Full Analysis Research Articles

Multicenter randomized controlled trial of intensive uric acid lowering therapy for CKD patients with hyperuricemia: TARGET-UA.

We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients. This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0mg/dL and < 5.0mg/dL) or the standard therapy group (serum UA level ≥ 6.0mg/dL and < 7.0mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment. Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23mg/dL at baseline and 6.13mg/dL at 52weeks. In the Intensive therapy group, mean serum UA was 8.15mg/dL at baseline and 5.25mg/dL at 52weeks. There was no significant difference in changes in log ACR at 52weeks between the Intensive therapy and the Standard therapy groups. This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146).

Efficacy and safety of tibial nerve stimulation using a wearable device for overactive bladder.

To evaluate the efficacy and safety of a wearable, smartphone-controlled, rechargeable transcutaneous tibial nerve stimulation (TTNS) device in patients with overactive bladder (OAB). This multicentre, prospective, single-blind, randomised clinical trial included eligible patients with OAB symptoms who were randomly assigned to the stimulation group or sham group. The primary efficacy outcome was change from baseline in voiding frequency/24 h after 4 weeks of treatment. The secondary efficacy outcomes included changes in bladder diary outcomes (urgency score/void, nocturia episodes/day, micturition volume/void, and incontinence episodes/day), questionnaires on Overactive Bladder Symptom Score (OABSS), Patient Perception of Bladder Condition (PPBC), and American Urological Association Symptom Index Quality of Life Score (AUA-SI-QoL) at baseline and after 4 weeks of treatment. Device-related adverse events (AEs) were also evaluated. In the full analysis set (FAS), the mean (sd) change of voiding frequency/24 h in the stimulation group and sham group at 4 weeks were -3.5 (2.9) and -0.6 (2.4), respectively (P < 0.01). Similar results were obtained in the per-protocol set (PPS): -3.5 (2.9) vs -0.4 (2.3) (P < 0.01). In the FAS and PPS, micturition volume/void significantly improved at 4 weeks (P = 0.01 and P = 0.02). PPBC improvement almost reached significance in the FAS (P = 0.05), while it was significant in the PPS (P = 0.02). In the FAS and PPS, AUA-SI-QoL significantly improved at 4 weeks in the two groups (P < 0.01 and P < 0.01), whereas there were no significant differences in urgency score/void, nocturia episodes/day or OABSS between the groups. Also, no device-related serious AEs were reported. The non-invasive neuromodulation technique using the novel ambulatory TTNS device is effective and safe for treating OAB. Its convenience and easy maintenance make it a new potential home-based treatment modality. Future studies are warranted to confirm its longer-term efficacy.

Probiotics plus vitamin D in irritable bowel syndrome: a prospective multicentric non-interventional study.

Patients with irritable bowel syndrome (IBS) experience recurrent symptoms and anxiety disorders that significantly impact their quality of life (QoL). The aim of the study was to assess in daily practice the benefit of the combination of three probiotic strains (Lactobacillus plantarum CETC 7484 and CETC 7485; Pediococcus acidilactici CECT 7483) plus vitamin D in patients with diarrhea-predominant IBS (IBS-D) or IBS with mixed bowel movements (IBS-M). This was a prospective, multicenter, non-interventional study in adult patients with IBS-D or IBS-M (Rome IV criteria) followed by private-practice gastroenterologists. Patients received daily one sachet of a combination of probiotics (3×109 CFU) and vitamin D (10 μg) for 42 days. The primary endpoint was the responder rate at D42 (≥50% and/or ≥100-point decrease of IBS-Severity Scoring System; IBS-SSS). Gut-related anxiety was measured with the Visceral Sensitivity Index (VSI). The full analysis set population included 246 patients (mean age, 51.2±15.4 years; women, 73.2%; IBS-D, 56.1%; IBS-M, 43.9%). At D42, among the 89 patients with evaluable data, the responder rate was 62.9% with a mean decrease of IBS-SSS of 146.6±125.9 (P<0.0001). Changes of IBS-SSS were significantly correlated with changes of IBS-QoL (r=-0.78; P<0.0001), HAD-anxiety (r=0.46; P<0.0001), HAD-depression (r=0.61; P<0.001) and VSI (r=0.74; P<0.0001). These real-life results are in line with a previous randomized clinical trial demonstrating the benefits of this combination in IBS-D and IBS-M. Symptom relief was associated with improvement of IBS-QoL, anxiety, depression and specifically gut-related anxiety.

