Benefits Of Therapy Research Articles

Combining [177Lu]Lu-DOTA-TOC PRRT with PARP inhibitors to enhance treatment efficacy in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive tumor with neuroendocrine origin. Although SCLC frequently express somatostatin receptor type 2 (SSTR2), a significant clinical benefit of SSTR2-targeted radionuclide therapies of SCLC was not observed so far. We hypothesize that combination treatment with a PARP inhibitor (PARPi) could lead to radiosensitization and increase the effectiveness of SSTR2-targeted therapy in SCLC. SSTR2-ligand uptake of the SCLC cell lines H69 and H446 was evaluated in vitro using flow cytometry, and in vivo using SPECT imaging and cut-and-count biodistribution. Single-agent (Olaparib, Rucaparib, [177Lu]Lu-DOTA-TOC) and combination treatment responses were determined in vitro via cell viability, clonogenic survival and γH2AX DNA damage assays. In vivo, we treated athymic nude mice bearing H69 or H446 xenografts with Olaparib, Rucaparib, or [177Lu]Lu-DOTA-TOC alone or with combination treatment regimens to assess the impact on tumor growth and survival of the treated mice. H446 and H69 cells exhibited low SSTR2 expression, i.e. 60 to 90% lower uptake of SSTR2-ligands compared to AR42J cells. In vitro, combination treatment of [177Lu]Lu-DOTA-TOC with PARPi resulted in 2.9- to 67-fold increased potency relative to [177Lu]Lu-DOTA-TOC alone. We observed decreased clonogenic survival and higher amounts of persistent DNA damage compared to single-agent treatment for both Olaparib and Rucaparib. In vivo, tumor doubling times increased to 1.6-fold (H446) and 2.2-fold (H69) under combination treatment, and 1.0 to 1.1-fold (H446) and 1.1 to 1.7-fold (H69) in monotherapies compared to untreated animals. Concurrently, median survival was higher in the combination treatment groups in both models compared to monotherapy and untreated mice. Fractionating the PRRT dose did not lead to further improvement of therapeutic outcome. The addition of PARPi can markedly improve the potency of SSTR2-targeted PRRT in SCLC models in SSTR2 low-expressing tumors. Further evaluation in humans seems justified based on the results as novel treatment options for SCLC are urgently needed.

YAP-LAMB3 axis dictates cellular resistance of pancreatic ductal adenocarcinoma cells to gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis and inadequate response to treatment, such as gemcitabine (Gem), the first-line chemotherapeutic drug. Understanding the molecular determinants that control drug resistance to Gem is critical to predict potentially responsive patients and improve the benefits of Gem therapy. Emerging evidence suggests that certain developmental pathways, such as Hippo signaling, are aberrated and play important roles in Gem resistance in cancers. Although Hippo signaling has been reported to play a role in chemoresistance in cancers, it has not been clarified which specific target gene(s) functionally mediates the effect. In the present study, we found that YAP serves as a potent barrier for the cellular sensitivity of PDAC cells to Gem. We then identified and characterized laminin subunit beta 3 (LAMB3) as a bona fide target of YAP-TEAD4 to amplify YAP signaling via a feedback loop. Such a YAP-LAMB3 axis is critical to induce epithelial-mesenchymal transition and mediate Gem resistance. Taken together, we uncovered that YAP-LAMB3 axis is an important regulator of Gem, thus providing potential therapeutic targets for overcoming Gem resistance in PDAC.

