Implications of Accumulation of Clonally Expanded and Senescent CD4 + GNLY+ T Cells in Immunological Non-responders of HIV-1 infection.

Increased CD4 + GNLY+ T cells have been confirmed to be inversely associated with CD4+ T cell count in immunological non-responders (INRs), however, the underlying mechanisms are unknown. This study aimed to elucidate the characteristics of CD4 + GNLY+ T cells and their relationship with immune restoration. Single-cell RNA sequencing, single-cell TCR sequencing, and flow cytometry were used to analyze the frequency, phenotypes, and function of CD4 + GNLY+ T cells. Moreover, Enzyme linked immunosorbent assay was performed to detect plasma cytokines production in patients. CD4 + GNLY+ T cells were found to be highly clonally expanded, characterized by higher levels of cytotoxicity, senescence, P24, and HIV-1 DNA than CD4 + GNLY- T cells. Additionally, the frequency of CD4 + GNLY+ T cells increased after ART, and further increased in INRs, and were positively associated with the antiretroviral therapy duration in INR. Furthermore, increased IL-15 levels in INRs positively correlated with the frequency and senescence of CD4 + GNLY+ T cells, suggesting that CD4 + GNLY+ T cells may provide new insights for understanding the poor immune reconstitution of INRs. In conclusion, increased, highly clonally expanded, and senescent CD4 + GNLY+ T cells may contribute to poor immune reconstitution in HIV-1 infection.

HIV-1-DNA/RNA and immunometabolism in monocytes: contribution to the chronic immune activation and inflammation in people with HIV-1.

BACKGROUND: Among people living with HIV-1 (PHIV), immunological non-responders (INR) experience incomplete immune recovery despite suppressive antiretroviral treatment (ART), facing more severe non-AIDS events than immunological responders (IR) due to higher chronic immune activation and inflammation (cIA/I). We analyzed the HIV-1 reservoir and immunometabolism in monocytes as a source of cIA/I. METHODS: Cross-sectional study in which 110 participants were enrolled: 25 treatment-naïve; 35 INR; 40 IR; and 10 healthy controls. Cell-associated HIV-1-DNA (HIV-DNA) and -RNA (HIV-RNA) were measured in FACS-isolated monocytes using digital droplet PCR. Intact, 5' deleted, and 3' deleted proviruses were quantified by the intact proviral DNA assay. Systemic inflammation, monocyte immunophenotype, and immunometabolism were characterized by immunoassays, flow cytometry, and real-time cellular bioenergetics measurements, respectively. FINDINGS: Monocytes from INR harbor higher HIV-RNA and HIV-DNA levels than IR. HIV-RNA was found in 14/21 treatment-naïve [2512 copies/106 TBP (331-4666)], 17/33 INR [240 (148-589)], and 15/28 IR [144 (15-309)], correlating directly with sCD163, IP-10, GLUT1high cells and glucose uptake, and inversely with the CD4+/CD8+ ratio. HIV-DNA was identified in all participants with detectable HIV-RNA, with intact provirus in 9/12 treatment-naïve [13 copies/106 monocytes (7-44)], 8/14 INR [46 (18-67)], and 9/13 IR [9 (7-24)]. INR presented glucose metabolism alterations and mitochondrial impairment; decreased coupling efficiency and BHI, and increased mitochondrial dysfunction inversely correlating with the CD4+/CD8+ ratio. INTERPRETATION: HIV-RNA, more than HIV-DNA, in monocytes and their altered metabolism are factors associated with the higher cIA/I that characterize INR. FUNDING: This work was supported by the European Regional Development Fund, ISCIII, grant PI20/01646. Other funding sources: Instituto de Salud Carlos III through the Subprogram Miguel Servet (CP19/00159) to AGV, PFIS contracts (FI19/00304) to EMM, (FI21/00165) to ASA, and (FI19/00083) to CGC, and a mobility grant (MV21/00103) to EMM, from the Ministerio de Ciencia e Innovación, Spain. AJM was granted by a CSL Centenary Award.

