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Background The CD4/CD8 ratio has been associated with the risk of AIDS and non-AIDS events. We describe trends in immunological parameters in people who underwent a switch to monotherapy or dual therapy, compared to a control group remaining on triple antiretroviral therapy (ART). Methods We included patients in Icona who started a three-drug combination ART regimen from an ART-naïve status and achieved a viral load ≤ 50 copies/mL; they were subsequently switched to another triple or to a mono or double regimen. Standard linear regression at fixed points in time (12-24 months after the switch) and linear mixed model analysis with random intercepts and slopes were used to compare CD4 and CD8 counts and their ratio over time according to regimen types (triple vs. dual and vs. mono). Results A total of 1241 patients were included; 1073 switched to triple regimens, 104 to dual (72 with 1 nucleoside reverse transcriptase inhibitor (NRTI), 32 NRTI-sparing), and 64 to monotherapy. At 12 months after the switch, for the multivariable linear regression the mean change in the log 10 CD4/CD8 ratio for patients on dual therapy was −0.03 (95% confidence interval (CI) –0.05, –0.0002), and the mean change in CD8 count was +99 (95% CI +12.1, +186.3), taking those on triple therapy as reference. In contrast, there was no evidence for a difference in CD4 count change. When using all counts, there was evidence for a significant difference in the slope of the ratio and CD8 count between people who were switched to triple (points/year change ratio = +0.056, CD8 = −25.7) and those to dual regimen (ratio = −0.029, CD8 = +110.4). Conclusions We found an increase in CD8 lymphocytes in people who were switched to dual regimens compared to those who were switched to triple. Patients on monotherapy did not show significant differences. The long-term implications of this difference should be ascertained.

The effectiveness of using only glucocorticoids (GCs) in mild multisystem inflammatory syndrome (MIS-C) cases was compared with combined treatment [GCs + Intravenous immune globulin (IVIG)]. This retrospective cohort study was conducted between June 1, 2020, and June 1, 2022, in a tertiary care center in Istanbul, Turkey. Clinical and investigational data of the MIS-C patients were analyzed. The patients were divided into two groups: those who received only GCs and those who received the GCs + IVIG combination. The primary outcome focused on assessing the deterioration of the patient's clinical condition, the occurrence of shock, admission to the pediatric intensive care unit (PICU), and the need for additional immunosuppressive medication. Secondary outcomes included evaluating the course of cardiovascular and infection-related complications observed at the one-year follow-up. Ninety-seven MIS-C patients with a median age of 41 (3‐ 214) months were enrolled. Fifty-six (57.7%) patients were male. All the patients had fever at admission with a temperature of 39 °C (37.5 °C–40.1 °C). Thirty-two patients (33%) had cardiac findings on echocardiography [left ventricular dysfunction (n= 13, 13.5%), coronary artery involvement (n= 11, 11.3%), and dilation of cardiac cavities and/or increased cardiac muscle thickness (n= 8, 8.2%)]. Thirteen patients (13.5%) required intensive care. All patients received GCs [only GCs (group I; n= 65, 67%)], and 32 patients (33%) with severe manifestations and/or cardiac involvement received GCs + IVIG (group II). No mortality was observed. None of the patients had any complaints at the one-year follow-up, and all echocardiography findings were normal. This study provides preliminary evidence that GC monotherapy is a safe treatment alternative for mild MIS-C cases without cardiac involvement.

Objective To evaluate and compare the effects of laser monotherapy with non-surgical mechanical instrumentation alone in untreated periodontitis patients. Materials and methods A focused question was formulated based on the Population, Intervention, Comparison, Outcome, and Study design criteria (PICOS): in patients with untreated periodontitis, does laser mono-therapy provide adjunctive effects on pocket probing depth (PPD) changes compared with non-surgical instrumentation alone? Both randomized controlled clinical trials (RCTs) and controlled clinical trials (CCTs) were included. The results of the meta-analyses are expressed as weighted mean differences (WMD) and reported according to the PRISMA guidelines. Results The search yielded 1268 records, out of which 8 articles could be included. With respect to PPD changes, a meta-analysis including 5 articles ( n = 148) failed to identify statistically significant differences in favor of laser monotherapy for PPD change (WMD = 0.14 mm; 95% CI: − 0.04/0.32; z = 1.51; p = 0.132) nor for clinical attachment level (CAL) (WMD = 0.04 mm; 95% CI: − 0.35/0.42; z = 0.19; p = 0.850). Data on cost-effectiveness are lacking. One study reported patient-related outcome measures (PROMS). Conclusions In untreated periodontitis patients, laser monotherapy does not yield superior clinical benefits compared with non-surgical mechanical instrumentation alone. Clinical relevance In untreated periodontitis patients, mechanical instrumentation with hand and/or ultrasonic instruments remains the standard of care.

