Toward a pan-SARS-CoV-2 vaccine targeting conserved epitopes on spike and non-spike proteins for potent, broad and durable immune responses.

BACKGROUND: The SARS-CoV-2 non-Spike (S) structural protein targets on nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, are grossly overlooked in COVID vaccine development. The current Spike-only vaccines bear an intrinsic shortfall for promotion of a fuller T cell immunity. Vaccines designed to target conserved epitopes could elicit strong cellular immune responses that would synergize with B cell responses and lead to long-term vaccine success. We pursue a universal (pan-SARS-CoV-2) vaccine against Delta, Omicrons and ever-emergent new mutants. METHODS AND FINDINGS: We explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation (N = 1,478) of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). This UB-612 booster vaccination is safe and well tolerated without SAEs. CONCLUSIONS: By targeting conserved epitopes on viral S2, M and N proteins, UB-612 could provide potent, broad and long-lasting B-cell and T-cell memory immunity and offers the potential as a universal vaccine to fend off Omicrons and new VoCs without resorting to Omicron-specific immunogens. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04773067; ClinicalTrials.gov ID: NCT05293665; ClinicalTrials.gov ID: NCT05541861.

High Neutralizing Antibody Levels Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.1 and BA.2 After UB-612 Vaccine Booster.

The highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has caused high rates of breakthrough infections in those previously vaccinated with ancestral strain coronavirus disease 2019 (COVID-19) vaccines. Here, we demonstrate that a booster dose of UB-612 vaccine candidate delivered 7-9 months after primary vaccination increased neutralizing antibody levels by 131-, 61-, and 49-fold against ancestral SARS-CoV-2 and the Omicron BA.1 and BA.2 variants, respectively. Based on the receptor-binding domain protein binding antibody responses, the UB-612 third-dose booster may lead to an estimated approximately 95% efficacy against symptomatic COVID-19 caused by the ancestral strain. Our results support UB-612 as a potential potent booster against current and emerging SARS-CoV-2 variants.

Effect of Anti-CD4 Antibody UB-421 on HIV-1 Rebound after Treatment Interruption.

BACKGROUND: Administration of a single broadly neutralizing human immunodeficiency virus (HIV)-specific antibody to HIV-infected persons leads to the development of antibody-resistant virus in the absence of antiretroviral therapy (ART). It is possible that monotherapy with UB-421, an antibody that blocks the virus-binding site on human CD4+ T cells, could induce sustained virologic suppression without induction of resistance in HIV-infected persons after analytic treatment interruption. METHODS: We conducted a nonrandomized, open-label, phase 2 clinical study evaluating the safety, pharmacokinetics, and antiviral activity of UB-421 monotherapy in HIV-infected persons undergoing analytic treatment interruption. All the participants had undetectable plasma viremia (<20 copies of HIV RNA per milliliter) at the screening visit. After discontinuation of ART, participants received eight intravenous infusions of UB-421, at a dose of either 10 mg per kilogram of body weight every week (Cohort 1) or 25 mg per kilogram every 2 weeks (Cohort 2). The primary outcome was the time to viral rebound (≥400 copies per milliliter). RESULTS: A total of 29 participants were enrolled, 14 in Cohort 1 and 15 in Cohort 2. Administration of UB-421 maintained virologic suppression (<20 copies per milliliter) in all the participants (94.5% of measurements at study visits 2 through 9) during analytic treatment interruption, with intermittent viral blips (range, 21 to 142 copies per milliliter) observed in 8 participants (28%). No study participants had plasma viral rebound to more than 400 copies per milliliter. CD4+ T-cell counts remained stable throughout the duration of the study. Rash, mostly of grade 1, was a common and transient adverse event; one participant discontinued the study drug owing to a rash. A decrease in the population of CD4+ regulatory T cells was observed during UB-421 monotherapy. CONCLUSIONS: UB-421 maintained virologic suppression (during the 8 to 16 weeks of study) in participants in the absence of ART. One participant discontinued therapy owing to a rash. (Funded by United Biomedical and others; ClinicalTrials.gov number, NCT02369146.).

