Clinical characterization and mutation spectrum of patients with hypertriglyceridemia in a German outpatient clinic.

BACKGROUND: Severe hypertriglyceridemia (HTG) has predominantly multifactorial causes (MCS). Yet a small subset of patients have the monogenetic form (FCS). It remains a challenge to distinguish patients clinically, since decompensated MCS might mimic FCS´s severity. Aim of the current study was to determine clinical criteria that could sufficiently distinguish both forms as well as to apply the FCS score proposed by Moulin and colleagues. METHODS: We retrospectively studied 72 patients who presented with severe HTG in our clinic during a time span of seven years and received genetic testing. We classified genetic variants (ACMG-criteria), followed by genetic categorization into MCS or FCS. Clinical data were gathered from the medical records and the FCS score was calculated for each patient. RESULTS: Molecular genetic screening revealed eight FCS patients and 64 MCS patients. Altogether, we found 13 pathogenic variants of which four have not been described before. The FCS patients showed a significantly higher median triglyceride level compared to the MCS. The FCS score yielded a sensitivity of 75% and a specificity of 93.7% in our cohort, and significantly differentiated between the FCS and MCS group (p<0.001). CONCLUSIONS: In our cohort we identified several variables that significantly differentiated FCS from MCS. The FCS score performed similar to the original study by Moulin, thereby further validating the discriminatory power of the FCS score in an independent cohort.

The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease.

Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual impairment with a poorly understood genetic basis. Our goal was to identify gene variants associated with these glaucoma types by assessing the mutational burden in 76 matrix metalloproteinase-related genes. We studied 101 childhood glaucoma patients with no identified monogenic alterations using next-generation sequencing. Gene expression was assessed through immunohistochemistry. Functional analysis of selected gene variants was conducted in cultured cells and in zebrafish. Patients presented a higher proportion of rare variants in four metalloproteinase-related genes, including CPAMD8 and ADAMTSL4, compared to controls. ADAMTSL4 protein expression was observed in the anterior segment of both the adult human and zebrafish larvae's eye, including tissues associated with glaucoma. In HEK-293T cells, expression of four ADAMTSL4 variants identified in this study showed that two variants (p.Arg774Trp and p.Arg98Trp) accumulated intracellularly, inducing endoplasmic reticulum stress. Additionally, overexpressing these ADAMTSL4 variants in zebrafish embryos confirmed partial loss-of-function effects for p.Ser719Leu and p.Arg1083His. Double heterozygous functional suppression of adamtsl4 and cpamd8 zebrafish orthologs resulted in reduced volume of both the anterior eye chamber and lens within the chamber, supporting a genetic interaction between these genes. Our findings suggest that accumulation of partial functional defects in matrix metalloproteinase-related genes may contribute to increased susceptibility to early-onset glaucoma and provide further evidence supporting the notion of a complex genetic inheritance pattern underlying the disease.

Unusual Presentation of Recurrent Calcinosis Cutis in the Right Thumb of a 16-Year-Old Female.

Calcinosis cutis is a quite unusual disease represented by abnormal accumulation of calcium salts in the skin and subcutaneous tissues. Repeated cutis calcinosis means recurrent calcium deposition in pre-existing areas. The case report illustrated the case of a 16-year-old female who had recurrent calcium deposits on the base of her right thumb. The patient initially had swelling at the base of her right thumb, which had been present for six months now. The patient described the dorsal solid mass on top of the thumb base, which was painful and had reduced thumb mobility. There was swelling that became painful, specifically located at the same site as the previous surgery, with thumb restriction and superadded infection at the metacarpophalangeal joint. Routine lab tests, including blood tests and rheumatologic and autoimmune work-ups, were normal. Plain radiographs and ultrasound examinations unveiled the characteristics of calcifications in the thumb tissues. A skin biopsy was done and the calcium deposits in subcutaneous tissue were confirmed, matching calcinosis cutis. The approach to the treatment of this condition entailed conservative measures. Some included physiotherapy to correct a flexion deformity, antibiotics, painkillers, and daily dressing. The patient was advised to follow up and to consider excision of the nodules. This case points out the clinical manifestations, investigations, and initial management of available strategies for recurrent calcinosis cutis. Further studies and long-term follow-up are necessary to determine the optimal treatment approaches and outcomes for this rare condition.

