Aging-induced memory loss due to decreased N1-acetyl-5-methoxykynuramine,a melatonin metabolite,in the hippocampus:a potential prophylactic agent for dementia

Melatonin(N-acetyl-5-methoxytryptamine)is known as the hormone of darkness because it is synthesized at night and involved in regulating the circadian clock.The hormone is primarily synthesized by the vertebrate pineal gland,but is ubiquitous among invertebrates,unicellular organisms,plants,and even cyanobacteria(Hattori and Suzuki,2024).Melatonin is well-conserved evolutionarily and possesses several physiological functions,such as immune response,bone and glucose metabolism,and memory formation besides regulating the circadian rhythm.

Recent progress in the applications of presynaptic dopaminergic positron emission tomography imaging in parkinsonism

Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.

Unraveling brain aging through the lens of oral microbiota

The oral cavity is a complex physiological community encompassing a wide range of microorganisms.Dysbiosis of oral microbiota can lead to various oral infectious diseases,such as periodontitis and tooth decay,and even affect systemic health,including brain aging and neurodegenerative diseases.Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration,indicating potential avenues for intervention strategies.In this review,we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases,and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration.We also highlight advances in therapeutic development grounded in the realm of oral microbes,with the goal of advancing brain health and promoting healthy aging.

Proteostasis failure:at the intersection between aging and Alzheimer's disease

Lifestyle and demographics of the world's population are causing serious health problems impacting the brain,increasing the incidence of Alzheimer's disease(AD)and other types of dementia.Although we have gained important insights into the pathogenic mechanisms of AD,only palliative care is available to patients.AD is characterized by the abnormal deposition of protein aggregates in the brain formed by amyloid β and hyper-phosphorylated,Tau in addition to neuroinflammation.

Diabetic foot attack:Managing severe sepsis in the diabetic patient

Diabetic foot attack(DFA)is the most severe presentation of diabetic foot disease,with the patient commonly displaying severe sepsis,which can be limb or life threatening.DFA can be classified into two main categories:Typical and atypical.A typical DFA is secondary to a severe infection in the foot,often initiated by minor breaches in skin integrity that allow pathogens to enter and proliferate.This form often progresses rapidly due to the underlying diabetic pathophysiology of neuropathy,microvascular disease,and hyperglycemia,which facilitate infection spread and tissue necrosis.This form of DFA can present as one of a number of severe infective pathologies including pyomyositis,necrotizing fasciitis,and myonecrosis,all of which can lead to systemic sepsis and multiorgan failure.An atypical DFA,however,is not primarily infection-driven.It can occur secondary to either ischemia or Charcot arthropathy.Management of the typical DFA involves prompt diagnosis,aggressive infection control,and a multidisciplinary approach.Treatment can be guided by the current International Working Group on the Diabetic Foot/Infectious Diseases Society of America guidelines on diabetic foot infections,and the combined British Orthopaedic Foot and Ankle Society-Vascular Society guidelines.This article highlights the importance of early recognition,comprehensive management strategies,and the need for further research to establish standardized protocols and improve clinical outcomes for patients with DFA.

Assessing healthcare workers’knowledge and confidence in the diagnosis,management and prevention of Monkeypox

BACKGROUND Monkeypox(Mpox),is a disease of global public health concern,as it does not affect only countries in western and central Africa.AIM To assess Burundi healthcare workers(HCWs)s’level of knowledge and confidence in the diagnosis and management of Mpox.METHODS We conducted a cross-sectional study via an online survey designed mainly from the World Health Organization course distributed among Burundi HCWs from June-July 2023.The questionnaire comprises 8 socioprofessional-related questions,22 questions about Mpox disease knowledge,and 3 questions to assess confidence in Mpox diagnosis and management.The data were analyzed via SPSS software version 25.0.A P value<0.05 was considered to indicate statistical significance.RESULTS The study sample comprised 471 HCWs who were mainly medical doctors(63.9%)and nurses(30.1%).None of the 22 questions concerning Mpox knowledge had at least 50%correct responses.A very low number of HCWs(17.4%)knew that Mpox has a vaccine.The confidence level to diagnose(21.20%),treat(18.00%)or prevent(23.30%)Mpox was low among HCWs.The confidence level in the diagnosis of Mpox was associated with the HCWs’age(P value=0.009),sex(P value<0.001),work experience(P value=0.002),and residence(P value<0.001).The confidence level to treat Mpox was significantly associated with the HCWs’age(P value=0.050),sex(P value<0.001),education(P value=0.033)and occupation(P value=0.005).The confidence level to prevent Mpox was associated with the HCWs’education(P value<0.001),work experience(P value=0.002),residence(P value<0.001)and type of work institution(P value=0.003).CONCLUSION This study revealed that HCWs have the lowest level of knowledge regarding Mpox and a lack of confidence in the ability to diagnose,treat or prevent it.There is an urgent need to organize continuing medical education programs on Mpox epidemiology and preparedness for Burundi HCWs.We encourage future researchers to assess potential hesitancy toward Mpox vaccination and its associated factors.

