Results Of Clinical Trials Research Articles

Patient scoring of outcomes for clinical trials that compare treatment options for bloodstream infections: a survey among adult inpatients

ObjectivesPatients' perspectives on outcomes of clinical trials is critical to the design of meaningful trials. As they are the primary recipients of treatment, it is important to focus on outcomes that are of value to the patients. We planned a study involving patients in defining and prioritizing endpoints for intervention trials for bloodstream infections (BSI). MethodsA survey was conducted at Rambam Health Care Campus, targeting hospitalized patients over 18 years old. Participants were asked to score the importance of various outcomes on a scale of 1 to 10, 10 being most important. We calculated the mean and median and dispersion measures per outcome. Results732 randomly selected patients were approached; 378 were not available due to technical reasons. Of the remaining 354 approached to take the survey, 300 consented and participated in the study. The median age was 51.9 years, with 55.3% female. Death was scored as the most important outcome, while the length of hospital stay was the least important. ConclusionsEliciting patient views on outcome importance was challenging but revealed key insights. Patients prioritized death, functional decline, and the development of secondary infections. Non-clinical outcomes, such as microbiological failure, were less clearly understood. Future studies should focus on clinical outcomes and include larger, more diverse patient populations to enhance the relevance of BSI trials.

Profile of Trofinetide in the Treatment of Rett Syndrome: Design, Development and Potential Place in Therapy.

Trofinetide is a first-in-class pharmacological treatment proposed for patients with Rett Syndrome. It is a long half-life derivative of glycine-proline-glutamate, the tripeptide normally excided from Insulin-like Growth Factor 1 upon degradation. Due to containing glutamate and glycine in its structure, trofinetide is thought to act through NMDA receptor modulation, thus providing a normalization of neuronal activity and survival. Trofinetide was tested in a series of short and long-term trials, showing good efficacy at improving scores on the Clinical Global Impression-Improvement scale and Rett Syndrome Behavior Questionnaire, with specific effect only on some subscales, ie General Mood subscale and Repetitive Face Movement subscale. No effects were documented on other subscales or on epilepsy, heart and bone -related symptoms. The main adverse effects of trofinetide, severe enough to determine discontinuation, include diarrhea, vomiting, and consequent weight loss. These may be scarcely avoidable, given the need to assume a very large amount of trofinetide per day. Other inherent limitations of use possibly regard the limited duration of drug supplies, as one bottle may last three days only, depending on weight, and the relatively high cost per bottle. Trofinetide has no direct competitors: single symptoms of the Rett Syndrome, for instance, seizures or aggressive behaviors, are currently treated with drugs that have been developed for patients without the Rett Syndrome. This leads to suboptimal efficacy and increased risk of adverse effects. The place in therapy of trofinetide is yet to be determined, based on the results of clinical trials, on its practical usability, and on the windows of opportunity for intervention. Moreover, trofinetide may be curative if given early enough during brain development, or merely symptomatic if given to young adults, and no data exist on this aspect. The place in therapy of trofinetide will require reassessment after competing treatments enter the market.

Safeguarding the brain from oxidative damage.

Oxidative stress imposes a substantial cellular burden on the brain and contributes to diverse neurodegenerative diseases. Various antioxidant signaling pathways have been implicated in oxidative stress and have a protective effect on brain cells by increasing the release of numerous enzymes and through anti-inflammatory responses to oxidative damage caused by abnormal levels of reactive oxygen species (ROS). Although many molecules evaluated as antioxidants have shown therapeutic potentials in preclinical studies, the results of clinical trials have been less than satisfactory. This review focuses on several signaling pathways involved in oxidative stress that are associated with antioxidants. These pathways have a protective effect against stressors by increasing the release of various enzymes and also exert anti-inflammatory responses against oxidative damage. There is no doubt that oxidative stress is a crucial therapeutic target in the treatment of neurological diseases. Therefore, it is essential to understand the discovery of multiple routes that can efficiently repair the damage caused by ROS and prevent neurodegenerative disorders. This paper aims to provide a concise and objective review of the oxidative and antioxidant pathways and their potential therapeutic applications in treating oxidative injury in the brain.