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, •C6H5-xFx (2 ≤ x ≤ 4).

Di-, tri-, and tetrafluorophenyl radicals each have three regioisomers, several of which can form multiple distinct radical structures. We present the photoelectron spectra of the di-, tri-, and tetrafluorophenide regioisomer anions generated from their associated fluorobenzene precursors. By comparing the spectra to the results of density functional theory calculations, we determine that in cases where more than one possible radical isomer is possible for a given regioisomer (radicals formed from 1,2-difluorobenzene, 1,3-difluorobenzene, 1,2,3-trifluorobenzene, and 1,2,4-trifluorobenzene) the most stable anion corresponds to a less stable neutral, suggesting that the reactive C-center on these fluorine-substituted phenyl groups can be controlled by charge state. Full analyses of the spectra and computational results yield further insights into the differences between the electronic and molecular structures of the fluorophenyl radicals and their associated anions.

Constraints on cosmic star formation history via a new modeling of the radio luminosity function of star-forming galaxies

Context. Radio wavelengths offer a unique possibility to trace the total star-formation rate (SFR) in galaxies, both obscured and unobscured. To probe the dust-unbiased star-formation history, an accurate measurement of the radio luminosity function (LF) for star-forming galaxies (SFGs) is crucial. Aims. We make use of an SFG sample (5900 sources) from the Very Large Array (VLA) COSMOS 3 GHz data to perform a new modeling of the radio LF. By integrating the analytical LF, we aim to calculate the history of the cosmic SFR density (SFRD) from z ∼ 5 onwards. Methods. For the first time, we use both models of the pure luminosity evolution (PLE) and joint luminosity+density evolution (LADE) to fit the LFs directly to the radio data using a full maximum-likelihood analysis, considering the sample completeness correction. We also incorporate updated observations of local radio LFs and radio source counts into the fitting process to obtain additional constraints. Results. We find that the PLE model cannot be used to describe the evolution of the radio LF at high redshift (z &gt; 2). By construct, our LADE models can successfully fit a large amount of data on radio LFs and source counts of SFGs from recent observations. The Akaike information criterion (AIC) also demonstrates that the LADE model is superior to the PLE model. We therefore conclude that density evolution is genuinely indispensable in modeling the evolution of SFG radio LFs. Our SFRD curve shows a good fit to the SFRD points derived by previous radio estimates. In view of the fact that our radio LFs are not biased, as opposed those of previous studies performed by fitting the 1/Vmax LF points, our SFRD results should be an improvement on these previous estimates. Below z ∼ 1.5, our SFRD matches a published multiwavelength compilation, while our SFRD turns over at a slightly higher redshift (2 &lt; z &lt; 2.5) and falls more rapidly out to high redshift.

The effects of cyclodextrin on plaque accumulation in healthy Japanese adults: A randomized, placebo-controlled, double-blind, parallel-group comparison study

Background: Cyclo-isomalto-oligosaccharides (CI) have been reported to inhibit glucosyltransferases (GTF) in vitro. GTF is an enzyme related to oral plaque synthesis. However, there are few clinical studies to investigate the effect of CI on oral plaque via inhibiting GTF activity. Objective: The purpose of this study was to evaluate the inhibitory effect of consuming CI-Dextran mix on plaque accumulation in healthy Japanese adults. Methods: This randomized, placebo-controlled, double-blind, parallel-group comparison study was conducted from May 26, 2022, to September 16, 2022. Individuals who agreed to participate in the study were randomly assigned to the CI-Dextran mix group with 60 mg/day (n = 22), the CI-Dextran mix group with 600 mg/day (n = 11), or the placebo group (n = 22). The intervention period was three days, and the outcome of this study was the plaque index (PlI), an indicator of plaque accumulation. Results: Our results showed that the CI-Dextran mix group (600mg/day) had significantly lower post-intervention PlI values than the placebo group in a full analysis set (FAS). In individuals identified as prone to plaque accumulation among the FAS, both CI-Dextran mix groups showed significantly lower PlI values than the placebo group. No adverse events were observed during the study period, and consumption of the test food under the study conditions was considered safe. Conclusions: Our results clearly indicated that a high dose of CI-Dextran mix (600 mg/day) could significantly reduce plaque formation in healthy Japanese adults, while a marginal reduction was noted for the group taking a low dose (60 mg/day). In particular, intake of both doses (CI-Dextran mix 60 mg/day and 600 mg/day) in individuals who were prone to plaque accumulation, could significantly inhibit plaque formation. Keywords: CI-Dextran mix, cyclodextran, plaque inhibition, functional carbohydrates, isomaltooligosaccharide, Randomized Controlled Trial Trial registration: UMIN000047901. Foundation: Nissin Sugar Co., Ltd.

