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Abstract Background Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein. Methods Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry. Results Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls. Conclusion Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.

Summary: Background: Despite successful antiretroviral therapy (ART), frequencies and immunological functions of memory CCR6+ Th17-polarised CD4+ T-cells are not fully restored in people with HIV (PWH). Moreover, long-lived Th17 cells contribute to HIV persistence under ART. However, the molecular mechanisms underlying these observations remain understudied. Methods: mRNA-sequencing was performed using Illumina technology on freshly FACS-sorted memory CCR6+CD4+ T-cells from successfully ART-treated (ST), elite controllers (EC), and uninfected donors (HD). Gene expression validation was performed by RT-PCR, flow cytometry, and in vitro functional assays. Findings: Decreased Th17 cell frequencies in STs and ECs versus HDs coincided with reduced Th17-lineage cytokine production in vitro. Accordingly, the RORγt/RORC2 repressor NR1D1 was upregulated, while the RORγt/RORC2 inducer Semaphorin 4D was decreased in memory CCR6+ T-cells of STs and ECs versus HDs. The presence of HIV-DNA in memory CCR6+ T-cells of ST and EC corresponded with the downregulation of HIV restriction factors (SERINC3, KLF3, and RNF125) and HIV inhibitors (tetraspanins), along with increased expression of the HIV-dependency factor MRE11, indicative of higher susceptibility/permissiveness to HIV-1 infection. Furthermore, markers of DNA damage/modification were elevated in memory CCR6+ T-cells of STs and ECs versus HDs, in line with their increased activation (CD38/HLA-DR), senescence/exhaustion phenotype (CTLA-4/PD-1/CD57) and their decreased expression of proliferation marker Ki-67. Interpretation: These results reveal new molecular mechanisms of Th17 cell deficit in ST and EC PWH despite a successful control of HIV-1 replication. This knowledge points to potential therapeutic interventions to limit HIV-1 infection and restore frequencies, effector functions, and senescence/exhaustion in Th17 cells. Funding: This study was funded by the Canadian Institutes of Health Research (CIHR, operating grant MOP 142294, and the Canadian HIV Cure Enterprise [CanCURE 2.0] Team Grant HB2 164064), and in part, by the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).

Abstract Researchers who aim to globally analyze the gastrointestinal immune system via flow cytometry have many protocol options to choose from, with specifics generally tied to gut wall layers of interest. To get a clearer idea of the approach we should use on full-thickness colon samples from mice, we first undertook a systematic comparison of three tissue dissociation techniques: two based on enzymatic cocktails and the other one based on manual crushing. Using flow cytometry panels of general markers of lymphoid and myeloid cells, we found that the presence of cell-surface markers and relative cell population frequencies were more stable with the mechanical method. Both enzymatic approaches were associated with a marked decrease of several cell-surface markers. Using mechanical dissociation, we then developed two minimally overlapping panels, consisting of a total of 26 antibodies, for serial profiling of lymphoid and myeloid lineages from the mouse colon in greater detail. Here, we highlight how we accurately delineate these populations by manual gating, as well as the reproducibility of our panels on mouse spleen and whole blood. As a proof-of-principle of the usefulness of our general approach, we also report segment- and life stage-specific patterns of immune cell profiles in the colon. Overall, our data indicate that mechanical dissociation is more suitable and efficient than enzymatic methods for recovering immune cells from all colon layers at once. Additionally, our panels will provide researchers with a relatively simple tool for detailed immune cell profiling in the murine gastrointestinal tract, regardless of life stage or experimental conditions.

HIV infection significantly affects the frequencies and functions of immunoregulatory CD3+CD4−CD8− double-negative (DN) T-cells, while the effect of early antiretroviral therapy (ART) initiation on these cells remains understudied. DN T-cell subsets were analyzed prospectively in 10 HIV+ individuals during acute infection and following early ART initiation compared to 20 HIV-uninfected controls. In this study, 21 Rhesus macaques (RMs) were SIV-infected, of which 13 were assessed during acute infection and 8 following ART initiation four days post-infection. DN T-cells and FoxP3+ DN Treg frequencies increased during acute HIV infection, which was not restored by ART. The expression of activation (HLA-DR/CD38), immune checkpoints (PD-1/CTLA-4), and senescence (CD28−CD57+) markers by DN T-cells and DN Tregs increased during acute infection and was not normalized by ART. In SIV-infected RMs, DN T-cells remained unchanged despite infection or ART, whereas DN Treg frequencies increased during acute SIV infection and were not restored by ART. Finally, frequencies of CD39+ DN Tregs increased during acute HIV and SIV infections and remained elevated despite ART. Altogether, acute HIV/SIV infections significantly changed DN T-cell and DN Treg frequencies and altered their immune phenotype, while these changes were not fully normalized by early ART, suggesting persistent HIV/SIV-induced immune dysregulation despite early ART initiation.

