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.
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.
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.
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.
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.
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.
Photochemical upconversion by annihilation of two triplet excitons to a higher-energy singlet state enables energy control of photons in optoelectronics and photonics. Upconversion initiated by a closed-shell sensitizer is limited by energy losses from singlet-triplet intersystem crossing. Here we explore open-shell organic radicals as sensitizers and their closed-shell hydrogenated analogues as annihilators in photon upconversion. The sensitizer combines optical transitions from a triphenylmethyl (TTM-1Cz) radical with energy-degenerate triplet states of an anthracene-based component (DPA) in one molecule (TTM-1Cz-DPA). The difference of one hydrogen atom in its closed-shell counterpart (HTTM-1Cz-DPA) switches the spin-optical properties to an annihilator that can mediate efficient upconversion. Red-to-blue photon upconversion by intermolecular energy transfer, from open-shell sensitizer to closed-shell annihilator, is demonstrated in solution with an apparent anti-Stokes shift higher than 0.9 eV and 7% quantum efficiency. We evaluate this mechanism against true 'single component' mixtures for upconversion and find that the presence of hydrogenated precursor with radicals is essential for high performance. Understanding the emergent spin-optical properties from paired open-shell and closed-shell systems enables new opportunities for energy management from the same molecular frame.
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.
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.
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.
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.
Heptazine (Hpz) derivatives display remarkable supramolecular organization governed by noncovalent interactions. Here, we explore how molecular chirality and structural variation influence the self-association and organization of three Hpz derivatives (two chiral and one nonchiral) in solution and in the condensed phase. Variable-temperature and concentration-dependent NMR studies allowed the determination of dimerization and supramolecular aggregation constants, as well as the calculation of the thermodynamic parameters of these processes. Computational studies -including conformational analysis and molecular dynamics-corroborated the experimental findings, confirming the energetic stability and geometry of the proposed dimers. Moreover, photophysical studies showed aggregation-induced emission (AIE) behavior, with blue light emission upon molecular association. Additionally, the introduction of chiral chains resulted in mirror-image circular dichroism (CD) responses for the two Hpz enantiomers, demonstrating retention of chirality in bulk. In contrast, the nonchiral analogue displayed liquid crystalline (LC) behavior at high temperatures, characterized by a smectic mesophase. These results reveal how subtle structural variations modulate the supramolecular, optical, and mesomorphic properties of Hpz derivatives, highlighting the versatility of the heptazine core for multifunctional supramolecular and optoelectronic materials.
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.
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.
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.
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.
Post-thyroidectomy hypocalcaemia is the most common complication after total thyroidectomy. Although perioperative calcium and vitamin D supplementation is widely used, the comparative effectiveness of different prophylactic strategies remains uncertain. A systematic review and Bayesian network meta-analysis of randomized clinical trials was performed according to PRISMA guidelines. PubMed, Scopus, Web of Science, and the Cochrane Library were searched from inception to 7 May 2026. Adult patients undergoing total or near-total thyroidectomy were included. Three strategies were compared: no routine supplementation, calcium alone, and calcium combined with vitamin D analogues. Primary outcomes were clinical hypocalcaemia, biochemical hypocalcaemia, and need for intravenous calcium supplementation; length of hospital stay was secondary. Random-effects network meta-analysis estimated odds ratios with 95% credible intervals. Risk of bias was assessed using RoB 2. The protocol was registered in PROSPERO (CRD420251068837). Twenty randomized trials including 3669 patients were analysed. Calcium plus vitamin D significantly reduced clinical hypocalcaemia versus no supplementation (odds ratio 0.31, 95% credible interval 0.17 to 0.51) and calcium alone (odds ratio 0.52, 0.25 to 1.04). Combination therapy also reduced biochemical hypocalcaemia compared with no supplementation (odds ratio 0.27, 0.17 to 0.42) and calcium alone (odds ratio 0.44, 0.22 to 0.83), and markedly decreased intravenous calcium requirements (odds ratio 0.15, 0.05 to 0.32). Calcium monotherapy showed no significant benefit. Combination therapy ranked as most effective and was associated with shorter length of hospital stay (mean difference 0.44 days). Perioperative calcium combined with vitamin D is the most effective strategy for preventing post-thyroidectomy hypocalcaemia and reducing intravenous calcium use, supporting routine postoperative implementation despite heterogeneity in supplementation protocols.
Observational studies have repeatedly reported lower cancer incidence among metformin users than nonusers, but findings are inconsistent and often affected by issues such as immortal time, unclear comparators, and use of total cancer as a composite outcome, which precludes adequate adjustment for site-specific confounding. These limitations can be mitigated by explicitly emulating a target trial with a suitable active comparator. We emulated a target trial using a Japanese claims database (April 2014-March 2024) to assess whether metformin reduces colorectal cancer (CRC) risk compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) in patients with type 2 diabetes. DPP-4is served as an active comparator because they are widely used as first-line alternatives in Japan and have no clear evidence of affecting CRC risk. We estimated the observational analogue of the per-protocol effect using pooled logistic regression with inverse probability weighting to adjust for baseline and time-varying confounders. Among 26 273 metformin users and 108 299 DPP-4i users, the 5-year risk of CRC was 1.55% (95% confidence interval, 1.16 to 2.04) versus 1.26% (1.13 to 1.41), yielding a risk difference of 0.29% (-0.12 to 0.79) and a risk ratio of 1.23 (0.91 to 1.66). Metformin use did not reduce the 5-year risk of CRC compared with DPP-4is. This finding is consistent with meta-analyses of randomized trials and contrasts with earlier observational reports of substantial benefit, which were likely inflated by methodological flaws. Explicitly emulating a target trial minimized design-related biases and provided estimates that support causal interpretation. Earlier observational studies often suggested that metformin might protect against cancer, but these findings were inconsistent and frequently affected by methodological issues, including misaligned start of follow‐up, unclear comparators, and use of “total cancer” as a composite outcome. Because different cancers have different causes, combining them can obscure important differences and limit accurate adjustment. To examine this issue more reliably, we used colorectal cancer (CRC) as a case study and applied a target trial emulation approach in patients with type 2 diabetes. This approach allowed us to compare sustained metformin use with sustained use of an appropriate alternative diabetes treatment, dipeptidyl peptidase‐4 inhibitors (DPP‐4is), which show no clear evidence of influencing CRC risk. We analyzed Japanese claims data from nearly 140 000 patients and followed each person for up to 5 years. The estimated 5‐year risk of CRC was 1.55% with metformin and 1.26% with DPP‐4is, corresponding to a risk difference of 0.29% and risk ratio of 1.23. In simple terms, our study did not find clear evidence that metformin reduces CRC risk over 5 years compared with DPP‐4is.
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.
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.