NNT and NNH: statistics and stochastics in the evaluation of added therapeutic value

Any pharmacological, invasive, surgical health intervention should have an added therapeutic value as well as the requirements of quality, safety, efficacy, to be considered as a medical device based on scientific evidence and of clinical utility for the patient. The intervention should be shared between the doctor and the patient who should have rigorous but simple tools to decide on the best therapy to undertake. Assessment of relative risk reduction is commonly used in the scientific literature to quantify both statistical and clinical significance. The reduction of the relative risk is independent of the baseline risk and is useful for comparing the results of trials conducted on populations at different risk levels. A biased reading of relative risk reduction can be used to emphasize the magnitude of the benefit for market innovation. The absolute risk reduction, on the other hand, is proportional to the magnitude of the baseline risk and is a more useful parameter for physicians and patients to understand the extent of benefit and harm, especially if the parameter is expressed in terms of the number needed to treat (NNT) or to harm (NNH). The mode of scientific communication is important for doctors' choices and patients' trust. Even true data can be fake in communication and perception by resorting to verbose paraphrases. Presenting the results of clinical trials in stochastic as well as statistical terms is useful for doctors and patients to verify whether it is worth practicing a certain treatment whose success sometimes has the probability of winning the lottery, also considering side effects and adverse events. One of the most important challenges in precision medicine will be understanding the relationship between probability and randomness.

Effect of Upper Robot-Assisted Training on Upper Limb Motor, Daily Life Activities, and Muscular Tone in Patients With Stroke: A Systematic Review and Meta-Analysis.

Upper limb rehabilitation robot is a relatively new technology, but its effectiveness remains debatable due to the inconsistent results of clinical trials. This article intends to assess how upper limb rehabilitation robots help the functional recovery of stroke patients. PubMed, Embase, Cochrane Library, and Web of Science databases were searched for eligible studies to explore the effect of upper limb rehabilitation robots on upper limb motor function, muscle tone, and daily living activities. Eighteen trials with 573 stroke patients met the inclusion criteria. The results showed that compared to conventional rehabilitation training, patients who received upper limb robotic therapy (RT) had significantly improved Fugl-Meyer Upper Extremity Motor Assessment (FMA-UE) scores (weighted mean differences [WMD]: 5.27, 95% confidence intervals [CI]: 3.36, 7.17), Action Research Arm Test (ARAT) scores (WMD: 4.07, 95% CI: -4.14, 12.28), Modified Barthel Index (MBI) scores (WMD: 9.55, 95% CI: 6.37, 12.73), and modified Ashworth Scale (MAS) scores (WMD: -0.28, 95% CI: -0.50, 0.06), with no significant heterogeneity. Upper limb robot-assisted training is superior to conventional training in terms of improving upper limb motor impairment, ability to perform daily living activities, and muscle tone recovery, which supports the application of robots in clinical practice.

Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma.

Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years. Recent therapies, notably immunotherapy and targeted therapy, have significantly improved the outcome of patients with metastatic melanoma. Previously dismal five-year survival rates of below 5% have shifted to over 50% of patients surviving the five-year mark, marking a significant shift in the landscape of melanoma treatment and survival. Unfortunately, about 50% of patients either do not respond to therapy or experience early or late relapses following an initial response. The underlying mechanisms for primary and secondary resistance to targeted therapies or immunotherapy and relapse patterns remain not fully identified. However, several molecular pathways and genetic factors have been associated with melanoma resistance to these treatments. Understanding these mechanisms paves the way for creating novel treatments that can address resistance and ultimately enhance patient outcomes in melanoma. This review explores the mechanisms behind immunotherapy and targeted therapy resistance in melanoma patients. Additionally, it describes the treatment strategies to overcome resistance, which have improved patients' outcomes in clinical trials and practice.

