Short-term Clinical Trials Research Articles

Cost-effectiveness of direct oral anticoagulants compared to low-molecular-weight-heparins for treatment of cancer associated venous thromboembolism in Spain

Aim Recent studies have compared the efficacy and safety of direct-acting oral anticoagulants (DOAC) and low-molecular-weight heparin (LMWH) for cancer-associated venous thromboembolism (VTE). However, there is no available cost-effectiveness analysis comparing DOAC and LMWH. The study aimed to conduct a cost-effectiveness analysis of DOAC (apixaban, edoxaban, and rivaroxaban) vs. LMWH for the treatment of cancer-associated VTE in Spain from the Spanish healthcare system perspective. Methods We developed a Markov model with a 12-month time horizon. The states included pulmonary embolism, deep vein thrombosis, major and non-major bleeding, chronic thromboembolic pulmonary hypertension, post-thrombotic syndrome, and death. The use of medical resources and drug costs were obtained from the 2021 Spanish Ministry of Health database, and the main references for obtaining the outcomes were derived from Caravaggio, Hokusai VTE Cancer, ADAM VTE, and SELECT-D trials. We performed a deterministic and probabilistic sensitivity analysis to validate the robustness. The Incremental Cost-Effectiveness Ratio (ICER) scores cost per life-year (€/LY) gained and cost per quality-adjusted life-year (€/QALY) gained. Results The 12-month cost of DOAC was 1,994€ (apixaban 1,944€, edoxaban 1,968€, rivaroxaban 2,122€) and 2,152€ for LMWH. The amount of QALY for DOAC was 0.54 (apixaban 0.55, rivaroxaban 0.53, and edoxaban 0.52) and 0.53 for LMWH. We observed similar results for LYs. ICER scores in terms both of €/LY and €/QALY show that DOAC is dominant over LMWH and apixaban showed the best profile. Limitations Our research is based on an indirect comparison of a short-term clinical trial. Conclusion Our results suggest that DOAC is cost-effective and cost-saving compared to LMWH in treating VTE.

Ruxolitinib in patients with polycythemia vera with hydroxyurea resistance or intolerance

The clinical triumvirate of polycythemia vera include disease-related symptoms, vascular events, and transformation to myelofibrosis or blast phase. However, regulatory approval for polycythemia vera directed therapy is dependent on the achievement of a complete hematological response or phlebotomy associated goals (short-term clinical trial endpoints) that might not affect the most clinically relevant outcome measures of thrombosis, progression, and overall survival due to longer time to event, and lower incidence, which make polycythemia vera a challenging disease to evaluate in prospective trials.

Demonstrating Benefit-Risk Profiles of Novel Therapeutic Strategies in Kidney Transplantation: Opportunities and Challenges of Real-World Evidence.

While great progress has been made in transplantation medicine, long-term graft failure and serious side effects still pose a challenge in kidney transplantation. Effective and safe long-term treatments are needed. Therefore, evidence of the lasting benefit-risk of novel therapies is required. Demonstrating superiority of novel therapies is unlikely via conventional randomized controlled trials, as long-term follow-up in large sample sizes pose statistical and operational challenges. Furthermore, endpoints generally accepted in short-term clinical trials need to be translated to real-world (RW) care settings, enabling robust assessments of novel treatments. Hence, there is an evidence gap that calls for innovative clinical trial designs, with RW evidence (RWE) providing an opportunity to facilitate longitudinal transplant research with timely translation to clinical practice. Nonetheless, the current RWE landscape shows considerable heterogeneity, with few registries capturing detailed data to support the establishment of new endpoints. The main recommendations by leading scientists in the field are increased collaboration between registries for data harmonization and leveraging the development of technology innovations for data sharing under high privacy standards. This will aid the development of clinically meaningful endpoints and data models, enabling future long-term research and ultimately establish optimal long-term outcomes for transplant patients.

