Recently, vitamin D is considered a pleiotropic hormone, and as such, it has also become a topic of renewed interest in neuropsychiatry for its proposed role in the aetiology and pathophysiology of different psychiatric conditions, including mood disorders (MDs). This seems particularly crucial while considering the relatively high and often neglected prevalence of hypovitaminosis D in the general population and in specific groups, such as patients suffering from the most common type of MDs, which are major depression (MDD) and bipolar disorders (BDs). Therefore, in view of the controversial literature and findings on this topic and its potential therapeutic implications, the present study aimed at evaluating vitamin D levels in the plasma of a sample of inpatients fulfilling the DSM-5 criteria for mood episodes within BDs. The clinical picture was assessed by means of specific rating scales. The results showed that the vitamin D levels  of the bipolar patients of our sample were significantly lower (14.58 ± 11.27 nmol/L) than the normative values (>30 nmol/L). Eleven patients had sufficient values and only 4 had optimal, while 19 showed insufficient, 18 critical, and 17 severely critical levels. No differences emerged according to different socio-demographic or clinical features. In our opinion, the present findings strengthen previous research highlighting decreased vitamin D levels in bipolar patients and support the role of this pleiotropic hormone in BDs. Nevertheless, further studies should follow to corroborate the data of this preliminary study and to address the potential benefits of vitamin D supplementation in the treatment of MDs. Mood disorders (MDs) show a high lifetime prevalence in the general population and represent a leading cause of disability worldwide . As repoCurrently, it is agreed that the aetiology and pathophysiology of BDs are complex and multifaceted, as probably they involve the intertwining between individual vulnerability that might also be based on genetics, epigenetics, neurotransmitters, immune and central nervous (CNS) systems, and environmental factors ,9,10,11.Recently, converging data highlighted that nutritional/dieting factors may show relevant relationships with the aetiology, evolution, prevention, and, possibly treatment of mental disorders . Given tIn spite of the increasing amount of data on the high prevalence of different degrees of hypovitaminosis D in the general population worldwide, this problem is largely underestimated, with the disappointing outcome that the achievement of the recommended vitamin D status is an objective far from being reached even in several most-advanced Western countries .Albeit increasing, scattered findings would indicate that patients suffering from different psychopathological conditions, such as psychotic disorders , anxietyThe same is true for MDs, as the overall findings are intriguing but still controversial, mainly for the paucity of available evidence. A link between depressive symptoms and lower vitamin D levels was reported in different samples of adult depressed patients ,37,38,39In BDs, vitamin D deficiency has been reported in acute manic episodes  and in pOn the other hand, most of the studies reported no significant differences in vitamin D levels between patients with BDs and other psychiatric disorders, such as depression, psychosis, obsessive-compulsive disorder (OCD), and dementia ,45,46. AIn spite of the evident, albeit controversial, findings existing in the literature, the hypothesis that vitamin D supplementation, a quite easy and tolerated treatment, might represent a useful therapeutic strategy to boost the treatment of both BDs and MDD patients is still an intriguing and debated topic. In one study, an eight-week supplementation with vitamin D3 could improve the symptoms of a manic episode . Again, On the contrary, a double-blind placebo-controlled trial did not replicate these results , as alsoGiven the limited and heterogeneous information currently available, together with the potential therapeutic impact, the aim of the present study was at evaluating vitamin D levels in a group of hospitalized patients suffering from BDs, well characterized from the clinical point of view. In addition, we assessed the possible existence of correlations between the biomarker and patients’ characteristics.Sixty-nine inpatients of both sexes  were recruited at the “Casa di cura Morana”  in the month’s March–June 2021. All patients had been hospitalized for BDs, according to DSM-5 criteria, given the severity of their mood episodes. They belonged to the same geographical area, with similar life habits and Mediterranean diet. The clinical examination and routine blood and urine tests excluded major medical diseases.The rating scales used to assess the quality and severity of the clinical characteristics were the following: Mini International Neuropsychiatric Interview (MINI) , HamiltoThe MINI is a structured clinical interview widely used by clinicians to diagnose the most common psychiatric disorders, according to DSM criteria. It is a rapid, sensitive, reliable instrument to be used easily in clinical practice .The 21-item HRSD represents the most used tool to assess clinical depression. It is a self-rating scale that is easy and fast to complete and takes into consideration both the extent and frequency of the symptoms . The sevThe mean HRSD total score of the patients in the depressed phase was 26 ± 4.The YMRS is an 11-item scale that explores the key symptoms of mania that are generally present throughout the entire clinical course (from the most modest to the most severe phases) .The mean YMRS total score of the patients in the manic phase was 40 ± 5.The CGI-S is a questionnaire to rate the severity of the patient’s illness at the time of the visit. The scale is endowed with three items. The ensuing scores are the following: 1. Healthy; 2. Borderline; 3. Slightly ill; 4. Moderately ill; 5. Markedly ill; 6. Severely ill; 7. Very high severity .All patients showed a score between 5 and 7.2 test (or Fisher’s exact test when appropriate) was applied to compare categorical variables. Pearson’s correlation coefficient or Spearman rank correlation was used to assess the possible correlations between different parameters and between subjects’ characteristics and biomarkers. All statistical analyses were carried out using SPSS, version 27 .All data for continuous variables were presented as ranges  and mean ± standard deviation (SD). Frequencies (numbers) and percentages were used to express categorical variables. The normality of the distribution of the variables was assessed by the Kolmogorov-Smirnov test. The intergroup differences were determined by the one-way analysis of variance (ANOVA). The χTen mL of venous blood was drawn from all fasting and sitting subjects between 8 and 9 a.m. The blood was then transferred to plastic tubes for vitamin D measurements by the common clinical-chemical method of competitive protein-binding (CPB) assay. All patients signed an informed written consent to collect their blood samples and to use their data on vitamin D for the aim of this study.The results showed that 27 patients fulfilled the DSM-5 criteria for the diagnosis of BDI, 15 of BDII, 16 of schizoaffective disorders, and 11 of MDD. Thirty-six patients were suffering from a depressive episode, 20 from mixed features, 7 from a hypomanic episode, and 6 from a manic episode, according to the MINI .Thirty-six patients showed psychotic symptoms: the majority of this group was suffering from BDI , 13 from schizoaffective disorder , and 4 from MDD. The absence of psychiatric comorbidity was detected in 40 patients, while 18 referred substance abuse , 11 had an anxiety disorder, and 10 had mild neurodevelopmental traits. Thirty-six patients were heavy smokers (more than 20 cigarettes daily). Fifty-seven patients had at least a relative with a psychiatric disorder, and 9 had a family history of suicide.Different psychotropic drugs had been prescribed to all patients, according to the effective requirements of the diagnosis and the polarity of the episode, as only 7 patients resulted to be drug-free at the assessment. Sixty-seven patients were taking mood stabilizers , of whom 34 were taking 2, and 20 were taking 3 of these compounds. Twenty-seven patients were also treated with antidepressants . Antipsychotics (first- and second-generation antipsychotics [FGAs and SGAs]) were given to 63, benzodiazepines to 20, and anticholinergic drugs (biperiden) to 4 patients.p < 0.001) was detected between patients and normative mean values (30 nm/L). Nineteen (27.54%) patients showed insufficient (12–20 nm/L: 15.70 ± 2.17) vitamin D levels, 18 (26.09%) had a critic deficiency (<12 nm/L: 9.10 ± 1.49), 17 (24.64%) had severe critic levels (<6.5 nm/L: 4.92 ± 1.12), 11 (15.94%) had sufficient (20–30 nm/L: 24.71 ± 3.40), and 4 (5.80%) had optimal values (>30 nm/L: 47.17 ± 16.85)  in the total sample was 14.58 ± 11.27, almost the same in the two sexes . A statistically significant difference (t = −11.36 and ± 16.85)   .No other significant intergroup differences  were noted .The same was true when comparing vitamin D according to diagnoses, the polarity of the episode, psychotropic drugs, type of onset, family history for psychiatric disorders, smoking, comorbidities, presence or absence of psychotic symptoms, abuse substances, or neurodevelopmental traits .The present study aimed at evaluating vitamin D levels, in comparison with normative values, in a group of adult patients suffering from BDs and hospitalized for a mood episode . All subjects were well characterized from the socio-demographic and clinical points of view. In addition, we explored the possible correlations between vitamin D values and the psychopathological characteristics of the patients.The results showed that the mean vitamin D levels of the patients were significantly lower (14.58 ± 11.27 nmol/L) than the normative values (>30 nmol/L). Eleven patients had sufficient values and only 4 had optimal, while 19 showed insufficient, 18 critical, and 17 severely critical levels.In our sample, no differences in vitamin D levels were noted between men and women or when individual and clinical features were considered and analyzed.Taken together, these data indicate that a large percentage  of patients affected by BDs showed decreased levels of vitamin D, and they add further information to the literature on this topic, as available data are meager and controversial. Previously, vitamin D deficiency has been reported in acute manic episodes . Specifi2+ concentration, typical of mania. Interestingly, vitamin D has been associated with reductions in Ca2+ levels ), an essential balance for maintaining healthy and functional neurons. While hypovitaminosis D increases Ca2+ and ROS by altering neural function, maintaining normal vitamin D levels leading to a reduction of Ca2+ might be another plausible mechanism for preventing or improving depression [Vitamin D would appear to play an important role in managing synthesis and maintenance of normal levels of 5-HT through 5-HT tryptophan hydroxylase 2 promoter activation while repressing 5-HT tryptophan hydroxylase 1 expression; this would indicate that vitamin D insufficiency would alter 5-HT production, with the resulting alteration in mood. There is also preclinical and clinical evidence of vitamin D’s capacity to increase brain levels of DA and NA. It would seem that it also triggers its effects by activating tyrosine hydroxylase, an enzyme with a DA synthesis-limiting function. Furthermore, vitamin D supplementation is known to increase DA and NA levels in different areas and circuits linked to mood. In addition, by controlling the expression of responsible genes, vitamin D participates in maintaining the homeostasis of Capression .The eventual efficacy of vitamin D addition as a booster of other psychotropic drugs is controversial. Adjunctive vitamin D supplementation seemed to be beneficial as a single parental dose  not only for depressive symptoms but also for the overall quality of life and illness severity . In addiThe efficacy of vitamin D addition may also be different according to other variables that should be taken into account, such as the presence of other clinical features that flank the merely depressive symptoms. Indeed, recent research might support these statements, as an amelioration of anxiety symptoms was noted in patients who were not depressed but had vitamin D deficiency . Again, Interestingly, vitamin D supplementation in combination with fluoxetine seems to be more effective than fluoxetine alone or plus placebo in reducing depressive symptoms . In threBesides, the spectra of vitamin D activities have been further broadened by the discovery of both the so-called nuclear vitamin D receptors (VDRs), which are widely distributed in the human body, and the vitamin D response elements (VDRE) present in the promoter regions of several genes ,70. VitaAccording to further data, the neuroprotective effect of vitamin D on the brain might be also due to its ability to lower plasma C-reactive protein