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Fractionalization is a phenomenon in which strong interactions in a quantum system drive the emergence of excitations with quantum numbers that are absent in the building blocks. Outstanding examples are excitations with charge e/3 in the fractional quantum Hall effect1,2, solitons in one-dimensional conducting polymers3,4 and Majorana states in topological superconductors5. Fractionalization is also predicted to manifest itself in low-dimensional quantum magnets, such as one-dimensional antiferromagnetic S = 1 chains. The fundamental features of this system are gapped excitations in the bulk6 and, remarkably, S = 1/2 edge states at the chain termini7-9, leading to a four-fold degenerate ground state that reflects the underlying symmetry-protected topological order10,11. Here, we use on-surface synthesis12 to fabricate one-dimensional spin chains that contain the S = 1 polycyclic aromatic hydrocarbon triangulene as the building block. Using scanning tunnelling microscopy and spectroscopy at 4.5 K, we probe length-dependent magnetic excitations at the atomic scale in both open-ended and cyclic spin chains, and directly observe gapped spin excitations and fractional edge states therein. Exact diagonalization calculations provide conclusive evidence that the spin chains are described by the S = 1 bilinear-biquadratic Hamiltonian in the Haldane symmetry-protected topological phase. Our results open a bottom-up approach to study strongly correlated phases in purely organic materials, with the potential for the realization of measurement-based quantum computation13.
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Coevaporation of formamidinium lead iodide (FAPbI3) is a promising route for the fabrication of highly efficient and scalable optoelectronic devices, such as perovskite solar cells. However, it poses experimental challenges in achieving stoichiometric FAPbI3 films with a cubic structure (α-FAPbI3). In this work, we show that undesired hexagonal phases of both PbI2 and FAPbI3 form during thermal evaporation, including the well-known 2H-FAPbI3, which are detrimental for optoelectronic performance. We demonstrate the growth of α-FAPbI3 at room temperature via thermal evaporation by depositing phosphonic acids (PAc) on substrates and subsequently coevaporating PbI2 and formamidinium iodide. We use density-functional theory to develop a theoretical model to understand the relative growth energetics of the α and 2H phases of FAPbI3 for different molecular interactions. Experiments and theory show that the presence of PAc molecules stabilizes the formation of α-FAPbI3 in thin films when excess molecules are available to migrate during growth. This migration of molecules facilitates the continued presence of adsorbed organic precursors at the free surface throughout the evaporation, which lowers the growth energy of the α-FAPbI3 phase. Our theoretical analyses of PAc molecule-molecule interactions show that ligands can form hydrogen bonding to reduce the migration rate of the molecules through the deposited film, limiting the effects on the crystal structure stabilization. Our results also show that the phase stabilization with molecules that migrate is long-lasting and resistant to moist air. These findings enable reliable formation and processing of α-FAPbI3 films via vapor deposition.
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Hopf et al. reported the high-temperature 6π-electrocyclization of cis-hexa-1,3-diene-5-yne to benzene in 1969. Subsequent studies using this cyclization have been limited by its very high reaction barrier. Here, we show that the reaction barrier for two model systems, (E)-1,3,4,6-tetraphenyl-3-hexene-1,5-diyne (1a) and (E)-3,4-bis(4-iodophenyl)-1,6-diphenyl-3-hexene-1,5-diyne (1b), is decreased by nearly half on a Au(111) surface. We have used scanning tunneling microscopy (STM) and noncontact atomic force microscopy (nc-AFM) to monitor the Hopf cyclization of enediynes 1a,b on Au(111). Enediyne 1a undergoes two sequential, quantitative Hopf cyclizations, first to naphthalene derivative 2, and finally to chrysene 3. Density functional theory (DFT) calculations reveal that a gold atom from the Au(111) surface is involved in all steps of this reaction and that it is crucial to lowering the reaction barrier. Our findings have important implications for the synthesis of novel graphene nanoribbons. Ullmann-like coupling of enediyne 1b at 20 °C on Au(111), followed by a series of Hopf cyclizations and aromatization reactions at higher temperatures, produces nanoribbons 12 and 13. These results show for the first time that graphene nanoribbons can be synthesized on a Au(111) surface using the Hopf cyclization mechanism.
