively track sleeping schedule. We used ActiLife 6.13.4 software to initialize, download, and analyzing PA and sleep data collected from wearing the activity monitor. A paired-samples t test indicated a significant increase in the average sedentary behavior during Ramadan from (1093 ±645 to 3367 ±1201 min/d; P<.001), a significant reduction in the average daily light activity during Ramadan from (119 ±63 to 37 ±47; P<.001), and a significant reduction in MVPA from (32.5 ±22.8 to 9.2 ±7.2 min/d; P<.001). Regarding sleep patterns, bedtime showed significantly different between before and during Ramadan (23:47 ±16 min vs 1:20 ±30 min, t = -3.01, p = 0.007), while there were not significant changes in waking time, sleep onset latency, total sleep time, and sleep efficiency. This study revealed that there were unfavorable significant changes in daily sedentary behavior, light activity, and moderate-to-vigorous activity during the month of Ramdan. This study found Ramadan fasting did significantly change the bedtime among the participants.

Whether lysine dihydroxyisobutyrylation (Khib), a recently identified post-translational modification, is involved in plant responses to low temperature is unknown. Here, we performed a comprehensive chloroplast proteome-wide dihydroxyisobutyrylation analysis in Dendrobium huoshanense to explore the potential function of Khib-modified proteins in response to low-temperature stress. We identified a total of 13,040 Khib sites in 3,281 chloroplast proteins that were significantly differentially regulated by low-temperature stress. Khib-modified proteins were found to be highly associated with proton transmembrane transporter activity, ATPase-coupled ion transmembrane transporter activity, and active monoatomic ion transmembrane transporter activity, among other processes. The identified Khib sites that were found to be differentially regulated in response to low- temperature stress were mainly concentrated in AKhib, KKhib, and EKhib motifs. Notably, D. huoshanense fructose-1,6-bisphosphate aldolase (FBA), an important chloroplast metabolic enzyme involved in the Calvin-Benson cycle, showed significant Khib modification after low-temperature treatment, with eight Khib sites undergoing modification. Site-directed mutagenesis of the DhFBA-encoding gene and its subsequent expression in yeast revealed that Khib modification at the K338 site is essential for maintaining DhFBA enzymatic activity and conferring low-temperature tolerance. Molecular dynamics simulation and surface electrostatic potential analysis further showed that Khib at K338 improved the structural stability of DhFBA by reducing its surface affinity to an optimal status, thus promoting its activity and low-temperature resistance.

Objective: This research aimed to describe the existing knowledge of midwives in South Africa regarding placental triage, considering its significance in identifying abnormalities and potential factors contributing to litigation cases. Design: A quantitative descriptive research design was employed, using a survey method to gather data from midwives. Setting: The study was conducted in South Africa amongst midwives working in both public and private hospitals, including educators and retired midwives. Population or Sample: A snowball sampling method was used to recruit participants and a total of 157 midwives participated in the study. Methods: An electronic questionnaire was developed with the guidance of midwifery and placental histology experts. Main Outcome Measures: The study gauged the percentage of midwives who routinely examined placentas, their awareness of placental histology services, their knowledge of macroscopic features of the placenta and their perceived need for further education on placental examination. Results: Among the participants, 64% reported routine examination of placentas and 61% had the availability of placental histology services in their units. The median knowledge score regarding macroscopic placental examination was 61.9%, with notable variability among respondents. The lowest obtained score was 14.3% and the highest score was 81%. Conclusions: The findings underscore a need for enhanced awareness and education among midwives regarding the importance of placental examination and histology. Notably, a considerable proportion of midwives expressed a desire for further education on these topics, highlighting opportunities for improving clinical practices and potentially reducing litigation risks in maternal and child health.

Gastrointestinal lesions complicated by systemic lupus erythematosus occur from time to time in clinical practice, but it is not common to have gastrointestinal lesions as the main clinical manifestation and negative typical antibodies. There is currently no unified diagnostic standard, which is easy to miss or misdiagnose. Recently, our department admitted a patient with this condition. This article summarizes the diagnosis and treatment experience in combination with relevant literature analysis.

Interpersonal trust decisions are guided by reputation. However, it remains unclear how positive and negative prior reputations that are inconsistent with a partner’s behavior are integrated at the behavioral and neural levels and how this informs daily trust decisions. In this two-part study, 54 subjects first played an iterated 20-trial Trust Game with four anonymous partners introduced as “cooperative” or “individualistic” while EEG was recorded. The partners’ behavior then either confirmed or contradicted this prior reputation. Subsequently, the subjects completed a three-day ecological assessment measuring trust in daily interactions. According to the results, negative prior reputations were associated with less trust decisions, even after being contradicted by cooperative behavior. The frequency of trust decisions remained high if positive prior reputations were confirmed, and decreased if they were contradicted. Trial-by-trial analyses showed that negative priors were still related to a lower trust choice probability, even if they were contradicted in the previous trial, paralleled by a decrease in fronto-lateral theta. Mean trust levels across laboratory conditions were descriptively associated with mean trust levels in daily interactions. In sum, these findings indicate that a person with a negative prior reputation is less trusted, even if this person behaves in a positive way.

