The application of molecular tumor profiles in clinical decision making remains a challenge. To aid in the interpretation of complex biomarkers, molecular tumor boards (MTBs) have been established worldwide. In the present study, we show that a multidisciplinary approach is essential to the success of MTBs. Our MTB, consisting of pediatric oncologists, pathologists, and pharmacists, evaluated 115 cases diagnosed between March 2016 and September 2021. If targetable mutations were identified, pharmacists aided in the evaluation of treatment options based on drug accessibility. Treatable genetic alterations detected through molecular testing most frequently involved the cell cycle. For 85% of the cases evaluated, our MTB provided treatment recommendations based on the patient’s history and results of molecular tumor testing. Only three patients, however, received MTB-recommended targeted therapy, and only one of these patients demonstrated an improved clinical outcome. For the remaining patients, MTB-recommended treatment often was not administered because molecular tumor profiling was not performed until late in the disease course. For the three patients who did receive MTB-recommended therapy, such treatment was not administered until months after diagnosis due to physician preference. Thus, the education of healthcare providers regarding the benefits of targeted therapy may increase acceptance of these novel agents and subsequently improve patient survival. Pediatric oncology has witnessed a rise in the development and use of targeted therapies, a trend which predictably aligns with the advancements and improved accessibility of whole-genome sequencing. Correlative studies linking genomic variants to clinical significance in malignancies are the foundation of “precision oncology” and have driven the expansion of precision clinical trials . This moMTBs draw on expertise across various disciplines to translate genetic profiles into actualized precision oncology. These multidisciplinary teams commonly include medical and radiation oncologists, pathologists, geneticists, bioinformaticians, and molecular biologists . HoweverOur MTB was established in 2019 at the initiative of our pediatric oncology team, with a goal to deliver greater awareness, edification, and applicable skill in precision oncology. Further, the MTB aimed to create access to alternative, cutting-edge treatment options for our patients. ALK p.F1174L mutation in neuroblastoma [TSC2 frameshift mutation in osteosarcoma [MED12 p.G44D mutation in Wilms tumor [At our institution, genomic profiling has been accomplished via Foundation One Medicine, Inc. to detect four main classes of genomic alterations: DNA and RNA genes implicated in solid tumors and/or hematologic cancers via NGS, microsatellite status (MS) via NGS, tumor mutation burden (TMB) via NGS, and programmed death ligand-1 (PDL-1) expression via immunohistochemistry. If targetable mutations are present, clinical pharmacists lead in weighing treatment options and exploring the logistics and feasibility of drug access. The targeted therapies recommended by the MTB are stratified according to three different levels of evidence: Level 1 recommendations have established clinical utility, targeting mutations that have been established in the literature as diagnostic, prognostic, and/or predictive of management in the specific tumor type tested, with an example including the blastoma . Level 2osarcoma . Level 3ms tumor . The finThe inclusion of pharmacists in our institutional MTB added a unique skill set to the multidisciplinary team by providing a medication-driven perspective in approaching the genetic findings and suggesting targeted therapies as applicable in a pediatric setting. They also contributed via their assessments of mechanisms, interactions, side effects, dosage forms, availability, and cost. Pharmacists also assist in literature searches, assessing investigational options, and facilitating discussions with pharmaceutical companies on unpublished data necessary for drug administration.In particular, if the drug was not available commercially, meaning that it was not approved by the Food and Drug Administration (FDA) or the patient’s insurance denied coverage, obtaining the drug via an investigational route became essential. In our experience, these medications were obtained via one of two mechanisms: an established clinical trial or expanded access through the FDA. If a trial was open, enrolling, and the patient qualified, we opened the trial at our site. Otherwise, an attempt was made to utilize the expanded access process established by the FDA. The pharmacist communicated with the drug company to obtain permission for the patient to receive the drug. The company allowed it if no clinical trials were available, and they believed the patient could benefit. If approval was granted, the request then went to the FDA, which weighed the risk versus the benefits for the patient and then decided on approval. If the FDA approved, our institution’s institutional review board also had to approve the protocol for use in the patient. Once all approvals had been received, the drug was ordered and administered. This route was both financially beneficial, as the drug was being provided at no cost, and opened up the potential for therapies that would otherwise not have been an option.The expertise of our clinical pharmacists, an essential component of our multidisciplinary approach, allowed significant cost avoidance in the management of each patient, achieved via single-use, FDA-approved targeted therapy. Financial burden is removed not only from our institution, but also our patients, while informing the use and outcomes of these new yet promising indications. The MTB evaluated 115 cases diagnosed between March 2016 and September 2021. The most common types of cancer evaluated by the MTB included osteosarcoma, leukemia/lymphoma, and sarcomas other than osteosarcoma A. SuppleTP53 , MLL , and CDKN2A/B . Many of the types of malignancy evaluated by the MTB only had one patient , or no common genomic findings were found among multiple patients with the same type of malignancy . Of note, out of the sixteen patients with osteosarcoma, 43.8% (7/16) exhibited a TP53 mutation, 43.8% (7/16) exhibited a C17orf39 mutation, 31.3% (5/16) exhibited a CCNE1 mutation, and 25% (4/16) exhibited an RB1 mutation. Other mutations were shared by patients, including, but not limited to, mutations in CCND3 (25% or 4/16), AURKA/B (25% or 4/16), CDK4 (18.8% or 3/16), and GNAS (18.8% or 3/16). Among nine patients with Ewing’s sarcoma, 88.9% (8/9) exhibited a EWSR1-FLI1 fusion. Out of nine patients with Langerhans cell histiocytosis, 44.4% (4/9) exhibited a MAP2K1 mutation, and 44.4% (4/9) exhibited a BRAF mutation.Using Foundation One Medicine testing, The therapy recommendations for the treatable alterations were classified as follows: 98 (52%) level 1 recommendations, 49 (26%) level 2 recommendations, and 42 (22%) level 3 recommendations. Overall, 3 of 82 patients received targeted therapy based on their identified alterations (“matched”). Of the 34 cases without treatable alterations, 6 were due to a lack of detectable genetic mutations, 9 were due to sample failure, and the remaining 25 patients had detectable but non-treatable genetic alterations.Among the 115 patients with previously treated disease and for whom the MTB recommended targeted treatment, three were subsequently treated with a MTB-recommended therapy . Here, we highlight the treatment histories of these three cases in which the recommendations of the MTB influenced management . AlthougRUNX1-FPL22 and RUNX1-MECOM gene fusions, an FLT3 mutation, a mitogen-activated extracellular signal-related kinase (MEK) mutation, and several other mutations of unknown clinical significance, including KRAS, NRAS, ATRX, BLM, and WT1 variants. Given his FLT-3 status, midostaurin, a kinase inhibitor approved by the FDA to treat FLT-3 mutation-positive AML, was added on day 10 of the second induction attempt, administered for the next 14 days, and repeated on days 8–21 of each cycle.Patient 2 was an 18-year-old male diagnosed with CNS3 acute myeloid leukemia (AML). Per an AML treatment protocol, the patient received induction chemotherapy but was noted to have 54% blasts at the end of the induction phase with low-dose ADE  followed by IDA-FLAG . The patient also received weekly intrathecal triple therapy for CNS involvement. Genomic profiling revealed 2 on days 1-5, venetoclax at a dose of 100 mg on days 1–14, and gilteritinib at a dose of 120 mg on days 1–28. Administration of venetoclax was ceased early on day 8 at the patient’s request due to concerns of prolonged myelosuppression.After a minimal residual disease (MRD) analysis via flow cytometry revealed 9.4% abnormal myeloblasts, a third induction attempt was initiated with cytarabine (days 1–4) and mitoxantrone (days 3–5). Due to persistent residual disease, a fourth induction attempt was initiated several weeks later consisting of cladribine ×5 days, idarubicin with dexrazoxane ×3 days, cytarabine ×3 days, venetoclax ×7 days, and gilteritinib ×14 days (substituting for midostaurin). After the fourth induction attempt, MRD was determined as 7%, at which point the lack of expectation of cure was explained, and the patient understood the need to shift to supportive care. The following month, the patient received individualized therapy with azacitidine dosed at 75 mg/mMEK inhibitors. Thus, upon the recommendation of the MTB, the patient began therapy with trametinib; however, this was stopped after a month due to signs of rhabdomyolysis. Due to a drastic blast count increase from 3% to 24%, trametinib was ultimately restarted at 50% of the original dose. The patient passed away three months later, one year after initial diagnosis.Based on the genomic profiling results, the MTB recommended therapy with binimetinib, cobimetinib, and/or trametinib, all of which are Patient 49 was an 18-year-old female diagnosed with leiomyosarcoma. She initially presented with a mass of the right calf and significant hypoxia and chest pain. Biopsy of the calf mass demonstrated leiomyosarcoma. The patient’s respiratory symptoms prompted imaging, which revealed lung lesions that were positron emission tomography (PET)-avid, consistent with tumor thrombi. The patient was extensively anticoagulated with heparin, rivaroxaban, and placement of an inferior vena cava filter and received one cycle of ifosfamide and adriamycin. During this cycle, she experienced complications of right heart strain requiring aggressive management with nitrous oxide, milrinone, and epinephrine. One month later, the patient was started on gemcitabine and docetaxel. She initially demonstrated clinical improvement but then experienced progression of disease after two cycles.PPFIBO1-ALK gene fusion, a CD36 N53fs*24 mutation, an anaplastic lymphoma kinase (ALK) mutation, and loss of CDKN2A/B. Based on these results, the MTB recommended therapy with entrectinib, a ROS1 and NTRK inhibitor, alectinib, an ALK inhibitor, brigatinib, an ALK and EGFR inhibitor, ceritinib, an ALK inhibitor, crizotinib, an ALK inhibitor, and/or lorlatinib, an ALK and ROS1 inhibitor. Upon the recommendation of the MTB, the patient began therapy with ceritinib. Simultaneously, she also received radiation therapy (45 Gy) to the right proximal calf, resulting in shrinkage of the lower extremity mass. Improvement in the size and PET-avidity of the lung metastases was also observed. Three months later, the calf mass was surgically resected with positive margins. She then received additional radiation therapy (15 Gy) directed at the lungs and the tumor bed in the area of positive margin on the right calf . Four months later, evidence of progressive disease was identified on imaging and confirmed via thoracoscopic biopsy. For her given apparent resistance to ceretinib, the patient was switched to lorlatinib, a third-generation ALK inhibitor, at a dose of 100 mg daily. Lorlatinib was eventually held due to complications of grade 1–2 edema. The patient passed away six months later, nearly two years after initial diagnosis.Genomic profiling revealed a Patient 59 was a 25-year-old female diagnosed with osteosarcoma of the left femur at age 12. She was initially treated with