Topsoil dilution by subsoil admixture had less impact on soil organic carbon stock development than fertilizer form and erosion state.

Enhancing the agroecosystems carbon (C) sink function for climate mitigation faced challenges, particularly with traditional measures with limited suitability for increasing soil organic carbon (SOC) stocks. Inducing a SOC undersaturation in the topsoil by abrupt subsoil admixture is a way to create an additional C sink. However, the deep tillage traditionally used for this topsoil dilution was not always successful. It was due to a lack of knowledge and suitable approaches to record the effect of all relevant factors in SOC recovery, including soil conditions and fertilizer forms. We addressed these problems by establishing a three-factorial experiment: I) "moderate topsoil dilution," II) "N fertilization form," and III) "soil erosion state," representing three soil types in the hummocky ground moraine landscape of NE Germany. SOC dynamics were determined over a year of winter rye cropping using a novel robotic chamber system capable of measuring CO2 exchange on 36 experimental plots with a reduced methodological bias than previous measuring systems. The averaged net ecosystem carbon balance, a proxy for SOC stock change, indicated that topsoil dilution only reduced further SOC losses. The N fertilizer form had a significantly stronger and more differentiated effect. While the mineral N fertilization consistently produced only C sources, the organic fertilization, in combination with the diluted topsoil, led to a C sink. This C-sink function was, however, more pronounced in the eroded soil than in the non-eroded soil. Overall, the results have made clear that the impact of topsoil dilution on the further development of the SOC stock is only possible if the effect of other relevant factors, such as N fertilizer form and erosion state, are taken into account.

[Geriatric syndromes: the importance of the problem, controversial issues of terminology.]

The foundation of healthy aging is the prevention of disability. In modern medical usage, a syndrome refers to a collection of symptoms and signs with a single underlying cause that may not yet be known. Geriatric syndromes, on the other hand, refer to multifactorial health conditions and occur when the accumulated effects of impairments in multiple systems make an older person vulnerable to situational changes. The use of the term "syndrome" in geriatrics emphasizes the multiple causes of a single manifestation involving an abundance of factors involving multiple organs and systems and is characterized by unique features of common health problems in older adults. It is the geriatric syndromes that can have a significant impact on quality of life and disability. Therefore, early detection of these medical conditions using targeted geriatric assessment is essential in geriatrics. Understanding the essence and feminology of geriatric syndromes, their correct positioning and interpretation is an extremely urgent problem. The main purpose of the presented review is precisely to try to answer these questions. In addition, it has not yet been determined whether geriatric syndromes should be included in the diagnosis (the only exception is sarcopenia syndrome, which was officially included in the 10th International Classification of Diseases in 2016).

Wild grass-derived alleles represent a genetic architecture for the resilience of modern common wheat to stresses.

This review explores the integration of wild grass-derived alleles into modern bread wheat breeding to tackle the challenges of climate change and increasing food demand. With a focus on synthetic hexaploid wheat, this review highlights the potential of genetic variability in wheat wild relatives, particularly Aegilops tauschii, for improving resilience to multifactorial stresses like drought, heat, and salinity. The evolutionary journey of wheat (Triticum spp.) from diploid to hexaploid species is examined, revealing significant genetic contributions from wild grasses. We also emphasize the importance of understanding incomplete lineage sorting in the genomic evolution of wheat. Grasping this information is crucial as it can guide breeders in selecting the appropriate alleles from the gene pool of wild relatives to incorporate into modern wheat varieties. This approach improves the precision of phylogenetic relationships and increases the overall effectiveness of breeding strategies. This review also addresses the challenges in utilizing the wheat wild genetic resources, such as the linkage drag and cross-compatibility issues. Finally, we culminate the review with future perspectives, advocating for a combined approach of high-throughput phenotyping tools and advanced genomic techniques to comprehensively understand the genetic and regulatory architectures of wheat under stress conditions, paving the way for more precise and efficient breeding strategies.

