Tolerability Issues Research Articles

HPB O03 - Snapshot Audit of RELEVANCE: REal worLd outcomEs of adjuVant therapy in pANcreatic CancEr

Abstract Background Evidence-based medicine plays a critical role in shaping clinical practices and setting patient expectations. While randomized controlled trials (RCTs) of adjuvant chemotherapy in pancreatic cancer have demonstrated improved survival rates with newer regimens, their selective inclusion criteria often favor patients with better prognoses. This study aims to compare real-world outcomes with those from RCTs to evaluate the effectiveness of adjuvant therapies in typical clinical settings. Method In this retrospective study, we examined overall survival (OS) among patients who received adjuvant chemotherapy (gemcitabine, gemcitabine-capecitabine, or FOLFIRINOX) following the resection of pancreatic ductal adenocarcinoma. We compared survival curves from RCTs (ESPAC 4, PRODIGE-24) with those from real-world cohorts selected based on RCT criteria. Data were collected retrospectively from medical records and institutional databases, covering OS, disease-free survival (DFS), and adverse events. Results From July 2014 to December 2019, 303 pancreatic ductal adenocarcinoma patients underwent resections, with 209 (69%) receiving adjuvant chemotherapy: 91 (44%) received gemcitabine, 69 (34%) gemcitabine-capecitabine, and 37 (18%) FOLFIRINOX. The median OS for gemcitabine was 21.6 months, close to ESPAC 4’s 25.5 months. Gemcitabine-capecitabine had a median OS of 25.2 months versus ESPAC 4’s 28 months. FOLFIRINOX had a lower median OS in our cohort (19.9 months) compared to PRODIGE 24’s 54.4 months. Additionally, gemcitabine OS in PRODIGE 24 was higher (35 months) than in our data. FOLFIRINOX had a 17% completion rate. Conclusion The real-world outcomes for gemcitabine-based adjuvant therapy align closely with RCT results, while FOLFIRINOX appears less effective in typical clinical settings, possibly due to tolerance issues. These findings highlight the importance of incorporating real-world data in clinical decision-making to better predict patient outcomes and improve treatment strategies for pancreatic cancer. Further research is needed to bridge the gap between RCTs and real-world practices, especially concerning patient selection and treatment tolerability.

Sodium Zirconium Cyclosilicate for Renin-Angiotensin-Aldosterone System Inhibitor Optimization in Patients with Heart Failure with Reduced Ejection Fraction: A Retrospective Analysis.

In this retrospective analysis, we evaluate the effectiveness of the potassium (K+) binder sodium zirconium cyclosilicate (SZC) in maintaining normokalemia and facilitating the initiation, optimization, and maintenance of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with heart failure (HF) with reduced ejection fraction (HFrEF). A total of 44 patients with HFrEF and a history of hyperkalemia who were receiving SZC to enable the prescription of RAASi were identified from two district general hospital sites. Retrospective analysis was performed to determine biochemical response, alterations in pharmacotherapy, and subsequent HF outcomes following initiation of SZC. Mean K+ was reduced by 0.9mmol/L within 1month of initiation of SZC; mean K+ after 12months of treatment was 4.8mmol/L with a median (interquartile range) duration of treatment of 13 (8.4-15.1) months. Following SZC treatment, 100% of patients received an angiotensin receptor-neprilysin inhibitor (18% increase) and 93% received a mineralocorticoid receptor antagonist (41% increase), with 59% and 37% achieving guideline-recommended dosing, respectively. Ninety-one percent of patients were able to receive triple or quadruple therapy with the addition of a beta-blocker and a sodium glucose co-transporter2 inhibitor. Reduced rates of hospitalization for HF (HHF) were observed with 12 episodes per 100 patient-years recorded (reduced from 21) in addition to improvements in mean left ventricular ejection fraction (29-36%) and median N-terminal pro-B-type natriuretic peptide (3458-2055ng/L, 45% median reduction). Renal function (creatinine clearance increased from 48.4 to 49.3ml/min) and systolic blood pressure (decreased from 124 to 122mmHg) were similar following optimization, and no tolerability issues were identified. Extended real-world treatment with the K+ binder SZC was effective at maintaining normokalemia, and was associated with a greater uptake of RAASi, a reduced rate of HHF, and improvements in cardiac biomarkers in patients with HFrEF.

Comparing the long-term effectiveness and safety of dolutegravir/lamivudine versus bictegravir/emtricitabine/tenofovir alafenamide fumarate as first-line regimens: a real life multicentre cohort.

