Among bone-material qualities, mineralization is pivotal in conferring stiffness and toughness to the bone. Osteomalacia, a disease ensuing from inadequate mineralization of the skeleton, is caused by different processes leading to decreased available mineral  or enzymatic alterations. Vitamin D deficiency, which remains the major cause of altered mineralization leading to inadequate intestinal calcium and phosphate absorption, may be also associated with other conditions primarily responsible for abnormal mineralization. Given the reality of widespread vitamin D inadequacy, a full biochemical assessment of mineral metabolism is always necessary to rule out or confirm other conditions. Both too-high or too-low serum alkaline phosphatase (ALP) levels are important for diagnosis. Osteomalacic syndrome is reversible, at least in part, by specific treatment. Osteomalacia and bone mineralization themselves constitute largely unexplored fields of research. The true prevalence of the different forms of osteomalacia and the recovery after proper therapy have yet to be determined in the real world. Although non-invasive techniques to assess bone mineralization are not available in clinical practice, the systematic assessment of bone quality could help in refining the diagnosis and guiding the treatment. This review summarizes what is known of osteomalacia recent therapeutic developments and highlights the future issues of research in this field. Osteomalacia is a metabolic bone disorder primarily characterized by altered mineralization .10(PO4)6(OH)2] into the bone matrix, in a proper pH environment and specific 3D structure [Skeletal mineralization refers to the series of events leading to the deposition and maintenance of crystals of hydroxyapatite [Ca10PO6(OH)2] iThis complex process is regulated by endocrine and paracrine factors and the availability of minerals, in particular calcium and phosphate. Biomineralization begins in prenatal life and continues throughout the life of living organisms, coexisting with both modeling and remodeling processes .Osteomalacia, often referred to as the “disease of soft bones”, is the histological and clinical outcome of inadequate mineralization ensuing from various causes . Thus, tThe first description of osteomalacia dates back to 1885, with an accurate histological description by Gustav Pommer, pointing out the distinctive features of rickets and osteomalacia with respect to other juvenile bone diseases , osteoporosis, and osteitis fibrosa . With thWhile rickets-related bone alterations in the growing age are seldom observed nowadays in developed countries and are mainly diagnosed in the context of rare, genetically determined diseases, osteomalacia is a widespread, often underrated condition and can greatly hamper the quality and quantity of life of affected individuals .While osteomalacia is a disease of bone metabolism characterized by impaired mineralization, osteoporosis is a systemic skeletal disease with decreased bone mass and altered bone micro- and microarchitecture, leading to brittle bones. Both conditions are characterized by altered bone quantity and quality and may lead to reduced bone strength, making them easier to break. When combined in a single patient, they concur independently from bone fragility .The aim of this review is to describe the pathogenesis and the multiple causes of impaired mineralization and the histopathological, clinical, and radiological features of osteomalacia. A classification of the different forms of the disease and a feasible biochemical evaluation for differential diagnosis for everyday practice are proposed. The main forms of inherited and acquired osteomalacia will also be briefly described, along with non-specific and targeted therapeutic opportunities. Lastly, possible future developments in this field will be highlighted. The deposition of organized hydroxyapatite crystals in the bone matrix is the key event of biomineralization. This dynamic process is regulated by multiple soluble paracrine and endocrine factors, an adequate amount of matrix deposited by osteoblasts, enzymes, availability of substrates, and a low concentration of mineralization inhibitors .2D/calcitriol) at usual doses ), restore calcium and phosphate homeostasis, correct secondary hyperparathyroidism, and revert to normal, at least in part, the radiographic and histological abnormalities relatively quickly, depending on the administered dosage ,57,58. AIn congenital or acquired diseases in which 25-hydroxylation or 1alpha-hydroxylation is lacking (VDDR1 or drugs), a specific vitamin D metabolite  is the therapy of choice. In end-organ resistance to calcitriol (VDDR2), large amounts of i.v. and oral calcium and oral calcitriol are needed in order to overcome the VDR multifunction.In inherited hypophosphatemic osteomalacia, the standard-of-care practice is the administration of phosphate salts together with calcitriol, to avoid secondary hyperparathyroidism. While this treatment is mandatory in children to avoid rachitic deformities, the administration of phosphate salts, which are poorly tolerated and associated with important short- and long-term side effects, has been questioned in adults . NonetheAsfotase alfa is the replacement enzyme approved for the treatment of hypophosphatasia in both children and adults ,70,71.To date, the diagnosis of osteomalacia is mainly clinical and biochemical, given the great limitations in defining osteomalacia by the widely available DXA. The systematic assessment of bone quality in osteomalacia, in order to find specific patterns of this disease, would help in refining the radiological diagnosis. Indeed, the trabecular bone score (TBS), an index to infer bone microarchitecture in DXA images, might help in differentiating osteomalacia from osteoporosis . Indeed,The application of old techniques in clinical practice such as scanning electron microscopy (SEM) to undecalcified bone biopsies is useful to analyze mineralization and establish the bone mineralization density distribution (BMDD) but has been progressively abandoned in clinical practice being an invasive technique . The empMore specific biomarkers of the diseases  could be studied in order to find specific patterns in osteomalacia . In addition, the medium- and long-term outcomes of specific therapies  still need be assessed in real-life long-term studies.Osteomalacia is a broad term that indicates inadequate mineralization of the skeleton, which may be caused by several defects in mineral metabolism. Osteomalacia can be genetically determined, so it is generally diagnosed in infancy because it is generally preceded by rickets. At the same time, osteomalacia can be a subtle disease in adults, since it resembles other disorders, so multiple phenocopies of this disease delay the diagnosis and, therefore, the commencement of specific treatment. Osteomalacia and bone mineralization itself, remain largely unexplored fields of research. The real prevalence of the different forms of osteomalacia and the specific recovery are yet to be determined in the real world. Finding specific biomarkers of these diseases and specific features using bone quality assessment and specific mineralization analysis (qBEI) will help in refining the diagnosis and quickly address the quality of life and disease burden in these patients.


The direct impact of chronic hepatitis B and hepatitis C on neurocognition remains elusive due to the frequent comorbidities, and the domains of the neurocognitive functions affected have rarely been investigated comprehensively. We cross-sectionally assessed the neurocognitive functions of the individuals with chronic hepatitis B, chronic hepatitis C, treated chronic hepatitis C with a sustained virologic response, and their healthy control counterparts. Laboratory examinations were used to investigate the impact of inflammation on neurocognition, exclude the medical conditions that could interfere with neurocognition assessment, and assess liver function and fibrotic severity of the liver of the participants. This study found the detrimental impact of chronic hepatitis B on language and executive functions. In contrast, individuals with chronic hepatitis C showed deficits in executive functions, psychomotor speed, memory, and attention. Successful elimination of hepatitis C resulted in improved liver function, but not neuropsychological test performance. Moreover, erythrocyte sedimentation rate level was found to mediate the deficits in the attention of individuals with chronic hepatitis C. These results demonstrate the neurocognitive deficits and the difference in the profiles of neurocognitive deficits in individuals with chronic hepatitis B and chronic hepatitis C. Our study also provided results suggesting the mediation by systemic inflammation on the attention deficit in individuals with chronic hepatitis C. In addition to the life-threatening complications, including cirrhosis and hepatocellular carcinoma, both HBV and HCV cause extrahepatic manifestations. More importantly, these extrahepatic manifestations cause an impaired quality of life and economic burden on patients with viral hepatitis2. Among the extrahepatic manifestations, the neuropsychiatric symptoms found in individuals with HCV have been reported previously. However, with depression, cirrhosis, thyroid disorders, cerebrovascular diseases, and end-stage renal diseases as common comorbidities associated with HCV and significantly interfering with the accurate evaluation of neurocognitive functions, the inclusion of patients with the common comorbidities associated with HCV in the previous studies prevents a clear demonstration of the direct effect of HCV infection on neurocognitive function changes. In addition, while the negative impact of HCV infection on neurocognitive functions has been shown across several studies, the investigation into the effects of HBV on cognition has rarely been reported. As HBV has an even higher prevalence than HCV and is still without the treatment for cure, an investigation to understand the long-term impact of HBV on neurocognitive functions is warranted.According to the global hepatitis report 2017 by the World Health Organization, in 2015, the global prevalence of HBV and HCV infection in the general population was estimated to be 3.5% and 1%, respectively3. However, a thorough evaluation of the neurocognitive functions covering all the major neurocognitive domains of patients with chronic viral hepatitis has rarely been investigated.Furthermore, several mechanisms through which HCV causes neurocognitive deficits have been proposed, but a definite conclusion remains to be explored due to the limited evidence available. Meanwhile, although the treatment regimens for HCV infection have advanced significantly, whether the neurocognitive deficit of patients with HCV is reversible and whether successful elimination of HCV infection causes improvement in neurocognitive functions remains unknown. Finally, as the concept of "neurocognitive functions" is a broad term and covers a wide range of complex mental processes, the elucidation of the neurocognitive functions attributable to specific conditions requires comprehensive assessments covering different domains of each ability area and a careful combination of tasks to reveal patterns of performance5. The prevalence was even reported to be up to 17.2% in Kaohsiung County, the southern part of Taiwan6. Although the prevalences of HBV and HCV have significantly decreased in recent years, the impact of chronic viral hepatitis on the generation born before the nationwide HBV vaccination program in 1986 has been long-lasting and remained not entirely clear. The situation is