Multifactorial analysis of willingness to undergo subcutaneous allergen immunotherapy in pediatric patients.

Objective: To explore factors influencing the acceptance of allergen immunotherapy (AIT) for the treatment of allergic respiratory diseases by pediatric patients and their families. Methods: A total of 406 children (210 males and 196 females) attending the pediatric outpatient clinics and wards of the Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2020 to April 2022. Those who met the criteria for the AIT treatment, were included in the survey. An online 20-item questionnaire was developed. Data on patient's general characteristics, allergic disease status, family history of allergies, general family information, parental knowledge of allergic diseases, and whether the AIT treatment was recommended by a physician, were collected. The patients were divided into two groups according to their willingness to receive AIT: a reluctant or neutral group (n = 182), and a willing group (n = 224). A univariate analysis of the willingness to undergo AIT was done to detect parameters that significantly differed between the groups, and the identified factors were used as independent variables in the multifactorial logistic regression analysis. Results: The severity of allergic disease, presence of drug allergy, occurrence of severe allergic reactions, mother's education, distance from home to the hospital, parental knowledge of allergic diseases, and whether the doctor recommended AIT were all statistically different between the groups (p < 0.05). Multifactorial logistic regression analysis showed that the degree of allergic rhinitis (AR), or asthma (AS), parental knowledge of allergic diseases, and doctor's recommendation of AIT were the factors that influenced the willingness of pediatric patients to receive AIT. Conclusions: The severity of AR and AS, parental knowledge of allergic diseases, and doctor's recommendation influenced the willingness of pediatric patients to receive AIT.

Neuropsychiatric symptoms and metamemory across the life span: psychometric properties of the German Multifactorial Memory Questionnaire (MMQ).

OBJECTIVE: We assessed the psychometric properties, established normative data for the German Multifactorial Memory Questionnaire (MMQ), and analyzed its association with neuropsychiatric factors across the life span to provide a validated metamemory assessment for a German-speaking population. METHODS: The three MMQ scales (memory satisfaction, self-rated ability, and strategy application) were translated into German, considering cultural, linguistic, and conceptual aspects. To validate the MMQ and assess associations with neuropsychiatric factors, the Complainer Profile Identification, Geriatric Depression Scale, Beck Anxiety Inventory, Pittsburgh Sleep Quality Index, and Short-Form-Health Survey were applied in an online study in 336 healthy participants with follow-up after 8 months. RESULTS: Psychometric evaluation of the German MMQ showed normal distribution of all scales and good to excellent validity, internal consistency, and retest reliability. We provide percentiles and normative data for z-score conversion. Importantly, even subclinically elevated scores in depressiveness and anxiety were associated with decreased memory satisfaction and self-rated ability. Furthermore, although the influence of age on the German MMQ scales was minimal, effects of neuropsychiatric factors such as sleep quality, anxiety, and depressiveness on MMQ Satisfaction and Ability varied across the life span. CONCLUSIONS: Our study provides a validated German translation of the MMQ with normative data and reliability measures, including reliable change scores. We show the impact of neuropsychiatric factors on the MMQ scales across the life span and emphasize the relevance of a multifactorial approach to metamemory as a measure of individualized everyday functionality and the importance of including neuropsychiatric factors into both research and clinical assessments of metamemory.

Epigenome-metabolism nexus in the retina: implications for aging and disease.

Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being a highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, and extracellular signals. Precise global epigenomic signatures guide development and homeostasis of the intricate retinal structure and function. Epigenomic and metabolic realignment are hallmarks of aging and highlight a link of the epigenome-metabolism nexus with aging-associated multifactorial traits affecting the retina, including age-related macular degeneration and glaucoma. Here, we focus on emerging principles of epigenomic and metabolic control of retinal gene regulation, with emphasis on their contribution to human disease. In addition, we discuss potential mitigation strategies involving lifestyle changes that target the epigenome-metabolome relationship for maintaining retinal function.

