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The intimate relationship between the epithelium and immune system is crucial for maintaining tissue homeostasis, with perturbations therein linked to autoimmune disease and cancer1–3. Whereas stem cell-derived organoids are powerful models of epithelial function4, they lack tissue-resident immune cells that are essential for capturing organ-level processes. We describe human intestinal immuno-organoids (IIOs), formed through self-organization of epithelial organoids and autologous tissue-resident memory T (TRM) cells, a portion of which integrate within the epithelium and continuously survey the barrier. TRMcell migration and interaction with epithelial cells was orchestrated by TRMcell-enriched transcriptomic programs governing cell motility and adhesion. We combined IIOs and single-cell transcriptomics to investigate intestinal inflammation triggered by cancer-targeting biologics in patients. Inflammation was associated with the emergence of an activated population of CD8+T cells that progressively acquired intraepithelial and cytotoxic features. The appearance of this effector population was preceded and potentiated by a T helper-1-like CD4+population, which initially produced cytokines and subsequently became cytotoxic itself. As a system amenable to direct perturbation, IIOs allowed us to identify the Rho pathway as a new target for mitigation of immunotherapy-associated intestinal inflammation. Given that they recapitulate both the phenotypic outcomes and underlying interlineage immune interactions, IIOs can be used to study tissue-resident immune responses in the context of tumorigenesis and infectious and autoimmune diseases.

Pregnancy in women with early-onset Parkinson’s disease (PD) is likely to have a higher frequency given the trend toward increasing maternal age, thus resulting in a greater overlap time between childbearing age and PD risk. Deep brain stimulation (DBS) therapy is nowadays offered to PD patients at earlier stage of the disease, when women can still be pre-menopausal. However, few data are available about DBS safety during pregnancy. From a review of the available literature, only one article was published on this topic so far. Therefore, we have developed a clinical consensus on the safety of DBS during pregnancy in PD patients.

Pregnancy in women with early-onset Parkinson’s disease (PD) is likely to have a higher frequency given the trend toward increasing maternal age, thus resulting in a greater overlap time between childbearing age and PD risk. Deep brain stimulation (DBS) therapy is nowadays offered to PD patients at earlier stage of the disease, when women can still be pre-menopausal. However, few data are available about DBS safety during pregnancy. From a review of the available literature, only one article was published on this topic so far. Therefore, we have developed a clinical consensus on the safety of DBS during pregnancy in PD patients.

IMPORTANCE: Cervical cancer is a common and lethal cancer worldwide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (or transforming growth factor β trap) fused via a flexible linker to the C-terminus of each heavy chain of an immunoglobulin G1 antibody blocking programmed cell death 1 ligand 1. OBJECTIVE: To evaluate the safety and response rates of bintrafusp alfa in patients with recurrent or metastatic cervical cancer. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 nonrandomized controlled trial evaluated bintrafusp alfa monotherapy in patients with recurrent or metastatic cervical cancer with disease progression during or after platinum-based chemotherapy. Data were collected from March 2020 to February 2022. INTERVENTION: Patients received bintrafusp alfa, 1200 mg, intravenously once every 2 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee. RESULTS: At data cutoff, 146 of 203 screened patients received 1 or more doses of bintrafusp alfa; of these, the median (range) age was 53 (24-79) years. The study met its primary end point of a 95% CI above the objective response rate benchmark of 15%, with a confirmed objective response rate of 21.9% (95% CI, 15.5-29.5) per the independent review committee. Of these patients, 19 (59.4%) had a durable response of 6 months or more. At data cutoff, responses were ongoing in 13 of 32 responders (40.6%). The most common treatment-related adverse events were anemia (25 [17.1%]), rash (21 [14.4%]), hypothyroidism (15 [10.3%]), and pruritus (15 [10.3%]). Any-cause adverse events of special interest included anemia (82[56.2%]), bleeding events (81 [55.5%]), and immune-related adverse events (49 [33.6%]). CONCLUSIONS AND RELEVANCE: This phase 2 nonrandomized controlled trial of bintrafusp alfa met its primary end point, which may support the potential of a bispecific therapy targeting transforming growth factor β and programmed cell death 1 ligand 1 in patients with recurrent or metastatic cervical cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04246489

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1–confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n= 101), ORR was 17% (17/101; 95% confidence interval (CI), 10–26%), and DCR was 61% (62/101; 95% CI, 51–71%). Median DOR was not reached (NR; 95% CI, 5.7 months–NR), and median PFS was 3.5 months (95% CI, 2.7–4.1 months), at a median follow-up of 10.3 months (range, 0.5–42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272.