Effect of TLC-NOSF Dressing on Epithelization of Diabetic Wounds: A Pilot Clinical Trial

Background: The positive effects of technology-lipid-colloid (TLC) dressings impregnated with nano-oligosaccharide factors (NOSF) have been well documented. However, there is insufficient study on the specific impact of TLC-NOSF dressings on epithelization in patients with diabetes who have partial-thickness wounds. This article presents the results of a pilot clinical trial conducted to address the aforementioned issue.Methods: Twenty patients with diabetes who underwent split-thickness skin grafting were enrolled in this study. Half of the donor site was covered with a TLC-NOSF dressing, whereas the other half was covered with a TLC dressing. The ratio of complete epithelialization within 14 days postoperatively was compared between the two groups. Furthermore, progress of epithelialization was assessed to determine whether the TLC or TLC-NOSF dressing promoted more rapid epithelialization.Results: Seventeen patients completed the study. The percentages of complete epithelialization in the TLC and TLC-NOSF dressing groups were 41% (7/17) and 53% (9/17), respectively (P = 0.49). Regarding the degree of epithelialization, the differences between the TLC-NOSF and TLC dressing were not statistically significant. The TLC-NOSF dressing was superior in nine patients, while the TLC dressing was superior in two patients. Six patients demonstrated “no significant difference” (P = 0.11).Conclusion: Based on the current results alone, it is difficult to definitively conclude that TLC-NOSF dressings are superior to TLC dressings. However, these findings suggest a potential positive effect of TLC-NOSF dressings. Further large-scale studies are required to validate these results.

Anti-Cancer Strategy Based on Changes in the Role of Autophagy Depending on the Survival Environment and Tumorigenesis Stages.

Autophagy is a crucial mechanism for recycling intracellular materials, and under normal metabolic conditions, it is maintained at low levels in cells. However, when nutrients are deficient or under hypoxic conditions, the level of autophagy significantly increases. Particularly in cancer cells, which grow more rapidly than normal cells and tend to grow in a three-dimensional manner, cells inside the cell mass often face limited oxygen supply, leading to inherently higher levels of autophagy. Therefore, the initial development of anticancer drugs targeting autophagy was based on a strategy to suppress these high levels of autophagy. However, anticancer drugs that inhibit autophagy have not shown promising results in clinical trials, as it has been revealed that autophagy does not always play a role that favors cancer cell survival. Hence, this review aims to suggest anticancer strategies based on the changes in the role of autophagy according to survival conditions and tumorigenesis stage.

Defining the molecular response to ischemia-reperfusion injury and remote ischemic preconditioning in human kidney transplantation

Background Ischemia-reperfusion injury (IRI) inevitably occurs during kidney transplantation and extended ischemia is associated with delayed graft function and poor outcomes. Remote ischemic preconditioning (RIPC) is a simple, noninvasive procedure aimed at reducing IRI and improving graft function. Experimental studies have implicated the kynurenine pathway as a protective mechanism behind RIPC. Methods First, paired biopsies from 11 living kidney donors were analyzed to characterize the acute transcriptomic response to IRI. Second, 16 living kidney donors were subjected to either RIPC (n = 9) or no pretreatment (n = 7) to evaluate the impact of RIPC on the transcriptomic response to IRI. Finally, the effect of RIPC on plasma metabolites was analyzed in 49 healthy subjects. Results There was a robust immediate response to IRI in the renal transcriptomes of living-donor kidney transplantation, including activation of the mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) pathways. Preconditioning with RIPC did not significantly alter the transcriptomic response to IRI or the concentration of plasma metabolites. Conclusions The present data validate living-donor kidney transplantation as a suitable model for mechanistic studies of IRI in human kidneys. The failure of RIPC to alter transcriptomic responses or metabolites in the kynurenine pathway raises the question of the robustness of the standard procedure used to induce RIPC, and might explain the mixed results in clinical trials evaluating RIPC as a method to attenuate IRI.

Histology Agnostic Drug Development: An Updated Review.

