Alkaline hydrogen evolution reaction (HER) is limited by slow water dissociation and by catalysts that degrade in saline electrolytes. Here we program vacancies to trigger selective Ni exsolution in multimetallic Prussian blue analogues (PBAs), creating cooperative defect-metal interfaces. Low-temperature annealing of FeMn@CoNi PBAs forms hollow nanocages (PBA-350) rich in cyanide vacancies and decorated with in situ exsolved Ni nanoparticles. Operando XRD/XAS, operando impedance, and theory reveal a dual-site mechanism: vacancy-stabilized Ni lowers the Volmer barrier, adjacent Co facilitates OH* removal, and the vacancy-modified lattice tunes H* binding toward thermoneutrality. PBA-350 delivers 28.4 mV at 10 mA cm-2 and a 56 mV dec-1 Tafel slope in 1.0 m KOH with negligible degradation over 100 h at -50 mA cm-2. An anion-exchange membrane electrolyzer reaches 1.76 V at 1.0 A cm-2, and PBA-350 remains stable in simulated seawater (1.0 m KOH + 0.5 m NaCl) by physically repelling chloride ions via hydration layers, establishing vacancy-assisted exsolution as a design rule for HER.
Ibogaine is a naturally occurring indole alkaloid with suggested therapeutic potential across substance use disorders, trauma-related conditions, mood disorders, and suicidality. However, its clinical translation has been hindered by safety concerns, regulatory barriers, and uncertainty regarding its complex pharmacology. Recent interest has surged in developing ibogaine analogs and derivatives that retain therapeutic efficacy while minimizing safety risks. Ibogaine pharmacology is complex with many affected targets, which complicates these efforts. Herein, the authors propose a conceptual framework that distinguishes between two primary strategies: (1) development of ibogaine-like compounds that preserve broad, polypharmacological effects while mitigating key safety liabilities, and (2) creation of more selective, purpose-built 'bespoke' analogs designed to optimally target specific neurobiological pathways and clinical indications - such as opioid use disorder (OUD), traumatic brain injury, or post-traumatic stress disorder (PTSD). Furthermore, the authors critically evaluate the current evidence supporting each approach, and discuss the translational trade-offs related to safety, efficacy, comorbidity, and scalability. The authors also highlight the importance of individual variability, including pharmacogenetics in treatment response. It is important, and particularly within policy-driven research initiatives, that this evolving field must resist oversimplified narratives that frame derivatives as uniformly superior or interchangeable. Greater conceptual clarity and mechanistic humility are also essential as ibogaine-based therapies move toward regulated medical use within Westernized healthcare models.
We report the synthesis of three chloropnictogenium cations [MSFluindECl]+ (2As, 2Sb and 2 Bi), which unravel different reaction pathways toward Et3SiH, leading to the formation of the neutral arylarsenic(III) dihydride MSFluindAsH2 (3), the cationic arylhydridostibenium(III) [MSFluindSbH]+ (4) and the dicationic aryltribismuth(I) ion [MSFluindBi3]2+ (7). In light of its reactivity, 4 can also be regarded as a protonated stibinidene(I), as demonstrated by the reaction with trimethylindium and gallium as well as diphenyldichalcogenides, leading to the stibinidene supported dimethylelement cations [MSFluindSbEMe2]+ (5Ga, 5In) and the chalcogenide cations [MSFluindSbChPh]+ (6S, 6Se, 6Te) featuring formal SbCh double bonds. The Bi3 dication 7 reveals substantial 2-electron-3-center bonding character within the Bi-C-Bi interaction, a feature unprecedented in the chemistry of group 15 elements.
There is little information available about the effect self-reported color/race has on glycemic control in patients with type 1 diabetes (T1D) in Brazil. Therefore, we aimed at evaluating the role of self-reported color/race on glycemic control and on the types of prescribed insulin in this population. This was a cross-sectional study with 1760 patients with T1D with data collection between August 2011 and August 2014 in Brazil. An adjusted linear regression model was used to compare the hemoglobin A1c HbA1c) of patients who self-reported as Black and Brown to those who self-reported as White. Adjusted logistic regression models were used to evaluate the relationship between self-reported color-race and types of prescribed insulin. Black patients presented a difference in HbA1c of 0·74% (p-value < 0·001) in the unadjusted model and of 0·58% (p-value 0·004) in the adjusted model compared to White patients. Black patients had 53% (95% CI: 26%-70%) and 66% (95% CI: 44%-79%) less odds of receiving analogues for bolus and basal insulin, respectively, than White patients in the adjusted models. Brown patients presented a difference in HbA1c of 0·42% (p-value < 0·001) in the crude model and 0.23% (p-value 0·04) in the adjusted model compared to White patients. Brown patients had 49% (95% CI: 35%-60%) and 43% (95% CI: 27%-55%) less odds of receiving analogues for bolus and basal insulin, respectively, in adjusted models than White patients. Black and Brown Brazilian patients with T1D presented with higher HbA1c and received less advanced diabetes therapies compared to White patients.