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Discerning the impact of the coherent motion of the nuclei on the timing and efficiency of charge transfer at the donor-acceptor interface is essential for designing performance-enhanced optoelectronic devices. Here, we employ an experimental approach using photocurrent detection in coherent multidimensional spectroscopy to excite a donor aromatic macrocycle and collect the charge transferred to a 2D acceptor layer. For this purpose, we prepared a cobalt phthalocyanine-graphene (CoPc-Gr) interface. Unlike blends, the well-ordered architecture achieved through the physical separation of the two layers allows us to unambiguously collect the electrical signal from graphene alone and associate it with a microscopic understanding of the whole process. The CoPc-Gr interface exhibits an ultrafast electron-transfer signal, stemming from an interlayer mechanism. Remarkably, the signal presents an oscillating time evolution modulated by coherent vibrations originating from the laser-excited CoPc states. By performing Fourier analysis on the beatings and correlating it with the Raman features, along with a comprehensive first-principles characterization of the vibrational coupling in the CoPc excited states, we successfully identify both the orbitals and molecular vibrations that promote the charge transfer at the interface.
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Mixed-cation and mixed-halide lead halide perovskites show great potential for their application in photovoltaics. Many of the high-performance compositions are made of cesium, formamidinium, lead, iodine, and bromine. However, incorporating bromine in iodine-rich compositions and its effects on the thermal stability of the perovskite structure has not been thoroughly studied. In this work, we study how replacing iodine with bromine in the state-of-the-art Cs0.17FA0.83PbI3 perovskite composition leads to different dynamics in the phase transformations as a function of temperature. Through a combination of structural characterization, cathodoluminescence mapping, X-ray photoelectron spectroscopy, and first-principles calculations, we reveal that the incorporation of bromine reduces the thermodynamic phase stability of the films and shifts the products of phase transformations. Our results suggest that bromine-driven vacancy formation during high temperature exposure leads to irreversible transformations into PbI2, whereas materials with only iodine go through transformations into hexagonal polytypes, such as the 4H-FAPbI3 phase. This work sheds light on the structural impacts of adding bromine on thermodynamic phase stability and provides new insights into the importance of understanding the complexity of phase transformations and secondary phases in mixed-cation and mixed-halide systems.
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Hierarchical models have been proposed to explain how the brain encodes actions, whereby different areas represent different features, such as gesture kinematics, target object, action goal, and meaning. The visual processing of action-related information is distributed over a well-known network of brain regions spanning separate anatomical areas, attuned to specific stimulus properties, and referred to as action observation network (AON). To determine the brain organization of these features, we measured representational geometries during the observation of a large set of transitive and intransitive gestures in two independent functional magnetic resonance imaging experiments. We provided evidence for a partial dissociation between kinematics, object characteristics, and action meaning in the occipito-parietal, ventro-temporal, and lateral occipito-temporal cortex, respectively. Importantly, most of the AON showed low specificity to all the explored features, and representational spaces sharing similar information content were spread across the cortex without being anatomically adjacent. Overall, our results support the notion that the AON relies on overlapping and distributed coding and may act as a unique representational space instead of mapping features in a modular and segregated manner.