a MAP  regimen. Six years later, a right intrathoracic metastasis was identified. The intrathoracic metastasis was initially managed with neoadjuvant ifosfamide and etoposide, resection with positive margins, and two cycles of adjuvant chemotherapy.VEGFR inhibitor, as salvage therapy, which was later stopped entirely due to gastrointestinal toxicity. The patient also received six cycles of doxorubicin with an initial positive response, followed by Yttrium-90 radioembolization of both hepatic lobes.While awaiting the initiation of radiation therapy, tumor regrowth was identified, requiring resection of a right lower lobe mass demonstrating parenchymal and pleural involvement with positive margins, which was followed with adjuvant radiation therapy. One year later, recurrence at the same site was identified and managed with gemcitabine and docetaxel; the patient was six months pregnant at the time. Complications of this treatment course included the development of peripheral edema and a pleural effusion causing significant dyspnea, both of which resolved with a pleurocentesis. Two months later, a progressive tumor in the right pleural base and dome of the liver was detected. The patient was started on pazopanib, a CDK4, RICTO, C17orf39, CCND3, and CDKN2A, loss of DAXX, and amplification of KDM4C. Based on these results, the MTB recommended therapy with palbociclib and ribociclib, both of which are CDK4/6 inhibitors. Thus, upon the recommendation of the MTB, the patient began therapy with palbociclib. After a year on palbociclib, she demonstrated increasing symptoms and signs of disease progression on imaging; therefore, therapy with regorafenib, another VEGFR inhibitor, was initiated. The patient passed away six months later, twelve years after initial diagnosis.Genomic profiling revealed mutations in MTBs are at the forefront of the shift towards the ever-increasing use of personalized medicine. Mounting clinical evidence indicates that genetically-informed (“matched”) anticancer therapy offers improved clinical benefits compared to non-informed (“non-matched”) therapy. The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial was the first biomarker-based study, and it examined 255 previously-treated lung cancer patients . In thisPer the American Cancer Society, the five-year survival rate for AML patients younger than age 20 is 68%, compared to 26% for patients aged 20 and older, suggesting that young age is a favorable factor impacting the overall survival of AML patients . AlthougTP53, ATRX, SMARCA4, and BRAF, indicating that recurrent tumors may be seeded by cells of the initial tumor at an early stage of development, and each tumor accumulates its own set of genomic alterations [Despite the numerous potential benefits of precision oncology, there are limitations that must be addressed. Specifically, targeted immunotherapies for recurrent disease may fail in part because the genomic alterations driving the growth of the recurrence may be unique compared to those that were present in the initial tumor. In a study conducted by Johnson et al., the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients were sequenced . In 43% erations .RB and AKT-mTOR pathways that are classically associated with TMZ-induced tumorigenesis [mTOR and MEK/RAF pathways [EGFR inhibitors, such as erlotinib and gefitinib, has been demonstrated to confer drug resistance through the acquisition of a specific mutation, p.T790M variant [Within the same study, tumors from 6 of the 10 patients treated with temozolomide (TMZ) followed a distinct evolutionary path to a high-grade glioma . At recuigenesis . Similarpathways ,17. Nota variant . ConsequThe outcomes of our study and others raise the question of whether primary or recurrent, metastatic lesions are more appropriate for genomic profiling. Unfortunately, in our study, genetic testing was often conducted months after the initial diagnosis. Thus, the MTB was limited to the analysis of genomic alterations identified in relapsed or previously-treated tumors, rather than those of the primary tumor, a shortcoming that we have attempted to overcome by encouraging the early performance of tumor genomic profiling.For example, in regards to patient 2, the tumor did not undergo genetic testing until 8 months after the initial diagnosis. Thus, the limited efficacy of the recommended therapy (trametinib) could be attributed to this late administration, as the patient had already received four rounds of induction chemotherapy. Similar to patient 2, patient 59 did not undergo tumor genomic profiling and receive targeted therapy until four years after initial diagnosis. Thus, future trials examining the impact of precision oncology may need to re-biopsy the malignancy multiple times throughout a patient’s disease course to ensure that the results of molecular analysis, which are used in clinical decision making, are most representative of the evolving heterogeneity of the tumor.Given that the MTB at our children’s hospital is fairly new, the MTBs at other institutions, such as the University of California San Diego (UCSD) Moores Cancer Center, provided insight into areas of improvement for our MTB. Similarly to our MTB, the physicians at UCSD ultimately made decisions regarding management in conjunction with the patients, even if such decisions did not follow the recommendations of the MTB, which were considered simply advisory . In our A study conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrates the need for standardization of the evidence supporting MTB recommendations . TargeteA systematic analysis of 40 studies, including 6,303 cases discussed in MTBs globally, demonstrated that the core members of an MTB should include clinical oncologists (present in 100% of studies) and pathologists (90.6%) . Other cOf these 40 studies, the mean turnaround time from when genomic profiling was requested to when MTB recommendations were provided was 38.4 days, with a range of 12.4 to 86 days . The medThe present study demonstrated the utility of a multidisciplinary approach and highlighted the need to perform genetic profiling and initiate matched therapy immediately after tumor detection. Our primary aim in describing the formation of our MTB and the application of our recommendations to three cases is to serve as a model to other institutions, particularly smaller, non-academic institutions such as ours, who may be considering establishing a MTB. In the future, we hope to publish a more comprehensive review with a larger sample size. Future precision oncology studies should also standardize MTB recommendations to maximize those based on level 1, or published evidence. Precision medicine will predictably become a pillar of standard care in pediatric oncology to meet the growing demand for alternative treatments that surpass traditional chemotoxic agents in potency and side effect profile. In the presence of an increasingly expansive and complex biomarker landscape, there is urgency to establish the interdisciplinary foundation of MTBs.


Primary thyroid lymphoma (PTL) occurs rarely, its diagnosis is a challenge, and the prognosis of these patients depends on the time of diagnosis. Even though fine-needle aspiration cytology (FNAC) is recognized as the most accurate tool for detecting thyroid malignancies, its sensitivity for PTL is poor. Both clinical and ultrasound presentation of PTL can be atypical, and laboratory tests fail to furnish relevant data. Consequently, the reliability of a cytopathologist facing PTL can be poor, even when he is aware of its clinical information. In addition, the cases described in the literature are extremely rare and fragmentary, and consequently, the molecular data currently available for this neoplasm are practically negligible. Here, we present a case report in order to discuss the intrinsic limitations in achieving a final diagnosis of PTL and how using molecular diagnostics to identify potential mutational models can improve the evaluation of this neoplasm.  Primary thyroid lymphoma (PTL) accounts for 1 to 5% of all thyroid malignancies and up to 2.5% of all extranodal non-Hodgkin lymphomas . The mosA 67-year-old man noticed a rapidly growing palpable neck mass corresponding to the right thyroid lobe. After the initial practitioner and surgeon examination, the surgical excision was indicated, and a fine-needle aspiration cytology (FNAC) and core needle biopsy (CNB) were planned, to better tailor the surgical approach . In particular, for the FNA, a 23-gauge needle was utilized, while for the CNB, a 21-gauge cutting needle was employed, as previously described ,11. Two Clinical data known before FNAC and CNB included: (1) autoimmune hypothyroidism on levothyroxine therapy (0.1 mg/d), with a current skewed TSH at 8.0 mlU/L; (2) growth of the lesion in 2 days to a solid mass; (3) onset of hoarseness and dyspnea; (4) at ultrasound (US), replacement of the right thyroid lobe by a 6 cm nodule, with poorly defined edges, strong hypoechogenicity, sparse internal echoes, heterogeneous and mild peripheral vascularization, and intense posterior echo ; (5) at ® platform  using a coverage >500×. All results were analyzed using the Myriapod NGS Data Analysis Software (version 5.0.8) (Diatech Pharmacogenetics), and a minimum variant allele frequency (VAF) of 5% was applied for variant filtering. Each variant was investigated for its potential pathogenic role, using the publicly available databases Catalogue of Somatic Mutations in Cancer (COSMIC) “https://cancer.sanger.ac.uk/cosmic (accessed on 10 April 2023)”, ClinVar “https://www.ncbi.nlm.nih.gov/clinvar/ (accessed on 10 April 2023)”, and the bioinformatic software VarSome “https://varsome.com/ (accessed on 10 April 2023)”.Following the above information, at the time of FNAC, several diagnostic hypotheses could be considered: papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, goiter due to the uncorrected autoimmune hypothyroidism, metastasis from other organs, primary thyroid lymphoma, or lymphoma invading the thyroid gland. Both the cytopathologist and the surgeon were aware that the reliability of FNAC in these lesions was quite different, being high in papillary carcinoma and metastases from other cancers, and low/poor in the other conditions. Calcitonin was proven normal, and therefore, the scenario of a medullary carcinoma was virtually not possible. Then, FNAC was performed, and the samples showed a discrete population of round lymphocytes, two to three times larger than normal mature lymphocytes, and nuclei with finely dispersed chromatin, with scanty and pale cytoplasm. Occasional clusters of thyroid follicular cells were seen. The FNAC report was of the high-risk indeterminate category, namely TIR3B, according to the Italian classification . The impThe results of the analysis indicated the presence of an insertion in exon 20 of ERBB2 gene c.2313_2324dupATACGTGATGGC  with a VAF of 37.84% and classified as likely pathogenic according to the ACMG guidelines .Diagnosing PTL is still a challenge. There is no typical clinical presentation, there are no specific US features, and the cytological examination hides many pitfalls. Therefore, when we are facing a patient with a rapidly growing neck mass, we should consider several scenarios. The accuracy of the cytopathologic diagnosis of primary malignant lymphoma of the thyroid depends on several factors, such as the adequacy of the specimen and proper cytopreparatory technique, as well as the interpreter’s familiarity with their cytopathologic patterns. Lymphoma cells are very fragile and dry quickly unless wet-fixed immediately for Papanicolaou stain. May Grunwald Giemsa (MG.G.) or Diff-Quik stains reduce artifacts, and as the smears are dried in the air, the cytoplasmic paleness of lymphocytes colored in blue is highly obvious. In our experience, this procedure improves diagnostic accuracy. Zhang et al., in a retrospective review of FNAC to diagnose primary thyroid lymphomas, showed that FNA sensitivity in diagnosing PTL was 72% when FNA reports “suspicious for” and “diagnostic of” PTL were considered together . Ota et https://www.cbioportal.org/, accessed 10 April 2023) show that ERBB2 mutations are present in 6.38% of diffuse large B-cell lymphoma cases. However, the mutation spectrum does not include insertion variants