Combining principal component analysis and logistic regression for multifactorial fall risk prediction among community-dwelling older adults.

Falls require comprehensive assessment in older adults due to their diverse risk factors. This study aimed to develop an effective fall risk prediction model for community-dwelling older adults by integrating principal component analysis (PCA) with machine learning. Data were collected for 45 fall-related variables from 1630 older adults in Taiwan, and models were developed using PCA and logistic regression. The optimal model, PCA with stepwise logistic regression, had an area under the receiver operating characteristic curve of 0.78, sensitivity of 74 %, specificity of 70 %, and accuracy of 71 %. While dimensionality reduction via PCA is not essential, it aids practicality. Our framework combines PCA and logistic regression, providing a reliable method for fall risk prediction to support consistent screening and targeted health promotion. The key innovation is using PCA prior to logistic regression, overcoming conventional limitations. This offers an effective community-based fall screening tool for older adults.

Soil, rhizosphere, and root microbiome in kiwifruit vine decline, an emerging multifactorial disease.

Kiwifruit vine decline syndrome (KVDS) is characterized by severe root system impairment, which leads to irreversible wilting of the canopy. Plants usually collapse rapidly from the appearance of the first aboveground symptoms, without recovery even in the following seasons. The syndrome has been negatively impacting kiwifruit yield in different areas of Italy, the main producing European country, since its first outbreak in 2012. To date, a unique, common causal factor has yet to be found, and the syndrome is referred to as multifactorial. In this article, we investigated the whole biotic community (fungi, bacteria, and oomycetes) associated with the development of KVDS in three different belowground matrices/compartments (soil, rhizosphere, and root). Sampling was performed at both healthy and affected sites located in the main kiwifruit-producing area of Northwestern Italy. To address the multifactorial nature of the syndrome and to investigate the potential roles of abiotic factors in shaping these communities, a physicochemical analysis of soils was also performed. This study investigates the associations among taxonomic groups composing the microbiome and also between biotic and abiotic factors. Dysbiosis was considered as a driving event in shaping KVDS microbial communities. The results obtained from this study highlight the role of the oomycete genus Phytopythium, which resulted predominantly in the oomycete community composition of diseased matrices, though it was also present in healthy ones. Both bacterial and fungal communities resulted in a high richness of genera and were highly correlated to the sampling site and matrix, underlining the importance of multiple location sampling both geographically and spatially. The rhizosphere community associated with KVDS was driven by a dysbiotic process. In addition, analysis of the association network in the diseased rhizosphere revealed the presence of potential cross-kingdom competition for plant-derived carbon between saprobes, oomycetes, and bacteria.

Effectiveness of Non-Pharmacological Interventions for Dementia among the Elderly: A Randomized Controlled Trial.

(1) Background: Up until now, there is still no medicine that can cure dementia, but there are some that can only help slow down the progression of the disease and reduce some symptoms. Pharmacological interventions for dementia have many side effects and are expensive, so non-pharmacological treatments for dementia become more urgent. This study aimed to evaluate the effectiveness of multifactorial non-pharmacological interventions in dementia patients; (2) Methods: This is a randomized controlled trial conducted in Hai Duong from July 2021 to December 2022. Selected subjects included 88 patients diagnosed with very mild, mild, and moderate dementia, of whom 44 patients were assigned to the intervention group and 44 patients to the control group; (3) Results: For the effectiveness of the non-pharmacological multifactorial intervention on depression severity: in the intervention group, the GDS 15 depression score decreased from 4.8 to 2.9, while, in the control group, the GDS 15 depression score increased by 1.3 points after six months of no intervention. For the effect of the non-pharmacological multifactorial intervention on the level of sleep disturbance, in the intervention group, the PSQI sleep disturbance score decreased by nearly half (from 10.2 to 5.6), while, in the control group, this trend was not clear. For the effect of the non-pharmacological multifactorial intervention on daily functioning: in the intervention group, the ADL and IADL scores improved (1.02 ± 1.32 and 1.23 ± 1.75), while, in the control group, the ADL and IADL scores decreased (0.93 ± 1.2 and 0.98 ± 2.19). For the effect of the non-pharmacological multifactorial intervention on quality of life: in the intervention group, the EQ-5D-5L scores improved (0.17 ± 0.19), while, in the control group, the EQ-5D-5L scores decreased (0.20 ± 0.30); (4) Conclusions: Non-pharmacological multifactorial interventions, including physical activity, cognitive training, listening to educational lectures, and organizing miniature social models, have been shown to improve mental health, self-control, and quality of life.