similar for those infected with HCV before the wide availability of effective treatment against HCV. Therefore, in the current study, we comprehensively evaluated the neurocognitive functions  after HCV treatment. All the participants with HBV had a chronic infection as determined by HBsAg positivity for six months or more or the presence of HBV DNA by polymerase chain reaction six months or more after the initial HBsAg positivity. The number of participants in the phase of HBeAg positive chronic infection, HBeAg positive chronic hepatitis, HBeAg negative chronic infection, and HBeAg positive chronic hepatitis were 1, 7, 27, and 36, respectively, and 43 of the participants with HBV were taking antiviral medication against HBV. All the participants with untreated HCV had chronic HCV as determined by the persistent presence of HCV RNA by polymerase chain reaction for six months or more until the neuropsychological test. The definition of SVR was based on the absence of HCV RNA by polymerase chain reaction six months after the end of anti-HCV therapy before the assessment with the neuropsychological test. The demographic data, including age, sex, education, hypertension (HTN), diabetes mellitus (DM), signs of polyneuropathy, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), alanine transaminase (ALT), and FIB-4 index of the participants within each study group are shown in Table The profiles of the neurocognitive functions of each study group's participants are shown in Table However, as shown in Table Meanwhile, the patients with HCV showed significantly worse performance in perceptual reasoning and similarities of WAIS-IV and the trial 1 of CTT than the healthy control counterparts. The results suggest that HCV causes a deficit in executive functions and psychomotor speed. For the SVR group, the patients showed significantly worse performance in the immediate recall of visual production in WMS-III and verbal comprehension index of WAIS-IV than their healthy control counterparts. Compared with the patients with HBV, the SVR group still showed worse performance in both the immediate and delayed recall of the logical memory of WMS-III and shorter longest digit span forward. The results indicate that HCV patients have deficits in memory and attention, and the worse performance in memory and attention can still be observed in those after successful treatment of HCV obtaining SVR. No statistically significant difference was observed when comparing the HCV patients with those whose HCV had been treated and obtained SVR. The results suggest that successful HCV treatment does not significantly improve the neurocognitive function deficit of individuals with viral hepatitis. However, a significant improvement in hepatic injury was observed, as evidenced by the ALT level.In addition, we hypothesize that the systemic inflammation induced by HCV may be the mediator for developing neurocognitive deficits, which was examined with a regression-based analysis carried out with PROCESS macro on SPSS. The mediation effects of ESR and CRP on the neurocognitive functions affected by HCV compared with HBV are shown in Table 7. In one study applying single-cell laser capture methods to assess the full range of microglia-specific expression, HBV was found to be expressed in the microglia. Besides, with immunohistochemical analysis using HBV-core antibody as HBV-positive control, HBV immunoreactivity was found to be increased from amnestic mild cognitive impairment to HBV-positive AD cases as disease pathology increased8.Previous studies rarely investigated the neurocognitive deficit of individuals with chronic HBV or HCV infection in parallel with a detailed neuropsychological test battery covering all the major neurocognitive domains. In the present study, we found neurocognitive deficits in both individuals with chronic HBV and chronic HCV with the comprehensive neuropsychological test battery, and the deficits seem to have different patterns. Patients with chronic HBV were found to have significantly worse performance in verbal comprehension index, information, and matrix reasoning of WAIS-IV than the healthy control group and worse language function assessed with MMSE than the HCV group. These results suggest that chronic HBV causes a neurocognitive deficit in the domains of language function and executive function. Although the negative effect of chronic HBV infection on neurocognitive functions has never been definitely reported, the extrahepatic manifestation of HBV involving the central nervous system has been suggested by previous studies. A retrospective cohort study reported the association between HBV and Parkinson's disease (PD), with a standardized rate ratio of PD following HBV infection found to be 1.76 based on 44 observed compared with 26 expected cases9. One recent study showed the progressive impairment of dynamic functional network connectivity in patients with HBV-related cirrhosis, although whether the impairment is due to HBV or cirrhosis remains unknown10. These previous studies suggest the detrimental impact of HBV on CNS degeneration. The current study demonstrates the effect of chronic HBV infection on neurocognitive functions, with a deficit in language and executive functions.Moreover, in one study investigating the influence of HCV on cognition where HBV was recruited as the control group, the impairment was similar between HBV and HCV in verbal learning/memory when assessed with Rey Auditory Verbal Learning Test12, while other studies found the detrimental effect in tasks associated with memory and psychomotor speed15. There were also several studies revealing no definite changes in neurocognitive functions that could be attributable to HCV18. The conflicting results across the different studies may be due to the difference in the participants' demographic characteristics (such as age and education levels) and the different sensitivity in the tasks used to assess neurocognitive functions.In addition to the detrimental impact of chronic HBV on language and executive functions, the current study also found that patients with chronic HCV infection showed poorer performance in the tasks associated with executive functions, psychomotor speed, memory, and attention, while visuospatial and language functions remain unaffected. Previous studies had attempted to investigate the impact of HCV on neurocognitive functions, but the findings diverged and varied across different studies. Several studies showed worse performance in tasks associated with attention and executive functions in HCV patients19. Meanwhile, HCV has also been shown to increase the risk of kidney injury20, thyroid disorder21, and cerebrovascular events22, all of which are associated with neurocognitive impairment. In the current study, to investigate the direct impact of chronic HCV infection on neurocognitive function, we excluded the participants with a history of cerebrovascular disease, brain surgery, thyroid disorder, end-stage renal disease, signs suggestive of decompensated liver cirrhosis, psychiatric disorders, and illicit recreational drug usage. Our results showing the worse performance in tasks associated with executive functions, psychomotor speed, memory, and attention suggest the direct impact of chronic HCV infection on cognition.Moreover, although common comorbidities associated with HCV significantly influence neurocognitive functions, few studies have excluded the patients with depression, cirrhosis, thyroid disorders, cerebrovascular diseases, and end-stage renal diseases in one study to examine the direct impact of HCV on neurocognitive functionsWe also compared the neurocognitive functions of patients with chronic HCV and those successfully treated and obtained SVR. In the current study, significant improvement in the ALT level, but not the neurocognitive function profiles, was noted, suggesting that the successful elimination of chronic HCV caused improvement in liver function but not neurocognitive functions. However, the results do not necessarily rule out the potentially beneficial effect of successfully eliminating HCV in decreasing the neurocognitive decline rate after the successful treatment. Long-term follow-up is needed to understand the beneficial impact of HCV treatment on neurocognitive function.23. Moreover, as systemic inflammation has been suggested to cause neurocognitive deficits26, systemic inflammation induced by HCV was also proposed to be involved in the decline of neurocognitive functions. However, no direct evidence has been provided except for the current study27. Besides, the mediation effect of ESR on the cognitive domains of attention revealed in the present study may also be in agreement with the pathogenic mechanisms of chronic hepatitis as immune complex diseases29. Last but not least, HBV- and HCV-infected individuals had been shown to have dysbiosis and change in the composition of intestinal bacteria33, and the inflammatory responses induced by the translocated microbial products, such as lipopolysaccharide (LPS), were proposed to be one of the pathogenic mechanisms associated with HBV or HCV infection34. The association between LPS and the inflammation-mediated attention deficit observed in this study may need further investigation to clarify the liver-gut-brain association.Furthermore, the current study found systemic inflammation seems to partially mediate the neurocognitive deficit of individuals with chronic HCV. The significant mediation effect of ESR on the performance in tasks associated with attention suggests that chronic HCV patients' attention deficit is mediated by systemic inflammation. Several mechanisms have been proposed for the neurocognitive deficit associated with HCV. One proposed mechanism suggests that HCV infects the microglia/macrophages in the central nervous system, and the release of proinflammatory cytokines from the infected microglia/macrophages results in neurocognitive deficits35 when interferon-α suppresses the release of CRP. Whether the decline in attention induced by HCV is also associated with pathways related to interferon-α needs further investigation.Meanwhile, CRP was not shown to mediate the neurocognitive dysfunction found in HCV patients in the current study. The dissociation between ESR and CRP in mediating the detrimental effect of HCV suggests the decline in attention associated with HCV is more closely related to the inflammatory conditions that cause elevation of ESR without elevation of CRP. One condition for such dissociation was observed in autoimmune diseases36. The results suggest the diverging pathogenic mechanisms of chronic HBV and HCV on neurocognitive functions. In the present study, we focused on the long-term effect of the chronic infections of HBV and HCV on neuropsychological function decline. The neurocognitive function declines found in the chronic HBV and HCV patients and the mediation effect by systemic inflammation shown in the present study suggest a gradual process, in which the waxing and waning disease activity of chronic viral hepatitis causes systemic inflammation that drives the neurodegeneration.Also noteworthy is the difference in the profiles of the neurocognitive function impairment of chronic HBV and chronic HCV patients. While chronic HBV causes deficits in the domains of language and executive functions, chronic HCV was found to cause functional decline in executive functions, psychomotor speed, memory, and attention. The different deficit profiles revealed in the neuropsychological tests may also reflect the potential difference in the mechanisms causing the neurocognitive impairment in chronic HBV or chronic HCV patients. Based on previous studies' results, the