Outcomes for patients with severe chronic neutropenia treated with granulocyte colony-stimulating factor

AbstractSevere chronic neutropenia (SCN), defined as blood neutrophils <0.5 × 109/L for >3 months, is an uncommon hematological condition associated with recurrent and severe bacterial infections. After short-term clinical trials showed the benefits of granulocyte colony-stimulating factor (G-CSF) treatment for SCN, SCNIR (Severe Chronic Neutropenia International Registry) opened to determine the long-term benefits and safety of this treatment. This report summarizes findings from more than 16 000 patient-years of prospective observations for patients with congenital and acquired SCN. We observed that adverse outcomes depend on the underlying etiology. Myelodysplasia (MDS) and acute myeloid leukemia (AML) occur infrequently and largely in patients with congenital neutropenias. Having cyclic or chronic autoimmune/ idiopathic neutropenia portends a favorable prognosis. A few patients with idiopathic neutropenia evolve to develop lymphoid malignancies, but they do not appear to be at increased risk of myeloid malignancies, even with very long-term G-CSF therapy. Progression to systemic autoimmune diseases, bone marrow (BM) failure, aplastic anemia, or nonmyeloid malignancies are not expected consequences of SCN or treatment with G-CSF.

Treatment and clinical endpoints in polycythemia vera: seeking the best obtainable version of the truth

AbstractPolycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm driven by the JAK2 V617F (or rarely exon 12) mutation. Its natural history can extend over a few decades, and therefore treatment planning is predicated on continual reassessment of traditional risk features (age, prior thrombosis) to evaluate the need for cytoreduction besides foundational therapy with low-dose aspirin and stringent phlebotomy. Shorter- and longer-term patient goals should be considered in light of several variables such as comorbid conditions (especially cardiovascular risk factors), disease symptoms, and the risk-benefit profile of available drugs. While hydroxyurea has been the pro forma choice of cytoreduction for many practitioners over the last half-century, the more recent regulatory approvals of ruxolitinib and ropeginterferon-alfa-2b, based on phase 3 randomized trials, highlight an expanding portfolio of active drugs. Obtaining high-level evidence for short-term clinical trial endpoints such as hematocrit control, symptom burden/quality of life, splenomegaly, and JAK2 V617F allele burden lies within the timeline of most studies. However, in many cases, it may not be possible to adequately power trials to capture significant differences in the typically low event rates of thrombosis as well as longer-horizon endpoints such as evolution to myelofibrosis and acute myeloid leukemia and survival. This Perspective highlights the challenges of addressing these data gaps and outstanding questions in the emerging treatment landscape of PV.

The Effect of Elexacaftor/Tezacaftor/Ivacaftor on Hospitalizations and Intravenous Antibiotic Use.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective cystic fibrosis transmembrane conductance regulator modulator. It has been shown to improve lung function and decrease pulmonary exacerbations in short-term clinical trials. The effect of ETI on hospitalization and intravenous (IV) antibiotic rates is not known. We performed a single-institution, retrospective review comparing these rates before and after the initiation of ETI. Among patients taking the cystic fibrosis modulator ETI, we compared the cumulative number of days per month hospitalized and cumulative number of days per month on IV antibiotics before and after the initiation of ETI. Electronic medical records from 37 patients were reviewed from 2016 through 2020 to identify demographic data, hospitalizations, and antibiotic use. Results were then stratified by severity of lung disease. Following the initiation of ETI, there was a decline in days per month hospitalized and on IV antibiotics. The cumulative average number of days per month patients were hospitalized decreased 86% from 27 to 4 after starting ETI. The cumulative average number of days per month on IV antibiotics decreased by 80% (32.5 to 6.4). Most of these reductions occurred among patients with severe lung disease. At our institution, we saw a decline in cystic fibrosis-related hospitalizations and in the use of outpatient IV antibiotics following the initiation of ETI. These reductions were most pronounced among patients with severe lung disease. The initiation of ETI was associated with a decline in days hospitalized and days on IV antibiotics.

Durability of the Clinical Benefit of Droxidopa for Neurogenic Orthostatic Hypotension During 12 Weeks of Open-Label Treatment.