We compared the effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG + 3TC) in our cohort of treatment-naive people with HIV (PWH). In a multicentre cohort of treatment-naive PWH starting a first-line regimen with either dolutegravir plus lamivudine or BIC/FTC/TAF, Kaplan-Meier survival analysis was used to estimate time to virological failure (VF) and time to treatment discontinuation (TD), whereas Cox regression was used to evaluate predictors of VF and TD. Changes in CD4+ cell count were assessed via non-parametric tests, and linear regression analyses were performed to explore predictors of CD4+ cell count changes. One hundred and seventy individuals were included: 66 started dolutegravir plus lamivudine (DTG group) and 104 started BIC/FTC/TAF (BIC group). During follow-up, we observed two VFs in the DTG group [1.7 per 100 person-years of follow-up (PYFU)] and two in the BIC group (1.7 per 100 PYFU). Estimated probability of remaining free from VF at Week 144 was 95.9% in the DTG group and 95.2% in the BIC group (log-rank P = 0.955). Four TDs were observed in the DTG group (3.4 per 100 PYFU) and 21 in the BIC group (17.6 per 100 PYFU). Estimated probability of maintaining the study regimen at Week 144 was 90.3% in the DTG group and 70.0% in the BIC group; individuals in the BIC group had a higher probability of TD (log-rank P = 0.003). In both groups, the CD4+ count improved significantly during follow-up. Our study shows that both strategies are effective and safe, with few VFs and TDs due to tolerability issues.

Safety, tolerability, and basic pharmacokinetic parameters of AUX-001, a once-daily extended release nicorandil in healthy volunteers under fasting and fed conditions

Abstract Introduction Chronic-stable angina pectoris (CSAP) is one of the most common cardiovascular conditions in the developed world with a rising prevalence in both Europe and North America. Mounting evidence from chronic angina outcomes studies, including COURAGE, BARI, ORBITA and recently ISCHEMIA, has reemphasized optimized medical therapy (OMT) as first-line treatment for most chronic-stable angina pectoris (CSAP) patients over coronary revascularization. Yet, there has been a lack of development of new antianginal medications since 2006. To lessen polypharmacy and enable better long-term compliance in CSAP patients, AUX-001, a once-daily (QD), extended-release (ER) nicorandil is in clinical development for treating CSAP as an innovative, novel version of the immediate-release (IR) antianginal. Objective To test the safety, tolerability, and basic pharmacokinetic (PK) parameters of AUX-001 QD in fasting and fed conditions in healthy volunteers during this first-in-human phase 1a study. Methods 16 healthy adult volunteers were enrolled. Vital signs (HR, BP, respiratory rate) and any adverse events were collected during screening, pre-dose, 1, 2, 6, 12, 24-h, and 48-h post-dose and at end-of-study for the two respective periods (fasting and fed). Results Evaluable information was available on 16 patients for fasting and 15 for fed conditions with one patient excluded due to protocol violation. No patient discontinued due to safety or tolerability. No severe AEs were recorded. AEs observed during period 1 included headaches (n=12), asymptomatic hypotension (n=3), palpitation (n=1) and nasal congestion (n=1). In period 2, leading AEs were headaches (n=11), neck pain (n=1) and decreased hemoglobin (n=1). Most AEs were mild and transitory and did not trigger medical intervention or discontinuation. AUX-001 pharmacokinetics exhibited a reduced Cmax, a right-hand shift in Tmax, and an extension of T1/2 beyond 9 hours compared to the historical data of the commercially available IR nicorandil. AUX-001 had a small, temporary effect on heart rate and systolic and diastolic blood pressure but within the normal compensatory haemodynamic steady-state stability. The peak effect with the current AUX-001 prototype was at 6 hours, independent of the food effect. Conclusion AUX-001 was safe and well tolerated. Initial vasodilator-induced headaches were manageable by using simple OTC NSAIDs and led to no dropouts. No patients discontinued due to AEs or tolerability issues. There were no lasting significant haemodynamic effects of AUX-001 beyond 24hours. PK parameters of AUX-001 are characteristic of an ER formulation. Observed pharmacokinetics indicates that the achieved T1/2 is substantially longer than with IR nicorandil (~1hour vs >9h) and shows promise for a potential once daily treatment of exercise induced chronic angina.AUX-001 Study Data ESC Abstract 2024

Real-World Experience with Diroximel Fumarate in Patients with Multiple Sclerosis: A Prospective Multicenter Study.

