Strategies to address inequity of uncorrected refractive error in the Western Pacific: A modified Delphi process.

PURPOSE: Uncorrected refractive error is the leading cause of vision impairment globally; however, little attention has been given to equity and access to services. This study aimed to identify and prioritise: (1) strategies to address inequity of access to refractive error services and (2) population groups to target with these strategies in five sub-regions within the Western Pacific. METHODS: We invited eye care professionals to complete a two-round online prioritisation process. In round 1, panellists nominated population groups least able to access refractive error services, and strategies to improve access. Responses were summarised and presented in round 2, where panellists ranked the groups (by extent of difficulty and size) and strategies (in terms of reach, acceptability, sustainability, feasibility and equity). Groups and strategies were scored according to their rank within each sub-region. RESULTS: Seventy five people from 17 countries completed both rounds (55% women). Regional differences were evident. Indigenous peoples were a priority group for improving access in Australasia and Southeast Asia, while East Asia identified refugees and Oceania identified rural/remote people. Across the five sub-regions, reducing out-of-pocket costs was a commonly prioritised strategy for refraction and spectacles. Australasia prioritised improving cultural safety, East Asia prioritised strengthening school eye health programmes and Oceania and Southeast Asia prioritised outreach to rural areas. CONCLUSION: These results provide policy-makers, researchers and funders with a starting point for context-specific actions to improve access to refractive error services, particularly among underserved population groups who may be left behind in existing private sector-dominated models of care.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

Targeted PMP22 TATA-box editing by CRISPR/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice.

Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted TATA-box of human PMP22 promoter to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multiple copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a proof-of-concept that CRISPR/Cas9-mediated targeting of TATA-box can be utilized to treat CMT1A.

Villous adenoma of the prostatic urethra.

Primary villous adenoma originating from the urinary tract is an infrequent entity. We present a rare case of villous adenoma arising from a prostatic urethra with no sign of malignant transformation. Villous adenoma should be considered as one of the differential diagnoses of urethral lesions, especially if it has similar magnetic resonance imaging features as its colonic counterpart. Due to its potential for malignant transformation, its complete resection is mandatory.

Prognostic implication of the neoadjuvant rectal score and other biomarkers of clinical outcome in Hong Kong Chinese patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer, for which pathological complete response is typically used as a surrogate survival endpoint. Neoadjuvant rectal score is a new biomarker that has been shown to correlate with survival. The main objectives of this study were to investigate factors contributing to pathological complete response, to validate the prognostic significance of neoadjuvant rectal score, and to investigate factors associated with a lower neoadjuvant rectal score in a cohort of Hong Kong Chinese. METHODS: Data of patients with locally advanced rectal cancer who received neoadjuvant chemoradiotherapy from August 2006 to October 2018 were retrieved from hospital records and retrospectively analysed. RESULTS: Of 193 patients who had optimal response to neoadjuvant chemoradiotherapy and surgery, tumour down-staging was the only independent prognostic factor that predicted pathological complete response (P<0.0001). Neoadjuvant rectal score was associated with overall survival (hazard ratio [HR]=1.042, 95% confidence interval [CI]=1.021-1.064; P<0.0001), disease-free survival (HR=1.042, 95% CI=1.022-1.062; P<0.0001), locoregional recurrence-free survival (HR=1.070, 95% CI=1.039-1.102; P<0.0001) and distant recurrence-free survival (HR=1.034, 95% CI=1.012-1.056; P=0.002). Patients who had pathological complete response were associated with a lower neoadjuvant rectal score (P<0.0001), but pathological complete response was not associated with survival. For patients with intermediate neoadjuvant rectal scores, late recurrences beyond 72 months from diagnosis were observed. CONCLUSION: Neoadjuvant rectal score is an independent prognostic marker of survival and disease recurrence in a cohort of Hong Kong Chinese patients who received neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

Compassion within conflict: Toward a computational theory of social groups informed by maternal brain physiology.

Benevolent intersubjectivity developed in parent-infant interactions and compassion toward friend and foe alike are non-violent interventions to group behavior in conflict. Based on a dyadic active inference framework rooted in specific parental brain mechanisms, we suggest that interventions promoting compassion and intersubjectivity can reduce stress, and that compassionate mediation may resolve conflicts.