The effects of cyclodextrin on plaque accumulation in healthy Japanese adults: A randomized, placebo-controlled, double-blind, parallel-group comparison study

Background: Cyclo-isomalto-oligosaccharides (CI) have been reported to inhibit glucosyltransferases (GTF) in vitro. GTF is an enzyme related to oral plaque synthesis. However, there are few clinical studies to investigate the effect of CI on oral plaque via inhibiting GTF activity. Objective: The purpose of this study was to evaluate the inhibitory effect of consuming CI-Dextran mix on plaque accumulation in healthy Japanese adults. Methods: This randomized, placebo-controlled, double-blind, parallel-group comparison study was conducted from May 26, 2022, to September 16, 2022. Individuals who agreed to participate in the study were randomly assigned to the CI-Dextran mix group with 60 mg/day (n = 22), the CI-Dextran mix group with 600 mg/day (n = 11), or the placebo group (n = 22). The intervention period was three days, and the outcome of this study was the plaque index (PlI), an indicator of plaque accumulation. Results: Our results showed that the CI-Dextran mix group (600mg/day) had significantly lower post-intervention PlI values than the placebo group in a full analysis set (FAS). In individuals identified as prone to plaque accumulation among the FAS, both CI-Dextran mix groups showed significantly lower PlI values than the placebo group. No adverse events were observed during the study period, and consumption of the test food under the study conditions was considered safe. Conclusions: Our results clearly indicated that a high dose of CI-Dextran mix (600 mg/day) could significantly reduce plaque formation in healthy Japanese adults, while a marginal reduction was noted for the group taking a low dose (60 mg/day). In particular, intake of both doses (CI-Dextran mix 60 mg/day and 600 mg/day) in individuals who were prone to plaque accumulation, could significantly inhibit plaque formation. Keywords: CI-Dextran mix, cyclodextran, plaque inhibition, functional carbohydrates, isomaltooligosaccharide, Randomized Controlled Trial Trial registration: UMIN000047901. Foundation: Nissin Sugar Co., Ltd.

Hybrid genome assembly of colistin-resistant mcr-1.5-producing Escherichia coli ST354 reveals phylogenomic pattern associated with urinary tract infections in Brazil

The rapid and global spread of Escherichia coli carrying mcr-type genes at the human-animal-environmental interface has become a serious global public health problem. To perform a genomic investigation of a colistin-resistant E. coli strain (14005RM) causing urinary tract infection, using a hybrid de novo assembly of Illumina/Nanopore sequence data, presenting phylogenomic insights into the relationship with mcr-1-positive strains circulating at the human-animal-environmental interface, in Brazil. Genomic DNA was sequenced using both the Illumina NexSeq and Nanopore MinION platforms. De novo hybrid assembly was performed by Unicycler. Genomic data were assessed by in silico prediction and bioinformatic tools. The genome assembly size was 5 333 039 bp. The mcr-1.5-positive E. coli strain 14005RM belongs to the sequence type ST354 and presented a broad resistome (antibiotics, heavy metals, disinfectants, and glyphosate) and virulome. The mcr-1.5 gene was carried by an IncI2 plasmid (p14005RM, sizing 65,458 kb). Full genome SNP-based phylogenetic analysis reveals that mcr-1.5-producing E. coli strain 14005RM is highly related (> 98% identity) to colistin-resistant mcr-1.1-positive ST354 lineages associated with urinary tract infections in Brazil since 2015. Mobile colistin resistance within the Brazilian One Health microbiosphere is mediated by mcr gene variants propagated by IncX4, IncHI2, and IncI2 plasmids, circulating among global clones of E. coli.

Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201)

BackgroundAdvanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer.MethodsThis multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma.DiscussionGEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer.Trial registrationThis study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

Efficacy and safety of cadonilimab in previously treated recurrent or metastatic nasopharyngeal carcinoma(COMPASSION-06): A phase II multicenter study

ObjectiveThis study was designed to assess the efficacy and safety of cadonilimab monotherapy, a first-in-class, bi-specific PD-1/CTLA-4 antibody, in patients with previously treated recurrent or metastatic nasopharyngeal carcinoma (R/M−NPC). Patients and MethodsThis multicenter, open-label, single-arm, phase II clinical trial enrolled patients with R/M−NPC who had failed first-line platinum-based chemotherapy and second-line single agent or combined chemotherapy, and immunotherapy-naive. Patients received cadonilimab for 6 mg/kg once every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) in full analysis set (FAS) assessed by investigators according to RECIST v.1.1. The secondary endpoint included progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR) and safety. ResultsA total of 23 patients were assessed. The median time from first dose to data cutoff was 16.56 (range, 0.8–25.2) months. ORR was 26.1 % (95 %CI:10.2–48.4). The ORR were 44.4 % (95 %CI: 13.7–78.8) and 14.3 % (95 %CI:1.8–42.8) in patients with tumor PD-L1 expression ≥50 % and <50 %, respectively. ORR was achieved in 40.0 % (95 %CI:12.2–73.8) of patients with EBV-DNA level <4000 IU/ml (n = 10) and 15.4 % (95 %CI:1.9–45.4) of those with ≥4000 IU/ml. The median PFS was 3.71 months (95 %CI: 1.84–9.30). respectively. Median OS was not reached, and the 12-month OS rate was 79.7 % (95 % CI:54.5–91.9). Only two patients (8.3 %) experienced Grade ≥3 treatment-related adverse events (TRAEs) with hypothyroidism (30.4 %), rash (21.7 %) and pruritus (21.7 %) being the most prevalent TRAEs. ConclusionCadonilimab monotherapy demonstrated a promising efficacy and manageable toxicity in patients with previously treated R-M/NPC and provide an efficacious salvage treatment option.

Application analysis of data mining in shopping APP

Dingdong Buying Vegetable is a cohort of emerging entities that have swiftly gained prominence within the business domain in recent times. The data mining function of its data platform APP is undeniably linked to the underlying factor contributing to its commercial success. This article examines the fundamental principles, practical manifestations, and pertinent research instances of data mining. It specifically centers on the primary interface of the Dingdong Buying Vegetable APP, scrutinizing its design and distinctive attributes tailored to specific customers. Furthermore, it conducts an in-depth analysis of the correlation between the platforms commercial success and its data mining functionality. The primary aspect in which the data mining function of the Dingdong Buying Vegetable APP is expected to be manifested is through extensive data mining. The process of mining client data and conducting a full comparison and analysis of sales data for all products sold is a highly intricate and exhaustive endeavor. The use of these data mining functions serves multiple purposes. Firstly, it efficiently identifies customers genuine requirements on the client side, enabling the recommendation of suitable products and fostering customer reliance on the application. Additionally, it facilitates accurate decision-making in marketing products on the product side by comparing and analyzing diverse data pertaining to the sold products. This approach helps prevent the sale of unsought items and effectively minimizes company expenditure.

The Molecular Epidemiology of Epizootic Hemorrhagic Disease Viruses Identified in Israel between 2015 and 2023.

Epizootic hemorrhagic disease (EHD) is an infectious, non-contagious viral disease seriously affecting cattle and some wild ruminants and has a worldwide distribution. All viruses can be subdivided into "Eastern" and "Western" topotypes according to geographic distribution via the phylogenetic analysis of internal genes. In Israel, during the last decade, three outbreaks were registered: caused by EHDV-6 in 2015, by EHDV-1 in 2016, and by EHDV-7 in 2020. Additionally, RNA of EHDV-8 was found in imported calves from Portugal in 2023. During the same period in other countries of the region, non-Israeli-like EHDV-6 and EHDV-8 were identified. Full genome sequencing, BLAST, and phylogenetic analyses of the locally and globally known EHDV genomes allowed us to presume the probable route and origin of these viruses detected in Israel. Thus, EHDV-6 has probably been circulating in the region for a long period when EHDV-1 and -8 appeared here for the last years, while their route of introduction into the new areas was probably natural; all of them belonged to the "Western" topotype. In contrast, EHDV-7 probably had the "Eastern", anthropogenic origin. Data from the study can facilitate the evaluation of the appearance or reappearance of EHDVs in the Mediterranean area and enhance the planning of prevention measures.