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

Introduction: While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Methods: Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Results: Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Discussion: Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.

Cardiovascular and cardiorespiratory effects of high-intensity interval training in body fat responders and non-responders.

This study aimed to investigate cardiovascular and cardiorespiratory adaptations to exercise intervention among participants who showed higher (responders-RSBFP) and lower (non-responders-NRSBFP) levels of body fat percentage (BFP) responsiveness. Adolescents (42.5% males) participated in a ten-week school-based high-intensity interval training (HIIT), followed by a comparison of BFP, blood pressure (BP), and cardiorespiratory fitness (CRF). RSBFP age of 16.15 ± 0.36 years, body height 170.82 ± 8.16 cm, weight 61.23 ± 12.80 kg, and BMI 20.86 ± 3.29 kg/m2. Meanwhile, NRSBFP age of 16.04 ± 0.36 years, body height 168.17 ± 8.64 cm, weight 57.94 ± 8.62 kg, and BMI 20.47 ± 2.24 kg/m2. HIIT intervention impacted BFP, with a higher decrease in the RSBFP than the NRSBFP (ΔBFPRs = - 2.30 ± 3.51(10.34%) vs. ΔBFPNRs = 1.51 ± 1.54(6.96%) p < 0.001). The primary comparison showed a statistically significant interaction effect in relation to CRF (F(1,71) = 14.12; p < 0.001). Detailed comparisons showed large and significant CRF changes in RSBFP (7.52%; d = 0.86; p < 0.001) but not in NRSBFP (2.01%; d = 0.11; p = 0.576). In addition, RSBFP and NRSBFP benefited equally in SBP (5.49%, d = 0.75; p < 0.001; 4.95%, d = 0.74; p < 0.001, respectively). These findings highlight that exercise benefits on body fat may be mainly related to gains in CRF. Due to substantial intra-individual variability in adaptation, there is a need for personalized intervention tailored for those with different reaction thresholds in body mass components.

HIV-Induced Thymic Insufficiency and Aging-Related Immunosenescence on Immune Reconstitution in ART-Treated Patients.

The mechanisms underlying unsatisfactory immune reconstitution in HIV-1 positive patients under ART have not been fully elucidated, even after years of investigation. Thus, this study aimed to assess the correlation between age and thymic production profile, and its influence on inadequate immunological recovery. Here, 44 ART-treated patients with undetectable plasma HIV-1 load (<40 copies/mL) were classified as 31 immunological responders (IR) and 13 immunological non-responders (INR), according to their CD4+ T-cell count after 18 months of ART. The thymic function was assessed by identifying recent thymic emigrants (RTEs) CD4+ T cells (CD4+/CD45RA+CD31+) in PBMCs using flow cytometry. Clinical data were also analyzed from medical records. The INR group showed a higher age at ART initiation (41 ± 3.0) compared to the IR (33.7 ± 2.1) group (p = 0.041). Evaluating RTE CD4+ T-cells, we observed a lower percentage in the INR group (19.5 ± 6.3) compared to the IR group (29.9 ± 11.5) (p = 0.012). There was a strong negative correlation between age at ART initiation and RTE CD4+ T-cells in INRs (r = -0.784, p = 0.004). Our study has highlighted the thymic insufficiency and aging-related immunosenescence with unsatisfactory immunological recovery during ART in HIV-1 positive patients.

Surgical Intervention in Allergic Rhinitis: Stuffy Versus Sneezy Runny Nose.