Roadways are the main transportation mode in Brazil for both cargo and people. This strong dependence on road transport makes paving highways extremely important for the country's development. A common way to recover deteriorated pavement is through a superficial reinforcement called overlay. The whitetopping overlays are made of Portland cement concrete. The technique basically consists of building a concrete pavement over the existing asphalt pavement. The existing pavement acts as a sub-base for the concrete overlay. The addition of fibers to concrete has been increasingly frequent, especially for industrial floors and pavements, bringing longer performance life for same traffic, climate and concrete strength. The fibers promote the improvement of several characteristics of the concrete paste, such as the increase in post-cracking toughness, energy absorption, and fracture energy. This work evaluates the flexural response of composite beams of concrete and asphalt layers and the influence of adding fibers to the concrete. An experimental program is set and supports the development and validation of a finite element numerical model. The numerical model is then applied to a parametric study where tendifferent concrete mixes with different types of fibers and contents are analysed. Steel and synthetic fibers are used. The composite beams are simulated indicating the concrete mixes that best supported loads in the post-cracking regime, with some mixes managing to maintain around 90% of the peak load for large crack openings.

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed‐dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open‐label, randomized, single‐dose, 2‐period, 2‐way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed‐dose combination tablets with a 7‐day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography‐tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration‐time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%‐125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice.

This article examines pedagogical materials and Catholic youth magazines to uncover how, between 1926 and 1939, the Juventud Católica Femenina Mexicana (JCFM) pursued peasant moralization campaigns driven by young women’s shared distrust of Indigenous and mixed-race campesinas. It unearths the authoritarian dimensions of the group’s educational initiatives and exposes these efforts as fundamentally racial, gendered, and class-conscious political and religious projects. Moreover, this article traces how the JCFM, as an influential upper-class laywomen’s group, tried—and failed—to establish a nationwide educational curriculum grounded in Church doctrine to counter the influence of Protestant missions and Mexico’s nascent Secretariat of Public Education. It attributes these shortcomings to laywomen’s adherence to social hierarchy and their reluctance to offer meaningful solutions to peasant women’s economic hardships.

Compound-specific isotope analysis (CSIA) is an established tool to track the in situtransformation of organic chemicals at contaminated sites. In this work, we evaluated the potential of multi-element CSIA to assess biodegradation of 2,3-dichloroaniline (2,3-DCA), which is a major industrial feedstock. Using controlled laboratory experiments, we determined, for the first time, negligible carbon (<0.5‰) and hydrogen (<10‰) isotope fractionation and a significant inverse nitrogen isotope fractionation (>10‰) during aerobic 2,3-DCA biodegradation by a mixed enrichment culture. The tentative identification of a glutamate conjugate of 2,3-DCA as a reaction intermediate indicates that the initial multistep enzymatic reaction may be rate-limiting. The formation of the glutamate adduct would increase the bond energy at the N atom, thus likely explaining the observed inverse N isotope fractionation. The corresponding nitrogen enrichment factor was +6.8 ± 0.6‰. This value was applied to investigate the in situ2,3-DCA biodegradation at a contaminated site where the carbon and nitrogen isotope signatures from field samples suggested similar aerobic processes by native microorganisms. Under the assumption of the applicability of the Rayleigh model in a pilot wetland treating contaminated groundwater, the extent of biodegradation was estimated to be up to 80–90%. This study proposes multi-element CSIA as a novel application to study 2,3-DCA fate in groundwater and surface water and provides insights into biodegradation pathways.