Immunisation with UB-312 in the Thy1SNCA mouse prevents motor performance deficits and oligomeric α-synuclein accumulation in the brain and gut.

Alpha synuclein has a key role in the pathogenesis of Parkinson's disease (PD), Dementia with Lewy Bodies (LBD) and Multiple System Atrophy (MSA). Immunotherapies aiming at neutralising toxic αSyn species are being investigated in the clinic as potential disease modifying therapies for PD and other synucleinopathies. In this study, the effects of active immunisation against αSyn with the UB-312 vaccine were investigated in the Thy1SNCA/15 mouse model of PD. Young transgenic and wild-type mice received an immunisation regimen over a period of 6 weeks, then observed for an additional 9 weeks. Behavioural assessment was conducted before immunisation and at 15 weeks after the first dose. UB-312 immunisation prevented the development of motor impairment in the wire test and challenging beam test, which was associated with reduced levels of αSyn oligomers in the cerebral cortex, hippocampus and striatum of Thy1SNCA/15 mice. UB-312 immunotherapy resulted in a significant reduction of theαSyn load in the colon, accompanied by a reduction in enteric glial cell reactivity in the colonic ganglia. Our results demonstrate that immunisation with UB-312 prevents functional deficits and both central and peripheral pathology in Thy1SNCA/15 mice.

Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet is associated with lower presence of non-alcoholic fatty liver disease in middle-aged and elderly adults.

OBJECTIVE: Previous studies have shown that the Dietary Approaches to Stop Hypertension (DASH) diet might contribute to managing risk factors of non-alcoholic fatty liver disease (NAFLD), but evidence is limited. We examined the association of DASH diet score (DASH-DS) with NAFLD, as well as the intermediary effects of serum retinol-binding protein-4 (RBP4), serum high-sensitivity C-reactive protein (hs-CRP), serum TAG, homeostasis model assessment of insulin resistance (HOMA-IR) and BMI. DESIGN: We performed a cross-sectional analysis of a population-based cohort study. Dietary data and lifestyle factors were assessed by face-to-face interviews and the DASH-DS was then calculated. We assessed serum RBP4, hs-CRP and TAG and calculated HOMA-IR. The presence and degree of NAFLD were determined by abdominal sonography. SETTING: Guangzhou, China. PARTICIPANTS: Guangzhou Nutrition and Health Study participants, aged 40-75 years at baseline (n 3051). RESULTS: After adjusting for potential covariates, we found an inverse association between DASH-DS and the presence of NAFLD (Ptrend = 0·009). The OR (95 % CI) of NAFLD for quintiles 2-5 were 0·78 (0·62, 0·98), 0·74 (0·59, 0·94), 0·69 (0·55, 0·86) and 0·77 (0·61, 0·97), respectively. Path analyses indicated that a higher DASH-DS was associated with lower serum RBP4, hs-CRP, TAG, HOMA-IR and BMI, which were positively associated with the degree of NAFLD. CONCLUSIONS: Adherence to the DASH diet was independently associated with a marked lower prevalence of NAFLD in Chinese adults, especially in women and those without abdominal obesity, and might be mediated by reducing RBP4, hs-CRP, TAG, HOMA-IR and BMI.

Proteomic analysis of a high aluminum tolerant yeast Rhodotorula taiwanensis RS1 in response to aluminum stress.

Rhodotorula taiwanensis RS1 is a high-aluminum (Al)-tolerant yeast that can survive in Al concentrations up to 200mM. The mechanisms for the high Al tolerance of R. taiwanensis RS1 are not well understood. To investigate the molecular mechanisms underlying Al tolerance and toxicity in R. taiwanensis RS1, Al toxicity-induced changes in the total soluble protein profile were analyzed using two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry. A total of 33 differentially expressed proteins responding to Al stress were identified from approximately 850 reproducibly detected proteins. Among them, the abundance of 29 proteins decreased and 4 increased. In the presence of 100mM Al, the abundance of proteins involved in DNA transcription, protein translation, DNA defense, Golgi functions and glucose metabolism was decreased. By contrast, Al treatment led to increased abundance of malate dehydrogenase, which correlated with increased malate dehydrogenase activity and the accumulation of intracellular citrate, suggesting that Al-induced intracellular citrate could play an important role in detoxification of Al in R. taiwanensis RS1.