Abstract Few studies have examined preventative behaviour practices with respect to COVID-19 among people living with HIV (human immunodeficiency virus). Using a cross-sectional survey from a Canadian Institutes of Health Research Canadian HIV Trials Network study (CTN 328) of people living with HIV on vaccine immunogenicity, we examined the relationships between participant characteristics and behavioural practices intended to prevent COVID-19 infection. Participants living in four Canadian urban centers were enrolled between April 2021–January 2022, at which time they responded to a questionnaire on preventative behaviour practices. Questionnaire and clinical data were combined to explore relationships between preventive behaviours and (1) known COVID-19 infection pre-enrolment, (2) multimorbidity, (3) developing symptomatic COVID-19 infection, and (4) developing symptomatic COVID-19 infection during the Omicron wave. Among 375 participants, 49 had COVID-19 infection pre-enrolment and 88 post-enrolment. The proportion of participants reporting always engaging in preventative behaviours included 87% masking, 79% physical distancing, 70% limiting social gatherings, 65% limiting contact with at-risk individuals, 33% self-isolating due to symptoms, and 26% self-quarantining after possible exposure. Participants with known COVID-19 infection pre-enrolment were more likely to self-quarantine after possible exposure although asymptomatic (65.0% vs 23.4%, p

Background and purpose: Osteoporosis and periodontitis are two diseases associated with bone loss and are common among postmenopausal women. There are many contradictory results on the effect of osteoporosis on periodontal tissue. This study aimed to determine the association between osteoporosis and periodontal status in postmenopausal women. Materials and methods: This cross-sectional study was part of the second phase of the Amir kola Health and Aging Project (AHAP), in which 210 postmenopausal women were randomly divided into three groups (n=70 per group); normal bone density group, osteopenic group, and osteoporotic group. Periodontal status was measured using Periodontal Disease Index (PDI), Plaque Index (PI), and Simplified Oral Hygiene Index (OHI-S). Bone mineral density (BMD) was measured by Dual-energy X-ray absorptiometry (DEXA). Data were analyzed in SPSS V17 applying ANOVA, Kruskal-Wallis, and Pearson correlation coefficient. Results: The average age of the participants was 65.24±4.36 years. There were no statistically significant differences between the mean OHI (2.26±1.40), PDI (2.76±1.42), and PI (1.23±0.87) in the osteoporotic group, and the mean OHI (2.01±1.62), PDI (2.56±1.61), and PI (1.35±0.91) in the osteopenia group, and mean OHI (1.73±1.37), PDI (2.47±1.43), and PI (1.23±0.87) in the normal group (P>0.05). The OHI, PDI, and PI had a slight but insignificant negative correlation with BMD. Conclusion: According to this study, there is no link between osteoporosis and periodontal status in postmenopausal women.

Introduction: Nifedipine (NF) is a calcium channel blocker that accelerates wound healing and subsequently relieves pain and discomfort. The aim of the present study was to investigate the local effect of this drug on the wound-healing process of the palate. Materials & Methods: In this triple-blind clinical trial study, 31 patients who were referred to the Periodontology Department of Babol Dental School (14 in the experimental group and 17 in the control group) were examined. They were candidates for gingival surgery and needed a palate transplant. Mucotom was used to create identical wounds in the palate (transplant donor). After a free gingival grafting, the active ingredient of 0.3% NF was applied as a mucosal adhesive (made of chitosan) in the area of the graft (palate). Patients were examined and recorded on days 2, 4, 7, 14, and 30 after surgery for wound closure and healing criteria (Landry & Manchester scar scale) and pain (VAS). Sutures were removed on day 7 of the study. Data were analyzed with SPSS 20 and chi-square, Kruskal-Wallis and Mann-Whitney tests. The significance level was set at 0.05. Results: Based on Landry and Manchester criteria, the wound healing process in the two groups was not significant (p=0.125). There was no significant difference between mean wound size reduction and VAS in both treatment and control groups (p=0.253). Conclusion: Topical NF has no effect on the natural process of healing oral mucosal ulcers and reducing pain.

Introduction: Considering that nutrition plays a prominent role in the health of the elderly, oral health and the associated quality of life are very important for a healthy diet. The aim of this study was to investigate the association between the frequency of fruit and vegetable consumption and oral health-related quality of life (OHRQoL) among the elderly in Amirkola. Materials & Methods: This study was part of the second phase of the Amirkola elderly cohort study conducted on 750 older people who underwent a special oral and dental examination in 2016-2020 using the Oral Health Questionnaire. The frequency of fruit and vegetable consumption was assessed with the Semi-Quantitative Food Frequency Questionnaire (SQFFQ), OHRQoL was assessed with the General Oral Health Assessment Index (GOHAI), and information on age, sex, history of systemic diseases, and the number of teeth was extracted from the full data set completed by specialists for each patient. Data were analyzed with SPSS 20 using the chi-square statistical test, ANOVA, and Pearson correlation coefficient. A value of p

COVID-19 breakthrough infection (BTI) can occur despite vaccination. Using a multi-centre, prospective, observational Canadian cohort of people with HIV (PWH) receiving ≥2 COVID-19 vaccines, we compared the SARS-CoV-2 spike (S) and receptor-binding domain (RBD)-specific IgG levels 3 and 6 months post second dose, as well as 1 month post third dose, in PWH with and without BTI. BTI was defined as positivity based on self-report measures (data up to last study visit) or IgG data (up to 1 month post dose 3). The self-report measures were based on their symptoms and either a positive PCR or rapid antigen test. The analysis was restricted to persons without previous COVID-19 infection. Persons without BTI remained COVID-19-naïve until ≥3 months following the third dose. Of 289 participants, 92 developed BTI (31.5 infections per 100 person-years). The median days between last vaccination and BTI was 128 (IQR 67, 176), with the most cases occurring between the third and fourth dose (n = 59), corresponding to the Omicron wave. In analyses adjusted for age, sex, race, multimorbidity, hypertension, chronic kidney disease, diabetes and obesity, a lower IgG S/RBD (log10 BAU/mL) at 1 month post dose 3 was significantly associated with BTI, suggesting that a lower IgG level at this time point may predict BTI in this cohort of PWH.