at the level of exon 20 of the gene , as in our case. ERBB2 exon 20 insertions are most frequently detected in NSCLC, urothelial, biliary tract, and breast cancers. These pathogenic variants occur in the α-C helix and in the loop following the α-C helix (from residues 770 to 783) that act as a regulatory element determining the activation state of ERBB2 [In this regard, our finding of a pathogenic mutation for the ERBB2 gene allows us to draw some considerations. Data from the cBioPortal for Cancer Genomics database (of ERBB2 . In this regard, a newly published study revealed the effectiveness of trastuzumab deruxtecan, an antibody–drug combination, on a variety of HER2-mutated hard-to-treat advanced solid tumors, indicating its potential as an agnostic tumor treatment for these different types of cancer . In factOn the basis of these considerations, it is expected that in the future, the adoption of a mutational screening in NGS will support the diagnosis and also provide more information on the biology, prognostic factors, and potential targeted therapy of the disease.The finding of ERRB2 mutations, while by itself cannot be considered a specific or pathognomonic finding, can open, in similar cases, perspectives for a personalized therapy and can offer insights on the prognosis of the disease.Until the routine adoption of these recent significant technological innovations in the medical field, diagnosing PTL is still a relevant challenge in clinical practice. Cytopathologists addressing patients with potential PTL should be aware of its clinical, laboratory, and imaging information. Therefore, it is equally crucial that the Molecular Tumor Board, which was established to address the enormous gap between clinical knowledge and the promise of molecular diagnostics in cancer practice, serves as the focal point of this organizational paradigm . A multi


Pesticides are the most effective way to control diseases, insects, weeds, and fungi. The central nervous system (CNS) is damaged by pesticide residues in various ways. By consulting relevant databases, the systemic relationships between the possible mechanisms of pesticides damage to the CNS causing cognitive impairment and related learning and memory pathways networks, as well as the structure–activity relationships between some natural substances (such as polyphenols and vitamins) and the improvement were summarized in this article. The mechanisms of cognitive impairment caused by pesticides are closely related. For example, oxidative stress, mitochondrial dysfunction, and neuroinflammation can constitute three feedback loops that interact and restrict each other. The mechanisms of neurotransmitter abnormalities and intestinal dysfunction also play an important role. The connection between pathways is complex. NMDAR, PI3K/Akt, MAPK, Keap1/Nrf2/ARE, and NF-κB pathways can be connected into a pathway network by targets such as Ras, Akt, and IKK. The reasons for the improvement of natural substances are related to their specific structure, such as polyphenols with different hydroxyl groups. This review’s purpose is to lay a foundation for exploring and developing more natural substances that can effectively improve the cognitive impairment caused by pesticides. As an indispensable input, pesticides play an important role in agricultural production, so global pesticide production is increasing rapidly. Studies have demonstrated that without the use of pesticide application, fruit yield would be lost by 78%, vegetables by 54%, and cereals by 32% . So far,The brain is the most advanced nerve center that regulates body’s function, and its structural integrity is crucial to cognitive function . The reaBased on consulting a large number of databases, the mechanisms and cascade pathways of the cognitive impairment caused by pesticides were systematically studied and discussed in this review, and how to screen the natural substances that can effectively improve the cognitive impairment caused by pesticides and the corresponding improvement mechanisms. It is expected to find the connection between them and explore their effects on brain injury and repair caused by pesticides as an organic whole. Those will lay a foundation for finding effective functional factors to improve cognitive impairment caused by pesticide poisoning.2.2.1.Because the brain requires high oxygen consumption, low antioxidant activity, and rich polyunsaturated fatty acids, it is very vulnerable to oxidative damage . A numbe2.2.2+ concentration. When pesticides enter the organism, ROS accumulates in the brain tissue, which reduces mitochondrial membrane potential, resulting in membrane integrity damage and mitochondrial DNA (mtDNA) release , prompting the dissociation of Cyt-C from the inner mitochondrial membrane and thus its release into the cytoplasm. For example, the pesticide MCP significantly upregulated ROS, Cyt-C, and lipid peroxide in PC12 cells , and the regulation of calcium and ROS homeostasis, which is the basis of the normal CNS . Mitocho release . The acc12 cells . Cyt-C b12 cells , upregul2.3.Various pesticides have been shown to elevate inflammatory factors levels, leading to neuroinflammation, neuronal cell death, and cognitive impairment . Microgl2.4.Synapses are the key site for information transmission between neurons, and neurotransmitters are crucial for maintaining brain function, as important information transmission substances between nerve cells. Abnormal release and transmission of neurotransmitters can affect the formation of the neurological basis of learning and memory long-term potentiation (LTP)  and leadThe neurotransmitters affected by pesticide-induced brain injury are mainly divided into choline, free amino acids, and monoamines. (1) Choline substances, such as acetylcholine (ACh) and acetylcholinesterase (AChE), together constitute the central acetylcholinergic neuron system . Normall2.5.It is found that the intestinal microbiota is closely related to the physiological function and disease of the CNS. The intestinal microbiota is linked to the brain through the nervous system, immune system, and endocrine system by neurotransmitters , immune factors (such as 1L-1β and TNF-α), and endocrine hormones (such as cortisol and corticotropin), thereby directly or indirectly affecting the brain function , 45. TheActinobacteria (Corynebacterium), Firmicutes (Lactobacillus), and Bacteroidetes in the gut was decreased after acute (one administration of 0.3 mL), sub-chronic, and chronic exposure (250 or 500 mg/kg/d for 6 and 12 weeks) to GLY-based herbicides. The elevated plus maze and tail suspension test showed that the mouse showed anxiety and depression-like symptoms, indicating that intestinal ecological disorders may lead to neurobehavioral changes. By establishing a mice model of chronic Rotenone-induced Parkinson’s disease (PD), Zhao et al. , and transmission electron microscopy showed that the intestinal barrier and blood–brain barrier were damaged. The destruction of the intestinal microbiota induced the increase of its metabolite LPS in colon, serum and substantia nigra. LPS promoted the activation of the TLR4/MyD88/NF-κB signaling pathway and enhanced the expression of inflammatory factors , thereby causing damage to neurons. The study showed that rotenone-induced microbiota imbalance may mediate inflammation caused by LPS-TLR4 signaling pathways, thus participating in the occurrence of PD through the microbiota–gut–brain axis. Based on these studies, it can be speculated that intestinal dysfunction may be the key to cognitive impairment caused by pesticides, but there are few related studies at present. Therefore, we think it is necessary to deeply explore the specific mechanism of gut microbiota affecting brain function through information exchange between the gut–brain axis, which may rewrite the definition of a healthy diet and life, and human beings will find new microecological methods to prevent and improve cognitive impairment in pesticides poisoning.It is found that intestinal microbiota is, indeed, related to brain cognitive function. Aitbali et al.  found th2+, and triggers mitochondrial dysfunction. Oxidized mtDNA promotes the activation of NLRP3 inflammasomes, releases a large number of inflammatory factors, and causes neuroinflammatory reactions, forming three feedback loops. Excessive free radicals in oxidative stress can also attack the structure and function of cholinergic neurotransmitter receptors, change cholinesterase activity, and damage the cholinergic system. Oxidative stress affects the expression of Gly; Gly is a constituent amino acid of the endogenous antioxidant reduced Glu in free amino acids. Acetyl-CoA is the raw material for the synthesis of ACh in the cholinergic system, which needs to be synthesized in mitochondria, and Glu is formed by multiple steps in the mitochondria of astrocytes  compensation increases, resulting in calmodulin-dependent protein kinase II (CaMKII) expression  is a Glu excitatory nerve receptor, which is mainly distributed in the presynaptic and postsynaptic membranes of the cerebral cortex, hippocampus, thalamus, and striatum. It plays an important role in synaptic plasticity and synaptic transmission . At restorganism , neuronspression . It alsopression . PSD-95 pression . NR2A an3.2.A number of studies suggest that PI3K/Akt is an important oxidative signaling pathway and is closely related to learning and memory ability . PI3K/Ak3.3.Mitogen-activated protein kinase is a group of serine–threonine protein kinases that can be activated by cytokines, neurotransmitters, hormones, and cell stress, which is an important information transmission chain . The mai3.4.Keap1/Nrf2/ARE signaling pathway plays an important role in cellular resistance to endogenous or exogenous oxidative stress and inflammation . Normal 3.5.NF-κB is a multiple nuclear transcription-inducing factor that exists in almost all animal cells. It participates in the response of cells to external stimuli. It plays a key role in cellular immune response and inflammatory response and is closely related to learning and memory . NF-κB p2+ influx and activation of downstream PI3K/Akt and MAPK signaling pathways through CaM and Ras. The γ subtype of PI3K plays a key role in NMDAR receptor-mediated synaptic plasticity and hippocampal-dependent learning and memory ability. PI3K can activate CREB related to the ERK pathway, and its over-activation can reduce the probability of ERK entering the nucleus. As an important injury junction, Akt can attenuate the expression of the Nrf2 nuclear transcription factor in the Keap1/Nrf2/ARE pathway, and reduce the activities of antioxidant enzymes such as SOD. It can also promote the initiation of the NF-κB pathway and release a large number of inflammatory factors such as TNF-α and IL-1β. NF-κB can also initiate the Bcl apoptosis pathway, resulting in cell damage and death. All three branches of MAPK will promote the production of inflammatory factors finally, and it is believed that MAPK and NF-κB pathways are inextricably linked. By constructing the pathway network, it is not difficult to guess that the related signaling pathways in pesticide-induced cognitive impairment are an organic whole and closely related to the action mechanism. These pathways together lead to cognitive impairment caused by pesticide poisoning.After sorting out, it is found that each pathway is not independent but has interconnected targets, which establishes a huge pathways system  and toge4.4.1.4.1.1.Kaempferol has a neuroprotective effect on brain damage caused by neurodegenerative diseases , 88. HusKaempferol is a flavonol compound with a molecular weight (MW) of 286.236. Its structure is C ring , aromatic A ring (two hydroxyl groups), and aromatic B ring (one hydroxyl group). One study compared the improvement of cognitive impairment between kaempferol and two other flavonol substances with similar structures (A ring and C ring are the same), namely galangin (there is no hydroxyl group on the B ring) and myricetin (there are three hydroxyl groups on the B ring). The results showed that the increase of hydroxyl number on the B ring significantly upregulated the expression of the ERK1/2-CREB pathway in brain tissues of cognitively impaired mice, thus exerting neuroprotective effects. At the same