Upregulation of CoQ shifts ferroptosis dependence from GPX4 to FSP1 in acquired radioresistance.

Acquired radioresistance is the primary contributor to treatment failure of radiotherapy, with ferroptosis is identified as a significant mechanism underlying cell death during radiotherapy. Although resistance to ferroptosis has been observed in both clinical samples of radioresistant cells and cell models, its mechanism remains unidentified. Herein, our investigation revealed that radioresistant cells exhibited greater tolerance to Glutathione Peroxidase 4 (GPX4) inhibitors and, conversely, increased sensitivity to ferroptosis suppressor protein 1 (FSP1) inhibitors compared to their sensitive counterparts. This observation suggested that FSP1 might play a dominant role in the development of radioresistance. Notably, the knockout of FSP1 demonstrated considerably superior efficacy in resensitizing cells to radiotherapy compared to the knockout of GPX4. To elucidate the driving force behind this functional shift, we conducted a metabolomic assay, which revealed an upregulation of Coenzyme Q (CoQ) synthesis and a downregulation of glutathione synthesis in the acquired radioresistance cells. Mechanistically, CoQ synthesis was found to be supported by aarF domain containing kinase 3-mediated phosphorylation of CoQ synthases, while the downregulation of Solute carrier family 7 member 11 led to decreased glutathione synthesis. Remarkably, our retrospective analysis of clinical response data further validated that the additional administration of statin during radiotherapy, which could impede CoQ production, effectively resensitized radioresistant cells to radiation. In summary, our findings demonstrate a dependency shift from GPX4 to FSP1 driven by altered metabolite synthesis during the acquisition of radioresistance. Moreover, we provide a promising therapeutic strategy for reversing radioresistance by inhibiting the FSP1-CoQ pathway.

The effect of trans-provincial immediate reimbursement for healthcare expenses on inequity in the utilization of healthcare services for migrants.

BACKGROUND: Improving the accessibility of public services for migrants is an important endeavor to promote equity in economic and social development. As a response to the large-scale movement of migrants and the fragmentation of China's health insurance system, the Chinese Government has launched a policy of trans-provincial immediate reimbursement for healthcare expenses. The present study hopes to examine the effect of immediate reimbursement policy on the utilization of healthcare services for migrants in China. METHODS: This study used two waves of data from the China Migrants Dynamic Survey (CMDS) collected in 2013 and 2017, with the sample comprising 13,540 individuals. We constructed a difference-in-differences (DID) model to investigate the impact of the policy on the utilization of healthcare services for migrants. Meanwhile, we also analyzed the heterogeneity of the policy effect by grouping the samples by industry, gender, income, and education level. RESULTS: The results found that the trans-provincial immediate reimbursement significantly promoted the probability of migrants' utilization of quality healthcare services (average treatment effect on the treated = 0.072, p < 0.05). Heterogeneity analyses revealed that the policy effect was more pronounced among higher-income and better-educated migrants. In addition, the policy effect was more significant for female migrants, and the benefits were more marked for migrants in high-risk industries. CONCLUSIONS: The trans-provincial immediate reimbursement policy has improved the inequity of healthcare services utilization among migrants as a whole; however, within the migrants, inequity still exists. More attention should also be paid to low-income or low-education groups in future policy design.

Case-control virtual histology elucidates cell types associated with cortical thickness differences in Alzheimer's disease.

Many neuropsychiatric disorders are characterised by altered cortical thickness, but the cell types underlying these changes remain largely unknown. Virtual histology (VH) approaches map regional patterns of gene expression with regional patterns of MRI-derived phenotypes, such as cortical thickness, to identify cell types associated with case-control differences in those MRI measures. However, this method does not incorporate valuable information of case-control differences in cell type abundance. We developed a novel method, termed case-control virtual histology (CCVH), and applied it to Alzheimer's disease (AD) and dementia cohorts. Leveraging a multi-region gene expression dataset of AD cases (n = 40) and controls (n = 20), we quantified AD case-control differential expression of cell type-specific markers across 13 brain regions. We then correlated these expression effects with MRI-derived AD case-control cortical thickness differences across the same regions. Cell types with spatially concordant AD-related effects were identified through resampling marker correlation coefficients. Among regions thinner in AD, gene expression patterns identified by CCVH suggested fewer excitatory and inhibitory neurons, and greater proportions of astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, and endothelial cells in AD cases vs. controls. In contrast, original VH identified expression patterns suggesting that excitatory but not inhibitory neuron abundance was associated with thinner cortex in AD, despite the fact that both types of neurons are known to be lost in the disorder. Compared to original VH, cell types identified through CCVH are more likely to directly underlie cortical thickness differences in AD. Sensitivity analyses suggest our results are largely robust to specific analysis choices, like numbers of cell type-specific marker genes used and background gene sets used to construct null models. As more multi-region brain expression datasets become available, CCVH will be useful for identifying the cellular correlates of cortical thickness across neuropsychiatric illnesses.