in patients with psychiatric disorders and to modulate inflammation by suppressing pro-inflammatory cytokines. There is evidence of vitamin D exerting significant anti-inflammatory effects by activating the Th2 anti-inflammatory branch and decreasing pro-inflammatory Th1 cytokines. Through this pathway, vitamin D might decrease the associated pro-inflammatory state widely reported in some patients with depression .The present study suffers from a few limitations to be acknowledged. First, the majority of our patients were taking one or more psychotropic drugs to manage their clinical picture, and only seven were drug-free. It should be underlined that it is uncommon to recruit untreated bipolar inpatients, and, in any case, we did not find any difference between treated or drug-free patients or between patients taking one or more drugs. Second, there was a preponderance of women than men, however, this is almost the rule in samples of bipolar patients; in addition, no sex-related differences were noted in the clinical parameters or vitamin D levels. Third, all patients were recruited in a short period of time (March–June 2021) to reduce the impact of differential exposure to the light on vitamin D levels. Again, it should be underlined that they belonged to the same geographical area, with similar life habits and Mediterranean diet. Third, although the numerosity of our sample was consistent as compared with those of similar studies and composed of both men and women within a small age range, maybe it was not sufficient to ascertain intergroup differences in the biomarkers in patients at different phases of the illness. Another limitation was that we compared the vitamin D levels with the normative values rather than with control subjects, as we are planning to do in future studies.Our study, albeit preliminary, supports the evidence of decreased vitamin D in a large sample of BDs. This is an intriguing finding that obviously requires to be substantiated in future studies in order to deepen the possible role of vitamin D in this and, possibly, other neuropsychiatric disorders. Indeed, it is now evident that it regulates and modulates a multiplicity of brain and bodily functions that may be involved in psychopathological disorders. Specifically, vitamin D insufficiency would interfere with the function of neurons and neural circuits linked to mood fluctuations. It indicates plausible pathways for understanding that hypovitaminosis D alters brain function and, on a secondary basis, causes mood instability. It also explains plausible mechanisms for the preventive effects of prior suitable levels and the clinical improvement brought by adding vitamin D to conventional treatment for MDs.Further and controlled studies will be necessary to assess the potential benefits of vitamin D per se or as an augmentation agent, at least in those patients showing decreased levels. In any case, taken together, although drug regulatory agencies in different countries may warn against excessive prescriptions of vitamin D, these findings and the literature suggest the importance of regular assessments of vitamin D and its supplementation when needed.


Pneumocystis jirovecii pneumonia (PCP) in patients with rheumatoid arthritis (RA). Data regarding the clinical background, treatment modalities, and disease activity indicators of RA at the onset of PCP (baseline), and 6 months and 12 months after treatment were extracted. Of the 37 patients with RA-PCP , chemical prophylaxis was administered to 8.1%. Six patients died during PCP treatment. The serum C-reactive protein (CRP) levels and the prednisolone (PDN) dose at baseline in the PCP death group were significantly higher than those in the survivor group. Multivariate analysis using a Cox regression model showed that PDN dose at baseline was a predictor of death from PCP in patients with RA. During the 12 months from baseline, the RA disease activity significantly decreased. A high dose of corticosteroids for RA may result in a poor prognosis when PCP is complicated. In the future, preventive administration techniques must be established for patients with RA who need PCP prevention.This multicenter retrospective study aimed to clarify the prognostic factors for mortality and changes in treatment modalities and disease activities after the onset of  Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and destruction . PatientPneumocystis jirovecii (PC) is a fungal pathogen that causes pneumonia in infancy and in compromised hosts with decreased cell-mediated immunity [immunity ,6. The uimmunity ,7. In paimmunity ,9.Risk factors for developing PCP in patients with RA include older age, male sex, corticosteroid use, and pulmonary lesions . Howevern = 37) who fulfilled the inclusion criteria. The baseline characteristics of the participants are shown in The study population was selected from all patients with RA-complicated PCP (RA-PCP) in the ANSWER cohort  mixture.The treatment details and outcomes of patients with PCP are presented in p = 0.035), other laboratory findings did not differ between the two groups. The PDN dose of 9.0 (5.75–19.4) mg/day in the PCP death group was significantly higher than that in the survivor group of 3.0 (0–5.0) mg/day (p = 0.006), but other treatment modalities for RA did not differ between the two groups.During the 12-month follow-up period, 6 patients died due to PCP, and the duration between baseline and death was 13 (6.5–24.3) days. We compared the baseline clinical characteristics and treatment regimens of the 6 patients in the PCP death group and the 31 in the survivor group . There wWe also compared the baseline respiratory conditions, including duration of respiratory symptoms and PaO2/FiO2 ratio, between the PCP death group and the survival group. The duration of respiratory symptoms could be extracted for 14 (9–39) days in 3 PCP deaths and 7 (4–13) days in 23 survivors, and the PaO2/FiO2 ratio could be extracted for 64.6 (46.7–251.9) in all PCP deaths and 238.1 (188.8–344.2) in 21 survivors. Although there was no difference in the duration of respiratory symptoms between the two groups, the PaO2/FiO2 ratio was significantly lower in the PCP death group compared with the survival group.p = 0.003). Multivariate analysis also showed that PDN dose at baseline was a predictor of death from PCP in patients with RA (p = 0.003).Serum CRP levels and PDN dose at baseline were identified as risk factors for death from PCP. To confirm these findings, we performed univariate and multivariate analyses using a Cox proportional hazards model . Age wasp = 0.046 and <0.001, respectively). During the 12-month period from baseline, DAS28-CRP, SDAI, and serum CRP levels significantly decreased . There was no significant change in RA disease activity between 6 and 12 months.Risk factors for PCP complications in patients with RA have been reported to be older age, male sex, existing lung lesions, and the use of corticosteroids, MTX, and bDMARDs ,11. In JPentamidine inhalation, atovaquone, and TMP/SMX have been used to prevent PCP. The need for prophylaxis against PCP has been advocated receiving immunosuppressive drugs in addition to prednisolone 20 mg/day or higher . HoweverExisting lung lesions have been reported to affect the mortality and prognosis of patients with RA-PCP ,12. AlthIn the present study, the MTX concomitant rate/dose decreased, and the PDN concomitant rate increased 6 months after the onset of PCP. Owing to excessive immunosuppression and the risk of drug-induced pneumonia, the use of MTX might be avoided after the onset of PCP. The suppression of RA disease activity may depend on concomitant/increased doses of corticosteroids for the treatment of PCP. In the present study, ETN and ABT were the most common bDMARDs used after PCP onset. In postmarketing studies of each bDMARD in patients with RA, PCP was complicated in 0.44% of patients for IFX , 0.18% fTo date, details of changes in RA disease activity after PCP onset have not been reported. In the present study, comparing each RA activity index at the time of PCP onset and 12 months later, DAS28CRP and SDAI decreased significantly, but CDAI did not change. The components of DAS28CRP and SDAI include serum CRP values, which may be affected by corticosteroids for PCP treatment. Therefore, regarding the evaluation of RA disease activity after the onset of PCP, it was suggested that it might be appropriate to use the CDAI, which does not include inflammatory reactions as components. As these clinical measures alone may not be sufficient to assess RA disease activity after PCP complications, a combination of objective measures, such as joint ultrasonography, may be useful.As this was a multicenter cohort study, there were some limitations in the clinical data extraction and interpretation of the results. First, this study was a retrospective cohort study with a small sample size, and there was a possibility of bias due to missing values regarding various data. Second, because PCP was diagnosed by each attending physician at many facilities, the details of the diagnosis and severity of PCP could not be extracted. Third, all of the research participants were Japanese, and it may not be possible to generalize the results to other races. Fourth, the survivor group was skewed, with five times as many patients as non-survivors, which could confound the results. To resolve these limitations, further studies with more races and more cases are needed in the future.The Kansai Consortium for Well-being of Rheumatic Disease Patients (ANSWER) cohort is a multicenter observational registry of patients with RA in the Kansai district of Japan ,30,31. DThe representative facility of this registry was Kyoto University, and this observational study was conducted in accordance with the Declaration of Helsinki with the approval of the ethics committees of the following seven institutes: Kyoto University , Osaka University , Osaka Medical and Pharmaceutical University , Kansai Medical University , Kobe University , Nara Medical University , and the Osaka Red Cross Hospital . At institutes other than Osaka University Hospital, written informed consent was obtained from the participants. The Osaka University Hospital Ethics Committee board waived the requirement for patient informed consent because of the anonymous nature of the data.Pneumocystis jirovecii in the sputum or bronchoalveolar lavage fluid (BALF) by polymerase chain reaction (PCR) or microscopic examination [P. jirovecii DNA.PCP was diagnosed by the attending physicians based on the clinical and laboratory findings. In the present study, PCP was suspected when a patient had the following clinical symptoms: fever, non-productive cough, dyspnea on exertion, relatively homogenous ground glass opacity in the bilateral lung fields on chest images, elevated serum (1-3)-β-D-glucan (βDG), and progressive hypoxia. PCP was diagnosed as positive for mination . A PCR mData were extracted from the patients’ medical records. In the baseline demographic data, age, sex, duration of RA, complications, and outcomes were extracted. Laboratory findings included white blood cell (WBC) and lymphocyte counts, serum albumin, creatinine, lactate dehydrogenase (LD), C-reactive protein (CRP), Krebs von den lungen 6 (KL-6), immunoglobulin G (IgG), and serum βDG levels. The respiratory conditions, including duration of respiratory symptoms and PaO2/FiO2 ratio at baseline, were also extracted. In addition, the disease activities of RA, treatment modalities for RA, prophylaxis, and treatment modalities for PCP were also extracted at baseline, at 6 and 12 months after treatment.Data regarding swelling joints, tender joints, the patient’s global assessment of disease activity using a visual analog scale (Pt-VAS), the physician’s global assessment of disease activity via a visual analog scale (Ph-VAS), and serum CRP levels were extracted as parameters related to RA disease activity. Data regarding the Disease Activity Score-28-CRP (DAS28-CRP), the Simplified Disease Activity Index (SDAI), the Clinical Disease Activity Index (CDAI) for RA disease activity, and the Health Assessment Questionnaire (HAQ) were also extracted ,36,37. Tp < 0.05. Data were analyzed using JMP version 14.0 .Data are presented as the median (interquartile range). Fisher’s exact test was used to compare categorical variables, and the Mann–Whitney U test was used to compare median values. The Wilcoxon signed-rank test was used to compare various pre- and post-treatment parameters. We compared the demographic and background characteristics between the two groups using univariate analysis, then estimated the hazard ratios of patient outcomes in univariate and multivariate analyses using a Cox regression model. Statistical significance was set at In this multicenter cohort study of Japanese patients with RA, the concomitant rate of PCP preventive drugs was low in patients with PCP, and a high dose of corticosteroids may have a poor prognosis for mortality. It is necessary to select patients with RA who require PCP prevention and to establish preventive administration methods in the future.