Summary: HIV persists in tissues during antiretroviral therapy (ART), but the relative contribution of different anatomical compartments to the viral reservoir in humans remains unknown. We performed an extensive characterization of HIV reservoirs in two men who donated their bodies to HIV cure research and who had been on suppressive ART for years. HIV DNA is detected in all tissues, with large variations across anatomical compartments and between participants. Intact HIV genomes represent 2% and 25% of all proviruses in the two participants and are mainly detected in secondary lymphoid organs, with the spleen and mediastinal lymph nodes harboring intact viral genomes in both individuals. Multiple copies of identical HIV genomes are found in all tissues, indicating that clonal expansions are common in anatomical sites. The majority (>85%) of these expanded clones are shared across multiple tissues. These findings suggest that infected cells expand, migrate, and possibly circulate between anatomical sites.

Background: Chemotherapy-related diarrhea reduces patients' quality of life and sometimes changes or interrupts their treatment regimen. This study aimed to evaluate the effect of yogurt with probiotics on diarrhea caused by chemotherapy.Method: The present study was a randomized controlled clinical trial. The sample consisted of 66 patients with colorectal cancer, recruited with convenience sampling method from patients who were referred to Buali Hospital of Tehran. The samples were randomly divided into three groups. The first group received yogurt with probiotics, the second group received yogurt alone, and the third group of control did not use yogurt during treatment. Data were gathered using the diarrhea section of adverse events. The number of defecations, the severity of diarrhea, and the consistency of stool in the seven days of the intervention were compared among the three groups. Analysis of variance and Tukey's post hoc test were performed through SPSS software.Results: The number of defecations in the yogurt group with probiotics and yogurt was significantly lower than the control group (P < 0.05). The severity of diarrhea in the yogurt group with probiotics decreased more rapidly (P < 0.05). Stool consistency in the yogurt group with probiotics was significantly better than the control group (P < 0.05).Conclusion: Based on the results of the present study, yogurt with probiotics can reduce and improve diarrhea caused by chemotherapy. The results also showed that yogurt alone can reduce diarrhea and improve its symptoms.

Identifying immune cells and anatomical tissues that contribute to the establishment of viral reservoirs is of central importance in HIV-1 cure research. Herein, we used rhesus macaques (RMs) infected with SIVmac251 to analyze viral seeding in the liver and lungs of either untreated or early antiretroviral therapy–treated (ART-treated) RMs. Consistent with viral replication and sensing, transcriptomic analyses showed higher levels of inflammation, pyroptosis, and chemokine genes as well as of interferon-stimulating gene (ISG) transcripts, in the absence of ART. Our results highlighted the infiltration of monocyte-derived macrophages (HLA-DR+CD11b+CD14+CD16+) in inflamed liver and lung tissues associated with the expression of CD183 and CX3CR1 but also with markers of tissue-resident macrophages (CD206+ and LYVE+). Sorting of myeloid cell subsets demonstrated that CD14+CD206–, CD14+CD206+, and CD14–CD206+ cell populations were infected, in the liver and lungs, in SIVmac251-infected RMs. Of importance, early ART drastically reduced viral seeding consistent with the absence of ISG detection but also of genes related to inflammation and tissue damage. Viral DNA was only detected in CD206+HLA-DR+CD11b+ cells in ART-treated RMs. The observation of pulmonary and hepatic viral rebound after ART interruption reinforces the importance of early ART implementation to limit viral seeding and inflammatory reactions.

BackgroundThe differentiation and function of immunosuppressive regulatory T cells (Tregs) is dictated by the master transcription factor FoxP3. During HIV infection, there is an increase in Treg frequencies in the peripheral blood and lymphoid tissues. This accentuates immune dysfunction and disease progression. Expression of FoxP3 by thymic Tregs (tTregs) is partially controlled by TGF-β. This cytokine also contributes to Treg development in the peripheral blood and lymphoid tissues. Although TGF-β mediates lymphoid tissue fibrosis and peripheral Treg differentiation in HIV-infected individuals, its role in the induction and maintenance of Tregs within the thymus during HIV infection remains unclear.MethodsThymocytes were isolated from fresh human thymic tissues obtained from pediatric patients undergoing cardiac surgery. Infection by both R5- and X4-tropic HIV-1 strains and TGF-β treatment of human thymocytes was performed in an in vitro co-culture model with OP9-DL1 cells expressing Notch ligand delta-like 1 without T cell receptor (TCR) activation.ResultsDespite high expression of CCR5 and CXCR4 by tTregs, FoxP3 + CD3highCD8- thymocytes were much less prone to in vitro infection with R5- and X4-tropic HIV strains compared to FoxP3-CD3highCD8- thymocytes. As expected, CD3highCD4+ thymocytes, when treated with TGF-β1, upregulated CD127 and this treatment resulted in increased FoxP3 expression and Treg differentiation, but did not affect the rate of HIV infection. FoxP3 expression and Treg frequencies remained unchanged following in vitro HIV infection alone or in combination with TGF-β1.ConclusionFoxP3 expression and tTreg differentiation is not affected by in vitro HIV infection alone or the combination of in vitro HIV infection and TGF-β treatment.

