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Biotechnological production of recombinant molecules relies heavily on fed-batch processes. However, as the cells' growth, substrate uptake, and production kinetics are often unclear, the fed-batches are frequently operated under sub-optimal conditions. Process design is based on simple feed profiles (e.g., constant or exponential), operator experience, and basic statistical tools (e.g., response surface methodology), which are unable to harvest the full potential of production.To address this challenge, we propose a general modeling framework, OptFed, which utilizes experimental data from non-optimal fed-batch processes to predict an optimal one. In detail, we assume that cell-specific rates depend on several state variables and their derivatives.Using measurements of bioreactor volume, biomass, and product, we fit the kinetic constants of ordinary differential equations. A regression model avoids overfitting by reducing the number of parameters. Thereafter, OptFed predicts optimal process conditions by solving an optimal control problem using orthogonal collocation and nonlinear programming.In a case study, we apply OptFed to a recombinant protein L fed-batch production process. We determine optimal controls for feed rate and reactor temperature to maximize the product-to-biomass yield and successfully validate our predictions experimentally. Notably, our framework outperforms RSM in both simulation and experiments, capturing an optimum previously missed. We improve the experimental product-to-biomass ratio by 19% and showcase OptFed's potential for enhancing process optimization in biotechnology.

A bench-scale study of river water treatment using composite polyethersulfone (PES) membrane was carried out. Polyethylene glycol-silver nanoparticles (PEG-AgNPs) additive was designed to support the simultaneous filtration and disinfection performance of PES membranes via in situ incorporation. Significant improvements in the PES membranes after modification with PEG-AgNPs were observed. The experimental results showed that the PEG-AgNPs increased the PES membrane water flux from 2.87 to 172.84 L/m2·h. The anti-fouling test of the PES membrane toward humic acid molecules after the addition of PES/PEG-AgNPs increased the reversible fouling and decreased the irreversible fouling. In terms of filtration performance, the PES/PEG-AgNP membranes showed high filtration performance, with a water disinfection ability of 99.99 %. Moreover, the leach of silver particles from the PES membrane forced by ultrasonication was

This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-β-lactamase (MBL) inhibitor (indole-2-carboxylate 58 (InC58)), and a serine-β-lactamase (SBL) inhibitor (avibactam (AVI)) for broad-spectrum activity against carbapenemase-producing bacteria. A diverse panel comprising MBL- and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method. The frequency of resistance (FoR) to MEM combined with InC58 was investigated. Mutants were sequenced and tested for cross resistance, fitness, and the stability of the resistance phenotype. Compared with the double combinations of MEM plus an SBL or MBL inhibitor, the triple combination extended the spectrum of activity to most of the isolates bearing SBLs (oxacillinase-48 (OXA-48) and Klebsiella pneumoniae carbapenemase-2 (KPC-2)) and MBLs (New Delhi metallo-β-lactamases (NDMs)), although it was not effective against Verona integron-encoded metallo-β-lactamase (VIM)-carrying Pseudomonas aeruginosa (P. aeruginosa) and OXA-23-carrying Acinetobacter baumannii (A. baumannii). The FoR to MEM plus InC58 ranged from 2.22 × 10−7 to 1.13 × 10−6. The resistance correlated with mutations to ompC and comR, affecting porin C and copper permeability, respectively. The mutants manifested a fitness cost, a decreased level of resistance during passage without antibiotic pressure, and cross resistance to another carbapenem (imipenem) and a β-lactamase inhibitor (taniborbactam). In conclusion, compared with the dual combinations, the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemase-producing bacteria, revealing a new strategy to combat β-lactamase-mediated antimicrobial resistance.

Large retrorectal tumors are rare and often a diagnostic and surgical challenge due to their anatomical location. We report the case of a 55-year-old patient with weight loss and changed bowel habits, where digital rectal examination revealed a retrorectal mass raising suspicion of a tumor. Magnetic resonance imaging (MRI) and computed tomography (CT) showed a large retrorectal tumor and histopathology after surgical resection showed undifferentiated spindle cell sarcoma. This tumor type has not been previously reported as the etiology of large retrorectal tumors. We discuss the implications of diagnostic imaging, especially MRI, in the approach to diagnosis and surgical treatment of retrorectal tumors with reference to the scientific literature and previously reported cases of retrorectal tumors.