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Mapeamento Encefálico , Gestos , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Fenômenos Biomecânicos/fisiologia , Adulto , Adulto Jovem , Encéfalo/fisiologia , Encéfalo/diagnóstico por imagem , Estimulação Luminosa/métodos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Guidelines on the treatment of oesophageal squamous cell carcinoma (SCC) recommend neoadjuvant chemoradiotherapy plus surgery or definitive chemoradiotherapy. The aim of this study was to evaluate the outcome of patients with a cCR after chemoradiotherapy who underwent active surveillance. METHODS: Patients with oesophageal SCC who were treated with chemoradiotherapy between January 2016 and June 2022 were identified from an institutional database. Survival and recurrence of patients with a cCR who underwent active surveillance were compared with those of patients who underwent planned surgery. Survival was calculated according to the Kaplan-Meier method and compared between groups using the log rank test. RESULTS: The 37 patients who underwent active surveillance were older and tumours were more often located in the middle/upper-third of the oesophagus than in the surgery group of 57 patients. Median follow-up was 28.1 (i.q.r. 17.2-47.1) months for the active surveillance group and 20 (12.9-39.1) months for the surgery group. Overall survival was comparable between the two groups, with 3-year survival rates of 50 (95% c.i. 31 to 67) and 59 (40 to 73)% for the active surveillance and surgery groups respectively (P = 0.55). Three-year progression-free survival for patients who underwent active surveillance was better than in the surgery group: 70 (43 to 85) versus 58 (40 to 72)% (P = 0.02). Overall and progression-free survival was comparable between patients in the active surveillance group and 23 patients in the surgery group who had a pCR (ypT0 N0). The overall recurrence rate was comparable between the groups: 7 of 37 (19.4%) in active surveillance group versus 16 of 49 (32.6%) in surgery group (P = 0.26). Locoregional recurrence was noted more often in the active surveillance group and systemic recurrence in the surgery group. CONCLUSION: Active surveillance is feasible and safe for patients with oesophageal SCC who have a cCR after chemoradiotherapy.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/terapia , Conduta Expectante , Quimiorradioterapia , Bases de Dados Factuais , Neoplasias Esofágicas/terapiaRESUMO
Atomically precise graphene nanoflakes called nanographenes have emerged as a promising platform to realize carbon magnetism. Their ground state spin configuration can be anticipated by Ovchinnikov-Lieb rules based on the mismatch of π electrons from two sublattices. While rational geometrical design achieves specific spin configurations, further direct control over the π electrons offers a desirable extension for efficient spin manipulations and potential quantum device operations. To this end, we apply a site-specific dehydrogenation using a scanning tunneling microscope tip to nanographenes deposited on a Au(111) substrate, which shows the capability of precisely tailoring the underlying π-electron system and therefore efficiently manipulating their magnetism. Through first-principles calculations and tight-binding mean-field-Hubbard modeling, we demonstrate that the dehydrogenation-induced Au-C bond formation along with the resulting hybridization between frontier π orbitals and Au substrate states effectively eliminate the unpaired π electron. Our results establish an efficient technique for controlling the magnetism of nanographenes.
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In 2014, for the first time, visible hyperintensities on unenhanced T1-weighted images in the nucleus dentatus and globus pallidus of the brain were associated with previous Gadolinium-based contrast agent (GBCA) injections and gadolinium deposition in patients with normal renal function. This led to a frenzy of retrospective studies with varying methodologies that the European Society of Magnetic Resonance in Medicine and Biology Gadolinium Research and Educational Committee (ESMRMB-GREC) summarised in 2019. Now, after 10 years, the members of the ESMRMB-GREC look backward and forward and review the current state of knowledge of gadolinium retention and deposition. CLINICAL RELEVANCE STATEMENT: Gadolinium deposition is associated with the use of linear GBCA but no clinical symptoms have been associated with gadolinium deposition. KEY POINTS : ⢠Traces of Gadolinium-based contrast agent-derived gadolinium can be retained in multiple organs for a prolonged time. ⢠Gadolinium deposition is associated with the use of linear Gadolinium-based contrast agents. ⢠No clinical symptoms have been associated with gadolinium deposition.
