The need to address sexual and reproductive health and rights (SRHR) in humanitarian settings is more urgent than ever, especially among young refugees. We conducted a scoping review to identify and synthesise the literature on perceived barriers and facilitators to SRHR among young refugees and interventions created to address their needs.We searched three databases  for peer-reviewed and grey literature published in English between January 2008 and June 2018 that reported on SRHR barriers, facilitators and interventions for young refugees aged 10 to 24 years. We extracted data using standardised templates and assessed the quality of studies according to study design. Data were charted using qualitative content analysis and organised in line with a socio-ecological framework .We screened 1,169 records and included 30 publications  across 22 countries; 15 were peer-reviewed articles and 15 were from the grey literature. Twenty-two publications reported on young people in refugee camps or alternatives to camps (e.g. sustainable settlements), and eight referred to young refugees who had been resettled to a third country. We identified 19 sub-categories for barriers and 14 for facilitators at the individual, social and community, institutional and health system, and structural levels. No publications discussed the SRHR challenges faced by young homosexual, bisexual, transgender or queer refugees, or those living with HIV. Nine publications described interventions, which tended to focus on the provision of SRHR services and information, and the training of peers, parents, religious leaders and/or service providers.Findings highlight that while young refugees experience similar barriers to SRHR as other young people, many of these barriers are exacerbated by the refugee context. The limited number of publications and evidence on interventions underlines the immediate need to invest in and evaluate SRHR interventions in refugee contexts. Universal access to sexual and reproductive health (SRH) is a fundamental human right that is central to achieving the 2030 Agenda, as emphasised in the Sustainable Development Goals related to good health and wellbeing, and gender equality . Young pThe need to address the SRHR of young people in humanitarian contexts is especially pressing. As of 2019, an estimated 70.8 million people had been forcibly displaced worldwide; of those, around 25.9 million were refugees and over half were under the age of 18 , 7, in aIn order to improve SRHR and identify tailored interventions in the context of conflict and displacement, there is an urgent need to gather information to ensure that the needs of young refugees are respected, protected and fulfilled in line with international human rights standards , 15. TheTo close this gap, we reviewed and synthesised the literature on perceived barriers and facilitators to SRHR among young refugees globally, and the interventions developed to address their needs. We focused on two central research questions:What has been reported on the perceived barriers and facilitators to SRHR for young refugees worldwide?What has been reported on current SRHR interventions that target young refugees?For the purpose of the current review, we use the term ‘refugee’ to refer to any person who has undergone forced international migration, including asylum seekers. Different sub-populations of refugees (e.g. victims of trafficking) face different risks and challenges associated with their specific migration process and context–whether they are in transit, being resettled to a new country or voluntarily repatriating. Throughout this scoping review, we differentiate between refugees residing in camps or alternatives to camps, and refugees who have been resettled to a third country. In line with classifications used by UNHCR, the former is used in this review to group publications that report on refugees living in camps and spontaneous settlements, as well as those who have alternative arrangements, such as urban refugees living independently amongst host populations . In refuWe referred to a model by Kaufman et al.  when devWe conducted a scoping review, exploring both quantitative and qualitative publications, to achieve our aim. Scoping reviews have become increasingly popular in health research given their usefulness for mapping the range and nature of evidence in relation to complex topics and for identifying gaps in the literature , 31. TheWe considered primary research studies of all designs as well as grey literature across all geographical regions; reviews were excluded as they did not add new primary data. In order to be included, studies had to meet the following inclusion criteria :published in the English language;published between 2008 and 2018, given the most recent increase in international migrants during this time period;focus on young people between 10–24 years of age: ‘adolescents’ (10-19-year-olds), ‘youth’ (15-24-year-olds), or people across these age brackets ;focus on refugees  ; andreport on perceived SRHR barriers, facilitators and/or interventions.Accordingly, studies were excluded if they focused on internal migrants, such as rural-urban migrants, or migrant workers. Publications that presented data for young people plus other age groups, or refugees plus nationals, were only included if data were disaggregated by population.We searched the peer-reviewed literature in two databases  and grey literature in one database (POPLINE) from 1 January 2008 to 15 February 2018. Our search strategy was built in four steps using free-text and controlled vocabulary (e.g. MeSH terms): 1) sexual and/or reproductive health and rights  AND barriers and/or facilitators including interventions (e.g. barrier* OR facilitator* OR intervention*) AND young people (e.g. adolescent* OR young OR youth) AND refugee (e.g. refugee* OR "asylum seekers") . The seaAfter the initial database searches, we reviewed the abstracts to identify the most common and relevant keywords; these included ‘sociocultural’, ‘planning’, ‘teenage’ and ‘resettlement’. We then performed a second search across all included databases using the original search strategy plus the identified keywords. In addition, we conducted a third search in June 2018 to check for any newly published articles. In February 2020, we re-conducted the original PubMed search and removed filters that relied on publications having been indexed with MeSH terms by PubMed (e.g. Humans), to enable publications that had not yet been indexed to be included.We imported all records into an online article management application  and remoWe conducted a charting process to sort and organise the included publications and elicit information and insights relevant to our review, focusing on the study region, setting, sample size and participants. Findings were analysed using qualitative content analysis and synthesised using a thematic, narrative approach , 39. SpeWe conducted a critical appraisal to assess the quality of all included primary studies. Two authors (JC and VT) independently assessed the quality of all included publications according to study design, using the Cochrane Collaboration Qualitative Methods Group’s criteria for the critical appraisal of qualitative research  and the Twenty publications employed a qualitative study design, nine employed mixed methods, and one employed a quantitative design. Study settings included, but were not limited to, Australia (6 publications) , 53–57, Twenty-three publications reported on studies conducted with both males and females, while seven were specific to females; no publications referred only to young male refugees. Half (15 publications) described studies with youth aged 15 years and above, and the other half also included younger adolescents (10 to 14 years); however, very few presented results disaggregated by age. In terms of the migration context, we found that 22 publications focused on young people living in refugee camps or alternatives to camps , 58–72 aDuring the critical appraisal of the qualitative content, 10 publications were rated as high quality, 15 publications were rated as moderate quality, and 5 publications were rated as low quality in line with the Cochrane Collaboration Qualitative Methods Group’s criteria . Of the Tables Ten publications reported comprehension of SRHR as both a barrier and a facilitator , 69, 72.Four publications highlighted the role of skills and empowerment for young people in camps , 67, 71.Six publications reported on risk-taking behaviours in refugee camps , 60, 62,Fourteen publications reported that GBV, including sexual harassment, sexual violence, forced sex, home invasion and rape, exploitation and discrimination occurred frequently in camps and alternatives to camps , 71, 72.In terms of facilitators, three studies conducted in Tanzanian and Ethiopian refugee camps identified the value of supportive community organisations for SRHR. In particular, training of community leaders on child protection and confidentiality for survivors of GBV was considered a facilitator , 60, 62.Two studies reported lack of confidentiality and adolescent-friendly health services as barriers to SRHR , 53. ForTwelve publications reported that inadequate infrastructure and security were barriers to young refugees’ SRHR when residing in refugee camps or alternatives to camps , 69–72. Correspondingly, 10 publications discussed effective camp management as a key facilitator for SRHR , 69–71. Finally, six studies in different refugee camps reported structural regulations such as public policy and laws , 62, polSimilar to what was found in refugee camps, nine publications reported low awareness of SRHR among refugees who had been resettled to a third country such as Australia or the United Kingdom , 52–57. Three publications identified poor risk perceptions and misunderstandings as key barriers to SRHR for refugees who had been resettled , 54, 56.Two publications that studied resettled young refugees identified a disparity between the norms of a refugee’s country of origin and the norms of their host country , 56, forIn line with this, twelve publications described how addressing sociocultural norms , 59, 70 A lack of provider support was identified as a barrier by young refugees who had been resettled to Australia and the United Kingdom , 53. ForThree publications reported that refugees felt constrained by resettlement needs such as finding housing, a job and navigating their new society, and therefore could not prioritise their health, including SRH , 53, 56.In addition to describing facilitators and barriers, nine publications also reported on specific interventions to improve SRHR among young refugees , 68–71. To the best of our knowledge, this scoping review is the first to map what has been reported on perceived barriers and facilitators, as well as interventions, related to SRHR for young refugees at a global level. We found that most publications reported on barriers, rather than facilitators, including lack of knowledge and information, GBV, sociocultural norms, stigma and shame, lack of social support, and lack of infrastructure and security.At first glance, many of these barriers to SRHR are similar to those faced by other young people, including stigma and shame surrounding young people’s sexual activity , 68, 70,However, not all publications evaluated or identified facilitators or interventions in relation to the reported barriers. While the most commonly reported facilitators  directly tackle some challenges, we did not identify any facilitators to address peer pressure, social exclusion or stigma for young refugees. In particular, very few studies addressed conflicting sociocultural beliefs related to individual versus family norms which can play a central role when young people transition through puberty and adolescence , 76, leaOnly nine publications described SRHR interventions for young refugees , 68–71, Young refugees are a highly heterogeneous population–yet, most publications did not present disaggregated data by characteristics such as age, sex, sexual orientation, race/ethnicity, socioeconomic background or physical and psychological impairments. Four publications specifically referred to young refugees with disabilities , 66, 67,Furthermore, we found that little attention is given to the sexual and reproductive rights of young refugees in the literature. While several publications focus on GBV, few discuss sexual rights including an individual’s right to choose if, when and with whom to be in a relationship and have sex, as well as reproductive rights related to abortion. This conclusion is supported by Hartmann et al. who found that while many SRH interventions address gender inequalities, very few involve rights . As suggThis scoping review highlights SRHR barriers and facilitators for young refugees globally and identifies major research gaps. Key strengths include: the scoping approach, which allowed the mapping of literature across different countries and refugee contexts while drawing on diverse methodologies; the fact that most data came from young refugees themselves; the use of the socio-ecological framework to synthesise the data; the critical appraisal of all primary studies; and the presentation of findings by type of refugee context . Our aim was to establish a knowledge base and identify knowledge gaps, rather than merely comparing and contrasting findings across different settings. Even though we strived for a comprehensive search, it is possible that we missed relevant studies as we restricted the review to publications written in English within the last 10 years. During initial revisions of the manuscript, we noted that the inclusion of certain filters (e.g. Humans) in the original PubMed search resulted in the omission of publications that had not yet been indexed. We therefore removed the filters and re-conducted the original PubMed search with the same date restrictions, resulting in the inclusion of five additional publications. Furthermore, few publications reported results disaggregated by age and sex, undermining efforts to conduct stratified analyses to better understand the needs of specific sub-groups. Finally, due to the cross-sectional design of many studies, it is possible that some of the reported barriers and facilitators to SRHR were experienced before the study participants became refugees.Our review identified several avenues for future research, such as institutional and structural facilitators  for resettled young refugees where literature is currently missing. In addition, further research could differentiate between experiences faced by younger versus older adolescents, and males versus females to support age and gender perspectives in analyses. More evidence is needed on facilitators and effective interventions, particularly for young refugees who have been resettled. Future research could also investigate whether any of the identified barriers, facilitators or interventions are applicable in refugee settings other than those included in the current review. In addition, as no publications reported on SRHR barriers and facilitators for young lesbian, gay, bisexual, transgender, queer or intersex refugees, this points to a large gap in the literature to be addressed in future studies and interventions.In the foreseeable future, war and civil unrest, poverty and climate change will continue to forcibly displace people from their countries of origin. Our results highlight that young refugees are among the world’s most vulnerable populations and have specific SRHR needs. While they experience similar barriers to SRHR as other young people, many of these are exacerbated by the refugee context, such as the high risk of sexual abuse and exploitation as well as other forms of GBV. It is crucial that effective interventions are implemented to improve SRHR outcomes for all refugees, with a particular focus on the safety and security of young people. Addressing these needs will help young men, women and non-binary individuals in refugee contexts to live healthy and productive lives now and in the future. Despite international commitments to ensure young refugees’ SRHR, such as the Global Strategy for Women’s, Children’s and Adolescents’ Health, few interventions actually address their specific needs–calling for further investment and commitment from the global health community to strengthen and protect the SRHR of young people in refugee contexts.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S3 Appendix(PDF)Click here for additional data file.S4 Appendix(PDF)Click here for additional data file.S5 Appendix(PDF)Click here for additional data file.S6 Appendix(PDF)Click here for additional data file.S7 Appendix(PDF)Click here for additional data file.S8 Appendix(PDF)Click here for additional data file.S9 Appendix(PDF)Click here for additional data file.