To detect proportion and surgical outcome of adult patients with allergic rhinitis non-responsive to medical treatment. To identify clinical candidacy for submucous turbinoplasty of inferior turbinate resection or soft tissue reduction. A prospective descriptive study of adults with clinical allergic rhinitis was done. Non-responders to medical therapy were identified and outcome of surgical intervention analyzed. There were 393 patients. Eighty-one patients (21%) were refractory to medical therapy. Presenting symptoms were sneezing with watery rhinorrhea among 72% and nasal obstruction in 28% patients All patients in the latter group had hypertrophied inferior turbinates with associated deviated nasal septum in 36.6%. Bony and mucosal inferior turbinate hypertrophy among 73.3% and mucosal hypertrophy among 26.7% were identified by a negative or positive response to on-table local vasoconstrictor application respectively. Submucosal inferior turbinoplasty with turbinate resection in the former and soft tissue reduction in the latter group were done, along with septoplasty among 36%. All patients revealed significant reduction in postoperative SNOT score. Crusting was more during early postoperative period among those with soft tissue reduction and simultaneous septoplasty, necessitating meticulous endoscopic follow-up. Adult allergic rhinitis presenting predominantly with nasal obstruction ('stuffy nose'), could be non-responsive to medical therapy unlike sneezy, runny nose, especially when obstructive symptoms are more than two years among older patients, suggesting presence of hypertrophied inferior turbinates. On-table response to vasoconstrictors is a reliable clinical indicator for submucous inferior turbinoplasty: negative and positive response suggesting turbinate resection among majority and soft tissue reduction among minority respectively.

HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity.

Introduction: Immunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects. Methods: The 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli. Results: The discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production. Conclusions: INR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.

Missingness mechanisms and generalizability of patient reported outcome measures in colorectal cancer survivors - assessing the reasonableness of the "missing completely at random" assumption.

BACKGROUND: Patient-Reported Outcome Measures (PROM) provide important information, however, missing PROM data threaten the interpretability and generalizability of findings by introducing potential bias. This study aims to provide insight into missingness mechanisms and inform future researchers on generalizability and possible methodological solutions to overcome missing PROM data problems during data collection and statistical analyses. METHODS: We identified 10,236 colorectal cancer survivors (CRCs) above 18y, diagnosed between 2014 and 2018 through the Danish Clinical Registries. We invited a random 20% (2,097) to participate in a national survey in May 2023. We distributed reminder e-mails at day 10 and day 20, and compared Initial Responders (response day 0-9), Subsequent Responders (response day 10-28) and Non-responders (no response after 28 days) in demographic and cancer-related characteristics and PROM-scores using linear regression. RESULTS: Of the 2,097 CRCs, 1,188 responded (57%). Of these, 142 (7%) were excluded leaving 1,955 eligible CRCs. 628 (32%) were categorized as initial responders, 418 (21%) as subsequent responders, and 909 (47%) as non-responders. Differences in demographic and cancer-related characteristics between the three groups were minor and PROM-scores only marginally differed between initial and subsequent responders. CONCLUSION: In this study of long-term colorectal cancer survivors, we showed that initial responders, subsequent responders, and non-responders exhibit comparable demographic and cancer-related characteristics. Among respondents, Patient-Reported Outcome Measures were also similar, indicating generalizability. Assuming Patient-Reported Outcome Measures of subsequent responders represent answers by the non-responders (would they be available), it may be reasonable to judge the missingness mechanism as Missing Completely At Random.

Prognostic Factors in Intra-articular Platelet-Rich Plasma Treatment for Knee Osteoarthritis: A Comparative Analysis of Responders and Nonresponders.