Current literature and a real-world study suggest that diroximel fumarate (DRF) is safer than dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). However, no real-world study to date has significantly addressed the efficacy of this treatment. This study aims to elucidate the safety, tolerability, and efficacy of DRF in a real-world setting, utilizing data from a Spanish national registry of patients commencing DRF therapy post-market introduction. In this multicenter, prospective observational study, data were collected from MS patients who initiated DRF treatment. The study monitored demographic and clinical characteristics, safety outcomes (including adverse events, reasons for discontinuation, and lymphocyte counts), and efficacy outcomes (radiological and clinical activity). A total of 195 MS patients across 26 neurological departments were included, predominantly female (79.5%), with a mean age of 42.17 years, and a mean duration of treatment with DRF of 6.3 months. Most patients (70.3%) reported no adverse events, while gastrointestinal issues and flushing were the most common adverse events observed. The majority of patients (84.6%) continued with DRF treatment, with tolerability issues being the primary reason for discontinuation. Efficacy analysis showed low relapse rates post-DRF initiation, with most patients exhibiting stable or improved Expanded Disability Status Scale scores and radiological assessments demonstrating minimal activity. This comprehensive analysis provides valuable insights into the real-world application of DRF, confirming its safety and tolerability while offering preliminary evidence of its efficacy in managing MS.

Visualization Detection of Ultralow Temperature Based on Flexible Cross–linked Polymer Systems

AbstractUltralow temperature storage has sparked considerable attention with the development of the economy, showing promising applications ranging from biomedical to national defense and other fields. However, the development of ultralow temperature detection is constrained by the brittleness of current materials at low temperatures and the complexity of detection techniques. Consequently, the challenge exists in finding efficient solutions to material tolerance issues and achieving rapid detection of ultralow temperature. Herein, a novel flexible cross–linked polymer TPTA@PU film with long afterglow, high phosphorescence quantum efficiency, and excellent mechanical properties are successfully fabricated. Interestingly, the obtained TPTA@PU films demonstrate a notable thermoresponsive behavior, with the afterglow color shifting rapidly from blue to green within the temperature ranges from 80 to 280 K. Additionally, there is a positive linear correlation between the RGB values of the afterglow color and the corresponding temperature. Based on these prominent features, an ultralow temperature sensor is realized by utilizing TPTA@PU films as thermoresponsive elements. This work can be expected to provide more inspiration and possibilities for using RTP materials in a more cutting‐edge field.

Fostering the Value of Religious Tolerance among Students through the Development of Potential Issues

Religious tolerance is a global priority amidst diverse beliefs and interests. This research explores potential issues in student religious tolerance for educational stakeholders. The study uses a qualitative bibliometric approach with descriptive data analysis. Findings indicate an increasing but modest trend in religious tolerance research over the past 14 years (2010-2024), peaking in 2023 with 65 articles. Electronic journals (e-journals) are the largest source of such research, with 150 publications. Four productive researchers from Jambi University produced two publications: Arizal Dwi Kurniawan, Nur Aini, Marlina Susanti, and Anisa Andrian. The study identifies several potential future research areas in student religious tolerance, including religion, mutual respect, analysis, tolerance, character education, data, institutions, teachers, Islamic religion, literature review, Islamic education, school, challenges, literacy, strategy, teacher, multicultural Islamic education, student ability, integration, multicultural education, society, tolerance, literature study, child, and concept.

Adsorption behavior of in-house developed CO2-philic anionic surfactants

Incorporating CO2-philic functionalities into surfactant structure is proposed to address the drawbacks of conventional foaming agents such as premature rupture of lamellae in contact with oil, surfactant loss due to adsorption on rock or partitioning between oil and water, and salinity and temperature tolerance issues. Increased activity at the gas/water interface and less surfactant adsorption to the rock due to the presence of CO2-philic chains results in higher foam durability in the presence of oil. In the present paper, a comprehensive study on the adsorption of anionic CO2-philic surfactants onto sandstone rock surface is performed to understand adsorption mechanisms through the addition of CO2-philic tail groups in surfactant structure by observing the changes in concentration, static adsorption, and point of zero charge measurements. The static adsorption tests, Fourier Transform Infrared, and the X-ray Photoelectron Spectroscopy techniques were employed to investigate the interaction of surfactants with crushed Berea sandstone core sample at 90 °C. The static adsorption values of the S (single-tail), D (double-tail), and T (triple-tail) anionic surfactants were reported to be 0.53, 0.40, and 0.6 mg /g, respectively. The effect of alkali on the adsorption process of surfactants was also investigated and the adsorption of synthesized surfactants was found significantly low in alkaline conditions. A variety of analyses, including model fitting along with kinetics and thermodynamics studies at 30, 40, and 50 °C were performed to predict the adsorption behavior. The adsorption isotherm was found to best fit in Langmuir model. The process showed the best fit in the pseudo-second-order reaction kinetics model. The spontaneity of the adsorption process was verified by thermodynamic feasibility studies of the process.