time, kaempferol and myricetin can significantly improve the spatial learning and memory ability of mice, while galangin has no significant improvement effect. However, all three inhibited oxidative stress, and there was no significant difference . This su4.1.2.Quercetin has multiple biological effects and a good puzzle effect , 93. BegQuercetin (MW: 302.236) is a flavonol compound. Its C ring and aromatic A ring are the same as kaempferol and myricetin; the difference is that there are two adjacent hydroxyl groups on the aromatic B ring . A simpl4.1.3.It has protective and therapeutic effects on cancers, diabetes, PD, and AD , 98. DhaMyricetin (MW: 318.235) is a flavonol compound. The study found that the hydroxyl group of myricetin B ring and C ring can regulate the expression of PI3K, and the ketone group and double bond on the C ring can inhibit the anti-inflammatory activity of COX-2 expression , which m4.1.4.in vitro. It inhibited the accumulation of ROS, ATP deficiency, caspase-3 activation, mitochondrial membrane potential dissipation, and mitochondrial swelling, which suggested that baicalein may be a mitochondrial-targeted antioxidant and has a neuroprotective effect on rotenone-induced neurotoxicity.Baicalein has been used for the treatment of hypertension, cardiovascular disease, cancer, and cognitive impairment. Li et al.  found thBaicalein (MW: 270.237) is a flavonoid. Its C ring contains a double bond and a ketone group. The aromatic A ring has three hydroxyl groups and the B ring does not contain hydroxyl groups . It can 4.1.5.Luteolin, with a variety of biological activities , has beeThe flavonoid compound luteolin (MW: 286.236) is similar to baicalein, with the C ring (one double bond and one ketone group) and A ring (three hydroxyl groups), but its aromatic B ring has two ortho hydroxyl groups more than baicalein. These functional groups may be responsible for conferring its neuroprotective effects , 105. It4.1.6.Curcumin has various biological activities such as anti-inflammation and anti-oxidation , 107. HaSmall molecule (MW: 368.39) curcumin is a phenolic compound. It contains many phenolic hydroxyl groups, ketone groups, and double bonds; these make it have an antioxidant effect. It has also been found that the olefin saturation of the linkage bond at the seventh C atom of curcumin and the 4-hydroxyphenyl in its structure affect the anti-inflammatory effect of curcumin . These s4.1.7.1 and R2 of the B ring can be replaced by different substituents , resulting in six common categories. The MW of anthocyanins is 287.240~—. Large MW anthocyanins have to be metabolized into small molecules in order to be absorbed and improved. Anthocyanins are powerful antioxidants that protect the eyes and liver and prevent and treat diabetes, cancer, and CNS diseases  has many biological activities, such as inhibiting oxidative stress and inflammation , 114, anCarnosic acid is a natural phenolic diterpene with an MW of 332.434. It is speculated that the two hydroxyl groups on the benzene ring in its molecule are one of the key reasons for its antioxidant activity. However, whether other characteristics of CA structure are related to the improvement of cognitive impairment needs to be verified.4.3.4.3.1.Melatonin (MEL) is an important nervous system regulator and antioxidant , 118. ShMelatonin (MW: 232.278), also known as N-acetyl-5-methoxytryptamine, is the synthetic material for the neurotransmitter 5-HT. . It can 4.3.2.Progesterone (PROG) is an important female hormone, which can protect the fetus, promote pregnancy, and regulate the body temperature center, and is also an important regulator of the nervous system function , 123. ShProgesterone (MW: 314.462) is a neurosteroid hormone secreted by the ovary. Its structure includes a ketone group and a double bond. This may be the reason why it is easier to combine with the oxygen-free radicals caused by pesticides to avoid oxidative stress in the human body, thus producing neuroprotective effects .4.4.4.4.1.Vitamin B6 (VB6) can be used to prevent and treat lip splitting, seborrheic dermatitis, and diabetic vascular complications. In recent years, it has been found that VB6 can be used to prevent and treat CNS diseases . Li et aVB6 (MW: 231.144) is a water-soluble vitamin; the three hydroxyl groups in the structure endow it with antioxidants and other activities. VB6 mainly reacts with nearly 100 enzymes in the human body in the form of pyridoxal phosphate (PLP) and exerts biological effects. For example, it can participate in the synthesis of neurotransmitters  . These m4.4.2.Vitamin C (VC) is a natural strong antioxidant and cofactor of various enzymes, thus improving various diseases. Ambali et al.  intervenVitamin C (MW: 176.124), also known as ascorbic acid, is a water-soluble vitamin containing hydroxyl and carbonyl groups (C=O−). Hydroxyl and o-carbonyl groups can form hydrogen bonds to participate in the hydroxylation reaction, thereby promoting the synthesis of neurotransmitters . The structural characteristics of VC make it have strong antioxidant and neuroprotective effects .4.4.3.Vitamin E (VE) can promote the secretion of sex hormones, improve fertility and blood circulation, effectively combat free radicals, and inhibit the production of lipid peroxidation. In recent years, more and more attention has been paid to its improvement in CNS diseases . Kosta eVitamin E is a fat-soluble vitamin antioxidant with MW is 430.706. Its phenolic hydroxyl group is the active group. The hydroxyl group may provide a hydrogen atom to reduce ROS levels and exert antioxidant activity, thereby participating in the improvement of cognitive impairment. It was speculated that the number and position of methyl groups on the benzene ring, the side chain, and the stereo structure in the molecule also affected the activity.Based on the analysis of natural substances that can improve the cognitive impairment caused by pesticides , it was 5.2+, leading to mitochondrial dysfunction. The mutation accumulation of mitochondrial mtDNA and the decrease of ATP would also increase ROS level and aggravate oxidative stress. Pesticide-induced cognitive impairment is also accompanied by the regulation of NMDAR, PI3K/Akt, MAPK, Keap1/Nrf2/ARE, NF-κB, and other multiple learning and memory pathways, which can be formed into an organic whole through the crosslinking targets such as RAS, Akt, and IKK. In this article, the characteristics of some natural substances that improve the cognitive impairment of different pesticides were also summarized. It is found that polyphenols, biological hormones, and vitamins are functional factors that can play a good role in improvement. Most of the molecular weights of these natural substances are about 150~450 Da, which may be one reason why they are very suitable for biological activity across the blood–brain barrier. Second, the location and number of structural functional groups  in natural substances may affect their efficacy in improving cognitive impairment. Our speculations may be used to screen natural substances with good neuroprotective effects. For example, the increase of the number of hydroxyl groups in the structure of natural substances is beneficial to the enhancement of the antioxidant effect, which makes it play a better role in improving cognitive impairment. Finally, the mechanisms and related pathways of pesticide-induced cognitive impairment are not limited to those presented in this article. The research on the improvement mechanisms of natural substances is not deep enough, and our speculation needs to be verified and supplemented by a large number of studies in the future. More progress will be beneficial to the research and development of healthy food for the prevention and alleviation of cognitive impairment diseases, thus promoting the healthy development of mankind.Pesticide poisoning has seriously increased the risk of CNS diseases and become a serious potential safety hazard in people’s daily life. It was summarized that pesticides could damage brain tissue through action mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, neurotransmitter abnormalities, and intestinal dysfunction, and these mechanisms were interrelated and had feedback effects. For example, the excessive accumulation of ROS in oxidative stress could lead to the increase of mitochondrial mtDNA and CaLW and XM: investigation and formal analysis, writing – original draft, review and editing. JD: formal analysis and editing. XT: investigation and editing. YH: conceptualization, project administration, and writing – review and editing. YW and FZ: conceptualization, supervision, and formal analysis. All authors contributed to the article and approved the submitted version.This research was funded by the Jilin Provincial Science and Technology Department, grant number: 20210202105NC and 20210101043JC.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Falls in older people have a significant impact on public health. The scientific literature has provided evidence about the necessity for older adults to be physically active, since it reduces the incidence of falls, several diseases, and deaths, and can even slow down some effects of aging. The primary aim of our study is to identify if physical performances and risk of falling are related to 1-, 2-, 3-, 4-, and 5-year mortality. Its secondary aim is to establish if people with both severely impaired physical performance and a high risk of falling also present impairment in other geriatric domains. Methods: In this prospective study, we enrolled subjects aged 65 years or more, subjected them to comprehensive assessment , and followed them for 5 years. Results: We included 384 subjects, 280 of whom were women (72.7%), with a median age of 81 years. Our results showed that physical performances and risk of falling are highly correlated to each other (rho = 0.828). After divided the sample into three groups , we found that the more severe the disability and risk of falling were, the more compromised the other geriatric domains were. Moreover, the survival probability progressively increased following the same trend, amounting to only 41% in severely compromised people, 51.1% in moderately compromised people, and 62.8% in people without physical compromise nor an augmented falling risk (p = 0.0124). Conclusions: Poor physical performance combined with a high risk of falling, correlated with each other, are associated with higher mortality and impairment in multiple domains in older adults. The aging of the population represents an increasing concern worldwide . In ItalSince poor physical capacities and the co-presence of several risk factors for falling are indeed multifactorial ,40, aparTaking the above into consideration, we decided to design the present prospective study, the primary aim of which is to identify if physical performance and risk of falling is related to 1-, 2-, 3-, 4-, and 5-year mortality, and the secondary aim of which is to establish if people with both severely impaired physical performance and a high risk of falling also present impairment in other geriatric domains.This prospective observational cohort study included subjects who were evaluated at the Geriatric Outpatient Service of the University Hospital of Monserrato, Cagliari, Italy, from January 2010 to December 2017, and followed for sixty months.The given confidence level: 95%, confidence interval: 5%, standard deviation (SD): 0.5, Z-score (z): 1.96, and error margin (e): 5%, according to the following formula:The final sample (N) consisted of 384 subjects.Subject age ≥ 65 years; having been subjected to two tests assessing physical performance: Physical Performance Test (PPT) and Performance Oriented Mobility Assessment (POMA)Comorbidity Index Rating Scale (CIRS) > 30.PPT , for thePOMA , for theCIRS , for theMini Mental State Examination (MMSE) , for cogGeriatric Depression Scale (GDS) , for mooActivities of Daily Living (ADL), expressed as Barthel Index, and Instrumental Activities of Daily Living (IADL) , for theMini Nutritional Assessment (MNA) ,47, for Number of different drugs taken.The enrolled subjects were evaluated with the following assessments:p-values > 0.1 excluded by the model), the results of which were expressed as odds ratios (ORs), and Area Under the Receiver Operating