BACKGROUND: Knee osteoarthritis (KOA) is a chronic joint disease affecting activities of daily living (ADL) and quality of life due to pain and limited range of motion, afflicting a large number of patients worldwide. However, it is difficult to prevent the progression of the disease. Therapeutic strategies for KOA aim to maintain ADL and QOL by alleviating pain or managing locomotive function. Recently, intra-articular injection of platelet-rich plasma (PRP) has been gaining attention. In this study, the clinical results of PRP treatment in our institution were reported and compared between responders and non-responders using patient characteristics and imaging data assessed from plain X-rays and magnetic resonance imaging (MRI). METHODS: Participants in the study were KOA patients with varus deformity assessed as grade 2 or higher in the Kellgren-Lawrence classification who received PRP treatment from January 2022 to November 2023 and were followed up for at least three months. PRP was prepared with 27 mL of blood collected from the patient, and 2.7 mL of PRP was prepared using the PEAK©ï¸ŽPRP System from DePuy Synthes (Raynham, MA). Intra-articular injections of PRP were performed under echo-guided procedures, and responders or non-responders were determined using the Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) criteria evaluated by the Japanese Knee Injury and Osteoarthritis Outcome Score (J-KOOS) at three months after PRP injection. The clinical efficacy of PRP treatment for KOA was assessed in this study, and a dichotomous analysis was performed comparing the responder group and the non-responder group using patient characteristics and assessed data from plain X-ray images and MRI to determine prognostic factors for PRP treatment. RESULTS: The study population included 36 knees with a mean age of 70.6. ± 9.2 years, comprising six knees in men and 30 knees in women. The responder group consisted of 16 knees (44.4%), and the non-responder group consisted of 20 knees (55.6%). J-KOOS subscores at pre-treatment elicited that each subscale in the R group was significantly lower than that in the NR group at pretreatment. A dichotomous analysis for the two groups revealed the distribution of sex and past medical history of hyperlipidemia to be significantly different between the two groups. Multivariable logistic regression analysis showed that the coexistence of hyperlipidemia was the main prognostic factor for the efficacy of PRP therapy. DISCUSSION: In this study, comparisons were conducted between responders and non-responders to estimate prognostic factors for the efficacy of PRP therapy. Surprisingly, responders to the treatment tended to show lower J-KOOS scores and to have hyperlipidemia. A literature review revealed conflicting reports on prognostic factors for PRP therapy in KOA, highlighting the need for further research.

Transcriptomic crosstalk between viral and host factors drives aberrant homeostasis of T-cell proliferation and cell death in HIV-infected immunological non-responders.

BACKGROUND: Immunological non-responders (INRs) among people living with HIV have inherently higher mortality and morbidity rates. The underlying immunological mechanisms whereby failure of immune reconstitution occurs in INRs require elucidation. METHOD: HIV-1 DNA and HIV-1 cell-associated RNA (CA-HIV RNA) quantifications were conducted via RT-qPCR. Transcriptome sequencing (RNA-seq), bioinformatics, and biological verifications were performed to discern the crosstalk between host and viral factors. Flow cytometry was employed to analyze cellular activation, proliferation, and death. RESULTS: HIV-1 DNA and CA-HIV RNA levels were observed to be significantly higher in INRs compared to immunological responders (IRs). Evaluation of CD4/CD8 ratios showed a significantly negative correlation with HIV-1 DNA in IRs, but not in INRs. Bioinformatics analyses and biological verifications showed IRF7/INF-α regulated antiviral response was intensified in INRs. PBMCs of INRs expressed significantly more HIV integrase-mRNA (p31) than IRs. Resting (CD4+CD69- T-cells) and activated (CD4+CD69+ T-cells) HIV-1 reservoir harboring cells were significantly higher in INRs, with the co-occurrence of significantly higher cellular proliferation and cell death in CD4+ T-cells of INRs. CONCLUSION: In INRs, the systematic crosstalk between the HIV-1 reservoir and host cells tends to maintain a persistent antiviral response-associated inflammatory environment, which drives aberrant cellular activation, proliferation, and death of CD4+ T-cells.

Unique cytokine signature in ocular Stevens-Johnson syndrome non-responders.