The leading mechanisms through which air pollutants exert their damaging effects are the promotion of oxidative stress, the induction of an inflammatory response, and the deregulation of the immune system by reducing its ability to limit infectious agents’ spreading. This influence starts in the prenatal age and continues during childhood, the most susceptible period of life, due to a lower efficiency of oxidative damage detoxification, a higher metabolic and breathing rate, and enhanced oxygen consumption per unit of body mass. Air pollution is involved in acute disorders like asthma exacerbations and upper and lower respiratory infections, including bronchiolitis, tuberculosis, and pneumoniae. Pollutants can also contribute to the onset of chronic asthma, and they can lead to a deficit in lung function and growth, long-term respiratory damage, and eventually chronic respiratory illness. Air pollution abatement policies, applied in the last decades, are contributing to mitigating air quality issues, but more efforts should be encouraged to improve acute childhood respiratory disease with possible positive long-term effects on lung function. This narrative review aims to summarize the most recent studies on the links between air pollution and childhood respiratory illness. Outdoor air pollution represents one of the leading environmental risks to human health. Exposure to air pollutants is ubiquitous, and according to the World Health Organization (WHO), every day, around 93% of children under the age of 15 years breathe polluted air, which puts their health at serious risk [2.5) or 10 µm (PM10), ozone (O3), nitrogen oxides , sulfur oxides , and carbon monoxide (CO) are the principal conventional metrics used to quantify exposure to air pollution. Computing air pollution levels provide a measure of exposure used as a surrogate for risk. Numerous studies have linked such air quality data to adverse health outcomes. It is also used to advise vulnerable groups (such as children or the elderly) on risk management. It follows that the closer the metric is to the actual harmful component of the exposure, the better the risk management and the relationship to adverse health effects in epidemiological studies are likely to be. When exposure is transmitted into an internal dose, mechanistic toxicologists, whose job is to address biological mechanisms, identify the proper harmful entity in the dose as the biologically effective dose (BED). The BED is the entity that drives the adverse effect(s). The gap between the BED and the total dose, as derived from the exposure metric, can be considerable, especially in the case of ambient particles [2.5 has received particular attention. There is evidence of causal relationships between exposure to PM2.5 air pollution and all causes of mortality and several diseases, including lung cancer, stroke, respiratory infections, and pulmonary diseases [2.5 (or PM10) mass is not ideal but represents a surrogate for the BED. This debate is based on the fact that much of the ambient particle mass consists of low-toxicity components, such as inorganic salts and mineral dust [Air pollution involves chemical and biological materials discharged into the atmosphere  and is carticles . Among adiseases . In the diseases . In mostdiseases ). Howeveral dust . These cral dust ,12 and dChildren are more vulnerable to the harmful effects of air pollution than adults because their lungs are still developing. Lung development in children is a long-term process that starts in utero and continues through life. The highest percentage of alveoli, respiratory bronchioles, epithelium, and immune cell populations develop in the post-neonatal period, and changes in the lung continue through adolescence. This suggests that during the first years of life, the lung is highly vulnerable to acute injury ,13,14.The pediatric population is also more vulnerable to air pollutants due to (1) a lower efficiency of oxidative damage detoxification systems, (2) a higher metabolic and breathing rate, and (3) enhanced oxygen consumption per unit of body mass. In addition, children spend more time outdoors than adults, so they have increased exposure to outdoor air pollution . FurtherIn addition to studies highlighting the short-term effects of exposure to air pollution on lung function, many studies suggest long-term adverse effects on lung function and growth .The purpose of this narrative review is to summarize the most recent research on air pollutants and their impact on childhood respiratory disease, with a focus on the major outdoor air pollutants and their composition, the pathogenic and biological mechanisms by which pollutants affect health, and the impact on children’s respiratory systems in the short and long term.10 or PM2.5 daily mass), which are now recognized as not ideal for representing the multiple and specific factors involved in the pathogenesis of non-communicable diseases resulting from exposure to air pollution as a whole. The ambient atmosphere is a dynamic system in which the mixture of air pollutants changes quickly over time. The fluctuation of important atmospheric parameters influencing ambient PM concentrations and chemical composition , such as particle sources’ emission strengths, gaseous precursors, temperature, relative humidity, mixing height, wind direction, and speed, occurs on time scales much shorter than a few hours. For this reason, daily air quality monitoring cannot be adequate to fully assess the physicochemical properties of atmospheric pollution involved in the causal mechanisms associated with the BED. In the last 15 years, there has been a growing literature pointing to potential alternative metrics, and a particular focus has been dedicated to specific health effects in association with cellular oxidative stress initiated by the formation of reactive oxygen species (ROS) at the surface of and within target cells [Numerous studies have documented associations between air pollution and mortality and morbidity in adults and children , with fiet cells ,10. The 3, NO, NO2, SO, and SO2—are still being studied for their health effects because they are linked to a cascade of inflammatory processes. They are produced mainly by anthropogenic sources and are thus tracked and regulated by governments and air-quality monitoring agencies. Ground-level O3 is typically formed by photochemical reactions between solar radiation and other gaseous precursors, such as NO, NO2, and volatile organic compounds (VOCs), especially in warm summer conditions. NO, and NO2 are formed primarily by the reaction of O3 with nitric acid emitted during fossil fuel combustion. The primary sources of SO and SO2 in the developed world are primary emissions during energy production or industrial processes. Although exposure to SO2 has been greatly reduced in the developed world through treatment for emissions from coal-fired power plants and energy sources other than coal combustion, it remains an issue in developing countries . These gaseous pollutants vary substantially in their environmental persistence and oxidizing capacity; whereas O3 is a potent oxidizing agent, NO2 is a relatively weak oxidant. Controlled NO2 exposure appears to have a mild airway inflammatory effect at high levels of exposure that are unlikely to occur in non-experimental settings, but it causes minor lung inflammation at typical ambient concentrations. NO2 is supposed to have a deeper penetration into the respiratory tree, which could cause microlesions in the respiratory tract and increase susceptibility to infections [2 dilemma”, surrounds whether the epidemiological associations found for fossil combustion-related air pollution are due to direct effects of NO2 or if it is just a marker and the causes of pulmonary diseases are associated with the broader mixture of correlated components. Indeed, studies report strong associations between NOx and health outcomes  that mimic other specific properties of traffic PM [2 is a reductant, it probably causes pulmonary diseases through a different mechanism. Extensive research has been conducted on the effects of short-term controlled exposure to O3 and SO2 at relevant concentrations [3 exposure results in airway inflammation, airway hyper-responsiveness, and lung function decrees in healthy and fragile individuals, whereas SO2 causes more prominent bronchoconstriction, mostly in fragile individuals [Highly reactive gaseous pollutants—such as Ofections . Howeveraffic PM , such astrations ,21. O3 eividuals .0.1) particles based on their size and mean diameters: coarse particles have a diameter of more than 2.5 μm, fine particles are considered those with diameters in the range 0.1–2.5 μm, and ultrafine particles have diameters <0.1 μm. Particles are characterized by a myriad of primary and secondary components and complex chemical mechanisms, encompassing both natural and anthropogenic sources. These lead to very heterogeneous physical and chemical properties, varying in relation to the mix of pollutants/components, season, and geography.PM is the crucial ingredient in polluted air concerning increases in cardiac and respiratory morbidity and mortality. To prevent this staggering loss of life and cost to society, it is essential to understand the characteristics of the toxic particles and gain insight into how they are related to adverse health effects. PM is composed of