Recent advancements in oncology have led to the development of histology-agnostic therapies, which target genetic alterations irrespective of the tumor's tissue of origin. This review aimed to provide a comprehensive update on the current state of histology-agnostic drug development, focusing on key therapies, including pembrolizumab, larotrectinib, entrectinib, dostarlimab, dabrafenib plus trametinib, selpercatinib, trastuzumab deruxtecan, and reprotrectinib. We performed a detailed analysis of each therapy's mechanism of action, clinical trial outcomes, and associated biomarkers. The review further explores challenges in drug resistance, such as adaptive signaling pathways and neoantigen variability, as well as diagnostic limitations in identifying optimal patient populations. While these therapies have demonstrated efficacy in various malignancies, significant hurdles remain, including intratumoral heterogeneity and resistance mechanisms that diminish treatment effectiveness. We propose considerations for refining trial designs and emerging biomarkers, such as tumor neoantigen burden, to enhance patient selection. These findings illustrate the transformative potential of histology-agnostic therapies in precision oncology but highlight the need for continued research to optimize their use and overcome existing barriers.

Association between improved erectile function and dietary patterns: a systematic review and meta-analysis.

Erectile dysfunction (ED) is prevalent among men, but its relationship with dietary habits is uncertain. The aim of our study was to assess whether dietary patterns enhance erectile function by reviewing the literature published before August 1, 2022, via PubMed, Web of Science, and EMBASE databases. The data compiled included author details; publication dates, countries, treatments, patient numbers, ages, follow-ups, and clinical trial outcomes, such as ED cases, odds ratios (ORs), confidence intervals (CIs), and International Index of Erectile Function-5 (IIEF-5) scores with means and standard deviations. An analysis of 14 studies with 27 389 participants revealed that plant-based diets (OR = 0.71, 95% CI: 0.66-0.75; P < 0.00001), low-fat diets (OR = 0.27, 95% CI: 0.13-0.53; P = 0.0002), and alternative diets such as intermittent fasting and organic diets (OR = 0.54, 95% CI: 0.36-0.80; P = 0.002) significantly reduced ED risk. High-protein low-fat diets (hazard ratio [HR] = 1.38, 95% CI: 1.12-1.64; P < 0.00001) and high-carb low-fat diets (HR = 0.79, 95% CI: 0.55-1.04; P < 0.00001) improved IIEF-5 scores. Combined diet and exercise interventions decreased the likelihood of ED (OR = 0.49, 95% CI: 0.28-0.85; P = 0.01) and increased the IIEF-5 score (OR = 3.40, 95% CI: 1.69-5.11; P < 0.0001). Diets abundant in fruits and vegetables (OR = 0.97, 95% CI: 0.96-0.98; P < 0.00001) and nuts (OR = 0.54, 95% CI: 0.37-0.80; P = 0.002) were also correlated with lower ED risk. Our meta-analysis underscores a strong dietary-ED association, suggesting that low-fat/Mediterranean diets rich in produce and nuts could benefit ED management.

Evolution of Molecular Biomarkers and Precision Molecular Therapeutic Strategies in Glioblastoma.

Glioblastoma is the most commonly occurring malignant brain tumor, with a high mortality rate despite current treatments. Its classification has evolved over the years to include not only histopathological features but also molecular findings. Given the heterogeneity of glioblastoma, molecular biomarkers for diagnosis have become essential for initiating treatment with current therapies, while new technologies for detecting specific variations using computational tools are being rapidly developed. Advances in molecular genetics have made possible the creation of tailored therapies based on specific molecular targets, with various degrees of success. This review provides an overview of the latest advances in the fields of histopathology and radiogenomics and the use of molecular markers for management of glioblastoma, as well as the development of new therapies targeting the most common molecular markers. Furthermore, we offer a summary of the results of recent preclinical and clinical trials to recognize the current trends of investigation and understand the possible future directions of molecular targeted therapies in glioblastoma.

Use of immunomodulatory treatment for non-infectious uveitis: an International Ocular Inflammation Society report of real-world practice

BackgroundNon-infectious uveitis is a diverse group of inflammatory conditions that collectively account for substantial blindness worldwide. Expert guidelines and results of clinical trials guide treatment, but real-world clinical care is...

Dry eye disease – how our lifestyle choices can affect the disease?