PURPOSE: To clinically define a subset of patients with chronic ocular Stevens-Johnson syndrome non-responders (SJS-NR) and analyze their cytokine profile compared to clinical responders (SJS-CR). METHODS: A total of 32 SJS cases (n = 32, 64 eyes) managed over a period of three years were segregated into clinical responders (n = 24, 48 eyes) and non-responders (n = 8, 16 eyes). Cases were determined as non-responders based on persistent, refractory, and non-mechanical inflammation of the conjunctiva. Age- and sex-matched healthy controls (n = 25, 50 eyes) were recruited. Tear specimens collected using Schirmer's strip were profiled for 27 cytokines using an immunoassay-based 27-bioplex array. RESULTS: Tear cytokine profiling revealed 18 cytokines to be differentially expressed in SJS-NR compared to SJS-CR. While PDGF-BB, IL-4, IL-1ß, VEGF, IL-12p70, IFN-γ, IL-9, and IL-1RA were upregulated, GM-CSF, eotaxin, IP-10, IL-10, MCP-1, G-CSF, IL-6, IL-13, and bFGF were downregulated in SJS-NR compared to SJS-CR. The cytokines IL-13, IL-10, and IP-10 were decreased in both SJS-NR and SJS-CR compared to controls. CONCLUSION: The inflammation in SJS-NR continues to worsen despite the correction of mechanical causes, resulting in progressive deterioration of the cornea. The cytokine profile of SJS-NR was remarkably different from that of SJS-CR, indicating a T helper 2-type protective proliferative response and an impaired migratory potential of the conjunctival epithelium. These factors could possibly lead to poor healing of the corneal epithelium in a markedly pro-inflammatory and pro-angiogenic milieu. The top four differentially expressed cytokines, PDGF-BB, IL-4, IL-10, and IL-6, are proposed as potential biomarkers of SJS-NR.

Single Anastomosis Duodeno-Ileal bypass (SADI-S) as Primary or Two-Stage Surgery: Mid-Term Outcomes of a Single Canadian Bariatric Center.

PURPOSE: Compare primary single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) and two-stage SADI after sleeve gastrectomy (SG) in terms of weight loss, reduction/remission of comorbidities, and morbidity. METHODS: Retrospective study including 179 patients treated laparoscopically between 2016 and 2020. A 50Fr bougie was used for the SG in the primary SADI-S (group 1) and 36/40Fr for the two-stage procedure (group 2). The duodeno-ileal anastomosis was performed at 250 cm from the ileocecal valve and at least 2 cm after the pylorus. RESULTS: Mean age was 44.1 years old, and there were 148 women and 31 men. There were 67 (37.4%) patients in group 1 and 112 (62.6%) in group 2, with 67% completing the 4-year follow-up. Mean preoperative body mass index (BMI) was 51.1 kg/m2 and 44.6 kg/m2 for groups 1 and 2, respectively. Preoperative comorbidities were obstructive sleep apnea, hypertension, type 2 diabetes, and dyslipidemia in 103 (57.5%), 93 (52%), 65 (36.3%), and 58 (32.4%) of cases. At 4 years postoperatively, excess weight loss (EWL) was 67.5% in group 1 and 67% in group 2 (p = 0.1005). Both groups had good comorbidity remission rates. Early postoperative morbidity rate was 10.4% in group 1 and 3.6% in group 2. In group1, there were mostly postoperative intra-abdominal hematomas managed conservatively (n = 4). Two revisional surgeries were needed for duodeno-ileal anastomosis leaks. Postoperative gastroesophageal reflux disease (GERD), daily diarrhea, vitamin, and protein levels were similar in both groups. CONCLUSION: Both types of strategies are efficient at short and mid-term outcomes. Preoperative criteria will inform surgeon decision between a primary and a two-stage strategy.