The Discount Rate for Investment Analysis Applying Expected Utility

In decision analysis, expected utility of discounted cash flows is the traditional approach to incorporate risk aversion into the evaluation of a project. The choice of discount rate as well as the convergence with the beta-adjusted approach from finance have always been in question. To address this gap, we adopt a risk-sharing setup in which investors have both treasuries and the stock market as alternatives to the project. For a full utility analysis of all the investor’s capital, we provide a unique discount rate that allows setting the horizon at the termination of the project. For a traditional analyst who conducts expected utility of discounted cash flows and ignores the capital not allocated to the project, we recommend an adjusted discount rate that compensates for double-counting the systematic risk.

Full sample analysis of cerebral venous sinus thrombosis in ophthalmology inpatients

We hope that by analyzing the clinical features of cerebral venous sinus thrombosis (CVST), we can help ophthalmologists reduce misdiagnosis or delayed diagnosis. We evaluated 47 patients with CVST in terms of clinical manifestations. All cases were analyzed in terms of risk factors, clinical symptoms, ophthalmic examination, imaging examination and lumbar puncture. The body mass indices (BMIs) of 41 patients (87.2%; 95% CI, 77.7-96.8%) were≥24, which is overweight by Chinese standards. There were 22 patients (46.8%; 95% CI, 32.5-61.1%) with BMIs≥28, who were considered obese. Thirteen were hypertensive (27.7%; 95% CI, 14.9-40.5%). The initial symptoms included blurred vision (23, 48.9%; 95% CI, 34.6-63.2%), amaurosis fugax (13, 27.7%; 95% CI, 14.9-40.5%), headache (11 patients, 23.4%; 95% CI, 11.3-35.5%), dizziness (3, 6.4%; 95% CI, -0.6-13.4%), and bilateral diplopia (3, 6.4%; 95% CI, -0.6-13.4%). There were 9 patients (9, 19.2%; 95% CI, 7.9-30.4%) with blindness, 23 patients (48.9%; 95% CI, 34.6-63.2%) with pupillary abnormalities, and 40 patients (85.1%; 95% CI, 74.9-95.2%) with papilledema. Forty-three of the 45 patients who successfully underwent a routine lumbar puncture showed high intracranial pressure (91.7%; 95.6% CI, 89.6-101.6%). Finally, two cases are reported in greater detail for illustrative purposes. The main reasons interfering with the diagnosis of CVST might be its nonspecific ocular symptoms and the physicians' clinical thought process being limited to the scope of common ophthalmological diseases.

Treatment of cognitive impairment in patients with cerebral infarction in the internal carotid arteries circulation system: results of a multicentre, randomized, double-blind, placebo-controlled clinical trial

Objective: to evaluate the efficacy and safety of the Prospecta drug in the treatment of cognitive impairment (CI) in patients with ischemic stroke (IS) in the carotid vascular territory.Material and methods. The double-blind, placebo-controlled, randomized clinical trial enrolled 246 patients aged 40 to 75 years with IS in the carotid vascular territory within 72 hours of stroke onset, moderate CI (&lt;26 points on the Montreal Cognitive Assessment, MoCA), full consciousness (15 points on the Glasgow Coma Scale), moderate severity of stroke (8–12 points on the National Institute of Health Stroke Scale, NIHSS), moderate impairment of activity (2–3 points on the – Modified Rankin Scale, mRs). At visit 1, complaints and medical history were collected, vital signs (VS) and laboratory parameters were recorded, CI was assessed according to MoCA and the Glasgow Coma Scale, NIHSS and mRs were filled out. Patients were randomized into two groups: in the first group they received Prospecta for 90 days, in the second group placebo (PL) following a similar regimen. The groups were comparable in terms of demographic and baseline clinical characteristics. After 90 days, complaints, medical history, VS, laboratory parameters and assessment of CI according to MoCA were recorded, and NIHSS and mRs questionnaires were filled out again. The intention-to-treat (ITT) efficacy analysis was performed based on the results of the treatment and follow-up of the Full analysis set (FAS), which comprised 241 patients (122 patients in the Prospecta group and 119 patients in the PL group; 4 patients were excluded from the ITT analysis because they were erroneously included in the study). The results of the per-protocol (PP) analysis are shown in square brackets.Results. The 90-day use of Prospecta reduced the severity of CI in patients with carotid IS compared with placebo therapy. MoCA scale scores increased from 20.7±3.5 [20.9±3.0] to 24.6±2.9 [25.2±2.5] points in the Prospecta group and from 21.7±2.4 [21.6±2.4] to 24.5±3.0 [24.8±2.8] points in the PL group (p=0.0006 [p=0.0014]). 42 adverse events (AEs) were recorded in 32 (26.0%) patients in the Prospecta group and 37 AEs in 28 (23.0%) patients in the PL group (p=0.656). All AEs in the Prospecta group were not significantly related to the use of the drug. No deaths or recurrent IS were recorded.Conclusion. Prospecta is an effective and safe treatment for CI in patients with carotid IS