Immunoglobulin G-mediated food intolerance and metabolic syndrome influence the occurrence of reflux esophagitis in Helicobacter pylori-infected patients

BACKGROUND Reflux esophagitis has an increasing prevalence and complex and diverse symptoms.Identifying its risk factors is crucial to understanding the etiology,prevention,and management of the disease.The occurrence of reflux esophagitis may be associated with food reactions,Helicobacter pylori(H.pylori)infection,and metabolic syndromes.AIM To investigate the risk factors for reflux esophagitis and analyze the effects of immunoglobulin(Ig)G-mediated food intolerance,H.pylori infection,and metabolic syndrome on reflux esophagitis.METHODS Outpatients attending the Second Medical Center of the PLA General Hospital between 2017 and 2021 were retrospectively enrolled.The patients’basic information,test results,gastroscopy results,H.pylori test results,and IgG-mediated food intolerance results were collected.Multivariate logistic regression analysis was used to analyze risk factors for reflux esophagitis.Statistical mediation analysis was used to evaluate the effects of IgG-mediated food intolerance and metabolic syndrome on H.pylori infection affecting reflux esophagitis.RESULTS A total of 7954 outpatients were included;the prevalence of reflux esophagitis,IgG-mediated food intolerance,H.pylori infection,and metabolic syndrome were 20.84%,61.77%,35.91%,and 60.15%,respectively.Multivariate analysis showed that the independent risk factors for reflux esophagitis included IgG-mediated food intolerance(OR=1.688,95%CI:1.497-1.903,P<0.00001)and metabolic syndrome(OR=1.165,95%CI:1.030-1.317,P=0.01484),and the independent protective factor for reflux esophagitis was H.pylori infection(OR=0.400,95%CI:0.351-0.456,P<0.00001).IgG-mediated food intolerance had a partially positive mediating effect on H.pylori infection as it was associated with reduced occurrence of reflux esophagitis(P=0.0200).Metabolic syndrome had a partially negative mediating effect on H.pylori infection and reduced the occurrence of reflux esophagitis(P=0.0220).CONCLUSION Patients with IgG-mediated food intolerance and metabolic syndrome were at higher risk of developing reflux esophagitis,while patients with H.pylori infection were at lower risk.IgG-mediated food intolerance reduced the risk of reflux esophagitis pathogenesis in patients with H.pylori infection;however,metabolic syndrome increased the risk of patients with H.pylori infection developing reflux esophagitis.

Simple procedure for assessing diffuse subarachnoid hemorrhage successfully created using filament perforation method in mice

The murine model of subarachnoid hemorrhage(SAH)is a valuable experimental tool for investigating molecular and cellular mechanisms,and the endovascular filament perforation technique can be used to simulate prominent pathophysiological features observed after human SAH;however,current validation methods for assessing an appropriate SAH model are limited.Here,we introduce a simple procedure for se-lecting a mouse model of diffuse SAH.SAH was induced in 24 mice using a standard filament perforation method.After confirming survival at 24 h,SAH was scored 0-1 based on T2*-weighted images on whole-brain magnetic resonance imaging(MRI)and visual surveillance of the cisterna magna(CM)through the dura mater.The CM-based SAH grading correlated well with a reference parameter defined by extracted brain(r^(2)=0.53,p<0.0001).The receiver operating characteristic curve revealed a sensi-tivity of 85%and a specificity of 91%for detecting diffuse SAH,with a similar area under the curve(0.89±0.06[standard error of the mean])as the MRI-based grading(0.72±0.10,p=0.12).Our data suggest that confirming an SAH clot in the CM is a valuable way to select a clinically relevant diffuse SAH model that can be used in future experimental studies.