Comparison of Long-term Response and Remission to Omalizumab and Anti-IL-5/IL-5R Using Different Criteria in a Real-life Cohort of Severe Asthma Patients

Background: Evaluation of biologic therapy response is vital to monitor its effectiveness. Authors have proposed various response criteria including good responder, super-responder, non-responder, and clinical remission.ObjectivesTo ascertain the prevalence of response and clinical remission after long-term treatment (>6 months) of anti-IgE and anti-IL-5/IL-5Rα biologics, compare these results with existing criteria, and identify predictors for non-responders and clinical remission.MethodsA multicenter, real-life study involving severe asthma patients in Spain. Various outcomes were assessed to gauge response and clinical remission against established criteria.ResultsThe study included 429 patients, 209 (48.7%) omalizumab, 112 (26.1%) mepolizumab, 19 (4.4%) reslizumab and 89 (20.7%) benralizumab, with a mean treatment duration of 55.3±38.8 months. In the final year of treatment, 218 (50.8%) were super-responders, 173 (40.3%) responders, 38 (8.9%) non-responders, and clinical remission in 116 (27%), without differences among biologics. The short-term non-responders (<6 months) were 25/545 (4.6%). Substantial variations in response and clinical remission were observed when applying different published criteria. Predictors of non-response included higher BMI (OR:1.14; 95% CI:1.06–1.23; p<0.001), admissions at ICU (2.69; 1.30–5.56; p=0.01), high count of SAE (1.21; 1.03–1.42; p=0.02) before biologic treatment. High FEV1% (0.96; 0.95–0.98; p<0.001), a high ACT score (0.93; 0.88–0.99; p=0.01) before biologic treatment or NSAID-ERD (0.52; 0.29–0.91; p=0.02) showed strong associations with achieving clinical remission.ConclusionA substantial proportion of severe asthma patients treated long-term with omalizumab or anti-IL5/IL-5Rα achieved a good response. Differences in response criteria highlight the need for harmonization in defining response and clinical remission in biologic therapy to enable meaningful cross-study comparisons. (AU)

Using the AS04C-adjuvanted hepatitis B vaccine in patients classified as non-responders.

BACKGROUND: Chronic hepatitis B (HB) remains a significant global health concern, despite the widespread availability of the HB vaccine. While the standard vaccine demonstrates an impressive serological response rate exceeding 90%, a subset of individuals exhibit suboptimal immunity. This study aims to elucidate the efficacy of the AS04C-adjuvanted HB vaccine in addressing non-responsiveness. METHODS: Conducted at the Preventive Medicine Service of the University Albacete Hospital in Spain from 2017 to 2021, this single-center observational study enrolled 195 patients. Among them, 126 (65%) were classified as non-responders following one or two complete standard vaccination courses. RESULTS: After the administration of a complete four-dose regimen of the AS04C-adjuvanted vaccine, 73.81% of non-responder patients exhibited antibody titers indicative of robust immunity (anti-HBs >10). CONCLUSIONS: These findings underscore the pivotal role of the AS04C-adjuvanted HB vaccine in addressing non-responsiveness, emphasizing its potential as a crucial tool in augmenting immunization strategies for various populations. This includes non-responders to standard vaccination, individuals with chronic kidney disease, those requiring seroprotection due to factors like immunosuppression or occupational hazards, as well as patients for whom conventional revaccination strategies have proven futile. Additional research is needed to expand on the promising results obtained through our protocol.

Increasing the transplant dose and repeating faecal microbiota transplantation results in the responses of male patients with IBS reaching those of females.

BACKGROUND: Faecal microbiota transplantation (FMT) performed with a proper protocol is a safe treatment for IBS that has high efficacy and durable effects. Females have been reported to respond better than males to FMT. The present study aimed at determining whether increasing the transplant dose or repeating FMT improve the responses of males to FMT. METHODS: This study included 186 IBS patients (131 females and 55 males) who were randomized at a 1:1:1 ratio to receive 90 g of donor faeces once into the large intestine, once into the small intestine or twice into the small intestine. Patients completed five questionnaires that assessed their symptoms and quality of life, and provided faecal samples at baseline and at 3, 6 and 12 months after FMT. The faecal bacterial profile and dysbiosis index were determined using 16S rRNA gene PCR DNA amplification covering variable genes V3-V9. RESULTS: The response rates to FMT at all observation times did not differ significantly between females and males regardless of the transplant administration route or whether it was repeated. Faecal Alistipes levels were higher in females than in males at baseline and increased in both females and males after FMT. In the repeated group, the Alistipes levels did not differ between females and males after FMT. CONCLUSIONS: Increasing the transplant dose and repeating FMT results in the responses of male IBS patients to FMT reaching those of females regardless of the administration route. Alistipes spp. levels appear to play a role in this improvement.www.clinicaltrials.gov (NCT04236843).