Introduction: In today’s world, we know how important it is to keep healthy habits because many diseases begin with daily lifestyle choices. Dry eye disease is a disease of the ocular surface and there are many risk factors, that lead to developing this disorder. As the possible factors we can underline deficiency of vitamin D or Omega-3 fatty acids, lack of physical exercise, long screen time, or smoking tobacco. Aim of the study: This review seeks to highlight the issue of dry eye disease linked to everyday routines by examining clinical trial outcomes. Furthermore, it offers an analysis of potential strategies to prevent ocular alterations by critically evaluating the existing data. State of knowledge: The listed lifestyle choices cause a higher risk of developing dry eye disease and affect ocular health on many levels, leading to unpleasant feelings and affecting people’s lives. However, with some lifestyle changes, the risk of developing this disease can be decreased, and negative symptoms can be minimized. It is important to remember vitamin D, and Omega-3 supplementation, daily physical activity, minimalization of the time spent in front of the visual display terminals, and quitting smoking. Conclusions: Many daily habits are connected to developing dry eye disease, and it is very important to remember about the small daily changes, which can decrease the risk of the disease.

Advances in Cancer Treatment: Harnessing Antibody-Drug Conjugates and Oncolytic Viruses for Targeted Therapy

Effective cancer treatment remains a major challenge due to its heterogeneity and complexity. However, emerging therapies such as antibody-drug conjugates (ADCs) and oncolytic viruses show great potential in leveraging the body's natural defenses to selectively target and destroy cancer cells. These promising treatments have demonstrated encouraging results in clinical trials, and ongoing research and development are expected to further enhance their efficacy and improve patient outcomes.

Distal versus conventional transradial access for coronary angiography: a pooled analysis from the randomized RAPID trial

Abstract Background Transradial access (TRA) is the recommended approach for coronary procedures considering safety benefits over femoral access with radial artery occlusion (RAO) being the most frequent complication. Although usually not clinically significant, the presence of RAO affects potential future procedures and medical treatments. Distal TRA (dTRA) has been suggested to reduce the risk of postprocedural RAO compared to conventional TRA (cTRA) with, however, inconsistent results in clinical trials. Purpose This study aimed to compare the efficacy and safety of dTRA versus cTRA in patients undergoing diagnostic coronary angiography. Methods The RAPID trial is a single-center, open-label, 2x2 factorial, randomized study of patients undergoing coronary angiography through a 6-F radial access. The trial was stopped early by the data and safety monitoring board after the second pre-planned interim analysis and inclusion of 600 participants. Patients were randomized to dTRA or cTRA with further stratification according to periprocedural heparin use and preexisting oral anticoagulation. The primary endpoints were the incidence of RAO assessed by vascular ultrasound and puncture-site related bleedings. Results The final study population consisted of 298 patients randomized to dTRA and 302 patients to cTRA. Periprocedural heparin was administered in 382 patients (63.7%) and percutaneous coronary intervention was performed in 161 cases (26.8%) without differences between the study groups (p=0.700 and p=0.465; respectively). Distal TRA was associated with a significantly increased number of puncture attempts (2.4 ± 2.0 versus 1.5 ± 1.2; p&amp;lt;0.001) and failed punctures leading to access site crossover (11.7% versus 5.0%; p=0.003). Consequently, the total procedure time was longer in the dTRA group (30 min versus 25 min; p=0.004) without increasing fluoroscopy time (p=0.320), dose area product (p=0.245), or contrast volume (p=0.884). Patent hemostasis was achieved in 91.7% of patients with cTRA. The rates of RAO (16.1% versus 15.6%, p=0.855) and puncture-site related bleedings (6.7% versus 8.3%; p=0.466) were similar in both groups. Conclusions According to this study, dTRA does not reduce the risk of RAO or bleeding events compared to cTRA.