Addressing the Practice of Religious Tolerance by Panji Gumilang (In the studies of Wahbah Az-Zuhaili and Quraish Shihab)

Studying the subject of religious tolerance is always fascinating. This research holds a significant place in the field of religion studies because to the fluctuations in relationships between religious groups throughout different regions of the world, including Indonesia. Numerous Islamic scholars, particularly those who study tafsir, attempt to define tolerance normatively by drawing on passages from the Quran. Wahbah al-Zuhayli is a modern scholar who takes tolerance very seriously. Al-Zuhayli's interpretation, while methodologically sound, generally adopts the methodology of ancient ulama literature. But the issue of tolerance that he highlights stems from the social reality that religious communities currently inhabit. Al-Zuhayli opens his discussion on tolerance by elucidating the notion of wasatiyyah al-Islam, or Islamic moderation. Al-Zuhayli then categorized the four primary themes of tolerance found in the Koran. First, the interactions amongst the Samawi faiths. Forming a moderate and tolerant mindset is made possible by the heavenly religion's shared core doctrines. The second is the freedom to select one's religion. This point demonstrates how Islamic law upholds the Ri'ayah al-Din concept. The third is the ban on inciting hate. Fourth, the advice to put justice first and the outlawing of acts of terror. Each and every person is entitled to protection for their soul's freedom. According to Al-Zuhayli's perspective, religious groups generally get along well and are tolerant of one another. This is also a scientific refutation of the violent ideologies that radical organizations frequently advance.

Accepting or criticizing religion in the process of globalization

Religion, a belief system closely linked to social life, is the subject of research analyzing religious tolerance and criticism in the struggle for human rights. The issue of religious tolerance and criticism will be clarified based on human rights and religious rights. In addition, the relationship between personal ethics and religious ethics is also different, in which the method of combining humanistic philosophy and social philosophy is used to clarify the complex relationships between religion, people, and society, especially the power and role of individuals in religious communities. Research shows that religion influences behavior and shapes people's value systems and rules of life. However, these value systems sometimes lead to discrimination and conflict. From there, the article concludes that religion is a product of human beings, and its existence can be both a positive and an opposing force in society, depending on specific historical conditions. Studying religious tolerance or criticism is essential to building a harmonious society. People must respect the diversity of beliefs and seek common values in reclaiming human rights in globalization.