solid and liquid particles, which can be classified into coarse, fine, or ultrafine  and 2.5-μm-diameter (PM2.5) particles as specified by the Code of Federal Regulations in the US and the European Committee for Standardization (CEN) standard in Europe. As these or equivalent methods are used in routine air quality monitoring networks, they have formed the basis of numerous epidemiological studies. However, the WHO report (2021) [1, has been suggested as possibly valuable for managing PM levels in the atmosphere, mainly because it provides better separation of the coarse mode and accumulation mode (and ultrafine) fractions than the 2.5 micron cut-off. Furthermore, WHO prioritized specific types of PM, i.e., Black Carbon (BC), Elemental Carbon (EC), heavy metals, and the concentration of ultrafine particles, but concluded that the quantitative evidence of independent adverse health effects from these pollutants was still insufficient for new air quality guideline levels [Currently, government and air-quality monitoring agencies track and regulate the size-specific mass of 10-μm-diameter  in wintertime , the mosIn conclusion, recent research indicates that the ROS generated by atmospheric processing significantly impacts the PM oxidative potential, which appears to play an important role in aerosol health effects and provides a direct link between atmospheric and physiological multiphase processes. Consequently, different techniques for its quantification are being tested as an alternative air quality metric in a significant number of studies worldwide. However, it remains the subject of intense research and discussion .2) and particles containing both non-volatile and semi-volatile components. The semi-volatile compounds may partition between the gas and particle phases in ambient conditions depending on their vapor pressure and degree of atmospheric dilution and participate in photochemical reactions in the atmosphere [Road traffic is a significant source of air pollution in urban environments. In recent decades, many studies linking air pollution and health effects in the urban atmosphere have focused on traffic-related air pollution (TRAP). mosphere .Consequently, the physical and chemical characteristics of combustion-generated PM change dramatically with background conditions, atmospheric dilution, and processing, which may alter their toxic properties and influence their role in population exposures and public health. Combustion particles also derive from various sources other than motorized road traffic, including wood and coal burning, shipping, and industrial sources, and these sources may contribute significantly to ambient combustion particle concentrations, even in urban areas. As mentioned in the previous section, semi-volatile PM contains a wide variety of organic micropollutants, many of which possess genotoxic and carcinogenic characteristics, such as dioxins, PAHs, and their derivatives. Some of these semi-volatile organic species trigger a chain of biochemical reactions in cells, change their redox state, and exert oxidative stress. Polar organic compounds, such as quinones, oxygenated PAHs, and aldehydes, are reported to induce oxidative stress in cells. BC, also known as soot, is a significant source of combustion PM and has been repeatedly proposed as a PM metric candidate to reflect better the health effects of combustion-related air pollution than PM mass because it is relatively easy and not expensive to measure . TrafficTRAP is associated, with children, with low birth weight, Intrauterine Growth Restriction (IUGR), preterm birth, asthma exacerbation, chronic asthma, and lower respiratory infections . MoreoveAir pollution can cause respiratory diseases and affect lung function and growth, depending on the type of pollutant, its concentration, and its dimensions . Polluta3. Compared with controls, O3-exposed monkeys had markedly increased airway resistance at baseline, fewer airway generations, hyperplastic bronchiolar epithelium, and impaired smooth muscle in the terminal and respiratory bronchioles. These results suggest that episodic exposure to environmental pollutants alters postnatal tracheobronchial airway morphogenesis and development [To study the impact of acute exposure to pollutants on the developing lung, Fanucchi and colleagues examined the postnatal lung morphogenesis and function of a group of infant monkeys—which have human-like airway structure and postnatal lung development—subjected to cyclic exposure to Oelopment .The main direct and indirect damage mechanisms to the respiratory system are represented in Air pollutants trigger pulmonary oxidative stress and inflammation pathways . The defThe pro-inflammatory state promoted by pollutants is primarily due to the oxidative stress resulting from the production of ROS and the reduction of endogenous antioxidants. Oxidative stress can directly damage cellular proteins and DNA, create neoantigens by protein oxidation, and activate pro-inflammatory signaling cascades, such as NF-kB and MAPK pathways. Oxidative stress affects Antigen Presenting Cells (APCs) function and co-stimulation, T helper (Th) lymphocyte imbalance favoring Th2 response, and interferon (IFN)-gamma production . Alveola3, PM, and aldehydes were identified as the most responsible pollutants [In response to the inflammatory state, children chronically exposed to high levels of air pollutants show structural changes in the airway mucosa. A study by Calderón-Garcidueñas and colleagues compared by electron microscopy the nasal epithelium of children living in a polluted city with that of peers living in a city with low levels of air pollution . The firllutants .Long-term exposure to pollutants leads to a loss of lung function due to progressive airway remodeling and fibrosis of the lung due to oxidative stress, according to several animal model studies ,52. MoreCell studies and animal models proved that air pollution could affect both innate and adaptive immune systems  because Air pollutants damage epithelial cells, induce granulocyte and mast cell migration and activation, enhance pro-inflammatory cytokines  production, and reduce macrophage phagocytosis and clearance. Pollutants stimulate a pro-inflammatory immune response by triggering several pathways, including Toll-Like Receptors (TLRs), which detect pathogen-associated molecular patterns of infectious microorganisms and analogous injurious triggers, like pollutants. PM, for example, can activate the TLRs pathway because they frequently transport microbial molecules such as lipopolysaccharide and fungal spores, as well as cellular damage products like oxidized phospholipids and nucleic acids .2 increases Th2 cytokines and ICAM-1 (Intercellular Adhesion Molecule-1) epithelium expression, facilitating respiratory infections since ICAM-1 is a receptor for Rhinovirus and respiratory syncytial virus (RSV) [Pollutants enhance the Th2 immune response, IgE, IL-5, IL-13, and leukotriene production, resulting in asthma and allergies exacerbation and an inappropriate antimicrobic environment. Air pollution can also impair anti-viral immune responses by suppressing the Th1 pathway, deregulating IFN-gamma, and reducing macrophage phagocytosis and clearance capacity. For instance, NOus (RSV) .Pollutants can reduce immune tolerance because pro-inflammatory cytokines reduce regulatory T cell responses. Protein oxidation leads to neo-antigen formation, triggering autoinflammatory and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus. PM is proven to act as an adjuvant on APCs, increasing the immunogenicity of antigens .Epigenetic changes regulate the expression of many genes without changing the DNA sequence itself, including those involved in the inflammatory immune response and lung growth. Environmental factors can alter epigenetic states, and a growing number of studies are looking into the effects of air pollutants on epigenetic mechanisms. DNA methylation, which involves the attachment of a methyl group to the C5 position of cytosine to form 5-methylcytosine, is a crucial epigenetic mechanism that modulates gene expression  and seem2 [2.5 [10 [2 exposure was associated with DNA methylation changes in mitochondria-related genes and antioxidant defense pathways [The effects of air pollution on DNA methylation have been investigated both in the prenatal and postnatal periods. Several studies analyzed samples obtained from the placenta or cord blood and showed that environmental exposure to air pollutants during pregnancy has a significant impact on DNA methylation in newborns , with pa2 , PM2.5 [2 [2.5 , and PM1[2.5 [10 . In addi[2.5 [10 ,59; NO2 pathways .2, O3, CO, SO2, VOC, BC, EC, OC, and PAH) is associated with global methylation loss, telomere reduction, and epigenetic alterations involving genes related to oxidative stress response, mitochondrial function, inflammation, and fetal growth [A systematic review conducted by Isaevska and colleagues showed that prenatal exposure to different pollutants  increases the risk of asthma onset in healthy young children [NOoduction . In addiand UFPs , are assand UFPs , and theand UFPs ,77,100. children .Furthermore, some studies have shown that the anti-pollution measures adopted during the SARS-CoV-2 pandemic and restrictions on the circulation of motor vehicles during public events can lead to a reduction in the primary environmental pollutants