Immunoglobulin G4-related disease (IgG4-RD) is a recently established systemic disease that is characteristically associated with elevated serum immunoglobulin G4 (IgG4) levels and believed to be caused by autoimmune mechanisms. The clinical features of IgG4-RD include (i) systemic distribution, (ii) imaging findings of swelling, nodules, and/or wall thickening, (iii) high serum IgG4 levels, (iv) abundant IgG4-bearing plasma cell infiltration and fibrosis in affected organs, (v) a favorable response to corticosteroid therapy, and (vi) coexistence with other IgG4-RD manifestations simultaneously or in a metachronous fashion. The concept of IgG4-RD was established based on the culmination of specific discoveries. Specifically, a close association between autoimmune pancreatitis (AIP) and high serum IgG4 levels, massive IgG4-bearing plasma cell infiltration in pancreatic tissues affected by AIP, and systemic other organ involvements in AIP with similar IgG4-bearing plasma cell features opened the gateway from AIP to IgG4-RD. The systemic distribution of IgG4-RD seems to be capable of affecting every organ, causing well-established members including AIP, lacrimal and salivary gland lesions such as Mikulicz’s disease, respiratory diseases, sclerosing cholangitis, kidney diseases, and retroperitoneal fibrosis. IgG4-RD has been diagnosed worldwide, and international collaboration efforts on the disease have led to consensus publications on its nomenclature, pathology findings, and management approach. The algorithms developed for the comprehensive diagnostic criteria for IgG4-RD have remarkably increased detection sensitivity. Oral glucocorticoids are the first-line agents for remission induction, and certain patients with high disease activity may benefit from maintenance therapy afterwards. Originally, IgG4-RD had been considered reversible and to have a good prognosis; however, long-term afflictions sometimes result in transition to advanced-stage conditions with dysfunction and/or complicating malignancy. The immunological abnormalities in IgG4-RD have been reported in both innate and adaptive immune systems; however, it remains unclear whether IgG4 has a pathogenic role or a protective one in disease onset and progression. IgG4-RD can be caused by autoimmune mechanisms, with following clinical features: (i) systemic distribution, (ii) imaging findings of swelling, nodules, and/or wall thickening, (iii) high serum IgG4 levels (2), (iv) abundant IgG4-bearing plasma cell infiltration and fibrosis in affected organs (3), (v) a favorable response to corticosteroid therapy, and (vi) coexistence with other IgG4-RDs simultaneously or in a metachronous fashion.Immunoglobulin G4-related disease (IgG4-RD) is a recently established systemic disease that is characteristically associated with IgG4 The systemic distribution of IgG4-RD seems to be capable of affecting every organ, causing well-established members including autoimmune pancreatitis (AIP), Mikulicz’ disease, respiratory disease, sclerosing cholangitis, kidney disease, and retroperitoneal fibrosis . With ne(4); (2) a close association between AIP and high serum IgG4 levels (2); (3) abundant IgG4-bearing plasma cell infiltration in affected pancreatic tissues of AIP (3); (4) systemic other organ involvements (OOIs) in AIP also responding to corticosteroid therapy (6); (5) OOIs also exhibiting abundant IgG4-bearing plasma cell infiltration (3); and (6) these findings combining to establish the concept of a systemic disease consisting of AIP and other systemic OOIs, i.e., IgG4-RD (7). These sequential discoveries led the way right from AIP to IgG4-RD.The establishment of IgG4-RD was based on the culmination of specific discoveries: (1) the proposal of AIP presumably caused by autoimmune mechanisms (8). In 1978, Nakano reported a case of Sjögren’s syndrome (Mikulicz’s disease) with a pancreatic tumor successfully treated with corticosteroids (9). In 1991, Kawaguchi described a new pancreatic disease with lymphoplasmacytic infiltration, storiform fibrosis, and obstructive phlebitis as lymphoplasmacytic sclerosing pancreatitis (10). The following year, Toki reported a new pancreatic disease with peculiar imaging findings of diffuse irregular narrowing of the main pancreatic duct (11). In 1995, Yoshida proposed the concept of AIP based on the clinical findings of these newly reported cases, which also included hypergammaglobulinemia, autoantibody positivity, lymphoplasmacytic infiltration in the pancreas, and a favorable response to corticosteroid treatment (4).Pancreatitis is mainly caused by alcohol abuse. In 1961, Sarles described that pancreatitis is presumably caused by autoimmune mechanisms that showed hyperglobulinemia and marked lymphocytic infiltration (2). Protein electrophoresis of sera of patients with AIP showed β-γ bridging, which was a polyclonal band in the rapidly migrating fraction of γ-globulins .In 2002, we described the characteristic histological features of abundant IgG4-bearing plasma cell infiltration in affected pancreatic tissues, which constituted another pathological hallmark of AIP  (3).(6). Similar to AIP, these OOIs also favorably responded to corticosteroid therapy (5).Detailed studies using computed tomography (CT) and magnetic resonance imaging (MRI) revealed that over 90% of AIP patients possessed various OOIs, including dacryoadenitis-sialadenitis (48%), bile duct lesions (78%), kidney lesions (14%), and retroperitoneal fibrosis (20%) (3).In 2002, we witnessed that OOIs featured abundant IgG4-bearing plasma cell infiltration and fibrosis similar to AIP, indicating that AIP and systemic OOIs shared a common pathological background (13), and a number of nomenclatures were postulated for this systemic condition (16). In 2010, the new disease concept of IgG4-RD was proposed by experts in Japan (17). This entity was accepted in 2011 at an international conference in Boston (7).The fact that AIP and its OOIs shared the common clinical features of abundant IgG4-bearing plasma cell infiltration and a good response to corticosteroids implied the presence of a systemic disease consisting of AIP and systemic OOIs that was closely associated with IgG4. In previous studies, experts in the field of rheumatology have revealed that Mikulicz’s disease also exhibited complicating systemic extra-glandular lesions associated with IgG4 Recent studies have identified several new members of IgG4-RD, and representative works for these are summarized in (18).IgG4-related pituitary and stalk lesions exhibit the clinical findings of compressive optic neuropathy, panhypopituitarism, pituitary hypothyroidism, adrenocortical insufficiency, and syndromic inappropriate secretion of antidiuretic hormone, all of which require differentiation from primary hypophysitis (19).Hypertrophic pachymeningitis is a rare fibroinflammatory lesion that causes thickening of the dura in the cranium and/or spinal canal and presents as radiculomyelopathy, headache, and cranial nerve palsy. This condition was considered to be a member of multifocal idiopathic fibrosclerosis (MIF), a portion of which is equivalent to IgG4-RD (20).IgG4-related lacrimal and salivary gland lesions constitute a representative of IgG4-RDs and correspond to the existing diseases of Mikulicz’s disease and Küttner tumor. Characteristic clinical findings include symmetrical swelling of the lacrimal and salivary glands  with mil(21).Patients with IgG4-related lacrimal gland lesions sometimes develop complicating ocular adnexa lesions, such as trigeminal nerve branch enlargement, extraocular muscle enlargement, diffuse orbital fat lesions, orbital mass lesions, eyelid lesions, and nasolacrimal duct lesions, all of which might occur independently. IgG4-related ophthalmic diseases were newly proposed to integrate ocular adnexa lesions with IgG4-related lacrimal gland lesions (22). Hashimoto’s thyroiditis is classified as either IgG4 or non-IgG4 thyroiditis based on immunostaining profiles (23), whereas Riedel’s thyroiditis is a chronic fibrosing disorder of an unknown etiology that is considered to be a member of MIF (24).AIP and IgG4-RD are significantly associated with hypothyroidism, which supports the existence of IgG4-related thyroiditis (25).IgG4-related respiratory disease includes the imaging findings of intrathoracic lesions, such as hilar/mediastinal lymphadenopathy, bronchial wall/bronchovascular bundle thickening, interlobular septal wall thickening, nodular shadow, infiltrative shadow, pleural thickening, and effusion. IgG4-related lung disease develops through the lymphatic routes of the lungs and exhibits various clinical characteristics (26).AIP exhibits the typical clinical features of IgG4-RD: elderly male preponderance, high serum IgG4 levels, lymphoplasmacytic infiltration, obstructive phlebitis, storiform fibrosis, IgG4-bearing plasma cell infiltration, and a favorable response to corticosteroid therapy. Other hallmark AIP features include obstructive jaundice and pancreatic swelling, which may mimic pancreatic cancer. Several autoantibodies are positive in IgG4-RD-associated AIP, whereas other disease-specific ones, such as anti-SSA/Ro, anti-SSB/La, and anti-mitochondrial antibodies, are negative. The imaging results of irregular narrowing of the main pancreatic duct  and caps(27).IgG4-related sclerosing cholangitis (IgG4-SC) is widely distributed throughout the biliary system; therefore, lower bile duct lesions need differentiation from pancreatic cancer and intra-hepatic or hilar lesions of primary sclerosing cholangitis or biliary malignancies . IgG4-SC(28). Some lesions mimic those observed in autoimmune hepatitis (AIH), fulfill its diagnostic criteria, and as such are designated as IgG4-related AIH (29).IgG4-related liver disease includes some histological changes, all of which are collectively designated as IgG4 hepatopathy (32).IgG4-related kidney disease (IgG4-RKD) is characterized by uriniferous tubules displaying tubulointerstitial nephritis and sparse glomerular lesions with membranous