Innovative pathological network-based multitarget approaches for Alzheimer's disease treatment.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities toward two or more drug targets of interest. These multitarget-directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade.

Spatiotemporal characteristics analysis of multi-factorial air pollution in the Jing-Jin-Ji region based on improved sequential ICI method and novel grey spatiotemporal incidence models.

Air pollution shares the attributes of multi-factorial influence and spatiotemporal complexity, leading to air pollution control assistance models easily falling into a state of failure. To address this issue, we design a framework containing improved data fusion method, novel grey incidence models and air pollution spatiotemporal analysis to analyze the complex characteristics of air pollution under the fusion of multiple factors. Firstly, we improve the existing data fusion method for multi-factor fusion. Subsequently, we construct two grey spatiotemporal incidence models to examine the spatiotemporal characteristics of multi-factorial air pollution in network relationships and changing trends. Furthermore, we propose two new properties that can manifest the performance of grey incidence analysis, and we provide detailed proof of the properties of the new models. Finally, in the Jing-Jin-Ji region, the novel models are used to study the network relationships and trend changes of air pollution. The findings are as follows: (1) Two highly polluted belts in the region require attention. (2) Although the air pollution network under multi-factorial fusion obeys the first law of geography, the network density and node density exhibit significant variations. (3) From 2013 to 2021, all pollutants except O3 show improvement. (4) Recommendations for responses are presented based on the above-mentioned results. (5) The parameter analyses, model comparisons, Monte Carlo experiments and model feature summaries illustrate that the proposed models are practical, interpretable and considerably outperform various prevailing competitors with remarkable universality.

Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia.

BACKGROUND AND AIMS: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG. METHODS: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS. RESULTS: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone. CONCLUSIONS: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.

Pancreatitis polygenic risk score is associated with acute pancreatitis in multifactorial chylomicronemia syndrome.

BACKGROUND: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). The risk of AP is heterogenous and is associated with increased level of triglycerides (TG) and presence of rare variants in TG metabolism-related genes. OBJECTIVE: To determine if the accumulation of common variants in pancreatitis susceptibility genes, measured with a weighted polygenic risk score (PRS), is associated with AP in MCS patients. METHODS: A total of 114 patients with MCS underwent genetic testing for eight single nucleotide polymorphisms (SNPs) in known pancreatitis susceptibility genes (ABCG8, CLDN2, CTRB1/2, CTRC, PRSS1, PRSS2, SPINK1 and TWIST2). A weighted PRS was calculated to account for the phenotypic effect of each SNP locus. RESULTS: A high pancreatitis-PRS score (≥ 0.44) was associated with a 2.94-fold increase risk of AP (p = 0.02) among patients with MCS. MCS patients with a high pancreatitis-PRS and a rare variant in TG metabolism-related gene have a 9.50-fold increase risk of AP (p = 0.001), compared to those with a low-PRS and no rare variant. A multivariate analysis including the presence of rare variants, the maximal TG values and a high pancreatitis-PRS explained 26% of the variability in AP in MCS patients. CONCLUSION: This study shows for the first time that the accumulation of common variants in pancreatitis susceptibility genes is associated with AP in MCS patients. Pancreatitis-PRS could help clinicians to identify MCS patients who may be at higher risk of AP and who may benefit from more aggressive treatment.

