Topical betamethasone and systemic colchicine for treatment of recurrent aphthous stomatitis: a randomised clinical trial.

BACKGROUND: Recurrent Aphthous Stomatitis (RAS) is painful oral ulceration frequently treated with topical steroids. There is limited published evidence for the efficacy of any treatment for RAS and there remains a need for longitudinal randomised clinical trials to evaluate and compare the effectiveness of different therapies in the management of RAS. The aim of the current project was to assess the efficacy of betamethasone mouthwash and colchicine tablets, individually and combined, for the treatment of RAS, and to establish the optimum treatment period necessary for a significant reduction in the disease severity. METHODOLOGY: A randomised, prospective, parallel-group clinical trial was conducted over one year, to compare the efficacy of three therapies in RAS. One hundred and six patients were randomized into three groups; 35 received betamethasone mouthwash, 35 had colchicine tablets and 36 received both therapies. The response was evaluated quantitatively every 3 months for 1 year, using the Ulcer Severity Score (USS). RESULTS: For all three treatment regimes, the mean USS decreased by about 30% in the first 3 months (p < 0.001). Further improvement was noted for up to 9 months. At the end of the study, the mean USS had improved by 50% from 34.9 ± 7.2 before treatment to 17.5 ± 8.9 after treatment (p < 0.001). Of included participants, 86% showed significant clinical improvement by the end of the study. There were no significant differences in outcomes between the three regimes (p < 0.05). CONCLUSIONS: This clinical trial has provided evidence for the efficacy of betamethasone mouthwash and for colchicine tablets in the treatment of RAS and has shown that at least six months of treatment may be required for optimum effect. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN3267716. Date of clinical trial registration: 15/04/2018.

Needs-led human resource planning for Sierra Leone in support of oral health.

BACKGROUND: In Sierra Leone (SL), a low-income country in West Africa, dental care is very limited, largely private, and with services focused in the capital Freetown. There is no formal dental education. Ten dentists supported by a similar number of dental care professionals (DCPs) serve a population of over 7.5 million people. The objective of this research was to estimate needs-led requirements for dental care and human resources for oral health to inform capacity building, based on a national survey of oral health in SL. METHODS: A dedicated operational research (OR) decision tool was constructed in Microsoft Excel to support this project. First, total treatment needs were estimated from our national epidemiological survey data for three key ages (6, 12 and 15 years), collected using the 'International Caries Classification and Management System (ICCMS)' tool. Second, oral health needs were extrapolated to whole population levels for each year-group, based on census demographic data. Third, full time equivalent (FTE) workforce capacity needs were estimated for mid-level providers in the form of Dental Therapists (DTs) and non-dental personnel based on current oral disease management approaches and clinical timings for treatment procedures. Fourth, informed by an expert panel, three oral disease management scenarios were explored for the national population: (1) Conventional care (CC): comprising oral health promotion (including prevention), restorations and tooth extraction; (2) Surgical and Preventive care (S5&6P and S6P): comprising oral health promotion (inc. prevention) and tooth extraction (D5 and D6 together, & at D6 level only); and (3) Prevention only (P): consisting of oral health promotion (inc. prevention). Fifth, the findings were extrapolated to the whole population based on demography, assuming similar levels of treatment need. RESULTS: To meet the needs of a single year-group of childrens' needs, an average of 163 DTs (range: 133-188) would be required to deliver Conventional care (CC); 39 DTs (range: 30-45) to deliver basic Surgical and Preventive care (S6P); 54 DTs for more extended Surgical and Preventive care (S5&6P) (range 38-68); and 27 DTs (range: 25-32) to deliver Prevention only (P). When scaled up to the total population, an estimated 6,147 DTs (range: 5,565-6,870) would be required to deliver Conventional care (CC); 1,413 DTs (range: 1255-1438 DTs) to deliver basic Surgical and Preventive care (S6P); 2,000 DTs (range 1590-2236) for more extended Surgical and Preventive care (S5&6P) (range 1590-2236); and 1,028 DTs to deliver Prevention only (P) (range: 1016-1046). Furthermore, if oral health promotion activities, including individualised prevention, could be delivered by non-dental personnel, then the remaining surgical care could be delivered by 385 DTs (range: 251-488) for the S6P scenario which was deemed as the minimum basic baseline service involving extracting all teeth with extensive caries into dentine. More realistically, 972 DTs (range: 586-1179) would be needed for the S5&6P scenario in which all teeth with distinctive and extensive caries into dentine are extracted. CONCLUSION: The study demonstrates the huge dental workforce needs required to deliver even minimal oral health care to the Sierra Leone population. The gap between the current workforce and the oral health needs of the population is stark and requires urgent action. The study also demonstrates the potential for contemporary epidemiological tools to predict dental treatment needs and inform workforce capacity building in a low-income country, exploring a range of solutions involving mid-level providers and non-dental personnel.