Characteristic (ROC) curve (AUC).Variables were expressed as medians and interquartile ranges (IQR) or in percentages (%), where appropriate. The Kolmogorov–Smirnov test was used to test normal distribution. Spearman’s coefficient of rank correlation (rho) was used to correlate the PPT and POMA scores. The Kruskal–Wallis test for independent sample was used to compare the groups on dependent variables. The Conover test was used for post-hoc analysis. Kaplan–Meier curves were designed in order to estimate the survival probability: their results were expressed as hazard ratios (HRs), for the comparison of which the Log-rank test was used. The multivariate analysis was conducted with a logistic regression—stepwise .The results are reported indicating MedCalc software  was used for the statistical analysis.The study included 384 community-dwelling people aged 65 years or more, of whom 280 were women (72.7%), with a median age of 81 years. The characteristics of the sample are shown in p < 0.0001) (The PPT and POMA scores were compared with Spearman’s correlation coefficient (rho), which was 0.828  .p = 0.913). ADL, IADL, and MNA scores were significantly lower in group 3 than in group 2, and also in group 2 than in group 1 (p < 0.0001); similarly, the GDS scores were significantly higher in group 3 than in group 2, and in group 2 than in group 1 (p < 0.0001). The CIRS scores (p < 0.0001) and number of drugs taken (p = 0.0009) were significantly higher in group 3 than in the other two groups. Finally, the MMSE scores were higher in group 1 than in the other two groups (p = 0.001).We divided the sample into three groups, according to the abovementioned scores, thus obtaining group 1 , group 2 , and group 3 . As in 2 = 8.78, p = 0.0124) in group 1 than in group 2 and 3, and in group 2 than in group 3, as shown in According to the Kaplan–Meier model  the overp < 0.0001), the logistic regression considered age (OR: 1.08), GDS (OR: 0.89), and MNA (OR: 0.84) independently associated with the outcome. The other variables were excluded by the model , with a median age of 81 years, and followed them for five years. We decided to exclude people with CIRS > 30, meaning a significant comorbidity burden, in order to avoid potential confounding factors: it was in fact demonstrated that comorbidity burden is an independent risk factor for deaths . We did Our data showed a strong correlation between physical performance and risk of falling (rho = 0.828), emphasizing that in older subjects, various domains follow the same trend, and a person with the inability to carry out standardized activities also presents a higher risk of falling. Accordingly, we divided the sample into three groups: the first, made up of people without an augmented risk of falling and able to perform adequate physical activity, the second, made up of people with a moderate risk of falling and/or disability, and the third, made up of people with a severe risk of falling and/or disability. Our analysis suggested that people belonging to the third group, in addition to the worse physical abilities, also revealed higher comorbidities , worse cognitive capacities, more deflected mood, reduced autonomies, and more deficient nutritional status, according to the above. Moreover, the prospective study showed that poor physical capacities and a high risk of falling were associated with an increased risk of death, with the survival curves spreading with increasing follow-up months, reaching 41% 5-year survival in severely impaired people, 51.1% survival in moderately impaired people, and 62.8% survival in people with adequate physical abilities and a falling risk. In order to deepen such results, we conducted a multivariate analysis to consider a possible relationship between death and impaired geriatric domains, highlighting age, mood, and nutritional status as significant regressors of the outcome. In particular, older age showed the lowest hazard ratio, while poorer nutritional status (116%) and better mood (111%) were more clearly independently associated with death. If the direct proportionality with age and worse nutritional status is consistent with the literature ,55, the The strengths of our study are represented by the 5-year follow-up, and the fact that it was performed using common and easy-to-administer screening tools, also easily reproducible in everyday clinical practice. It did not take into account some variables, such as fear of falling , sarcopeIn conclusion, our study tries to address the necessity of screening for risk of falling ,61,62, c


Human adenovirus 36 (HAdV-36) has been associated with obesity and changes in glucose and lipid metabolism. The virus has been reported to increase insulin sensitivity and paradoxically promote weight gain. Because of its effects on metabolism, infection with the virus could alter the response to several drugs used to treat type 2 diabetes (DM2), such as metformin. The aim of this study was to test whether HAdV-36 affects the response to metformin in a group of obese patients with DM2. Methods: In a prospective cohort study, 103 obese patients with newly diagnosed DM2 were divided into two groups based on their HAdV-36 seropositivity (+HAdV-36 and −HAdV-36). Weight, glucose, cholesterol, triglycerides, body mass index, body fat percentage, and waist and hip circumference were measured and compared in both groups at baseline and after 45 days of metformin treatment. Results: Only glucose was significantly lower in the +HAdV-36 group at baseline, while all other variables were similar between the two study groups. After 45 days of follow-up, it was observed that the effect of metformin did not differ between the groups, but the variables improved significantly after treatment. Conclusions: In this study, we did not find that HAdV-36 had an effect on the response to metformin in obese patients with DM2. Type 2 diabetes (DM2) is a chronic disease that has reached epidemic levels. Despite major efforts to control the disease, the number of cases is steadily increasing, with the number of patients with DM2 estimated to be 537 million worldwide in 2021 and projected to rise to 783 million by 2045 [The risk of morbidity and mortality associated with DM2 is reduced by early diagnosis and timely initiation of treatment .Among the most widely used drugs in the management of DM2, metformin has been considered first-line pharmacotherapy for more than two decades ,5. In adSLC2A2, SLC22A1, SLC47A1, SLC47A2 and others have been associated with changes in drug response. [Pharmacogenetics have dominated studies aimed at explaining variation in patient response to metformin. For example, variants in the genes esponse. ,9. Howevesponse. .HAdV-36 was isolated for the first time in 1978 from a human fecal sample; however, the peak of research on this virus occurred in early 2000, when it was discovered that HAdV-36 was associated with obesity in humans but paradoxically also lowered cholesterol and triglyceride levels ,12. ThesIt was soon discovered that, like TZDs, HAdV-36 upregulates peroxisome proliferator-activated receptors γ (PPARγ), which increases levels of adiponectin and the glucose transporters GLUT1 and GLUT4, thereby improving insulin sensitivity. However, PPARγ activation also favors adipogenesis, adipocyte differentiation and proliferation, as well as fatty acid absorption and storage, which explains the improvement in lipid profile and weight gain ,15,16.The relationship between TZD and metformin has been extensively studied and there is evidence that the combination of pioglitazone with metformin results in better-glycosylated hemoglobin (HbA1C), decreased markers of inflammation and lower cholesterol and triglyceride levels, conferring greater cardiovascular protection than metformin as monotherapy ,18,19. HAdditionally, it has been observed that the E4 open reading frame 1 (E4orf1) gene of HAdV-36 upregulates the AKT/GLUT4 pathway, enhancing GLUT4 translocation, even in the presence of proinflammatory cytokines, allowing better glucose uptake in adipose tissue and skeletal muscle . IncreasIn light of the above, the present study aimed to investigate whether HAdV-36 influences the response to metformin monotherapy in obese patients with DM2. This work is pioneering in investigating whether virus-induced metabolic changes can be used to predict drug response.This study was a prospective cohort design. The follow-up period for each subject was 45 days, taking into account that metformin monotherapy can improve the glycemic profile within six weeks . Two mea2) and new-onset DM2 who met American Diabetes Association (ADA) diagnostic criteria [A total of 103 volunteers were enrolled in this study, of which 36 (34.9%) were male and 67 (65.04%) were female, with a mean age of 48.82 ± 9.46 years old. All patients were referred from the Unidad Metabólica de Atención Nutricional Especializada (UMANE) in Ciudad Guzmán, Jalisco, Mexico. Only volunteers who met the following characteristics were included in this study: (a) subjects > 18 years of age with obesity  patNutritional follow-up was provided by UMANE staff, with regular dietary check-ups every 15 days. Patients who did not attend all appointments were excluded from the study. The study was conducted between 1 November 2019 and 31 July 2020.® San Diego, CA, USA. Kit No. MBS705802) and a BiotekSynergy TH® multimodal plate reader Winooski, VT, USA. The microplate reader was calibrated at a wavelength of 450 nm with which the optical density of each well was determined. Positive and negative values were calibrated according to the supplier’s instructions. According to the manufacturer’s instructions, the samples with optic density relation ≥2.1 compared with negative control were considered as positive samples for HAdV-36. The intra-assay precision mentioned by the supplier was within-test and between-test (inter-test precision), with a coefficient of variability of <15%.Volunteers’ blood samples were collected with at least eight hours of fasting for the determination of HAdV-36 serology and measurements of glycemic and lipid profiles. Blood was obtained by venipuncture of the forearm, using a vacuum-extraction blood sampling system. Samples for HAdV-36 serology were collected in 5 mL tubes without additives; immediately after collection, they were centrifuged at 3000 RPM for 10 min. The serum used for HAdV-36 identification was frozen at −20 °C until analysis. Virus identification was performed by enzyme-linked immunosorbent assay (ELISA) using the HAdV-36 ELISA antibody  The glucose hexokinase (ref: 1001201), cholesterol CHOD-POD Sant Esteve de Bas, Spain (ref: 41021) and triglyceride GPO-POD Sant Esteve de Bas, Spain (ref: 1001313) kits from Spinreact® were used. All studies were performed at the Clinical Analysis Laboratory of the University Center of the South, University of Guadalajara.Glucose and lipid analysis was performed on a semi-automated clinical chemistry analyzer SpinlabAn anthropometric assessment was performed at baseline and the end of the study, employing bioelectric impedance analysis (BIA) using a Tanita Ironman BC-558 body composition monitor. Height was measured using a Seca 206 wall stadiometer, and waist circumference was measured using a Lufkin W606PMMX metal tape measure. Body mass index (BMI) was calculated as weight (kg)/height (m) squared to include obese subjects.The present study was conducted in accordance with the “Ethical Principles for Medical Research Involving Human Subjects” of the Declaration of Helsinki and was approved by the local ethics committee of the Centro Universitario del Sur of the University of Guadalajara. All subjects signed a written informed consent prior to enrolment, in accordance with ethical guidelines.t-test for parametric variables or the Mann–Whitney U test for nonparametric variables. Comparison of quantitative variables at baseline and the end of the cohort was performed using paired t-test or the Wilcoxon rank sum test, depending on the nature of the variables. A value of p < 0.05 was considered statistically significant. All analyses were performed using R version 4.1.2.Data were presented as mean ± standard deviation (SD) or 95% confidence interval (95% CI) as appropriate. Normality analysis was performed using the Kolmogorov–Smirnov test. The comparison of