glomerulonephritis. Most patients are diagnosed based on incidental imaging abnormalities and have only mild urinary dysfunction, whereas some develop acute or progressive renal failure (31).IgG4-related retroperitoneal fibrosis is disclosed by the CT or MRI findings of soft tissue density or masses around the aorta and ureter. Peri-ureteral lesions sometimes cause symptoms of lumbago or back pain due to hydronephrosis, which may result in renal atrophy and failure (35).The periaortic lesions originally found in retroperitoneal fibrosis later shows systemic distribution, which has led to the proposal of the distinct systemic disease entity of IgG4-related periaortitis/periarteritis. IgG4-related arterial lesions are characterized by arterial wall thickening mainly in the adventitia that responds well to corticosteroid treatment. However, patients with prior luminal dilatation have shown symptom exacerbation after therapy (36).Patients with IgG4-RD sometimes display ameliorated prostatic symptoms after corticosteroid treatment, suggesting the presence of IgG4-related prostate diseases that present as a symmetrically affected, nontender, swollen prostate in imaging analyses (37).Many other organ manifestations have been proposed as candidates of IgG4-RD, including lesions of the skin, gastrointestinal tract, mesentery, bone, and joints, mainly due to the pathological findings of IgG4-bearing plasma cell infiltration and fibrosis as well as simultaneous existence of other IgG4-RD members. In addition, each IgG4-RD may present with uncommon manifestations, many of which were reported as case reports and need further studies to confirm their association with IgG4-RD A 72-year-old man was found to have a localized mass in the pancreatic body by abdominal ultrasonogram during a routine medical checkup. Since his serum IgG4 concentration was high at 412 mg/dl, localized AIP was suspected, and he was referred to Shinshu University Hospital for further examination. Contrast-enhanced CT revealed a localized attenuated mass at the pancreatic body  that app(40). The diagnostic criteria of IgG4-RD used in the routine clinical care of patients are generally heterogeneous and reflect the various features of the disease to identify as many people with condition as possible (41). The comprehensive diagnostic criteria for IgG4-RD were at first intended by Japanese researchers to be used by general physicians and nonspecialists (42). Although IgG4-RD manifestations in several organs exhibit clinical and pathological differences, a consensus has been reached on two points for the definite diagnosis of IgG4-RD: (i) serum IgG4 levels >135 mg/dl and (ii) >40% of IgG+ plasma cells being IgG4+, with >10 IgG4+ cells per high-power field of a biopsied sample. These criteria also require precise differentiation from malignant tumors and mimicking conditions using additional histopathological examination. However, it can be difficult to obtain tissue samples from certain organs, such as the pancreas; organ-specific diagnostic criteria including those for AIP (43), IgG4-related sialadenitis and dacryoadenitis (44), IgG4-RKD (45), IgG4-SC (46), and IgG4-related respiratory disease (25) are therefore available for such lesions in the form of diagnostic algorithms. The framework of these organ-specific criteria is largely based on that of AIP to include combinations of the following: (i) characteristic imaging findings, (ii) elevation of serum IgG4 levels, (iii) histopathological findings of abundant IgG4-positive plasma cell and lymphocyte infiltration, storiform fibrosis, and/or obliterative phlebitis, (iv) association with other IgG4-RDs, and (v) a favorable response to steroids. The algorithms involved in this diagnostic process have remarkably increased detection sensitivity.With IgG4-RD now being diagnosed worldwide, international collaboration has produced consensus publications on its nomenclature, pathological findings, and management approaches (41). Classification criteria for IgG4-RD to differentiate between IgG4-RD and mimickers are needed.Classification criteria are standardized definitions that are primarily intended to create well-defined, relatively homogeneous cohorts for clinical research. They are not intended to capture the entire universe of possible patients but rather to capture the majority of patients with key shared features of the condition (49). Not all forms of IgG4-RD require immediate treatment, and simple observation is sufficient in some cases (7). Following a successful course of induction therapy, patients with high disease activity may benefit from maintenance therapy (50). Although several immunomodulatory agents have been adopted as steroid-sparing agents for IgG4-RD, only little evidence is available supporting the effectiveness of these drugs (51). B-cell depletion with Rituximab (RTX) has been effective for treating IgG4-RD, even for patients refractory to conventional steroid-sparing agents; high complete remission rates following RTX therapy were reported in groups of patients whose disease had been resistant to, or who had contraindications for, steroids or conventional steroid-sparing agents (51). Moreover, the number of plasmablasts that were largely IgG4-positive and played a role in disease activity sharply decreased after RTX treatment, presumably due to depletion of CD20+ precursors (52).Oral glucocorticoids are the first-line agents for remission induction in patients with active IgG4-RD or in whom vital organs are involved or serious organ dysfunction or failure is likely (53).The IgG4-RD Responder Index (RI) was developed to help investigators assess treatment efficacy in a structured manner. RI guides examiners through assessments of disease activity and damage, incorporating higher weights for disease manifestations that require urgent treatment or worsen despite therapy. An international multispecialty study has confirmed RI as a valid and reliable disease activity assessment tool to measure treatment response IgG4-RD had originally been considered an acute-phase condition due to its favorable response to corticosteroids and pathological findings of lymphoplasmacytic infiltration, both of which suggest a reversible condition with a good prognosis. However, recent studies have found that long-term disease affliction may instead transition to (1) advanced-stage conditions with dysfunction or (2) complicating malignancy.(54). Since frequent recurrences had a significant impact on the progression to a chronic stage, measures to prevent them might improve long-term prognosis.Some AIP cases showed pancreatic calcification and atrophy during the long-term course, which were the hallmarks of chronic pancreatitis with functional abnormality. Based on cumulative imaging and functional study outcomes, we proposed a sequential progression mechanism of AIP to chronic pancreatitis, whereby pancreatic head swelling during the acute stage leads to long-standing narrowing of pancreatic ducts in the head region that may then cause pancreatic juice stasis in the upstream pancreatic duct. In concert with multiple recurrences, these events can severely damage pancreatic tissues and ultimately result in severe calcification of the entire pancreas and pancreatic atrophy  (54). Si(20). IgG4-RKD responded well to corticosteroid therapy in the long-term course, but eventual renal atrophy was associated with lower pretreatment estimated glomerular filtration rate, suggesting a risk of chronic stage progession (32). Finally, despite IgG4-related periaortitis generally responding favorably to corticosteroid treatment, some cases of prior luminal dilatation showed disease exacerbation after therapy (35).In a previous study, IgG4-related dacryoadenitis and sialadenitis have also been reported to recur over time; delayed treatment-induced fibrosis progression resulted in exocrine dysfunction due to diminished salivary secretion In summary, IgG4-RDs tend to respond well to corticosteroid therapy over the long-term course and exhibit a good outcome. However, progression to a chronic, dysfunctional state appears to be closely related to the number of recurrences and/or degree of pretreatment or early functional impairment.(55) and Shiokawa et al.(56) that was presumably due to persistent inflammatory tissue damage or impaired immunosurveilance. However, other studies including those by Hirano et al. (57) and Hart et al.(58) have contradicted these relationships because most of the cases of IgG4-RD were based on imaging tests in large-volume centers that included patients more likely to be diagnosed with malignancies, especially during the first year after diagnosis. Indeed, we also identified a close association between IgG4-RD and malignancy within 12 years after diagnosis, particularly during the first year and mostly during the first 5 years. An active IgG4-RD state is suspected to be a strong risk factor for malignancy development (59). Further studies are needed to clarify this notion.A close association of IgG4-RD with malignancy in the elderly has been reported by Yamamoto et al. (60). The immunological abnormalities in IgG4-RD have been related to both (1) adaptive and (2) innate immune systems.The immune system is broadly divided into innate and adaptive components. The innate immune system functions immediately after exposure to pathogens, followed by adaptive immune function as a result of clonal expansion. The main distinction of these systems lies in the mechanisms and receptors used for immune recognition. In the adaptive immune system, an extremely diverse repertoire of receptors is randomly generated, and lymphocytes bearing specific receptors are subsequently selected for clonal expansion after encountering specific antigens. Such receptors cannot be genetically passed to the next generation. In contrast, innate immune recognition is mediated by germ line-encoded receptors, meaning that the specificity of each receptor is genetically predetermined. The strategy of the innate immune response may not be to recognize every