UB-612 pan-SARS-CoV-2 T cell immunity-promoting vaccine protects against COVID-19 moderate-severe disease.

UB-612 pan-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine targets the monomeric Spike S1-receptor binding domain (RBD) subunit protein along with five sequence-conserved T cell epitopes found on Spike S2 and non-Spike M and N proteins. UB-612 vaccination safely induces potent, broad, and long-lasting immunity against SARS-CoV-2. A phase-2 trial-extended observational study during the Omicron BA.2-/BA.5-dominated outbreak was conducted to investigate UB-612's protective effect against COVID-19 hospitalization and intensive care unit (ICU) admission (H-ICU). Additionally, memory viral-neutralizing titer and T cell immunity behind disease protection were explored. No cases of H-ICU were reported beyond 14 months post-second dose or beyond 10 months post-booster (third dose). The positive outcome correlates with strong cytotoxic CD8 T cell immunity, in line with the results of an ongoing phase-3 heterologous booster trial showing that UB-612 can enhance anti-BA.5 seroconversion rate and viral-neutralizing titer for mRNA, adeno-vectored, and virus-inactivated vaccine platforms. The UB-612 multitope vaccine may serve as an effective primer and booster for those at risk of SARS-CoV-2 infection.

A periodic array of nano-scale parallel slats for high-efficiency electroosmotic pumping.

It is known that the eletroosmotic (EO) flow rate through a nano-scale channel is extremely small. A channel made of a periodic array of slats is proposed to effectively promote the EO pumping, and thus greatly improve the EO flow rate. The geometrically simple array is complicated enough that four length scales are involved: the vertical period 2L, lateral period 2aL, width of the slat 2cL as well as the Debye length λD. The EO pumping rate is determined by the normalized lengths: a, c, or the perforation fraction of slats η=1-(c/a) and the dimensionless electrokinetic width K=L/λD. In a nano-scale channel, K is of order unity or less. EO pumping in both longitudinal and transverse directions (denoted as longitudinal EO pumping (LEOP) and transverse EO pumping (TEOP), respectively) is investigated by solving the Debye-Hückel approximation and viscous electro-kinetic equation. The main findings include that (i) the EO pumping rates of LEOP for small K are remarkably improved (by one order of magnitude) when we have longer slats (a≫1) and a large perforation fraction of slats (η > 0.7); (ii) the EO pumping rates of TEOP for small K can also be much improved but less significantly with longer slats and a large perforation fraction of slats. Nevertheless, it must be noted that in practice K cannot be made arbitrarily small as the criterion of φc≈0 for the reference potential at the channel center put lower bounds on K; in other words, there are geometrical limits for the use of the Poisson-Boltzmann equation.

Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 2a study.

BACKGROUND: Anti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating Alzheimer's disease. UB-311 is an anti-amyloid-ß active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase 1 trial. This phase 2a study assessed the safety, immunogenicity, and preliminary efficacy of UB-311 in participants with mild Alzheimer's disease. METHODS: A 78-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2a study was conducted in Taiwan. Participants were randomised in a 1:1:1 ratio to receive seven intramuscular injections of UB-311 (Q3M arm), or five doses of U311 with two doses of placebo (Q6M arm), or seven doses of placebo (placebo arm). The primary endpoints were safety, tolerability, and immunogenicity of UB-311. Safety was assessed in all participants who received at least one dose of investigational product. This study was registered at ClinicalTrials.gov (NCT02551809). FINDINGS: Between 7 December 2015 and 28 August 2018, 43 participants were randomised. UB-311 was safe, well-tolerated, and generated a robust immune response. The three treatment-emergent adverse events (TEAEs) with the highest incidence were injection-site pain (14 TEAEs in seven [16%] participants), amyloid-related imaging abnormality with microhaemorrhages and haemosiderin deposits (12 TEAEs in six [14%] participants), and diarrhoea (five TEAEs in five [12%] participants). A 97% antibody response rate was observed and maintained at 93% by the end of the study across both UB-311 arms. INTERPRETATION: These results support the continued development of UB-311. FUNDING: Vaxxinity, Inc. (Formerly United Neuroscience Ltd.).