deficits found in chronic HBV patients in the language functions in the current study may be associated with cortical dementia syndromes. In contrast, chronic HCV patients' deficits in attention and memory may be more closely related to subcortical dementia syndromes39. More importantly, we have used Quade's test to eliminate the effect of the potential confounding factors. The other limitation of the current study is the lack of the laboratory results of ESR and CRP of the healthy control group, which prevents the detailed exploration of the mechanism for the cause of the neurocognitive deficit induced by viral hepatitis, especially HBV. The lack of the healthy control group's laboratory results also prevented the exclusion of patients with end-stage renal diseases and thyroid disorders and may underestimate the detrimental impact of viral hepatitis. However, such underestimation would not cause a significant difference in the main results of the present study.The present study has potential limitations. The significant differences in age and sex ratio between the study groups may cause selection bias. The difference in the education years may interfere with the results of the neurocognitive profile assessment. However, the difference may be inevitable and may reflect the difference in the epidemiological profile of chronic HBV and HCV among Taiwanese, with the prevalence of HBV and HCV in Taiwan being higher in males and females, respectively41, and the coinfection of HIV and viral hepatitis is frequent in some areas around the world42. However, the transmissions of HBV and HCV in the Taiwanese generation older than 50 years old were mainly due to vertical transmission and iatrogenic factors, respectively5, while the major risk groups for HIV are those with a history of illegal intravenous drug usage or homosexual practices with men. The prevalence of HIV in the participants recruited in the present study should be low, especially after excluding those with a history of illegal recreational drug usage or same-sex relationship or those with abnormalities suggestive of HIV coinfection during the evaluation by physicians, based on history taking, physical examinations, and laboratory examinations during the clinical follow-up. Therefore, the impact of potential HIV coinfection may be minor, although such a possibility could not be totally excluded in the present study.The other limitation of this study is the lack of laboratory results confirming the absence of human immunodeficiency virus in the participants recruited due to the strict regulations in screening human immunodeficiency virus (HIV) in Taiwan to prevent confidentiality breaches. As the detrimental impact of HIV on neurocognitive functions is significant and well-establishedBesides, the wide availability of direct-acting antiviral agents against HCV in Taiwan has significantly reduced the number of untreated HCV patients recruited in the present study. Meanwhile, the strict inclusion criteria for participant recruitment in the present study to minimize confounding factors limited the number of participants in the current study and precluded the comparison of the neurocognitive functions across the different disease spectrums. However, the sample size did not cause restriction in the power detecting the neurocognitive deficits and the potential mechanism found in the present study, which focuses on the long-term effect of the chronic infections of HBV and HCV. Future studies with a larger sample size are warranted to validate the detrimental impact of chronic HBV and HCV infection and compare the difference in the neurocognitive deficit conferred across different disease spectrums.In conclusion, the present study found the detrimental effect of chronic HBV on language and executive functions and showed the negative impact of chronic HCV on executive functions, psychomotor speed, memory, and attention. Also, the neurocognitive function deficit was not reversible after obtaining SVR. Besides, systemic inflammation was found to mediate the deficits in attention in chronic HCV patients. The present study enables a more in-depth understanding of the extrahepatic manifestations of viral hepatitis and also provides evidence for the potential mechanisms of the neurocognitive function deficit induced by viral hepatitis. Lastly, the findings will also raise the awareness of the detrimental impact of viral hepatitis, especially the previously unknown HBV, on neurocognitive functions.st of September 2017 to the 24th of March 2020. Out of the 88 HCV patients, 65 have obtained SVR for more than six months before recruitment in the study. Among the 23 participants without SVR, 22 participants were treatment naïve except for one participant who had received peginterferon and ribavirin 17 years ago. Among the 65 participants obtaining SVR, 35 obtained SVR with peginterferon and ribavirin, and 30 obtained SVR after direct-acting antiviral agents. The decision to initiate antiviral therapy for HBV was primarily based on the presence or absence of cirrhosis, the ALT level, and the HBV DNA level following the EASL 2017 guidelines for HBV infection43. All participants were between 40 and 80 years old with an education level equal to or more than six years to fully understand the content of the neuropsychological assessment. We excluded patients with a history of cerebrovascular disease, brain surgery, thyroid disorder, malignancy, alcohol abuse, end-stage renal disease, signs suggestive of decompensated cirrhosis , psychiatric disorders, and current pregnancy or breastfeeding. We also excluded patients with signs suggestive of organic brain lesions after a neurological examination by a board-certified neurologist, including 1 individual with HBV, 2 individuals with untreated HCV, and 6 individuals with treated HCV before the recruitment. Participants with HIV or a history of illicit recreational drug usage and tattooing were excluded to minimize the possibility of recruiting patients with HIV in the study. Meanwhile, individuals in same-sex relationships were also not recruited. Participants with end-stage renal disease were excluded based on the estimated glomerular filtration rate < 30 mL/min/1.73m2 calculated with CKD-EPI Creatinine Equation. The exclusion of participants with decompensated cirrhosis was based on history taking and clinical assessment by the hepatologists referring the patients.This study cross-sectionally recruited a total of 199 participants, including 39 healthy volunteers, 72 patients diagnosed with HBV, and 88 patients diagnosed with HCV between the 21The participants' written informed consent was obtained before enrollment, following the ethical standards outlined in the 1975 Declaration of Helsinki. All study procedures were approved by the ethical research committee of Kaohsiung Medical University Hospital (KMUHIRB-G(I)-20170022), and National Cheng Kung University Hospital (-/B-ER-104-082), and all methods were performed following the approved guidelines.45 or intracranial lesions46 that are associated with viral hepatitis. Participants with signs suggestive of peripheral nervous system disorders were not excluded as the degeneration of the peripheral nervous system and the neurocognition may share common pathogenic mechanisms47.All participants in the disease groups were assessed with a neurological examination. The neurological examination performed by a board-certified neurologist is composed of the examinations of cranial nerves, motor functions, sensory functions, coordination, and reflexes. Participants with signs suggestive of organic brain lesions were not recruited for further evaluation to exclude the presence of stroke48. The disease state of chronic viral hepatitis and the state of sustained virologic response had been confirmed with laboratory tests before the evaluation of neuropsychological assessment. Logical Memory-I&II and Visual Reproduction-I&II in the WMS-III were used to assess memory49. Trial 1 of CTT50, Digit Symbol Substitution, and Symbol Search were used for psychomotor speed evaluation. Stroop Color and Word Test51, Digit Span of WAIS-IV52, PASAT53, and serial seven of MMSE54 were used to evaluate attention. Block Design of WAIS-IV was used for visuospatial function evaluation. Similarities, Matrix Reasoning, Information, Letter-Number Sequencing of WAIS-IV, Semantic Association of category verbal fluency55, trial 2 of CTT, and M-WCST56 were used to assess executive function. Naming, repetition, verbal comprehension, and writing of MMSE were used for language function evaluation. The raw scores of the neuropsychological tests were used for the analysis. The neuropsychological tests used for the assessment of the major neurocognitive domains are summarized in Table All study participants were assessed with a comprehensive neuropsychological battery composed of tests evaluating all the major neurocognitive domains, including memory, psychomotor speed, attention, visuospatial, executive function, and language function, similar to our previous investigation on the cognitive profiles of patients with PDth of May 2019. The creatinine levels of all the participants in the study group of HBV, HCV, or SVR were also examined to rule out the possibility of neurocognitive impairment attributable to end-stage renal disease. Levels of the ALT of chronic hepatitis patients were examined to evaluate their liver function. In addition, aspartate transaminase (AST) and platelet count of chronic hepatitis patients were examined to obtain the FIB-4 index, as an indicator of cirrhosis. Levels of ESR and CRP were also examined among the participants with HBV, HCV, or SVR to evaluate systemic inflammation status. The laboratory examinations for ALT, creatinine, ESR, and CRP were collected within the one-month period from the date of neuropsychological tests. The date of the sample collection for the laboratory results used to calculate FIB-4, including AST, ALT, and platelet count, was within the six-month period from the date of neuropsychological tests. There were two participants in the SVR group whose ESR and CRP were not examined.The diagnosis of HBV was based on the serological test positive for HBsAg, and the diagnosis of HCV was based on the serological test positive for the anti-HCV antibody. The presence of the HCV virus in the HCV patients was confirmed with polymerase chain reactions. The laboratory tests used to diagnose viral hepatitis were collected between the 11th of April 2001 and the 857, proportions were calculated for qualitative variables, and means and standard deviations were calculated for quantitative variables. We used the Kolmogorov–Smirnov test for the normality test. Afterward, we examined quantitative variables with the Kruskal–Wallis test and qualitative variables with a chi-square test. We controlled the impact of confounding variables  with Quade's test58. Statistical significance was predetermined with an alpha level less than 0.05. The statistical analysis was performed by a commercially available software program . A regression-based analysis was carried out with PROCESS macro on SPSS59 to calculate the mediation effect of systemic inflammation on neurocognitive functions in hepatitis C patients. Helmert coding was used for the grouping of patients with HBV , HCV , and treated HCV with SVR . Bias-corrected bootstrap confidence intervals for the effect based on 5000 bootstrap samples were calculated and used to determine whether ESR or CRP mediated the neurocognitive function changes in hepatitis C patients. All the associated data not provided within the paper are available on request from Rwei-Ling Yu.Similar to our previous publicationSupplementary Information.