possible antigen but rather to focus on several highly conserved structures, i.e., pathogen-associated molecular patterns (PAMPs) that are present in large groups of microorganisms (63). Increased peripheral Tregs are positively correlated with serum IgG4 levels. Inducible costimulator (ICOS)-positive Tregs may influence IgG4 production via IL-10, whereas ICOS-negative Tregs may modulate fibrosis via TGF-β (64).IgG4-RD is associated with Th2-type immune balance and abundant infiltration of regulatory T-cells (Tregs) into target organs. The cytokine profile of IgG4-RD includes Th2 cytokines  as well as regulatory cytokines (IL-10 and TGF-β) (65) demonstrated that subcutaneous injection of IgG1 or IgG4 from AIP patients, but not control IgGs, caused pancreatic and salivary gland injury in neonatal mice. Since the potent pathogenic activity of IgG1 was significantly inhibited by simultaneous IgG4 injections, circulating IgG4 in AIP patients was considered to exert both pathogenic and protective roles. Moreover, the autoantibodies in AIP serum reacted to molecules involved in cell-extracellular matrix adhesion, which could explain the systemic distribution of this disease (65). Their recent study identified autoantibodies against laminin 511-E8 in many AIP patients and autoantibodies against integrin α6β1, a ligand for laminin 511, in a limited number of patients, and immunization with laminin 511-E8 induced histological changes of acinar atrophy, fibrosis, dense infiltration of plasma cells and lymphocytes, and obliterative phlebitis in the pancreas of mice. These autoantibodies may exert pathogenic activities by targeting laminin 511/integrin α6β1 binding and provide a good marker for the diagnosis and therapeutic effects (66).The pathological effects of IgG4 and other autoantibodies have been reported to evoke IgG4-RD. Shiokawa et al. Helicobacter pylori infection may trigger AIP, possibly as a result of the substantial homology between human carbonic anhydrase (CA) II and H. pylori alpha-CA. The homologous segments contain the binding motif of the HLA molecule DRB1*04:05, which is closely associated with AIP (67). The HLA-DRB1*04:05 allele was also an important risk factor for AIP in functional studies using a transgenic mouse model (68). These data indicated that the DRB1*0405-restricted peptide of CA II was present in genetically predisposed subjects, which resulted in reactive T-cells injuring pancreatic tissue via interactions with the CA II of pancreatic ductal cells (69).Molecular mimicry by either a virus or bacteria has also been hypothesized to initiate or exacerbate autoimmune responses through sequence or structural similarities with self-antigens. (60). The complement activation system may play a role in the pathogenesis of IgG4-RD, since decreased serum levels of complement proteins are sometimes found in IgG4-RD, especially in IgG4-RKD. Sugimoto et al. (70) observed that both the classical and mannose-binding lectin pathways might participate in the complement activation system of IgG4-RD. However, we uncovered significantly higher serum IgG1 levels and decreased C3 and C4 values in an elevated immune complex group, which indicated that IgG1, and not IgG4, contributed to complement activation via the classical pathway (71).Functionally, the pattern-recognition receptors of the innate immune system can be divided into three classes: secreted, endocytotic, and signaling. Mannan-binding lectin is a secreted pattern-recognition receptor that binds to microbial carbohydrates to initiate the lectin pathway of complement activation (73). Activated basophils enhance IgG4 production in B-cells by B-cell-activating factor, leading to the differentiation of inflammatory monocytes into M2 macrophages that affect the Th2 immune environment and promote fibrosis through secretion of TGF-β. TLRs recognize PAMPs and damage-associated molecular patterns (DAMPs). PAMPs derived from abundant gut bacteria or DAMPs from necrotic cells in damaged organs may induce tissue injury and inflammation via their TLR or NDR signaling pattern-recognition molecules (63).Basophils seem to be the key players in the innate immune system of IgG4-RD via their signaling pattern-recognition molecules of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NDRs) (63) proposed a hypothesis and a diagram for the pathogenesis of type 1 AIP based on their studies as follows: In the initial stage of type 1 AIP, because of the decreased naïve Tregs and CD19+ CD24high CD27+ Bregs, effector T-cells are involved in tissue damage. IL-10 and TGF-β from increased inducible Tregs induce the switch from B-cells to IgG4-producing plasma cells and fibrosis, respectively. Basophils lead to differentiation of inflammatory monocytes into M2 macrophages, affect production of IgG4 via TLR signaling, and influence the Th2 immune environment. M2 macrophages also contribute to fibrosis and Th2 immune reaction (63).Uchida and Okazaki Escherichia coli to produce marked cellular infiltration with fibrosis in the exocrine pancreas and salivary glands (74). One representative antigen reacting with the serum of E. coli-inoculated mice was FliC (75). These findings indicate that avirulent bacteria and other silently infiltrating microorganisms can engage PAMPs and activate the innate immune system to elicit a host immune response to the target antigen by molecular mimicry, which can ultimately lead to AIP.Animal models of AIP have been developed by exposing C57BL/6 mice to heat-killed (76).The pathogenesis of autoimmune diseases is multifactorial and involves the complex interplay of multiple genetic and environmental factors. To elucidate the genetic elements that influence disease susceptibility, two approaches have been employed: (1) the candidate-gene approach by association studies and (2) genome-wide association study (GWAS) of large numbers of single-nucleotide polymorphisms DRB1*0405 and DQB1*0401 are significantly higher in AIP patients. In the Japanese population, DRB1*0405 is known to be in strong linkage disequilibrium with DQB1*0401, resulting in the DRB1*0405-DQB1*0401 haplotype (67). We have identified several other candidate genes involved in the pathogenesis of AIP, including Fc receptor-like 3 (FCRL3)and the cytotoxic T lymphocyte antigen 4(CTLA4) (76).Among the major histocompatibility complex class I and II molecules, the HLA serotypes of DR4 and DQ4 are the markers most frequently associated with AIP. Specifically, the frequencies of KCNA3). KCNA3 is involved in the immunomodulation of autoreactive effector T-cell- and memory T-cell-mediated autoimmune diseases (77). GWAS results have also identified candidate genes in the development of lachrymal/salivary gland lesions complicated with AIP (76).A large association analysis of AIP using microsatellite markers revealed relationships with potassium voltage-gated channel, shaker-related subfamily, member 3 ((65) reported that IgG4 from AIP patients caused pancreatic and salivary gland injuries in neonatal mice but also attenuated the injurious effects of injected IgG1.Although IgG4 has a key role in the diagnosis of IgG4-RD, it is unclear whether it also has a pathogenic role or a protective one or if it is merely an innocent bystander. The pathogenic function of IgG4-type autoantibodies on self-antigens caused injury in limited settings, such as in pemphigus vulgaris, idiopathic membranous glomerulonephritis, acquired thrombotic thrombocytopenic purpura, and muscle-specific kinase myasthenia gravis. In agreement with this, Shiokawa et al. (78). This may be, in part, due to the inherent instability of IgG4, whereby the interchain disulfide bonds in the hinge region are labile, thus allowing the molecule to split and exchange monovalent halves, called Fab-arm exchange ((79). It has been estimated that up to half of IgG4 molecules may be dissociated, existing as single heavy-chain and light-chain molecules in the serum. Such weak antigen binding of IgG4 monomers or bivalent Fab molecules could prevent the formation of immune complexes of other IgG subclasses (78). Although IgG4 bound to IgG exerted rheumatoid factor activity, IgG4 binding to IgG Fc occurred via Fc–Fc interactions and not rheumatoid activity per se (80). Different IgG4 molecules with the same antigen reactivity may associate through Fc–Fc interactions and then exchange molecule halves, resulting in Fab-arm exchange with different epitope reactivity.In contrast to the other IgG subclasses, IgG4 lacks the conventional IgG activity of complement-Fcγ receptor binding and has a relatively low serum concentration, both of which suggest that IgG4 has regulatory rather than inflammatory or antigen-clearance functions exchange  (79). ItThe discovery of a close association between AIP and IgG4 has opened the door to the new disease concept of IgG4-RD, which shows the unique clinical features never encountered previously. In order to understand the whole picture of IgG4-RD, researchers need to clarify the precise spectrum of IgG4-RD and real global prevalence, rational treatment strategies, long-term outcomes, pathogenesis, and finally the exact role of IgG4. Many individuals with IgG4-RD worldwide have been overlooked or misdiagnosed. Expanding the global awareness of IgG4-RD will result in enhanced diagnosis, improved treatment, and the scope for larger international studies in the future.NoneThis work was partially supported by a Grant-in-Aid for ‘‘Research for Intractable Diseases’’ Program from the Ministry of Labor and Welfare of Japan, grant number [H29-Nanchitou-(Nan)-Ippan-058].We thank Dr. Takayuki Watanabe and Dr. Yasuhiro Kuraishi for their assistance in figures preparation and Mr. Trevor Ralph for his English editorial assistance.Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; ANDDrafting the work or revising it critically for important intellectual content; ANDFinal approval of the version to be published; ANDAgreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.This manuscript is a review article and does not need approval by IRB.