Implications in the quantification of SARS-CoV2 copies in concurrent nasopharyngeal swabs, whole mouth fluid and respiratory droplets.

OBJECTIVE: Association of SARS-CoV2 burden in the aerodigestive tract with the disease is sparsely understood. We propose to elucidate the implications of SARS-CoV2 copies in concurrent nasopharyngeal swab (NPS), whole mouth fluid (WMF) and respiratory droplet (RD) samples on disease pathogenesis/transmission. METHODS: SARS-CoV2 copies quantified by RT-PCR in concurrent NPS, WMF and RD samples from 80 suspected COVID-19 patients were analysed with demographics, immune response and disease severity. RESULTS: Among the 55/80 (69 %) NPS-positive patients, SARS-CoV2 was detected in 44/55 (80 %) WMF (concordance with NPS-84 %; p = 0.02) and 17/55 (31 %) RD samples. SARS-CoV2 copies were similar in NPS (median:8.74 × 10^5) and WMF (median:3.07 × 10^4), but lower in RD (median:3.60 × 10^2). The 25-75 % interquartile range of SARS-CoV2 copies in the NPS was significantly higher in patients who shed the virus in WMF (p = 0.0001) and RD (p = 0.01). Multivariate analyses showed that hospitalized patients shed significantly higher virus copies in the WMF (p = 0.01). Hospitalized patients with more severe disease (p = 0.03) and higher IL-6 values (p = 0.001) shed more SARS-CoV2 virus in the RD. CONCLUSIONS: WMF may be used reliably as a surrogate for diagnosis. High copy numbers in the NPS probably imply early disease onset, while in the WMF and RD may imply more severe disease and increased inflammation.

Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma.

OBJECTIVES: To explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren's syndrome (SS) patients. METHODS: Salivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production. RESULTS: Transcriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4+CXC-motif chemokine receptor 5 (CXCR5)+programmed cell death protein 1 (PD1)+ICOS+ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4+CD45RO+ICOS+PD1+ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5+CD4+PD1+ICOS+Foxp3- Tfh-cells and a uniquely expanded population of CXCR5-CD4+PD1hiICOS+Foxp3- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α). CONCLUSIONS: Overall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.

Global inequalities in HIV infection.

HIV infection continues to be one of the world's greatest pandemics, affecting nearly every country on the globe. By September 2018, it is estimated that 38 million people were living with HIV, 30 million people are aware of their status, and 23 million people are taking anti-retroviral therapy (8 million in 2010). Thus, currently 8 million people living with HIV are not aware that they are HIV-positive and 15 million persons are not being treated. There are nearly 15 million orphans (aged 0-17). There is widespread inequality both in the prevalence of HIV infection and in the access to therapy. However, although the number of people living with HIV continues to increase, the number of new infections shows a steady decrease over the last 9 years and in 2018 was 1.7 million. Deaths from AIDS in 2018 also decreased to 750,000 from 1.2 million in 2010. The world prevalence of HIV is about 0.23% but is over 0.3% in South-East Asia, Latin America, North America and Eastern Europe and with particularly high prevalence in the Caribbean (1.1%) and sub-Saharan Africa (5.5%). It is approximately 0.5% in Indonesia. There were approximately 5,000 new HIV infections (adults and children) a day during 2018. About 61% were in sub-Saharan Africa, nearly 50% were in females and 500 were in children. HIV therapy seems to have had a global impact, with AIDS-related deaths decreasing by 33% since 2010, and new infections decreasing by 16%. Nevertheless, the majority of the world's HIV is in low and middle resource countries and social determinants are strongly related. Many people living with HIV or at risk for HIV still do not have access to prevention, care and treatment, and there is still no cure.