With the objective of finding new classes of cognitive enhancers with potential for the treatment of neurodegenerative disorders, such as Alzheimer's disease, small molecule inhibitors of insulin-regulated aminopeptidase (IRAP) were designed and synthesized. IRAP is a member of the M1 family of zinc aminopeptidases and is abundantly expressed in areas of the brain associated with cognition, such as the amygdala, hippocampus and cerebral cortex. IRAP inhibitors were previously shown to enhance memory and learning in animal models. A comprehensive high throughput screening of 400,000 small molecules from the European Lead Factory library provided a series of 50 promising compounds in a qualified hit list (QHL). More than 30 IRAP inhibitors with an IC50 below 3.5 μM were identified. Herein, selected compounds from this QHL were assayed for solubility and permeability. Most of the selected compounds displayed good solubility, but further permeability studies on the best compounds revealed low blood brain barrier (BBB) permeability and high efflux in cells overexpressing P-gp pumps, rendering them less promising as starting points in drug discovery processes. Two compounds from the QHL were prioritized for further structural optimization; the pyridyl-substituted isoxazole 1a (QHL27) and the benzylhydroxamic acid derivative 1b (QHL1), both demonstrating fair BBB permeability and no indication of efflux. While our attempts to improve the isoxazole derivative 1a were not fruitful, a structural modification of 1b to provide the chloro-substituted benzylhydroxamic acid 14b resulted in a ten-fold improvement of the IRAP inhibition with an IC50 value of 60 nM. The binding modes of 1b and 14b were determined by free energy perturbation (FEP) analysis performed on candidate docking poses, determining a binding mode that accurately explained the experimental SAR. Further FEP studies of compound 14b suggested that it exhibits selectivity towards IRAP over Aminopeptidase N (APN), indicating its potential for targeted therapeutic applications.

Food-based antioxidants reduce oxidative stress caused by metabolic processes, scavenge free radicals, promote cardiovascular health, and preventing oxidative-stress related diseases, among other health advantages. The current study aims to investigate the low-viscosity banana juices’ bioactive compounds and antioxidant capacity dependence on cultivars and ripening stages. Five banana cultivars were studied: Mbilabile, Pisang Awak (PSA), Yangambi km5 (YKM5), Ndeshi, and Mlonga. An improved mechanical extraction method involving malaxation of peeled banana pulp until low-viscosity banana juice separates from the pulp was used to extract banana juice. Considered ripening stages were stage 3; more green than yellow, 4; more yellow than green, 5; yellow with a trace of green, 6; all yellow, and 7; all yellow with brown spots. It was revealed that banana juice is rich in polyphenolic compounds 145.02–320 mg GAE/L and ascorbic acid, 0.45–1.40 g/L. In addition, the composition of total phenolic compounds (TPC) and ascorbic acid varied with banana cultivars and ripening stages. Furthermore, banana juice could reduce 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radicals by 67–93 %. The antioxidant capacity of banana juice varied with cultivars and ripening stages (p < 0.05). Correlation analysis suggested ascorbic acid influenced banana juice free radical scavenging capacity.

A direct measurement of the ground-state-to-ground-state electron-capture decay Q value of 95Tc has been performed utilizing the double Penning trap mass spectrometer JYFLTRAP. The Q value was determined to be 1695.92(13) keV by taking advantage of the high resolving power of the phase-imaging ion-cyclotron-resonance technique to resolve the low-lying isomeric state of 95Tc (excitation energy of 38.910(40) keV) from the ground state. The mass excess of 95Tc was measured to be −86015.95(18) keV/c2, exhibiting a precision of about 28 times higher and in agreement with the value from the newest Atomic Mass Evaluation (AME2020). Combined with the nuclear energy-level data for the decay-daughter 95Mo, two potential ultra-low Q-value transitions are identified for future long-term neutrino-mass determination experiments. The atomic self-consistent many-electron Dirac–Hartree–Fock–Slater method and the nuclear shell model have been used to predict the partial half-lives and energy-release distributions for the two transitions. The dominant correction terms related to those processes are considered, including the exchange and overlap corrections, and the shake-up and shake-off effects. The normalized distribution of the released energy in the electron-capture decay of 95Tc to excited states of 95Mo is compared to that of 163Ho currently being used for electron-neutrino-mass determination.