12256 Sustained Efficacy Of Weekly Somapacitan In Children With GHD: 3-year Results From Phase 3 REAL4 Study

Abstract Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Ascendis Pharma, BioMarin, Bristol-Myers Squibb, EMD Serono, Endo Pharmaceuticals, Novo Nordisk, Orchard Therapeutics, Pfizer, Provention Bio, Tolmar. Grant Recipient; Self; Alexion, Abbvie, Aeterna Zentaris, Amgen, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health Pfizer, Prevail Therapeutics, Sangamo Therapeutics. J.C. Blair: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Ipsen. Other; Self; Novo Nordisk. M. Højby Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. A. Maniatis: Research Investigator; Self; Novo Nordisk, Ascendis, OPKO, Pfizer. J. Mori: Advisory Board Member; Self; Novo Nordisk. Consulting Fee; Self; JCR. Speaker; Self; Novo Nordisk, Pfizer, JCR. V. Böttcher: Advisory Board Member; Self; Merck. Speaker; Self; Novo Nordisk, Merck. Other; Self; Ferring, Lilly, Merck, Novo Nordisk. H. Kim: None. M. Polak: Advisory Board Member; Self; Ipsen, Novo Nordisk, Pfizer. Grant Recipient; Self; Ipsen, Novo Nordisk, Pfizer, Sandoz, Merck, Sanofi. Speaker; Self; Novo Nordisk, Pfizer, Ipsen. R. Horikawa: Advisory Board Member; Self; Novo Nordisk, Pfizer, Ascendis, Lumos Pharma. Grant Recipient; Self; Sandoz. Speaker; Self; Novo Nordisk, Pfizer, JCR. Growth hormone (GH) replacement therapy for children with GH deficiency (GHD) traditionally required daily subcutaneous injections. Somapacitan (Novo Nordisk A/S) is a reversible albumin-binding GH derivative administered once-weekly and the only long-acting GH (LAGH) approved for the treatment of both adults and children with GHD. REAL4 is a randomized, open-label, multi-national, phase 3 trial, consisting of a 52-week main phase and a three-year (week 52 to 208) extension period (NCT03811535). The trial included 200 GH-treatment-naïve, prepubertal children with GHD. Participants received either once-weekly somapacitan (0.16 mg/kg; n=132) or once-daily GH (Norditropin® 0.034 mg/kg; n=68) for 52 weeks. Afterwards, participants receiving daily GH switched to 0.16 mg/kg/week somapacitan (switch group), while those receiving somapacitan continued treatment (soma/soma group). Growth-related endpoints included height velocity (HV), HV standard deviation score (SDS), height SDS, and bone age. The 3-year (156-week) results are presented here. A total of 188 participants (125 in the soma/soma group and 63 in the switch group) completed 3 years of treatment. Improvements in HV, HV SDS, height SDS, and bone age were similar between the groups. In year 3 (week 104 to 156), mean (SD) HV was 7.4 (1.5) cm/year in the soma/soma group and 7.8 (1.4) cm/year in the switch group. The mean (SD) change in height SDS from baseline to week 156 was 2.04 (0.85) in the soma/soma group and 2.38 (1.14) in the switch group, with mean (SD) height SDS at week 156 of -0.95 (0.98) and -1.08 (0.93) in the soma/soma and switch groups, respectively. Mean BMI SDS remained within normal range in both groups at week 156. No safety or tolerability issues were identified. During the extension period (week 52 to 156), a low proportion of the participants reported injection site reactions. No neutralizing antibodies were detected at any of the visits. In conclusion, once-weekly somapacitan showed sustained efficacy and tolerability for three years, as well as for two years following the switching from daily GH treatment in this pivotal phase 3 REAL4 trial. The safety profile of somapacitan was similar to the well-known safety profile of daily GH. Presentation: 6/3/2024

A Novel Protection and Repair Skincare Regimen Shows Efficacy for Improving Environmental Skin Aging.

Skin aging is accelerated by environmental exposures including solar radiation and pollutants. Thus, protecting skin from environmental exposure and repairing ensuing damage is essential for keeping skin healthy and appearing youthful. To evaluate the clinical benefits of a novel skincare regimen designed to provide comprehensive environmental protection in the daytime and repair environmentally damaged skin at night. Thirty participants, including males and females, with mild-to-moderate extrinsic aging, were enrolled in a 12-week single-site study. Participants used the regimen (The Essential Six, RATIONALE, Victoria, Australia) comprised of 3 products to protect the skin in the morning and 3 products to repair the skin at night. Participants were seen at baseline and evaluated for efficacy and tolerability at weeks 2, 6, and 12. Non-invasive measurements to evaluate hydration, transepidermal water loss, skin tone, and elasticity were conducted. The dermatologist investigator noted across-the-board improvement in all evaluated parameters, except deep wrinkles. By week 12, there were statistically significant (P<0.001) improvements in radiance (43%), tactile roughness (48%), visual roughness (44%), firmness (32%), clarity/even skin tone (21%), and overall appearance (29%). Fine lines improved 16% at week 12 (P=0.002). Participant self-assessment revealed statistically significant and progressive improvement in all evaluated parameters over time. No tolerability issues were identified by the investigator, while a small number of participants reported mild stinging and some dryness that resolved over time. This was likely due to the high concentration of active ingredients found in this regimen. Corneometry revealed improved skin hydration of 28% as early as week 2. The data presented confirms that this novel protection and repair regimen improves the appearance of environmentally aged skin. J Drugs Dermatol. 2024;23(10):866-872. doi:10.36849/JDD.8274.