Long-Term Clinical Safety of the Ad26.ZEBOV and MVA-BN-Filo Ebola Vaccines: A Prospective, Multi-Country, Observational Study.

In this prospective, observational study (ClinicalTrials.gov Identifier: NCT02661464), long-term safety information was collected from participants previously exposed to the Ebola vaccines Ad26.ZEBOV and/or MVA-BN-Filo while enrolled in phase 1, 2, or 3 clinical studies. The study was conducted at 15 sites in seven countries (Burkina Faso, France, Kenya, Tanzania, Uganda, the United Kingdom, and the United States). Adult participants and offspring from vaccinated female participants who became pregnant (estimated conception ≤28 days after vaccination with MVA-BN-Filo or ≤3 months after vaccination with Ad26.ZEBOV) were enrolled. Adults were followed for 60 months after their first vaccination, and children born to female participants were followed for 60 months after birth. In the full analysis set (n = 614 adults; median age [range]: 32.0 [18-65] years), 49 (8.0%) had ≥1 serious adverse event (SAE); the incidence rate of any SAE was 27.4 per 1000 person-years (95% confidence interval: 21.0, 35.2). The unrelated SAEs of malaria were reported in the two infants in the full analysis set, aged 11 and 18 months; both episodes were resolved. No deaths or life-threatening SAEs occurred during the study. Overall, no major safety issues were identified; one related SAE was reported. These findings support the long-term clinical safety of the Ad26.ZEBOV and MVA-BN-Filo vaccines.

Thermal reaction of firebrand accumulation in construction materials

This paper presents research concerning the thermal firebrand reaction due to its accumulation in specimens of current construction materials commonly applied to the exterior of dwellings in southern Europe. An extensive fire experimental campaign is undertaken, in which firebrands are deposited on the plane surfaces of the material specimens and the temperature is measured on the top and bottom construction specimen surfaces. The materials chosen for this work are currently applied to either the roof, exterior walls and windows, and were recommended as either fire resistance or good behaviour for high temperatures. It will be possible to verify their firebrand reaction, more precisely, the type of ignition, the smoke, droplet production, and even their insulation capabilities. It is also tested for the efficiency of a metal mesh to prevent the entrance of firebrands into the air vents of façades and chimneys in dwellings. A thermal numerical model is also used to study the efficiency of the insulation properties of some construction materials for firebrand deposition by measuring the level of heat flux circulation during the full time analysis.

Phage vB_Ec_ZCEC14 to treat antibiotic-resistant Escherichia coli isolated from urinary tract infections