Background/purpose: To investigate a quantitative method for assessing image quality of low dose lung computed tomography (CT) and find the lowest exposure dose providing diagnostic images. Methods: Axial volumetric lung CT acquisitions (256 slice scanner) were performed on three different sized anthropomorphic phantoms at different dose levels. The maximum steepness of sigmoid curves fitted to line density profiles was measured at lung-to-pleura interfaces. For each phantom, image sharpness was calculated as the median of 468 measurements from 39 different locations. Diagnostic image quality for the adult and paediatric phantom was rated by three radiologists using 4-point Likert scales. The image sharpness cut-off for obtaining adequate image quality was determined from qualitative ratings. Results: Adequate diagnostic image quality was reached at a median steepness of 713 HU/mm in the adult phantom with a corresponding CTDIvol of 0.14 mGy and an effective dose of 0.13 mSv at a dose level of 100 kVp and 10 mA. In the paediatric phantom diagnostic image quality was reached at a median steepness of 1139 HU/mm with a corresponding CTDIvol of 0.13 mGy and an effective dose of 0.08 mSv at a dose level of 100 kVp and 10 mA. Conclusions: Determination of image sharpness on line density profiles can be used as quantitative measure for image quality of lung CT. Sufficient-quality lung CT can be achieved at effective radiation doses of 0.13 mSv (adult phantom) and 0.08 mSv (paediatric phantom). These findings suggest that substantial dose reduction is feasible without compromising diagnostic accuracy.

Radiation transport simulations of the deuterium Lyman line series using EIRENE predict a factor of 2 increase of Balmer-α emission in the JET-ILW low confinement divertor plasmas in high-recycling and detached conditions caused by the re-absorption of Lyman-β emission. The photon tracing model in the EIRENE code is applied to SOLPS-ITER pure deuterium plasma solutions of JET-ILW to evaluate the contribution of Lyman-β capture towards the population density of D(p=3) and, consequently, the Balmer-α emission. The local population escape factors of Lyman-α and Lyman-β lines in the JET-ILW divertor show steep spatial gradients and indicate local regions with high opacity in high-recycling and detached conditions. The relative contribution of Lyman-β capture towards the population density of D(p=3) is significant in high-recycling and detached conditions. This observation is further corroborated by line-integrated calculations using Balmer-α diagnostic line-of-sights.

Adoptive cell transfer with chimeric antigen receptor (CAR)-expressing T cells can induce remarkable complete responses in cancer patients. Therapeutic success has been correlated with central and stem cell-like memory T cell subsets in the infusion product, which are better able to drive efficient CAR T cell in vivo expansion and long-term persistence. We previously reported that inhibition of the mitochondrial pyruvate carrier (MPC) during mouse CAR T cell culture induces a memory phenotype and enhances antitumor efficacy against melanoma. Here, we use a novel MPC inhibitor, MITO-66, which robustly induces a stem cell-like memory phenotype in CD19-CAR T cells generated from healthy donors and patients with relapsed/refractory B cell malignancies. MITO-66-conditioned CAR T cells were superior in controlling human pre-B cell acute lymphoblastic leukemia in mice. Following adoptive cell transfer, MITO-66-conditioned CAR T cells maintained a memory phenotype and protected cured mice against tumor rechallenge. Furthermore, in an in vivo B cell leukemia stress model, CD19-CAR T cells generated in the presence of MITO-66 largely outperformed clinical-stage AKT and PI-3Kδ inhibitors. Thus, we provide compelling preclinical evidence that MPC inhibition with MITO-66 during CAR T cell manufacturing dramatically enhances their antitumor efficacy, thereby paving the way to clinical translation.

Characterizing seeds of tropical weeds is crucial for future research to understand their ability to disperse in space and time through their seeds, and building up seed banks. Seeds of 55 weed species occurring on Reunion Island were collected and characterized. Seeds were described by their shape, size, color, texture, hairiness, or particular markings. Seed traits were recorded in a database in French and English. It has been published on the CIRAD AMATROP dataverse, which centralizes datasets on tropical weeds. It will be updated as new weed seeds from tropical regions are characterized. In a long-term perspective, these data allow for creating a multicriteria identification key to identify seeds to study seed stocks in agricultural fields.