and a consequent decrease in emergency department visits due to asthmatic exacerbations ,102.2.5 are significantly associated with an increased risk of hospitalization for bronchiolitis and that the risk depends on the concentration of PM  [10 exposure, particularly in the two previous weeks [2 and PM10 exposure, and high temperature, highlighting the combined effect of meteorological factors and air pollutants [2.5 and PM10 levels are significantly associated with the severity of bronchiolitis [2, PM10, and PM2.5 [Bronchiolitis is the most common cause of lower respiratory infection and hospitalization in children younger than one year, and it is characterized by airway inflammation and obstruction of the lower respiratory tract ,104. Sevn PM2.5) . Anotherus weeks , becauseus weeks . PM can us weeks . UFPs caus weeks . Likewisllutants . PM2.5 ahiolitis . RSV brond PM2.5 ,71.2.5, PM10, SO2, NO2, and CO [2 exposure has been linked to persistent cough [2, OR 1.47; PM10, OR 1.77; PM2.5, OR 4.06) and pneumonia and identified the first year of life as the most vulnerable period [3 and PM2.5 were associated with more severe pneumonia [2 increases children’s risk of developing an acute respiratory infection [3 and primary traffic pollutants  on hospital admissions for pneumonia and upper respiratory infections among children between 0 and 4 years old; moreover, the study highlights the carbon component in the PM2.5 mixture as particularly damaging for respiratory infections in children [10 favors the replication of RNA viruses through the inhibition of innate immunity and the upregulation of several genes related to metabolic pathways, supporting the idea that PM10 exposure is associated with increased severity of pulmonary infections [Exposure to air pollution, especially PM, seems to be linked to upper and lower respiratory infections in children of any age ,107, lik, and CO , and chint cough . A meta-e period . Glick eneumonia . A studynfection . This evchildren . Exposurchildren . A studyfections .10, SO2, and NO2 [A Chinese study also shows that exposure to highly polluted areas increases the risk of tuberculosis, especially in children exposed to PM and NO2 .3 in PM2.5 and PM10 levels increases infection risk by 12% and 8%, respectively, and an increase of 1 μg/m3 in NO and NO2 levels spreads COVID-19-related mortality risk by 1.5% and 2.5%, respectively. Although the underlying mechanism is unclear, several hypotheses have been proposed, including the inflammatory state promoted by long-term exposure to pollutants and inhibition of the antimicrobial response. However, the relative weight of air pollution in increasing cases of SARS-CoV-2 infection has yet to be definitively determined, due to the several confounding factors and the numerous variables to take into consideration, such as particles’ size and chemical composition, the population’s age distribution, density, and social habits, the restrictive measures applied, and the weather conditions [Furthermore, several studies conducted in adults have linked long-term exposure to air pollutants to novel human coronavirus disease 2019 (COVID-19) infection and mortality rates ,115. In nditions .Because of their tiny size, large surface area, and high density, deposition, and penetration, UFPs may be more toxic than larger air pollutants. UFPs are associated with increased access to the emergency department for main respiratory diseases, such as pneumonia , bronchitis , and upper respiratory infections  . The rel1) and forced vital capacity (FVC) [1, and maximum mid-expiratory flow, known as MMEF) was reduced in children exposed to higher levels of air pollution. These deficits have been associated with NO2, SO2, PM2.5, and EC, and the authors hypothesized that the main mechanisms involved were a reduction in alveolar growth and airway inflammation. Molter et al. [10 and NO2 is associated with reductions in lung volume growth.Injuries to the developing lung, both during pregnancy and in the first years of life, have been shown to have long-term effects on the respiratory system. In the long term, pollution can damage lung function, affecting patterns of growth and causing early function decline, as measured by forced expiratory volume in one second (FEVty (FVC) . A studyty (FVC)  followedr et al.  demonstr2.5 exposure can decrease the number of alveoli in mice [3 exposure is associated with acute lung function reduction in healthy and asthmatic children, and toxicologic studies involving animals show that O3 negatively affects lung development. Similarly, acute and chronic NO2 exposure can impair lung function [2.5 exposure is associated with slower lung function growth in children; on the contrary, the evidence for PM10 is less robust due to the lower availability of long-term models [10 exposure and child lung function [Similarly, pre- and post-natal PM in mice . O3 expofunction . Long-tem models . Some stfunction ,122.The exposure during lung development seems to be associated with a negative impact on lung function that may ultimately result in COPD. Low childhood lung function is a risk factor for developing COPD or asthma-COPD overlap syndrome in adulthood, according to a study of 1389 patients who underwent spirometry in childhood and then in adulthood . The mai2.5 and PM0.1 alters lung and immune system development, increasing the risk of acute and chronic pulmonary diseases .The development of the human respiratory system is a complex process that begins early during the embryonic stage and lasts long after birth, with complete alveoli development occurring in adolescence. Growth and transcription factors and their interactions with the extracellular matrix coordinate all the steps in lung morphogenesis. During its differentiation and development, the lung is highly vulnerable to exposure to environmental pollutants . Recent 1, and the effect of prenatal exposure to PM1 was more pronounced in males [Epidemiological studies suggest maternal exposure to environmental hazards, such as combustion-generated PM, is associated with an increased childhood asthma incidence . Accordiin males . The stuin males .2 during pregnancy is associated with an increased risk of respiratory infections in infants [Air pollution, particularly TRAP, is recognized to be an important predisposing factor for childhood pneumonia, and the retrospective cohort study performed by Lu and colleagues highlighted that preconception (up to one year before conception) and prenatal exposure to industrial air pollution play a role in the onset of childhood pneumonia . Similar infants .2) and higher ventilatory demand (PM10) [2, PM10, and PM2.5, was also proven to harm children’s lung function and development [25–75) and FEV1 [The study by Latzin et al. discovered that prenatal exposure to outdoor air pollution is associated with airway inflammation (NOd (PM10) . Furtherelopment ,67. In aelopment ,118 and and FEV1 ,126.Air pollution exposure during pregnancy and after birth can eventually alter the adult lung function trajectory, leading to multimorbidity .2.5, PM10, NO2, and O3 exposure both in the first and last month of pregnancy [Moreover, several meta-analyses show that prenatal exposure to air pollution increases the risk of intrauterine growth restriction and low-birth-weight offspring ,129, mairegnancy . In addiregnancy , which cThe effects of prenatal exposure to air pollutants on respiratory disease are summarized in Outdoor air pollutants affect children’s lung development, even during pregnancy, increase the risk of acute illnesses such as respiratory infections, bronchiolitis, and asthma, and eventually can contribute to COPD and decreased lung function in adulthood. Evidence suggests that there is no safe limit for air pollution exposure . DifferePollution is a more significant topic in low-income settings. Air pollution inequality widens not only between rich and developing nations but also between rich and poor people within the same country. The latter tend to live in polluted suburbs, with more highways and worse air quality. Similarly, lower-income countries tend to have lax regulations regarding air pollution and vehicle emissions ,135.While governments should enforce air quality standards by monitoring air pollution levels and adopting policies to reduce pollution, pediatricians could suggest other measures to mitigate exposure to traffic pollution, such as (1) using masks, (2) preferring active transport rather than motorized vehicles, (3) choosing travel routes that minimize vehicle air pollution exposure, (4) monitoring air pollution levels and consequently avoiding outdoor activities when and where air pollution is higher, and (5) preferring a healthy diet rich in antioxidants or anti-inflammatory agents .Future national and international policies should prioritize public health issues, especially in poorer countries and suburbs, to enhance air quality, mitigate the harmful effects of pollutants, and ultimately improve children’s health.Despite the considerable consistency of epidemiological findings irrespective of the specific physicochemical properties of the major PM components, in the last decade, more and more studies have suggested that pro-inflammatory and oxidative responses to the respiratory system in humans are driven by specific sources of pollution in combination with the general state and dynamics of the atmosphere  ,139,140.