Consequences of NMDA receptor deficiency can be rescued in the adult brain.

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 can be restored to wild type by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive functions, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.

Cardiac-specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP-binding proteins.

The mevalonate pathway is essential for cholesterol biosynthesis. Previous studies have suggested that the key enzyme in this pathway, farnesyl diphosphate synthase (FDPS), regulates the cardiovascular system. We used human samples and mice that were deficient in cardiac FDPS (c-Fdps-/- mice) to investigate the role of FDPS in cardiac homeostasis. Cardiac function was assessed using echocardiography. Left ventricles were examined and tested for histological and molecular markers of cardiac remodeling. Our results showed that FDPS levels were downregulated in samples from patients with cardiomyopathy. Furthermore, c-Fdps-/- mice exhibited cardiac remodeling and dysfunction. This dysfunction was associated with abnormal activation of Ras and Rheb, which may be due to the accumulation of geranyl pyrophosphate. Activation of Ras and Rheb stimulated downstream mTOR and ERK pathways. Moreover, administration of farnesyltransferase inhibitors attenuated cardiac remodeling and dysfunction in c-Fdps-/- mice. These results indicate that FDPS plays an important role in cardiac homeostasis. Deletion of FDPS stimulates the downstream mTOR and ERK signaling pathways, resulting in cardiac remodeling and dysfunction. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Separate effects of auditory and visual room size on auditorium seat preference: a virtual reality study.

Audiovisual integrations and interactions happen everywhere, including in music concerts, where combined visual and auditory perception contributes to overall enjoyment. Thirty-three participants evaluated their overall subjective preference at various seats in four virtual auditoria, which comprised congruent and incongruent auditory and visual renders of two auditoria that differ only in size. Results show no significant difference between participants who completed the experiment in a fully calibrated and standardized laboratory environment and participants who completed remotely using various VR equipment in various environments. Both visual and auditory auditorium size have significant main effects, but no interaction. The larger hall is preferred for both conditions. Audiovisual congruency does not significantly affect preference.

Iron-doped cerium/nucleotide coordination polymer as highly efficient peroxidase mimic for colorimetric detection of fluoride ion.

A new coordination polymer (Ce-Fe-GMP) with excellent catalytic activity was prepared by a facile route, which was further applied to the detection of F- with high sensitivity and selectivity. The simple doping of Fe3+ into the coordination network can easily modulate the mixing ratio of Ce3+ and Ce4+ in the presence of H2O2, which can extremely improve the catalytic ability of Ce-Fe-GMP. Based on the synergistic effect, the Ce-Fe-GMP with dual-active sites shows better peroxidase activity than that of Ce-GMP. In addition, we found that F- can inhibit the peroxidase activity of Ce-Fe-GMP because of the coordination structure fragmentation and the regulation of Ce3+/Ce4+ ratio. Therefore, different concentrations of F- can be detected by the colorimetric reaction based on this mechanism. The absorption at 652 nm displays a good linear relationship versus the concentration of F- over the range 2.0 to 100.0 µM. Furthermore, F- in real mineral-mixed samples can be measured with satisfactory results. The colorimetric strategy based on the peroxidase activity of Ce-Fe-GMP is simple and low-cost, which shows the potential applications in the field of on-site environment measurement.

A Novel Patient Values Tab for the Electronic Health Record: A User-Centered Design Approach.