The measures in the fight against COVID-19 have reshaped the functions of urban facilities, which might cause the associated crimes to vary with the occurrence of the pandemic. This paper aimed to study this phenomenon by conducting quantitative research. By treating the area under the jurisdiction of the police station (AJPS) as spatial units, the residential burglary and non-motor vehicle theft that occurred during the first-level response to the public health emergencies (pandemic) period in 2020 and the corresponding temporal window (pre-pandemic) in 2019 were collected and a practical study to Beijing was made. The impact of urban facilities on crimes during both periods was analyzed independently by using negative binomial regression (NBR) and geographical weight regression (GWR). The findings demonstrated that during the pandemic period, a reduction in the count and spatial concentration of both property crimes were observed, and the impact of facilities on crime changed. Some facilities lost their impact on crime during the pandemic period, while other facilities played a significant role in generating crime. Additionally, the variables that always kept a stable significant impact on crime during the pre- and pandemic periods demonstrated a heterogeneous impact in space and experienced some variations across the periods. The study proved that the strategies in the fight against COVID-19 changed the impact of urban facilities on crime occurrence, which deeply reshaped the crime patterns. The sudden outbreak of COVID-19 caused a huge impact on social life. In order to curb the spread of the virus, countries and regions all over the world adopted a series of prevention and control measures including lockdowns, social distancing, stay-at-home orders, etc. However, the implemented measures simultaneously generated a versatile impact on offending activities in the city. Recently, many studies have contributed to uncovering the impact of COVID-19 prevention and control on crime. The common conclusions conducted from these studies are that the pandemic-related prevention and control measures induced a reduction in general crime . Lately,This paper plans to conduct an empirical study on residential burglary and non-motor vehicle theft that occurred during the pre- and pandemic periods in Beijing and tries to uncover whether the associations between occurred crimes and urban facilities across the periods changed. The rest of this paper is organized as follows. First, the relevant research associated with this study is summarized, then the data and methods are described. After that, the corresponding analysis results are shown, and finally, the major conclusions and prospects of future work are presented.The COVID-19 pandemic provided an opportunity for a rare natural experiment, allowing scholars from various countries and regions to examine the potential impact of pandemic prevention and controls on crime in urban settings. The initial research focused on describing the crime variation by time in specific cities and found that most crimes in different countries and cities had been observed to reduce. For example, many studies proved that residential burglary was significantly reduced during the pandemic period ,18,19,20After experiencing the study on crime variation by cities in the early stage of the pandemic, people have begun to continuously investigate crime variation in smaller spatial units. For example, Campedelli et al.  found thIn recent studies, people have started to include social and economic variables to interpret the spatial distribution of crime variation in the context of COVID-19 prevention and control. The variables include population mobility, ethnic characteristics, and economic factors et al. For example, Estevez-Soto  conducteThus far, people have conducted a great many descriptive and quantitative studies on crime in the context of COVID-19 prevention and control. At present, investigating crime’s variation in space from the social and economic perspectives has received more attention, as including the social and economic backcloth could help enhance the understanding of crime variation in space by the impact of the pandemic. However, some shortcomings still exist in the current research, as the social and economic variables have mainly focused on population, unemployment, etc., but less attention has been paid to urban facilities. As a matter of fact, urban facilities play important roles in attracting or generating crime opportunities , and somhttps://nj.tjj.beijing.gov.cn/nj/main/2020-tjnj/zk/indexch.htm, accessed on 1 November 2022), the main urban districts are about 1385 km2, and the population living in the main urban districts is about 10.988 million. The Beijing government officially confirmed the discovery of the first COVID-19 case on 20 January 2020, and then launched a first-level response to the public health emergencies (FRPHE) to cope with the challenges of the COVID-19 virus spreading on 24 January. After maintaining a series of prevention and control measures for 14 weeks, Beijing officially announced that the spread of the COVID-19 virus had been controlled and from 30 April 2020 , the emergency response was adjusted from the first-level to the second-level. http://wjw.beijing.gov.cn/, accessed on 1 November 2022). It could be recognized that at the end of January, the cumulative number of confirmed cases rose rapidly (red line). The first “turning point” appeared in mid-February, when the number of daily reported confirmed cases began to decline (blue line). At the second “turning point”, the cumulative curve kept flattening (red line), and the daily reported confirmed cases kept declining (blue line). By 30 April, the cumulative number of cured cases (green line) approached the cumulative number of confirmed cases (red line), and the daily reported confirmed cases were reduced to zero level, which indicates that the spread of the COVID-19 virus in Beijing was successfully controlled.The study area included the main urban districts of Beijing, which administratively includes Xicheng, Dongcheng, Chaoyang, Haidian, Fengtai, and Shijingshan Districts. According to the Annual Statistic Report in 2020 , and the crime types used for research were residential burglary and non-motor vehicle theft. According to the Penalty Code in China, residential burglary refers to the offense of breaking into the owner of the room without permission, and includes those that occurred in residential areas and merchants. Being a typical property crime, residential burglary has received much attention ,43. Non-www.amap.com) platform. A total of 29 types of POIs were collected and treated as potential attractors of property crime [The urban facilities used for analysis were from the POI data, which was openly accessed from AMap β represents the constant for location i; kβ represents the estimated parameter for independent variable kx at location i; and iε is the independently and identically distributed residual at location i [GWR is a local regression model that allows for spatial variation in the estimated parameters: one for each areal unit (AJPS). Once the appropriate global model was identified, GWR models were estimated for both types of crime. GWR can be represented using the following equation:cation i ,48,49.p < 0.001 level, which reflects that the pandemic posed a significant negative effect on the occurrence of property crime.First, the basic temporal and spatial patterns of residential burglary and non-motor vehicle theft during the pre- and pandemic periods were investigated and compared. The boxplots of the crime count by day during the two periods in Beijing were generated. As shown in p-values were all less than 0.05, which proved that the crimes distributed by the AJPS did not obey normal distribution, while the variance of the sample was larger than the mean value, so using the NBR model to analyze the data was supported. Following that, all independent variables  aggregated by the AJPS were simultaneously tested by using the VIF (variance inflation factor) method to see whether multicollinearity existed among the variables. The results indicate that all independent variables were less significantly correlated, so they could be input into the NBR model directly. In order to better detect the attractiveness of the urban facilities to crimes, green parks, open-air squares, train and shuttle bus stations, subway stations, and bus stops were removed from the independent variable list of regression for residential burglary as they are not the typical and appropriate targets for residential burglary offenders.The descriptive analysis showed that the occurrence of residential burglary and non-motor vehicle theft were suppressed and that their spatial concentrations were reduced during the pandemic period. The phenomenon indicated that crime opportunities were enormously controlled by the pandemic prevention-related measures. Hence, in order to further uncover how pandemic-related measures impact the occurrence of crime, a regression analysis was carried out to examine whether the associations between crime and facilities varied across the pre- to pandemic periods. First, both types of crime being aggregated by the AJPSs were examined using the K–S (Kolmogorov–Smirnov) test. The findings showed that p < 0.05) were identified for residential burglary that occurred during the pre-pandemic period, but only specialized hospitals, gym rooms, arts and museums, and road density for vehicles demonstrated positive associations with crime, while low-priced hotels, temples and churches, and road density for only pedestrians showed a negative impact on crime. However, during the pandemic period, specialized hospitals, low-priced hotels, arts and museums, temples and churches, and road density for vehicles were no longer significant, and only the gym rooms and road density for pedestrians maintained a stable impact on crime. The comparison of the regressions demonstrated that most facilities lost their impact on residential burglary during the pandemic period.The regression was run using STATA and the results are shown in Comparatively, for non-motor vehicle theft, five variables demonstrated a significant impact on offense during the pre-pandemic period, and community clinics, kindergartens, and road density for vehicles were positively associated with the offense, while wholesale markets and road density for only pedestrians demonstrated a negative effect. While during the pandemic period, the impact of wholesale markets, kindergartens, and road density for only pedestrians on crime disappeared, community clinics and road density for vehicles maintained a stable impact on crime, and more importantly, middle schools, bars and pubs, KTVs, and bus stops became new ones that significantly decided whether the crime occurred during the pandemic period.The findings from the NBR model proved that although the significant impact of facilities on crime was observed during the pre-pandemic period, some of their impact on the offenses was reduced by the pandemic prevention-related measures during the pandemic period. For example, because entertainment activities were ordered to cease, gym rooms were empty and became potential positive attractors to residential burglary offenders, and as no customers presented, the bicycles and electric-driven bicycles concentrated around the bars and pubs, KTVs and community clinics were unguarded and crime opportunities appeared for offenders during the pandemic period. Moreover, as public traffic flow was reduced to a low level to prevent the spread of the virus, the passenger flow playing natural guardianship around bus stops was decreased and the bicycles that concentrated around the sites became suitable targets for offenders. Additionally, it was interesting