A molecular networking-guided investigation of extracts from the growth medium of the endophytic fungus Trichoderma harzianum MLJ-4 resulted in the isolation of eight new polycyclic-fused cytochalasins (CYTs), triharziachalasins A-H (1-8), along with six known analogues (9-14). Their structures, including absolute configurations, were elucidated by comprehensive spectroscopic analysis, NMR calculations with DP4+ analysis, theoretical ECD simulations, and single-crystal X-ray diffraction. Compounds 1-3 feature a rare 5/6/5/8-fused tetracyclic system, while 4-8 possess a novel 5/6/6/7/5-fused pentacyclic scaffold. Compound 1 is the first cytochalasin analogue containing a cis-fused 5/8 ring within the 5/6/5/8 framework. All CYTs were evaluated for antiliver fibrosis activity in TGF-β1-stimulated LX-2 cells using high-content screening assays. The most promising compound, triharziachalasin H (8), dose-dependently suppressed the expression of key fibrotic markers, including fibronectin (FN), collagen I, and α-smooth muscle actin (α-SMA). Mechanism studies revealed that its antiliver fibrosis effect is mediated via inhibition of the NF-κB signaling pathway. This work expands the structural diversity of bioactive CYTs and reveals the antiliver fibrosis activity of this novel polycyclic-fused architecture, highlighting its potential as a lead compound for antiliver fibrosis drug development.
A small library of piperazine and piperazinone derivatives carrying an imidazole ring was synthesized, with the aim to find selective carbonic anhydrase (CA) modulators. These compounds can be regarded as reduced-flexibility analogues of histamine and histidine, two well-known CA activators. Their activating properties were evaluated against human CA I, II, VA, VII, and XIII. Activity was observed exclusively on CA VA and CA XIII, with KA values in the medium and low micromolar range, respectively. Among the tested molecules, compound (R)-2 emerged as a promising lead compound for the development of selective CA XIII activators. Conversely, introduction of a 4-sulfamoylbenzoyl group on the piperazine nitrogen atom switched the activity from activation to inhibition, yielding compound 6 as a potent inhibitor of hCA II.
This study reports the radiosynthesis and biological evaluation of 99mTc-Amygdalin, using a newly developed chromatographic 99Mo/99mTc generator based on alumina doped with terbium oxide. The prepared sorbent was successfully synthesized and characterized as a structurally stable oxide matrix exhibiting high Mo(VI) sorption capacity (117 mg/g), excellent adsorption selectivity at pH 4, and minimal 99Mo breakthrough, enabling the production of high-purity 99mTc suitable for radiopharmaceutical applications. Amygdalin was efficiently radiolabeled under optimized reductive conditions, achieving radiochemical purity exceeding 90%. In addition, a corresponding rhenium analogue complex was synthesized to support the proposed coordination behavior of the radiocomplex. Biodistribution studies in Ehrlich solid tumor-bearing mice demonstrated rapid blood clearance, favorable systemic distribution, and progressive tumor uptake, reaching 8.5 ± 0.65%ID/g at 120 min post-injection, with target-to-non-target ratios approaching 17 at later time points. The obtained pharmacokinetic profile highlights the potential applicability of 99mTc-Amygdalin as a promising tumor-targeting radiotracer for diagnostic imaging.