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Meios de Contraste , Gadolínio , Compostos Organometálicos , Humanos , Núcleos Cerebelares/patologia , Gadolínio DTPA , Imageamento por Ressonância Magnética/métodos , Estudos RetrospectivosRESUMO
Magnetic resonance imaging (MRI) is the most sensitive technique for detecting inflammatory demyelinating lesions in multiple sclerosis (MS) and plays a crucial role in diagnosis and monitoring treatment effectiveness, and for predicting the disease course. In clinical practice, detection of MS lesions is mainly based on T2-weighted and contrast-enhanced T1-weighted sequences. Contrast-enhancing lesions (CEL) on T1-weighted sequences are related to (sub)acute inflammation, while new or enlarging T2 lesions reflect the permanent footprint from a previous acute inflammatory demyelinating event. These two types of MRI features provide redundant information, at least in regular monitoring of the disease. Due to the concern of gadolinium deposition after repetitive injections of gadolinium-based contrast agents (GBCAs), scientific organizations and regulatory agencies in Europe and North America have proposed that these contrast agents should be administered only if clinically necessary. In this article, we provide data on the mode of action of GBCAs in MS, the indications of the use of these agents in clinical practice, their value in MS for diagnostic, prognostic, and monitoring purposes, and their use in specific populations (children, pregnant women, and breast-feeders). We discuss imaging strategies that achieve the highest sensitivity for detecting CELs in compliance with the safety regulations established by different regulatory agencies. Finally, we will briefly discuss some alternatives to the use of GBCA for detecting blood-brain barrier disruption in MS lesions. CLINICAL RELEVANCE STATEMENT: Although use of GBCA at diagnostic workup of suspected MS is highly valuable for diagnostic and prognostic purposes, their use in routine monitoring is not mandatory and must be reduced, as detection of disease activity can be based on the identification of new or enlarging lesions on T2-weighted images. KEY POINTS: ⢠Both the EMA and the FDA state that the use of GBCA in medicine should be restricted to clinical scenarios in which the additional information offered by the contrast agent is required. ⢠The use of GBCA is generally recommended in the diagnostic workup in subjects with suspected MS and is generally not necessary for routine monitoring in clinical practice. ⢠Alternative MRI-based approaches for detecting acute focal inflammatory MS lesions are not yet ready to be used in clinical practice.
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Meios de Contraste , Esclerose Múltipla , Gravidez , Criança , Humanos , Feminino , Esclerose Múltipla/diagnóstico , Gadolínio , Imageamento por Ressonância Magnética/métodos , Progressão da Doença , Encéfalo/patologiaRESUMO
AIMS: Lacosamide is a third-generation antiepileptic drug used as adjunctive therapy for partial seizures. Since its approval in 2008 very few cases of lacosamide overdose have been described in literature. The aim of our study was to evaluate clinical characteristics of acute lacosamide poisoning. METHODS: A retrospective observational study was performed including all cases of acute lacosamide poisoning referred to Pavia Poison Control Centre from January 2012 to December 2021. For each patient age, sex, ingested dose, coingestants, clinical manifestations, treatment and outcome were collected. RESULTS: A total of 31 subjects (median age 39 years, [interquartile range: 26.5-46.5]; females 22/31) were included. The median lacosamide ingested dose was 1500 mg [650-2800]. In 35.5% of cases lacosamide was the single ingested substance, while in 64.5% coingestants were also present. Coingestants varied from a minimum of 1 to a maximum of 3, with the more common being benzodiazepines and valproic acid. Clinical manifestations were present in 87% patients the most common were: vomiting (29%); seizures (29%), coma (25.8%), drowsiness (25.8%), confusion (12.9%), agitation (12.9%), tachycardia (12.9%), tremors (9.7%), bradycardia (9.7%), headache (6.5%) and hypertension (3.2%). The median lacosamide ingested dose was significantly higher in patients that experienced coma compared to patient who did not (2800 vs. 800 mg; P = .0082). Orotracheal intubation was necessary in 32.3% of patients. All patients fully recovered. CONCLUSION: Lacosamide acute overdose may lead to a severe clinical picture. Dentral nervous system symptoms predominated, particularly seizures and coma occurred in a high percentage of cases.
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Overdose de Drogas , Centros de Controle de Intoxicações , Adulto , Feminino , Humanos , Anticonvulsivantes/uso terapêutico , Coma/induzido quimicamente , Coma/tratamento farmacológico , Overdose de Drogas/terapia , Overdose de Drogas/tratamento farmacológico , Lacosamida/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Estudos RetrospectivosRESUMO
The major human genes regulating Mycobacterium tuberculosis-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression in humans are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling. We hypothesized that common variants in CNBP, REL, and BHLHE40 were associated with IL-12 and IL-10 production from dendritic cells, and that these variants also influence adaptive immune responses to bacillus Calmette-Guérin (BCG) vaccination and TB susceptibility. We characterized the association between common variants in CNBP, REL, and BHLHE40, innate immune responses in dendritic cells and monocyte-derived macrophages, BCG-specific T cell responses, and susceptibility to pediatric and adult TB in human populations. BHLHE40 single-nucleotide polymorphism (SNP) rs4496464 was associated with increased BHLHE40 expression in monocyte-derived macrophages and increased IL-10 from peripheral blood dendritic cells and monocyte-derived macrophages after LPS and TB whole-cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL-2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and rs842618 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618 was associated with increased risk for TB meningitis. In summary, we found that genetic variations in REL and BHLHE40 are associated with IL-12 and IL-10 cytokine responses and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.