Defibrillator shocks and their effect on objective asian patient outcomes: results of the painfree SST clinical trial

Abstract Background The implantable cardioverter defibrillator (ICD) reduces mortality in patients at risk of sudden cardiac death. However, the effect of ICD shock on device-measured activity is unknown. The aim of this analysis was to analyze the acute and long-term effects of ICD shock on objective behavioral data. Methods The PainFree SST study was a prospective, multicenter, global study that enrolled 2770 patients including 225 from from Asia (181 from Japan, 25 from India, and 19 from Malaysia). Patient physical activity was determined from the device built-in accelerometer. The device translates the accelerometer output into a count of active minutes, which is stored as a daily total value in device memory for a rolling window of 425 days. Obviously, activity is measured only after device implantation. Early after implant, activity is reduced due to the procedure and thus not representative. Therefore, no baseline can be reported for activity. The follow-up activity data was analyzed with a linear mixed model, with a random effect for patient and an auto-regressive correlation matrix for subsequent measurements of individual patients. Results Figure 1 shows average daily activity between 90 days before and 90 days after a shock. The dashed vertical line indicates the day of shock. Both patients from Asia and from other countries show a drop in activity after a shock with recovery in the subsequent 30-60 days. The curve for Asian patients is more variable than the curve for other countries due to the lower number of patients (there were 33 Asian patients with shocks contributing data). Figure 2 shows average daily activity before and after ATP therapy. Any post shock measurement is excluded. Contrary to the temporary reduction in activity around a shock (Figure 1), ATP therapies do not seem to have an impact on activity. In patients from the other countries, activity is significantly reduced when patients are hospitalized (-66.3 minutes/day, p&amp;lt;0.0001), but not in Asian patients (-5.1 minutes/day, p=0.71). Both in Asian and other countries, activity is significantly reduced after an ICD shock (Asian: -47.5 minutes/day, p=0.0002; Other countries: -21.5 minutes/day, p&amp;lt;0.0001). The effect of shock for Asian is greater than the other countries (p=0.054). In the month after the shock there is a significant recovery, +34.8 minutes/day in Asian patients (p=0.0077) and +7.7 minutes/day in patients from other countries (p=0.031). The recovery is trended to be bigger in Asian patients (p=0.058). Conclusions ICD shocks have a lasting adverse impact on objective, device-measured physical activity, particularly among Asian individuals. Successful management of patients with an ICD necessitates specific attention to clinically relevant behavioral outcomes, aiming to expedite recovery and facilitate a return to activities of daily living, with a particular focus on the Asian population.

Prediction of cardiovascular risk in patients type 2 diabetes using the SCORE2-Diabetes risk score

Abstract Background/Introduction The SCORE2-Diabetes risk score was developed to predict the risk of cardiovascular events (CV-death, non-fatal MI and non-fatal stroke) in patients with T2DM without known cardiovascular disease. Current ESC guidelines recommend the use of this risk score to tailor treatment strategies in this population. Purpose We sought to determine whether the SCORE2-Diabetes risk score was able to appropriately stratify an international cohort of patients from recent cardiovascular clinical outcomes trials. Furthermore, we sought to determine the accuracy and precision of the model including in patients with and without known cardiovascular disease. Methods Patients from 4 randomized cardiovascular outcome trials (DEVOTE, LEADER, PIONEER-6, SUSTAIN-6) were included (n=23,464). Mean follow-up was 2.6 years and outcomes were adjudicated. The SCORE2-Diabetes risk score was calculated using the uncalibrated version which does not account for risk-region. Patients were stratified into low (&amp;lt;5%), moderate (5-&amp;lt;10%), high (10-&amp;lt;20%), and very high risk (≥20%) groups. The SCORE2-Diabetes risk predication model was designed to predict 10-year risk; however, given the mean follow-up from the cohort, outcomes were reported at 36 months. The Brier score, which evaluates estimated risk, and c-index, which evaluates the ability to discriminate between participants, were used to evaluate the precision of the risk score. We further compared the risk score with an estimated risk of MACE calculated using a cause specific Cox model that accounts for competing risk. Results Most patients in the cohort did not have prior myocardial infarction or stroke (57.4%, n=13,467). The SCORE2-Diabetes risk score was able to stratify patients into low, moderate, high, and very high risk cohorts (Figure 1). Observed cardiovascular events at 36 months were higher than the SCORE2-Diabetes risk score predicted (Table 1). The risk score, when included in a regression model, independently predicted cardiovascular death, myocardial infarction, or stroke (HRadj 1.03, p&amp;lt;0.001) and non-cardiovascular death (HRadj 1.05, p&amp;lt;0.001). Including the score in models with only age and sex improved the discrimination and performance of the model. The c-index for the risk score in the overall cohort was 0.62 and was 0.66 in the cohort without known cardiovascular disease. When using the Brier score to evaluate the utility of the model, the Brier score of the SCORE2-D model was 0.08 which is no different than a null model which assumes a baseline risk of 10% in all patients. Conclusion In a cohort of patients that was older, more geographically diverse, and at higher risk of cardiovascular events, the SCORE2-D risk score appropriately stratified patients into categories of risk. However, the overall risk prediction underestimated the risk of cardiovascular events and the discrimination of the risk score was modest.Figure:CV events over timeTable:CV events by risk group