Corrigendum: Non-alcoholic fatty liver disease is associated with aortic calcification: a cohort study with propensity score matching.

[This corrects the article DOI: 10.3389/fendo.2022.880683.].

Association between Periodontitis and Aortic Calcification: A Cohort Study.

The present study investigated the association between the presence of periodontitis and aortic calcification (AC) risk among Chinese adults. A total of 6059 individuals who underwent regular health check-ups and received a diagnosis of periodontitis between 2009 and 2016 were included. The outcome was AC, assessed by a chest low-dose spiral CT scan. Cox proportional hazards regression analysis was used to assess the association between periodontitis and AC risk after adjusting for several confounders. After a median follow-up period of 2.3 years (interquartile range: 1.03-4.97 years), 843 cases of AC were identified, with 532 (12.13%) and 311 (18.59%) patients in the non-periodontitis group and periodontitis group, respectively. Multivariate analyses demonstrated that, compared with those without periodontitis, the hazard ratio and 95% confidence interval for AC risk in participants with periodontitis was 1.18 (1.02-1.36) (P = .025) in the fully adjusted model. Stratified analyses showed that the positive relationship between periodontitis and AC was more evident in males and participants <65 years of age (pinteraction = .005 and .004, respectively). Our results show that the presence of periodontitis was positively associated with AC among Chinese adults, especially among males and younger participants.

Non-alcoholic Fatty Liver Disease Is Associated With Aortic Calcification: A Cohort Study With Propensity Score Matching.

Objectives: Non-alcoholic fatty liver disease (NAFLD) greatly affects cardiovascular disease, but evidence on the associations between NAFLD and markers of aortic calcification is limited. We aim to evaluate the association between NAFLD and aortic calcification in a cohort of Chinese adults using propensity score-matching (PSM) analysis. Methods: This prospective cohort study involved adults who underwent health-screening examinations from 2009 to 2016. NAFLD was diagnosed by abdominal ultrasonography at baseline, and aortic calcification was identified using a VCT LightSpeed 64 scanner. Analyses included Cox proportional-hazards regression analysis and PSM with predefined covariates (age, gender, marital and smoking status, and use of lipid-lowering drugs) to achieve a 1:1 balanced cohort. Results: Of the 6,047 eligible participants, 2,729 (45.13%) were diagnosed with NAFLD at baseline, with a median age of 49.0 years [interquartile range, 44.0-55.0]. We selected 2,339 pairs of participants with and without NAFLD at baseline for the PSM subpopulation. Compared with those without NAFLD, patients with NAFLD were at a higher risk of developing aortic calcification during follow-up; significant results were observed before and after matching, with the full-adjusted hazard ratios and corresponding 95% confidence intervals being 1.19 (1.02-1.38) and 1.18 (1.01-1.38), respectively (both p < 0.05). In subgroup analyses, no interaction was detected according to age, gender, smoking status, body mass index, total cholesterol, low-density lipoprotein cholesterol, use of lipid-lowering drugs, hypertension, or type 2 diabetes. Conclusions: NAFLD may be independently associated with aortic calcification. Further studies are warranted to elucidate the possible underlying mechanisms.

IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms.

Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

A novel RBD-protein/peptide vaccine elicits broadly neutralizing antibodies and protects mice and macaques against SARS-CoV-2.

The development of safe and effective vaccines to respond to COVID-19 pandemic/endemic remains a priority. We developed a novel subunit protein-peptide COVID-19 vaccine candidate (UB-612) composed of: (i) receptor binding domain of SARS-CoV-2 spike protein fused to a modified single-chain human IgG1 Fc; (ii) five synthetic peptides incorporating conserved helper and cytotoxic T lymphocyte (Th/CTL) epitopes derived from SARS-CoV-2 structural proteins (three from S2 subunit, one from membrane and one from nucleocapsid), and one universal Th peptide; (iii) aluminum phosphate as adjuvant. The immunogenicity and protective immunity induced by UB-612 vaccine were evaluated in four animal models: Sprague-Dawley rats, AAV-hACE2 transduced BALB/c mice, rhesus and cynomolgus macaques. UB-612 vaccine induced high levels of neutralizing antibody and T-cell responses, in all animals. The immune sera from vaccinated animals neutralized the SARS-CoV-2 original wild-type strains and multiple variants of concern, including Delta and Omicron. The vaccination significantly reduced viral loads, lung pathology scores, and disease progression after intranasal and intratracheal challenge with SARS-CoV-2 in mice, rhesus and cynomolgus macaques. UB-612 has been tested in primary regimens in Phase 1 and Phase 2 clinical studies and is currently being evaluated in a global pivotal Phase 3 clinical study as a single dose heterologous booster.