Combining user-centered design and behavioral theory to enhance health technologies: A personas-based approach for a primary-care based multifactorial falls risk assessment tool.

INTRODUCTION: Multifactorial falls risk assessment tools (FRATs) can be an effective falls prevention method for older adults, but are often underutilized by health care professionals (HCPs). This study aims to enhance the use and implementation of multifactorial FRATs by combining behavioral theory with the user-centered design (UCD) method of personas construction. Specifically, the study aimed to (1) construct personas that are based on external (i.e., needs, preferences) and intrinsic user characteristics (i.e., behavioral determinants); and (2) use these insights to inform requirements for optimizing an existing Dutch multifactorial FRAT (i.e., the 'Valanalyse'). METHODS: Survey data from HCPs (n = 31) was used to construct personas of the 'Valanalyse.' To examine differences between clusters on 68 clustering variables, a multivariate cluster analysis technique with non-parametric analyses and computational methods was used. The aggregated external and intrinsic user characteristics of personas were used to inform key design and implementation requirements for the 'Valanalyse,' respectively, whereby intrinsic user characteristics were matched with appropriate behavior change techniques to guide implementation. RESULTS: Significant differences between clusters were observed in 20 clustering variables (e.g., behavioral beliefs, situations for use). These variables were used to construct six personas representing users of each cluster. Together, the six personas helped operationalize four key design requirements (e.g., guide treatment-related decision making) and 14 implementation strategies (e.g., planning coping responses) for optimizing the 'Valanalyse' in Dutch geriatric, primary care settings. CONCLUSION: The findings suggest that theory- and evidence-based personas that encompass both external and intrinsic user characteristics are a useful method for understanding how the use and implementation of multifactorial FRATs can be optimized with and for HCPs, providing important implications for developers and eHealth interventions with regards to encouraging technology adoption.

Climate Change-The Rise of Climate-Resilient Crops.

Climate change disrupts food production in many regions of the world. The accompanying extreme weather events, such as droughts, floods, heat waves, and cold snaps, pose threats to crops. The concentration of carbon dioxide also increases in the atmosphere. The United Nations is implementing the climate-smart agriculture initiative to ensure food security. An element of this project involves the breeding of climate-resilient crops or plant cultivars with enhanced resistance to unfavorable environmental conditions. Modern agriculture, which is currently homogeneous, needs to diversify the species and cultivars of cultivated plants. Plant breeding programs should extensively incorporate new molecular technologies, supported by the development of field phenotyping techniques. Breeders should closely cooperate with scientists from various fields of science.

Research Progress on Plant Responses to Stress Combinations in the Context of Climate Change.

In the context of climate change, the frequency and intensity of extreme weather events are increasing, environmental pollution and global warming are exacerbated by anthropogenic activities, and plants will experience a more complex and variable environment of stress combinations. Research on plant responses to stress combinations is crucial for the development and utilization of climate-adaptive plants. Recently, the concept of stress combinations has been expanded from simple to multifactorial stress combinations (MFSCs). Researchers have realized the complexity and necessity of stress combination research and have extensively employed composite gradient methods, multi-omics techniques, and interdisciplinary approaches to integrate laboratory and field experiments. Researchers have studied the response mechanisms of plant reactive oxygen species (ROS), phytohormones, transcription factors (TFs), and other response mechanisms under stress combinations and reached some generalized conclusions. In this article, we focus on the research progress and methodological dynamics of plant responses to stress combinations and propose key scientific questions that are crucial to address, in the context of plant responses to stress assemblages, conserving biodiversity, and ensuring food security. We can enhance the search for universal pathways, identify targets for stress combinations, explore adaptive genetic responses, and leverage high-technology research. This is in pursuit of cultivating plants with greater tolerance to stress combinations and enabling their adaptation to and mitigation of the impacts of climate change.