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Mycobacterium bovis , Mycobacterium tuberculosis , Proteínas Proto-Oncogênicas c-rel/genética , Tuberculose , Adulto , Vacina BCG , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Criança , Proteínas de Homeodomínio , Humanos , Interleucina-10/genética , Interleucina-12/genética , Tuberculose/genéticaRESUMO
Boundaries between distinct topological phases of matter support robust, yet exotic quantum states such as spin-momentum locked transport channels or Majorana fermions1-3. The idea of using such states in spintronic devices or as qubits in quantum information technology is a strong driver of current research in condensed matter physics4-6. The topological properties of quantum states have helped to explain the conductivity of doped trans-polyacetylene in terms of dispersionless soliton states7-9. In their seminal paper, Su, Schrieffer and Heeger (SSH) described these exotic quantum states using a one-dimensional tight-binding model10,11. Because the SSH model describes chiral topological insulators, charge fractionalization and spin-charge separation in one dimension, numerous efforts have been made to realize the SSH Hamiltonian in cold-atom, photonic and acoustic experimental configurations12-14. It is, however, desirable to rationally engineer topological electronic phases into stable and processable materials to exploit the corresponding quantum states. Here we present a flexible strategy based on atomically precise graphene nanoribbons to design robust nanomaterials exhibiting the valence electronic structures described by the SSH Hamiltonian15-17. We demonstrate the controlled periodic coupling of topological boundary states18 at junctions of graphene nanoribbons with armchair edges to create quasi-one-dimensional trivial and non-trivial electronic quantum phases. This strategy has the potential to tune the bandwidth of the topological electronic bands close to the energy scale of proximity-induced spin-orbit coupling19 or superconductivity20, and may allow the realization of Kitaev-like Hamiltonians3 and Majorana-type end states21.
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Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.
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Interleucina-23/antagonistas & inibidores , Interleucina-23/metabolismo , Células Supressoras Mieloides/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Androgênios/deficiência , Animais , Benzamidas , Proliferação de Células , Sobrevivência Celular , Humanos , Interleucina-23/sangue , Interleucina-23/imunologia , Masculino , Camundongos , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/imunologia , Nitrilas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Interleucina/metabolismo , Transdução de SinaisRESUMO
Lipomatous hypertrophy of the interatrial septum (LHIS) is a benign cardiac mass determined by abnormal deposition of adipose tissue in the interatrial septum. The quantitative relationship between LHIS and visceral adiposity has not been explored to date.In this retrospective study, three groups of consecutive patients undergoing CT imaging were enrolled: L + with LHIS, L- without LHIS, and LO- without both LHIS and history of malignancies. Areas of total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and LHIS areas were calculated on CT images. The relationship between LHIS and abdominal fat distribution was investigated with linear regression models. Bonferroni correction was applied to account for multiple testing. Statistical significance was set at 5%. In this study we enrolled a total of 175 subjects: 58 (33.14%) with LHIS (L +), 51(29.14%) without LHIS (L-) and 66 (37.71%) without both LHIS and medical history of malignancies (LO-). VAT (coeff: 105.82; 95% CI 59.37-152.27), SAT (coeff: 74.59; 95% CI 31.63-117.54), and TAT (coeff: 190.37; 95% CI 115.02-265.72), were significantly higher in L + patients. Moreover, VAT (coeff: 24.95; 95% CI 6.94-42.96) and TAT (coeff: 36.58; 95% CI 8.75-64.41) were statistically significant linear predictors for LHIS area. Here, we report a novel association between LHIS and visceral adiposity using a quantitative CT-based imaging approach. The results are of great importance also because they might drive early identification of subjects with LHIS at risk for visceral obesity, and trigger lifestyle interventions aimed at weight loss.