CD40L-stimulated B cells for ex-vivo expansion of polyspecific non-human primate regulatory T cells for translational studies.

The therapeutic applications of regulatory T cells (Tregs ) include treating autoimmune diseases, graft-versus-host disease and induction of transplantation tolerance. For ex-vivo expanded Tregs to be used in deceased donor transplantation, they must be able to suppress T cell responses to a broad range of human leukocyte antigen (HLA). Here, we present a novel approach for the expansion of polyspecific Tregs in cynomolgus macaques that was adapted from a good manufacturing practice-compliant protocol. Tregs were isolated by fluorescence-activated cell sorting (FACS) and expanded in the presence of a panel of CD40L-stimulated B cells (CD40L-sBc). Prior to Treg culture, CD40L-sBc were expanded in vitro from multiple major histocompatibility complex (MHC)-disparate macaques. Expanded Tregs expressed high levels of forkhead box protein 3 (FoxP3) and Helios, a high percentage of Treg -specific demethylated region (TSDR) demethylation and strong suppression of naïve T cell responses in vitro. In addition, these Tregs produced low levels of inflammatory cytokines and were able to expand post-cryopreservation. Specificity assays confirmed that these Tregs were suppressive upon activation by any antigen-presenting cells (APCs) whose MHC was shared by CD40L-sBc used during expansion, proving that they are polyspecific. We developed an approach for the expansion of highly suppressive cynomolgus macaque polyspecific Tregs through the use of a combination of CD40L-engineered B cells with the potential to be translated to clinical studies. To our knowledge, this is the first report that uses a pool of MHC-mismatched CD40L-sBc to create polyspecific Tregs suitable for use in deceased-donor transplants.

Polytobacco product use among current cigarette smokers in Hong Kong, China: results from population surveys (2015-17).

BACKGROUND: Polytobacco product use is increasingly popular, but little is known about the prevalence, trend, and factors of such use particularly in non-western countries. METHOD: A representative sample of 1139 current cigarette smokers aged 15+ (84.1% male) were telephone interviewed in Tobacco Control Policy-related Surveys in 2015-2017. Information collected included poly-tobacco use (PTU), smoking and socio-demographic characteristics. Associations of current PTU with related factors were analyzed using logistic regression with adjustment for confounders. Prevalence was weighted by age and sex of current cigarette users in the general population. RESULTS: Eighty-four point one percent (95% CI 81.4-86.6%) were exclusive cigarette smokers. Fifteen point nine percent (13.4-18.6%) were current polytobacco product users, 12.3% (10.2-14.8%) used one tobacco product and 2.52% (1.59-3.97%) used two tobacco products in addition to cigarette. Cigarette use with cigar was more common (6.28%, 4.75-8.27%), and the least used product with cigarette was e-cigarette (1.05%, 0.44-2.50%). The changes in overall prevalence of PTU by number of products use varied in 3 years. Current PTU was associated with being male (AOR 2.01, 95% CI 1.12-3.61), younger age (AORs range from 1.34-4.65, P for trend < .001) and less ready to quit (2.08, 1.09-3.97). CONCLUSIONS: Prevalence of PTU increased slowly by year, one tobacco product use with cigarette was more common. The most used tobacco product with cigarette was cigar. Being male, younger and less ready to quit were associated with current PTU.

Application of virome capture sequencing in shellfish sold at retail level in Singapore.

During the period from late 2019 to early 2020, we performed a foodborne virus detection from shellfish collected in Singapore at retail level. Multiple human enteric viruses were included as our targets including human noroviruses (NoVs) GI and GII, hepatitis A virus, hepatitis E virus and rotavirus. Out of the 60 shellfish samples, 23 (38·3%) were detected to be positive by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) with human enteric viruses. Six samples were selected to proceed with virome capture sequencing with positive control samples spiked with serially diluted NoV GII clinical samples in oyster extract. As a result, the natural sample with comparable Ct values (34·0-35·0) of the spiked sample as detected by RT-qPCR generated much lower read counts (>7-log2 cumulative sum scaling difference) and genome coverage (406 nt. vs 3715 nt.), suggesting that the RT-qPCR positive signals detected from the shellfish samples collected at the retail market were likely from degraded RNA derived from inactive virus particles.