The Grey Relation Entropy (GRE) theory is used to analyze the sensitive pore size that affects the compressive strength of concrete. The relationship between the strength and pore structure is revised based on the sensitivity coefficient. The revised model is used to calculate the compressive strength of concrete. In order to verify the validity of the proposed model, the calculated results are compared with experimental ones, showing satisfactory agreement with a larger correlation than existing methods. Concrete is a composite material with a porous structure, which affects its strength, impermeability and durability, but mostly its strength ,2. The mBecause of the complexity of concrete composition, the factors affecting its strength are various. In order to establish the relationship between concrete strength and pore structure, the grey correlation analysis method has been applied the main factors that affect the system ,21,22. HTherefore, based on the GRE theory, this article analyzes the most sensitive factors that affect the strength of concrete. Considering the most influencing factors, such as cement content, porosity, average pore size and sensitive pore size distribution, the quantitative relationship between the pore structure of concrete and its compressive strength is proposed. Hence, this paper provides a new method for establishing the connection law between the microstructure and macroscopic properties of concrete.In order to solve the problem of partial correlation tendency and loss of individual information, which cause significant deviation of the grey correlation degree and affect the analysis results, based on grey correlation analysis, GRE theory is introduced to quantitatively describe the relation degree between various factors. The calculation theory is as follows.X0(k) and the comparative data column is iX(k). Firstly, equalization with X0(k) and iX(k) is taken into account based on the formula Y0(k) and iY(k) is obtained. The correlation coefficient is calculated according to Equation (1) [ρ is the resolution coefficient, generally 0.5.The reference sequence is tion (1) ,30:(1)RiiR(k) is calculated by Equation (2) [H(iR) is the value of GRE; hP is the density value of the mapping distribution of correlation coefficient series i(kR), h = 1,2, … m.The value of GRE for correlation coefficient series tion (2) ,30.(2)HD(ix) is calculated by Equation (3) [max is the maximum grey relation entropy and Hmax = lnm, m is the number of data elements.The relation degree of GRE tion (3) ,30.D method was used to test the pore characteristics of concrete materials; this method can accurately detect the porosity, pore radius distribution and other pore properties . Hence, C, the average pore radius mr, the porosity P, and the distribution rate of four different pore radii. The values of corresponding relation degree of GRE are shown in The concrete strength was used as the target magnitude, and 7 indicators were taken into account as the comparison sequence, which are the cement content D(x5) > D(x3) > D(x6) > D(x4) > D(x7) > D(x1) > D(x2). The sensitive pore radius is the pore radius corresponding to the factor with the largest sensitivity coefficient. The maximum value of the relation degree is D(x5)—thus, the distribution rate of 10.6–53 nm pore radius is the most sensitive. Based on the above values, it was noted that the cement content can also significantly influence the concrete strength, so it should also be included in the strength formula.The values of relation degree of GRE, calculated by Equation (3) and listed in The pore structure parameter data of concrete, mixed with 9 kinds of air-entraining agents, named as data II, were retrieved from  and are mr, porosity P and distribution rate of six different pore radius.In the same way, the GRE analysis was performed on the test data II. The concrete strength was used as the target magnitude and 8 indicators were considered as the comparison sequence, which are the average pore radius D(x6) > D(x2) > D(x3) > D(x7) > D(x5) > D(x8) > D(x1) > D(x4). In this case, the maximum value of relation degree is D(6x), thus the distribution rate of 600–800 µm pore radius is the most sensitive.The values of relation degree, shown in Based on the GRE method analysis results of the test data I and data II, it was found that: (1) the cement content is a significant influencing factor for concrete strength; (2) among the concrete pore structure parameters, the pore radius distribution rate is considerably sensitive for the calculation of concrete macroscopic strength; (3) for different types of concrete, the sensitive pore radius that affects the strength of concrete is different, and it needs to be determined by GRE method analysis according to the pore radius distribution rate in the micropore structure parameters.A, the number of pores is n0, the pore area is 0A, the porosity is P, the average pore radius is mr, the number of sensitive pores is ns, the average pore radius of sensitive pores is msr, and the sensitive pore area is sA. The sensitive pore radius distribution rate is sB which is defined as the ratio of the sensitive pore area to the pore area, sB = sA/0A. Taking into account that 0A = 0nπm2r and SA = snπms2r, the calculation of the sensitive pore radius distribution rate is shown in Equation (4).Based on the analysis of sensitive factors, it can be noted that the distribution rate of pore radius has a greater influence on the concrete’s compressive strength than other factors in the microporous structure. The sensitive pore is the pore corresponding to the factor with the largest sensitivity coefficient. Because the radii of sensitive pores are within a range, the average value of the pore radii is the average pore radius of sensitive pores. In the following it is assumed that the cross-sectional area of concrete sample is ƞ =msr/mr was defined as the ratio of the average pore radius of sensitive pore msr over the average pore radius mr. This coefficient was used to measure the geometric characteristics of sensitive pores, directly reflecting relative size that the sensitive void relative to the total void. The test constant α was also defined as α = (n0/sn)1/2, with α > 1, which can be obtained by fitting test data. Replacing ƞ and α into Equation (4), Equation (5) is formed, in which it is noted that the sensitivity coefficient ƞ is proportional to the arithmetic square root of the sensitive pore radius distribution rate sB.The sensitivity coefficient It should be noted that the sensitive pore radius is the pore radius corresponding to the factor with the largest sensitivity coefficient which is obtained through GRE analysis. Thus, the sensitive pore radius has the greatest influence on the strength of the concrete. Equations (4) and (5) are formulas based on certain assumptions that each pore is an independent circle in a certain section of concrete. P and average pore radius mr, also introducing the cement content parameter, denoted as C, and a test constant K2, which can be obtained by fitting test data, as shown in Equation (6) [K2 is a test constant which is mainly related to the strength of the concrete matrix and is related to factors such as the type of aggregate, the type of cement and the cement content.Kumar and Bhattacharjee  quantitation (6) .(6)σ=K2ƞ, which is used as evaluation index, into the concrete relationship defined by Equation (6). Equation (6) is revised and a new strength-pore structure model is proposed, as given by Equation (7).In this paper, the influence of the sensitive pore radius is taken into account, introducing the sensitivity coefficient Substituting Equation (5) into Equation (7), Equation (8) is obtained.Based on Equation (8), it was noted that the compressive strength of concrete can be determined by the cement content, porosity, average pore radius and sensitive pore radius distribution rate.Of note, Equation (8) proposed in this paper firstly performs GRE analysis to find the sensitive pore size, which leads to certain limitations in the use of Equation (8). The use of Equation (8) requires that the pore structure data must meet conditions that the pore radius range is consistent and the concrete strength grade and age should also be consistent.Balshin , SchilleThe linear relationship is given by Equation (9) .(9)σ=σ0The power exponent relationship is given by Equation (10) .(10)σ=σThe exponential relationship is given by Equation (11) .(11)σ=σThe logarithmic relationship is given by Equation (12) .(12)σ=kAtzeni et al. proposed the strength and pore structure relationship, as shown in Equation (13) .(13)σ=Kσ0 is the compressive strength when porosity is zero; K, N, B, k and n are test constants.In above formulas: In order to compare the common strength-pore structure models with the revised strength model described by Equation (8), the 36 groups of test data I are considered and analyzed. The results based on the fitting regression analysis are shown in It should be noted that Equations (9)–(12), which consider only the impact of porosity on the concrete’s strength, the correlation coefficient reaches 0.535 on average; Equation (13), considering the factors of average pore radius and porosity, has a correlation coefficient of 0.578; Equation (6), taking into account the average pore radius, porosity, and cement content, has a correlation coefficient of 0.780; Equation (8) has the largest fitting accuracy, reaching 0.850, and the concrete’s strength is related not only to porosity, but also to average pore radius, cement content and sensitive pore radius. Considering the influence of the sensitive pore radius on the strength of concrete, it is more reasonable to predict the strength of concrete with Equation (8) proposed in this paper.The fitting results are also shown in In order to verify the applicability of the proposed model, test data II was also used. The fitting results of the strength model proposed by Kumar and Bhattacharjee  Based on the GRE theory, it was concluded that the most sensitive factors that affect the compressive strength of concrete is the distribution rate of the pore radius with the maximum value of relation degree.(2)A new strength and pore structure model is proposed, considering the influence of sensitive pore radius and introducing the concept of sensitivity coefficient.(3)The revised model proposed in this paper and the existing strength model, used to calculate the compressive strength of concrete, are compared with test results, which shows that the revised model and the test results are in better agreement.(4)In the revised model, the concrete’s strength is related not only to porosity, average pore radius and cement content, but also to sensitive pore radius. The consideration of the influence of the sensitive pore radius on the strength of concrete leads to a better estimation of the concrete’s strength.(5)This paper only considers the influence of the sensitive pore radius on the strength of concrete, but does not consider the influence of capillary pores, gel pores, location of pores, and interconnectivity of pores on concrete strength. In the future, the author intends to conduct a porosity test on studied concrete, taking into account the influence of the pore structure on the permeability of the concrete and the influence of internal and external temperature differences on the sensitive pore radius.