Amides and trifluoromethyl groups are among the most widely used structural motifs in materials science, medicinal chemistry, and agrochemistry. In contrast, their direct combination as N-trifluoromethyl amides and the closely related N-trifluoromethyl carbamates and ureas has remained largely unexplored. This disconnect has primarily stemmed from the lack of synthetic methods and their unknown stabilities and physicochemical properties. Enabled by recently developed methodologies to synthesize N-trifluoromethyl carbonyl compounds, we systematically evaluated their aqueous stability and drug-relevant properties to assess their usefulness for compound optimization. All investigated N-trifluoromethyl derivatives display high aqueous stability at pH 7.4, including in human plasma, except for one N-trifluoromethyl carbamate series. N-Trifluoromethyl carbonyl motifs have a lipophilicity and Caco-2 permeability similar to their N-isopropyl analogues, while, in several cases, offering improved pharmacokinetic profiles. These findings establish N-trifluoromethyl carbonyl motifs as highly attractive functionalities, providing medicinal chemists with a framework for their incorporation into future drug-discovery programs.
Percutaneous renal biopsy (PRB) is an essential diagnostic procedure for kidney diseases, yet postbiopsy perirenal hematoma and pain remain frequent complications. Vitamin C has emerging evidence supporting its role in reducing perioperative bleeding and pain, but its efficacy in the context of PRB is unknown. This single-center, prospective, open-label, randomized controlled trial enrolled 710 adults with chronic kidney disease (CKD) scheduled for an ultrasound-guided native kidney biopsy. Participants were randomly assigned (1:1) to receive perioperative intravenous vitamin C (20 mg/kg at 6 h before and 18 h after biopsy) or standard care alone. The primary outcomes were the area of perirenal hematoma on renal ultrasound at 24 h and self-reported pain intensity (Visual Analogue Scale, VAS) at 2, 12, and 24 h post-biopsy. All 710 randomized participants were included in the analysis. The adjusted mean difference in hematoma area at 24 h was 4.44 mm² (95% CI, -52.31 to 61.18; P = 0.878). After multiple testing correction, there were no significant differences in the primary pain outcome (VAS scores) between groups at any time point; however, an exploratory analysis of pain severity categories indicated a less favorable distribution in the Vitamin C group at 12 h (P for trend =0.033). The incidence of any perirenal hematoma was 56.3% in the vitamin C group versus 50.1% in the control group (risk ratio, 1.12; 95% CI, 0.98-1.29; P = 0.098). Rates of other bleeding complications and adverse events were low and comparable between groups. In CKD patients undergoing PRB, perioperative intravenous vitamin C did not reduce the size of perirenal hematoma, alleviate postbiopsy pain, or decrease the incidence of bleeding complications within 24 h. These findings do not support the routine use of vitamin C for preventing complications after kidney biopsy.
Port-site incisional hernia (PIH) remains a clinically relevant complication of laparoscopic surgery, particularly at 10-12 mm trocar sites and in patients with obesity or other predisposing factors. Despite the large number of fascial closure methods reported, no universally accepted standard has emerged, and the cost or limited availability of dedicated devices may restrict their routine use. In this context, we evaluated the safety and feasibility of a novel Veress needle-based port-site closure technique and, in parallel, performed a structured literature review to contextualize its potential value among currently available strategies. In this prospective single-center cohort study, 15 adult patients underwent closure of 32 trocar sites using the proposed double-arc Veress technique. Intraoperative events, postoperative complications, and closure-site pain were systematically assessed. Follow-up included both clinical and ultrasonographic evaluation over 6-18 months. Concurrently, 40 port-site closure techniques were identified through a structured review and analyzed according to technical concept, clinical outcomes, and cost implications. No vascular or visceral injury, bleeding, infection, or PIH was observed in our cohort. Postoperative pain was minimal, with mean Visual Analogue Scale (VAS) scores of 2.0 on Postoperative Day (POD) 1 and 1.6 on POD 2. The literature review revealed substantial heterogeneity across techniques, with reported hernia rates ranging from 0 to 0.6% and marked variation in device complexity and economic burden. The double-arc Veress needle technique appears safe, reproducible, and cost-efficient, and may represent a pragmatic alternative for routine practice, particularly in resource-constrained settings.