Effects of opioids on the parental brain in health and disease.

The epidemic of opioid use disorder (OUD) directly affects millions of women of child-bearing age. Unfortunately, parenting behaviors - among the most important processes for human survival - are vulnerable to the effects of OUD. The standard of care for pregnant women with OUD is opioid maintenance therapy (OMT), of which the primary objective is to mitigate addiction-related stress. The aim of this review is to synthesize current information specific to pregnancy and parenting that may be affected by OUD. We first summarize a model of the parental brain supported by animal research and human neuroimaging. We then review animal models of exogenous opioid effects on parental brain and behavior. We also present preliminary data for a unifying hypothesis that may link different effects of exogenous opioids on parenting across species and in the context of OMT. Finally, we discuss future directions that may inform research and clinical decision making for peripartum women with OUD.

Factors predicting screen time related to physical and behavioural complaints in primary school children.

BACKGROUND AND OBJECTIVE: Physical and behavioural problems from extended usage of electronic devices are issues among primary school children. This study is aimed to investigate the prevalence of physical and behavioural complaints arising from the electronic device usage and to identify the potential factors that predicted the complaints. METHODS: This was a primary school-based cross-sectional study using multistage cluster sampling, conducted at Bau district in Sarawak, Malaysia in 40 primary schools. A questionnaire was used to collect information of usage pattern in insufficient lighting, timing and position. The physical and behavioural complaints were traced. Data analysis was performed using SPSS version 22. A p-value < 0.05 with 95% CI was considered as statistically significant. RESULTS: About 52.8% of the 569 students used digital devices in a bright room, 69.8% in the day time and 54.4% in sitting position. The physical complaints were headache (32.9%), neck, shoulder and back pain (32.9%) followed by by eye strain (31.8%). Regarding behavioural problems, 25.7% of the students had loss of interest in study and outdoor activities (20.7%), skipped meals (19.0%) and arguments/disagreements with parents (17.9%). After logistic regression analysis, the lying position (OR=1.71, 95% CI: 1.096, 2.688) and darkroom lighting (OR=2.323 95% CI: 1.138, 4.744) appeared to be potential predictors of the complaint. CONCLUSION: One-quarter of the students studied experienced physical complaints, and one-fifth had behavioural problems associated with the use of electronic devices. Lying position and darkroom lighting are the potential predictors of complaints. Therefore, we suggest that the children should use electronic devices in the sitting position with adequate room lighting.

RELT negatively regulates the early phase of the T-cell response in mice.

RELT (tumor necrosis factor receptor superfamily member 19-like, TNFRSF19L) is a TNFR superfamily member that is primarily expressed in immune cells and lymphoid tissues, but whose immunological function is not well-defined. Here, we show that RELT is expressed by naive T cells and DCs, and their activation or maturation decreases RELT expression. Using RELT knockout (RELT-/- ) mice, we demonstrate that RELT deficiency selectively promotes the homeostatic proliferation of CD4+ T cells but not CD8+ T cells, and enhances anti-tumor CD8+ T-cell responses. We also demonstrate, using an adoptive transfer model in which RELT is knocked-out in either the transferred transgenic CD8+ T cells or the recipient melanoma-bearing mice, that RELT on multiple immune cells limits the hyper-response of tumor-specific CD8+ T cells. Hyper-responsiveness of RELT-deficient T cells was induced by promoting their proliferation. Taken together, our findings suggest that RELT acts as a negative regulator that controls the early phase of T-cell activation probably by promoting T-cell apoptosis.

Improvement of bone mineral density and markers of proximal renal tubular function in chronic hepatitis B patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide.