Low-Dose Amitriptyline: A Potential Therapeutic Option for Chronic Pain in Older PeopleTakayuki Suga, DDS, PhD1; Trang Thi Huyen Tu, DDS, PhD1,2; Motoko Watanabe, DDS, PhD1; Takahiko Nagamine MD, PhD1,3; and Akira Toyofuku, DDS, PhD11 Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo2 Department of Basic Dental Sciences, Faculty of Odonto- stomatology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam3 Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Yamaguchi, Japan.Word count:798Acknowledgements: noneConflict of interest statement: There are no conflicts of interest to declare.Keywords: psychopharmacology, safety Pharmacology, chronic pain, antidepressive agents, older adultCorrespondence to:Takayuki Suga, DDS, PhD1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.Phone number: +81358035898; Fax: +81358035898; Email: suga.ompm@tmd.ac.jpThe use of antidepressants in older adults with chronic pain is controversial. We found Dr. Narayan et al.’s article, titled “Efficacy and Safety of Antidepressants for Pain in Older Adults: A Systematic Review and Meta-Analysis,” on the use of antidepressants in older people with chronic pain to be highly engaging. (Narayan et al., 2024) They conducted a systematic review and meta-analysis on the efficacy and safety of antidepressants for chronic pain in older people. Due to various limitations, they concluded that the benefits and harms of antidepressant medicines for most types of chronic pain, especially knee OA, are unclear.Conducting clinical research with older adults poses challenges, often excluding them due to pre-existing conditions. Randomized controlled trials (RCTs) in this population are particularly difficult for several reasons:1. Comorbidities and Polypharmacy: older people often have multiple chronic conditions and take various medications, complicating group allocation, the isolation of the intervention’s effects and increasing the risk of drug interactions.2. Heterogeneity and Follow-up Challenges: Due to mobility impairments and other factors, it is difficult for older people to make regular visits to hospitals conducting RCTs, leading to high dropout rates.3. Ethical Considerations: The older people are often regarded as a vulnerable population, requiring ethical considerations when involving them in risk-related interventions.Despite these challenges, studies using real-world data suggest that, when used carefully, antidepressants might help manage chronic pain in older adults, particularly for conditions like burning mouth syndrome (BMS).BMS, a common type of chronic orofacial pain affecting mainly postmenopausal women, has uncertain pathophysiology.We previously reported that low doses of amitriptyline are effective in managing pain in older people with BMS. (Suga et al., 2019) Furthermore, even in patients over 80 years old, amitriptyline demonstrates efficacy when used in low doses with careful administration. (Watanabe et al., 2022) Regarding common side effects, managing these side effects in elderly patients will be effective through regular visits and examination. (Suga et al., 2019; Watanabe et al., 2022) Hence, it is crucial to monitor for anticholinergic side effects such as drowsiness, dry mouth, and constipation, as well as potential falls due to dizziness and any changes in cognitive function in clinical assessment.A therapeutic window exists for the dosages of amitriptyline that are effective in managing chronic pain, indicating that its efficacy is not dose-dependent. (Nagamine, 2024) In contrast to the doses used in psychiatry for depression (typically 100 mg/day or more), amitriptyline is effective at doses of 5-20 mg/day in the treatment of BMS. The use of amitriptyline at this dosage is considerably lower than the doses employed in the RCTs included in the authors’ study, suggesting a reduced risk of side effects and withdrawal symptoms.The challenges of administering antidepressants to older people with chronic pain are not limited to concerns about side effects but also encompass issues related to their overall efficacy in this population. Serotonin’s role in pain modulation is complex, as it can either exacerbate or alleviate pain depending on the receptor subtype activated. This bidirectional effect is attributed to the distinct pathways involved in serotonin-mediated pain processing, with some receptors promoting analgesia and others enhancing nociception. (Bannister & Dickenson, 2016) Additionally, the elevation of serotonin levels might disrupt the delicate equilibrium with dopamine, thus hindering pain inhibition via the reward pathway. Therefore, increasing serotonin levels alone may exacerbate pain rather than produce therapeutic benefits.Moreover, chronic pain modulation involves not only serotonin but also other monoamines, such as dopamine and noradrenaline. Consequently, antidepressants that modulate serotonergic, noradrenergic, or dopaminergic pathways may exhibit therapeutic potential in managing chronic pain. (Bannister & Dickenson, 2016) This is also reflected in the study by Narayan et al., which demonstrated the efficacy of duloxetine, a dual serotonin and noradrenaline reuptake inhibitor, albeit with a modest effect size. Amitriptyline, which similarly targets both serotonin and noradrenaline, and to some dopamine transporters, may offer superior efficacy compared to other antidepressants. However, as previously mentioned, its therapeutic effect does not appear to be dose-dependent, suggesting that there may be an optimal therapeutic window at lower doses. Although not specifically in older people, other reports have also demonstrated the effectiveness of low-dose amitriptyline (5-25 mg/day) in managing conditions such as lower back pain, chronic neck pain, and chest pain. (Maarrawi et al., 2018; Park et al., 2013; Urquhart et al., 2018) Given the above, it is conceivable that low doses of certain antidepressants, such as amitriptyline, may be effective and safe for patients with other types of chronic pain. Research on the use of antidepressants for chronic pain in older people is still limited; therefore, as the authors have pointed out, there is a need for more prospective studies and numerous real-world investigations. In conclusion, careful clinical management and the accumulation of treatment data are essential for the effective treatment of chronic pain in older people using antidepressants.ReferencesBannister, K., & Dickenson, A. H. (2016). What do monoamines do in pain modulation? Curr Opin Support Palliat Care , 10 (2), 143-148. https://doi.org/10.1097/SPC.0000000000000207Maarrawi, J., Abdel Hay, J., Kobaiter-Maarrawi, S., Tabet, P., Peyron, R., & Garcia-Larrea, L. (2018). Randomized double-blind controlled study of bedtime low-dose amitriptyline in chronic neck pain. Eur J Pain , 22 (6), 1180-1187. https://doi.org/10.1002/ejp.1206Nagamine, T. (2024). Amitriptyline at low dose for burning mouth syndrome. Oral Diseases , 30 (7), 4650-4652. https://doi.org/10.1111/odi.14966Narayan, S. W., Naganathan, V., Vizza, L., Underwood, M., Ivers, R., McLachlan, A. J., Zhou, L., Singh, R., Tao, S., Xi, X., & Abdel Shaheed, C. (2024). Efficacy and safety of antidepressants for pain in older adults: A systematic review and meta-analysis. Br J Clin Pharmacol . https://doi.org/10.1111/bcp.16234Park, S. W., Lee, H., Lee, H. J., Park, J. C., Shin, S. K., Lee, S. K., Lee, Y. C., & Kim, J. E. (2013). Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain. World J Gastroenterol , 19 (30), 4958-4965. https://doi.org/10.3748/wjg.v19.i30.4958Suga, T., Takenoshita, M., Watanabe, T., Tu, T. T. H., Mikuzuki, L., Hong, C., Miura, K., Yoshikawa, T., Nagamine, T., & Toyofuku, A. (2019). Therapeutic Dose of Amitriptyline for Older Patients with Burning Mouth Syndrome. Neuropsychiatric Disease and Treatment ,Volume 15 , 3599-3607. https://doi.org/10.2147/ndt.S235669Urquhart, D. M., Wluka, A. E., van Tulder, M., Heritier, S., Forbes, A., Fong, C., Wang, Y., Sim, M. R., Gibson, S. J., Arnold, C., & Cicuttini, F. M. (2018). Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial. JAMA Intern Med ,178 (11), 1474-1481. https://doi.org/10.1001/jamainternmed.2018.4222Watanabe, M., Takao, C., Liu, Z., Nayanar, G., Suga, T., Hong, C., Tu, T. T. H., Yoshikawa, T., Takenoshita, M., Motomura, H., Nagamine, T., & Toyofuku, A. (2022). The Effectiveness and Adverse Events of Amitriptyline and Aripiprazole in Very Elderly Patients With BMS.Frontiers in Pain Research , 3 . https://doi.org/10.3389/fpain.2022.809207