Effects of extracorporeal shockwave therapy versus ultrasonic therapy and deep friction massage in the management of lateral epicondylitis: a randomized clinical trial

The study's goal was to compare and evaluate the benefits of deep friction massage and ultrasonic therapy (US) vs extracorporeal shockwave therapy (ESWT) for people with lateral epicondylitis. This double-blind, parallel-arm randomized clinical trial was conducted after ethical approval on a sample of 80 subjects with lateral epicondylitis. Participants were enrolled based on predefined eligibility criteria. They were randomly allocated to groups A and B. Group A received ESWT, while Group B received the US combined with deep friction massage. Data was collected using the Numeric Pain Rating Score (NPRS) and Patient-rated tennis elbow evaluation questionnaire (PRTEE) at baseline, at 3rd, and at 7th week of treatment. On the basis of the normality of the data, a non-parametric test was applied to evaluate between-group and within-group differences. P value ≤ 0.05 was considered significant. There was a significant difference between groups (p < 0.001). Comparisons of PRTEE scores at 3rd week and 7th week of intervention were found significant for both groups (p < 0.001). While considering between-group comparisons based on percentile scores of PRTEE at baseline, 3rd and 7th week of intervention, in group A Median (IQR) at the baseline was 24.00 (5.00), at 3rd week, 10.00 (5.00) and 7th week was 1.50 (2.50) and in group B Median (IQR) at the baseline was 25.00 (4.00), at 3rd week 19.50 (4.50) and at 7th week was 11.50 (2.50). The results were significant in both groups (p = 0.000), but between-group analysis revealed that ESWT is more effective in patients with lateral epicondylitis.

Unraveling epigenomic signatures and effectiveness of electroconvulsive therapy in treatment-resistant depression patients: a prospective longitudinal study

BackgroundElectroconvulsive therapy (ECT) benefits patients with treatment-resistant depression (TRD), but the underlying biological processes are unclear. We conducted an epigenome-wide association study in 32 TRD patients undergoing ECT to depict ECT-associated methylation changes. Illness severity and ECT outcomes were assessed with the Montgomery–Åsberg Depression Rating Scale at baseline (T0) and 1 month after its end (T1). Methylation was profiled at T0 and T1 with the Illumina Infinium Methylation EPIC BeadChip array.ResultsLongitudinal T0–T1 analyses showed 3 differentially methylated probes (DMPs) with nominal p values ≤ 10−5, with 2 annotated in the genes CYB5B and PVRL4. Including covariates, we found 4 DMPs for symptoms variation, annotated in FAM20C, EPB41, OTUB1 and ADARB1, and 3 DMPs for response status, with 2 annotated in IQCE and FAM20C. Regional analysis revealed 54 differentially methylated regions (DMRs) with nominal p value area ≤ 0.05, with 9 presenting adjusted p-value area ≤ 0.10, annotated in MCF2L, SLC25A24, RUNX3, MIR637, FOXK2, FAM180B, POU6F1, ALS2CL and CCRL2. Considering covariates, we found 21 DMRs for symptoms variation and 26 DMRs for response (nominal p value area ≤ 0.05), with 4 presenting adjusted p-value area ≤ 0.10 for response, annotated in SNORD34, NLRP6, GALNT2 and SFT2D3. None remained significant after false discovery rate correction. Notably, ADARB1 variants are associated with suicide attempt in patients with psychiatric disorders, and SLC25A24 relates to conduct disorder. Several DMPs and DMRs are annotated in genes associated with inflammatory/immune processes. Longitudinal analyses on females (n = 22) revealed statistically significant DMRs (adjusted p value area ≤ 0.05) and trend-significant DMRs (adjusted p value area ≤ 0.07) for symptoms variation and response status, annotated in genes related to psychiatric disorders (ZFP57, POLD4, TRIM10, GAS7, ADORA2A, TOLLIP), trauma exposure (RIPOR2) and inflammatory/immune responses (LAT, DLX4, POLD4, FAM30A, H19). Pathway analysis on females revealed enrichment for transcriptional activity, growth factors, DNA maintenance, and immune pathways including IRF7 and IRF2.ConclusionAlthough no significant results were found for the whole cohort, the study provides insights into ECT-associated methylation changes, highlighting DMPs and DMRs related to ECT outcomes. Analyses on females revealed significant DMRs and pathways related to psychiatric disorders and inflammatory/immune processes.

Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial.

Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin. Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors. We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004). Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). NCT04359654.

Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial

Background:Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.Methods:Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.Results:We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).Conclusions:Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.Funding:LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).Clinical trial number:NCT04359654.

Post-Ischemic Stroke Cardiovascular Risk Prevention and Management

Cardiac death is the second most common cause of death among patients with acute ischemic stroke (IS), following neurological death resulting directly from acute IS. Risk prediction models and screening tools including electrocardiograms can assess the risk of adverse cardiovascular events after IS. Prolonged heart rate monitoring and early anticoagulation therapy benefit patients with a higher risk of adverse events, especially stroke patients with atrial fibrillation. IS and cardiovascular diseases have similar risk factors which, if optimally managed, may reduce the incidence of recurrent stroke and other major cardiovascular adverse events. Comprehensive risk management emphasizes a healthy lifestyle and medication therapy, especially lipid-lowering, glucose-lowering, and blood pressure-lowering drugs. Although antiplatelet and anticoagulation therapy are preferred to prevent cardiovascular events after IS, a balance between preventing recurrent stroke and secondary bleeding should be maintained. Optimization of early rehabilitation care comprises continuous care across environments thus improving the prognosis of stroke survivors.

Drug-drug interactions and synergy: from pharmacological models to clinical application.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts such as concentration-response curves, additive effects, and predictive models are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. While various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected at bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care. Significance Statement Combining drugs with different mechanisms of action for synergistic interactions optimizes treatment efficacy and safety. Accurate interpretation of synergy requires the identification of the expected additive effect. Despite innovative models to predict the additive effect, consensus in drug interaction research is lacking, hindering the bench-to-bedside development of combination therapies. Collaboration among science, industry, and regulation is crucial for advancing combination therapy development, ensuring rigorous application of predictive models in clinical settings.

Effect of Medical Ozone Therapy in Preventing Compromised Nasal Skin in Revision Rhinoplasty.

Ozone is often used as an additive therapy for skin conditions like infectious diseases, wound healing, diabetic foot, and pressure ulcers. The viability of the nasal skin has crucial importance in revision rhinoplasty cases. The study investigates the potential benefits of medical ozone therapy in healing the nasal skin in multiple-operated cases. The study retrospectively examined 523 revision rhinoplasty patients operated by the first author from January 2017 to January 2024. Patients consenting to ozone therapy received 3 major autohemotherapy sessions post-surgery. Patients were divided into 2 groups: those with compromised nasal skin (infection, poor vascular supply) and those with normal healing. Age, gender, smoking, diabetes, previous surgeries, grafting materials, and techniques were considered. Of the 523 patients, 12 (2.3%) experienced major skin complications like infection and necrosis, while 511 (97.7%) had no or minor issues, such as discoloration. In total, 301 patients accepted and received ozone therapy. Of the patients without major complications, 299 (58.3%) received ozone therapy, while 212 (41.7%) did not. Among the 12 with major complications, two (16.7%) received ozone therapy, and the remaining 10 (83.3%) did not. Ozone therapy recipients showed statistically fewer skin problems (p<0.05). Costal cartilage as tip and septal extension graft was linked to skin issues (p<0.05). No major adverse effects from ozone therapy were noted. Our findings indicate that ozone therapy may be a safe and potentially effective option for patients undergoing revision rhinoplasty, especially those with compromised nasal skin. It appears to aid in skin healing and regeneration, possibly through enhancing oxygen delivery and modulation of the immune response. Ozone therapy is a promising adjunct treatment for managing skin complications in revision rhinoplasty patients. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Vestibular Rehabilitation: Improving Symptomatic and Functional Outcomes of Persons with Vestibular Schwannoma: A Systematic Review.