Due to the global pandemic of influenza and related respiratory diseases, rapid and accurate detection is in high demand to control virus spread and facilitate early treatment. However, most current molecular detection methods either require long turnaround times, suffer from low sensitivity and/or can only detect single pathogens. To overcome these challenges, we constructed a novel colorimetric gold nanoparticle (AuNPs) biosensor containing functionalized probes to detect multiple targets simultaneously. Utilizing the salt aging method, AuNPs were functionalized by the designed oligonucleotides to fabricate biosensors. This biosensor can show visible color change within 20 min, and could minimally detect the target influenza viruses at 10 nM. This detection technique presents high sensitivity in a short time, meanwhile identifying two different influenza viruses simultaneously. It opens a window to a multiplex-in-one strategy for a clinical viral diagnostic.

This work studies mathematical foundations for optimal boundary control of mixers which mix two fluid phases. Existence of optima is proved and the influence of common objective functionals is discussed.

Purpose: Randomized studies demonstrated the oncological equivalence of (ultra-)hypofractionation compared to a 5-week schedule in postoperative radiotherapy of breast cancer. Due to the low incidence and long latency of secondary malignancies, there are currently no reliable clinical data regarding the influence of fractionation regimens on the development of secondary malignancies. Material and methods: For 20 patients with right or left-sided breast cancer, postoperative treatment plans were created using 3D-CRT (n = 10) or VMAT (n = 10) for three different fractionation schedules: 5-week schedule with 50.4Gy in 1.8Gy (28fx), hypofractionation with 40.05Gy in 2.67Gy (15fx) and ultra-hypofractionation with 26Gy in 5.2Gy (5fx). The EARs (absolute additional cases of disease per 10,000 patient-years) for secondary malignancies in the lung, contralateral breast, esophagus, liver, thyroid, spinal cord, bones and soft tissue were calculated using a fraction-dependent dose-response model. Results: Based on risk modulation, (ultra-)hypofractionation resulted in significantly lower EARs for lung cancer (LC), contralateral breast cancer (CBC) and soft tissue sarcoma (STS) (p

Klebsiella pneumoniae is a ubiquitous nosocomial pathogen associated with various types of infections in hospitalized patients and different animal species. In the current study, 49 Klebsiella strains isolated from humans, dogs, and cats were investigated using NGS technology. MALDI-TOF failed to identify newly discovered K. variicola and K. quasipneumoniae isolates correctly. MLST analysis revealed different sequence types among K. pneumoniae isolates, and the most frequent STs were ST29, ST219, and ST37. Three ST23 that are generally known as hypervirulent type were identified but they lacked major discriminatory determinants for hypervirulent K. pneumoniae (hvKp). K. pneumoniae isolates showed high diversity, and several isolates from humans and animals were assigned to the same ST and were almost identical. Isolates from humans exhibited more pronounced resistance patterns compared to the animal isolates. High levels of resistance were observed for piperacillin, trimethoprim/sulfamethoxazole, and cephalosporins, and resistance to carbapenem compounds was only found in isolates of human origin. Three strains of human origin were extensively drug-resistant (XDR). A diverse range of resistance genes primarily confer resistance to beta-lactams., phenicol/quinolone, aminoglycoside, macrolide, sulfonamides, and fosfomycin were identified in silico. However, there were inconsistencies between the phenotypic characterization of isolates and the set of resistance genes detected in silico in this set of Klebsiella isolates. Further research using a larger number of isolates from various sources is necessary to fully comprehend the relationship between the presence of antimicrobial resistance determinants and phenotypic data. It is also necessary to monitor the spread of K. pneumoniae from a One Health perspective in Egypt.

With age, metabolic perturbations accumulate to elevate our obesity burden. While age-onset obesity is mostly driven by a sedentary lifestyle and high calorie intake, genetic and epigenetic factors also play a role. Among these, members of the large histone deacetylase (HDAC) family are of particular importance as key metabolic determinants for healthy ageing, or metabolic dysfunction. Here, we aimed to interrogate the role of class 2 family member HDAC5 in controlling systemic metabolism and age-related obesity under non-obesogenic conditions. Starting at 6 months of age, we observed adult-onset obesity in chow-fed male global HDAC5-KO mice, that was accompanied by marked reductions in adrenergic-stimulated ATP-consuming futile cycles, including BAT activity and UCP1 levels, WAT-lipolysis, skeletal muscle, WAT and liver futile creatine and calcium cycles, and ultimately energy expenditure. Female mice did not differ between genotypes. The lower peripheral sympathetic nervous system (SNS) activity in mature male KO mice was linked to higher dopaminergic neuronal activity within the dorsomedial arcuate nucleus (dmARC) and elevated hypothalamic dopamine levels. Mechanistically, we reveal that hypothalamic HDAC5 acts as co-repressor of STAT5b over the control of Tyrosine hydroxylase (TH) gene transactivation, which ultimately orchestrates the activity of dmARH dopaminergic neurons and energy metabolism in male mice under non-obesogenic conditions.