Targeting neutrophil serine proteases in bronchiectasis.

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis (BE). Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase, cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in BE, no drug that controls neutrophilic inflammation is licensed for the treatment of BE. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of neutrophil elastase) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in BE pathogenesis, and not just neutrophil elastase. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in BE and improve disease outcomes as a result. Clinical trials for CatC inhibitors in BE have reported positive Phase III results. In this narrative review, we discuss the role of high NSP activity in BE, and how this feature drives the associated morbidity and mortality seen in BE. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the BE lung, summarising clinical trial outcomes, and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in BE.

Treatment with flozins across the whole spectrum of heart failure in Poland between February 2022 and June 2023 based on Heart Failure Observational Study by Polish Cardiac Society.

Abstract Since the introduction of the ESC guidelines in 2021 and the increased level of recommendations in 2023, SGLT2 inhibitors (SGLT2i) have been widely used in all patients with heart failure (HF), improving their prognosis. Current guidelines recommend the use of SGLT2i across the entire spectrum of HF regardless of ejection fraction. The aim of the study was to summarize the usage of SGLT2i in patients with HF in Poland, based on data gathered in the Heart Failure Observational Study (HEROES) conducted by the Polish Cardiac Society. Overall, 1176 patients (enrolled between Feb 2022 and Jun 2023) were included in the analysis (hospitalizations: N=918, outpatient visits: N=258). Most of them were men (71.7%) with a median age of 69 years (IQR: 60-75). Patients with reduced ejection fraction (HFrEF) were the most numerous group (48%, N=565) followed by preserved (HFpEF, 22%, N=259) and mildly reduced (HFmrEF, 14%, N=166) ejection fraction. In 16% of cases, ejection fraction was not reported. Only fewer than 60% of subjects were reported to be treated with SGLT2i (overall: 59.5%; HFrEF: 82.3%; HFmrEF: 48.8%, HFpEF: 32.4%). We divided the whole study group into 4 even quartiles based on the number of consecutive patients enrolled (Q1: Feb 2022-Dec 2022; Q2: Sep 2022; Q3: Mar 2023; Q4: Jun 2023). Results showed an overall increasing number of patients treated with SGLT2i in consecutive quartiles, especially in HFmrEF group (Fig. 1). However, in the last quartile (Q4), less than 40% usage of SGLT2i in HFpEF patients was observed (38.2%). The analyzed period ended before the release of the 2023 focused update of HF guidelines that strengthened recommendations for SGLT2i use to the first class of recommendations regardless of ejection fraction. This document will probably further increase the usage of SGLT2i in the Polish HF population. Nevertheless, our data are worrying, as overall more than 1/3 of HF patients in the last quartile were not treated with one of the basic and effective drugs in HF. It is worth mentioning that the 2021 HF guidelines recommended SGLT2i in the first class of recommendations only in HFrEF, but by that time, current clinical trial results had already shown great benefit in HFmrEF and HFpEF patients.SGLT2i treatment in PL (Feb2022-Jun2023)