Abstract Background This study compared efficacy and safety of TA4415V, a trastuzumab biosimilar, with reference trastuzumab in patients with human epidermal growth factor receptor 2–positive (HER2-positive) early-stage breast cancer treated in the neoadjuvant setting in Iran. Methods Patients were randomly assigned to receive neoadjuvant TA4415V or reference trastuzumab concurrently with docetaxel (TH phase) for 4 cycles after treatment with 4 cycles of doxorubicin and cyclophosphamide (AC phase). Chemotherapy was followed by surgery. The primary endpoint was the comparison of pathologic complete response (pCR) rate in the per-protocol population. Secondary endpoints included comparisons of overall response rate (ORR), breast-conserving surgery (BCS), safety, and immunogenicity. Results Ninety-two participants were analyzed in the per-protocol population (TA4415V, n = 48; reference trastuzumab, n = 44). The pCR rates were 37.50% and 34.09% with TA4415V and reference drug, respectively. The 95% CI of the estimated treatment outcome difference (− 0·03 [95% CI − 0.23 to 0.16]) was within the non-inferiority margin. No statistically significant difference was observed between the groups for other efficacy variables in the ITT population: ORR (89.13% vs. 83.33%; p = 0.72) and BCS (20.37% vs. 12.96%; p = 0.42) in the TA4415V and reference drug group, respectively. At least one grade 3 or 4 adverse events occurred in 27 (50%) patients in the TA4415V group versus 29 (53.70%) in the reference trastuzumab group (p = 0.70). The decrease in left ventricular ejection fraction (LVEF), as an adverse event of special interest (AESI) for trastuzumab, was compared between treatment groups in TH phase. Results demonstrated an LVEF decrease in 7 (12.96%) and 9 (16.67%) patients in TA4415V and reference trastuzumab groups, respectively (p = 0.59). Anti-drug antibodies (ADA) were not detected in any samples of groups. Conclusions Non-inferiority for efficacy was demonstrated between TA4415V and Herceptin based on the ratio of pCR rates in HER2-positive early breast cancer patients. In addition, ORR and BCS, as secondary endpoints, were not significantly different. Safety profile and immunogenicity were also comparable between the two groups.

Statement of the Problem: Molar teeth with furcation involvement are one of the most common problems in patients with periodontal disease. Regeneration methods are of the most controversial treatment strategies for these lesions. Purpose: The purpose of this study was to determine the effect of plasma rich in growth factors (PRGF) with 1.2% Atorvastatin (ATV) in the treatment of furcation involvement of mandibular molars. Materials and Method: The present randomized clinical trial was conducted on 15 patients with moderate periodontitis and class II furcation involvements; 24 defects were located in four groups of six, including debridement, ATV1.2%, PRGF, PRGF with ATV1.2%. The parameters of vertical probing depth (VPD), vertical clinical attachment level (VCAL), gingival index (GI), horizontal probing depth (HPD) and gingival recession (GR) were measured at baseline (T0), immediately before surgery (T1), 3 (T2), and 6 (T3) months after surgery. Moreover, the bone conditions were evaluated by digital subtraction radiography before and six months after surgery. Data were analyzed using SPSS23 software. Results: No significant difference in radiographic parameters was observed among the groups (p= 0.08). There was no significant difference in the mean levels of VPD, VCAL and HPD among the groups at different times (p

Background: Hypertension is one of the most common chronic diseases in the world. The prevalence of hypertension in the elderly is increasing. Patients with high blood pressure have to take medication throughout their lives. In this study, the relationship between antihypertensive drugs and oral health-related quality of life in the elderly was evaluated. Methods: This modified cross-sectional study, which is the part of the second phase of the Amirkola Health and Ageing Project (AHAP), was performed on 900 elderly people. Participants included 300 people with hypertension under medical treatment, 300 people with hypertension without medication and 300 people with normal blood pressure. All patients’ blood pressure was recorded, and the standard xerostomia questionnaire and GOHAI questionnaire (Geriatric Oral Health Assessment Index) was completed for all participants. Then, the obtained data were analyzed by SPSS 17, whereby student’s t-test, ANOVA and chi square, Pearson correlation coefficient and logistic regression model were used. A p

Background and Objective: Periodontal disease is one of the most common chronic oral diseases worldwide. A variety of foods may affect periodontal health. Due to the importance of periodontal health in the old age, this study was designed to investigate the association between carbohydrate intake and periodontal health in the elderly in Amirkola, northern Iran. Methods: This cross-sectional study is part of the second phase of the Amirkola Health and Ageing Project (AHAP). The evaluated participants included 400 elderly people (200 men and 200 women). Socio-demographic data of all subjects were recorded in the information form. Periodontal status, including plaque index (PI), periodontal disease index (PDI) and Oral Hygiene Index (OHI) were evaluated. Then, the Semi-Quantitative Food Frequency Questionnaire (SQFFQ) was completed in order to receive daily carbohydrates in grams per day for all Participants. Then, the relationship between carbohydrate intake and periodontal health was evaluated. Findings: The participants consumed an average of 316±102.4 gr/day carbohydrates. The mean range of PI, OHI, PDI and in the high carbohydrate intake (>300 gr) group were 2.18±1.39, 2.84±1.51 and 1.51±0.86, respectively, and this rate was lower than the group with low carbohydrate intake (