Organophosphate esters (OPEs) are ubiquitous in various environmental matrices due to their extensive use as flame retardants and plasticizers in our daily life. Triphenyl phosphate (TPHP) and tris(2-butoxyethyl) phosphate (TBOEP), two typical analogues of OPEs, pose risk to the environment, aquatic organisms and human health. In this study, Pelophylax nigromaculatus tadpoles were selected for a 21-day exposure experiment to determine the bioaccumulation and metabolic pathways of these two substances. The logarithmic concentrations (Log C) of TBOEP in tadpoles exhibited an increase over time, while those of TPHP demonstrated a slightly declining trend. TPHP displayed higher bioconcentration factors compared to TBOEP. Differences in bioaccumulation may be attributed to biotransformation and species variability. There were four TPHP metabolites (TP-251, TP-343a, TP-343b, TP-357) and TBOEP metabolites (TB-415a, TB-415b, TB-429a, TB-429b) identified in tadpoles while three TPHP metabolites (TP-343a, TP-343b, TP-343c) and TBOEP metabolites (TB-299, TB-415a, TB-415b) in water. Among these, TB-415b exhibited the higher potential for bioaccumulation. It can be inferred that TPHP and TBOEP underwent hydrolysis (yielding TP-251 and TB-299), hydroxylation (producing TP-343a/b/c, TB-415a/b and TB-429a), and methylation reactions (generating TP-357 and TB-429b). This study provides significant insights into the bioaccumulation and biotransformation mechanisms of TPHP and TBOEP within amphibians.
Upper lumbar disc herniation (ULDH) is relatively uncommon and may present with atypical symptoms, including lower abdominal pain, which can complicate clinical diagnosis. The diagnostic challenge is even greater when multilevel lumbar degeneration is present and the symptomatic level is unclear. We report the case of a 65-year-old woman with right lower abdominal pain for more than 5 years. The pain worsened during the 3 months before admission and was accompanied by low back pain and radiating pain in the left lower limb. Repeated abdominal evaluations, including abdominal ultrasonography and gynecological and urological assessments, did not reveal any abnormality sufficient to explain her symptoms. Lumbar magnetic resonance imaging showed multilevel degenerative changes, including L2-3 disc herniation and L4-5 spinal canal stenosis with degenerative spondylolisthesis. Because the imaging findings did not fully correspond to the clinical presentation, fluoroscopy-guided right L2-3 selective nerve root block (SNRB) was performed to help identify the responsible level. After the block, the visual analogue scale (VAS) score for right lower abdominal pain decreased from 7 to 3, although the pain returned to the pre-block level 2 days later. The patient subsequently underwent right L2-3 transforaminal endoscopic lumbar discectomy (TELD), after which the VAS score for right lower abdominal pain decreased further to 2. Persistent low back pain and left lower-limb radiating pain were then treated with L4-5 posterior lumbar interbody fusion (PLIF), and the VAS score for left leg pain decreased to 2. This case suggests that radicular referred pain caused by ULDH should be considered in patients with long-standing lower abdominal pain and repeatedly negative abdominal evaluations, particularly when spinal symptoms coexist. In patients with multilevel degeneration and discordant clinical and imaging findings, SNRB may help localize the symptomatic level and support a staged, symptom-oriented surgical strategy.
DNA primases synthesize short primers required for genome replication, yet the mechanism of initial dinucleotide formation remains poorly understood. Here, we investigate the primase encoded by the pRN1 plasmid from the thermoacidophile archaeon Sulfolobus islandicus, a minimal model for primer synthesis. Using nucleotide analogues to slow the reaction, we capture transient intermediates of dinucleotide formation. Structural NMR and modeling reveal that the ancillary domain simultaneously binds the DNA template and two initiating nucleotides. Unexpectedly, only the second nucleotide base-pairs with the template, whereas the first remains unpaired, inducing template-base flipping and linker interaction. This interaction promotes a closed conformation in which the second nucleotide moves from the initiation to the elongation site and the first forms a base pair in the initiation site, positioning both nucleotides for catalysis. These findings reveal a mechanism for template recognition, nucleotide assembly, and proofreading during primer initiation that is likely conserved among primases.
The dynamic shear modulus and anelastic properties of MgAl2O4 spinel have been measured using a forced torsion pendulum between 600 K and 1400 K at frequencies of 0.01-10 Hz. A Debye-like peak in the internal frictionQ-1is observed at ~1057 K at 1 Hz, accompanied by a corresponding modulus defect in the shear modulusGof order 4 GPa (~20% of the unrelaxed modulus). Both the loss peak and the modulus dispersion are well described by a single thermally activated relaxation time, and the loss peak shifts systematically to higher temperature with increasing frequency, with no hysteresis between heating and cooling. Arrhenius analysis of the peak positions yields an activation energy of 331 kJ mol-1. The peak is approximately 1.8 times broader than an ideal single-relaxation-time Debye peak, and this excess width is independent of frequency, reflecting the distribution of local Mg-Al exchange environments. We attribute the relaxation to stress-induced, vacancy-mediated Mg-Al exchange between tetrahedral and octahedral sites, the direct anelastic analogue of Zener relaxation in substitutional alloys. The result provides a mechanical-spectroscopic demonstration of cation-exchange anelasticity in MgAl2O4, and shows that non-convergent order-disorder generates a distinct dynamical signature within the seismic frequency band.