Comparison of Long-term Response and Remission to Omalizumab and Anti-IL-5/IL-5R Using Different Criteria in a Real-life Cohort of Severe Asthma Patients.

BACKGROUND: Evaluation of biologic therapy response is vital to monitor its effectiveness. Authors have proposed various response criteria including good responder, super-responder, non-responder, and clinical remission. OBJECTIVES: To ascertain the prevalence of response and clinical remission after long-term treatment (>6 months) of anti-IgE and anti-IL-5/IL-5Rα biologics, compare these results with existing criteria, and identify predictors for non-responders and clinical remission. METHODS: A multicenter, real-life study involving severe asthma patients in Spain. Various outcomes were assessed to gauge response and clinical remission against established criteria. RESULTS: The study included 429 patients, 209 (48.7%) omalizumab, 112 (26.1%) mepolizumab, 19 (4.4%) reslizumab and 89 (20.7%) benralizumab, with a mean treatment duration of 55.3±38.8 months. In the final year of treatment, 218 (50.8%) were super-responders, 173 (40.3%) responders, 38 (8.9%) non-responders, and clinical remission in 116 (27%), without differences among biologics. The short-term non-responders (<6 months) were 25/545 (4.6%). Substantial variations in response and clinical remission were observed when applying different published criteria. Predictors of non-response included higher BMI (OR:1.14; 95% CI:1.06-1.23; p<0.001), admissions at ICU (2.69; 1.30-5.56; p=0.01), high count of SAE (1.21; 1.03-1.42; p=0.02) before biologic treatment. High FEV1% (0.96; 0.95-0.98; p<0.001), a high ACT score (0.93; 0.88-0.99; p=0.01) before biologic treatment or NSAID-ERD (0.52; 0.29-0.91; p=0.02) showed strong associations with achieving clinical remission. CONCLUSION: A substantial proportion of severe asthma patients treated long-term with omalizumab or anti-IL5/IL-5Rα achieved a good response. Differences in response criteria highlight the need for harmonization in defining response and clinical remission in biologic therapy to enable meaningful cross-study comparisons.

Interplay between inflammatory bowel disease therapeutics and the gut microbiome reveals opportunities for novel treatment approaches.

Inflammatory bowel disease (IBD) is a complex heterogeneous disorder defined by recurring chronic inflammation of the gastrointestinal tract, attributed to a combination of factors including genetic susceptibility, altered immune response, a shift in microbial composition/microbial insults (infection/exposure), and environmental influences. Therapeutics generally used to treat IBD mainly focus on the immune response and include non-specific anti-inflammatory and immunosuppressive therapeutics and targeted therapeutics aimed at specific components of the immune system. Other therapies include exclusive enteral nutrition and emerging stem cell therapies. However, in recent years, scientists have begun to examine the interplay between these therapeutics and the gut microbiome, and we present this information here. Many of these therapeutics are associated with alterations to gut microbiome composition and functionality, often driving it toward a "healthier profile" and preclinical studies have revealed that such alterations can play an important role in therapeutic efficacy. The gut microbiome can also improve or hinder IBD therapeutic efficacy or generate undesirable metabolites. For certain IBD therapeutics, the microbiome composition, particularly before treatment, may serve as a biomarker of therapeutic efficacy. Utilising this information and manipulating the interactions between the gut microbiome and IBD therapeutics may enhance treatment outcomes in the future and bring about new opportunities for personalised, precision medicine.

MRI Tumor Regression Grade Combined with T2-Weighted Volumetry May Predict Histopathological Response in Locally Advanced Rectal Cancer following Neoadjuvant Chemoradiotherapy-A New Scoring System Proposal.