For this purpose, the segregation index of the LWAC was obtained by means of the image analysis technique. In addition, to obtain their structural efficiency, the density and compressive strength were obtained at different heights of the tested specimens. The results show the vibration of the samples in two layers leads to a more efficient elimination of trapped air, a reduction in the risk of segregation, and better structural efficiency.Lightweight aggregate concretes (LWAC) are versatile and interesting materials for projects that require greater structural efficiency. Due to the difference that exists between the densities of the materials used in these types of concrete, during transport and mainly compaction, their aggregates tend to separate from the mortar matrix, floating towards the surface, a phenomenon called segregation. Segregation in LWAC can affect its durability properties, its density, and directly affect its structural efficiency. In this work, different concrete densities (1700 kg/m The ability of a concrete mixture to maintain the homogeneous distribution of all its components is key to success in the application of concrete . The segThe segregation and bleeding of fresh mixture has a dramatic negative impact on the mechanical properties ,8,9 of hThe inclusion of lightweight aggregates (LWA) in concrete in certain situations can affect its mechanical properties , its capc) and density (ρ) of material enables an analysis of its structural efficiency. To what extent should concrete segregation be predicted in an analysis like this? Would this be a phenomenon that would eventually be disregarded in the project, and could it possibly settle differences between the projected material and the material used in construction?Structural efficiency can be defined in many ways  but is uThis paper aims to verify the impact of the segregation phenomenon caused by excessive vibration in lightweight aggregate concrete samples on the density, mechanical strength, and structural efficiency of this material. Different types of lightweight aggregate concrete were manufactured and vibrated during their compaction, considering different levels of vibration.3 (LWAC1 and LWAC3) and 1900 kg/m3 (LWAC2 and LWAC4). The method proposed by Fanjul [Four different LWAC were produced using the Fanjul Method , with tay Fanjul  allows ty Fanjul  deals wi3 of cement and 210 kg/m3 of water to produce 1 m3 of concrete. CEM I 52.5 R white cement with an absolute density of 3176 kg/m3 was used for all the concretes; 2 types of expanded clay were used as coarse lightweight aggregate—its physical properties are listed in The bulk density of the LWAs was obtained according to the procedure described in the standard UNE EN 1097-3 . ParticlBefore mixing, and to avoid the loss of water from kneading by absorption, the LWAs were pre-saturated (reducing the uncertainty of lightweight aggregate water absorption during mixing ). DuringThe flowchart represented in In the present study, the cylindrical samples (150 mm of diameter and 300 mm height) were compacted using an electric needle vibrator  of 18,000 rpm/min and a 25 mm of diameter a. The spAfter being made and cured in the water at a temperature of 20 ± 1 °C for 28 days, the specimens were saw-cut through its longitudinal axis and their sections (identified as A and B) were photographed for image analysis b.The two halves of each cylinder were photographed at the same time. The images of the sections were used to calculate the volumetric segregation index (SI) according Solak et al.  applyingThe range of values of the SI varies from 0%  to 100% .Subsequently the specimen’s halves were then saw-cut into four equal parts, resulting in eighths . To evaluate the variations caused by the segregation in the density (ρ) along the height of the specimens, the specimen’s halves were then saw-cut into four equal parts, resulting in eighths, which had their bulk densities (ρ) determined c.c) along the height of the specimens, 50-mm diameter cores were extracted from the eighths always looking to extract it from the centroid area of the section  has been carried out qualitatively evaluating this parameter. The segregation index, whose values are between 12% and 49%, were contrasted with the values of average compressive strength—average between the four cores extracted from each half , indicating the existence of significant differences between them. As seen in ete type a and it Concretes vibrated in two layers (LWAC1 and LWAC2) have presented less segregation, for vibration times even higher than the concretes vibrated in one layer, and because of their better homogeneity presented minor variations in the compressive strength of its sections. These results were also discussed in previous works .From a safety point of view, the decrease in strength (sections that would contain an excessive amount of aggregates due to segregation) is more relevant than the increase in strength (sections that would contain an excessive amount of mortar), once those are mostly the areas where the concrete failure begins . Figure 3 presented higher reductions of compressive strength due segregation than concretes with theoretical densities of 1900 kg/m3 (one layer).The results are also consistent with ANOVA and Tukey’s test results. Concretes with SI lower than 25% do not present any correlation between ete type b and it In concretes vibrated in one layer, the displacement of the critical section towards the upper eighths is even more evident. In In general, the compaction in two layers led to a reduction in the overall density of the samples, most likely because the trapped air was removed more effectively in these cases. This can be seen when comparing the graphs in Two-layer compaction also affected the compressive strength results. When comparing the graph in 2 vary depending on the position of each eighth within the samples, in both one-layer and two-layer vibrating concretes, it can be seen through Although the trends and the results of RConcretes compacted in one layer have been shown to be more sensitive to vibration than concretes vibrated in two layers, especially in the upper region of the samples. When comparing To analyze if the segregation of concrete directly affects structural efficiency, the data were also analyzed using an ANOVA complemented by a Tukey test (HSD). The segregation results were contrasted with the values of average structural efficiency—average between the results of four cores extracted from each half , indicating the existence of significant differences between them. As seen in ete type a and it Like the results obtained by Solak et al. , concretete type b and it 2.For all structural efficiency parameters analysed  with an analysis of variations in the density, compressive strength, and structural efficiency of samples affected by segregation caused by excessive vibration. From the results presented in this study, the following conclusions are drawn:Although several parameters that affect segregation in LWAC have been evaluated in this article, other factors still need to be studied in future research. This article could be complemented with compression strength tests using conventional size samples, LWA with other sizes, and concretes with other dosages.


The shape memory effect of steel  enables the tensile strengthening of concrete against tensile stress and unexpected structural vibrations. For practical application, the corrosion resistance of shape-memorable Fe-based steel should be verified. In this study, the corrosion resistance of an Fe-based (Fe-16Mn-5Si-4Ni-5Cr-0.3C-1Ti) shape memory alloy (FSMA), a promising candidate for concrete reinforcement, was investigated by comparing it with general carbon steel (S400). The corrosion resistance of FSMA and S400 inserted in a cement mortar was evaluated using electrochemical methods. FSMA has a more stable passive oxide layer in aqueous solutions with various pH values. Thus, the corrosion resistance of the FSMA sample was much higher than that of the S400 carbon steel, which has a passivation layer in strongly alkaline solution. This stable oxide layer reduced the sensitivity of the corrosion resistance of FSMA to changes in the pH, compared to S400. Furthermore, owing to the stable passive oxide layer, FSMA exhibited a higher corrosion resistance in concrete and a lower decrease in corrosion resistance because of the neutralization of concrete. Therefore, FSMA is a promising candidate for providing reinforcement and reparability, resulting in stable and durable concrete. Considering their functionalities, shape memory alloys exhibiting superelasticity and shape recovery effects have been widely investigated for applications. It is well known that recovery of the original shape is caused by a phase transformation from martensite, formed by a stress-induced transformation, to austenite under heating ,2,3. Ti-Generally, concrete structures composed of cement-based composites and rebars have been used as a core material for construction. Cement-based composite with sand and gravel has excellent stability under compressive stress, whereas it is relatively weak under tensile conditions. Therefore, a rebar with a relatively high tensile strength is used as a reinforcement for cement-based composites. Prestressed concrete, which has a compressive stress, is employed to reduce the damage to concrete structures under tensile stress. The compressive stress in concrete can be induced by the tendon elongated in the elastic region. Therefore, with respect to the size of the concrete structure, various equipment and spaces for prestressing are required ,14,15,16Since Fe-based shape memory alloys can cause a compressive recovery stress of 200–500 MPa, they can be applied to prestressed concrete. Recently, Fe-Mn-Si-based alloys have been studied for potential applications in prestressed concrete. For instance, Dong et al.  demonstrEven though the recoverable mechanical properties of Fe-Mn-Si-based shape memory alloys were investigated, the stability of this alloy should be explored for actual application as a concrete reinforcement. To confirm the stability of the Fe-17Mn-5Si-5Cr alloy in concrete environments, we evaluated the corrosion properties by comparing them with general carbon steel (S400), which is typically used for reinforcing concrete. The corrosion properties were evaluated in NaCl solutions with various pH values while reinforcement metals were mounted in a mortar, considering the application conditions.An Fe-17Mn-5Si-5Cr shape memory alloy (FSMA) containing 1 Ti and 0.3 C  was prepThe chemical compositions of FSMA and S400 are summarized in An aqueous solution of 3.5 wt.% NaCl was used for the electrochemical corrosion test. Considering the concrete environment, the pH of the salt solution was adjusted with CaO. The corrosion resistance of the FSMA and the S400 in the concrete structure were evaluated with a potentiodynamic polarization test using a potentiostat at room temperature . Ag/AgCl and Pt wires were used as the reference and counter electrodes, respectively. The surface chemical composition and oxide state were analyzed using X-ray photoelectron spectroscopy . In addition, the microstructures of the FSMA and S400 samples were observed using a field-emission scanning electron microscope .To compare the corrosion resistance of S400 and FSMA, the samples with epoxy mounting were tested by potentiodynamic polarization in a 3.5 wt.% NaCl solution with pH values varying from 7 to 13, adjusted by adding CaO, considering the concrete condition. 