Farmers’ Knowledge and Awareness towards the Use of Agrochemicals in Vegetable Cultivation, Fako Cameroon

Agrochemicals are contemporary, omnipresent tool used in vegetable cultivation. Farmers’ knowledge and awareness of the proper usage of agrochemicals are critical for mitigating the negative effects on human health. This cross-sectional study was aimed at assessing the usage knowledge, risk awareness of toxicological and chemical classes, proper handling and use practices for agrochemicals homologated for use in vegetable farming, and the occurrence of health-related symptoms as a result of exposure among these farmers. The study included 93 vegetable growers from agricultural hotspot towns in Fako, southwest Cameroon. The field study, ran from November 2021 to December 2023, using a questionnaire to collect information on farmers demographic, and their knowledge of pesticide classes, and the related risk of associated with the handling of agrochemicals. Results show that all vegetable farmers, particularly those engaged in agribusiness, employ pesticide inputs to maximize production. Six pesticides, two fertilizer types, and one unknown substance were identified. While 23 active compounds were found, the most utilized were abamectin, emamectin (10.46%), dimethoate (9.30%,) and ethoprophos (8.13%). Two active chemicals, dimethoate and methalaxyl, are illegal yet remain in circulation. Toxicological classes I and II, with the greatest harmful effect on human health, were the most commonly utilized (64.27%). Thirty-nine percent of farmers never use personal protection equipment when working with agrochemicals, demonstrating a significant gap in knowledge and awareness of agrochemicals and their various applications and handling procedures in the field. The government should implement an intensive specialized educational program for on-field farmers with incentives in order to promote sustainable agriculture methods that ensure environmental and human safety.

Mapping the evolution of liver aging research:A bibliometric analysis

BACKGROUND With the increasing of the global aging population,healthy aging and prevention of age-related diseases have become increasingly important.The liver,a vital organ involved in metabolism,detoxification,digestion,and immunity,holds a pivotal role in the aging process of organisms.Although extensive research on liver aging has been carried out,no bibliometric analysis has been conducted to evaluate the scientific progress in this area.AIM To analyze basic knowledge,development trends,and current research frontiers in the field via bibliometric methods.METHODS We conducted bibliometric analyses via a range of analytical tools including Python,the bibliometrix package in R,CiteSpace,and VOSviewer.We retrieved publication data on liver aging research from the Web of Science Core Collection Database.A scientific knowledge map was constructed to display the contributions from different authors,journals,countries,institutions,as well as patterns of co-occurrence keywords and co-cited references.Additionally,gene regulation pathways associated with liver aging were analyzed via the STRING database.RESULTS We identified 4288 articles on liver aging,authored by 24034 contributors from 4092 institutions across 85 countries.Notably,the years 1991 and 2020 presented significant bursts in publication output.The United States led in terms of publications(n=1008,25.1%),citations(n=55205),and international collaborations(multiple country publications=214).Keywords such as“lipid metabolism”,“fatty liver disease”,“inflammation”,“liver fibrosis”and“target”were prominent,highlighting the current research hotspots.Notably,the top 64 genes,each of which appeared in at least 8 articles,were involved in pathways essential for cell survival and aging,including the phosphatidylinositol 3-kinase/protein kinase B,Forkhead box O and p53 signaling pathways.CONCLUSION This study highlights key areas of liver aging and offers a comprehensive overview of research trends,as well as insights into potential value for collaborative pursuits and clinical implementations.

Ageism: Millennial Persistence

This work develops the idea that is possible to affirm that beyond its nuances. Ageism has shown a surprising force of prevalence in western society. Nourished by mythical, empirical, ideological and health elements, it has been enormously successful in imposing an image of vulnerability, decrepitude and illness on older adults. Since 1969, when the first academic article on the subject was published, much has been written on the subject, but little progress has been made in terms of social and state policies and community awareness. When an attempt has been made to propose an alternative to decrepit (Aristotelian as we suggest in this paper) ageism, nothing has emerged but a new kind of ageism that has imposed the supposed need that the older adult “must” be “productive”, “young”, “vigorous”, posing the impossibility, in short, once again, of the older adult living spontaneously as an older adult.