BACKGROUND: The COVID-19 pandemic has shined a harsh light on a critical deficiency in our health care system: our inability to access important information about patients' values, goals, and preferences in the electronic health record (EHR). At Memorial Sloan Kettering Cancer Center (MSK), we have integrated and systematized health-related values discussions led by oncology nurses for newly diagnosed cancer patients as part of routine comprehensive cancer care. Such conversations include not only the patient's wishes for care at the end of life but also more holistic personal values, including sources of strength, concerns, hopes, and their definition of an acceptable quality of life. In addition, health care providers use a structured template to document their discussions of patient goals of care. OBJECTIVE: To provide ready access to key information about the patient as a person with individual values, goals, and preferences, we undertook the creation of the Patient Values Tab in our center's EHR to display this information in a single, central location. Here, we describe the interprofessional, interdisciplinary, iterative process and user-centered design methodology that we applied to build this novel functionality as well as our initial implementation experience and plans for evaluation. METHODS: We first convened a working group of experts from multiple departments, including medical oncology, health informatics, information systems, nursing informatics, nursing education, and supportive care, and a user experience designer. We conducted in-depth, semistructured, audiorecorded interviews of over 100 key stakeholders. The working group sought consensus on the tab's main content, homing in on high-priority areas identified by the stakeholders. The core content was mapped to various EHR data sources. We established a set of high-level design principles to guide our process. Our user experience designer then created wireframes of the tab design. The designer conducted usability testing with physicians, nurses, and other health professionals. Data validation testing was conducted. RESULTS: We have already deployed the Patient Values Tab to a pilot sample of users in the MSK Gastrointestinal Medical Oncology Service, including physicians, advanced practice providers, nurses, and administrative staff. We have early evidence of the positive impact of this EHR innovation. Audit logs show increasing use. Many of the initial user comments have been enthusiastically positive, while others have provided constructive suggestions for additional tab refinements with respect to format and content. CONCLUSIONS: It is our challenge and obligation to enrich the EHR with information about the patient as a person. Realization of this capability is a pressing public health need requiring the collaboration of technological experts with a broad range of clinical leaders, users, patients, and families to achieve solutions that are both principled and practical. Our new Patient Values Tab represents a step forward in this important direction.

The epidermis-specific cyclin CYCP3;1 is involved in the excess brassinosteroid signaling-inhibited root meristem cell division.

Cell division is precisely regulated and highly tissue-specific; studies have suggested that diverse signals in the epidermis, especially the epidermal brassinosteroids (BRs), can regulate root growth. However, the underlying molecular mechanisms that integrate hormonal cues such as BR signaling with other endogenous, tissue-specific developmental programs to regulate epidermal cell proliferation remain unclear. In this study, we used molecular and biochemical approaches, microscopic imaging and genetic analysis to investigate the function and mechanisms of a P-type cyclin in root growth regulation. We found that CYCP3;1, specifically expressed in the root meristem epidermis and lateral root cap, can regulate meristem cell division. Mitotic analyses and biochemical studies demonstrated that CYCP3;1 promotes cell division at the G2-M duration by associating and activating cyclin-dependent kinase B2-1 (CDKB2;1). Furthermore, we found that CYCP3;1 expression was inhibited by BR signaling through BRI1-EMS-SUPPRESSOR1 (BES1), a positive downstream transcription factor in the BR signaling pathway. These findings not only provide a mechanism of how root epidermal-specific regulators modulate root growth, but also reveal why the excess of BRs or enhanced BR signaling inhibits cell division in the meristem to negatively regulate root growth.

Correlations between quantitative parameters of contrast-enhanced ultrasound and vasculogenic mimicry in murine tumor model: a novel noninvasive technique for assessment?

OBJECTIVE: Vasculogenic mimicry (VM) is a novel mechanism of tumor blood supply distinct from endothelial vessel (EV). VM is associated with malignancy, invasion, metastasis, and poor prognosis. Hitherto a noninvasive method for the assessment of VM in vivo has been lacking. METHODS: Contrast-enhanced ultrasound (CEUS) was performed to evaluate the quantitative parameters of tumors in mice. CD31 immunohistochemistry-Periodic Acid-Schiff double staining was conducted to identify the VM or EV in tumor tissues. Correlations between perfusion parameters and VM density was analyzed by Pearson correlation test. RESULTS: By the 15th day after tumor inoculation, the EV and VM density was 31.15 ± 7.14 and 14.11 ± 2.99 per 200× field. The maximal intensity (IMAX) was 301.19 ± 191.56%, and the rise time (RT), time to peak (TTP) and mean transit time (mTT) were 17.38 ± 7.82 s, 20.27 ± 9.61 s and 58.09 ± 26.44 s, respectively. VM density positively correlated to RT (r = 0.3598, P = 0.0226), TTP (r = 0.3733, P = 0.0177) and mTT(r = 0.6483, P <  0.0001), whereas EV density positively correlated to IMAX (r = 0.4519, P = 0.0034). The vascular diameter of VM was substantially larger than that of EV (43.81 ± 5.88 µm vs 11.21 ± 4.13 µm). CONCLUSION: Three quantitative parameters related to VM were obtained and the relationships between CEUS and VM were established. CEUS might thus provide a novel noninvasive method to assess VM in vivo.