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Cútis Laxa/congênito , Hamartoma , Obesidade Abdominal , Anormalidades da Pele , Humanos , Estudos Retrospectivos , Adiposidade , Hipertrofia , Gordura Intra-Abdominal/diagnóstico por imagemRESUMO
BACKGROUND: There is limited epidemiological evidence on outcomes associated with dupilumab exposure during pregnancy; monitoring pregnancy outcomes in large populations is required. OBJECTIVE: To investigate the potential association between exposure to dupilumab in pregnant women with atopic dermatitis and any adverse pregnancy, neonatal, congenital and post-partum outcomes. METHODS: We performed a multicentre retrospective cohort study across 19 Italian tertiary referral hospital. Childbearing women were eligible if aged 18-49 years and carried out the pregnancy between 1 October 2018 and 1 September 2022. RESULTS: We retrospectively screened records of 5062 patients receiving dupilumab regardless of age and gender, identifying 951 female atopic dermatitis patients of childbearing age, 29 of whom had been exposed to the drug during pregnancy (3%). The median duration of dupilumab treatment prior to conception was 22.5 weeks (range: 3-118). The median time of exposure to the drug during pregnancy was 6 weeks (range: 2-24). All the documented pregnancies were unplanned, and the drug was discontinued in all cases once pregnancy status was reported. The comparison of the study cohort and the control group found no significant drug-associated risk for adverse pregnancy, congenital, neonatal or post-partum outcomes. The absence of a statistically significant effect of exposure on the event was confirmed by bivariate analysis and multivariate analysis adjusted for other confounding factors. CONCLUSIONS: This cohort of pregnant patients exposed to dupilumab adds to the existing evidence concerning the safety of biologic agents in pregnancy. No safety issues were identified regarding the primary outcome assessed. In clinical practice, these data provide reassurance in case of dupilumab exposure during the first trimester. However, the continuous use of dupilumab throughout pregnancy warrants further research.
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BACKGROUND: Guselkumab is a monoclonal antibody approved for treating moderate-to-severe plaque psoriasis. Long-term data on the effectiveness and safety of guselkumab in a real-world setting are still limited. MATERIALS AND METHODS: We conducted a 104-week monocentric retrospective study on 102 psoriasis patients, all treated with guselkumab for at least 16 weeks. At each visit, we used the Psoriasis Area and Severity Index (PASI): effectiveness endpoints were the percentages of patients achieving 75%/90%/100% (PASI 75/90/100) improvement in PASI compared with baseline. The Kaplan-Meier curve was used to assess the drug survival. RESULTS: At week 16, PASI 90 and PASI 100 were achieved by 49.02% and 32.35% of patients. At week 52, PASI 90 and PASI 100 were achieved by 71.58% and 55.79% of patients. After 2 years, PASI 90 and PASI 100 were achieved by 79.63% and 61.11% of patients. Obese and overweight patients had comparable PASI 90 and PASI 100 responses throughout the study. At week 104, no significant differences were observed between bio-naïve and bio-experienced patients regarding all effectiveness endpoints. No significant safety signals were reported in our study. After 24 months, 91.57% of our cohort was still on treatment with guselkumab. CONCLUSION: Our findings, although limited by the study's retrospective nature, confirm that guselkumab is a safe and effective therapeutic option for a "real-life" cohort of patients with psoriasis. J Drugs Dermatol. 2024;23(8):632-639. doi:10.36849/JDD.7486R1.