Objective: To test and evaluate a sofware dedicated to the follow-up of oncological CT scans for potential use in the Radiology department. Materials and methods: In this retrospective study, 37 oncological patients with baseline and follow-up CT scans were reinterpreted using a dedicated software. Baseline CT scans were chosen from the imaging reports available in our PACS (picture archiving and communicatin systems). Follow-up interpretations were independently assessed with the software. We evaluated the target lesion sums and the tumor response based on RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). Results: There was no significant difference in the target lesion sums and the tumor response assessments between the PACS data and the imaging software. There was no over or underestimation of the disease with the software. There was a sigificant deviation (progression versus stability) in three cases. For two patients, this difference was related to the evaluation of the response of non-target lesions. The difference in the third patient was due to comparison with a previous CT scan than to the baseline exam. There was a miscalculation in 13 % of the reports and in 28 % of the cases the examination was compared to the previous CT scan. Finally, the tumor response was not detailed in 43 % of the follow-up reports. Conclusion: The use of dedicated oncology monitoring software could help in reducing intepretation time and in limiting human errors.

Background: Limited access to ultrasound services in low and middle-income countries (LMICs) prompts the development of an intensive training program for midwives. The aim of this study was to evaluate the quality of ultrasound images produced by midwives and assess their competency in gestational age assessment using femur length. Methods: A cross-sectional study conducted in 11 healthcare facilities across four districts in Zambia involved the evaluation of 928 images captured during the implementation of the Training in Ultrasound to Determine Gestational Age (TUDA) program in 2021. TUDA, collaboration under the DIPLOMATIC Study, trained 24 midwives intensively for 14 days, followed by eight weeks of supervised scanning. Image assessment utilized the Sarries four-point tool, and statistical analyses included descriptive and inferential statistics. Results: Midwives achieved an 87.95 % competency level in basic ultrasound scans for gestational age determination using femur length. Assessment by four evaluators showed an average proportion of good-quality images also at 87.95 %. There were no statistically significant differences among assessors, indicating consistency in evaluations. Trainers and radiographers exhibited different average proportions of good-quality images at 91.5 % and 83.9 %, respectively, with no statistically significant differences observed between them.Furthermore, analysis of image quality revealed significant variation among different facilities. Specifically, in Chipata, 24.32 % of scans were classified as poor quality, while in George Clinic, only 2.30 % were considered poor quality. A Chi-square test indicated a substantial correlation between health facility and image quality (χ2 = 15.99, p = 0.025). However, no significant correlations were found between image quality and factors such as work experience, age group, or gender. Conclusion: This study provides critical evidence for successfully training midwives to competent produce high-quality ultrasound images for determining gestational age. These findings are essential for guiding interventions aimed at enhancing ultrasound service delivery and ensuring consistent, high-quality healthcare outcomes, because this is critical for effective prenatal care in Zambia. This has high potential to improve prenatal care. Recommendation: Zambia needs to train more midwives to provide routine ultrasound services during Antenatal Care (ANC) which may ultimately reduce preterm and still births. We recommend the inclusion of ultrasound scanning in-service and pre-service training and establishment of standardized protocols and guidelines for ultrasound scanning services during antenatal clinics.

Removing salinity has always been a challenge for wastewater treatment. Utilizing nanofiltration (NF) membranes is a promising approach. However, currently available NF membranes are less effective in monovalent salt removal. In this study, work toward the initial aim of fabricating charge mosaic membranes led to charge-patterned NF-selective films on polyether sulfone (PES) or polyacrylonitrile (PAN) support membranes, with similar rejection for mono- and divalent salts. The membranes were fabricated by a two-step layer assembly of first negatively charged polystyrene sulfonate (PSS) particles immobilized in a polyvinyl alcohol (PVA) layer, followed by coating a positively charged polyethyleneimine (PEI) layer. Both PVA and PEI were crosslinked using glutaraldehyde that had initially been impregnated into the support membrane. The type of support membrane, nanoparticle, PVA, and PEI concentrations during fabrication, as well as feed pH and salt concentration, play significant roles in separation performance of obtained composite membranes. Charge-patterned NF membranes fabricated using 0.5 wt.% PVA and 0.05 wt.% PSS for assembly of the first layer followed by coating 0.5 wt.% PEI solution had even somewhat higher rejection for monovalent salt (NaCl; ∼82%) compared to multivalent salts (Na2SO4, MgSO4, and MgCl2; ∼74%), at a permeance of 5.5 LMH/bar on the PES and 3.1 LMH/bar on the PAN support membrane.