Power Relations in Older Adults’ Cognitive Interaction in Clinical Setting: A Multimodal Pragmatic Perspective

This study explored the construction of power relations in the cognitive assessment of older adults within the Chinese clinical context.Data is derived from audio and video recordings that nine older adults produced in the cognitive assessment of the Chinese version of the Montreal Cognitive Assessment-Basic(MoCA-B),which were then annotated and analyzed from a multimodal pragmatic perspective.The study reveals that examiners and older adults employed various speech acts to achieve distinct communicative goals,with power relations between them being reflected through these speech acts.Examiners tend to claim high power,utilizing discourse strategies such as request,interruption,evaluation,rhetorical questions,and directive speech acts.In contrast,older adults assert high power through directive speech acts,rhetorical questions,and interruptions.Both parties also exhibit low power by using confirming questions and explanations.Additionally,gestures,smiles,prosody features,and other non-verbal communicative resources are synergistically employed to exercise power.The interactive mechanism of constructing power relations reveals that age affects older adults’power relations construction even in a professional setting of the Chinese context.The negotiation between the advanced age of older adults and the expertise of examiners jointly shapes power relations in their interactions.

The Applications of CRISPR Screening in Aging Research

The advancement of Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)gene editing technology has revolutionized the comprehension of human genome,propelling molecular and cellular biology research into unexplored realms and accelerating progress in life sciences and medicine.CRISPR-based gene screening,recognized for its efficiency and practicality,is widely utilized across diverse biological fields.Aging is a multifaceted process governed by a myriad of genetic and epigenetic factors.Unraveling the genes regulating aging holds promise for understanding this intricate phenomenon and devising strategies for its assessment and intervention.This review provides a comprehensive overview of the progress in CRISPR screening and its applications in aging research,while also offering insights into future directions.CRISPR-based genetic-manipulation tools are positioned as indispensable instruments for mitigating aging and managing age-related diseases.

Preventing brain aging by the artificial enforcement of the unfolded protein response:future directions

As the life expectancy of the world’s population increases,age-related diseases are emerging as one of the greatest problems facing modern society.The onset of dementia and neurodegenerative diseases is strictly dependent on aging as a major risk factor and has a profound impact on various aspects of the lives of individuals and their families.

In Vivo Improvements in Facial Appearance and in Vitro Changes in Gene Expression Using a Topical Formulation Designed to Repair Environmentally Induced DNA Damage

Background: While sunscreen has been accepted as a mainline defence against photodamage from ultraviolet, visible light and near-infrared radiation, there appears to be a lack of research into photorepair. The concept of protecting the skin during the day and repairing cellular damage at night is intuitive, yet specific strategies revolving around combinations of proven reparative active ingredients remain unelucidated. Purpose: To investigate the efficacy of a solar repair Formulation following ultraviolet and environmental exposure in order to improve overall skin health and appearance through three hypotheses: The Formulation increases expression of DNA repair mechanisms markers;The Formulation enhances overall skin appearance through reducing signs of inflammation, elevating hydration, reinforcing skin firmness and amplifying radiance;In-Vivo efficacy test results are aligned with measured gene expression changes. Methods: The Formulation (#6NIC1.V1.1-1) was tested for: In-vitro LDH cytotoxicity activity, In-vitro qPCR gene expression with and without ultraviolet exposure on a reconstructed 3-dimensional skin model, and In-Vivo efficacy study on a panel of 22 participants objectively and subjectively. Results: Skin radiance, firmness, hydration, redness, and inflammation are significantly improved after In-Vivo skin exposure to the Formulation and environmental challenges such as ultraviolet radiation. These outcomes were confirmed by in-vitro genetic testing on a reconstructed human skin model. Conclusion: The studies allowed us to identify and group results in four main skin functions that were significantly enhanced following the application of the Formulation: firmness, hydration, radiance and soothing.

Unlocking the potential of unlabeled data:Self-supervised machine learning for battery aging diagnosis with real-world field data

Accurate aging diagnosis is crucial for the health and safety management of lithium-ion batteries in electric vehicles.Despite significant advancements achieved by data-driven methods,diagnosis accuracy remains constrained by the high costs of check-up tests and the scarcity of labeled data.This paper presents a framework utilizing self-supervised machine learning to harness the potential of unlabeled data for diagnosing battery aging in electric vehicles during field operations.We validate our method using battery degradation datasets collected over more than two years from twenty real-world electric vehicles.Our analysis comprehensively addresses cell inconsistencies,physical interpretations,and charging uncertainties in real-world applications.This is achieved through self-supervised feature extraction using random short charging sequences in the main peak of incremental capacity curves.By leveraging inexpensive unlabeled data in a self-supervised approach,our method demonstrates improvements in average root mean square errors of 74.54%and 60.50%in the best and worst cases,respectively,compared to the supervised benchmark.This work underscores the potential of employing low-cost unlabeled data with self-supervised machine learning for effective battery health and safety management in realworld scenarios.

Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.

Physical activity and amyloid beta in middle-aged and older adults:A systematic review and meta-analysis

Background:One of the pathological hallmarks distinguishing Alzheimer’s disease from other dementias is the accumulation of amyloid beta(Aβ).Higher physical activity is associated with decreased dementia risk,and one potential path could be through Aβlevels modulation.We aimed to explore the relationship between physical activity and Aβin middle-aged and older adults.Methods:A systematic search of PubMed,Web of Science,PsycINFO,Cochrane Central Register of Controlled Trials,and SPORTDiscus was performed from inception to April 28,2022.Studies were eligible if they included physical activity and Aβdata in adults aged 45 years or older.Multi-level metaanalyses of intervention and observational studies were performed to examine the role of physical activity in modulating Aβlevels.Results:In total,37 articles were included(8 randomized controlled trials,3 non-randomized controlled trials,4 prospective longitudinal studies,and 22 cross-sectional studies).The overall effect size of physical activity interventions on changes in blood Aβwas medium(pooled standardized mean difference=-0.69,95%confidence interval(95%CI):-1.41 to 0.03;I^(2)=74.6%).However,these results were not statistically significant,and there were not enough studies to explore the effects of physical activity on cerebrospinal fluid(CSF)and brain Aβ.Data from observational studies were examined based on measurements of Aβin the brain using positron emission tomography scans,CSF,and blood.Higher physical activity was positively associated with Aβonly in the CSF(Estimate r=0.12;95%CI:0.05-0.18;I^(2)=38.00%).Conclusion:Physical activity might moderately reduce blood Aβin middle-aged and older adults.However,results were only near statistical significance and might be interpreted with caution given the methodological limitations observed in some of the included studies.In observational studies,higher levels of physical activity were positively associated with Aβonly in CSF.Therefore,further research is needed to understand the modulating role of physical activity in the brain,CSF,and blood Aβ,as well as its implication for cognitive health.

Surgical management of the diabetic foot:The current evidence

The prevalence of diabetes mellitus and its associated complications,particularly diabetic foot pathologies,poses significant healthcare challenges and economic burdens globally.This review synthesises current evidence on the surgical management of the diabetic foot,focusing on the interplay between neuropathy,ischemia,and infection that commonly culminates in ulcers,infections,and,in severe cases,amputations.The escalating incidence of diabetes mellitus underscores the urgency for effective management strategies,as diabetic foot complications are a leading cause of hospital admissions among diabetic patients,significantly impacting morbidity and mortality rates.This review explores the pathophysiological mechanisms underlying diabetic foot complications and further examines diabetic foot ulcers,infections,and skeletal pathologies such as Charcot arthropathy,emphasising the critical role of early diagnosis,comprehensive management strategies,and interdisciplinary care in mitigating adverse outcomes.In addressing surgical interventions,this review evaluates conservative surgeries,amputations,and reconstructive procedures,highlighting the importance of tailored approaches based on individual patient profiles and the specific characteristics of foot pathologies.The integration of advanced diagnostic tools,novel surgical techniques,and postoperative care,including offloading and infection control,are discussed in the context of optimising healing and preserving limb function.

Outcome of nonerosive gastro-esophageal reflux disease patients with pathological acid exposure

AIM： To assess the management and outcome of nonerosive gastro-esophageal reflux disease （NERD） patients who were identified retrospectively, after a 5-year follow-up. METHODS： We included patients with gastro-esophageal reflux disease （GERD） symptoms who had a negative endoscopy result and pathological 24-h esophageal pH-monitoring while off therapy. We interviewed them after an average period of 5 years （range 3.5-7 years） by means of a structured questionnaire to assess presence of GERD symptoms, related therapy, updated endoscopic data and other features. We assessed predictors of esophagitis development by means of univariate and multivariate statistical analysis. RESULTS： 260 patients （137 women） were included. Predominant GERD symptoms were heartburn and regurgitation in 103/260 （40%）. 70% received a maintenance treatment, which was proton pump inhibitor （PPI） in 55% of cases. An average number of 1.5 symptomatic relapses per patient/year of follow-up were observed. A progression to erosive gastro-esophageal reflux disease （ERD） was found in 58/193 （30.0%） of patients undergoing repeat endoscopy; 72% of these were Los Angeles grade A-B. CONCLUSION： This study to ERD occurs in about 5% shows that progression of NERD cases per year, despite therapy. Only two factors consistently and independently influence progression： smoking and absence of PPI therapy.