Intravenous versus oral iron for anaemia among pregnant women in Nigeria (IVON): an open-label, randomised controlled trial

Oral iron for anaemia in pregnancy is often not well tolerated, with poor adherence. Iron administered intravenously might address these tolerance and adherence issues. We investigated the effectiveness and safety of intravenous ferric carboxymaltose versus oral ferrous sulphate on anaemia and iron deficiency among pregnant women in Nigeria. We did a multicentre, open-label, parallel, randomised controlled trial of pregnant women (aged 15-49 years) with haemoglobin (Hb) concentrations of less than 10 g/dL at 20-32 weeks' gestation from 11 primary, secondary, or tertiary health facilities in Nigeria (five in Lagos and six in Kano). Exclusion criteria included vaginal bleeding, blood transfusion or major surgery within the past 3 months, symptomatic anaemia, anaemia known to be unrelated to iron deficiency, clinically confirmed malabsorption syndrome, previous hypersensitivity to any form of iron, pre-existing maternal depression or other major psychiatric illness, immune-related diseases, such as systemic lupus erythematosus or rheumatoid arthritis, or severe allergic reactions. Participants were randomly assigned (1:1) by nurses and doctors using a web-based randomisation service to either receive a single dose of intravenous ferric carboxymaltose (20 mg/kg to a maximum of 1000 mg) or oral ferrous sulphate (200 mg; 65 mg elemental iron) three times daily until 6 weeks postpartum. The study was primarily unmasked. Primary outcomes were maternal anaemia (Hb <11 g/dL) at 36 weeks' gestation and preterm birth at before 37 weeks' gestation, with analysis by intention to treat in participants with available data. This study was registered at the ISRCTN registry on Dec 10, 2020 (ISRCTN63484804) and on ClinicalTrials.gov (NCT04976179) on April 7, 2021. Between Aug 10, 2021, and Dec 15, 2022, 13 724 pregnant women were screened for eligibility. 12 668 were excluded due to ineligibility for inclusion, and 1056 provided consent to participate and were randomly assigned to either the intravenous or oral administration groups. 527 were assigned to the intravenous ferric carboxymaltose group and 529 were assigned to the oral ferrous sulphate group. 518 in the intravenous group were assessed at 36 weeks' gestational age and after 518 deliveries, and 511 completed the 6 weeks postpartum visit. 513 in the oral ferrous sulphate group were assessed at 36 weeks' gestational age and after 512 deliveries, and 501 completed the 6 weeks postpartum visit. No significant difference was found in anaemia at 36 weeks (299 [58%] of 517 in the intravenous group vs 305 [61%] of 503 in the oral group; risk ratio 0·95, 95% CI 0·85-1·06; p=0·36), nor in preterm birth (73 [14%] of 518 vs 77 [15%] of 513; 0·94, 0·70-1·26; p=0·66). There were no significant differences in adverse events. The most common adverse events were diarrhoea (in six participants) and vomiting (in three participants) in the oral group and fatigue (in two participants) and headache (in two participants) in the intravenous group. Although the effect on overall anaemia did not differ, intravenous iron reduced the prevalence of iron deficiency to a greater extent than oral iron and was considered to be safe. We recommend that intravenous iron be considered for anaemic pregnant women in Nigeria and similar settings. Bill & Melinda Gates Foundation.

DEVELOPMENT OF A METHODOLOGY FOR DATA NORMALISATION AND AGGREGATION TO ENHANCE SECURITY LEVELS IN INTERNET OF THINGS INTERACTIONS

The number of interacting devices is increasing every day, and with this constant innovation, serious security challenges arise. The concept of the Internet of Things is being actively applied in both domestic and industrial settings. Researchers are increasingly highlighting the challenges and importance of network security. Data preprocessing plays an important role in security by transforming the input data corresponding to algorithmic criteria and thereby contributing to the prediction accuracy. The data preprocessing process is determined by many factors, including the processing algorithm, the data, and the application. Moreover, in Internet of Things interactions, data normalisation and aggregation can significantly improve security and reduce the amount of data used further decision making. This paper discusses the challenges of data normalisation and aggregation in the IoT to handle large amounts of data generated by multiple connected IoT devices. A secure data normalisation and aggregation method promotes successful minimised data transfer over the network and provides scalability to meet the increasing demands of IoT deployment. The proposed work presents approaches used in data aggregation protocols that address interference, fault tolerance, security and mobility issues. A local aggregation approach using the run-length encoding algorithm is presented. The proposed technique consists of data acquisition, data preprocessing, data normalisation and data aggregation steps. Data normalisation was performed via the Z-score algorithm, and the LEACH algorithm was used for data aggregation. In the experimental study, the percentage of faulty nodes reached 35%. The performance of the proposed solution was 0.82. The results demonstrate a reduction in resource consumption while maintaining the value and integrity of the data.