Mesh fixation is not routinely required in most laparoscopic inguinal hernia repairs (LIHR); however, when indicated, the optimal fixation method remains uncertain. This study aimed to compare surgical glue versus absorbable tacks (AT) for mesh fixation in LIHR, focusing on postoperative pain and early complications. We searched PubMed, Embase, and Cochrane for randomized controlled trials (RCTs) comparing glue versus AT in elective LIHR. Effect estimates were pooled using random-effects models and expressed as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs). The primary outcome was postoperative pain assessed by the visual analogue scale (VAS). Secondary outcomes included complications and operative time. Risk of bias was assessed using the Cochrane RoB 2 tool. Trial sequential analysis (TSA) and prediction intervals (PI) were used to assess robustness. Nine RCTs comprising 1,289 patients were included. Glue fixation was associated with lower early postoperative pain at 7-14 days (MD - 0.77; 95% CI - 1.22 to - 0.33; p < 0.001; I2 = 83%). However, substantial heterogeneity and wide prediction intervals (- 2.33 to 0.79) indicated variability across settings. TSA suggested evidence of potential effect; however, this finding should be interpreted in the context of substantial heterogeneity. No significant difference was observed beyond 4 weeks, with insufficient cumulative evidence to draw firm conclusions. Glue fixation was associated with lower rates of hematoma and seroma, although the findings were uncertain given the prediction intervals and TSA. Other outcomes were underpowered or inconclusive. Glue fixation may be associated with lower early postoperative pain than absorbable tacks after LIHR; however, the available evidence remains heterogeneous and inconclusive for other postoperative outcomes. Further adequately powered randomized trials are required before definitive clinical recommendations can be made.
Patients undergoing percutaneous coronary intervention (PCI) frequently experience intraoperative angina and periprocedural myocardial injury (PMI), conditions associated with adverse clinical outcomes. Electroacupuncture (EA) demonstrated promising potential in analgesia and cardioprotection. This study aimed to evaluate the efficacy and safety of intraoperative EA in mitigating angina, attenuating PMI, and modulating the systemic inflammatory response in patients undergoing PCI. A total of 120 patients with angina pectoris undergoing percutaneous coronary intervention (PCI) were enrolled and randomly assigned to either an EA group (n = 60) or a sham-EA group (n = 60). The EA group received continuous intraoperative electrical stimulation at acupoints Neiguan (PC6) and Ximen (PC4), whereas the sham-EA group received sham intervention at non-acupoints. Evaluated outcomes included intraoperative angina severity assessed by the Visual Analogue Scale (VAS), the extent of myocardial injury determined by high-sensitivity cardiac troponin T (hs-cTnT) and CK-MB levels at 24 h post-PCI, levels of inflammatory biomarkers (TNF-α, IL-6, hs-CRP, IL-1β), and the incidence of adverse events. Patients in the EA group reported significantly lower intraoperative angina scores (VAS) compared to the sham-EA group (P < 0.001). Consistent with this symptomatic relief, the EA group demonstrated attenuated myocardial injury, evidenced by significantly lower hs-cTnT levels at 24 h post-PCI (median [IQR]: 25.27 [11.54, 108.65] vs. 35.37 [14.35, 237.25]; P = 0.042), whereas no significant difference was observed in CK-MB levels (P = 0.243). In terms of inflammatory response, concentrations of TNF-α and IL-6 were significantly lower in the EA group (P < 0.05 for both), while no significant inter-group differences were found for hs-CRP and IL-1β. The incidence of adverse events was comparable between the two groups (P > 0.05). Intraoperative electroacupuncture (EA) is a feasible and safe adjunctive strategy for effectively alleviating angina and potentially attenuating myocardial injury in patients undergoing PCI. These beneficial effects may be mediated through the modulation of inflammatory responses. However, given the preliminary nature of these findings, further validation in large-scale, multi-center trials is warranted.