The impact of the world Workshops on oral health and disease in HIV and AIDS (1988-2020).

The first World Workshop on Oral AIDS was held in San Diego in 1988, organized by John and Deborah Greenspan who saw the need and advantages of getting together all those health workers globally who were interested in oral aspects of HIV with a common purpose of advancing the field collectively and collaboratively. Since that time and over the following 30 years, World Workshops on oral HIV have been held every four years or so. The aims of the first and all subsequent Workshops were to bring together clinicians and non-clinical scientists who have an interest in the oral manifestations of HIV disease, to share worldwide perspectives, knowledge and understanding of oral health and disease in HIV infection, to agree on global definitions and classifications of oral diseases and to identify research needs taking account of the worldwide perspectives and opportunities. Thus, there have been clinical science, social science and basic science aspects of each World Workshop. The Workshops have achieved their aims and have had impact in all three fields, leading to robust research agendas, changes in national HIV policies and international collaborations. They have led to policy declarations of access to oral care as a basic human right for both HIV-positive and HIV-negative individuals and advancing the rights of all HIV-positive healthcare workers to perform clinical practice.

HIV in Indonesia and in neighbouring countries and its social impact.

HIV incidence is still increasing in parts of Indonesia and in several Asian Countries. New cases of HIV in Indonesia have risen from 7,000 per year in 2006 to 48,000 per year in 2017. In spite of this increase, the number of newly diagnosed cases of AIDS has decreased from a peak of over 12,000 in 2013 to a little over 9,000 in 2017. The mean prevalence of HIV in Indonesia is 0.41% but there is a ten-fold difference in the prevalence in different regions with the highest in Papua (5%). Women represent over 35% of new infections per year and of the total (640,000) in Indonesia. Over 50% of HIV diagnoses are made when patients already have AIDS. Stigma and discrimination are still strong barriers in prevention and treatment but also there are considerable challenges in access to appropriate anti-retroviral therapy. There is a need for further investment in HIV Programs in Indonesia so that prevention can be enhanced, and diagnosis made at an earlier stage. Health Professionals including dentists should be readily willing to provide joint prevention efforts and care to people at risk and with HIV and other infectious diseases to help meet the WHO aims of 2030. Public health programmes are needed to make certain that the general public is aware of HIV testing and the role of dental healthcare workers in facilitating this, thereby further normalising attitudes to people living with HIV.

Correction: Oral and Vaginal Epithelial Cell Lines Bind and Transfer Cell-Free Infectious HIV-1 to Permissive Cells but Are Not Productively Infected.

[This corrects the article DOI: 10.1371/journal.pone.0098077.].

Fortitude and resilience in service of the population: a case study of dental professionals striving for health in Sierra Leone.

OBJECTIVE: Sierra Leone (SL), with a population of over 7 million people, has a critical health workforce shortage. This research explores the views of key players on population oral health needs and demands, the challenges of oral and dental care delivery, and professional careers in dentistry, in order to inform future capacity building. MATERIALS AND METHODS: Semi-structured interviews were conducted with a purposive sample of key players in dentistry and healthcare, both in-country and externally. An interpretive phenomenological approach was used in exploring views of key-players on the oral needs and demands of population, challenges in the delivery of oral and dental care, professional careers of dental professionals in SL, and future workforce capacity building based on a topic guide drawn from the available literature. Interviews were audio-recorded, transcribed verbatim, anonymised and analysed using QSR NVivo 10 for data management and reported in accordance to the consolidated criteria for reporting qualitative research. RESULTS: Twenty-one informants, of whom 18 were male, 17 were in-country and 16 were dental professionals, participated in the research. Dental professionals reported clear consensus on a considerable level of unmet oral health needs, most notably dental caries and periodontal disease, together with life threatening oral conditions such as osteomyelitis, Ludwig's Angina and Burkitt's Lymphoma. Challenges associated with the delivery of dental care revolved around five themes: patients' predisposition for traditional remedies and urgent care; practical hindrances to the delivery of care; professional isolation and weak governance; and place with pressing local crises and lack of political will. An emerging typology of dental professionals included: demonstrating loyalty to their nation and family; exhibiting resilience in challenging circumstances; embracing opportunity most notably amongst expatriates; and striving to serve the needs of the population. There was support for innovative future capacity building developments. CONCLUSION: This paper provides important insights to the delivery of dental care in a low-income country with significant oral health needs and multiple challenges in the delivery of dental care, whilst also providing a vision for developing, building and retaining future human resources for oral health.