Biochar Addition Enhances Phenanthrene Fixation in Sediment.

Biochar is believed to be promising for soil contaminant stabilization due to its large adsorption capacity. However, study in sediment is rare, especially with the aging effect. In the present study, a plant biomass-derived biochar was added to phenanthrene polluted sediment, in order to investigate its performance in sediment remediation. During the incubation period of 60 days, it was observed that the partition coefficient of phenanthrene increased in sediment either with or without biochar addition, as a result of aging process. Whilst, the biochar-added sediments showed much higher partition coefficients, as well as more curved adsorption isotherms, suggesting larger retention of the contaminant. Under the extreme extraction by strong surfactant, the release ratio of phenanthrene from polluted sediment was significantly reduced from 60% to 5% by 0.5% (w/w) addition of biochar. These results suggested that biochar would be applicable for improving the adsorption of organic pollutant in sediment, and the adsorbed organic pollutant would be stably fixed during aging as a result of the increased affinity.

GSK3-like kinases positively modulate abscisic acid signaling through phosphorylating subgroup III SnRK2s in Arabidopsis.

Arabidopsis glycogen synthase kinase 3 (GSK3)-like kinases have versatile functions in plant development and in responding to abiotic stresses. Although physiological evidence suggested a potential role of GSK3-like kinases in abscisic acid (ABA) signaling, the underlying molecular mechanism was largely unknown. Here we identified members of Snf1-related kinase 2s (SnRK2s), SnRK2.2 and SnRK2.3, that can interact with and be phosphorylated by a GSK3-like kinase, brassinosteroid insensitive 2 (BIN2). bin2-3 bil1 bil2, a loss-of-function mutant of BIN2 and its two closest homologs, BIN2 like 1 (BIL1) and BIN2 like 2 (BIL2), was hyposensitive to ABA in primary root inhibition, ABA-responsive gene expression, and phosphorylating ABA Response Element Binding Factor (ABF) 2 fragment by in-gel kinase assays, whereas bin2-1, a gain-of-function mutation of BIN2, was hypersensitive to ABA, suggesting that these GSK3-like kinases function as positive regulators in ABA signaling. Furthermore, BIN2 phosphorylated SnRK2.3 on T180, and SnRK2.3(T180A) had decreased kinase activity in both autophosphorylation and phosphorylating ABFs. Bikinin, a GSK3 kinase inhibitor, inhibited the SnRK2.3 kinase activity and its T180 phosphorylation in vivo. Our genetic analysis further demonstrated that BIN2 regulates ABA signaling downstream of the PYRABACTIN RESISTANCE1/PYR1-LIKE/REGULATORY COMPONENTS OF ABA RECEPTORS receptors and clade A protein phosphatase 2C but relies on SnRK2.2 and SnRK2.3. These findings provide significant insight into the modulation of ABA signaling by Arabidopsis GSK3-like kinases.

Differential effects of NMDA receptor antagonism on spine density.

The authors demonstrate that different NMDAR antagonists (ketamine and MK-801) have varying effects on spine density depending on dose, drug regimen, and brain region. While acute ketamine treatment increases cortical spine density in mice, subchronic exposure to either drug reduces spine density in both the cortex and striatum.

Risk of atrial fibrillation in patients with multiple myeloma: what is known and directions for future study.