Bimodal imaging agents that combine MRI and optical signals can improve imaging and diagnostic precision by providing complementary anatomical and molecular information. Macromolecular MRI agents can deliver higher relaxivities than small-molecule analogues by using controlled architectures that slow rotational motion and enhance Gd(III)-water interactions. The combination of bimodal functionality with macromolecular designs represents a highly promising route to new imaging agents, but its potential has not yet been realized due to safety concerns over possible unchelated metals and difficulties in achieving reproducible large-scale production. Here, we present a simple, reproducible method to directly incorporate isostructural Gd(III) and Tb(III) complexes into amphiphilic core-shell block copolymer nanoparticles using a single macrocyclic methacrylate ligand. This modular design enables controlled spatial positioning of each MRI- and luminescence agent, achieving high relaxivity up to 30.2 mM-1s-1 per Gd(III) and long-lived (>1.30 ms) luminescence, providing a tunable platform for dual-modal MRI-luminescence applications.
Precise regulation of ligand-to-Eu energy-transfer pathways and the antenna effect is essential for constructing robust ratiometric luminescent sensors based on lanthanide metal-organic frameworks (Ln-MOFs). Here we report an isoreticular series of Eu-MOFs (SNNU-624-626) featuring stepwise amino-functionalized biphenyldicarboxylate linkers and demonstrate their use for detecting diethyl chlorophosphate (DCP), a sarin simulant. Progressive amino substitution reshapes the excited-state distribution and the balance between ligand-centered emission and Eu sensitization, giving rise to distinct photophysical signatures and sensing modes across the series. Notably, the monoamino framework SNNU-625 exhibits a clear ratiometric response (I468/I612): the ligand-centered emission at 468 nm is selectively amplified, while the Eu3+ emission at 612 nm serves as an internal reference, producing an easily visible color shift from pink to blue (limit of detection, 27 ppb; response time, <10 s). In contrast, the diamino analogue SNNU-626 shows a ligand-dominated turn-on response (LOD = 32 ppb), whereas the amino-free SNNU-624 remains essentially inactive. Mechanistic studies indicate that DCP preferentially engages pore-confined amino sites and initiates a hydrolysis-assisted protonation process; this reaction preserves the framework integrity yet attenuates ligand-to-Eu3+ energy transfer, thereby unleashing ligand-centered emission. These results establish a direct structure-energy-transfer-sensing relationship and provide a useful design principle for designing Ln-MOF-based ratiometric sensors for organophosphorus nerve-agent simulants.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the nasal mucosa and paranasal sinuses associated with severe nasal congestion, olfactory impairment, decreased quality of life, the need for repeated surgical interventions, and the use of systemic glucocorticosteroids. Real-world data on the use of tezepelumab in patients with severe relapsing CRSwNP remain limited. To describe the initial experience of tezepelumab application in real-world setting in patients with recurrent rhinosinusitis with nasal polyps and to evaluate early improvement of symptoms, quality of life, and tolerability of therapy based on available clinical data. We describe clinical observations of 8 patients with recurrent CRSwNP who received tezepelumab 210 mg subcutaneously every 4 weeks for 2 months. Patients were treated in a multidisciplinary day hospital. The total severity of symptoms was assessed using the visual analogue scale (VAS), quality of life - using the SNOT-22 questionnaire, the initial endoscopic picture - using the Lund-Kennedy score. In addition, peripheral blood eosinophils, treatment history, comorbidity and tolerability of therapy were evaluated. The primary assessment was performed at the baseline visit and approximately 2 months after the start of treatment. The analysis was descriptive. The series included 8 patients, 6 of whom were women; the mean age was 54.2±9.0 years. All patients had recurrent CRSwNP and a history of surgical interventions. Bronchial asthma was described in 5 of 8 patients, and intolerance to nonsteroidal anti-inflammatory drugs or Samster's triad - in 4 of 8. Initially, the average score for VAS was 30.2±1.7, for SNOT-22 - 63.8±3.9. After 2 months, the mean VAS score decreased to 11.0±1.2, the average absolute change amounted to 19.2±1.5 points. The mean SNOT-22 score decreased to 30.1±5.8, with an average absolute change of -33.6±5.9 points. Improvement in VAS and SNOT-22 scores was observed in all 8 patients. The course