IntroductionDroxidopa is approved to treat neurogenic orthostatic hypotension (nOH) symptoms in patients with autonomic failure based on short-term clinical trial data. Additional data on the long-term efficacy of droxidopa are needed. We have evaluated the 12-week efficacy and tolerability of droxidopa in patients with nOH in an open-label period of an ongoing phase 4 study .MethodsPatients received 12 weeks of open-label treatment with an individually optimized droxidopa dose (100–600 mg, 3 times daily) as identified during a preceding titration period. Patient-reported outcomes included the Orthostatic Hypotension Symptom Assessment (OHSA), Orthostatic Hypotension Daily Activity Scale (OHDAS), and clinician- and patient-rated Clinical Global Impression–Severity (CGI-S) scales. Supine blood pressure (BP) and adverse events (AEs) were recorded.ResultsData from 114 patients enrolled into the 12-week open-label period were available for analyses. After 12 weeks of droxidopa treatment, patients reported significant (P < 0.0001) improvements from baseline in OHSA and OHDAS composite and individual item scores and on clinician and patient CGI-S scores. Mean ± SD supine systolic and diastolic BP at week 12 increased by 15.5 ± 22.9 and 7.8 ± 11.7 mmHg from baseline, respectively (P < 0.0001 for both). The most frequently reported AEs were falls (17%), headache (13%), and dizziness (9%); one (0.9%) patient reported an AE of supine hypertension.ConclusionDuring 12 weeks of open-label treatment, droxidopa was associated with significant improvement from baseline in nOH symptoms and activities of daily living. No clinically important changes in supine hypertension or AEs of concern were observed. These results support the efficacy of droxidopa beyond 2 weeks of treatment. Trial RegistrationNCT02586623.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00317-5.

POS-203 LONG-TERM OUTCOMES OF ADD-ON DIRECT RENIN INHIBITION IN IMMUNOGLOBULIN A NEPHROPATHY: A RETROSPECTIVE, PROPENSITY SCORE-MATCHED COHORT STUDY

The addition of the direct renin inhibitor (DRI) aliskiren to an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEi) in IgA nephropathy (IgAN) has been shown to confer additional antiproteinuric effects in two short-term clinical trials. The long-term effect of this combination remains unknown and hence neglected in clinical practice. Thirty six patients with IgAN who had been treated with DRI and ARB for at least 6 months between 2009 to 2010 were identified and retrieved from a linked electronic database. A 1:1 propensity-score matching cohort from the same period that received ARB without aliskiren exposure was used to calculate the hazard ratio of reaching the primary endpoint, defined as a composite of a 40% reduction in estimated glomerular filtration rate (eGFR), initiation of kidney replacement therapy (KRT) and all-cause mortality. Secondary outcome measures included changes in mean urine protein-to-creatinine ratio (UPCR), blood pressure, eGFR, incidence of hyperkalemia and other adverse events during follow-up. After a median follow-up of 10.8 years, 25/36 (69.4%) patients in the aliskiren group and 21/36 (58.3%) patients in the control group reached the primary composite outcome (HR=2.17; 95% CI: 1.18 to 3.98; P=0.013). Aliskiren treatment was associated with an increased risk of >40% eGFR decline (HR=2.17; 95% CI: 1.18 to 3.98; P=0.013), initiation of KRT (HR=1.97; 95% CI: 0.92 to 4.21; P=0.079), and all-cause mortality (HR=2.08; 95% CI: 0.19 to 22.70; P=0.556). The incidence of hyperkalemia was significantly higher in the aliskiren group (HR=5.13; 95%CI: 1.68 to 15.63; P=0.004). After a follow up of 60 months, 16/36 (44.4%) in aliskiren and 9/36 (25.0%) in control group subjects reached the primary composite outcome (HR=2.19; 95%CI: 0.94 to 5.13, P=0.070). The mean UPCR reduction was 10.2% more in the aliskiren group (52.7% vs 42.5%; 95%CI: 0.63 to 2.35;P=0.556). Mean intergroup difference in eGFR decline over 60 months was 7.75±3.95 ml/min/1.73m 2 more in the aliskiren group (12.83 vs 5.08; 95%CI: -0.17 to 15.66; P=0.055). Although add-on aliskiren reduced proteinuria in short-term studies, it was associated with less favourable long-term kidney outcomes among patients with IgAN.

Efficacy of fibroblast growth factor 21 in non-alcoholic fatty liver disease in guinea pigs.