ABSTRACTDuponchelia fovealisis responsible for great losses in the strawberry production, and entomopathogenic fungi (EPF) are an alternative to control this larva. They can be used in combination with other natural compounds with insecticidal activity, such as plant extracts or essential oils (EOs). Thus, our objectives are to evaluate the effects of Baccharis dracunculifoliaand Baccharis uncinellaEOs on strawberry leaves and third instar larvae of D. fovealis, and to evaluate their in vitrocompatibility with strains of Beauveria bassianaand Cordyceps javanica. EOs were not phytotoxic to strawberry leaves at 2% v/v. Larval mortality ranged between 48% and 83% at 1% and 2%, and B. dracunculifoliaEO at 2% presented the higher mortality. EO of B. uncinella(BU) at 1% was compatible with two strains of B. bassianaand C. javanica. Therefore, the combined use of BU EO with EPF may be an alternative to control D. fovealis.

Background: Transversus abdominis release (TAR) is an effective technique for treating large midline and off-midline hernias. Recent studies have demonstrated that robotic TAR (rTAR) is technically feasible and associated with improved outcomes compared to open surgery. There is no published experience to date describing abdominal wall reconstruction using the novel robotic platform HUGO RAS System (Medtronic®). Methods: All consecutive patients who underwent a rTAR in our institution were included. Three of the four arm carts of the HUGO RAS System were used at any given time. Each arm configuration was defined by our team in conjunction with Medtronic® personnel. rTAR was performed as previously described. Upon completion of the TAR on one side, a redocking process with different, mirrored arms angles was performed to continue with the contralateral TAR. Operative variables and early morbidity were recorded. Results: Ten patients were included in this study. The median BMI was 31 (21–40.6) kg/m2. The median height was 1.6 m (1.5–1.89 m). A trend of decreased operative time, console time, and redocking time was seen in these consecutive cases. No intraoperative events nor postoperative morbidity was reported. The median length of stay was 3 (1–6) days. Conclusion: Robotic TAR utilizing the HUGO RAS system is a feasible and safe procedure. The adoption of this procedure on this novel platform for the treatment of complex abdominal wall hernias has been successful for our team.

Psychosis of epileptic origin can present a wide range of cognitive and affective symptoms and is often underrecognized. Usually occurring in the inter‐ and postictal phase, epileptic psychosis is mostly related to temporal lobe epilepsy. Here, we describe the clinical presentation and diagnostic workup including routine EEG recording and brain MRI of a 63‐year‐old woman expressing isolated nihilistic delusions comprising belief of being dead and denial of self‐existence. EEG showed an ictal pattern fulfilling the Salzburg criteria of nonconvulsive status epilepticus and brain MRI revealed extensive peri‐ictal hyperperfusion. Delusional symptoms and EEG abnormalities subsided after acute antiseizure treatment. Our case illustrates how nihilistic delusions can occur as a direct clinical correlate of seizure activity, thereby expanding the spectrum of ictal neuropsychiatric phenomena in temporal lobe epilepsy and highlighting the need to consider an epileptic origin in patients presenting with psychotic symptoms.

Considering the impacts of climate change in recent decades that have exacerbated the frequency and intensity of floods worldwide and especially in the Amazon region. The city of Rio Branco, located in the southwest of Brazil's Amazon region, has been severely affected by a combination of urbanization in flood-prone areas and increasing floods in the Acre River. In addressing this challenge, accurate inundation mapping plays a pivotal role in shaping effective flood risk reduction strategies. This study employs hydraulic simulations of the Acre River, utilizing the HEC-RAS 1D model. The modeling process integrates a high-resolution digital terrain model, acquired through Light Detection and Ranging (LiDAR), and a rich dataset encompassing conventional and unconventional information from the three most significant historical floods in Rio Branco in 2012, 2015, and 2023. To ensure the precision of the simulations, calibration of the roughness coefficient was conducted for steady-state scenarios, drawing upon a diverse range of observed stream-gauge data. The evaluation of water elevation in steady state reveals an impressive mean error of just 0.01 m, underscoring the model's accuracy. Moving beyond steady-state simulations, the study evaluates unsteady-state scenarios by calculating the root mean square error (RMSE). Results showcase commendable accuracies of 0.22, 0.25, and 0.26 m for the 2012, 2015, and 2023 floods, respectively. Flooding extent simulation was assessed using the Critical Success Index (C) from two optical aerial survey images recorded during the 2012 and 2015 floods and one optical satellite image recorded during the 2023 flood. The accuracy was 0.88 (2012) and 0.84 (2015) for optical aerial survey images and 0.97 for the optical satellite image (2023). Images from Google Street View recorded after 2012 flood event containing high-water marks were used to evaluate the accuracy of maximum water depth simulation along the floodplain and presented a mean error of 0.17 m.