Predictive value of ultrasound scoring in relation to clinical and histological parameters in xerostomia patients.

BACKGROUND: Salivary gland dysfunction is one of the main clinical features of Sjögren's syndrome (SS), manifested by xerostomia with subsequent complications and well-established effects on the person's quality of life. OBJECTIVES: To determine firstly whether selected tests of salivary gland function and structure, unstimulated whole salivary flow rate (UWSFR), parotid flow rate (PFR), clinical oral dryness score (CODS) and ultrasound score (USS), can discriminate SS from non-SS sicca patients and secondly whether these tests can differentiate between patients in different subgroups of SS. METHOD: Unstimulated whole salivary flow rate, PFR, CODS and USS were determined in 244 patients comprised of SS patients (n = 118), SS patients at higher risk of lymphoma (n = 30) or with lymphoma (n = 26), and non-SS sicca disease controls (n = 70). RESULTS: All assessments showed a significant difference between the overall SS group and the disease control group, attributed mainly to the lymphoma subgroups of SS (p < 0.0001 for all parameters). There was a significant correlation (Spearman r = 0.7, p value <0.0001) and 87.3% agreement between USS and the histology focus scores of 119 patients. CONCLUSION: The results suggest that salivary gland tests including USS can aid in differentiating between SS and non-SS dry mouth, especially the subgroups of SS with lymphoma or at higher risk of developing lymphoma.

Salivary S100A8/A9 in Sjögren's syndrome accompanied by lymphoma.

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune inflammatory disease that affects the exocrine glands. The absence of early diagnostic markers contributes to delays in its diagnosis. Identification of changes in the protein profile of saliva is considered one of the promising strategies for the discovery of new biomarkers for SS. OBJECTIVE: To identify salivary protein biomarkers with potential for use in discriminating between different lymphoma risk subgroups of SS. METHOD: Parotid and whole mouth saliva samples were collected from patients with SS, including those in subgroups at higher risk of developing or with confirmed lymphoma, non-SS sicca disease controls and healthy subjects. An initial proteomics analysis by mass spectrometry (LCMSMS) identified S100A8/A9 as a biomarker and was followed by validation with an enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant differences were found in levels of S100A8/A9 in parotid saliva but not whole mouth saliva between patients with SS compared with healthy and disease control subjects (P = 0.001 and 0.031, respectively). Subgroups of patients with SS based on lymphoma risk showed significant differences in salivary levels of S100A8/A9. CONCLUSION: The results suggest that salivary levels of S100A8/A9 can aid in differentiating between SS, disease control and healthy control subjects, especially the subgroups of SS with lymphoma or at higher risk of lymphoma.

Natural History and Predictors of Progression to Sjögren's Syndrome Among Participants of the Sjögren's International Collaborative Clinical Alliance Registry.

OBJECTIVE: To explore changes in the phenotypic features of Sjögren's syndrome (SS), and in SS status among participants in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry over a 2-3-year interval. METHODS: All participants in the SICCA registry who were found to have any objective measures of salivary hypofunction, dry eye, focal lymphocytic sialadenitis in minor salivary gland biopsy, or anti-SSA/SSB antibodies were recalled over a window of 2 to 3 years after their baseline examinations to repeat all clinical examinations and specimen collections to determine whether there was any change in phenotypic features and in SS status. RESULTS: As of September 15, 2013, a total of 3,514 participants had enrolled in SICCA, and among 3,310 eligible, 771 presented for a followup visit. Among participants found to have SS using the 2012 American College of Rheumatology (ACR) classification criteria, 93% again met the criteria after 2 to 3 years, and this proportion was 89% when using the 2016 ACR/European League Against Rheumatism (EULAR) criteria. Among those who did not meet ACR or ACR/EULAR criteria at baseline, 9% and 8%, respectively, had progressed and met them at followup. Those with hypergammaglobulinemia and hypocomplementemia at study entry were, respectively, 4 and 6 times more likely to progress to SS by ACR criteria than those without these characteristics (95% confidence interval 1.5-10.1 and 1.8-20.4, respectively). CONCLUSION: While there was stability over a 2-3-year period of both individual phenotypic features of SS and of SS status, hypergammaglobulinemia and hypocomplementemia at study entry were predictive of progression to SS.

Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry.

OBJECTIVE: The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets. METHODS: We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations. RESULTS: We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10-42 , P = 3 × 10-14 , and P = 9 × 10-10 , respectively), and several novel suggestive regions (those with 2 or more associations at P < 1 × 10-5 ). Two regions have been previously implicated in autoimmune disease: KLRG1 (P = 6 × 10-7 [Asian cluster]) and SH2D2A (P = 2 × 10-6 [all participants]). We observed striking differences between the associations in Europeans and Asians, with high heterogeneity especially in the MHC; representative single-nucleotide polymorphisms from established and suggestive regions had highly significant differences in the allele frequencies in the study populations. We showed that SSA/SSB autoantibody production and the labial salivary gland focus score criteria were associated with the first worldwide principal component, indicative of higher non-European ancestry (P = 4 × 10-15 and P = 4 × 10-5 , respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations. CONCLUSION: Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes.

Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis.

BACKGROUND: Orofacial granulomatosis (OFG) is a rare, inflammatory disorder of the mouth, in which some patients also have intestinal Crohn's disease (CD). The etiology remains largely unknown, although there is a high prevalence of atopy, and oral granulomas are also seen in other immune disorders particularly CD and sarcoidosis. We investigated whether genetic variants associated with an increased risk of CD, sarcoidosis, or atopy were also associated with susceptibility to OFG. METHODS: Patients were stratified clinically as isolated oral manifestations (OFG only) or concurrent intestinal CD (OFG+CD). We genotyped 201 patients and 1023 healthy controls for risk variants in NOD2, IRGM, IL23R, ATG16L1 (CD), BTNL2 (sarcoidosis), and FLG (atopy). The coding regions of the NOD2 gene were screened for rare, potentially pathogenic variants in OFG. RESULTS: A combined analysis of 3 CD-risk variants in NOD2 showed no association with any OFG subgroup. NOD2 p.L1007insC was associated with OFG+CD (P = 0.023) and IL23R p.R381Q with all OFG (P = 0.031). The sarcoidosis risk variant rs2076530 in BTNL2 was associated with all OFG (P = 0.013). We identified 7 rare missense NOD2 alleles in 8 individuals with OFG, 4 OFG-only patients and 4 patients with OFG+CD. There was a significant enrichment of NOD2 variants in the OFG+CD group compared to the OFG-only group (P = 0.008, common variants; P = 0.04, all common and rare variants). CONCLUSIONS: Our findings suggest that genetic variants in NOD2 are only associated with OFG in patients with concurrent intestinal disease. A genome-wide association scan is needed to fully define the genetic architecture of OFG.

Image-based DNA ploidy analysis aids prediction of malignant transformation in oral lichen planus.

OBJECTIVES: To investigate the potential of image-based DNA ploidy analysis to predict malignant transformation in patients with oral lichen planus (OLP). STUDY DESIGN: DNA ploidy analysis was performed on biopsy samples from 14 patients with OLP who underwent malignant transformation. As controls, 42 OLP lesions showing unusual clinical features suggesting a transformation risk and 68 samples of clinically and histologically typical OLP were included. Cases with dysplasia on initial biopsy were excluded. Eighty fibroepithelial polyps acted as methodologic controls. Epithelial nuclei were isolated from formalin-fixed paraffin embedded biopsy samples and monolayers stained with Feulgen for automated image cytometry to establish DNA content. Ploidy status was correlated to outcome using Kaplan-Meier analysis and log-rank Mantel-Cox tests. RESULTS: All controls and typical OLP were diploid and none underwent malignant transformation in mean follow-up of 14 years (10-18 years). One unusual OLP developed carcinoma and all were diploid. The 14 patients with transformation developed 21 carcinomas. In the 11 patients who had a prior biopsy, 4 were aneuploid. CONCLUSIONS: DNA ploidy analysis predicted malignant transformation in more than one third (36.4%) of patients with OLP with a preceding biopsy (n = 11). This premalignant nature could not have been diagnosed clinically or by histologic dysplasia assessment.