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Anticorpos Monoclonais Humanizados , Psoríase , Índice de Gravidade de Doença , Humanos , Psoríase/tratamento farmacológico , Psoríase/diagnóstico , Estudos Retrospectivos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto , IdosoRESUMO
In France, about 2000 new cases of anal cancer are diagnosed annually. Squamous cell carcinoma is the most common histological type, mostly occurring secondary to persistent HPV16 infection. Invasive cancer is preceded by precancerous lesions. In addition to patients with a personal history of precancerous lesions and anal cancer, three groups are at very high risk of anal cancer: (i) men who have sex with men and are living with HIV, (ii) women with a history of high-grade squamous intraepithelial lesions (HSILs) or vulvar HPV cancer, and (iii) women who received a solid organ transplant more than 10 years ago. The purpose of screening is to detect HSILs so that they can be treated, thereby reducing the risk of progression to cancer. All patients with symptoms should undergo a proctological examination including standard anoscopy. For asymptomatic patients at risk, an initial HPV16 test makes it possible to target patients at risk of HSILs likely to progress to cancer. Anal cytology is a sensitive test for HSIL detection. Its sensitivity is greater than 80% and exceeds that of proctological examination with standard anoscopy. It is indicated in the event of a positive HPV16 test. In the presence of cytological abnormalities and/or lesions and a suspicion of dysplasia on clinical examination, high-resolution anoscopy is indicated. Performance is superior to that of proctological examination with standard anoscopy. However, this technique is not widely available, which limits its use. If high-resolution anoscopy is not possible, screening by a standard proctological examination is an alternative. There is a need to develop high-resolution anoscopy and triage tests and to evaluate screening strategies.
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Neoplasias do Ânus , Lesões Pré-Cancerosas , Minorias Sexuais e de Gênero , Masculino , Humanos , Feminino , Papillomavirus Humano , Homossexualidade Masculina , Lesões Pré-Cancerosas/diagnóstico , Neoplasias do Ânus/diagnósticoRESUMO
INTRODUCTION: Our population-based study assessed whether clinically apparent Helicobacter pylori infection (CAHPI) is associated with the risk of Alzheimer's disease (AD). METHODS: We assembled a population-based cohort of all dementia-free subjects in the United Kingdom's Clinical Practice Research Datalink (UK CPRD), aged ≥50 years (1988-2017). Using a nested case-control approach, we matched each newly developed case of AD with 40 controls. Conditional logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with CAHPI compared with no CAHPI during ≥2 years before the index date. We also used salmonellosis as a negative control exposure. RESULTS: Among 4,262,092 dementia-free subjects, 40,455 developed AD after a mean 11 years of follow-up. CAHPI was associated with an increased risk of AD (OR, 1.11; 95% CI, 1.01-1.21) compared with no CAHPI. Salmonellosis was not associated with the risk of AD (OR, 1.03; 95% CI, 0.82-1.29). DISCUSSION: CAHPI was associated with a moderately increased risk of AD. HIGHLIGHTS: CAHPI was associated with an 11% increased risk of AD in subjects aged ≥50 years. The increase in the risk of AD reached a peak of 24% a decade after CAHPI onset. There was no major effect modification by age or sex. Sensitivity analyses addressing several potential biases led to consistent results.
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Doença de Alzheimer , Infecções por Helicobacter , Helicobacter pylori , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/complicações , Estudos de Casos e Controles , Infecções por Helicobacter/epidemiologia , Modelos Logísticos , Fatores de Risco , Masculino , Feminino , IdosoRESUMO
When a method throws an exception- its exception precondition-is a crucial element of the method's documentation that clients should know to properly use it. Unfortunately, exceptional behavior is often poorly documented, and sensitive to changes in a project's implementation details that can be onerous to keep synchronized with the documentation. We present wit, an automated technique that extracts the exception preconditions of Java methods and constructors. wit uses static analysis to analyze the paths in a method's implementation that lead to throwing an exception. wit's analysis is precise, in that it only reports exception preconditions that are correct and correspond to feasible exceptional behavior. It is also lightweight: it only needs the source code of the class (or classes) to be analyzed- without building or running the whole project. To this end, its design uses heuristics that give up some completeness (wit cannot infer all exception preconditions) in exchange for precision and ease of applicability. We ran wit on the JDK and 46 Java projects, where it discovered 30 487 exception preconditions in 24 461 methods, taking less than two seconds per analyzed public method on average. A manual analysis of a significant sample of these exception preconditions confirmed that wit is 100% precise, and demonstrated that it can document the exceptional behavior of Java methods.