Fibroblast growth factor 21 (FGF21) agonists have shown promising effects in preclinical models of non-alcoholic fatty liver disease (NAFLD) as well as in short-term clinical trials in patients with non-alcoholic steatohepatitis (NASH). Comparing drug formulation, dose, administration route and age, this exploratory study investigated effects of FGF21 on NAFLD-associated measures in a validated guinea pig model. In three separate studies, female guinea pigs received a high-fat diet prior to intervention with escalating doses of either recombinant native human FGF21 or a human FGF21 human recombinant analogue (FGF21/19 chimer) with an extended half-life. While no significant effects of native FGF21 on the investigated endpoints were observed, the long-acting FGF21/19 chimer significantly altered the levels of circulating lipids, increasing plasma concentrations of cholesterol (TC, LDLc and HDLc) in young guinea pigs (p < 0.01 for all three parameters). Relative liver weights were reduced in FGF21/19-treated young animals (p < 0.05) compared to mature animals, whereas FGF21/19 reduced body weights in both age groups (p < 0.001). The FGF21/19 chimer effects on dyslipidemia, body and liver weights particularly in young animals, support an age-associated difference in the FGF21 response. The limited effects of the native human FGF21 highlights potential species-associated differences of this compound.

Ulotaront, a novel TAAR1 agonist with 5-HT1A agonist activity, lacks abuse liability and attenuates cocaine cue-induced relapse in rats

BackgroundUlotaront (SEP-363856) is a trace amine-associated receptor 1 (TAAR1) agonist with 5-hydroxytryptamine type 1A (5-HT1A) agonist activity that is currently in Phase 3 clinical development for the treatment of schizophrenia. Unlike available antipsychotics, the efficacy of ulotaront is not mediated by blockade of dopamine D2 or serotonin 5-HT2A receptors. In a short-term randomized clinical trial, ulotaront has demonstrated significant efficacy in the treatment of adults with an acute exacerbation of schizophrenia. Given ulotaront’s novel mechanism of action a series of preclinical studies were performed to evaluate its potential abuse liability. MethodsA battery of studies were conducted in male and female rats to evaluate whether ulotaront produces behavioral changes suggestive of human abuse potential. In addition, studies were undertaken to probe the potential for ulotaront to block reinstatement of cocaine-seeking behavior in male rats. ResultsUlotaront was not self-administered by rats trained to self-administer amphetamine, cocaine, or heroin. The subjective qualities of ulotaront were distinct from those produced by amphetamine in a drug discrimination procedure. Ulotaront, and buspirone, a non-scheduled anxiolytic with 5-HT1A agonism, partially generalized to the interoceptive cue elicited by 3, 4-methylenedioxymethamphetamine (MDMA). In addition, ulotaront demonstrated a trend to reduce cocaine-primed induced reinstatement, and dose-dependently reduced cue-reinstated responding. ConclusionThe current results suggest that the TAAR1/5-HT1A agonist ulotaront is not likely to pose a risk for recreational abuse in humans and may have potential therapeutic utility as a treatment of substance use disorders.

Modification of High-Density Lipoprotein Functions by Diet and Other Lifestyle Changes: A Systematic Review of Randomized Controlled Trials.

High-density lipoprotein (HDL) functional traits have emerged as relevant elements that may explain HDL antiatherogenic capacity better than HDL cholesterol levels. These properties have been improved in several lifestyle intervention trials. The aim of this systematic review is to summarize the results of such trials of the most commonly used dietary modifications (fatty acids, cholesterol, antioxidants, alcohol, and calorie restriction) and physical activity. Articles were screened from the Medline database until March 2021, and 118 randomized controlled trials were selected. Results from HDL functions and associated functional components were extracted, including cholesterol efflux capacity, cholesteryl ester transfer protein, lecithin-cholesterol acyltransferase, HDL antioxidant capacity, HDL oxidation status, paraoxonase-1 activity, HDL anti-inflammatory and endothelial protection capacity, HDL-associated phospholipase A2, HDL-associated serum amyloid A, and HDL-alpha-1-antitrypsin. In mainly short-term clinical trials, the consumption of monounsaturated and polyunsaturated fatty acids (particularly omega-3 in fish), and dietary antioxidants showed benefits to HDL functionality, especially in subjects with cardiovascular risk factors. In this regard, antioxidant-rich dietary patterns were able to improve HDL function in both healthy individuals and subjects at high cardiovascular risk. In addition, in randomized trial assays performed mainly in healthy individuals, reverse cholesterol transport with ethanol in moderate quantities enhanced HDL function. Nevertheless, the evidence summarized was of unclear quality and short-term nature and presented heterogeneity in lifestyle modifications, trial designs, and biochemical techniques for the assessment of HDL functions. Such findings should therefore be interpreted with caution. Large-scale, long-term, randomized, controlled trials in different populations and individuals with diverse pathologies are warranted.