quantitative variables between patients with the presence or absence of anti-HAdV-36 antibodies was performed using the n = 43) of the patients had anti-HAdV-36 antibodies (+HAdV-36). Once the groups were established (+HAdV-36 and −HAdV-36), biochemical and anthropometric variables were compared between them, both at baseline and after 45 days of treatment with metformin as monotherapy.Volunteers were first classified according to the presence or absence of anti-HAdV-36 antibodies, which revealed that 41.7%  test and subsequently evaluated with the paired In addition, a statistical analysis was carried out, comparing the before and after metformin administration values of each variable according to the sex of the participants, both within and between groups.In both groups, after 45 days of metformin treatment, there was a decrease in the study variables in both men and women. In particular, the HAdV-36-negative group of men had greater weight loss than the positive group and, as a result, weight-dependent variables such as BMI, waist and hip circumference were lower in the negative group.In addition, the HAdV-36-negative group showed a greater decrease in blood glucose, but that is because the positive group started with an average blood glucose of 114 mg/dL and achieved normoglycemia with a slight decrease in blood glucose. The negative group started with a glucose level of 155.47 mg/dL and, although they lost 44.6 mg/dL on average, did not reach normoglycemia. The results can be seen in t-test or the Wilcoxon rank sum test.Data were initially analyzed with the Kolmogorov–Smirnov (KS) test and subsequently evaluated with the paired This is one of the few examples of research that studies the relationship between an infection and the response to a drug. The interaction between drug and infection has several causes. In some cases, drugs are metabolized by microorganisms before absorption; this phenomenon has been described in the gut microbiota, which, in some cases, carries out phase I and II reactions of drug metabolism .It has also been described that some viruses, such as the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), due to the inflammatory process it produces and, consequently, to the increase in cytokines, may decrease some cytochrome P450 (CYP) enzymes, such as CYP2B6 and CYP3A4, which may affect the pharmacokinetics of drugs metabolized by these enzymes .The effect of HAdV-36 on the response to metformin was investigated in this study. Although the virus has not been shown to alter the metabolism of the drug, the interaction may exist, as HAdV-36 causes metabolic changes similar to those of TZD and affects the metabolic pathways in which metformin acts and there may be a synergistic effect between the virus and the drug .In terms of seroprevalence, antibodies against HAdV-36 were found in 41.7% of the population studied, which is lower than the 73.9% reported in a Mexican obese children population . HoweverRegarding the gender distribution of seropositivity for HAdV-36 antibodies, the prevalence of antibodies was found to be higher in women than in men , similar to data reported in the United Arab Emirates (53% in women and 41% in men) . SimilarThe characteristics of the study groups (+HAdV-36 and −HAdV-36) were as expected according to the selection criteria. The groups were very homogeneous and no significant differences were found for most variables. BMI, body fat percentage, and waist and hip circumferences were very similar between the study groups. Plasma triglyceride levels were higher in the +HAdV-36 group, but the difference was not significant. Cholesterol levels were lower in the seropositive group but not significantly so.in vivo and in vitro studies that have identified cell signaling pathways modulated by HAdV-36 to influence cellular glucose metabolism and improve glycemic control [Despite these similarities between groups, glucose was lower in the +HAdV-36 group (120.5 ± 50.06 vs. 148.3 ± 69.83). This finding is consistent with  control ,34.Previously, HAdV-36 seropositivity was associated with lower fasting glucose and insulin levels only in normal-weight men and women , which dAfter treatment with metformin and a caloric-deficit diet, significant changes were observed. Both groups lost weight, with the +HAdV-36 group losing an average of 3.2% of body weight, while the −HAdV-36 group lost 2.7%; although the seropositive group lost more weight on average, the difference was not statistically significant. The effect of metformin on weight has been reported in several publications ,38. In aConsidering HAdV-36 as a benchmark, there are no other studies reporting weight loss in a population similar to this study; however, it has been reported that people lose weight similarly after multidisciplinary weight loss interventions regardless of HAdV-36 serotype ,40.In the present study, we observed that the HAdV-36-seropositive group of men lost less weight on average than the seronegative men; this difference was not observed in women. Nevertheless, the difference in weight loss observed in men may possibly be due to physical activity. In the trial, there was good follow-up of the diet plan, adherence to the diet, and medication use and the age of the groups was similar. However, no specific exercise plan was provided as part of the treatment, nor was a tool used to assess physical activity levels. It is, therefore, possible that this variable was a factor in the differences in outcomes.Consistent with weight loss, decreases in BMI, body fat percentage and waist and hip circumference were observed in all study groups. In terms of BMI and waist and hip circumference, it was observed that the HAdV-36-negative group performed better. This is because the HAdV-36-positive men lost less weight. In the women’s group, it was also observed that the range of hip and waist measurements was very wide. This is mainly because the age range of the women included (40–55 years) includes both postmenopausal and premenopausal women, who have a different distribution of body fat due to hormonal changes .HAdV-36-positive subjects had lower glucose levels at baseline. However, this result was expected as the virus increases glucose uptake by skeletal muscle cells .After metformin administration, we found that all groups had significantly lower glucose levels, which is in line with the findings previously reported regarding the fasting glucose levels and insulin resistance decreased after six weeks of metformin therapy, . HoweverAt baseline, there was no difference in cholesterol or triglyceride levels across study groups. In most of the study patients, cholesterol was normal and triglycerides were slightly higher. The reduction in cholesterol and triglyceride levels following metformin treatment was considerable in both groups, as has been described previously ,44.It is recommended that future studies test glucose values on multiple occasions to further assess the progression of the decline in glucose levels. It is also recommended to perform A1C and oral glucose tolerance tests in addition to fasting glucose, in order to have a more accurate assessment . On the It is important to consider that some of the study results may be influenced by the coincidence between the study period and the COVID-19 pandemic. During this period, there were important changes in lifestyle, both in terms of dietary habits and physical activity ,47. As tFinally, ELISA was used in this study to identify antibodies against HAdV-36. Serological tests are by far the most widely used in human HAdV-36 research, and ELISA is one of the most sensitive tests but not the most specific . Because


Beauveria bassiana alone, (2) early integrated pest management (IPM), which combined monitoring and sanitation with spraying B. bassiana, and (3) research-based IPM, which focused on CBB biology in Hawaii, optimization of monitoring, B. bassiana applications, and cultural controls. From 2011 to 2021, the economic benefits from managing CBB were USD 52 million using B. bassiana alone, USD 69 million from early IPM, and USD 130 million from research-based IPM, for a total of USD 251 million from all management. This suggests that all types of management provide economic benefits to Hawaii growers, but management strategies based on Hawaii-specific research have provided the greatest gains in coffee yield, price, and revenue. Our findings demonstrate that both research and outreach are critical for developing and implementing effective IPM strategies.Since its introduction to Hawaii in 2010, coffee berry borer (CBB) has dramatically reduced the quality and yield of coffee produced in the islands. We assessed the economic benefits of managing CBB based on three strategies that emerged in Hawaii over the last decade: (1) the use of the entomopathogenic fungus Beauveria bassiana alone, (2) early integrated pest management (IPM), which combined monitoring and sanitation with spraying B. bassiana, and (3) research-based IPM, which focused on CBB biology in Hawaii, optimization of monitoring, B. bassiana applications, and cultural controls. From 2011 to 2021, the economic benefits from managing CBB were USD 52 million using B. bassiana alone, USD 69 million from early IPM, and USD 130 million from research-based IPM, for a total of USD 251 million from all management. Our findings suggest that all types of management provide economic benefits to Hawaii growers, but management strategies based on Hawaii-specific research have provided the greatest gains in coffee yield, price, and revenue.Coffee berry borer (CBB) is considered the most damaging insect pest of coffee worldwide. CBB was first detected on Hawai‘i Island in 2010, and quickly spread throughout the state’s coffee-growing regions. With the introduction of this pest, Hawaii’s small yet economically important coffee industry was changed forever with growers facing significantly higher production and labor costs, as well as decreased yield and coffee quality. We assessed the economic benefits of managing CBB based on three strategies that emerged in Hawaii over the last decade: (1) the use of the entomopathogenic fungus  Coffee is the second most valuable agricultural commodity in Hawaii, with an estimated value of USD 113 million for green coffee and USD 161 million for roasted coffee in 2022 [There are just under 1000 coffee growers in Hawaii , and thoHypothenemus hampei Ferrari) (Coleoptera: Curculionidae) is widely considered the most damaging insect pest of coffee worldwide [Coffee berry borer  Vuill.  