to see that road density maintained a stable impact on both property crimes, but varied by the crime type. The road density for only pedestrians was negatively associated with residential burglary during both periods, which indicated that more accessible areas maintained a stable suppression effect on burglary regardless of the changes in the social environment. While the road density for vehicles was observed to be positively correlated with the occurrence of non-motor vehicle theft, this implies that bicycle-related offenses are more likely to occur within the areas with high vehicle flow concentrations.2s were more improved than the NBR model.The NBR regression analysis proved that the impact of urban facilities on crime varied from the pre- to pandemic period, but simultaneously, the impact from some facilities on crime occurrence remained stable. In order to better examine whether the variables had a stable impact on crime in space, the dependent and independent variables were input into the GWR model and run using ArcGIS 10.7. The regression findings are shown in The coefficient distribution of the identified stable independent variables was visualized in maps to detect whether the impact of the facilities on crime varied in space. Aiming to uncover how crimes associated with different urban facilities varied by the pandemic-related prevention measures, this paper executed a practical study on residential burglary and non-motor vehicle theft in Beijing. By treating the main urban districts as the targeted area and the AJPS as the spatial unit, the crime that occurred during the FERPH period in 2020 and corresponding temporal period in 2019 as well as 29 types of urban facilities, which were assumed to have potential attractiveness or impact on property crimes, were collected. Following this, a rough descriptive analysis and regression analysis were conducted and several major findings were obtained.(1)The results indicate that both types of property crime were significantly reduced during the pandemic period, which infers that the occurrence of the pandemic and its related prevention measures had an important negative impact on crime in Beijing. Furthermore, the concentrations of crimes in space were reduced and hot areas observed during the pre-pandemic period disappeared during the pandemic period.(2)The variations in the impact of urban facilities on residential burglary and non-motor vehicle theft across the pre- to pandemic periods were observed. Specifically, a couple of facilities that previously posed a significant impact on the occurrence of residential burglary lost their impact during the pandemic period, and some maintained stability at a significant level. While the phenomenon also occurred for non-motor vehicle theft, it was observed that some facilities  became significant ones conducive to the occurrence of crime during the pandemic period.(3)The stable variables that maintained a significant impact on crime during pre- and pandemic periods were also investigated at the AJPS level. The findings indicate that the impact of the variables on crime was heterogeneous in space and kept some variations across the pre- to pandemic period.This study, although based on an investigation in Beijing, still has some implications for environmental criminology in theoretical and practical aspects. First, at the theoretical level, this work proves that the environmental variation of some urban facilities significantly changed crime occurrence, which supports the opinions of crime opportunity theories and allowed for a reduction in crime during the pandemic period to become interpretable. Next, in the practical aspect, the study identified vulnerable facilities that are more exposed to the risk of crime, thus consequently, the crime prevention measures could be deployed more scientifically in the backdrop of pandemic prevention.Although this paper compared the impact of urban facilities on property crime between the pre- and pandemic periods, there are still some questions that need answers. For example, some facilities that had been assumed to be attractors for property crime actually showed a negative impact. According to the principle of routine activity opinion , whether


Neurodegenerative disorders are marked by neuronal death over time, causing a variety of cognitive and motor dysfunctions. Protein misfolding, neuroinflammation, and mitochondrial and protein clearance system dysfunction have all been identified as common pathways leading to neurodegeneration in recent decades. An altered microbiome of the gut, which is considered to play a central role in diseases as well as health, has recently been identified as another potential feature seen in neurodegenerative disorders. An array of microbial molecules that are released in the digestive tract may mediate gut-brain connections and permeate many organ systems, including the nervous system. Furthermore, recent findings from clinical as well as preclinical trials suggest that the microbiota of the gut plays a critical part in gut-brain interplay and that a misbalance in the composition of the gut microbiome may be linked to the etiology of neurological disorders ; the underlying mechanism of which is still unknown. The review aims to consider the association between the microbiota of the gut and neurodegenerative disorders, as well as to add to our understanding of the significance of the gut microbiome in neurodegeneration and the mechanisms that underlie it. Knowing the mechanisms behind the gut microbiome's role and abundance will provide us with new insights that could lead to novel therapeutic strategies. Before the 1990s, the concept of microbiome or gut-microbiota was unclear; therefore, only cultivable bacteria were known to people. The literature reveals that only approximately 30% of the entire gut microbiome is known .Progressive studies have established that the development of neurodegeneration has its strings attached to the gut-microbiome. Several structures have been identified to contribute to the establishment of cross-talk between the two . ResearcStudies on axenic mice, scientifically termed the “gnotobiotic” murine model, reveal that gut bacteria is a prerequisite for the proper performance of the digestive tract. Moreover, it has also been proven to possess a major significance in the sustenance of the accomplishment capability of enteric nervous system (ENS), the functioning of which is independent of the central nervous system (CNS). The neuronal circuit of the ENS is interpenetrated into the wall of the gut; moreover, the neurons associated with it are of the motor type, sensory type, and interneuron type .The microbiota is omnipresent and found at a differential location on or within the human being. These locations extensively include the cavities of the body such as the buccal cavity, inside the acoustic meatus, nasopharyngeal cavity, digestive tract, urogenital passage, and obviously on the surface of the epidermal layer . The digNeurodegeneration, as the name implies, refers to the degeneration of neurons. Although it can occur for a variety of reasons, it has been observed to occur more frequently in older people, such as the ability of cell renewal and repair declines.α-synuclein [α-synuclein gene have been ascertained by researchers  in the part of the brain known as substantia nigra (controls movements) and various other related functions that lead to the onset of several key non-motor and motor characteristics of Parkinson's disease (PD), such as dementia, tremor, bradykinesia, anxiety, digestive tract disability, rigidity, behavioral changes, and postural instability [α-syn clusters in peripheral locations, including the enteric nervous system (ENS), despite their most frequent location in the brain [Distorted tability . The conhe brain .α-synuclein's 53rd position to threonine, which is also denoted as A53T. The alanine residue at the 30th position of the α-synuclein peptide changes to proline in the second mutation, which is also represented as A30P [α-synuclein is the key element of Lewy bodies and Lewy neurites [The mutation results in the conversion of an alanine residue from  as A30P . Furtherneurites . Lewy boneurites .Alzheimer's disease (AD) is also one of the prevalent variants of dementia around the globe. Alzheimer's disease generally has 2 types: sporadic and familial. Another way of categorizing AD is via the age of onsets of the disorder, such as early onset or late onset. Although the primary cause for the generation and progression of AD is malfunctioning or nonfunctional neurons in specific regions of the encephalon, there are other factors that more or less contribute to the same.Recognizing physical and behavioral changes of AD-affected roles are sharp depletion of retention, difficulty, and discomfort in speech and writing, the capability of resolving problems reduced considerably, inability to retrace objects placed elsewhere, etc. These symptoms become life-threatening with advancement in the stages of the malady .β and Tau protein in the tissues of the encephalon [β accumulates towards the exteriors of the nerve cell. Tau protein is modified into a couple of helical filaments that further gather in association with each other to form neurofibrillary tangles [Investigations at the cellular and molecular levels have revealed two proteins that are potentially liable for the generation and progression of neurodegeneration. Researchers have revealed that patients suffering from the malady have an accumulation of amyloid-cephalon . It has  tangles . Both thβ readily diffuses into the synaptic cleft. This hinders the transmission of signals from one neuron to another, ultimately rendering the cell nonfunctional [Tau protein is involved in the polymerization of tubulin protein in microtubules. Generally, it is a protein associated with 2-3 phosphates per molecule; after hyperphosphorylation, the amount of phosphate abnormally increases to 5-9 phosphates per molecule of tau [tau towards the tubulin protein, which further affects the construction and maintenance of microtubules [Furthermore, after oligomerization, the amyloid-nctional . On the e of tau . Such hyotubules .An elevating number of researches point to a bidirectional association between the gut, bacteria, and brain, known as the gut-microbiota-brain axis that may play a significant function in the development of the brain . The micAmyotrophic lateral sclerosis (ALS) is considered as an exceptional but devastating neuronal toxic condition that kills people after 1 or 3 years of identification. The global incidence of amyotrophic lateral sclerosis is expected to be 1.75 per 100,000 person-years . Amyotrophic lateral sclerosis is among the most difficult diagnoses for clinical practitioners to make and affect due to its debilitating course and current lack of viable treatment. Despite this fact, observational studies have revealed a variety of risk variables. Amyotrophic lateral sclerosis, particularly sporadic ALS, is deemed to occur by a mixture of hereditary as well as non-genetic causes –30. PathDuring the last 10 years, there has been a striking increase in studies on the human microbiome, or the microscopic creatures that reside in the human body. In comparison to other colonization sites, such as the airway, skin, and urogenital tract, the alimentary canal hosts the majority of the human microbiota. Metabolism and adaptive immunity regulation are two important physiological roles of the microbiome of humans . As a coALS also known as motor neuron disease (MND) has been linked to an imbalance of the neurotransmitter gamma-aminobutyric acid (GABA) and other related modulators. The death of nerve cells (motor neurons) in ALS is thought by scientists to be a result of excessive glutamate exposure . Motor nThe production of