Escherichia coli is a commensal bacterial species in the human gastrointestinal tract; however, it could be pathogenic and cause severe infections in intra and extra-intestinal sites. Uropathogenic E. coli accounts for 80–90% of urinary tract infections that can result in urosepsis and septic shock. Consequently, multidrug-resistant uropathogenic E. coli poses a considerable risk to the healthcare system worldwide. Phage therapy is demonstrated as an optimistic solution to over-the-counter antibiotics that contribute to the global issue of multidrug-resistant bacteria. This study aims to isolate a novel phage that could be implemented to cure urinary tract infections mediated by multidrug-resistant E. coli. Twenty-seven E. coli isolates were collected from patients with urinary tract infections to assess the antibacterial efficacy of phage vB_Ec_ZCEC14. Phage kinetics were encountered against the E. coli strain (EC/4), in addition to evaluating phage stability under various temperatures, pH values, and UV exposure periods. Full genome sequencing and morphological analysis were conducted for further phage characterization, which revealed that phage vB_Ec_ZCEC14 belongs to the family Straboviridae. Phage vB_Ec_ZCEC14 showed thermal tolerance at 80 ℃, pH stability between pH 3 and pH 12, and endurance to UV exposure for 45 min. The phage-host interaction results revealed that phage vB_Ec_ZCEC14 has strong and steady antibacterial action at lower concentrations (MOI 0.1). The study findings strongly indicate that phage vB_Ec_ZCEC14 holds significant promise as a potential therapeutic alternative for treatment of antibiotic-resistant uropathogenic E. coli.

Effect of parental touch on relieving acute procedural pain in neonates and parental anxiety (Petal): a multicentre, randomised controlled trial in the UK

Touch interventions such as massage and skin-to-skin contact relieve neonatal pain. The Parental touch trial (Petal) aimed to assess whether parental stroking of their baby before a clinically required heel lance, at a speed of approximately 3 cm/s to optimally activate C-tactile nerve fibres, provides effective pain relief. Petal is a multicentre, randomised, parallel-group interventional superiority trial conducted in the John Radcliffe Hospital (Oxford University Hospitals NHS Foundation Trust, Oxford, UK) and the Royal Devon and Exeter Hospital (Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK). Neonates without neurological abnormalities who were born at 35 weeks gestational age or more and required a blood test via a heel lance in the first week of life were randomly assigned (1:1) to receive parental touch for 10 s either before (intervention group) or after (control group) the clinically required heel lance. Randomisation was managed at the Oxford site using a web-based minimisation algorithm with allocation concealment. The primary outcome measure was the magnitude of noxious-evoked brain activity in response to the heel lance measured with electroencephalography (EEG). Secondary outcome measures were Premature Infant Pain Profile-Revised (PIPP-R) score, development of tachycardia, and parental anxiety score. For all outcomes, the per-protocol effect was estimated via complier average causal effect analysis on the full analysis set. The trial is registered on ISRCTN (ISRCTN14135962) and ClinicalTrials.gov (NCT04901611). Between Sept 1, 2021, and Feb 7, 2023, 159 parents were approached to participate in the study, and 112 neonates were included. 56 neonates were randomly assigned to the intervention group of parental stroking before the heel lance and 56 to the control group of parental stroking after the heel lance. The mean of the magnitude of the heel lance-evoked brain activity was 0·85 arbitrary units (a.u.; SD 0·70; n=39; a scaled magnitude of 1 a.u. represents the expected mean response to a heel lance in term-aged neonates) in the intervention group and 0·91 a.u. (SD 0·76; n=43) in the control group. Therefore, the primary outcome did not differ significantly between groups, with a mean difference of -0·11 a.u. (lower in intervention group; SD 0·77; 95% CI -0·42 to 0·20; p=0·38; n=82). No significant difference was observed across secondary outcomes. The PIPP-R difference in means was 1·10 (higher in intervention group, 95% CI -0·42 to 2·61; p=0·15; n=100); the odds ratio of becoming tachycardic was 2·08 (95% CI 0·46 to 9·46; p=0·34, n=105) in the intervention group with reference to the control group; and the difference in parental State-Trait Anxiety Inventory-State score was -0·44 (higher in control group; SD 6·85; 95% CI -2·91 to 2·02; p=0·72; n=106). One serious adverse event (desaturation) occurred in a neonate randomly assigned to the control group, which was not considered to be related to the study. Parental stroking delivered at an optimal speed to activate C-tactile fibres for a duration of 10 s before the painful procedure did not significantly change neonates' magnitude of pain-related brain activity, PIPP-R score, or development of tachycardia. The trial highlighted the challenge of translating an experimental researcher-led tactile intervention into a parent-led approach, and the value of involving parents in their baby's pain management. Wellcome Trust and Bliss.

RNA Interference With Zilebesiran for Mild to Moderate Hypertension

Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. ClinicalTrials.gov Identifier: NCT04936035.