HIV infection significantly affects the frequencies and functions of immunoregulatory CD3+CD4−CD8− double-negative (DN) T-cells, while the effect of early antiretroviral therapy (ART) initiation on these cells remains understudied. DN T-cell subsets were analyzed prospectively in 10 HIV+ individuals during acute infection and following early ART initiation compared to 20 HIV-uninfected controls. In this study, 21 Rhesus macaques (RMs) were SIV-infected, of which 13 were assessed during acute infection and 8 following ART initiation four days post-infection. DN T-cells and FoxP3+ DN Treg frequencies increased during acute HIV infection, which was not restored by ART. The expression of activation (HLA-DR/CD38), immune checkpoints (PD-1/CTLA-4), and senescence (CD28−CD57+) markers by DN T-cells and DN Tregs increased during acute infection and was not normalized by ART. In SIV-infected RMs, DN T-cells remained unchanged despite infection or ART, whereas DN Treg frequencies increased during acute SIV infection and were not restored by ART. Finally, frequencies of CD39+ DN Tregs increased during acute HIV and SIV infections and remained elevated despite ART. Altogether, acute HIV/SIV infections significantly changed DN T-cell and DN Treg frequencies and altered their immune phenotype, while these changes were not fully normalized by early ART, suggesting persistent HIV/SIV-induced immune dysregulation despite early ART initiation. [ABSTRACT FROM AUTHOR]

Currently, there is no cure for human immunodeficiency virus type 1 (HIV-1) infection. However, combined antiretroviral therapy (cART) aids in viral latency and prevents the progression of HIV-1 infection into acquired immunodeficiency syndrome (AIDS). cART has extended many lives, but people living with HIV-1 (PLWH) face lifelong ailments such as HIV-associated neurocognitive disorders (HAND) that range from asymptomatic HAND to HIV-1-associated dementia. HAND has been attributed to chronic inflammation and low-level infection within the central nervous system (CNS) caused by proinflammatory cytokines and viral products. These molecules are shuttled into the CNS within extracellular vesicles (EVs), lipid bound nanoparticles, and are released from cells as a form of intercellular communication. This study investigates the impact of cannabidiol (CBD), as a promising and potential therapeutic for HAND patients, and a similar synthetic molecule, HU308, on the EVs released from HIV-1-infected myeloid cells as well as HIV-1-infected 3D neurospheres. The data shows that both CBD and HU308 decrease non-coding and coding viral RNA (TAR and env) as well as proinflammatory cytokines as IL-1β and TNF-α mRNA. This decrease in viral RNA occurs in in vitro differentiated primary macrophages, in EVs released from HIV-1-infected cells monocytes, and infected neurospheres. Furthermore, a 3D neurosphere model shows an overall decrease in proinflammatory mRNA with HU308. Finally, using a humanized mouse model of HIV-1 infection, plasma viral RNA was shown to significantly decrease with HU308 alone and was most effective in combination with cART, even when compared to the typical cART treatment. Overall, CBD or HU308 may be a viable option to decrease EV release and associated cytokines which would dampen the virus spread and may be used in effective treatment of HAND in combination with cART.

Chronic HIV infection is characterized by persistent inflammation despite antiretroviral therapy (ART). Cannabinoids may help reduce systemic inflammation in people with HIV (PWH). To assess the effects of oral cannabinoids during HIV, ten PWH on ART were randomized (n = 5/group) to increasing doses of oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (2.5:2.5–15:15 mg/day) capsules or CBD-only (200–800 mg/day) capsules for 12 weeks. Blood specimens were collected prospectively 7–21 days prior to treatment initiation and at weeks 0 to 14. Plasma cytokine levels were determined via Luminex and ELISA. Immune cell subsets were characterized by flow cytometry. HIV DNA/RNA were measured in circulating CD4 T-cells and sperm by ultra-sensitive qPCR. Results from both arms were combined for statistical analysis. Plasma levels of IFN-γ, IL-1β, sTNFRII, and REG-3α were significantly reduced at the end of treatment (p ˂ 0.05). A significant decrease in frequencies of PD1+ memory CD4 T-cells, CD73+ regulatory CD4 T-cells, and M-DC8+ intermediate monocytes was also observed (p ˂ 0.05), along with a transient decrease in CD28–CD57+ senescent CD4 and CD8 T-cells. Ki-67+ CD4 T-cells, CCR2+ non-classical monocytes, and myeloid dendritic cells increased over time (p ˂ 0.05). There were no significant changes in other inflammatory markers or HIV DNA/RNA levels. These findings can guide future large clinical trials investigating cannabinoid anti-inflammatory properties.

BackgroundTh17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown.ResultsHere, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART. In addition to the previously characterized CCR6(+)CCR4(+) (Th17) and CCR6(+)CXCR3(+) (Th1Th17) subsets, we reveal the existence of two novel CCR6(+) subsets, lacking (double negative, CCR6(+)DN) or co-expressing CXCR3 and CCR4 (double positive, CCR6(+)DP). The four subsets shared multiple Th17-polarization markers, a fraction of cells proliferated in response to C. albicans, and exhibited lineage commitment and plasticity when cultured under Th17 and Th1 conditions, respectively. Of note, fractions of CCR6(+)DN and Th17 demonstrated stable Th17-lineage commitment under Th1-polarization conditions. Among the four subsets, CCR6(+)DN expressed a unique transcriptional signature indicative of early Th17 development (IL-17F, STAT3), lymph-node homing (CCR7, CD62L), follicular help (CXCR5, BCL6, ASCL2), and self-renewal (LEFI, MYC, TERC). Cross sectional and longitudinal studies demonstrated that CCR6(+)DN cells were the most predominant CCR6(+) subset in the blood before and after ART initiation; high frequencies of these cells were similarly observed in inguinal lymph nodes of individuals receiving long-term ART. Importantly, replication competent HIV was isolated from CCR6(+)DN of ART-treated individuals.ConclusionsTogether, these results provide new insights into the functional heterogeneity of Th17-polarized CCR6(+)CD4(+) T-cells and support the major contribution of CCR6(+)DN cells to HIV persistence during ART.