Persons with vestibular schwannoma suffer from dizziness, imbalance, and decreased function leading to reduced quality of life. Other forms of peripheral vestibular hypofunction show improvements in these signs and symptoms with vestibular rehabilitation; however, the efficacy of this intervention for those with vestibular schwannoma is unknown. Therefore, the aim of this systematic review was to determine the effect of vestibular physical therapy on subjective and objective measures of vestibular symptoms and function in people with vestibular schwannoma. Four electronic databases were searched: PubMed, CINAHL, EMBASE, and Cochrane. Included studies were experimental or observational in design and featured patients with vestibular schwannoma who had undergone vestibular physical therapy. Screening and quality assessment was completed independently by 2 researchers. Risk of bias was assessed with a tool appropriate for study design (eg, Cochrane Risk of Bias 2.0 tool for randomized trials). The Grading of Recommendations Assessment, Development and Evaluation approach was used to synthesize findings. Twenty-three studies were included. Overall, the effect of vestibular physical therapy for patients with vestibular schwannoma was uncertain. Outcomes of dizziness, static and dynamic balance, and vestibular function all showed very low certainty on the Grading of Recommendations Assessment, Development and Evaluation assessment. Multimodal physical therapist interventions consistent with clinical practice guidelines (eg, gaze stability, habituation, balance training, gait training) demonstrated potential for improvement in dizziness, balance, and vestibular function, respectively. Results were mostly insignificant when a single modality was used. There may be benefit in multimodal vestibular physical therapy for people with vestibular schwannoma to improve symptoms and function. More high-quality studies specific to vestibular schwannoma prehabilitation and rehabilitation are needed to increase the certainty in the evidence. Physical therapists are encouraged to use multimodal vestibular rehabilitation for vestibular schwannoma in clinical practice in line with clinical guidelines for peripheral vestibular hypofunction.

Effect of Medical Ozone Therapy in Preventing Compromised Nasal Skin in Revision Rhinoplasty.

Ozone is often used as an additive therapy for skin conditions like infectious diseases, wound healing, diabetic foot, and pressure ulcers. The viability of the nasal skin has crucial importance in revision rhinoplasty cases. The study investigates the potential benefits of medical ozone therapy in healing the nasal skin in multiple-operated cases. The study retrospectively examined 523 revision rhinoplasty patients operated by the first author from January 2017 to January 2024. Patients consenting to ozone therapy received 3 major autohemotherapy sessions post-surgery. Patients were divided into 2 groups: those with compromised nasal skin (infection, poor vascular supply) and those with normal healing. Age, gender, smoking, diabetes, previous surgeries, grafting materials, and techniques were considered. Of the 523 patients, 12 (2.3%) experienced major skin complications like infection and necrosis, while 511 (97.7%) had no or minor issues, such as discoloration. In total, 301 patients accepted and received ozone therapy. Of the patients without major complications, 299 (58.3%) received ozone therapy, while 212 (41.7%) did not. Among the 12 with major complications, two (16.7%) received ozone therapy, and the remaining 10 (83.3%) did not. Ozone therapy recipients showed statistically fewer skin problems (p<0.05). Costal cartilage as tip and septal extension graft was linked to skin issues (p<0.05). No major adverse effects from ozone therapy were noted. Our findings indicate that ozone therapy may be a safe and potentially effective option for patients undergoing revision rhinoplasty, especially those with compromised nasal skin. It appears to aid in skin healing and regeneration, possibly through enhancing oxygen delivery and modulation of the immune response. Ozone therapy is a promising adjunct treatment for managing skin complications in revision rhinoplasty patients. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Dimethyl fumarate preserves brainstem and cervical spinal cord integrity in radiologically isolated syndrome.