Tenofovir alafenamide (TAF) is a novel prodrug that reduces tenofovir plasma levels by 90% compared to tenofovir disoproxil fumarate (TDF), resulting in decreased bone mineral density (BMD) loss and renal toxicity. We aimed to study changes in BMD and markers of renal function of chronic hepatitis B (CHB) patients previously treated with TDF who were switched to TAF in as early as 12 weeks. This was a prospective single-arm open-label study of 75 CHB patients treated with TDF 300 mg daily who were switched to TAF 25 mg daily and followed for 24 weeks. All patients had been treated with TDF for at least 12 months and had HBV DNA <21 IU/mL at the time of switch. BMD and markers of renal function were taken on the day of switch and repeated after 12 and 24 weeks of TAF treatment. Hip and spine bone mineral density significantly increased from baseline to week 12 (+12.9% and +2.4%, respectively, P < 0.01). There were significant decreases in urinary beta-2-microglobulin to creatinine and retinol-binding protein to creatinine ratios by week 12 (P < 0.01 for both). Mean estimated glomerular filtration rate (GFR) did not change. Tubular reabsorption of phosphate was decreased at week 24 (P < 0.05). In conclusion, CHB patients previously treated with TDF experienced significant improvement in bone density and some markers of renal tubular function and as early as 12 weeks after switching to TAF. Bone density changes associated with TDF may not be entirely related to renal handling of phosphate.

Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models.

The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1+/- knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1+/- mice. STEP61 protein is also increased in cortical lysates from the central nervous system-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons, from two independent SZ patient cohorts. In these selected SZ models, increased STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ.

The discriminative power of STOP-Bang as a screening tool for suspected obstructive sleep apnea in clinically referred patients: considering gender differences.

PURPOSE: Obstructive sleep apnea (OSA) is the most commonly seen clinical sleep disorder. STOP-Bang, a widely used screening tool, yields a composite score based on eight dichotomized items including male gender. This study was designed to validate STOP-Bang among clinically referred patients and tested alternative scoring designs on tool performance, with a focus on gender differences in OSA. METHOD: STOP-Bang was administered to 403 female and 532 male subjects, followed by comprehensive sleep evaluation that included measurement of apnea-hypopnea indexes. Gender differences in STOP-Bang scores, OSA diagnosis, and severities were explored, and gender-specific alternative score cutoffs evaluated. Optimal operating points (OOP) were tested for female body mass index (BMI) and male neck circumference to inform STOP-Bang threshold refinement. Receiver operating characteristic curves were used to compare conventional and modified STOP-Bang. RESULTS: STOP-Bang performance by gender showed extremely low specificity in males at the recommended cutoff of ≥3. Better utility was presented at a cutoff of 4 or 5 among clinically referred patients irrespective of gender differences. Screening performance was improved by modifying BMI and/or neck circumference thresholds using gender-triaged OOP estimation. Three gender-based model revisions outperformed conventional STOP-Bang. CONCLUSION: Our study suggests that gender-specific consideration needs to be incorporated into the application of STOP-Bang in a clinically referred patient population with a higher risk of OSA. Alternative scoring systems may improve predictive performance of STOP-Bang.

Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer.

Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes. Patients and methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17). Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.

Periodontitis and dental scaling associated with pyogenic liver abscess: A population-based case-control study.

BACKGROUND AND OBJECTIVES: The purpose of this study was to investigate the relationship between periodontitis, dental scaling (DS) and pyogenic liver abscesses (PLAs). MATERIAL AND METHODS: A nationwide population-based case-control study was applied using data from the National Health Insurance Research Database in Taiwan. We identified and enrolled 691 PLA patients, who were individually matched by age and sex to 2764 controls. RESULTS: Conditional logistic regression was applied to estimate adjusted odds ratios (aORs) in patients with exposure to periodontitis and DS before PLA. After adjusting for other confounding factors, periodontitis remained a risk factor for PLA among patients aged 20-40 years, with an aOR of 2.31 (95% confidence interval [CI] = 1.37-3.90, P = .0018). In addition, the average aOR for PLA was significantly lower among patients with one DS (aOR = 0.76, 95% CI = 0.59-0.96) and more than one DS (aOR = 0.61, 95% CI = 0.39-0.95) within 1 year before the index date. CONCLUSION: According to these results, we concluded that adult patients with periodontitis aged <50 years old are more at risk for PLA than controls, particularly when they have no DS. Moreover, from 20 years of age, non-periodontal patients subjected to at least 2 DS per year are less at risk for PLA than controls.