was approved for use on Hawaiian coffee . This entomopathogenic fungus is one of most important natural enemies of CBB and can result in mortality levels of up to 70% [When CBB was first reported in Hawaii, information from other coffee producing countries was identified for incorporation into an integrated pest management (IPM) program. The key components of this program include monitoring, cultural control practices, and the use of biological control agents ,18,19,20p to 70% ,14. B. bassiana, harvesting, and strip-picking [A second important milestone was introduction of the 30-tree sampling method  in 2012 -picking . We term-picking . B. bassiana subsidy program funded by HDOA, SHAC, and USDA-FAS. This program reimbursed growers for up to 75% of the costs associated with spraying approved B. bassiana products (up to USD 9000 per farmer/year) from 2014 to 2016. The program was extended several times, with the most recent programs (2018–2026) reimbursing growers for up to 50% of costs or up to USD 6000 per farmer/year. Since the inception of the subsidy program, the use of commercial B. bassiana products on Hawaii coffee farms increased from 80% of farms in 2013, to 85% of farms in 2015, and 95% of farms in 2016. Among surveyed farmers, ~95% found B. bassiana to be effective. Approximately 30% of surveyed farmers responded that without the subsidy, they would stop growing coffee or strongly consider terminating it as a crop [The last major milestone in the success of the early IPM was establishment of a s a crop . B. bassiana applications [Although the early IPM provided a starting point for CBB management in Hawaii, there were many unknowns regarding the basic biology of CBB under Hawaii’s unique environmental and agroecological conditions. In addition, the high production and labor costs and severe shortage of labor created major challenges for managing this new pest in a way that was economically feasible for growers. Several federal and state agencies, as well as farmer associations and coffee industry professionals worked together to address these issues and improve upon the early IPM based on scientific data collected in the islands. These studies resulted in a better understanding of CBB infestation patterns and flight activity ,25,26, dications ,37,38,39ications ,41, whicB. bassiana alone; (2) the implementation of early IPM, which combined monitoring and sanitation with spraying B. bassiana; and (3) the use of research-based IPM, which provided insights into CBB development, flight behavior, infestation patterns, monitoring techniques, and spray optimization. Findings from this study support the continued development and adoption of IPM strategies, which will increase yields, quality, and revenue to improve the livelihoods of coffee growers in Hawaii.In the present study, our aim was to estimate the economic benefits of managing CBB in Hawaii under three scenarios: (1) the use of To estimate economic benefits under the three scenarios, we first estimated the statewide and regional coffee-bearing acreage from 2006 to 2021 and then used CBB detection dates for each growing region to estimate the infested acreage over time. The rate at which CBB management recommendations were adopted by farmers in Hawaii was then estimated using Rogers’ theory of technology adoption . We thenStatewide bearing coffee acreage in Hawaii has been reported annually by the USDA National Agriculture Statistics Service since 1946. However, the State of Hawaii does not routinely report regional coffee acreage and has not previously attempted to measure CBB infested acreage. To model CBB spread, we developed a procedure to estimate both regional acreage and statewide infested acreage over time. From 2013 to 2016, the state reported regional bearing coffee acreage for most of the nine regions, but not every region and not every year. For our 16-year time-period (2006–2021) and nine growing regions . During 2013–2015, we apply Rogers’ theory of technology adoption assuming the adoption rate for early IPM (type C) to be 0.16 in the first year, 0.23 in the second year, and 0.50 in the third year. During 2016–2018, we apply Rogers’ theory of technology adoption assuming the adoption rate for research-based IPM (type D) to be 0.16 in the first year, 0.23 in the second year, 0.50 in the third year and so on. For years 2016–2019, we computed values of B. bassiana-only usage from survey data collected as part of the HDOA B. bassiana subsidy program  as 0.19, 0.20, 0.18, and 0.086. The remaining values for υjt for j = B, C, D were computed as 1 = υBt +υCt + υDt . We further assume that management reduces infestation and helps to improve yields and prices, and the more effective the management, the lower the infestation level.The economic model to evaluate the impact of infestation levels on yield and price are basic production and price functions between acreage, yield, prices, and management type. The baseline model replicates observed production and available management types. To generate the baseline, we used estimated regional acreage, estimated infested acreage, and rate of adoption for the three management types. Yields and prices were based on infestation and management type. Total production was based on acreage and yields. Total revenue was based on production and prices. ajt for each management type j and time t were calculated using:Estimates of coffee acreage t and values in jt we obtain the distribution of acreage for uninfested, infested, managed, and unmanaged acres  =1, infested unmanaged (ψE) = 0.5, managed by B. bassiana only (ψB) = 0.75, managed by early IPM (ψC) = 0.85, and managed by research-based IPM (ψD) = 0.95. Recall that ωjt represents the proportion of total coffee acreage that is infested, uninfested, managed, and unmanaged. We can derive the value of yFt as follows:Here yt, as the proportion of acreage, ωjt, multiplied by average yield, yjt, for j = B, C, D, E, F: We write coffee yield, Yjt = ψj yFt for all yjt (see Equation (19)): Into Equation (21), we substitute yFt:We rearrange Equation (22) to solve for coffee yield from uninfested acreage, yFt using ωBt in j as described in the previous paragraph, and Yt in j at time t, yjt, using:We can compute yjt are displayed in This method for calibrating yields preserves reported statewide yields since the weighted average of the calibrated yields equals statewide reported yields. Computed baseline yield values yjt to be price per pound of parchment received under management status j and ρjt to be the relative price parameter such that:Average coffee prices are reported annually by the USDA-NASS based on total revenue and total production. Actual prices received by farmers for their crops vary widely depending on coffee quality, supply, and demand. For this analysis, we assumed price decreases with increasing level of CBB infestation. While we do not observe CBB infestation of the coffee sold, we know CBB management reduces infestation ,15, whicFt is the premium price received per pound for uninfested parchment. Values of ρjt are ρBt =87%, ρCt =93%, ρDt =100%, ρEt = 45%, and ρFt =100%. We know that revenue is:Here pt is reported price, Qt is reported production, values for qjt are computed (qjt = yjtajt) using values of average yield yjt , and obtain the expression:Ft:We can rewrite the above equation to solve for pFt, and the corresponding values of pjt = ρjt pFt for the remaining j. This calibration method preserves reported statewide prices since the weighted average of the calibrated price equals the statewide reported price. Computed baseline price values are displayed in We compute premium price per pound for uninfested parchment, pTo quantify the value of CBB research, extension, and management, we developed a hypothetical scenario following the arrival of CBB in Hawaii in 2010. In the hypothetical scenario, there are no statewide efforts or responses from the government, coffee associations, or the university to help farmers manage the crop pest. Outreach, recommendations, subsidies, research, and strategy development are all absent. F) and infested (yE) coffee are the same as the values computed for the baseline, that is infested coffee yield is 50% of uninfested yield . We feel this is a reasonable assumption based on expert panel observations. We assume price for uninfested (pF) and infested (pE) coffee are the same as the values computed for the baseline, that is price for infested coffee is 45% of uninfested coffee i.e., ρE = 0.45 and ρE = ρEρF. This is a simplifying assumption and under this scenario, the price for infested and uninfested coffee could be higher or lower. Roasters may be willing to pay more for both low- and high-quality coffee if the high-quality coffee is in short supply. In addition, the price for low-quality coffee might be relatively closer to the price of high-quality coffee in which case for any given year in the past, the benefit from management could be slightly less than estimated. We assume bearing acreage At remains the same as in the baseline. Uninfested acreage Ut and infested acreage It are as shown in We assumed that CBB arrived in Hawaii and spread across the islands at the same rate as in the baseline (observed). This is a simplifying and conservative assumption as some management recommendations include measures designed to slow the rate of spread within a farm, across farms, and across regions. In the absence of management, it is possible that CBB might have spread faster. However, we feel this is a reasonable assumption given the relatively small (16%) rate of technology adoption in the first year of infestation and fast observed rate of CBB spread even with management. We assume yields for uninfested  early IPM that combined monitoring and sanitation with spraying B. bassiana, starting in 2013; and (3) the use of research-based IPM that focused on improving monitoring techniques, optimizing sprays of B. bassiana, and assessing the impact and feasibility of cultural controls, starting in 2016. Finally, adjustments in yield and prices were based on management effectiveness and bean quality. This study estimated the economic benefits from CBB management in Hawaii over the last 11 years (2011 to 2021) through a collaboration between coffee growers, industry representatives, scientists, extension educators, and economists. We used reported data on coffee acreage in combination with detection dates and expert knowledge to estimate CBB spread across the Hawaiian Islands and to inform model assumptions. Then, adoption rates of management types were based on Roger’s theory of technology adoption. These management types included: (1) the use of the entomopathogenic fungus B. bassiana at USD 50 M. Annually, when all three management types are adopted, the highest return is from research-based IPM. Over a 10-year period, management of CBB-infested acreage in Hawaii has increased from 8% in 2011 to 59% in 2021. During this same period, coffee yields increased by 32%, the price per pound increased by 41%, and revenue per acre increased by 60% due to the improvement of CBB management technology. From 2011 to 2021, the cumulative gain in revenue was USD 251 M with the highest benefit coming from research-based IPM at USD 130 M, followed by early IPM at USD 69 M, and B. bassiana, and compare the economics of various control strategies. Collectively, this project produced >25 peer-reviewed journal articles and six cooperative extension publications and demonstration videos. The findings were shared at multiple in-person and virtual conferences, newsletters, as well as an extension website. Findings from Hawaii-specific studies on CBB management were first incorporated into the 2016 IPM guidelines, marking the beginning of research-based IPM strategies for CBB in Hawaii. This was followed by the initiation of a five-year area-wide IPM grant in 2017, with the aim of developing, testing, and implementing suites of control measures that were specifically tailored to Hawaii’s unique and highly variable coffee-growing landscape. Under this grant, multiple research projects were initiated to simplify monitoring strategies, gain knowledge of CBB biology under varying environmental conditions, determine the feasibility of cultural controls such as frequent and efficient harvesting and strip-picking in different growing regions, optimize the use of B. bassiana early in the season during peak CBB flight activity, and (4) frequent and efficient harvesting [As a result, an improved location-specific research-based IPM was developed and implemented over the years that followed. IPM adoption in Hawaii was facilitated by grower associations and industry to provide long-term funding and extension support. Briefly, the research-based CBB IPM program is defined by four major practices: (1) field sanitation including pruning, weed removal, strip-picking, and stumping by blocks; (2) monitoring CBB populations using traps and/or a simplified method of surveying for berry infestation, (3) applying rvesting . Our fin