Modern studies focus on the discovery of innovative methods to improve the value of post-treatment magnetic resonance imaging (MRI) in the prediction of pathological responses to preoperative neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). The aim of this study was to assess the potential benefits of combining magnetic resonance tumor regression grade (mrTRG) with T2-weighted volumetry in the prediction of pathological responses to nCRT in LARC. This was a cohort study conducted on patients with histopathologically confirmed LARC in a period from 2020 to 2022. After histopathological verification, all patients underwent initial MRI studies, while the follow-up MRI was performed after nCRT. Tumor characteristics, MRI estimated tumor regression grade (mrTRG) and tumor volumetry were evaluated both initially and at follow-up. All patients were classified into responders and non-responders according to pathological tumor regression grade (pTRG) and mrTRG. A total of 71 patients, mostly male (66.2%) were included in the study. The median tumor volume reduction rate was significantly higher in nCRT-responders compared to non-responders (79.9% vs. 63.3%) (p = 0.003). Based on ROC analysis, optimal cut-off value for tumor volume reduction rate was determined with an area under the curve (AUC) value of 0.724 (p = 0.003). Using the tumor volume reduction rate ≥75% with the addition of response to nCRT according to mrTRG, a new scoring system for prediction of pTRG to preoperative nCRT in LARC was developed. Diagnostic performance of prediction score was tested and the sensitivity, PPV, specificity, and NPV were 81.8%, 56.3%, 71.4%, and 89.7%, respectively. The combination of mrTRG and T2-weighted volumetry increases the MRI-based prediction of pTRG to preoperative nCRT in LARC. The proposed scoring system could aid in distinguishing responders to nCRT, as these patients could benefit from organ-preserving treatment and a "watch and wait" strategy.

Severe intestinal barrier damage in HIV-infected immunological non-responders.

The intestinal epithelial barrier plays an important role during human immunodeficiency virus (HIV) disease progression. However, the extent to which the intestinal epithelial barrier is damaged in immunological non-responders (INRs) and immunological responders (IRs) is largely unknown. In this study, we investigated and compared the levels of intestinal gland damage and related molecules, including the tight junction protein claudin-1, apoptosis marker caspase-3, HIV DNA, CD4+ T cell count, and inflammation marker tumor necrosis factor-α (TNF-α) among the IRs (n = 10), INRs (n = 8), and healthy controls (HCs, n = 7). Intestinal damage was not completely restored in both INRs and IRs and was more serious in INRs than that in IRs. Moreover, intestinal damage was positively correlated with HIV DNA levels and negatively correlated with CD4+ T cell counts. These results provide insight into understanding the characteristics of intestinal epithelial barrier damage between IRs and INRs.

Recent advances in poor HIV immune reconstitution: what will the future look like?

Combination antiretroviral therapy has demonstrated proved effectiveness in suppressing viral replication and significantly recovering CD4+ T cell count in HIV type-1 (HIV-1)-infected patients, contributing to a dramatic reduction in AIDS morbidity and mortality. However, the factors affecting immune reconstitution are extremely complex. Demographic factors, co-infection, baseline CD4 cell level, abnormal immune activation, and cytokine dysregulation may all affect immune reconstitution. According to report, 10-40% of HIV-1-infected patients fail to restore the normalization of CD4+ T cell count and function. They are referred to as immunological non-responders (INRs) who fail to achieve complete immune reconstitution and have a higher mortality rate and higher risk of developing other non-AIDS diseases compared with those who achieve complete immune reconstitution. Heretofore, the mechanisms underlying incomplete immune reconstitution in HIV remain elusive, and INRs are not effectively treated or mitigated. This review discusses the recent progress of mechanisms and factors responsible for incomplete immune reconstitution in AIDS and summarizes the corresponding therapeutic strategies according to different mechanisms to improve the individual therapy.