High-frequency terahertz stimulation alleviates neuropathic pain by inhibiting the pyramidal neuron activity in the anterior cingulate cortex of mice.

Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system and is characterized by abnormal hypersensitivity to stimuli and nociceptive responses to non-noxious stimuli, affecting approximately 7-10% of the general population. However, current first-line drugs like non-steroidal anti-inflammatory agents and opioids have limitations, including dose-limiting side effects, dependence, and tolerability issues. Therefore, developing new interventions for the management of NP is urgent. In this study, we discovered that the high-frequency terahertz stimulation (HFTS) at approximately 36 THz effectively alleviates NP symptoms in mice with spared nerve injury. Computational simulation suggests that the frequency resonates with the carbonyl group in the filter region of Kv1.2 channels, facilitating the translocation of potassium ions. In vivo and in vitro results demonstrate that HFTS reduces the excitability of pyramidal neurons in the anterior cingulate cortex likely through enhancing the voltage-gated K+ and also the leak K+ conductance. This research presents a novel optical intervention strategy with terahertz waves for the treatment of NP and holds promising applications in other nervous system diseases.

The Clinical Efficacy of Lapachol in Facial Redness Reduction.

Facial erythema from acne, vascular rosacea, or photoaging is a common difficult-to-treat dermatologic challenge. The objective of this study was to examine the role of lapachol in alleviating facial erythema associated with a variety of common dermatologic conditions. Twenty-five healthy female and male subjects 35-65 years of age of Fitzpatrick skin types I-II with mild-to-moderate stable facial erythema from acne, rosacea or photoaging were enrolled in a single-site monadic study. Subjects received the study cream for twice daily application and were assessed at baseline, Week 4, and Week 8. The dermatologist investigator and subjects assessed efficacy and tolerability and facial photographic images were taken of all subjects at each visit. Noninvasive erythema assessments of the face were conducted using a colorimeter at baseline, Week 4, and Week 8 to document improvement in facial erythema. Twenty-five out of 25 subjects successfully completed the study without tolerability issues including 12 subjects with rosacea, 6 subjects with photoaging and 7 subjects with acne. After 8 weeks of use, the investigator rated a 44% decrease in facial erythema while the subjects rated a 40% decrease. Facial erythema was also noninvasively assessed with a colorimeter and dermaspectrophotometer (DSP). There was a 26% decrease in skin redness at Week 4 and a 31% decrease in skin redness at Week 8 on the colorimeter L*a*b* scale. This finding was collaborated by the DSP which registered a 29% decrease on the erythema scale at Week 8. Lapachol in a moisturizer formulation was found to be effective in reducing facial erythema from acne, rosacea, and photoaging.

Pinus densiflora 'Pendula' Weeping Japanese Red Pine

This document provides an overview of the Weeping Japanese Red Pine (Pinus densiflora ‘Pendula’), detailing its characteristics, growth habits, and care requirements. The tree is noted for its picturesque silhouette, with a crooked trunk and reddish-orange peeling bark. It thrives in full sun and well-drained, slightly acidic soil, and is suitable for USDA hardiness zones 3B through 7A2. The document also highlights its moderate drought tolerance, pest resistance, and potential issues such as needle blight and rusts. Additionally, it mentions several cultivars and their unique features. Original publication date October 1999.

Exploring Newer Topical Therapies for Inflammatory Skin Diseases: A Guide for Rheumatologists

Understanding the pathogenesis of many inflammatory skin diseases and their associated signalling pathways has revealed multiple promising therapeutic targets. Given the chronic nature of many of these conditions, products with long-term safety and efficacy are desired. While topical corticosteroids have been the mainstay of topical therapies for years, they are burdened by concerns over long-term safety (i.e., atrophy, striae, telangiectasias), risk of absorption with systemic glucocorticoid side effects, and patient apprehension regarding steroid use. Similarly, topical calcipotriol and retinoids may be ineffective and can cause irritation. Although topical calcineurin inhibitors (i.e., pimecrolimus, tacrolimus) have been approved for atopic dermatitis, their off-label use for many inflammatory conditions may be limited by tolerability issues such as stinging and burning, and lack of effectiveness. The emergence of newer targeted small molecules for topical application, including topical phosphodiesterase-4 inhibitors (PDE4i), topical Janus kinase inhibitors (JAKi), and a therapeutic aryl hydrocarbon modulating agent (TAMA), offer promising new options and will be reviewed here and summarized in Table 1.