We included 12,800 individuals, with a mean age of 50.5, in the final analysis. The means of the total and added sugar intake, total sugar (%E), and added sugar (%E) were 28.2 ± 0.2 g/d, 5.0 ± 0.1 g/d, 6.0 ± 0.0%, and 1.0 ± 0.0%, respectively. The overall prevalence of self-reported physician-diagnosed diabetes was 4.0%. A significant association between the total sugar intake and an increased risk of diabetes was found . The mediation analysis showed a significant mediation effect through the BMI of the effect of the total sugar on diabetes status (p < 0.001), where 11.7% (95% CI: 4.7–35.7%) of the effect of the total sugar on diabetes was mediated through the BMI. The total sugar intake had a significant direct effect on diabetes around the BMI . The overall total-sugar-intake–diabetes association remained significant in normal-weight participants in the subgroup analysis . In conclusion, although the BMI moderated and mediated the association between the total sugar intake and diabetes, the total sugar still showed some unique weight-independent diabetogenic effects. Our findings call for efforts to prevent and control diabetes by reducing sugar intake, and losing weight appropriately.Sugar intake has been linked to the global rise in diabetes. However, the unique diabetogenic effect of sugar, independent of weight gain, remains controversial. This study aimed to investigate the associations between total and added sugar intake and diabetes status, and to test whether the sugar–diabetes associations were moderated or mediated by the body mass index (BMI). We performed a nationwide cross-sectional study on 12,889 Chinese adults who were enrolled in the China Health and Nutrition Survey (CHNS) 2011. The data for the total and added sugar intake were measured using three consecutive 24 h recalls, and determined based on the U.S. Department of Agriculture (USDA) National Nutrient Database for Standard Reference, Release 28 (SR28), the Food Patterns Equivalents Database (FPED) 2015–2016, and the labeled ingredients and nutrient contents. A multivariable logistic regression model was used to analyze the associations between the total and added sugar intake and diabetes. A nutrient density model was used to adjust for the total energy intake. A mediation analysis for significant sugar–diabetes associations shown in multivariable logistic analysis ( Diabetes is an important global health issue affecting approximately 537 million adults aged 20–79 years, and imposing a substantial disease and economic burden on all countries ,2,3. AlaThe etiology of diabetes is believed to be multifactorial, and involves an interplay between genetic, dietary, physical activity, and environmental factors ,7,8. Of Therefore, this study aimed to use the China Health and Nutrition Survey (CHNS) 2011, a nationwide cross-sectional study with a representative sample of Chinese individuals and a standard design and strict quality control procedure, to investigate, for the first time in China, the associations between the total and added sugar intake and diabetes status, and to test whether the associations were mediated or moderated by the BMI.The data for this study were derived from the 2011 wave of the CHNS, the most recent national dietary data available from the CHNS to date. The CHNS is a nationwide prospective cohort study conducted every 2–4 years since 1989 using a multi-stage, random clustering process to draw a sample of over 30,000 participants in China . The samn = 12,889). Participants were excluded when no diabetes diagnosis information was available (n = 89), leaving 12,800 individuals. The CHNS was approved by the ethical review committees of the Chinese Center for Disease Control and Prevention, and the Carolina Population Center at the University of North Carolina at Chapel Hill. Signed, informed consent was obtained from all participants before the survey.This study included adults aged 18 years or older who participated in the CHNS in 2011 with dietary information for two or more days  and lifestyle information  were obtained through a structured interview. The weight and height of participants were measured based on the WHO standard, using calibrated beam scales and portable stadiometers, respectively. The BMI was defined as weight in kilograms divided by height in meters squared. Overweight and obese were defined as a BMI of 24.0–27.9 kg/min China . Physicain China ,24.As the outcome, diabetes was identified by using the questionnaire-based interview. Self-reported physician-diagnosed diabetes was considered if participants answered ‘yes’ to the question: “Has a doctor ever told you that you suffer from diabetes”?t-test, Mann–Whitney U test, or chi-squared test were used for the between-group comparisons, as appropriate. The total and added sugar intake, the percentage of total energy from total sugar ), and the percentage of total energy from added sugar (added sugar (%E)) were presented both as means with standard errors (SEs) and medians with IQR . Comparisons on %E between the low and high sugar groups were performed using the Mann–Whitney U test. Given the large sample size of the study, we expected a statistically significant difference between the two groups in most characteristics, but would consider a difference of at least 5% as clinically meaningful.The basic demographics and characteristics of the participants were summarized as means and standard errors (SEs) or medians and interquartile ranges (IQR)  for the continuous variables , and frequencies (percentages) for the categorical variables , both overall, and by total sugar intake. Specifically, participants were divided into Group 1 (lower sugar intake) and Group 2 (higher sugar intake) according to the median value of the total sugar intake (21.9 g/d), and participants’ demographics and characteristics were summarized by the sugar intake groups. Student’s 2, 24.0~27.9 kg/m2, or ≥28 kg/m2) to explore potential heterogeneous associations between sugar intake and diabetes in the BMI subgroups [In the nutrient density model, we used multivariable logistic regression models to analyze the associations between the total and added sugar intake per 1000 kcal and diabetes, while controlling for covariates. Specifically, the primary analysis was conducted using Model 1 to evaluate the sugar-intake–diabetes association, while controlling for basic demographics (age and gender); Model 2 was used to investigate the robustness of the sugar-intake–diabetes association found in Model 1, after further controlling for lifestyle variables  . Given tubgroups . The medp < 0.05 (two-tailed tests). The mediation analysis was conducted with R statistical package 4.2.2 (http://www.r-project.org (accessed on 21 January 2023)), using the “mediation” package. Other analyses were performed using International Business Machines (IBM) Statistical Package for the Social Sciences (SPSS) version 26.0 .All tests were two-sided, and statistical significance was determined at p < 0.05). However, the magnitude of the differences in age and the distribution of age group, gender, and smoking status between the groups was not considered clinically meaningful  were female. The mean age was 50.5 years. The higher-sugar-intake group was significantly younger, and contained more males, overweight or obese people, non-smokers, and never-drinkers, and those with higher physical activity, total energy intake, total fat intake, total protein intake, and total carbohydrate intake than the lower-sugar-intake group . A similar phenomenon was observed for the total sugar intake among participants aged 60 years or older (p = 0.004). These four variables were higher in diabetic males than in non-diabetic males . In addition, normal-weight diabetics had a higher total sugar (%E) than non-diabetics in the same BMI category (p = 0.011). Overweight diabetics also had higher total sugar (%E), added sugar intake, and added sugar (%E) than overweight non-diabetics . All of the above differences between diabetics and non-diabetics were clinically meaningful.Our result showed that the overall prevalence of self-reported, physician-diagnosed diabetes was 4.0%. The total sugar intake, added sugar intake, total sugar (%E), and added sugar (%E) by age, gender, and BMI categories among participants with different diabetes statuses are presented in In the multivariable logistic analysis on the association between the total and added sugar intake and diabetes, we found that a higher total sugar intake was significantly associated with higher odds of diabetes in Model 1 (adjusted for age and gender) and Model 2 . There were no associations between the added sugar intake and diabetes in either model .p < 0.001), but also has a significant indirect effect on diabetes through the BMI, which mediated 11.7%  of the total-sugar–diabetes association (The mediation analysis demonstrated that total sugar not only has a significant direct effect on diabetes around the BMI (estimated coefficient = 0.0004, ociation .2 in either the minimally adjusted or fully adjusted models (In the subgroup analysis according to the BMI category, a significant association between the total sugar intake and diabetes was observed in participants with a BMI value < 24.0 kg/md models .In this nationwide cross-sectional study, with data collected from 12,800 adults in the CHNS 2011, we provide the first evidence of a significant association between total sugar intake and increased odds of diabetes in China, which remained significant only in normal-weight participants in the subgroup analysis, after adjusting for participants’ age, gender, and lifestyle. In addition, we found that although the BMI mediated 11.7% of the total-sugar–diabetes association, the total sugar intake still exhibits significant unique weight-independent diabetogenic effects.Consistent with our study, the associations between sugar intake and diabetes have been previously reported by a number of studies. For instance, based on a large cohort of 38,480 initially healthy postmenopausal women followed for an average of 6 years, Janket, S. J. et al. reported a definitive effect of sugar intake on the risk of developing type 2 diabetes, after adjusting for age and smoking . A syste2, whereas no association was observed in those with higher BMI values, after controlling for participants’ age, gender, and lifestyle. Our findings in the normal-weight group suggest that the total sugar intake has some unique weight-independent diabetogenic effects. This speculation was confirmed by our mediation analysis of the pathway from the total sugar intake to the BMI to diabetes, which showed that the total sugar not only had an indirect effect on diabetes via the BMI, but also had a direct effect on diabetes around the BMI. This can be explained by some biological mechanisms. In addition to elevating the blood glucose [To explore the moderating and mediating effect of the BMI on total-sugar–diabetes associations, we conducted a subgroup analysis according to the BMI status, and mediation analysis. Interestingly, in the subgroup analysis, we found that the total sugar intake was positively associated with diabetes in participants with a BMI value < 24.0 kg/m glucose , the sug glucose , which h glucose ,30. With glucose ,32. The  glucose ,14. ThisWith the largest number of adults aged 20–79 years with diabetes in 2021 , a limitTo the best of our knowledge, this is the first study to provide data on the total and added sugar intake among Chinese adults. This is also the first to estimate the sugar–diabetes association in China, taking into account both the moderating and mediating effects of the BMI. The strengths of this study also include its standardized design, nationally representative sample size, and rigorous dietary-measurement procedures, allowing us to provide a relatively accurate report of the sugar–diabetes association in the largest developing country, with the largest number of diabetic adults, in the world.Our study had several limitations. Firstly, as the data on the total and added sugar content are not yet available in the China Food Composition, the SR28 and FPED 2015–2016 combined for the labeled ingredients and nutrient contents were used, which may not fully apply to Chinese foods. Secondly, our study relied on self-reported physician-diagnosed diabetes. The prevalence of diabetes was likely underestimated. Thirdly, because the CHNS has not yet published dietary data after 2011, our study used data from the CHNS 2011, which are the most recent national dietary data available from the CHNS to date.In conclusion, in this nationwide cross-sectional study of 12,800 participants, we report a significant association between total sugar intake and increased odds of diabetes, which remained significant in normal-weight participants in the subgroup analysis. In addition, we found a significant mediation effect of the total sugar, through the BMI, on diabetes status. The total sugar intake also had a significant direct effect on diabetes around the BMI. Taken together, our study provides further evidence that although the BMI moderated and mediated the association between the total sugar intake and diabetes, the total sugar still exhibits direct diabetogenic effects. These findings call for efforts to tackle diabetes by encouraging people to reduce their sugar intake and lose weight appropriately.