We utilized a novel all-in-one method to fabricate porous polyethersulfone (PES) membranes containing bimetallic PdIn as catalyst and a cationic ionomer to introduce charged surface groups. Our fabrication is based on in situ solidification of dissolved palladium and indium ions in a PES-ionomer casting-reaction solution, directly followed by preparation of porous catalytic membranes through film casting and phase separation in water. We employed as-prepared membranes in the catalytic reduction of NO3− (50 mg/L, 0.81 mM) to NH3 in water using formic acid (FA) as electron source. The in situ solidification of PdCl42− and In3+ generated PdIn species with the highest catalytic activity, compared to Pd2+ and In3+ or a sequential solidification of Pd followed by In. Moreover, positively charged ionomer in a Pd3In1-PES membrane boosted NO3− conversion rate in flow-through at pH 7 from 2.5 to 17 mmol/m2h and NH3 selectivity from 4 % to 34 %, likely by promoting interaction between nitrate and formate anions with catalyst sites. Reducing the flow rate from 100 to 50 L/m2h further enhanced NH3 selectivity to 55 % (NH3 production rate of 189 µg/h mg), illustrating that a longer residence time in the membrane promotes NH3 formation. Additionally, we achieved 90 % electron efficiency for NO3− reduction with FA in flow-through compared to 60 % in batch, highlighting that a short contact time between catalyst and FA limits excess consumption through dehydrogenation. Finally, we demonstrated continuous NH3 production from NO3− for 11 h of flow-through, and found indications that PdIn catalyzes NO3− reduction through an electron/oxygen transfer cycle.

Summary: Impaired sleep is a common aspect of aging and often precedes the onset of Alzheimer’s disease. Here, we compare the effects of sleep deprivation in young wild-type mice and their APP/PS1 littermates, a murine model of Alzheimer’s disease. After 7 h of sleep deprivation, both genotypes exhibit an increase in EEG slow-wave activity. However, only the wild-type mice demonstrate an increase in the power of infraslow norepinephrine oscillations, which are characteristic of healthy non-rapid eye movement sleep. Notably, the APP/PS1 mice fail to enhance norepinephrine oscillations 24 h after sleep deprivation, coinciding with an accumulation of cerebral amyloid-β protein. Proteome analysis of cerebrospinal fluid and extracellular fluid further supports these findings by showing altered protein clearance in APP/PS1 mice. We propose that the suppression of infraslow norepinephrine oscillations following sleep deprivation contributes to increased vulnerability to sleep loss and heightens the risk of developing amyloid pathology in early stages of Alzheimer’s disease.

Although the mediating role of the stress hormone systems in memory for single— especially emotional— events is well-stablished, less is known about the influence of stress on memory for associated contextual information (source memory). Here, we investigated the impact of acute stress on the neural underpinnings of emotional contextual source memory. Participants underwent a stress or a control manipulation before they encoded objects paired with pleasant, neutral, or unpleasant backgrounds. One week later, item and contextual source memory were tested. Acute stress modulated the neural signature of item and contextual source memory in an opposite fashion: stressed participants showed larger activation in the precuneus and the medial prefrontal cortex (mPFC) during the retrieval of items, while the retrieval of contextual unpleasant information was associated with lower activation in the angular gyrus (AG) and mPFC. Furthermore, as revealed by cross-region representational similarity analyses, stress also reduced the memory reinstatement of the previously encoded visual cortex representations of object/unpleasant background pairings in the AG and mPFC. These results suggest that pre-encoding stress induction increases the activity of memory-related regions for single items but reduces the activity of these regions during the retrieval of contextual unpleasant information. Our findings provide new insights into the dissociative effects of stress on item and contextual source memory which could have clinical relevance for stress-related disorders.