neuroactive metabolites and toxins by microbiota may have a direct impact on the CNS and neuronal health, while immune response, dietary compounds, and drug metabolism may have an indirect impact . For insHtt), which encodes the protein huntingtin, is present in all humans in two copies (Htt). The mutant huntingtin protein (mHtt) is prone to cluster formation. These peptides are retrogradely translocated into the cell body for digestion by lysosomes during the normal clearance process of cells. Under inflammatory conditions, these mutant polypeptides assemble and disrupt the retrograde transit of molecular components that causes damage to microtubules and molecular motors, resulting in cellular damage and leading to chronic neuron degeneration [The aggregation of various specific proteins inside the CNS is comparable to neurodegenerative health conditions like PD, ALS, and AD. Protein misfolding appears to occur in AD, resulting in an accumulation of abnormally folded tau-proteins and beta-amyloid in the neurons. A transmembrane protein called amyloid-precursor protein (APP) is essential for the growth of neurons, survival, and repair (post-injury) under optimum conditions . Howeverneration .2•. Furthermore, H2O2 is emitted directly during the amyloid-beta aggregation process. By reducing divalent metal ions , amyloid-beta can transform O2 into H2O2. ROS accumulation exacerbated by amyloid-beta causes lipid peroxidation and the subsequent production of cytotoxic plaques. Amyloid-beta also causes neurotoxicity by disrupting Ca2+ homeostasis [There is a link between ROS inequity and neurofibrillary tangles proteins. In comparison to the previously described phenomenon of oxidative stress causing the formation and agglomeration of amyloid plaques, misfolded proteins could also cause excessive ROS, resulting in neurotoxicity. Amyloid-beta formation encourages ROS production, according to various lines of evidence. A causes the pro-oxidative enzyme NADPH-dependent oxidase to be activated, resulting in the generation of Oeostasis .Inflammation of neurons known as neuroinflammation is a well-studied ALS pathogenic process marked by a composite dysregulation of both peripheral and resident immune lymphocytes. The principal characteristics are astrocyte and microglia activation, T-cell infiltration, and enhancement of proinflammatory cytokines . The micShort-chain fatty acids (SCFAs) are minute organic monocarboxylic acids with 4 to 6 carbon atoms that are formed inside the intestine by the microbiota during microbial digestion of nondigestible poly-saccharides such as dietary fiber and complex carbohydrates . AlthougSCFA mixtures have been discovered to suppress the generation of inflammatory markers (cytokines), promote T cell proliferation in diverse directions, reinstate functionality maturation of microglia, and cause the phenotype metamorphosis of microglia to reduce inflammation. As a result, the combination of SCFAs plays a fundamental task in the immunological modulation of abnormalities of CNS .βγ–PLC beta–MAPK pathway, which modulates the organism's energy requirement and regulates physiological balance. Changing the quantity of SCFAs and ketone bodies generated from them within the liver, in addition to their ratio, induces changes in energy metabolism and the sympathetic nervous system function. Besides providing energy to the central nervous system's cells, SCFAs including propionate and butyrate impact intracellular potassium levels, implying that SCFAs are involved in the functioning of cellular signaling pathways. Certain SCFAs, specifically, affect the transcription of the gene encoding tryptophan hydroxylase, a crucial enzyme in the serotonin manufacturing pathway, as well as tyrosine hydroxylase, an enzyme that is implicated in the biosynthesis of noradrenaline, dopamine, and adrenaline in their rate-limiting step and hence has an impact on brain neurochemistry [Short-chain fatty acids are considered to play a vital role in communication between the microbiota, brain, and gut. In addition to giving energy to cells and regulating microglial maturation, these microbial metabolites play a role in influencing neuronal activity. SCFAs have been shown to affect neurotransmitter and neurotrophic factor levels . Previouhemistry .Clostridia) in the digestive canal can endorse serotonin biosynthesis by raising the expression of genes of tryp-hydroxylase 1 enzyme (TPH1) (rate-limiting) in colon cells (enterochromaffin cells), and even some metabolic products generated by such bacteria have indeed been distinguished as the molecules that prompt this activity. Staphylococci have also been shown to produce serotonin via decarboxylating the precursor 5-hydroxytryptophan (5-HTP) using Staphylococcal aromatic amino acid decarboxylase (Sada) [Serotonin is produced primarily in the central nervous system by serotonergic nerve cells in the raphe nuclei. Impaired serotonin expression and activity in the brain have been linked to the pathophysiology of psychiatric conditions such as depression and anxiousness. It is vital to note that roughly 85-90 percent of serotonin is generated inside the human body's peripheral tissues, primarily through specific cells known as enterochromaffin in the epithelium of the intestine. On the other hand, serotonin cannot pass the blood-brain barrier, although its precursor tryptophan can. Enterochromaffin cells in the gut use tryptophan from protein intake as a precursor to producing serotonin, which is controlled by the bacterial kynurenine production pathway. Microbes that form spores (mostly e (Sada) .Modification in the transcription of cognition-relevant neuromodulators such as the serotonin transporter, neurological neurotrophic factor, receptor subunit 2B (N-methyl-D-aspartate), and Y-neuropeptide system may be associated with this cognitive deficit . Neurotrβ-proteins. Given the strong correlation between gut dysfunction and neuropathies, fecal microbiome transplantation (FMT) has been discovered to be a successful treatment approach for restoring a healthy bacterial community inside the gut and has been shown to benefit several diseases, including Alzheimer's. Bacterio-therapy via oral gavage with probiotic supplementation has emerged as a promising potential treatment for neurological illnesses such as Alzheimer's. As a result, the 3xTg murine animal model of AD administered with probiotics early on demonstrated a significant lowering in inflammatory markers and lowered mental impairment, which was correlated with less brain damage and amyloid-beta aggregates accumulation. Furthermore, several research have indicated that probiotic and butyrate administration improve mental health, and memorizing capacity in a D-galactose paradigm of increasing age, a state is known to associate with the development and progress of AD [SCFAs may also influence important neuropathological events underlying AD, according to mounting data. AD is the major prevalent type of neuronal, distinguished by increasing cognitive deficits. Given that Alzheimer's disease has complicated pathogenesis and that appropriate therapies to prevent disease development are still absent, numerous studies have examined the advantages of having a healthy microbiota in reducing AD advancement, as well as the link between dysregulation and progression of the disease. SCFAs inhibit the construction of neurotoxic fibrils, the primary toxins accountable for synaptic disruption and cognitive deficits in AD, by interfering with the protein-protein interplay between Ass of AD .There are possible mechanisms through which short-chain fatty acids regulate gut and brain connection: SCFAs are the primary metabolic products generated via the intestinal tract microbiome by the anaerobic process of indigestible carbohydrates such as dietary fiber and starch. SCFAs may affect gut-brain connection and cognitive ability, either directly or indirectly. SCFAs are taken by colon cells mostly via sodium- (Na-) dependent monocarboxylate transporters (SMCTs) or H + -dependent monocarboxylate transporters (MCTs) . SCFAs rEpigenetic control, which involves chromatin remodeling, DNA methylation, histone modifications, and noncoding RNA regulation, has been illustrated to play a central role in nervous system growth and neurodegenerative disorders such as Amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease. Nucleosomes are the basic building elements of chromosomes, consisting of 147 base pairs of DNA surrounded by double-copy histones . The nucleosome regulates gene expression through two important mechanisms: ATP-dependent chromatin complex remodeling, resulting in fast genomic rearrangements . The ATPThe nexus between the brain and gut is generally termed “the gut-brain axis.” The respective axis is presumed to aid in the establishment of cross-talk between the ENS of the GI tract and the CNS of the encephalon. Furthermore, this task is accomplished via the aid of hemoglobin, the vagal/vagus nerve, and passive diffusion .The vagus nerve innervates the viscera via an enormous efferent and afferent network and serves as an intermediary between upper CNS circuits and brain stem parasympathetic control circuitry. It is a multimodal autonomic nerve that originates in the medulla oblongata and travels bilaterally from the brain stem through the neck  and esophagus before diverging peripherally to activate the viscera. The activation and stimulation of the vagus nerve (VNS) can act as a therapeutic alternative to neurodegenerative disorders such as AD, PD, and ALS .Ursodeoxycholic acid and its taurine-conjugate are endogenous water-soluble bile acids with anti-programmed cell death and neuroprotective characteristics, in part by interfering with the mitochondrial mechanisms of apoptosis, hindering the production of unstable free oxygen radicals, limiting the stress of endoplasmic reticulum, and stabilizing the response of misfolded protein, implying a therapeutic potential advantage in neuroapoptosis. Both bile salts are accessible via oral gavage and accessible to the BBB epithelium, penetrating the in vitro human neuronal microvascular endothelial cells monolayer, making neurodegenerative illnesses an appealing topic of research. Ursodeoxycholic acid and its taurine analog, tauroursodeoxycholic acid (TUDCA), were identified in the parenchyma of the brain of rodents after administration, and in the cerebrospinal fluid of individuals with amyotrophic lateral sclerosis after oral dosage. TUDCA has been shown to have antiapoptotic and therapeutic properties in various experimental models of neurodegenerative ailments. TUDCA's antiapoptotic activity in AD drew huge attention after it was shown that these bile moieties inhibited cell death in primary murine neurons exposed to amyloid peptides [The USA Food and Drug Administration (FDA) authorized vagus nerve activation (VNS) for therapeutic application in 1997, and it is an effective and safer adjunctive therapy for refractory various neurological disorders including neurodegeneration. Recent reports discovered that activating the dermatome of the vagus nerve inside the external ear similarly may have a neuronal-protective outcome. Particularly, auricular-vagus nerve stimulation (A-VNS) is the least persistent VNS method that is safest and easiest to conduct, and it is having a parallel restorative impact on VNS. As a result, VNS is particularly equipped for clinical applications. VNS has been shown to successfully decrease postischemic inflammation and oxidative stress, resulting in improved rehabilitative outcomes. In various animal models, VNS-induced neuroprotection is related to the stimulation of central 7-nicotinic acetylcholine receptors. Emerging evidence suggests that 7 7-nicotinic acetylcholine receptors can attenuate inflammatory reactions in Parkinson's disease