Sodium-glucose cotransporter 2 inhibitors and anemia among diabetes patients in real clinical practice.

Aims/IntroductionSodium–glucose cotransporter 2 inhibitors (SGLT2i) were reported to increase hemoglobin levels in short‐term clinical trials. Whether it is also true in real clinical practice is unknown.Materials and MethodsThis is a retrospective cohort study. Inclusion criterion was diabetes patients who visited our outpatient clinic from January 2019 to August 2020. Exposure of interest was the use of SGLT2i. Outcomes were hemoglobin levels. For the cross‐sectional analyses, non‐linear regression models were fitted with restricted cubic splines to investigate the association between hemoglobin levels and estimated glomerular filtration rate (eGFR) for users and non‐users of SGLT2i. For the case–control study, cases (anemia defined as hemoglobin <120 g/L for men, <110 g/L for women or the use of erythropoiesis stimulating agents) and controls were matched by age, sex and eGFR.ResultsAmong 2,063 diabetes patients, 723 were taking SGLT2i. In the cross‐sectional analyses, hemoglobin levels were higher among SGLT2i users compared with non‐users at eGFR >15 mL/min/1.73 m2. For the case–control study, 197 cases and controls were matched. Conditional logistic regression showed that the use of SGLT2i was associated with significantly lower prevalence of anemia (odd ratio 0.35, 95% confidence interval 0.21–0.58). Adjusted mean differences in hemoglobin levels between users and propensity score‐matched non‐users of SGLT2i were 7.0 g/L (95% confidence interval 3.0–10.0 g/L) at 6 months. Among SGLT2i users, the odds of an increase in 6‐month hemoglobin were similar across eGFR categories, except for eGFR <15 mL/min/1.73 m2.ConclusionsThe use of SGLT2i was associated with higher hemoglobin levels and lower prevalence of anemia in real clinical practice.

Titanium Nitride Coated Implant Abutments: From Technical Aspects And Soft tissue Biocompatibility to Clinical Applications. A Literature Review.

To review the most up to date scientific evidence concerning the technical implications, soft tissue biocompatibility, and clinical applications derived from the use of titanium nitride hard thin film coatings on titanium alloy implant abutments. A review was performed to answer the following focused question: "What is the clinical reliability of nitride coated titanium alloy abutments?". A MEDLINE search between 1980 and 2021 was performed for investigations pertaining to the clinical use of nitride coated titanium alloy implant abutments (TiN) in case reports, case series, and short- and long-term non/randomized controlled clinical trials. Literature analysis led to addition evaluation of research related to the technical and biological aspects, as well as the physicochemical characteristics of TiN hard thin film coatings and their impact on titanium abutment biocompatibility, mechanical properties, macroscopic surface topography, and optical properties. Therefore, preclinical data from biomechanical and in vitro investigations were also considered as inclusion criteria. The limited number of clinical investigations published made a systematic review and meta-analysis not possible, therefore a narrative review was conducted. TiN coatings have been applied to dental materials and instruments to improve their clinical longevity. Implant abutments are coated with titanium nitride to mask the titanium oxide surface and enhance its surface characteristics providing the TiN abutment surface with a low friction coefficient and a very high chemical inertness. TiN coating is suggested to reduce early bacterial colonization and biofilm formation and enhance fibroblast cell proliferation, attachment and adhesion when compared to Ti controls. Additionally, studies indicate that hard thin film coatings enhance the mechanical properties (hardness and wear resistance) of titanium alloy and appears as a yellow color when deposited on the titanium alloy substrate. To date, clinical investigations show that nitride coated titanium abutments provide promising short-term clinical outcomes. Published research on nitride-coated abutments is still limited, however, the available biomedical research, mechanical engineering tests, in vitro investigations, and short-term clinical trials have, to date, reported promising mechanical, biological, and esthetic outcomes.