MicroRNAs (miRNAs) have become essential modulators in many brain disorders, such as neurodegenerative diseases, psychiatry disorders, and chronic pain syndromes, and they play a critical role in controlling gene expression. This review investigates how disorders of the nervous system and pain research are affected by malfunctions in the miRNA biogenesis machinery. Despite tremendous progress, we still don’t fully understand how these molecular regulators affect neuropathological processes. Even with the increasing amount of research, little is known about the malfunctions of the miRNA machinery, especially when it comes to the nervous system and the diseases that are linked to it. The results of recent research are compiled in this review, which emphasizes the role that disruptions in miRNA processing enzymes, including Drosha, Dicer, Argonaute, and RISC proteins, play in neurological conditions like Parkinson’s and Alzheimer’s disease, as well as more general neurodegeneration. We also go over current studies on the stimulus-dependent, temporal, and spatial expression patterns of these essential miRNA biogenesis components in pain. These discoveries broaden our knowledge of the fundamental processes behind pain-related illnesses and present prospective directions for focused therapeutic approaches.

We report a squaramide-catalyzed aza-Michael/Michael cyclization of nitroalkenes with 3-benzoylacylamides, facilitating the asymmetric synthesis of γ-lactams. This method efficiently generates a range of optically pure γ-lactams, in yields ranging from 25% to 90% and enantioselectivities exceeding 99%. Performed under mild conditions, this method highlights the significance of γ-lactams as versatile scaffolds in drug discovery, showcasing the high stereocontrol and adaptability of this synthetic strategy.