A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants.

BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 µg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 µg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 µg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

Electro-osmotic flow in polygonal ducts.

The paper presents semi-analytical solutions to electro-osmotic (EO) flow through polygonal ducts under the Debye-Hückel approximation. Analytical series solutions assisted with numerical collocations are found to yield very fast convergence. The solutions have practical applications as the pores of EO membranes are mostly hexagonal, stacked densely in a beehive-like matrix. In addition, we develop simple asymptotic approximations that would be applicable to all EO tube flows of small as well as large dimensionless electrokinetic width. This facilitates investigation of analytical structures of general EO flows in all shapes of tubes, including the present geometries. In particular, for thick electrical double layers, the flow rate of EO is related to the corresponding viscous Poiseuille flow rate, while for thin electrical double layers, the flow rate is shown to be characterized by the cross-sectional area and the perimeter length of the tubes.

Unsteady electroosmosis in a microchannel with Poisson-Boltzmann charge distribution.

The present study is concerned with unsteady electroosmotic flow (EOF) in a microchannel with the electric charge distribution described by the Poisson-Boltzmann (PB) equation. The nonlinear PB equation is solved by a systematic perturbation with respect to the parameter λ which measures the strength of the wall zeta potential relative to the thermal potential. In the small λ limits (λ<<1), we recover the linearized PB equation - the Debye-Hückel approximation. The solutions obtained by using only three terms in the perturbation series are shown to be accurate with errors <1% for λ up to 2. The accurate solution to the PB equation is then used to solve the electrokinetic fluid transport equation for two types of unsteady flow: transient flow driven by a suddenly applied voltage and oscillatory flow driven by a time-harmonic voltage. The solution for the transient flow has important implications on EOF as an effective means for transporting electrolytes in microchannels with various electrokinetic widths. On the other hand, the solution for the oscillatory flow is shown to have important physical implications on EOF in mixing electrolytes in terms of the amplitude and phase of the resulting time-harmonic EOF rate, which depends on the applied frequency and the electrokinetic width of the microchannel as well as on the parameter λ.

Association between serum prostate-specific antigen concentrations and the risk of developing type 2 diabetes mellitus in Chinese men: A cohort study.

AIMS/INTRODUCTION: The current literature suggests that men with diabetes have a lower prostate-specific antigen concentration than men without diabetes, but the causal association remains unclear. We aimed to investigate the association between serum prostate-specific antigen concentrations and the risk of type 2 diabetes mellitus in a cohort study of a Chinese population. MATERIALS AND METHODS: We designed a cohort study that comprised 16,811 initially non-diabetic Chinese men who received annual health checkups between 2009 and 2016. The outcome of this study was type 2 diabetes mellitus, identified by medical diagnosis, self-reportage, medication use, fasting glucose, 2-h post oral glucose or glycated hemoglobin measurements. Cox proportional hazards models were carried out to evaluate the association. RESULTS: During a median follow-up period of 3.8 years (interquartile range 1.91-5.73 years), 1,260 participants developed incident type 2 diabetes mellitus. The multivariable model, adjusted for various potential confounders, showed that serum prostate-specific antigen concentrations were inversely related to type 2 diabetes mellitus risk (P for trend = 0.014). Compared with the lowest quartile of serum prostate-specific antigen, the hazard ratio and 95% confidence intervals of type 2 diabetes mellitus risk for quartile 2-4 were 0.84 (0.66-1.07), 0.75 (0.59-0.94) and 0.77 (0.62-0.96), respectively. Subgroup analyses suggested the inverse relationship was more prominent in overweight or obese participants (P for interaction = 0.013). CONCLUSIONS: High serum prostate-specific antigen concentration was associated with a low risk of type 2 diabetes mellitus in Chinese men. Future studies are required to confirm these findings and investigate underlying mechanisms.