The effect of viscous soluble dietary fiber on glucose and lipid metabolism in type 2 diabetes mellitus (T2DM) remains controversial, and the dose–response relationship of its effect on blood glucose and blood lipid level is still unclear.We conducted comprehensive searches in several databases up to 17 January 2023. We conducted a dose–response analysis of randomized controlled trials (RCTs) to investigate the effect of viscous dietary fiber on glucose and lipid metabolism in patients with T2DM.Statistical significance was observed in the decreases of glycosylated hemoglobin (HbA1c) (mean difference) , fasting blood glucose (FBG) , total cholesterol (TC) , and low-density lipoprotein and cholesterol (LDL-C) . Contrarily, no difference was observed regarding the level of high-density lipoprotein cholesterol (HDL-C) or triglyceride (TG). In addition, the effect on fasting insulin remains unclear. Results from the subgroup analyses showed that an intervention duration longer than 6 weeks had a significant effect on the HbA1c level; a treatment dosage higher than 8.3 g/day had a significant effect on the FBG level.Supplementation of viscous dietary fiber is beneficial to control blood glucose and blood lipid in T2DM. Type 2 diabetes mellitus (T2DM) is a non-communicable chronic disease that is prevalent worldwide. The incidence of T2DM is increasing, posing a heavy burden on the global healthcare system. As estimated, there were 463 million people with diabetes worldwide in 2019, and the number of people with diabetes is estimated to reach 578 million and 700 million by 2030 and 2045, respectively  guidelines.We systematically searched for relevant articles published until 17 January 2023: PubMed, Web of Science, Embase, and Cochrane Library. The keywords were related to the research objectives. In our search strategy, we combined MeSH and non-mesh keywords without date or language restrictions. The search terms were as follows: ; ; and . In addition, we manually searched the reference lists of each study to supplement relevant studies that may have been overlooked.This study strictly included original research according to the following criteria: (1) the study was an RCT with a parallel or crossover design with an experimental period of more than 2 weeks; (2) the study subjects were adults with T2DM (aged ≥ 18 years); (3) the intervention of interest was the supplementation of viscous soluble dietary fiber , with a placebo, insoluble fiber, or without fiber supplementation in the control group; (4) the outcome indicators included at least one blood glucose control indicator  and one blood lipid control indicator ; and (5) the data were complete and could provide the basis for subsequent analyses.We excluded literature based on the following criteria: (1) studies with subjects who had type I diabetes, gestational diabetes, or metabolic syndrome; studies with subjects who were adolescents or children; (2) experiments with a study period that was too short (< 2 weeks); (3) studies that combined interventions or could not separate the effect of viscous soluble dietary fiber on blood glucose or blood lipids; (4) cytological studies, animal experiments, non-controlled trials, or non-clinical studies; and (5) trials with incomplete or irrelevant data.Two researchers independently evaluated the included literature and extracted the following data by reading the full text: name of the first author, year of publication, types of study design, country, sample capacity, gender, average age of participants, BMI, duration of diabetes, type of fiber in the experimental group, substance in the control group, daily intake of viscous soluble dietary fiber, and cycles of intervention. In addition, the mean and standard deviation of blood glucose control indicators  and blood lipid control indicators  in each literature were extracted. If not reported, they were converted based on available data .The literature included in the study was evaluated for risk bias using the Cochrane Bias Risk Tool, which assesses seven validity questions as follows: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. The bias risk of each validity question is divided into low risk, high risk, and unclear risk.change = (SDbaseline × SDendpoint) 1/2, with a correlation coefficient R = 0.5 , fasting insulin was converted to μIU/mL  , and blo R = 0.5 . The hetThe specific process of literature retrieval and screening is shown in The characteristics of each study are shown in The risk of bias assessment of the included studies is shown in p < 0.001, I2 = 57.3%, p = 0.004, A total of 14 datasets from 12 studies were included in the HbA1c analysis, and the random effect model showed that the supplementation of viscous soluble dietary fiber could significantly reduce the HbA1c level  or guar gum  and those in which the duration of viscous dietary fiber was >6 weeks .The subgroup analysis results showed that the heterogeneity of HbA1c between studies disappeared when grouped by region , study type , fiber type , and the intervention period of viscous soluble dietary fiber . It remained high when subgroup analysis was performed by supplementation dosage . In addition, viscous soluble dietary fiber was effective in reducing FBG in trials conducted in North America  and Europe , in trials with β-glucan , psyllium , and glucomannan  or guar gum , and in trials with doses >8.3 g/day .For FBG, the inter-study heterogeneity disappeared when subgroup analysis was performed by the study region , p = 0.010], the effect of viscous soluble dietary fiber supplementation was significant in T2DM subjects.Additionally, the study heterogeneity also disappeared in subgroup analyses concerning fasting insulin. In parallel trials , increasing by 2.17. After excluding the studies of Cugnet-Anceau et al. . Similarly, when Ziai et al. study was removed . However, when these two studies were deleted separately, the overall effect variable of TC barely changed. For LDL-C, after removing the studies of Chen et al. , but the change in the overall effect variable could be ignored. Similarly, after removing the study conducted by Ziai et al. , and the overall effect variable was almost negligible. For FBG and TG, there was no significant change in heterogeneity or population effect variables after deleting any studies.Sensitivity analysis was performed, excluding one or two studies at a time to observe their impact on the overall results. The results are shown in l. study , the oveu et al.  and Ziaiu et al.  was remon et al.  and Cugnn et al. , the ovep-values of HbA1c: p = 0.236; FBG: p = 0.870; fasting insulin: p = 0.502; TC: p = 0.315; LDL-C: p = 0.190; HDL-C: p = 0.382; and TG: p = 0.652 were all greater than 0.05, and there was no evidence of potential publication bias in the combined results.The publication bias of HbA1c, FBG, fasting insulin, TC, LDL-C, HDL-C, and TG was initially assessed by funnel plot, and no significant asymmetry was found . In addiAlthough a large number of studies have reported the beneficial effects of dietary fiber in the human body, the effect was actually associated with the type of dietary fiber . This syAlthough previous meta-analyses have shown that some sticky soluble dietary fibers are not effective in controlling certain glycemic indices , 42, 43,Similarly, FBG is also an important indicator for evaluating the effectiveness of blood glucose control. Previous studies have shown that sticky soluble dietary fiber can significantly reduce FBG levels in patients with T2DM , 49. In Patients with T2DM are often accompanied by insulin resistance, and the fasting insulin level is positively correlated with insulin resistance . A cohorPreviously, it was found that long-term supplementation of medium to high doses of sticky soluble fiber (psyllium and guar gum) improved metabolic indices in patients with metabolic syndrome. By the fourth month of intervention, the reduction in FBG and LDL-C ranged from 9.3 to 16.4% and from 4.3 to 4.4%, respectively. The beneficial effect was more obvious by the 6th month of intervention, with the reduction range of FBG increasing to 11.1–27.9%, that of LDL-C decreasing by 7.9–8.5%, and that of TC decreasing by 6.3–7.5%; by the 6th month, psyllium supplement improved TG concentration significantly (−13.3%) . The effDue to the high heterogeneity between studies, subgroup analysis of HbA1c, FBG, and fasting insulin was performed. Except for the dose in the FBG index, the heterogeneity among the other subgroups changed significantly. According to the comprehensive results, all the factors for subgroup analysis may be the sources of heterogeneity. To further determine the source of heterogeneity, we also conducted a meta-regression analysis. Accordingly, the region and fiber type were confirmed as potential sources of heterogeneity in the regression of HbA1c. Furthermore, sensitivity analysis was conducted to evaluate the stability of the results to exclude studies that affected the heterogeneity. We found that removing the study conducted by Ziai et al.  significAlthough some previous studies have suggested that sticky soluble dietary fiber is beneficial for glycemic and lipid control in patients with T2DM, this meta-analysis synthesized and quantified the effect of sticky soluble dietary fiber on adults with T2DM. Additionally, a dose–response analysis was performed to investigate the effect of supplemental dose and intervention period on the efficacy of sticky dietary fiber. Furthermore, the studies we included were across several ethnic and geographic groups, which enhanced the generalizability of the results. In this meta-analysis, the risk of bias was considered to be low, and the results were evaluated objectively, which provided some reliability for the final results and conclusions.Results from the present meta-analysis suggested that viscous soluble dietary fiber can be used as a dietary supplement for the management of T2DM. However, it should be noted that the high viscosity of viscous fiber can lead to excessive viscosity during swallowing and reduce the palatability of food. Hence, the development of palatable viscous fiber foods is still a challenge. At present, the commonly used food processing method involves adding viscous fibers to proteins, starches, or beverages or adding acidic fruit films to stimulate saliva secretion . Fiber iIt should be admitted that this meta-analysis has several limitations. Firstly, our study did not separate male and female patients with diabetes, so we could not observe the differences in the control of sticky soluble dietary fiber in blood glucose and blood lipid between these two groups. Secondly, the longest study period among the included studies was only 16 weeks, since only a few studies with a longer period met the inclusion criteria, and only one article had an intervention period of 52 weeks . To mainThis meta-analysis confirmed that the supplementation of viscous soluble dietary fiber has potential benefits for the control of blood glucose and lipids in patients with T2DM. In addition, the recommended supplemental dose is from 8.3 g to 10.2 g/day, and the recommended duration of supplemental treatment is more than 6 weeks.The original contributions presented in the study are included in the article/KL: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing—original draft. TY: Writing—original draft, Data curation, Investigation. XC: Writing—original draft, Data curation, Investigation. HX: Writing—review and editing. SW: Writing—review and editing. GS: Writing—review and editing. LC: Writing—review and editing. WL: Funding acquisition, Methodology, Writing—original draft, Conceptualization.