0, indicating metal bonding [0 metal peak can be found for the surfaces without rust.The surface oxide layers of the S400 and the FSMA were expected to affect the corrosion resistance. Thus, XPS analysis was conducted after immersion of the sample for a day in deionized water with various pH values adjusted by CaO.  bonding ,29. The  bonding ,29. Ther3+, indicating Cr2O3, Cr(OH)3, and CrOOH [0) can be found at ~639 eV in the Mn 2p3/2 spectra . The dissolved CaO increased the pH of the concrete and the concrete with a high pH also increased the pH of the corrosive solution . A higher pH is effective for enhancing the corrosion resistance of iron-based alloys by forming a passivation layer. However, since the pH inside the concrete block was lower than the pH of the leachate, the pH of the mortar decreased with immersion time for more than a day. Because of this decrease in pH inside the concrete block, the free corrosion current density increased, and the polarization resistance significantly decreased. Owing to the immersion of mortar in the aqueous solution for 28 days, the polarization resistance of the S400 decreased to 1.0 Ω∙cm2, which is only ~0.4% of the polarization resistance for immersion for a day. The FSMA also showed a significant decrease in polarization resistance after immersion for 28 days—9.6 Ω∙cm2, which is ~2.8% of the polarization resistance for immersion for a day. Nevertheless, the FSMA showed a lower rate of corrosion resistance and a higher corrosion resistance than the S400. These results indicate that the corrosion resistance of FSMA is less sensitive to the change in pH compared to S400 carbon steel. In addition, the polarization resistance of the FSMA in the concrete was greater than that of the S400 by 1.5-, 1.7-, 5.8-, 13.4-, and 9.6-fold for the immersion in salt water for 1, 3, 7, 14, and 28 days, respectively. These results suggest that FSMA has higher corrosion resistance in a concrete environment than S400 carbon steel.Owing to the Mn and Cr, the shape-memorable Fe-17Mn-5Si-5Cr alloy forms a stable passivation oxide layer in alkaline environments, which has a similar pH to concrete.This passivation oxide layer enabled the Fe-17Mn-5Si-5Cr alloy to obtain a higher corrosion resistance than S400 carbon steel in salt water (more than 140% in the pH range of 7–13).Because of the dipping in salt water for 28 days, the corrosion resistance of the Fe-17Mn-5Si-5Cr alloy decreased by 97.2%, whereas that of the S400 decreased by 99.6%, indicating a lower corrosion sensitivity of the Fe-17Mn-5Si-5Cr alloy to the change in mortar pH.The Fe-17Mn-5Si-5Cr alloy showed a higher corrosion resistance than the S400 (more than 150% in the mortar), indicating better chemical stability in the concrete structure.These results indicate that the Fe-17Mn-5Si-5Cr shape memory alloy exhibits a higher corrosion resistance than S400 carbon steel (commonly used for reinforcing concrete) and that it is a potential candidate for fabricating structures based on prestressed concrete and reinforced concrete.The corrosion resistance of the Fe-17Mn-5Si-5Cr alloy, which has a shape memory property enabling application to the reinforcement of prestressed concrete, was investigated by comparing it to general S400 carbon steel. Based on the experimental results, the following conclusions were reached:


Mycobacterium avium complex (MAC) species are the most commonly isolated nontuberculous mycobacteria to cause pulmonary infections worldwide. The lengthy and complicated therapy required to cure lung disease due to MAC is at least in part due to the phenomenon of antibiotic tolerance. In this review, we will define antibiotic tolerance and contrast it with persistence and antibiotic resistance. We will discuss physiologically relevant stress conditions that induce altered metabolism and antibiotic tolerance in mycobacteria. Next, we will review general molecular mechanisms underlying bacterial antibiotic tolerance, particularly those described for MAC and related mycobacteria, including Mycobacterium tuberculosis, with a focus on genes containing significant sequence homology in MAC. An improved understanding of antibiotic tolerance mechanisms can lay the foundation for novel approaches to target antibiotic-tolerant mycobacteria, with the goal of shortening the duration of curative treatment and improving survival in patients with MAC. Mycobacterium avium complex (MAC) comprises multiple genetically similar species that are often not differentiated in the clinical microbiology laboratory, including M. avium, Mycobacterium intracellulare, Mycobacterium arosiense, Mycobacterium bouchedurhonense, Mycobacterium chimaera, Mycobacterium colombiense, Mycobacterium marseillense, Mycobacterium timonense, Mycobacterium vulneris, and Mycobacterium yongonense. Mycobacterium avium complex species, and specifically M. avium and M. intracellulare, are the most common cause of pulmonary infection worldwide among the nontuberculous mycobacteria (NTM), and typically occurs in the setting of pre-existing lung disease. Disseminated MAC occurs primarily in patients with severe immune deficiency, such as those with advanced HIV infection, hematologic malignancy, or a history of immunosuppressive therapy, such as anti-tumor necrosis factor-α (TNF-α) therapy  and GDP-mannose , components of the TCA cycle , and those involved in fatty acid biosynthesis .In vitro biofilm studies revealed that extracellular DNA, a key component of the structural integrity of MAH biofilms, plays a role in antibiotic tolerance. Thus, DNase treatment significantly increased the bactericidal activity of moxifloxacin and clarithromycin against MAH in biofilms . Using aM. tuberculosis, GDP-mannose has been found to be an important modulator of the immune response, acting as a lipid anchor of lipoarabinomannan  is highly homologous to the corresponding genes from the two M. avium annotated genomes . The M.M. tuberculosis have demonstrated that the stringent response enzyme, RelMtb, plays an important role in antibiotic tolerance. RelMtb is a dual-functioning enzyme which is able to synthesize and hydrolyze (p)ppGpp (M. tuberculosis lacking RelMtb (rv2583) is unable to induce the stringent response and is defective in long-term survival in nutrient starvation and progressive hypoxia in vitro ppGpp . M. tubein vitro , as wellin vitro . RelMtb nfection ,b and innfection . Recentlsoniazid , which hrsisters . Given tM. avium and M. intracellulare from AIDS patients, susceptibility to the macrolides clarithromycin and erythromycin was increased in the presence of efflux pump inhibitors, such as thioridazine, chlorpromazine, and verapamil  in the encoding gene. In a study of clinical isolates of erapamil . Collect rv1258c , could brculosis .M. tuberculosis upon exposure to antibiotics, possibly contributing to antibiotic tolerance. Isoniazid exposure induces expression of rv2459, bacA (rv1819c), rv3728, mmr (rv3065), efpA (rv2846), mmpL7 (rv2942), p55 (rv1410c), and the tap-like gene rv1258c. These genes encode transporters or probable proteins belonging to the ATP binding cassette (ABC) family, major facilitator superfamily, or small multidrug resistance family  and phoY2 (rv0821c), have 40 and 44% sequence homology to E.coli phoU, respectively, and also appear to contribute to M. tuberculosis tolerance to antibiotics , which is 94% homologous to M. tuberculosis phoY2 (rv0821c). Further studies are required to elucidate the potential role of MAV_0768 in antibiotic tolerance of MAC species.PhoU, initially identified as conferring antibiotic tolerance in rculosis . The homibiotics . In M. t3 system , which i3 system . In addiarvation . A doublarvation . In a serifampin . A phoY2Mycobacteria are among the oldest known human pathogens, yet they continue to take a major toll on global health. Infections due to mycobacteria require complicated and lengthy antibiotic regimens, which pose challenges for medical adherence, thereby contributing to the emergence of antibiotic resistance. In order to develop novel, abbreviated therapies, a deeper understanding of the mechanisms of antibiotic tolerance in mycobacteria is needed.Like other bacteria, MAC displays reduced susceptibility to antibiotics within biofilms. In theory, degradation of the extracellular matrix of biofilms by hydrolytic enzymes and other bioactive agents could improve antibiotic penetration and reverse the metabolic downshift of the mycobacteria within biofilms, rendering them more susceptible to killing by conventional antibiotics . HoweverM. avium homologs of various M. tuberculosis factors, which have been implicated in antibiotic tolerance, including the stringent response and phosphate-sensing pathways. Recombinant strains of MAC deficient in these factors/pathways should be generated to determine their role in antibiotic tolerance under various in vitro stress conditions and in relevant animal models. Specifically, an inducible CRISPR interference (CRISPRi) system  system  can be uHP and PK designed and directed the project. HP, RL, and JR performed the literature search. All authors wrote the article.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.


There are concerns that general dentists (GDs) and dental specialists may be prescribing antibiotics inappropriately. This study explored the prescribing habits and decision-making processes of GDs versus oral and maxillofacial surgeons (OMFSs). A case-based online questionnaire was used to examine the prescribing of therapeutic and prophylactic antibiotics in two clinical scenarios. Stratified and systematic sampling strategies were implemented to provide a representative sample. The final valid sample was 60 GDs and 18 OMFSs. The majority of OMFSs (61.1%) routinely prescribed antibiotics for the surgical removal of third molars, which was significantly greater than for GDs (23.5%). For implant placement procedures, 72.2% of OMFSs and 62.1% of GDs prescribed antibiotics. Amoxicillin was the most selected agent for both scenarios. All OMFSs would prescribe antibiotic prophylaxis for patients with uncontrolled diabetes mellitus in both cases, but only 56.0–63.0% of GDs would do this. GDs based prescribing decisions primarily on information from prescribing guides, while OMFSs relied more on information gained from specialist training. Surgical prophylaxis protocols differed considerably between groups. Both groups used surgical prophylaxis for some situations that are outside current recommendations. Education with regards to discrepancies between clinical practice and current guidelines for antimicrobial therapy is needed to progress antimicrobial stewardship. Antibiotic resistance has become a serious global public health concern due to the increasing prevalence of infections resulting from multidrug-resistant bacteria ,2,3. WheAntibiotics are the most commonly prescribed antimicrobial agents in dentistry . GloballDental practitioners prescribe antibiotics for both therapeutic and prophylactic reasons. However, indications for antibiotic treatment in dentistry are limited, as the majority of dental infections can be treated effectively with direct operative measures ,4,7,11. Prophylactic use of antibiotics in dentistry is intended to prevent metastatic infections  or the local or systemic spread of infection ,14. In mCorrespondingly, it has been suggested that dentists may be prescribing antibiotics in situations where they are not necessary . AlthougWhen looking at Australian dentists’ antibiotic prescribing practices specifically, Jaunay et al.  conducteWhile the aforementioned studies report on the prescribing patterns and trends of dentists as a prescribing group, the research on clinicians’ knowledge, attitudes, and behaviors regarding antibiotic use is limited. Results from previous studies assessing medical physicians indicate that patient demands and expectation, providers’ perceptions related to patient expectations, fear of litigation, and diagnostic uncertainty are important factors that may lead to overprescribing ,30. SimiThe present study was designed to compare the prescribing habits of general and specialist dental clinicians practicing within Australia, and to explore practitioners’ rationale for antibiotic prescribing, in addition to the factors behind their prescribing practices for select dental procedures and patient circumstances.A total of 243 general dentists (GDs) and 68 oral and maxillofacial surgeons (OMFSs) were invited formally to participate in the survey. The final valid sample was 60 GDs and 18 OMFSs, which represented 0.3% of GDs and 8.1% of OMFSs in all of Australia.GD practitioners surveyed graduated from their primary dental degree between 1964 and 2015. OMFS practitioners obtained their primary dental degrees between 1959 and 1998. The majority of GDs (91.7%) and OMFSs (82.4%) obtained their primary dental degree in Australia. A wide range (5 to 48 years) of specialist practice was recorded for OMFS, with an average of 23 years.Workplace environments differed significantly between GDs and OMFSs. GDs predominantly worked in the private sector only , while OMFSs were split between a public-private sector combination  and private sector