Pioglitazone transiently stimulates paraoxonase-2 expression in male nonhuman primate brain: Implications for sex-specific therapeutics in neurodegenerative disorders

Paraoxonase-2 (PON2) enhances mitochondria function and protects against oxidative stress. Stimulating its expression has therapeutic potential for diseases where oxidative stress plays a significant role in the pathology, such as Parkinson's disease. Clinical and preclinical evidence suggest that the anti-diabetic drug pioglitazone may provide neuroprotection in Parkinson's disease, Alzheimer's disease, and stroke, but the biochemical pathway(s) responsible has not been fully elucidated. To determine the effect of pioglitazone on PON2 expression we treated male African green monkeys with oral pioglitazone (5 mg/kg/day) for 1 and 3 weeks. We found that pioglitazone increased PON2 mRNA and protein expression in brain following 1 week of treatment, however, by 3 weeks of treatment PON2 expression had returned to baseline. This transient increase was detected in substantia nigra, striatum, hippocampus, and dorsolateral prefrontal cortex The short-term impact of pioglitazone on PON2 expression in striatum may contribute to the discrepancy in the potency of the drug between short-term animal models and clinical trials for Parkinson's disease. Both PON2 and pioglitazone's receptor, peroxisome proliferator-activated receptor gamma (PPARγ), possess sex- and brain region-dependent expression, which may play a role in the short-term effect of pioglitazone and provide clues to extending the beneficial effects of PON2 activation.

COVID-19 Breakthrough Infections and Transmission Risk: Real-World Data Analyses from Germany's Largest Public Health Department (Cologne).

Background and Methods: Vaccination is currently considered the most successful strategy for combating the SARS-CoV-2 virus. According to short-term clinical trials, protection against infection is estimated to reach up to 95% after complete vaccination (≥14 days after receipt of all recommended COVID-19 vaccine doses). Nevertheless, infections despite vaccination, so-called breakthrough infections, are documented. Even though they are more likely to have a milder or even asymptomatic course, the assessment of further transmission is highly relevant for successful containment. Therefore, we calculated the real-world transmission risk from fully vaccinated patients (vaccination group, VG) to their close contacts (CP) compared with the risk from unvaccinated reference persons matched according to age, sex, and virus type (control group = CG) utilizing data from Cologne’s health department. Results: A total of 357 breakthrough infections occurred among Cologne residents between 27 December 2020 (the date of the first vaccination in Cologne) and 6 August 2021. Of the 979 CPs in VG, 99 (10.1%) became infected. In CG, 303 of 802 CPs (37.8%) became infected. Factors promoting transmission included non-vaccinated status (β = 0.237; p < 0.001), male sex (β = 0.079; p = 0.049), the presence of symptoms (β = −0.125; p = 0.005), and lower cycle threshold value (β = −0.125; p = 0.032). This model explained 14.0% of the variance (corr. R2). Conclusion: The number of transmissions from unvaccinated controls was three times higher than from fully vaccinated patients. These real-world data underscore the importance of vaccination in enabling the relaxation of stringent and restrictive general pandemic control measures.

Effects of l-arginine and l-ornithine supplementations on the treatment of chronic periodontitis: A preliminary randomized short-term clinical trial