ObjectivesBesides CD4 regulatory T-cells (Tregs), immunosuppressor FoxP3+ CD8 T-cells are emerging as an important subset of Tregs, which contribute to immune dysfunction and disease progression in HIV infection. However, FoxP3+ CD8 T-cell dynamics in acute HIV infection and following early antiretroviral therapy (ART) initiation remain understudied.MethodsSubsets of FoxP3+ CD8 T-cells were characterized both prospectively and cross-sectionally in PBMCs from untreated acute (n=26) and chronic (n=10) HIV-infected individuals, early ART-treated in acute infection (n=10, median of ART initiation: 5.5 months post-infection), ART-treated in chronic infection (n=10), elite controllers (n=18), and HIV-uninfected controls (n=21).ResultsAcute and chronic infection were associated with increased total, effector memory, and terminally differentiated FoxP3+ CD8 T-cells, while early ART normalized only the frequencies of total FoxP3+ CD8 T-cells. We observed an increase in FoxP3+ CD8 T-cell immune activation (HLADR+/CD38+), senescence (CD57+/CD28-), and PD-1 expression during acute and chronic infection, which were not normalized by early ART. FoxP3+ CD8 T-cells in untreated participants expressed higher levels of immunosuppressive LAP(TGF-β1) and CD39 than uninfected controls, whereas early ART did not affect their expression. The expression of gut-homing markers CCR9 and Integrin-β7 by total FoxP3+ CD8 T-cells and CD39+ and LAP(TGF-β1)+ FoxP3+ CD8 T-cells increased in untreated individuals and remained higher than in uninfected controls despite early ART. Elite controllers share most of the FoxP3+ CD8 T-cell characteristics in uninfected individuals.ConclusionsAlthough early ART normalized total FoxP3+ CD8 T-cells frequencies, it did not affect the persistent elevation of the gut-homing potential of CD39+ and LAP(TGF-β1)+ FoxP3+ CD8 T-cell, which may contribute to immune dysfunction.

Cannabis-based medicines (CBMs) could help reduce systemic inflammation in people with HIV (PWH). In a prospective, randomized pilot study we enrolled participants from August 2021–April 2022 with HIV, aged ≥18 and on antiretroviral therapy and randomly assigned them to cannabidiol (CBD) ± Δ9-tetrahydrocannabinol (THC) capsules for 12 weeks with the primary objective being to assess safety and tolerability. Here we report on timeliness to study initiation, enrolment, compliance and retention rates. The target sample size was not reached. Two hundred and five individuals were approached, and 10 consented and were randomized; the rest refused (reasons: cannabis-related stigma/discomfort; too many study visits/insufficient time; unwillingness to undergo a "washout period" for three weeks) or were not eligible. The age of those randomized was 58 years (IQR 55–62); 80% were male. Only three met all criteria (30% enrolment compliance); seven were enrolled with minor protocol deviations. Compliance was excellent (100%). Eight (80%) participants completed the study; two (20%) were withdrawn for safety reasons (transaminitis and aggravation of pre-existing anemia). Time to study initiation and recruitment were the most challenging aspects. Ongoing work is required to reduce stigma related to CBMs. Future studies should find a balance between the requirements for safety monitoring and frequency of study visits. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is the most common modality for cancer management, but it is associated with many side effects. Objectives: This study evaluated the effects of Thai massage on comfort and symptoms among female cancer patients receiving chemotherapy. Methods: This randomized clinical trial was conducted in 2017–2018 with a two-group pre-posttest design. Participants were sixty female patients with cancer selected from Bu-Ali Hospital in Tehran, Iran, and randomly allocated to a control and an intervention group. Participants in the control group received routine care, while their counterparts in the intervention group received both routine care and ten-session massage therapy. A demographic questionnaire, the Kolcaba's General Comfort Questionnaire, and the Edmonton Symptom Assessment Scale were used for data collection. Data were analyzed using the Chi-square, Fisher's exact, independent-samples t, and paired-samples t-tests. Results: There was no statistically significant difference between the groups respecting the pretest mean scores of comfort and symptoms (P > 0.05). After the intervention, the mean score of comfort in the control group was statistically significantly greater than the intervention group (137.4 ± 6.8 vs. 131.53 ± 9.61; P = 0.008). Moreover, the posttest mean scores of pain, fatigue, nausea, depression, anxiety, and drowsiness in the intervention group were significantly less than the control group (P < 0.05). Conclusion: Massage therapy is effective in significantly reducing symptoms among female cancer patients receiving chemotherapy.