Efficacy and safety of statins, ezetimibe and statins-ezetimibe therapies for children and adolescents with heterozygous familial hypercholesterolaemia: Systematic review, pairwise and network meta-analyses of randomised controlled trials

Background and aimsStatins, ezetimibe and statins-ezetimibe combination therapy are recommended lipid-lowering therapies (LLTs) in children with heterozygous familial hypercholesterolaemia (HeFH). However, their relative effectiveness is not well understood. We aimed to compare the safety and efficacy of these therapies using direct and indirect comparisons. MethodsWe conducted systematic review, pairwise and network meta-analyses (NMAs) of randomised-controlled trials (RCTs) of statins, ezetimibe and statins-ezetimibe combination therapy in people <18 years with HeFH. Comprehensive bibliographic searches were conducted in December 2022, and a Medline update in January 2024. NMA models accounted for drug class, statin type and dosage. ResultsThirteen RCTs were included (n = 1649, median age 13 years, follow-up 6 weeks-2 years). All LLTs reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol; statins led to increases in high-density lipoprotein cholesterol and reductions in triglycerides. Statins reduced LDL-C by 33.61 % against placebo (95 % CI 27.58 to 39.63, I2 = 83 %). Adding ezetimibe to statins reduced LDL-C by an additional 15.85 % (95 % CI 11.91 to 19.79). NMAs showed intermediate-dose statins reduced LDL-C by an additional 4.77 % compared with lower-doses statins (95 % CrI −11.22 to 1.05); higher-dose statins and intermediate-dose statins + ezetimibe may be similarly effective and are probably superior to ezetimibe, intermediate-and lower-dose statins. There was no evidence of differences in maturation, safety or tolerability between LLTs and placebo. ConclusionsStatins, ezetimibe and statins-ezetimibe are all effective treatments for children with HeFH, but the magnitude of LDL-C reductions varies and may depend on treatment dosage and combination. No safety or tolerability issues were found. Longer-term safety and effectiveness are uncertain.

P054 REDUCTION OF BLOOD PRESSURE AND CARDIOVASCULAR RISK WITH IMPROVEMENT OF GLUCOSE AND LIPID METABOLISM BY A NUTRACEUTICAL BASED IN MULBERRY LEAF AND FENUGREEK IN SUBJECTS WITH PREDIABETES

Background and Objective: In Spain there are &gt;5000000 prediabetic subjects, of which &gt;500000 develop type 2 diabetes annually. Alpha-glucosidase inhibitors such as acarbose have been shown to prevent type 2 diabetes and reduce blood pressure, development of hypertension and cardiovascular risk. White mulberry (Morus alba) leaves contain 1-deoxynojirimycin, a powerful competitive alpha-glucosidase inhibitor. A nutraceutical containing Reducose (standardized white mulberry leaf extract), fenugreek (Trigonella foenum-graecum, an AMP-kinase activator), inuline (soluble fiber), Lactiplantibacillus plantarum (probiotic), niacin (vitamin B3), chromium and zinc (oligoelements) has been developed for use in patients with prediabetes. We endeavored to study its tolerability and efficacy on the metabolic profile, blood pressure and cardiovascular risk of the patients, with the change in the HOMA2-IR index of insulin resistance (as a proxy for the risk of developing type 2 diabetes) as the main outcome. Methods: In this ongoing open study, adult patients with prediabetes have been recruited to receive the mentioned nutraceutical daily for 6 months with an intermediate visit after 3 months. BMI, blood pressure, fasting glucose, insulin, lipid profile and HOMA2-IR were determined at each visit. Results: Of 94 recruited patients, 37 have completed the second visit. The HOMA-2 IR dropped by 21.5% (p=0.0016), the cardiovascular risk estimated by SCORE2 by 14.6% (p=0.0009), fasting glycemia by 7.6 mg/dL (p=0.0005), HbA1c by 0.22% (p&lt;0.0001), non-HDL cholesterol by 12.4 mg/dL (p=0.0037), systolic blood pressure by 6.3 mmHg (p=0.0001), diastolic blood pressure by 5.2 mmHg (p=0.0236); the body weight and BMI did not change significantly, and there were no withdrawals due to adverse effects or serious tolerance issues. Conclusions: This nutraceutical was well tolerated and improved the metabolic (both glycemic and lipidic) profile, the blood pressure and the cardiovascular risk of patients with prediabetes. At present there are no licensed drugs for prediabetes in Spain, but this nutraceutical may be an option for these patients in combination with lifestyle changes.