Association between brachial-ankle pulse wave velocity and risk of type 2 diabetes mellitus: results from a cohort study.

INTRODUCTION: Brachial-ankle pulse wave velocity (ba-PWV), as a simple and easily measured marker of arterial stiffness, has not been prospectively explored for its role in type 2 diabetes mellitus (T2DM) risk among the general population. This study aimed to explore the association between baseline ba-PWV value and new-onset T2DM among Chinese adults. RESEARCH DESIGN AND METHODS: Using data from Xiaotangshan Hospital, we conducted a prospective cohort study among those who underwent annual or biennial health check-up examinations and who had their ba-PWV measured from 2009 to 2016. We explored the risk of new-onset T2DM across ba-PWV tertiles using Cox proportional-hazards regression analysis. RESULTS: Of 6122 adults (68.9% male; mean age: 51.0 (SD 13.0) years) without T2DM and with ba-PWV measured at baseline, 599 participants developed T2DM during an average of 3.8 (SD 2.3) years of follow-up. After multivariable adjustment, ba-PWV was positively related to T2DM risk (p for trend=0.008). Compared with the lowest ba-PWV tertile, the HRs and their 95% CIs were 1.57 (1.18 to 2.10) for the second and 1.66 (1.24 to 2.22) for the third tertile. The risk across ba-PWV tertiles increased steadily from 1000 cm/s to 1400 cm/s and then reached a plateau. Subgroup analyses indicated a significantly higher risk among those aged <65 years and current smokers (p for interactions: <0.001 and 0.006). CONCLUSIONS: Our findings suggest that ba-PWV might be a useful and independent predictor of new-onset T2DM with ba-PWV ranging between 1000 cm/s and 1400 cm/s, especially among younger individuals and current smokers.

Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy.

BACKGROUND: Alpha-synuclein (α-Syn) aggregation is the primary characteristic of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Immunotherapy targeting α-Syn has shown promising results in animal models of the disease. This study investigates the target specificity of three different active vaccines for pathological α-Syn aggregates found in human brain tissue from synucleinopathies. METHODS: Guinea pigs were immunised with 3 vaccines developed by United Neuroscience, and IgG fractions purified from the resulting immune sera (IGG-1, IGG-2 or IGG-3) were used to perform immunohistochemical staining of human cases of PD, DLB and MSA. The resulting immunoreactivity was compared to a commercially available α-Syn antibody from Novacastra (NOV) commonly used for diagnostic purposes. Images were captured from the substantia nigra (SN), temporal lobe, internal capsule, insular cortex and putamen and quantified for the percentage area with α-Syn immunoreactivity. Lewy bodies (LB) and Lewy neurites (LN) were further analysed in PD and DLB cases. RESULTS: Vaccine-generated antibodies detected more α-Syn pathology compared to NOV. The levels of α-Syn immunoreactivity varied between brain region and disease type with IGG-3 recognising the highest levels of α-Syn in most cases and in all brain regions that are affected early in disease progression. IGG-3 had a high recognition for glial inclusions found in MSA which are known to have a more compact conformation. Slot blot analysis confirmed the specificity of IGG-3 for native oligomers and fibrillar α-Syn. Higher levels of α-Syn were recognised by IGG-2 in cortical regions, and by IGG-3 in SN of PD and DLB cases. This was due to increased immunolabelling of LNs in these brain regions suggesting that IGG-2 and IGG-3 recognised additional α-Syn pathology compared to IGG-1 and NOV. Whether the unique binding properties of the antibodies produced in guinea pigs will translate in the clinic remains to be addressed, which is the main limitation of this study. CONCLUSIONS: These vaccines induce antibodies that bind α-Syn oligomers and aggregates in the human brain and specifically support the choice of the vaccine generating IGG-3 (i.e. UB-312) as a candidate for clinical trials for synucleinopathies.