The growing interest in the possibilities of modulating macrophages in inflammatory diseases with therapeutic purpose has prompted the development of new approaches for the treatment of periodontitis. This randomized add-on open preliminary clinical study evaluated the short-term effects of L-arginine or L-ornithine as an adjuvant to scaling and root planing (SRP) in patients with chronic periodontitis. Materials and methodsSeventy-five periodontitis patients were recruited and monitored clinically and immunologically at baseline (before SRP) and 30 ± 5 days after SRP. All patients were assigned by stratified randomization to SRP (SRP only, n = 25), Arg (SRP + L-arginine, n = 25) or Control (SRP + L-ornithine, n = 25) Group. The medicines were used according to available instructions for 10 and 15 days, respectively. During the study, all patients were on a stable diet, without changing their rations and regiments. As immunological monitoring immunohistochemical study of CD68+ and CD163 + single positive gingival macrophages for 5 patients per group in the same time-point was conducted. The data were statistically analyzed. ResultsReduction of periodontal pocket depth (PPD) and bleeding on probing (BoP) was observed in all groups, with significant between-group differences for BoP in the Arg Group (p < 0.0001) at 30 days. The SRP and Arg groups demonstrated nonsignificantly increased density of CD68+ and CD163 + cells. The Orn Group showed an increase in the density of CD68+ and CD163 + macrophages at intragroup (p = 0.0066 and p < 0.0001) and between-group levels (p = 0.001 and p < 0.0001), and these changes corresponded to clinical PPD and BoP reduction. In the Arg and Orn groups at 30 days, CD163 + macrophages significantly predominated over CD68+ (p = 0.013, p < 0.0001). ConclusionThe use of L-arginine and L-ornithine as an adjunct to SRP promotes additional limited immunological benefit in the treatment of periodontitis. Metabolic stimulation with L-ornithine, but not L-arginine, is preferable for CD163+ Mφs subpopulation in periodontitis-affected gingiva.

Effect of drops containing Lactobacillus reuteri (DSM 17938 and ATCC PTA 5289) on plaque acidogenicity and other caries-related variables in orthodontic patients

BackgroundThe purpose of the study was to investigate the effect of probiotics on biofilm acidogenicity and on the number of salivary Streptococcus mutans and lactobacilli in orthodontic patients.MethodsThis RCT was conducted on 28 young adults who were undergoing orthodontic treatment. The short-term prospective clinical trial lasted for three weeks. The test group rinsed daily with drops containing two Lactobacillus reuteri strains diluted in water, while the placebo group used drops without probiotics. The subjects were enrolled eight months since the beginning of orthodontic treatment. Plaque-pH, saliva and dental biofilm samples were obtained at baseline, one week and three weeks post intervention.ResultsTwenty-seven subjects successfully completed the trial period, only one drop out in the test group. No side effects were reported. A statistically significant increase in plaque pH at three weeks post-intervention was found for the test group (p < 0.05), while insignificant changes in the pH value were found for the placebo group in comparison to baseline (p > 0.05). In addition, the AUC7.0 showed a significant difference at three weeks between the test and placebo (p = 0.00002). The three-week samples of stimulated whole saliva showed a statistically insignificant difference in the number of S. mutans and lactobacilli between the two groups (p > 0.05). The qPCR analysis showed the ability of the two strains to get colonized in the dental biofilm without a significant effect on the microbial counts.Conclusion/clinical implicationsA mixture of Lactobacillus reuteri has the ability to reduce the pH fall at the three-week follow-up. However, the short-term use of probiotics does not appear to have an effect on the number of salivary Streptococcus mutans and lactobacilli in saliva and on the dental biofilm.Trial registrationClinicaltrial.gov (Identifier: NCT04593017/ (19/10/2020)).

Long-term personalized low FODMAP diet improves symptoms and maintains luminal Bifidobacteria abundance in irritable bowel syndrome.

Short-term trials demonstrate the low FODMAP diet improves symptoms of irritable bowel syndrome (IBS) but impacts nutrient intake and the gastrointestinal microbiota. The aim of this study was to investigate clinical symptoms, nutrient intake, and microbiota of patients with IBS 12months after starting a low FODMAP diet. Participants enrolled in a previous short-term clinical trial and who had been through structured FODMAP restriction, reintroduction, and personalization were invited to participate in a follow-up study at one time point at 12months. Gastrointestinal symptoms, stool output, dietary intake, and quality of life were recorded. Stool samples were collected and analyzed for microbiota (qPCR) and short-chain fatty acids (SCFA). Data were compared with baseline (prior to any intervention in the original clinical trial) using non-parametric statistics. Eighteen participants were included in the study. Adequate relief of symptoms occurred in 5/18 (28%) at baseline and increased to 12/18 (67%) following long-term personalized low FODMAP diet (p=0.039). There was a reduction in IBS-SSS total score between baseline (median 227, IQR 99) and long term (154, 89; p<0.001). Bifidobacteria abundance was not different between baseline (median 9.29 log10 rRNA genes/g, IQR 1.45) and long term (9.20 log10 rRNA genes/g, 1.41; p=0.766, q=0.906); however, there were lower concentrations of total SCFA, acetate, propionate, and butyrate. In this long-term analysis, two thirds of patients reported adequate relief of symptoms after 12months of personalized low FODMAP diet that did not result in differences from baseline in Bifidobacteria. FODMAP reintroduction and personalization may normalize some of the effects of short-term FODMAP restriction.