Background Background: Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) is involved in immune dysregulation during HIV infection. Niacin (vitamin B3) could control the excess of tryptophan depletion and represents a potential strategy to improve immune functions and CD4 count recovery in immunological non-responder HIV-infected individuals on antiretroviral therapy (ART). Methods Methods: In the CTN PT006 phase 2 pilot randomized trial, 20 adults on ART with CD4 ≤ 350 cells/µl, despite an undetectable viral load (VL) for at least 3 months, received 2000 mg of extended-release (ER)-niacin orally once daily for 24 weeks. Side effects, VL, CD4/CD8 counts, lipid profile, T-cell activation and senescence, Tregs and Th17 cell frequencies, Kyn/Trp ratio, and levels of IL-6, IP-10, sST2, I-FABP, and LBP were assessed following ER-niacin treatment. Results Results: Thirteen participants completed the study. Treatment was interrupted in 4 patients due to loss of follow-up or personal reasons and 3 patients were discontinued due to comorbidity risks. All participants maintained a VL < 40 copies/ml, while ER-niacin did not affect CD4 and CD8 cell counts. Plasma levels of triglycerides, total, and LDL cholesterol significantly decreased, following ER-niacin treatment. ER-niacin also diminished Kyn plasma levels and slightly decreased CD4 T-cell activation. However, no improvement in CD8 subsets, Kyn/Trp ratio, Th17/Treg balance, and plasma inflammatory markers was observed. Conclusions Conclusions: Although ER-niacin combined with ART was well-tolerated among immune non-responders and decreased plasma lipids, it did not improve systemic inflammation, Kyn/Trp ratio, and CD4 cell recovery. Overall, ER-niacin was not effective to overcome chronic inflammation in PLWH.

Statement of the Problem: The tunnel technique has shown promising results in treatment of gingival recession. Plasma rich in growth factors (PRGF) is considered effective for soft tissue regeneration since it is a rich source of growth factors. Purpose: This clinical trial aimed to assess the efficacy of PRGF along with the tunnel technique and connective tissue graft for treatment of gingival recession. Materials and Method: In this controlled clinical trial, 20 areas around anterior and posterior teeth in 3 patients with gingival recession were bilaterally selected. The tunnel technique was used with and without PRGF in the test and control groups, respectively (10 areas in each group). The keratinized gingival width (KGW), clinical attachment level (CAL), clinical probing depth (PD), cementoenamel junction (CEJ) to mucogingival junction (MGJ) distance, and the esthetic visual analog scale (EVAS) score were evaluated preoperatively and at 6 weeks and 3 months, postoperatively. The gingival recession width (RW) and vertical recession depth (VRD) were assessed preoperatively and at 2 weeks and 3 months, postoperatively. The pain visual analog scale (PVAS) score was measured at 1, 3 and 7 days, post-treatment and the healing index (HI) was measured at 1, 3 and 7 days and 1 month, postoperatively. The root coverage percentage was assessed during 3 months. Paired t-test and repeated measures ANOVA were used for statistical analyses. p Value< 0.05 was considered statistically significant. Results: Significant improvements were noted in all tested parameters in both groups (p< 0.05). The mean root coverage percentage after 6 months was 88.68%±20.69% and 78.77%±24.94% in the test and control groups, respectively. None of the tested parameters were significantly different between two groups (p> 0.05). Conclusion: Treatment of gingival recession with the tunnel technique can yield favorable clinical outcome, irrespective of the employment of PRGF.

Background and purpose: Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, and a metabolic disorder affecting patientschr('39') general health in various ways. The present study aimed to evaluate the oral health-related quality of life (OHRQoL) among older adults of Amirkola, Northern Iran. Materials and Methods: A case-control study was conducted with a sample of 500 elderly people (250 with T2DM and 250 healthy controls) who answered geriatric oral health assessment index (GOHAI) questionnaire and a questionnaire evaluating xerostomia. Then, all participants underwent clinical dental examinations. The obtained data were then analyzed by t-test, chi-square test, and Pearsonchr('39')s correlation coefficient, and p < 0.05 was considered significant. Results: The prevalence of xerostomia was not statistically significant between the T2DM patients and control groups (p < 0.079). Greater number of patients suffering T2DM reported xerostomia according to the records; however, the correlation between this disorder and periodontal disease index (PDI), Plaque index (PI), oral health index-simplified (OHI-S), and geriatric oral health assessment index (GOHAI) in the subjects of the two study groups was not significant (p < 0.0001). Conclusion: In the present study, there was no significant relationship between GOHAI and periodontal indices, demonstrating no difference in the OHRQoL of elderly patients with T2DM and older healthy adults.

Background. This study aimed to evaluate the effect of acellular dermal matrix allograft (ADMA) for the treatment of gingival recession as a substitute for subepithelial connective tissue graft (SCTG). Methods. In this controlled clinical trial, 18 teeth were selected in nine subjects with bilateral gingival recession. One side was treated with SCTG and a coronally displaced flap as the control group, and the other side was treated with ADMA and a coronally displaced flap as the test group. Probing pocket depth (PPD), clinical attachment level, vertical recession depth, recession width, gingival thickness, keratinized tissue width, and the root coverage percentage were measured before the surgery and at 1-, 3-, and 6-month postoperative intervals. The healing index, pain index, and patient satisfaction were also investigated. The data were analyzed with a general linear model (GLM) repeated measures and paired t-test. Results. All the parameters improved except for PPD; however, a comparison between the groups did not reveal statistically significant differences. Only root coverage percentage and pain index were significantly lower in the test group. The average percentage of root coverage in the control and test groups were 82.01±16.62% and 64.44±9.4%, respectively. Conclusion. Both methods resulted in improvements in the clinical results. However, the use of the ADMA led to less pain and root coverage in comparison with the SCTG method.