only . There were no OMFSs who worked in the public sector only (0.0%) while 3 GDs worked in the public sector only (3.9%) and 2 worked in a public-private combination (2.6%).Participant characteristics are recorded in p < 0.01). The majority of OMFSs (61.1%) routinely prescribed antibiotics for the surgical removal of third molars; this frequency was significantly lower for GDs (23.5%). In implant placement procedures, the frequency of prescription was high for both the GD (62.1%) and OMFS (72.2%) groups.If selected, the administration of antibiotics was predominantly chosen to be postoperative only. This was the case for both the surgical procedures of third molar removal (60.9%) and implant placement (38.7%). There were no significant differences between the GD and OMFS groups for preferred timing of administration. The timing of administration alternatives chosen were preoperative only, perioperative only, and combinations of preoperative or perioperative antibiotics in addition to postoperative administration.The preferred timing of antibiotic administration for practitioners who prescribed antibiotics are recorded in Amoxicillin used alone was the preferred antibiotic agent for the majority of practitioners who chose to prescribe antibiotic agent/s in both case scenarios. The alternative antibiotic agents chosen were amoxicillin/clavulanic acid, phenoxymethylpenicillin, cephalexin, and metronidazole plus amoxicillin in combination.The preferred antibiotic agent/s for practitioners who prescribed antibiotics are recorded in The most frequently selected justifications for the prescription of antibiotics for third molar removal were ‘better healing’ (43.5%) and ‘routine protocol’ (39.1%). Likewise, ‘routine protocol’ (50.0%) was the most common rationale for the use of antibiotic prophylaxis in implant placement. Contrarily, the reasoning for practitioners who did not normally prescribe was often that antibiotics were of ‘no benefit/not indicated’ for the procedure.There were no significant differences between practitioner groups in the frequency of antiseptic disinfection prior to treatment for the investigated procedures.p < 0.05), very significant (p < 0.01), and extremely significant (p < 0.001) statistical differences were observed between the GD and OMFS practitioner groups’ antibiotic prophylactic frequencies for medically compromised patients.Significant (p < 0.001). OMFSs were also more likely to prescribe antibiotic prophylaxis to patients who were HIV positive (p < 0.05) or had a history of injecting drug use (p < 0.01).For third molar surgical extraction, all OMFSs (100.0%) opted to provide antibiotic prophylaxis for patients with uncontrolled diabetes mellitus. This difference was extremely significant when compared to the GD group, where just over half (56.0%) would prescribe antibiotic prophylaxis (p < 0.01). OMFSs were also more likely to prescribe antibiotic prophylaxis for patients with a history of intravenous bisphosphonate therapy (p < 0.05).In implant dentistry, all OMFSs (100.0%) would again prescribe antibiotic prophylaxis for patients with uncontrolled diabetes mellitus. Similarly, this was a significantly higher frequency than for the GD group (63.0%)  was the most popular in the OMFS group, with 68.8% of OMFSs selecting the guide. This guide was also highly selected for GDs (60.0%). The most widely used prescribing guide for GDs was the Australian Therapeutic Guidelines (ATG) Oral and Dental, with 80.0% of GD respondents using the guide in their clinical practice. This was significantly higher than the OMFSs’ use of this guide (43.8%) (p < 0.01). The more recently published ATG Antibiotic, however, was used by fewer GD practitioners (25.0%), with a two-fold uptake in the OMFS group (50.0%). Similarly, the Australian Medicines Handbook was not a commonly selected guide for the GD group (8.3%), but uptake was significantly higher (31.3%) with OMFSs (p < 0.05). Data on the types of prescribing guides used by practitioners are displayed in Of those who used a prescribing guide in their practice , the Over half of the OMFSs (52.9%) had previously observed adverse drug reactions to antibiotics that required medical referral. This was significantly higher compared to the GD group, where only 10.0% of practitioners had observed these reactions. Reactions observed by respondents included anaphylactic reactions to penicillin/amoxicillin and cephalosporin, tetracycline allergies, skin rashes, erythema multiforme, and death.p < 0.01). For single dental implant placement, most OMFSs (72.2%) and GDs (62.1%) prescribed antibiotics routinely. The differences between the antibiotic protocols of the GD and OMFS practitioner groups may be attributed to different training and varied resources. Many practitioners who prescribed antibiotics cited ‘better healing’, a reduction of post-operative infection, or ‘routine protocol’, while those who did not prescribe claimed ‘no benefit/not indicated’. These two schools of thought are in stark contrast to one another, and this may reflect in part incongruences in the current literature and in guidelines that are used globally.This study investigated the use of therapeutic and prophylactic antibiotics by general dental practitioners and oral and maxillofacial surgeons with respect to third molar surgical extractions and dental implant placement. Discrepancies were observed between the antibiotic protocols of different practitioner groups for both case scenarios. The majority of OMFSs (61.1%) opted to prescribe antibiotics for surgical third molar extraction. This was significantly greater than the GD group (23.5%)  has also highlighted the use of antimicrobials in dentistry, with preoperative antiseptic rinses recommended to reduce the viral load of the etiologic agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the oral environment . HoweverIn the present study, the largest differences between the prescribing practices of respondent groups were in the use of antibiotics for medically compromised patients. While overall the results figures are consistent with findings from previous studies, including Jaunay et al.  and PalmOne important area of contention is surgical prophylaxis for patients with orthopedic implants. The majority of the GD (59.3%) and OMFS (76.5%) groups opted to prescribe antibiotics for these patients. Late infections of joint replacements are primarily associated with skin commensal staphylococci and β-hemolytic streptococci; these microorganisms are rarely isolated from dentally related bacteremia, as they do not form part of the normal oral flora ,40. The ATG [ATG [When considering the agent of choice, the present study found amoxicillin to be the overwhelming favorite of most respondents for all scenarios. These findings parallel those of both local and foreign studies of dental prescribing ,23,41,42ATG  for odonATG [ATG  recommenATG [ATG . There iATG [ATG . In addiATG [ATG ,22. DespAustralian Therapeutic Guidelines (ATG) Oral and Dental was updated in late 2019 [ATG Oral and Dental [ATG Antibiotic [Practitioners’ preferred reference to support and shape their antibiotic prescribing habits was explored in the present study. The differences between the prescribing practices of the GD and OMFS practitioner groups may be attributed to differences in training, the preferred use of different prescribing guides and resources, and the varied rank of importance given to the various prescribing resources. The results of this study show a variety of responses for practitioners’ opinions of the most important factor behind their prescribing practices. General dental practitioners were most likely to refer to a prescribing guide as their first-line reference for antibiotic prescribing, while OMFSs were more likely to refer to their specialist training. This may explain why OMFSs were more likely to routinely prescribe antibiotics for surgical prophylaxis than other groups. OMFSs may be more considerate or cognizant of general surgical principles for clean-contaminated surgery , in lineate 2019 . This upd Dental  and ATG tibiotic  might haDefined as the appropriate, safe, and discriminate use of antimicrobials for therapy and prophylaxis, antibiotic stewardship has been championed by governments, international health organizations, and initiatives to reduce issues associated with antibiotic-resistant pathogens ,11. WithThe results of this study provide a macroscopic broad overview of the prescribing practices and rationale of registered practicing dentists in Australia. It is, to date, the largest exploratory study into the prescribing habits of dental practitioners to be completed in Australia. The inclusion of different practitioner groups, with a large proportion of specialists, allows significant comparisons to be drawn between GDs and specialists. Many other studies internationally, with even larger sample sizes, lacked involvement of or comparison with specialists ,23,24,25The combination of explorative clinician-based research to understand the status quo and controlled investigations into the impact of antimicrobials on procedural outcomes may inform subsequent practitioner education. Further studies are needed to explore how well dental practitioners are aware of drug interactions and other consequences of excessive prescribing. The streamlining of training, professional development, resources, and guidelines is essential for clinicians to deliver minimized risk and evidence-based dentistry to patients in the era of antibiotic resistance.A cross-sectional survey was conducted on registered general dentists (GDs) and dental specialists using an online case-based questionnaire incorporating clinical case scenarios for prophylactic and therapeutic prescription.For comparing GDs and OMFSs, two clinical case scenarios formed the basis of the questionnaire: One for third molar surgical extraction and another for single dental implant placement. Both procedures were completed under local anesthetic only  to test the clinical case scenarios for applicability and ease of understanding, as well as to evaluate the readability and reduce any ambiguity of wording before distribution. The final survey operated via the SurveyMonkeyThe dental directory: 2016 edition [® online survey and the participant information sheet attached. A total of 243 GDs and 68 OMFSs were invited. Two follow-up emails were sent to all respondents. Informed consent was obtained for all participants at the commencement of the online survey and prior to their inclusion in the study.The dental practitioner directory published by the Australian Dental Association (ADA),  edition , was app edition , practit edition . Clinici® website. Data from the survey was collected by the SurveyMonkey® web form and downloaded for analysis after the close of the survey. The survey link was open for a period of four months. All survey responses were collected and stored in a de-identified form.Participants accessed the survey through a provided link to the online survey, hosted on the SurveyMonkey® Excel software. Descriptive statistics were computed and comparative analysis between groups performed using Chi-squared and Fisher’s exact tests. A value of p < 0.05 was considered statistically significant.Data was coded and reported using MicrosoftThis study was approved by The University of Queensland School of Dentistry Ethics Committee, and conducted in full accordance with the regulations governing experimentation on humans (Project reference number: 1813).Variations in the prescribing habits between general dentists and specialists for routine procedures within the fields of oral surgery and implant dentistry were observed, especially with regards to antibiotic prophylaxis for medically compromised patients. Surgical prophylaxis protocols differed between clinician groups. Practitioners were found to rank resources guiding the prescription of antibiotic agents differently, which may have an impact on their clinical practice. Practitioner education with regards to discrepancies between clinical practice and current guidelines for antimicrobial therapy should be addressed. Ultimately, there remains a crucial need for clear evidence-based guidelines on the prescribing of antibiotics by dental practitioners, especially for surgical prophylaxis, to reduce the inappropriate use of systemic antibiotics in dentistry.