BACKGROUND: Multiple myeloma (MM) is a prevalent hematological tumor, and recent clinical data have highlighted the significance of atrial fibrillation (AF) as a crucial complication affecting the prognosis of MM. This review aims to consolidate findings from published clinical studies, focusing on the epidemiological characteristics of AF in MM patients and the associated risks arising from MM treatments such as autologous hematopoietic stem cell transplantation, proteasome inhibitors, and immunomodulatory agents. MAIN BODY: While existing data partially demonstrate a strong correlation between MM and AF, further clinical studies are necessary to comprehensively investigate their association. These studies should encompass various aspects, including the risk of AF resulting from MM treatment, the impact of AF-induced embolic events and heart failure on MM prognosis, as well as the influence of AF management methods like catheter ablation or left atrial appendage closure on MM prognosis. CONCLUSIONS: The supplementation of future data will provide more precise guidance for managing MM patients. By incorporating information regarding AF risk associated with MM treatment and examining the effects of AF management strategies on MM prognosis, healthcare professionals can enhance their decision-making process when caring for individuals with MM.

Effect of long-term care insurance in a pilot city of China: Health benefits among 12,930 disabled older adults.

BACKGROUND: The surge of disabled older people have brought enormous burdens to society. The aim of this study was to examine the impact of long-term care insurance (LTCI) implementation on mortality and changes in physical ability among disabled older adults. METHODS: This was a prospective observational study based on data from the government-led LTCI program in a pilot city of China from 2017 to 2021. Administrative data included the application survey of activities of daily living (ADL), the baseline characteristics and all-cause mortality. Return visit surveys of ADL were conducted between August 2021 and December 2021. A regression discontinuity model was used to analyze the impact of LTCI on mortality. RESULTS: A total of 12,930 individuals older than 65 years were included in this study, and 10,572 individuals were identified with severe disability and participated in the LTCI program. LTCI implementation significantly reduced mortality by 5.10 % (95 % CI, -9.30 % to -0.90 %) and extended the survival time by 33.74 days (95 % CI, 13.501 to 53.970). The ADL scores of the LTCI group dropped by 2.5 points on average, while the ADL scores of those did not participated in LTCI dropped by 25.0 points. The heterogeneity analysis revealed that the impact of LTCI on mortality reduction was more significant among females, individuals of lower age, those who were married, cared for by family members, and who lived in districts with rich care resources. CONCLUSIONS: LTCI implementation had a favorable impact on the mortality and physical ability of participants.

Severe hypoxemia after radiofrequency ablation for atrial fibrillation in palliatively repaired tetralogy of Fallot: A case report.

BACKGROUND: Patients with tetralogy of Fallot (TOF) often have arrhythmias, commonly being atrial fibrillation (AF). Radiofrequency ablation is an effective treatment for AF and does not usually cause severe postoperative hypoxemia, but the risk of complications may increase in patients with conditions such as TOF. CASE SUMMARY: We report a young male patient with a history of TOF repair who developed severe hypoxemia after radiofrequency ablation for AF and was ultimately confirmed to have a new right-to-left shunt. The patient subsequently underwent atrial septal occlusion and eventually recovered. CONCLUSION: Radiofrequency ablation may cause iatrogenic atrial septal injury; thus possible complications should be predicted in order to ensure successful treatment and patient safety.

Piezoelectric hydrogel for treatment of periodontitis through bioenergetic activation.

The impaired differentiation ability of resident cells and disordered immune microenvironment in periodontitis pose a huge challenge for bone regeneration. Herein, we construct a piezoelectric hydrogel to rescue the impaired osteogenic capability and rebuild the regenerative immune microenvironment through bioenergetic activation. Under local mechanical stress, the piezoelectric hydrogel generated piezopotential that initiates osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLSCs) via modulating energy metabolism and promoting adenosine triphosphate (ATP) synthesis. Moreover, it also reshapes an anti-inflammatory and pro-regenerative niche through switching M1 macrophages to the M2 phenotype. The synergy of tilapia gelatin and piezoelectric stimulation enhances in situ regeneration in periodontal inflammatory defects of rats. These findings pave a new pathway for treating periodontitis and other immune-related bone defects through piezoelectric stimulation-enabled energy metabolism modulation and immunomodulation.

CHRNA5 links chandelier cells to severity of amyloid pathology in aging and Alzheimer's disease.

Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to neuropathology in Alzheimer's Disease (AD). Protective and cognitive-enhancing roles for the nicotinic α5 subunit have been identified, but this gene has not been closely examined in the context of human aging and dementia. Therefore, we investigate the nicotinic α5 gene CHRNA5 and the impact of relevant single nucleotide polymorphisms (SNPs) in prefrontal cortex from 922 individuals with matched genotypic and post-mortem RNA sequencing in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We find that a genotype robustly linked to increased expression of CHRNA5 (rs1979905A2) predicts significantly reduced cortical ß-amyloid load. Intriguingly, co-expression analysis suggests CHRNA5 has a distinct cellular expression profile compared to other nicotinic receptor genes. Consistent with this prediction, single nucleus RNA sequencing from 22 individuals reveals CHRNA5 expression is disproportionately elevated in chandelier neurons, a distinct subtype of inhibitory neuron known for its role in excitatory/inhibitory (E/I) balance. We show that chandelier neurons are enriched in amyloid-binding proteins compared to basket cells, the other major subtype of PVALB-positive interneurons. Consistent with the hypothesis that nicotinic receptors in chandelier cells normally protect against ß-amyloid, cell-type proportion analysis from 549 individuals reveals these neurons show amyloid-associated vulnerability only in individuals with impaired function/trafficking of nicotinic α5-containing receptors due to homozygosity of the missense CHRNA5 SNP (rs16969968A2). Taken together, these findings suggest that CHRNA5 and its nicotinic α5 subunit exert a neuroprotective role in aging and Alzheimer's disease centered on chandelier interneurons.

Air pollution and timing of childbirth: a retrospective survey analysis based on birth registration data of Chinese newborns.

Objectives: Currently, there is a lack of research on whether people will take action to avoid the harm of air pollution and the heterogeneous behavior of different groups. The goal of this paper is to examine the effects of air pollution on the resulting differential effects on newborns and the timing of pregnancy. Methods: Based on a survey of newborns in a total of 32 hospitals in 12 cities across China in 2011, and after matching with city-level air pollution data, a multiple regression statistical method is then used to examine how the pollution level in a certain period is related to the number of conceptions in that certain period, after controlling for region and season fixed effects. Results: We first demonstrate that exposure to air pollution during pregnancy is associated with a significant increase in adverse birth outcomes. Most importantly, the empirical results show that the number of conceptions decreased significantly during periods of severe air pollution. Conclusion: Evidence suggests that air pollution may be causing some families to delay conception to reduce the possible adverse impact on neonatal outcomes. This helps us to understand the social cost of air pollution more, and then make more accurate environmental policies.

Efficacy and safety of negative allosteric modulators of 5-hydroxytryptamine 2A receptors in the treatment of Alzheimer's disease psychosis: A systematic review and meta-analysis.

BACKGROUND: Psychosis is a very common feature of Alzheimer's disease (AD) that can emerge as the neurodegenerative disease progresses. The 5-hydroxytryptamine (5-HT2A) receptors are located postsynaptically to serotonergic neurons in the frontal cortex and mediate both excitatory and inhibitory neurotransmissions. However, the effectiveness and tolerance of negative modulators of 5-HT2A receptors in Alzheimer's disease psychosis (ADP) are uncertain. OBJECTIVES: To detect the negative modulators of the 5-HT2A receptor as a cure for ADP. MATERIAL AND METHODS: The primary outcome indicator was the total Neuropsychiatric Inventory (NPI) score. Other prognostic indicators included Mini-Mental State Examination (MMSE), the Katz Index of Independence in Activities of Daily Living (KATZ), the discontinuation rate, and adverse events. RESULTS: Compared to placebo, 5-HT2A inverse agonists significantly reduced the NPI total score, the KATZ and the MMSE score. The pooled odds ratio (OR) was 1.64 (95% confidence interval (95% CI): 1.01-2.65) and the heterogeneity variance was estimated at Tau2 = 0.52 with an I2 value of 90%, a χ2 value of 111.31, p = 0.04, and z-value of 2.01. The risk difference (RD) between the 5-HT2A receptor negative modulators and placebo groups was 0.12 (95% CI: 0.00-0.24) and the heterogeneity was estimated at Tau2 = 0.03, χ2 value of 127.23, degrees of freedom (df) value of 9, I2 value of 93%, z-value of 1.92, and p-value of 0.01 (<0.05). CONCLUSION: Our results suggest that negative modulators of 5-HT2A receptors are beneficial and well-tolerated in the treatment of ADP.