Recent studies have shown similar safety and efficacy of short-term dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor (P2Y12i) monotherapy when compared with standard DAPT. However, the optimal DAPT duration and regimen in acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention is still unclear. Online databases were searched for randomized controlled trials evaluating P2Y12i monotherapy after short DAPT (≤3 months) versus standard DAPT (≥12 months) in ACS patients. The outcomes of interest were all-cause death, cardiovascular death, myocardial infarction, stent thrombosis, target-vessel revascularization, and major bleeding. Random-effects model was used to calculate pooled odds ratios (OR) and 95% confidence intervals (CI). Six randomized controlled trials with a total of 23,884 patients (n = 11,904 P2Y12i monotherapy, n = 11,980 standard DAPT) were included. Compared with standard DAPT, P2Y12i monotherapy after short DAPT was associated with similar odds of all-cause death (OR 0.86, 95% CI 0.65 to 1.12, p = 0.26) and cardiovascular death (OR 0.75, 95% CI 0.43 to 1.29, p = 0.29) at 1 year. Similarly, there were no significant differences in rates of myocardial infarction (OR 1.09, 0.83 to 1.43, p = 0.53), stent thrombosis (OR 1.09, 95% CI 0.71 to 1.67, p = 0.70) and target-vessel revascularization (OR 0.81, 95% CI 0.65 to 1.01, p = 0.07) between the P2Y12i monotherapy and standard DAPT arms. The P2Y12i monotherapy group had significantly lower major bleeding (OR 0.49, 95% CI 0.38 to 0.64, p < 0.001) when compared with standard DAPT. In conclusion, in patients with ACS who underwent percutaneous coronary intervention, P2Y12i monotherapy after short DAPT significantly reduces bleeding without increasing ischemic risk when compared with standard DAPT therapy. [Display omitted]

Pancreatic cancer remains a challenging disease with limited treatment options, resulting in high mortality rates. The predominant approach to managing pancreatic cancer patients continues to be systemic cytotoxic chemotherapy. Despite substantial advancements in immunotherapy strategies for various cancers, their clinical utility in pancreatic cancer has proven less effective and durable. Whether administered as monotherapy, employing immune checkpoint inhibitors, tumor vaccines, chimeric antigen receptors T cells, or in combination with conventional chemoradiotherapy, the clinical outcomes remain underwhelming. Extensive preclinical experiments and clinical trials in the realm of pancreatic cancer have provided valuable insights into the complexities of immunotherapy. Chief among the hurdles are the immunosuppressive tumor microenvironment, limited immunogenicity, and the inherent heterogeneity of pancreatic cancer. In this comprehensive review, we provide an overview and critical analysis of current clinical immunotherapy strategies for pancreatic cancer, emphasizing their endeavors to overcome immunotherapy resistance. Particular focus is placed on strategies aimed at reshaping the immunosuppressive microenvironment and enhancing T cell-mediated tumor cell killing. Ultimately, through deeper elucidation of the underlying pathogenic mechanisms of pancreatic cancer and the refinement of therapeutic approaches, we anticipate breakthroughs that will pave the way for more effective treatments in this challenging disease.

BackgroundImmune-checkpoint inhibitors (ICIs) emerged as a novel class of drugs for the treatment of a broad spectrum of malignancies. ICIs can produce durable antitumor responses but they are also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs.MethodsThis study aimed to quantify association of endocrine adverse events (AEs) and ICI therapy and also to characterize the profiles of ICI-related endocrine complications from real-world practice. Data from the first quarter of 2014 to first quarter of 2019 in FDA Adverse Event Reporting System (FAERS) database were gathered to conduct disproportionality analysis. The definition of endocrine AEs relied on the preferred terms (PTs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Two signal indices based on statistical shrinkage transformation, reporting odds ratios (ROR) and information component (IC), were used to evaluate correlations between ICIs and endocrine events. For ROR, it was defined a signal if the lower limit of the 95% confidence interval (ROR025) more than one, with at least 3 cases. For IC, lower end of the 95% confidence interval of IC (IC025) exceeding zero was deemed statistically significant.ResultsA total of 29,294,336 records were involved, among these 6260 records related to endocrine AEs after ICIs treatment were identified. In general, male had a slightly lower reporting frequencies for ICIs-related endocrinopathies compared with female but not significant (ROR = 0.98 95%CI: 0.93–1.04) and the difference varied in several common endocrine AEs. Notably, in general, ICI drugs were significantly associated with over-reporting frequencies of endocrine complications, corresponding to IC025 = 2.49 and ROR025 = 5.99. For monotherapy, three strategies (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing endocrine events. Different reporting frequencies emerged when anti-CTLA-4 therapy was compared with anti-PD-1/PD-L1 medications for endocrine toxicities, corresponding to ROR = 1.68 (95%CI 1.55–1.83), ROR = 2.54 (95%CI 2.20–2.93), respectively. Combination therapy was associated with higher risk of endocrinopathies compared with monotherapy (ROR = 2.00, 95%CI 1.89–2.11). When further analysis, the spectrum of endocrine AEs differed in immunotherapy regimens. Hypothyroidism (N = 885,14.14%), adrenal insufficiency(N = 730,11.66%), hypophysitis (N = 688,10.99%) and hyperthyroidism (N = 472,7.54%) were top 4 ranked endocrine events after ICI therapy and their reporting frequency also differed in ICI immunotherapies.ConclusionOur pharmacovigilance analysis shows a high reporting frequency of endocrine AEs provoked by ICI monotherapy (especially anti-CTLA-4 therapy) and further reinforced by combination therapy. In addition, treatment with different ICI immunotherapies may result in a unique and distinct profile of endocrinopathies. Early recognition and management of ICI-related endocrine irAEs is of vital importance in clinical practice.

Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use as monotherapy and adjunctive therapy. A systematic review and a meta-analysis were conducted on randomized placebo-controlled trials (RCTs) that reported on the efficacy and safety/tolerability of antipsychotics for the treatment of adults with MDD. Data of both monotherapy and adjunctive antipsychotic use were extracted, but analyzed separately using a random-effects model. Co-primary outcomes were study-defined-treatment response and intolerability-related discontinuation. We also illustrated the risk/benefit balance of antipsychotics for MDD, using two-dimensional graphs representing the primary efficacy and safety/tolerability outcome. Secondary outcomes included psychopathology, remission, all-cause-discontinuation, inefficacy-related discontinuation, and adverse events. Forty-five RCTs with 12 724 patients were included in the analysis. In monotherapy (studies = 13, n = 4375), amisulpride [1.99 (1.55-2.55)], sulpiride [1.50 (1.03-2.17)], and quetiapine [1.48 (1.23-1.78)] were significantly superior to placebo regarding treatment response. However, intolerability-related discontinuations were significantly higher compared to placebo with amisulpride and quetiapine. In adjunctive therapy (studies = 32, n = 8349), ziprasidone [1.80 (1.07-3.04)], risperidone [1.59 (1.19-2.14)], aripiprazole [1.54 (1.35-1.76)], brexpiprazole [1.41 (1.21-1.66)], cariprazine [1.27 (1.07-1.52)], and quetiapine [1.23 (1.08-1.41)] were significantly superior to placebo regarding treatment response. However, of these antipsychotics that were superior to placebo, only risperidone was equivalent to placebo regarding discontinuation due to intolerability, while the other antipsychotics were inferior. Results suggest that there are significant differences regarding the risk/benefit ratio among antipsychotics for MDD, which should inform clinical care.

Infliximab (IFX) is effective in the treatment of inflammatory bowel disease; however, the effect is often not durable. It is unknown if proactive therapeutic concentration monitoring (TCM) of IFX improves outcomes.MethodsThis is a retrospective observational study examining the use of proactive TCM and titration of IFX to a target concentration for patients with inflammatory bowel disease in clinical remission at a tertiary care center. The primary aim was to describe the clinical course of patients who had proactive TCM. A secondary analysis was done to assess if this strategy was superior to the standard of care.ResultsForty-eight patients were identified as having proactive TCM. Fifteen percent had an initial undetectable trough concentration. Twenty-five percent (12 of 48) of patients escalated IFX after the first proactive TCM while 15% (7 of 48) of patients de-escalated IFX therapy over the study period. A control group of 78 patients was identified. Patients who had proactive TCM had a greater probability of remaining on IFX than controls (hazard ratio, 0.3; 95% confidence interval, 0.1–0.6; log rank test; P = 0.0006). The probability of remaining on IFX was greatest for patients who achieved a trough concentration >5 μg/mL (hazard ratio, 0.03; 95% confidence interval, 0.01–0.1; P < 0.0001 versus trough <5 μg/mL). Fewer patients in the proactive TCM group stopped IFX (10% versus 31%, P = 0.009).ConclusionsIn this pilot observational study, proactive TCM of IFX frequently identified patients with low or undetectable trough concentrations and resulted in a greater probability of remaining on IFX.

AbstractObjectiveTo evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis.DesignInvestigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study.SettingTwenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018.ParticipantsPatients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein.InterventionsRandomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab.Main outcome measuresThe primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms.Results812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms.ConclusionsAll four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.Trial registrationEudraCT2011-004720-35, NCT01491815.