The first randomized placebo-controlled therapeutic trial in radiologically isolated syndrome (RIS), ARISE, demonstrated that treatment with dimethyl fumarate (DMF) delayed the onset of a first clinical event related to CNS demyelination and was associated with a significant reduction in new and/or newly enlarging T2-weighted hyperintense lesions. The purpose of this study was to explore the effect of DMF on volumetric measures, including whole brain, thalamic, and subcortical gray matter volumes, brainstem and upper cervical spine three-dimensional (3D) volumes, and brainstem and upper cervical spine surface characteristics. Standardized 3T MRIs including 3D isotropicT1-weighted gradient echo images were acquired at baseline and end-of-study according to the ARISE study protocol. The acquired datawere analyzed using Structural Image Evaluation Using Normalization of Atrophy (SIENA), FreeSurfer v7.3, and an in-house pipeline for 3D conformational metrics. Multivariate mixed models for repeated measures were used to analyze rates of change in whole brain, thalamic, subcortical gray matter, as well as change in the 3D surface curvature of the dorsal pons and dorsal medulla and 3D volume change at the medulla-upper cervical spinal cord. The study population consisted of 64 RIS subjects (DMF:30, placebo:34). No significant difference was seen in whole brain, thalamic, or subcortical gray matter volumes in treated vs. untreated RIS patients. A significant difference was observed in dorsal pons curvature with the DMF group having a lower least squares mean change of -4.46 (standard estimate (SE): 3.77) when compared to placebo [6.94 (3.71)] (p = 0.036). In individuals that experienced a first clinical event,a greater reduction in medulla-upper cervical spinal cord volume (p = 0.044) and a decrease in surface curvature was observed at the dorsal medulla (p = 0.009) but not at the dorsal pons (p = 0.443). The benefit of disease-modifying therapy in RIS may extend to CNS structures impacted by neurodegeneration that is below the resolution of conventional volumetric measures.

Effect of catheter ablation versus medical therapy on mental health and quality of life in patients with atrial fibrillation: a systematic review and meta-analysis of randomized controlled trials.

The association between atrial fibrillation (AF) and mental health is well-documented, but the relative benefits of catheter ablation versus medical therapy on mental health and quality of life are not clearly understood. This study assesses the impact of these interventions on AF patients' mental health and quality of life. Through a systematic review of PubMed, Scopus, and Cochrane databases, randomized controlled trials (RCTs) comparing catheter ablation to medical therapy for AF were analyzed. The study focused on a range of outcomes, particularly mental health and quality of life, measured by tools including the SF-36 mental component, HADS, SF-36 physical component, and AFEQT scores, among others. Analyses were stratified by AF type (paroxysmal versus persistent) and synthesized using random or fixed-effects models to calculate mean differences (MDs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs). From 24 RCTs totaling 6,353 patients (51.4% receiving catheter ablation, 71.1% male, average age 59), catheter ablation was found to significantly improve mental health (SMD 0.34; 95% CI 0.05-0.63; p = 0.02) and quality of life as indicated by PCS SF-36 (MD 2.64; 95% CI 1.06-4.26; p < 0.01) and AFEQT scores (MD 6.24; 95% CI 4.43-8.05; p < 0.01), with no significant difference in outcomes between AF subtypes. Catheter ablation offers significant improvements in mental health and quality of life over medical therapy for AF patients, demonstrating its efficacy across different types of AF.

Blood pressure during long-term cilostazol-based dual antiplatelet therapy after stroke: a post hoc analysis of the CSPS.com trial.

We determined the associations of follow-up blood pressure (BP) after stroke as a time-dependent covariate with the risk of subsequent ischemic stroke, as well as those of BP levels with the difference in the impact of long-term clopidogrel or aspirin monotherapy versus additional cilostazol medication on secondary stroke prevention. In a sub-analysis of a randomized controlled trial (CSPS.com), patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone, or a combination of cilostazol with aspirin or clopidogrel. The percent changes, differences, and raw values of follow-up BP were examined. The primary efficacy outcome was the first recurrence of ischemic stroke. In a total of 1657 patients (69.5 ± 9.3 years, female 29.1%) with median 1.5-year follow-up, ischemic stroke recurred in 74 patients. The adjusted hazard ratio for ischemic stroke of a 10% systolic BP (SBP) increase from baseline was 1.19 (95% CI 1.03-1.36), that of a 10 mmHg SBP increase was 1.14 (1.03-1.28), and that of SBP as the raw value with the baseline SBP as a fixed (time-independent) covariate was 1.14 (1.00-1.31). Such significant associations were not observed in diastolic BP-derived variables. The estimated adjusted hazard ratio curves for the outcome showed the benefit of dual therapy over a wide SBP range between ≈120 and ≈165 mmHg uniformly. Lower long-term SBP levels after ischemic stroke were associated with a lower risk of subsequent ischemic events. The efficacy of dual antiplatelet therapy including cilostazol for secondary stroke prevention was evident over a wide SBP range.