No effect of approved fibromyalgia drugs on the social pain (invalidation) contrary to physical pain: an open-label short-term randomized clinical trial.

The social pain or invalidation denoting painful feeling following social conflicts or misunderstanding about illness legitimacy has been proposed as a salient disabling symptom besides physical pain or non-pain symptoms in fibromyalgia (FM). We sought to evaluate the effect of 1-month administration of duloxetine or pregabalin on the invalidation dimensions in FM patients with respect to the comparison of these two drugs on this issue. This open-label randomized clinical trial study was performed on FM patients whose diagnoses were confirmed by a rheumatologist based on the 2016 American College of Rheumatology (ACR). Primary outcome measure (Illness Invalidation Inventory (3*I)) and secondary outcome measures (Beck Depression Inventory-II (BDI-II), widespread pain index (WPI), and polysymptomatic distress scale (PSD)) were compared before and after treatment, using paired t test or Wilcoxon signed test. Of 81 eligible FM patients, 44 patients in the duloxetine arm and 27 patients in the pregabalin arm completed the study protocol. Overall, no significant improvement was seen in 3*I scores after treatment with either duloxetine or pregabalin, except in the lack of understanding of medical professionals which improved after treatment with pregabalin (2.43 ± 1.38 to 1.79 ± 0.94, p value: 0.01). There were no intragroup and intergroup differences in the effects of duloxetine and pregabalin on 3*I scores when adjusted with the cofounders. Both duloxetine and pregabalin improved WPI, BDI-II, and PSD scores significantly. Short-term FM pharmacological treatment had no effect on social pain. This finding was regardless of drug type, improvement of physical pain, and depression.

Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review.

Intranasal form of esketamine, the S-enantiomer of racemic ketamine, was approved by the US FDA in 2019 for treatment-resistant depression (TRD) in adults. Since intranasal esketamine is a newly approved drug with a novel mechanism of action, much still remains unknown in regard to its use in TRD. The objective of this study is to systematically review the latest existing evidence on intranasal esketamine, and provide a better insight into its safety and efficacy in TRD in adults.PubMed, MEDLINE (through PubMed), and Google Scholar were systematically searched from 2016 to 2021, using automation tools. After removal of duplicates and screening on the basis of title/abstract, eligibility criteria were applied and quality appraisal was done independently by two reviewers.A total of 10 studies were selected for the final review which included five clinical trials (three short-term trials, one withdrawal design relapse prevention study, and one long-term study), three post hoc studies, one case/non-case study, and one review article. Out of three short-term clinical trials, only one demonstrated a statistically significant difference between treatment with esketamine plus oral antidepressant (OAD) vs placebo plus OAD. The result of the relapse prevention study showed significantly delayed relapse of depressive symptoms in esketamine plus OAD arm when compared to placebo plus OAD arm. Similarly, the result of the long-term clinical trial showed that the improvement in depressive symptoms was found to be sustained in those using esketamine. The most common adverse effects of esketamine included nausea, dizziness, dissociation, headache, vertigo, somnolence, and dysgeusia (altered sense of taste); most were mild-moderate in severity. One case/non-case study reported rare adverse effects including panic attacks, mania, ataxia, akathisia, self-harm ideation, increased loquacity (talkativeness), and autoscopy.Intranasal esketamine has shown efficacy in reducing depressive symptoms in clinical trials, but the clinical meaningfulness of the treatment effect in the real-world population still needs to be explored. Although the safety profile of esketamine appears to be favorable in most clinical trials, some serious side effects are being reported to the FDA Adverse Event Reporting System, and therefore requires further investigation. More robust clinical trials, especially long-term randomized controlled trials are needed which can help provide a better assessment on the efficacy and safety of intranasal esketamine in the treatment of TRD.