High-strength metastable β-titanium alloys like Ti-5553 (Ti–5Al–5Mo–5V–3Cr) are frequently used in highly loaded aerospace components. Such aerospace parts tend to be expensive to traditionally manufacture due to current industry process limitations such as inflexibility for complex geometries, costs related to tooling for large forgings, extended lead times, poor machinability and high material waste. These challenges are leading to increased interest in exploring alternative manufacturing routes. This work investigates the use of additive manufacturing to deposit cost-effective and machinable Ti-64 (Ti–6Al–4V) alloy onto a forged Ti-5553 alloy substrate. The microstructure evolution, microhardness and tensile properties have been investigated for both the as-deposited as well as for stress relief heat-treated conditions. The results confirmed the formation of coarse columnar β grains with a fine basketweave α structure. The heat affected zones (HAZs) developed in the Ti-5553 substrate material from the cyclic thermal fluxes introduced from the melt-pool were characterized by a gradient microstructure of dissolving constituent phases with nearing proximity to the fusion zone. Tensile testing in the as-deposited condition was characterised with a UTS of 884 MPa and a ductility of 15%. Tensile samples extracted across the substrate-deposit interface all failed in the WAAM Ti-64 material and demonstrated comparatively greater strength but poorer ductility. A band of tensile residual stresses was imparted along the substrate, but was adequately stress relieved after heat-treatment at 600 °C. The heat-treatment led to the formation of more homogeneous α-phase laths throughout the HAZ of the Ti-5553 material and provided overall improvements to the strength and ductility.

The expansion of open access entails a responsibility for supporting this public access with a guide to why, in an ‘Age of Misinformation’, research may be trustworthy.Such a guide can also provide a check on predatory journals, a fear of which may be unduly limiting researchers tapping into the expanding global scale of research activity.Journal publishing platforms offer opportunities for automating the gathering and presenting of relevant data for assessing journal adherence to scholarly standards.Industry organizations, such as ORCID, Crossref, and DOAJ, offer trust and verification networks that can be employed to further strengthen scholarly publishing integrity.

Cutaneous leishmaniasis (CL) is a neglected disease widely distributed in Maranhão, Brazil and presents a significant public health problem. However, its transmission dynamics and determining factors are not clearly understood. In this context, geospatial technologies help interpret the process. This study, then, characterized the space–time dynamics and the influence of social vulnerability on CL in an endemic area in Northeast Brazil. This is an ecological study about new cases of CL in Maranhão, from 2007 to 2020, obtained directly from the Notifiable Diseases Information System. The incidence rate was smoothed using a spatial empirical Bayesian method. Subsequently, global and local Moran statistics and their association with social vulnerability indicators were determined. Disease distribution was not random but grouped in space and time. All Social Vulnerability Index domains were positively correlated with the CL incidence. A likely cluster was detected in western Maranhão (P< 0.001), which encompassed 18 municipalities, from January 2007 to December 2013, with a high relative risk (5.06). The research findings suggest that planning public health actions and allocating resources should be prioritized in these areas to help effectively reduce the incidence of the disease.

This work shows the first example of using intramolecular London dispersion interactions to control molecular geometry and quantum transport in single-molecule junctions. Flexible σ-bonded molecular junctions typically occupy straight-chain geometries due to steric effects. Here, we synthesize a series of thiomethyl-terminated oligo(dimethylsilmethylene)s that bear [CH2–Si(CH3)2]nrepeat units, where all backbone dihedral states are sterically equivalent. Scanning tunneling microscopy break-junction (STM-BJ) measurements and theoretical calculations indicate that in the absence of a strong steric bias concerted intramolecular London dispersion interactions staple the carbosilane backbone into coiled conformations that remain intact even as the junction is stretched to its breakpoint. As these kinked conformations are highly resistive to electronic transport, we observe record-high conductance decay values on an experimental junction length basis (β = 1.86 ± 0.12 Å–1). These studies reveal the potential of using intramolecular London dispersion interactions to design single-molecule electronics.

The objective of this study was to compare feedlot performance, carcass traits, and value of beef × Holstein (B × HO) and Holstein (HO) feedlot steers.