Unlocking the Potential: Angiotensin Receptor Neprilysin and Sodium Glucose Co-Transporter 2 Inhibitors for Right Ventricle Dysfunction in Heart Failure

This review article examines the mechanism of action of Angiotensin Receptor–Neprilysin Inhibitors (ARNIs) and Sodium–Glucose Co-Transporter 2 Inhibitors (SGLT2is) in managing chronic right ventricular (RV) dysfunction. Despite advancements in heart failure (HF) treatment, RV dysfunction remains a significant contributor to morbidity and mortality. This article explores the The article explores the impact of ARNIs and SGLT2is on RV function based on clinical and preclinical evidence, and the potential benefits of combined therapy. It highlights the need for further research to optimize patient outcomes and suggests that RV function should be considered in future clinical trials as part of risk stratification for HF therapies. This review underscores the importance of the early initiation of ARNIs and SGLT2is as per guideline-directed medical therapy for eligible HFrEF and HFpEF patients to improve co-existing RV dysfunction.

HIV and hepatitis C virus-related misinformation may contribute to rising rates of infection and suboptimal clinical outcomes among persons with substance use

ABSTRACT HIV and hepatitis C virus (HCV) infection rates among persons, who use drugs, have risen during the US overdose crisis. We elicited patient perspectives about these interconnected infections to identify the areas of misinformation that might prevent appropriate management. We used in-depth interviews and thematic analysis of coded data collected from patients (N = 24) at detox and from key informants (N = 10). Seventy-one per cent reported injecting drugs. We found that patient narratives included misinformation about HIV and HCV transmission, natural history and treatment. Some participants thought that activities such as sharing drinkware or food with persons with HIV could lead to infection, while others believed that mainly men who have sex with men were at risk. Despite significant improvements in treatment, some participants still believed that HIV was a fatal condition, while others noted that treatment was only necessary at later stages. Some participants thought that HCV was a common, mild infection that might not need immediate attention, and others stated that individuals who were actively using drugs were ineligible for treatment. The current study exposes a considerable level of misinformation about HIV prevention and about the importance and benefits of HCV therapy. Educational interventions are necessary to counter misinformation identified.

North American Fetal Therapy Network: Maternal Outcomes in Fetal Aqueductal Stenosis.

Fetal aqueductal stenosis (AS) affects approximately 1:1,000 pregnancies. Obstruction of cerebral spinal fluid (CSF) circulation occurs at the aqueduct of Sylvius, leading to progressive hydrocephalus, often necessitating cesarean section (CS) with a classical uterine incision. The purpose of this study is to describe maternal outcomes associated with fetal aqueductal stenosis. This study is conducted through the North American Fetal Therapy Network (NAFTNet). Subjects were recruited at the diagnosis of severe CNS ventriculomegaly and were followed longitudinally. Maternal events around the delivery of fetuses with AS were recorded and analyzed. Thirty-seven subjects with fetal AS confirmed by neonatal neuroimaging were analyzed. The average gestation at delivery was 36.7 weeks. Overall, 86% were delivered by cesarean section (CS), and 62% of these were elective. Sixty-two percent were delivered electively by cesarean section (CS). Eighty-six percent were delivered by cesarean section. Ninety one percent of CSs were performed through a Pfannenstiel abdominal incision. A classical uterine incision was required in 13% of cesarean deliveries. The peripartum complication rate was 27%. Women carrying a fetus with AS were at risk for preterm birth, cesarean delivery, a classical uterine incision, and peripartum complications. These data highlight the maternal morbidity associated with fetal AS, and the potential benefit of in-utero therapy not only for neonatal but also maternal outcomes.