Staphylococcus aureus. The synthesized AgNPs were analyzed by various techniques, including UV-Vis spectroscopy, SAED, TEM, XRD, FTIR, and Raman. The results demonstrate the formation of ultra-small, monodisperse, quasi-spherical AgNPs with an average particle size of 2.42 nm for AgNPs produced with mixed extracts. XRD analysis indicated that the AgNPs have a crystal size of 9.71 to 16.23 nm. The AgNPs exhibited potent inhibitory activity against resistant S. aureus, with a minimum inhibitory concentration (MIC) of 15.625 to 62.50 ppm. The findings suggest that the ultra-small nanometer size of the AgNPs could be attributed to the synthesis method that employs ambient conditions and the presence of polyphenolic compounds from citrus peel. Consequently, AgNPs obtained through sustainable green synthesis hold significant potential in combating clinical multi-resistant bacterial strains that are challenging to treat and eradicate. This approach also contributes to the revaluation of citrus residues in the region, which is an ongoing environmental issue today.The present study centers on the synthesis of ultra-small silver nanoparticles (AgNPs) with antibacterial properties using citrus peel residues  as reducing and stabilizing agents, and on assessing their antibacterial activity against multidrug-resistant clinical  The use of nanomaterials in biomedical applications is becoming increasingly popular, with metallic nanoparticles being derived from metals such as gold, silver, zinc, and iron due to their advantageous chemical and biological properties. To ensure the sustainability of this process, novel ecological and environmentally friendly approaches to synthesize these nanoparticles must be explored ,2,3.Staphylococcus aureus [S. aureus [S. aureus [The inappropriate use of antibiotics has become a major global health concern as it has led to the emergence and spread of antibiotic-resistant bacteria. Due to inadequate access to antibiotics without a prescription, inadequate diagnosis of the underlying condition, and widespread and indiscriminate use of antibiotics, the threat of antibiotic resistance is increasing rapidly . Examples aureus , ampicil. aureus , or mult. aureus . Therefo. aureus .Escherichia coli [Staphylococcus aureus [Pseudomona aeruginosa [Aspergillus flavus [These nanoparticles can have a range of sizes from 1 to 100 nm, with a variety of morphologies such as spherical , trianguhia coli , Staphyls aureus , Pseudomruginosa , and Asps flavus , among oAcacia rigidula [Eriobotrya japonica leaf [Carica papaya peel [Rosa Chinensis L. [Morinda citrifolia L. [Lately, many sustainable AgNP synthesis routes have been reported using fruit and vegetable extracts such as rigidula , Eriobotica leaf , Carica aya peel , cauliflaya peel , Rosa Chensis L. , Morindafolia L. , banana folia L. , and walfolia L. .According to the Food and Agriculture Organization of the United Nations (FAO), in 2020, the total global production of citrus was 158 million tons. Processing one ton of oranges results in up to 0.6 tons of citrus solid waste, 0–9% of a ton of seeds, 60–75% of a ton of peels, and 23–33% of a ton of membrane waste .To reduce the environmental problems of the final disposal of citrus waste such as lemon, orange, and grapefruit, extracts have been used for the synthesis of silver nanoparticles , as wellSida cordifolia [Andeli’ [Mentha aquatica leaf [In relation to this, different investigations of ultra-small metallic nanoparticles have found that these nanomaterials can easily pass through the pores of the cell wall of bacteria and can be internalized within them, disrupting their function and promoting the generation of reactive oxygen species (ROS) that cause the oxidation of the bacterial membrane, altering bacterial metabolism . Furtherrdifolia , Rosa ‘A[Andeli’ , and Menica leaf . Thus, aStaphylococcus aureus. The extract was also found to possess antioxidant properties which enabled it to reduce silver metal ions. Thus, making use of extracts from orange, lemon, and grapefruit peels as reducing and stabilizing agents is an effective alternative for the fabrication of ultra-small antibacterial silver nanoparticles.The present study employed an extract of orange, lemon, grapefruit, and mixture  peels to synthesize ultra-small AgNPs with potent antibacterial activity against a multi-drug resistant strain of Citrus sinensis (orange), Citrus aurantifolia (Mexican lemon), and Citrus paradisi (grapefruit) peels were collected from January to March in Nuevo León, Mexico. These peels were thoroughly washed with distilled water, cut to a size of 1 cm2. With respect to each of the three different peels, 20 g were weighed, and in the case of the mixture with three citrus peels, a total of 20 g was also obtained, consisting of 6.67 g of each of the peels. Individual aqueous extracts were prepared for each citrus peel and the mixture. An amount of 20 g of the citrus peels, in combination, were added to 100 mL of distilled water in a beaker. The mixture was covered with aluminum and stored for 24 h at room temperature without shaking. Then, this mixture was filtered and stored at 4 °C for subsequent use.First, 20 mL of citrus peel extract was put into a 50 mL Corning tube. Then, 20 mL of an aqueous solution of 0.1 M silver nitrate was added to the tube. The tube was placed on a rack and left to react at room temperature for 24 h. During this time, the formation of AgNPs was observed by a color change in the mixture, which went from amber to brownish black. After 24 h, the particles were separated from the mixture through centrifugation using a Thermo Scientific Sorvail Legend XFR machine, which was set to 9000 rpm for 15 min. The separated particles were then filtered and the remaining residue was washed twice with 96% ethanol to get rid of any impurities and organic material. Finally, this process resulted in stable AgNPs.−1 using a Micro-Raman Horiba XploRA instrument with a 532 nm laser.The AgNPs that were obtained underwent various types of analyses to determine their characteristics. UV-visible spectrophotometry was used to study them with a Thermo Scientific Multiskan GO machine. To assess the structural and morphological traits of the AgNPs, they were examined with transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) utilizing the FEI-TITAN microscope that operates at an acceleration voltage of 300 kV. In addition, energy-dispersive spectrometry (EDS) was conducted to identify the elements present in the samples. The same TEM equipment was used to carry out selected area electron diffraction (SAED), while X-ray diffraction (XRD) analyses were performed on a PANalytical X’Pert Pro machine. A Fourier transform infrared (FT-IR) spectrophotometer  was used to acquire IR-spectra. The Raman analysis was carried out in frequency range of 2000–200 cmStaphylococcus aureus  isolated at the Hospital San Vicente de Monterrey, Nuevo León, Mexico.The gram-positive bacteria used in the antimicrobial trials were a multidrug-resistant clinical To culture the bacteria, the overnight method was used, which involved allowing the bacteria to grow for 17 h at 37 °C and 100 rpm using a Lab Companion IS-971.After the incubation period, the cultures were diluted by a factor of 1:100 in LB medium and then the inoculum (taken from the culture) was allowed to grow for 2–3 h. Subsequently, a sample of the bacterial culture was taken, adjusting with fresh medium until the optical density at 600 nm reached a reading of 0.2 ± 0.02 in a final volume of 1 mL, using OPTIZEN 2120UV measurement equipment. This resulting suspension was then diluted by a factor of 1:100 in LB medium to create the bacterial working solution.S. aureus solution was added to each well of the assay, and the 96-well plate was incubated at 37 °C. The optical density was measured every hour for a total of 23 h. The concentration at which bacterial growth was inhibited was defined as the MIC. All tests were performed in triplicate.MIC assays were conducted in 96-well plates. First, AgNPs stocks were prepared using LB medium as a vehicle, with a final concentration of 1 mg/mL. This stock of AgNPs was added to the 96-well plate until the concentration reached 250 μg/mL in a final volume of 200 μL. Serial dilutions of AgNPs were then performed by taking 100 μL of the previous solution to the next well, adding 100 μL of culture medium, and discarding the last 100 μL of the previous dilution. The concentrations of AgNPs tested ranged from 250–15.625 μg/mL. Next, 100 μL of the MIC tests for citrus peel extracts. A solution of 20 microliters of the extract  was prepared in 380 microliters of LB medium and the same procedure as for the MICs of AgNPs was followed.Furthermore, the X-ray diffraction (XRD) pattern of the AgNPs synthesized with lemon peel extract is illustrated in The Scherrer equation was used to calculate the crystal size of the synthesized AgNPs by analyzing the X-ray diffraction data. The equation considers the full width at half maximum (FWHM) of the peaks obtained from the XRD patterns, which corresponds to the size of the crystallites. The Bragg angle (θ) for the X-ray diffraction was 2θ = 38°, corresponding to the (111) plane of the face-centered cubic structure of silver.Scherrer’s constant, commonly taken as 0.9, and the wavelength of Cu K radiation (1.54 Å) were used in the Scherrer equation. The half maximum full width (β) was determined from the peak at 2θ = 38° for each sample. The average crystal size was obtained by calculating the value of D for each sample.The crystal size of the silver nanoparticles synthesized with lemon, orange, grapefruit, and a mixture of these citrus peels extracts was determined using the Scherrer equation. The average crystal size of the AgNPs synthesized with lemon peel extract was found to be 9.71 nm. In the case of the AgNPs synthesized with orange peel extract, it was 16.23 nm. The crystal size for the extracts of grapefruit peel and for the combination was found to be 10.70 nm and 9.86 nm, respectively.The morphology of the AgNPs was determined by TEM and HRTEM images . These wThe TEM images for each extract showed a spherical shape with a narrow size distribution. The orange extract-synthesized nanoparticles  had an a−1 are attributed to the stretching of C-C bonds, while the peak at 941.09 cm−1 corresponds to the stretching of C-H bonds. The peaks at 1555.3 and 1571.7 cm−1 are attributed to the stretching vibrations of C=O bonds, and the peak at 2299.6 cm−1 corresponds to the stretching of O-H bonds. In the case of orange extract-synthesized silver nanoparticles  was evaluated using the serial dilution method. As the concentration of AgNPs decreased, bacterial growth increased. However, the AgNPs synthesized with lemon peel extract and a combination of extracts exhibited the lowest concentration (15.625 μg/mL) at which the bacteria grew, while the AgNPs synthesized with orange peel extract showed inhibition at 62.5 μg/mL. Notably, the AgNPs synthesized with grapefruit peel extract exhibited no bacterial growth at all. The minimum inhibitory concentration (MIC) values of the citrus peel extracts and the AgNPs were determined over a 22-h interval, and the results are shown in S. aureus.The antibacterial activity of the synthesized AgNPs against clinical multidrug-resistant It is known that the extracts of plants, fruits, and vegetables contain secondary metabolites such as flavonoids, phenolic acids, terpenoids, and alkaloids. These molecules contain hydroxyl groups which are used to carry out the redox reactions that are responsible for the synthesis of AgNPs since they are involved in the reduction of silver ions into metallic silver atoms which then agglomerate and grow to form nanostructures .Much of the flavonoids in citrus are flavanones bound together as glycosides. In the orange and tangerine peel, hesperidin predominates; in grapefruit, naringin and narirutin stand out; finally, eriocitrin and hesperidin stand out in lemon and lime ,41.The synthesis of AgNPs using citrus peel extracts has been extensively studied due to their potential applications in various fields. In this study, the UV-Vis spectrum was used to confirm the presence of AgNPs in samples synthesized using an aqueous solution containing extracts of orange, lemon, grapefruit, or their mixture. Sida cordifolia [Mentha aquatica leaf extract [Andeli’ [The TEM images presented in this study reveal that the synthesized AgNPs exhibit a spherical shape with a narrow size distribution. Interestingly, the orange extract-synthesized nanoparticles had an average size of 4.25 nm with a positively skewed histogram, indicating the presence of smaller nanoparticles, while the mixed extract-synthesized nanoparticles had an average size of 2.42 nm with a normal distribution histogram, indicating a relatively even distribution of sizes. These results are consistent with other reports in the literature that have utilized green synthesis methods to produce ultra-small AgNPs. For example, ultra-small AgNPs of sizes between 3 and 6 nm have been obtained with extracts of rdifolia ; using M extract , sizes o[Andeli’ .The physical and chemical characterization of these ultra-small AgNPs gives a helpful guideline showing that aqueous extracts of lemon, orange, grapefruit, and a mixture of these citrus peels can carry out an adequate reduction of silver ions and, in addition, stabilize their surface .The Scherrer equation and TEM imaging are both important tools for determining the size of nanoparticles. However, it is important to note that the Scherrer equation provides an estimate of the crystal size, while TEM imaging provides a more accurate measure of the particle size. This difference in measurement is due to the Scherrer equation providing an average size of the crystal, while TEM imaging measures the size of the individual particles.Muntingia Calabura [In the SAED analysis, the clear and distinct circular patterns observed can be attributed to the (111), (200), (220), (311), (331), and (222) planes of the face-centered cubic (fcc) metallic silver, as confirmed by the Joint Committee on Powder Diffraction Standards file number 87-0720. At the same time, the EDS analysis confirms that the ultra-small AgNPs obtained are made up of metallic silver and evidences their crystalline nature D. FurtheCalabura  have beeThe FTIR spectra of the silver nanoparticles synthesized using different citrus extracts showed unique functional groups and chemical compositions, which can be attributed to the presence of different organic compounds in each extract. In the case of silver nanoparticles synthesized using lemon extract, the observed peaks are attributed to the stretching of C-C and C-H bonds, while in the case of orange extract-synthesized silver nanoparticles, the peaks are attributed to the stretching vibrations of C-H, C-O, and C-N bonds. Similarly, grapefruit extract-synthesized silver nanoparticles showed peaks corresponding to the bending vibrations of C-H bonds and the stretching vibrations of C-N bonds. The results indicate that the choice of extract has a significant impact on the functional groups and chemical composition of silver nanoparticles.−1 in the Raman spectra suggest the interaction of AgNPs with the functional groups present in the citrus extract. The peak at 1165.41 cm−1 confirms the presence of reducing agents in the extract, while the peaks at 1280.98 and 1348.6 cm−1 suggest the presence of aliphatic compounds and amines, respectively.Raman spectroscopy was also used to analyze the synthesized silver nanoparticles and the obtained spectra confirmed the presence of AgNPs. The peaks observed at 487.52, 662.52, and 961.62 cmS. aureus, whereas the extracts obtained alone do not have an antibacterial effect  of AgNPs in the literature is reported to be 5 μg/mL for a size of 4.7 nm and 2000 μg/mL for 42 nm [Our study demonstrates that the MIC values of these ultra-small AgNPs are more efficient than those reported in previous studies , indicator 42 nm .S. aureus strains compared to other investigations using AgNPs  has displayed remarkable potential as an effective antimicrobial agent against drug-resistant bacteria. The study findings suggest that AgNPs exhibit bacteriostatic effects at low concentrations and bactericidal effects at higher concentrations, positioning them as an attractive alternative to conventional antibiotics. The ultra-small size of AgNPs, their strong penetration properties, and their larger surface area provide them with an advantage in crossing the bacterial cell wall and generating reactive oxygen species that affect cellular function, thus augmenting their antimicrobial activity.Furthermore, the use of citrus peels as a source of reducing and stabilizing agents in the synthesis of AgNPs represents an eco-friendly and sustainable approach. It offers numerous benefits, such as the valorization of citrus waste, the use of less toxic solvents and reagents, a reduction in energy consumption and process steps, and a substantial contribution to environmental preservation.The green synthesis of AgNPs using citrus peels provides a sustainable solution for the citrus industry, as it employs the abundant waste produced by these fruits. This study demonstrates more efficient minimum inhibitory concentration (MIC) than existing antimicrobial agents, rendering it a valuable strategy to combat drug-resistant bacterial infections while also contributing to environmental protection.


Magnetic resonance imaging (MRI)-detected lesions are often category 2 or 3 lesions on initial ultrasound examination. In addition, in the case of new non-mass lesions detected on MRI, one would expect to find lesions with ductal dilatation with minimal secretory accumulation, single short lesions with ductal dilatation, cyst-like lesions less than 5 mm in size, mammary gland-like lesions less than 8 mm in size, and very indistinct lesions. Detection is expected to be even more difficult. Currently, there are no clear uniform criteria for the indication of second-look ultrasonography (US) for MRI-detected lesions, so it is not possible to make a general comparison, but recent studies have indicated that the ratio of mass to non-mass MRI-detected lesions is 7:3. And it has been pointed out that the percentage of malignancy is about 30% for each. Before about 2012, the US detection rate was about 70%, and MRI-guided biopsies of undetected lesions showed a small percentage of malignant lesions. Therefore, some observers believe that lesions not detected on US should be followed up, while others believe that MRI-guided biopsy should be performed. Recently, however, the use of surrounding anatomical structures as landmarks for second-look US has increased the detection rate to as high as 87–99%, and the percentage of malignancy remains the same. In addition, recent surveillance of high-risk breast cancer requires careful management of MRI-detected lesions. In this review, we will discuss the literature on MRI-detected lesions and describe ultrasound techniques to accurately detect small lesions and reliably reveal pale lesions based on their structural differences from their surroundings. Breast magnetic resonance imaging (MRI) is used as a routine diagnostic tool for preoperative diagnosis of cancer extent, preoperative evaluation of the contralateral breast, chemotherapy efficacy determination, close examination of abnormal nipple blood secretion, and when other breast imaging studies yield suspicious results. Recently, insurance coverage for the treatment of patients with hereditary breast and ovarian syndrome (HBOC) was extended in Japan in 2020), and breast MRI surveillance is now being performed . MRI-gui020, and This review describes lesions that are not noted as abnormal findings on first-look US but are newly detected on MRI (MRI-detected lesions) and the ultrasound techniques required for second-look US.MRI is a test with high sensitivity and low specificity . TherefoThere are no uniform criteria for detection of lesions on MRI or for the indication of second-look US, even among radiologists . Many reThus, the percentage of MRI-detected lesions varies from report to report because uniform criteria have not been established Table  4, 9, 1, 23–28. The US detection rate of MRI-detected lesions varied from 23 to 71% in reports from 2003 to 2012 , 23–26. However, the detection rate was as high as 86.6% for masses and 87.5% for NMEs in a 2015 report by Hong et al. , and 99%Comparing US-detected versus undetected lesions by the malignancy rate of MRI-detected lesions in the 2003–2012 report, there was more cancer 43% vs. 14%) and more invasive cancer (78% vs. 50%)  among th% and morThe malignancy rate of MRI-guided biopsy of lesions not detected on US is 9–21%, with some reports suggesting that lesions not detected on US should be considered for MRI-guided biopsy , 25, 27.The histological type of NMEs is listed as focal adenosis, fibro-cystic, radial scar, complex sclerosing lesion, inflammatory changes, intraductal papilloma, flat epithelial atypia, lobular carcinoma, diffuse invasive breast cancer, invasive ductal carcinoma, and DCIS –41.NME is noted as the primary lesion in about 20% of cases, of which 20.8% are malignant and 84% are noninvasive ductal carcinoma of the breast , 42. On Therefore, in the case of NMEs for MRI-detected lesions, one would expect to find lesions with ductal dilatation with minimal secretory accumulation, single short lesions with ductal dilatation, cyst-like lesions less than 5 mm in size, mammary gland-like lesions less than 8 mm in size, and very indistinct lesions.Breast MRI must be performed in the supine position the first time. Failing to do so will result in reduced spatial resolution and difficulty diagnosing the cancer extent , 53. TheTable To effectively use the (2) surrounding tissues landmark and (3) vascular routes , it is necessary to understand the anatomy of the "pattern of fat and mammary gland distribution in the breast" and " deformation and displacement” .First, "pattern of fat and mammary gland distribution in the breast " are described. The breast is glandular tissue distributed within the subcutaneous fascial layer and anatomically developed in the gaps between fat lobes called the protective adipofascial system (PAFS) , 56, 57 Next, " deformation and displacement " are described. As mentioned earlier, the mammary glands are distributed in the PAFS and are fixed to the skin in the anterior position. Posterior to the mammary gland is the lubricant adipofascial system (LAFS) , 56, 57.When NME is seen in the peripheral mammary gland, the outer border of the mammary region becomes an anatomic landmark. However, in areas with more fat and fewer mammary glands Fig. d, e, theIf the NME is a small submammary line or foci, observation of the submammary ductal run is especially important. In the back-lying position, the breast fits into a small thickness of space, and the submammary area is often occupied by the medial glandular lobe due to the mobility of the LAFS. The boundary surface between the inner and outer glandular lobes can be seen on both MRI and US, which can give an idea of the degree of inclination of the mammary gland Fig. b 28]. D. D28]. DMarking: New lesions are found in 20–63% of ipsilateral and 10% of contralateral surgical specimens –63. The On the other hand, there are reports that there was no significant difference in the reoperation rate between the group for which MRI was used before breast cancer surgery (816 cases) and the group for which MRI was not used (807 cases) , and conFollow-up: At follow-up, it is necessary to observe the same areas as before without mistake and to notice the appearance of indistinct pale lesions. Depending on the histologic composition, such as invasive carcinoma with a predominant intraductal component, the lesion may not be at a hypoechoic level, and isoechoic lesions may be indistinguishable from the surrounding area at small sizes Fig. . The preMRI-detected lesions are lesions that have not been the subject of close examination on first-look US, so the US BI-RADS category is also often 2 or 3. It is difficult to distinguish between benign and malignant based on conventional US imaging , 67. TheFuture issues include the following. (1) Whether the use of US equipment, such as high-frequency probes (18–24 MHz), will enable morphological distinction between invasive and noninvasive cancer, and whether low blood flow display and contrast-enhanced US will increase the malignant diagnosis rate compared to MRI. (2) Distinguishing between background parenchymal enhancement and NME is difficult even for radiologists . Breast