BACKGROUND AND OBJECTIVE: Chronic periodontitis is a slow-growing inflammatory disease that often occurs in adults. In the elderly, periodontal indices may also change due to a number of psychological factors, such as depression and consequent changes in cortisol levels. Therefore, this study was performed to investigate the relationship between depression and periodontal indices in the elderly in Amirkola, Northern Iran. METHODS: This case-control study, which is part of the second phase of the Amirkola Health and Ageing Project (AHAP) to investigate the health status of the elderly in this city, was performed on 300 elderly people. After examination, subjects were divided into two groups: periodontitis (n=100) and control (n=200). In both groups, the presence of depressive symptoms was assessed using the Geriatric Depression Scale (GDS), in which a score of 5 or higher is a sign of depression, and periodontal indices including OHIS and PDI were examined based on PDI≥4 periodontitis criterion. Then, the two groups were compared in terms of the association between periodontal indices and depression. FINDINGS: In this study, 133 were female (44.3%) and 167 were male (55.7%). 35 patients (35%) in the case group and 61 patients (30.5%) in the control group had symptoms of depression. The mean GDS score in patients with periodontitis (3.70±3.68) was slightly higher than healthy individuals (3.49±3.40), but no significant correlation was observed between GDS and PDI. Old age, male gender, lower level of education and smoking were higher in patients with periodontitis, which was statistically significant only in smoking and level of education (p=0.042 and p=0.009, respectively). In this study, a positive and weak relationship was observed between age and PDI (r=0.19 and p=0.001). CONCLUSION: The results showed that there is a relationship between periodontal indices and depression. Although it was not statistically significant, it is clinically noteworthy.

Despite the success of antiretroviral therapy (ART), people living with HIV continue to suffer from high burdens of respiratory infections, lung cancers and chronic lung disease at a higher rate than the general population. The lung mucosa, a previously neglected HIV reservoir site, is of particular importance in this phenomenon. Because ART does not eliminate the virus, residual levels of HIV that remain in deep tissues lead to chronic immune activation and pulmonary inflammatory pathologies. In turn, continuous pulmonary and systemic inflammation cause immune cell exhaustion and pulmonary immune dysregulation, creating a pro-inflammatory environment ideal for HIV reservoir persistence. Moreover, smoking, gut and lung dysbiosis and co-infections further fuel the vicious cycle of residual viral replication which, in turn, contributes to inflammation and immune cell proliferation, further maintaining the HIV reservoir. Herein, we discuss the recent evidence supporting the notion that the lungs serve as an HIV viral reservoir. We will explore how smoking, changes in the microbiome, and common co-infections seen in PLWH contribute to HIV persistence, pulmonary immune dysregulation, and high rates of infectious and non-infectious lung disease among these individuals.

People living with HIV (PLWH) may be at risk for poor immunogenicity to certain vaccines, including the ability to develop immunological memory. Here, we assessed T-cell immunogenicity following three SARS-CoV-2 vaccine doses in PLWH versus uninfected controls. Blood was collected from 38 PLWH on antiretroviral therapy and 24 age-matched HIV-negative controls, pre-vaccination and after 1st/2nd/3rd dose of SARS-CoV-2 vaccines, without prior SARS-CoV-2 infection. Flow cytometry was used to assess ex vivo T-cell immunophenotypes and intracellular Tumor necrosis factor (TNF)-α/interferon(IFN)-γ/interleukin(IL)-2 following SARS-CoV-2-Spike-peptide stimulation. Comparisons were made using Wilcoxon signed-rank test for paired variables and Mann–Whitney for unpaired. In PLWH, Spike-specific CD4 T-cell frequencies plateaued post-2nd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose. PLWH had higher frequencies of TNFα+CD4 T-cells and lower frequencies of IFNγ+CD8 T-cells than seronegative participants post-3rd dose. Regardless of HIV status, an increase in naive, regulatory, and PD1+ T-cell frequencies was observed post-3rd dose. In summary, two doses of SARS-CoV-2 vaccine induced a robust T-cell immune response in PLWH, which was maintained after the 3rd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose.

Background: The aim of this study was to compare the clinical, histological, and histomorphometrical outcomes of CenoBone® allograft with and without plasma rich in growth factor (PRGF) for the preservation of edentulous ridge in the dental sockets. Materials and Methods: This study is experimental clinical trial that 14 dental sockets were included the sockets required ridge preservation followed by implant placement in the premolar and molar of the mandible. After extraction of the teeth, the CenoBone® allograft and PRGF were used in the test group and CenoBone® allograft was used alone in the control group. During the first stage of surgery and 5 months later, in the second stage of surgery (implant placement), the vertical changes of the ridge were measured. Furthermore, using Core-Biopsy in the second stage of surgery, criteria of histologic and histomorphometric were determined. Data were analyzed with t-test, Mann–Whitney U-test, and Fisher's exact test at the level of significance of P < 0.05. Results: The mean trabecular thickness in the test group (52.18 ± 5.53) was significantly higher than that in the control group (41.53 ± 10.40) (P = 0.344). However, there were no significant differences in the mean values of vertical bone absorption, bone percentage, remaining biomaterials, inflammation, and blood vessels between the two groups. There was no case of foreign body reaction and the bone was vital in all the cases and in direct contact with the biomaterial. Conclusion: Although CenoBone® allograft with PRGF was effective in some histomorphometric factors such as trabecular thickness, it did not lead to significant clinical changes.

Background: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed. Methods: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0–2 scores). Results: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate. Conclusions: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.

Background: HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied. Methods: Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIV-infected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology. Findings: Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1)+ Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-β1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different. Interpretation: Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression. Funding: This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).