Synergistic effects of thermosensitive liposomal doxorubicin, mild hyperthermia, and radiotherapy in breast cancer management: an orthotopic mouse model study.

Liposome formulations of the cancer drug doxorubicin have been developed to address the severe side effects that result from administration of this drug in a conventional formulation. Among them, thermosensitive liposomal doxorubicin presents enhanced tumor targeting and efficient drug release when combined with mild hyperthermia localized to the tumor site. Exploiting the radiosensitizing benefits of localized thermal therapy, the integration of radiation therapy with the thermally activated liposomal system is posited to amplify the anti-tumor efficacy. This study explored a synergistic therapeutic strategy that combines thermosensitive liposomal doxorubicin, mild hyperthermia, and radiotherapy, using an orthotopic murine model of breast cancer. The protocol of sequential multi-modal treatment, incorporating low-dose chemotherapy and radiotherapy, substantially postponed the progression of primary tumor growth in comparison to the application of monotherapy at elevated dosages. Improvements in unheated distant lesions were also observed. Furthermore, the toxicity associated with the combination treatment was comparable to that of either thermosensitive liposome treatment or radiation alone at low doses. These outcomes underscore the potential of multi-modal therapeutic strategies to refine treatment efficacy while concurrently diminishing adverse effects in the management of breast cancer, providing valuable insight for the future refinement of thermosensitive liposomal doxorubicin applications.

Acceptability and perceived benefits of validated pruritus assessment instruments in the dermatological office and clinic: Theperspectives of patients and physicians.

Several patient-reported outcome measures (PROMs) have been developed for research to assess the multiple dimensions of chronic pruritus (CP). The acceptability and perceived benefits of their use in clinical practice remain unknown. To assess the acceptability and perceived benefits of validated PROMs from the perspective of patients and physicians in dermatological offices and clinics. Patients with CP due to atopic dermatitis, psoriasis, chronic prurigo or chronic urticaria were recruited at 10 dermatological offices and two dermatological clinics in Germany. Patients completed a set of validated PROMs on pruritus intensity (numerical rating scale, NRS), symptom control (itch-controlled days, ItchCD), quality of life (Dermatology Life Quality Index, DLQI; 5-pruritus life quality, 5PLQ) and general health status (EuroQol, EQ-VAS). Acceptability (relevance, difficulty of completion, length) and benefits (usefulness, feasibility) of these tools were assessed on a NRS (0-10) by patients and physicians, respectively. Data were analysed descriptively. Linear regression was used to study potential associations between age, sex, occupation, office versus clinic, change of therapy and physician-reported benefits. N = 523 patients (46% male, average age: 53.5 years) participated. Acceptability of PROMs by patients was high, indicated by low difficulty (Md = 0, IQR = 0-1 for all PROMs) and high relevance (Md = 8, IQR = 4-10 for all PROMs). Also, most patients (89-95%) rated length of the questionnaires as 'exactly right'. Physicians rated the NRS as the most beneficial instrument (feasibility: Md = 8, IQR = 6-10; usefulness: Md = 9, IQR = 7-10). Hierarchical linear regression revealed that only recruitment site (dermatological office vs. clinic) was significantly associated with usefulness and feasibility (higher ratings for clinical context; βs = 0.149-0.258, ps <0.05; except feasibility for EQ5d, β = ns). PROMs are welcomed by patients, while physicians consider instruments measuring pruritus intensity and impairment of quality of life as beneficial for the clinical routine. Widespread implementation of PROMs in daily clinical work is needed to improve care.

Evaluating the Benefits of Occupational Therapy in Children With Autism Spectrum Disorder Using the Autism Behavior Checklist

Evaluating the Benefits of Occupational Therapy in Children With Autism Spectrum Disorder Using the Autism Behavior Checklist