pathogenesis. Furthermore, 7-nicotinic acetylcholine receptors are engaged in the implementation of murine splenic CD4+ T-cell development. In information on published data on VNS, it was anticipated that VNS could improve inflammation and immunological balance in neurodegenerative disorders . In addipeptides .Nitric oxide, also referred to as NO, is the chief neurotransmitter of NANC (nonadrenergic and noncholinergic) of the ENS in both animals and humans . The relEscherichia coli (E. coli) is capable of converting nitrite into NO at pH 7. Moreover, the strain Klebsiella, belonging to the Proteobacteria phylum, along with the Clostridial strain of the phylum Firmicutes, which forms the vital composition of gut microbiota, have been identified to have the potential to fix nitrogen in the gut of humans [nifH gene in the fecal sample Neuronal nitric oxide Inducible nitric oxide Endothelial nitric oxide , through the transition of (L) arginine to citrulline through enzymatic action. Various distinguishable genes of NOS are manifested. They are as follows:nNOS and eNOS produce an nM concentration of the NO molecule and exert an important neuroprotective effect. On the other hand, iNOS produces μM concentrations of NO, which elicits a neuronal toxic response to pro-inflammatory stimulus [stimulus . In partstimulus . Moreovestimulus .The other aspect is that a plethora of NO can be extremely harmful and it may be subjected to a redox reaction, which may further lead to the generation of toxic substances such as RNS (reactive nitrogen species). RNS has been identified to possess the potential to render the cell impaired, encourage degeneration of neurons, and induce neurodegenerative maladies .The review successfully established that the interconnection between the brain and the gut for the generation of neurodegenerative maladies is crucial. Both aerobic and archaebacteria form the basis of the make-up of the gut microbiome. It has been witnessed in the works of the literature discussed above that the fetus when inside the womb is devoid of a microbiome in the gut. Further comprehensive efforts in the field of research towards gut flora have illustrated that the establishment of microbes in the gut is initiated at birth but is completely achieved in the upcoming three years of birth. There are several reasons to which the disturbance of gut-microbiota is linked, but the most potent reason for it is exposure to antibiotics. As the review is directed toward the recognition of the nexus between the microbiome of the gut and its effects on neurodegeneration, both major types of neurodegenerations have been generally discussed to mention the conventional pathways of the generation of the maladies, addition to the disruption of the gut microbiome. Furthermore, NO, which is the chief neurotransmitter for NANC, plays a crucial part in the generation of the ailments. Both Parkinson's and Alzheimer's diseases are linked to the NO pathway. However, it has also been recognized that the source of NO is not only gut-associated microbes but also external environmental and dietary elements that equally contribute to it. Moreover, several genes have been recognized to endogenously produce NO, which further validates that the generation of neurodegeneration has its strings attached to that of the microbiota of the digestive tract. The link between the microbiota of the gut and neurological diseases is generating a rising amount of research interest. A rising body of evidence recommends that the microbiota plays a larger role in the inflection of a variety of pathological and physiological situations, and it is now widely accepted that two-way communications between the microbiota of the gut and brain are required to maintain homeostasis. The neuroendocrine, CNS, neuroimmune systems, enteric nervous system, autonomic nervous system, and microbiota of the colon are all part of the gut-brain axis. Probiotics  have been shown to help with a range of ailments, including metabolic abnormalities, behavioral issues, and cognitive functioning.


Efficient DNA repair processes are essential for the maintenance of genomic integrity and therefore cellular homeostasis. Due to their post-mitotic nature, neurons cannot be replenished like other cell types and thus they must deal with DNA lesions throughout their lifespan, implying that DNA damage is particularly deleterious to these cells. DNA damage accumulates in neurodegenerative diseases, and thus may contribute to the selective death of specific types of neurons. However, DNA lesions are required for the regulation of neuronal gene expression and synaptic function and thus DNA damage is significant in normal physiological processes. Whilst recent evidence has shed new light on the increasingly complex roles of DNA damage and its repair in neurons, these processes are not sufficiently understood.This special issue discusses our current understanding of the role of DNA damage and repair processes in neurons in both normal cellular physiology and the development of neurodegenerative diseases such as Huntington's disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD).Gangwani and Cuartas review our current knowledge of the role of R-loop-associated DNA damage in transcriptionally active genomic regions in spinal muscular atrophy (SMA). R loops are DNA-RNA hybrids that form normally during transcription, but their timely resolution is critical in avoiding R-loop-related genomic instability and maintaining genomic fidelity. In SMA and several other neurodegenerative disorders where the non-homologous end-joining (NHEJ) DNA repair pathway is defective, R-loop formation leads to aberrant genomic modifications and an altered transcriptional landscape. This process is particularly important for post-mitotic neurons, and the authors thoroughly discuss this mechanism in the context of other motor function diseases, such as ataxia telangiectasia (AT), ataxia oculomotor apraxia 2 (AOA2), ALS and AD, in this review. In conclusion, the authors suggest that defective R-loop biology could be a convergent factor among all the known neurodegenerative diseases, where the persistent accumulation of DNA double-strand breaks in repair-inefficient motor neurons ultimately leads to aggressive disease phenotypes. However, further investigation into this possibility is warranted to better understand the common disease-causing mechanisms in these conditions.Pradhan et al. summarize the current understanding of disease mechanisms related to DNA damage in HD, focusing on the role of huntingtin (HTT) in transcription-coupled DNA repair (TCDR) in motor neurons. While wildtype HTT facilitates DNA repair by stimulating TCDR in HD, mutant HTT (containing polyglutamine repeat expansions) forms toxic aggregates, interferes with transcription, induces synaptic dysfunction, and impairs DNA repair processes. Thus, persistent DNA damage within actively transcribing genes or promoter regions may impede transcription of a variety of neuronal genes, impacting overall neuronal health and function in HD. In addition, the expansion of polyglutamine repeats in HTT causes DNA damage, thereby triggering neurotoxicity in HD. The authors state that neither the transcriptional signatures nor the activity patterns of any two classes of neurons are likely to be identical, thus different classes of neurons may display different patterns of DNA damage.Gangwani and Cuartas, and Pradhan et al., are also presented by Konopka and Atkin and Li et al.. These articles link DNA damage and defective DNA repair with the selective vulnerability of specific classes of neurons in neurodegenerative diseases.Similar views as those described by Konopka and Atkin discuss the importance of the physiological roles of DNA damage and repair in neural and synaptic plasticity, which underlies processes including learning and memory, brain development, sensorial training, and recovery from brain lesions. Putatively, DNA damage and repair processes alter neurotransmission, as well as neural and synaptic connections, thereby modulating the functions of specific types of neurons. Furthermore, activity-induced DNA lesions in neurons are known to regulate the expression of early response genes, including those involved in neural and synaptic plasticity. Thus, dysfunction of these physiological DNA damage and repair processes may lead to the selective death of neurons in neurodegeneration (depending on the genes targeted), and the functions served by specific neurons. The authors also summarize our current knowledge of the relationship between neuronal plasticity and DNA damage in neurodegenerative diseases such as ALS, AD, HD, and PD.Li et al. provide a comprehensive discussion of the role of DNA and RNA polymerases in cell type-specific DNA repair and its significance in neurological and neurodegenerative diseases. Importantly, terminally differentiated neurons remain in the G0/G1 phase of the cell cycle, hence, transcription-uncoupled repair pathways are major contributors to genome maintenance. The authors focus on the sources of DNA damage, DNA repair pathways, and structure-function relationships of a wide variety of DNA/RNA polymerases that are specifically activated in neurons. They also discuss the implications of cell-type specific activation of DNA repair pathways in response to both endogenous and exogenous genomic insults to neurons. A better understanding of the role of polymerases in DNA repair may reveal how long-lived, post-mitotic neurons cope with DNA lesions. Furthermore, this may increase our knowledge of how dysfunction in these processes contributes to disease onset, despite the diversity of neurodegenerative diseases.In summary, dysfunction in DNA repair is common across neurodegenerative diseases. Therefore, understanding the precise mechanisms responsible for the impartment of DNA repair in neurodegeneration offers the opportunity to develop new, more effective therapies. Interestingly, neurodegenerative diseases are characterized by the selective death of a specific group of neurons, and this may originate during the impairment of DNA repair processes that govern normal neuronal functions. It is therefore worth noting that potential therapies based on DNA repair in neurodegenerative diseases should be considered carefully so that they do not interfere with the normal protective functions of DNA repair in neurons.AK wrote the first draft of the manuscript, which was developed with the input of JA and JM. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Orthodontic clear aligners constitute an alternative and increasingly used orthodontic treatment modality, offering enhanced esthetics with potential consequences regarding patients’ oral health-related quality of life (OHRQoL). Objective: Summarize and systematically evaluate existing evidence on the OHRQoL of patients treated with orthodontic clear aligners compared to treatment with conventional metal, fixed appliances. Search methods: We searched without limitations six databases and searched manually the reference lists of relevant studies up to the end of October 2022. Selection criteria: We looked for data from prospective studies that compared OHRQoL, using instruments that had undergone full psychometric validation, between orthodontic patients with clear aligners and labial, fixed, metal orthodontic appliances. Data collection and analysis: We extracted the data from the located studies, and we assessed the risk of bias with the Cochrane Collaboration suggested tools. The quality of available evidence was based on the GRADE approach. Results: Three studies were identified. OHRQoL was impacted less by clear aligners compared to treatment with conventional labially placed, fixed, metal appliances. The exploratory meta-regression, with the time point of assessment as predictor, did not reveal any statistically significant effect. The quality of the available evidence ranged from very low to low. Conclusions: According to the exploratory synthesis of the limited available dataset, treatment with clear aligners could be associated with better OHRQoL ratings compared to treatment with conventional labially placed, metal, fixed appliances. However, the quality of the presented evidence renders further high-quality studies warranted to be able to reach safer conclusions. Nowadays, the need for esthetic orthodontic appliances has shown a surge due to the increasing portion of adult orthodontic patients . The claThe concept of quality of life (QoL) is defined as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns” . The parA recent systematic review investigated the effect of clear aligner treatment on OHRQoL . HoweverTo summarize and systematically evaluate existing evidence on the OHRQoL of patients treated with orthodontic clear aligners, compared to treatment with conventional metal, fixed appliances. Pertinent methodological guidelines were followed to form the review protocol ,22,23,24The PICOS acronym domains determined the eligibility criteria . The seaClinicalTrials.gov, WHO’s ICTRP, KoreaMed and Cochrane Review Groups’ Specialized Registers, and records identified by handsearching), Cochrane Database of Systematic Reviews (Cochrane Library), Scopus, Web of Knowledge  and ProQuest Dissertation and Theses (ProQuest)) on 30 October 2022 and was developed by EGK (The search was conducted in six databases (Medline (PubMed), CENTRAL  independently, and pertinent information was documented in predetermined forms. If further clarifications were needed in regard to the published data, or additional materials were necessary, we tried to contact the corresponding authors via email.Two authors (AEA and MAM) assessed the risk of bias in individual studies independently with ROBINS-I for non-randomized and with the RoB2 tool for RCTs ,27. Asse2 statistic [Data on total OHRQoL ratings were reported as standardized mean differences and 95% Confidence Intervals (CI), because the method of calculation of the aggregate score varied across studies. The data at each point of observation were pooled on an exploratory basis with the random effects method for meta-analysis since they were expected to differ across studies due to clinical and methodological diversity. In order to further facilitate the interpretation of the total OHRQoL ratings difference, the standardized mean differences (SMDs) were re-expressed into the initial scale of OHIP-14, based on the information from Jaber et al. , and comtatistic . All anatatistic ).We did not perform the subgroup analyses or analyses for “small-study effects” and publication bias included in the protocol due to the lack of adequate data . Meta-reThe flow of records is depicted in The searches were conducted in six databases on 30 October 2022 and were developed by EGK . Languag® technique [The characteristics of the eligible studies (published between 2020 and 2022) can be found in echnique , while iechnique . OHRQoL No differences were noted in total OHRQoL ratings between patients treated with clear aligners and conventional labial, metal appliances at the start and the end of treatment. During treatment, patients treated with clear aligners reported fewer impacts  Supplem. The difBased on the findings of the exploratory synthesis of OHRQoL data from psychometrically validated instruments, which was presented in the current systematic review, treatment with aligners may bring additional benefits to the reported increases in OHRQoL conferred by orthodontic correction ,14,15,16Nowadays, it can no longer be argued that patient-reported outcomes are paramount when addressing the impact from a disease and its treatment, at least in non-life-threatening conditions . HoweverMiller and co-workers  studied Furthermore, another two prospective studies examined the adjustment of adults over the first two weeks of treatment with labial-metal-fixed and clear aligner orthodontic appliances ,40. A sa® technique and another 30 with conventional labial fixed appliances) who filled out a questionnaire evaluating oral impacts and treatment satisfaction. The authors concluded that treatment with orthodontic aligners is not always more pleasant, but it can be easily tolerated, as it fulfils needs regarding food consumption and helps eliminate ulcerations of the mucosa. Nevertheless, clear aligners may influence speech regarding pronunciation and delivery in the short run.Alajmi et al.  conducte® technique. The questionnaire included items on daily routine, the consumption of food and possible oral symptoms 1 week after the activation of the appliances. Patients in the fixed appliance group reported having more pain, difficulties in sleeping, impaction of food and irritations on the tongue and cheeks after the first week of treatment [Similar results were found in the study of Baseer et al. . They careatment .The exploratory synthesis of OHRQoL data from psychometrically validated instruments suggested statistically significant superior OHRQoL ratings for the clear aligner group at all time points assessed during treatment, which is consistent with the findings of the exploratory meta-regression that did not reveal any statistically significant effect of the time point of OHRQoL assessment. Although the differences for most points did not exceed the Minimally Important Difference for the total OHIP-14 scale as reported by Lau et al. (2022) , at 6 moMeanwhile, at the timepoint of the end-of-treatment assessment, a “plot twist” was detected; the group treated with conventional labial metal brackets reported better OHRQoL compared to those treated with clear aligners. This unanticipated, at-first-sight result could be attributed to the imbalance present also at the baseline assessment . It is pIn the same context, it is worth mentioning that OHRQoL may be affected by factors other than the type of appliance. Age and tooth extractions, combined with orthodontic treatment, socioeconomic factors and other parameters, could affect patient perceptions ,36. SomeAlthough the issues of the efficiency and effectiveness of clear aligner orthodontic treatment in comparison to conventional fixed appliances mechanotherapy are not part of this report, it should be noted that there is a discrepancy between the advanced, rapid pace of developments in the field of clear aligner orthodontic therapy and the status of relevant scientific documentation and evidence. Therefore, clear aligner treatments require further and comprehensive documentation regarding their evidence-based outcome perspectives .The strengths of the present review include using an established methodology and focusing exclusively on comparative studies between patients treated with aligners or metal fixed appliances. The search strategy employed was as exhaustive and comprehensive as possible, covering grey literature, as well as electronic and manually searched, up to the end of October 2022. The heterogeneity ensuing from the clinical and methodological variability was incorporated in the random effects model employed in the exploratory quantitative data synthesis . LimitatFuture well-designed studies could focus on the use of psychometrically validated questionnaires and should limit potential confounding factors that could have an impact on OHQRoL.Based on the exploratory synthesis of the limited available dataset, treatment with clear aligners could be associated with better OHRQoL ratings compared to treatment with conventional labially placed, metal, fixed appliances. However, the quality of the presented evidence renders further high-quality studies warranted in order to be able to reach safer conclusions.


Pandemics affect every aspect of life, and Coronavirus Disease 2019 (COVID-19) is no exception. The impact of COVID-19 might be even greater in medical education, which involves close contact with patients. This comment reviews current trends in medical education in response to COVID-19, especially in the pre-clerkship curriculum, and discusses opportunities and challenges in medical education in the post-pandemic era. COVID-19 has accelerated the adoption of online teaching and learning and is expected to boost innovation in medical education. First, blended learning, which is a mix of online and offline learning intended to incorporate the best of both worlds, is expected to become more widespread. Second, more novel approaches to learning that involve student-led initiatives likely become popular mediated by various technologies. Third, there will be more use of online learning resources and assessments. As online learning is expected to play a prominent role in the post-COVID-19 era, such transitions offer both opportunities and challenges. These challenges include faculty development on online teaching skills, creation and sharing of online resources, and effective design and implementation of online assessments. This comment calls for institutional support and collaborations for faculty development and for the development and sharing of learning resources, more models and guidelines for effective technology integration, and use of the virtual learning environment to promote student-centered learning to embrace the challenges as opportunities to improve medical education in the post-COVID era. Pandemics have worldwide repercussions, as has been amply demonstrated by Coronavirus Disease 2019 (COVID-19), and their effects on medical education are substantial because it requires close contact with patients. Historically, this was also experienced during SARS, which was prevalent in 2003. To prevent class interruptions caused by SARS outbreaks, online Problem-Based Learning (PBL) was introduced at a medical school in China and was subsequently continued because of excellent feedback from professors and students  is attracting attention as an important learning method for online learning, and learning resources incorporated in the MOOC, such as lecture videos, online reading materials, and quizzes can also be used for classroom teaching (de Jong et al. Learning resources may include assessment items, which can be used to provide feedback or assess the academic achievements of learners. Online assessments have the advantage of mediating technology to provide more robust assessments, which is emphasized in the concept of ‘technology-enhanced assessment’ (Dennick, Wilkinson, and Purcell The COVID-19 pandemic is expected to bring about several changes in medical education. Future trends in medical education include blended learning, more student-centered learning and curricula mediated by various technologies, and more use of online learning resources and assessments. The digital transformation is expected to offer medical students with the opportunities for technology-enhanced learning and the learning environment that promotes lifelong learning (Belovich et al. This comment has implications for moving forward to embrace the challenges as opportunities to improve medical education, particularly in the pre-clerkship phase of basic medical education. First, faculty development is warranted for medical faculty to help them acquire the competencies for the changing and various roles of teachers in the technology-mediated learning environment. Second, more models and guidelines for effective technology integration are needed to improve the current practice of online teaching and learning in medical education that moves beyond replacing or amplifying traditional teaching. Third, collaborations are suggested for medical schools to develop and share learning resources and to provide medical students with more innovative and noble learning environments in which medical students reach out and collaborate in a wide variety of settings.