of treatment was continued for all patients due to clinical improvement. In this small case series, tezepelumab was associated with an early reduction in symptom burden and improved quality of life in patients with severe recurrent rhinosinusitis with nasal polyps. The obtained observation results are preliminary. Confirmation in larger, systematically assembled cohorts with longer follow-up and standardized assessment of endoscopic, radiographic symptoms and safety indicators is needed. Хронический риносинусит с назальными полипами (ПРС) представляет собой хроническое воспалительное заболевание слизистой оболочки носа и околоносовых пазух, ассоциированное с выраженной заложенностью носа, нарушением обоняния, снижением качества жизни, необходимостью повторных хирургических вмешательств и применением системных глюкокортикостероидов. Данные реальной клинической практики о применении тезепелумаба у пациентов с тяжелым рецидивирующим ПРС остаются ограниченными. Описать первый опыт применения тезепелумаба в реальной клинической практике у пациентов с рецидивирующим риносинуситом с назальными полипами, оценить раннюю динамику симптомов, качества жизни и переносимость терапии на основании доступных клинических данных. Приведено описание клинических наблюдений 8 пациентов с рецидивирующим ПРС, получавших тезепелумаб 210 мг подкожно каждые 4 нед в течение 2 мес. Пациенты проходили лечение в условиях многопрофильного дневного стационара. Оценивали суммарную выраженность симптомов по визуальной аналоговой шкале (ВАШ), качество жизни по опроснику SNOT-22, исходную эндоскопическую картину по шкале Лунда–Кеннеди, эозинофилы периферической крови, анамнез лечения, коморбидность и переносимость терапии. Основную оценку проводили во время исходного визита и приблизительно через 2 мес после начала лечения. Анализ был описательным. В серию вошло 8 пациентов, из них 6 женщин; средний возраст составил 54,2±9,0 года. У всех пациентов выявлено рецидивирующее течение ПРС и отмечены хирургические вмешательства в анамнезе. Бронхиальная астма описана у 5 из 8 пациентов, непереносимость нестероидных противовоспалительных препаратов или аспириновая триада — у 4 из 8. Исходно средняя сумма баллов по ВАШ составляла 30,2±1,7, по SNOT-22 — 63,8±3,9. Через 2 мес средняя сумма баллов по ВАШ снизилась до 11,0±1,2, среднее абсолютное изменение составило –19,2±1,5 балла. Средняя оценка по SNOT-22 снизилась до 30,1±5,8, среднее абсолютное изменение составило –33,6±5,9 балла. Улучшение оценок по ВАШ и SNOT-22 наблюдалось у всех 8 пациентов. Курс лечения продолжен всем пациентам в связи с положительной клинической динамикой. В данной небольшой серии случаев применение тезепелумаба ассоциировано с ранним уменьшением симптоматической нагрузки и улучшением качества жизни у пациентов с тяжелым рецидивирующим риносинуситом с назальными полипами. Полученные результаты наблюдения являются предварительными. Необходимо подтверждение в более крупных систематически собранных когортах с более длительным наблюдением и стандартизированной оценкой эндоскопических, рентгенологических симптомов и показателей безопасности.
Macrocycles and cyclic peptides represent a compelling therapeutic modality for engaging historically challenging biological targets, yet their inherent structural complexity and laborious synthetic demands pose significant hurdles in drug discovery. Given the high resource investment required for macrocyclic synthesis, the integration of rigorous, physics-based computational methods provides a critical advantage for accurately prioritizing design candidates. While Free Energy Perturbation (FEP) has emerged as a transformative method for affinity prediction, its application to complex, beyond-rule-of-five (bRo5) macrocycles demands specialized enhanced sampling protocols and careful consideration of receptor conformational states to effectively navigate their multidimensional conformational landscapes. Here, we present a retrospective validation of the FEP+ framework across five diverse macrocyclic and cyclic peptide inhibitor series: KRAS, PCSK9, MCL-1, JAK2, and Cyclin A/B. Encompassing over 230 unique peptidic and nonpeptidic analogues, our analysis of this consolidated data set demonstrates robust predictive accuracy (global pairwise RMSEΔΔG = 1.06 kcal/mol) and reveals critical insights into the complex interplay between ligand preorganization, hydration dynamics, and binding energetics. The results demonstrate reliable intraseries rank-ordering and robust absolute accuracy across an experimental dynamic range exceeding 10 kcal/mol (>7 orders of magnitude in binding affinity), establishing FEP+ as an effective computational method for derisking and accelerating the discovery of clinically viable bRo5 therapeutics.