Background & Aims: The LiverRisk score has been proposed as a blood-based tool to estimate liver stiffness measurement (LSM), thereby stratifying the risk of compensated advanced chronic liver disease (cACLD, LSM ≥10 kPa) and liver-related events in patients without known chronic liver disease (CLD). We aimed to evaluate its diagnostic/prognostic performance in tertiary care. Methods: Patients referred to two hepatology outpatient clinics (cohort I, n = 5,897; cohort II, n = 1,558) were retrospectively included. Calibration/agreement of the LiverRisk score with LSM was assessed, and diagnostic accuracy for cACLD was compared with that of fibrosis-4 (FIB-4)/aspartate aminotransferase-to-platelet ratio index (APRI). The prediction of hepatic decompensation and utility of proposed cut-offs were evaluated. Results: In cohort I/II, mean age was 48.3/51.8 years, 44.2%/44.7% were female, predominant etiologies were viral hepatitis (51.8%)/metabolic dysfunction-associated steatotic liver disease (63.7%), median LSM was 6.9 (IQR 5.1–10.9)/5.8 (IQR 4.5–8.8) kPa, and 1,690 (28.7%)/322 (20.7%) patients had cACLD.Despite a moderate correlation (Pearson’s r = 0.325/0.422), the LiverRisk score systematically underestimated LSM (2.93/1.80 points/kPa lower), and range of agreement was wide, especially at higher values.The diagnostic accuracy of the LiverRisk score for cACLD (area under the receiver operator characteristics curve [AUROC] 0.757/0.790) was comparable to that of FIB-4 (AUROC 0.769/0.813) and APRI (AUROC 0.747/0.765). The proposed cut-off of 10 points yielded an accuracy of 74.2%/81.2%, high specificity (91.9%/93.4%), but low negative predictive value (76.6%/84.5%, Cohen’s κ = 0.260/0.327).In cohort I, 208 (3.5%) patients developed hepatic decompensation (median follow-up 4.7 years). The LiverRisk score showed a reasonable accuracy for predicting hepatic decompensation within 1–5 years (AUROC 0.778–0.832). However, it was inferior to LSM (AUROC 0.847–0.901, p

ABSTRACT: Glyphosate-based herbicides (GBH) are the most extensively used herbicides worldwide. Despite a presumed nondangerousness for animals, several studies reported negative effects after a GBH exposure in several animal models including birds, notably on reproductive functions. Several studies concerning the advantages of Vitamin E (VE) for antioxidant activity but also growth and reproduction have been reported in birds. However, it remains unclear whether VE could alleviate the negative effect of GBHs on chicken ovarian cells. Here we exposed chicken primary granulosa cells (GCs) from F1 and F3/4 follicles to growing doses of GBH (0.036, 0.36, 3.6, and 36 gly eq/L), with or without VE supplementation (1 mg/L) and investigated cell viability, proliferation, oxidative stress and steroidogenesis. GBH exposure did not affect F1 and F3 GCs viability but it increased cell proliferation only in F1 GCs and this effect was not altered by VE. In both F1 and F3/4 GCs, GBH exposure increased total oxidant status (TOS), reduced total antioxidant status (TAS) and consequently increased index of oxidative stress (OSI) in dose dependent manner. This latter effect for GBH 36 mg eq gly/L was totally abolished in response to VE. In both F1 and F3/4 GCs, GBH exposure reduced progesterone secretion in a dose dependent manner and this effect with GBH 0.36 and 1.8 mg eq glyphosate/L was alleviated by VE. However, we did not observe any effect of GBH and VE on the gene expression of several components of the steroidogenesis process. Taken together, these results show that GBH may have endocrine disruptor effects, and that these effects might be alleviated by antioxidant VE supplementation.

ABSTRACT: Sulfonamides (S) are old bacteriostatic antibiotics which are widely prescribed in combination with trimethoprim (TMP) for the treatment of various diseases in food-producing animals such as poultry. Nowadays, the 1:5 dose ratio of TMP/S used in broilers is a direct transposition of the ratio determined in Human decades ago for TMP/sulfamethoxazole (SMX), aiming to obtain a supposed synergistic plasma concentration ratio of 1:19. However, major pharmacokinetics (PK) differences exist according to the sulfonamide used in the combination. Here, we generated new PK data in broilers after a cross-over design with IV and the oral administration of 2 major sulfonamides, sulfadiazine (SDZ) and SMX, in combination with TMP, and analyzed the data via a population pharmacokinetic (popPK) modeling approach. Results showed that TMP has a greater plasma to tissue distribution than both sulfonamides with a higher volume of distribution (0.51 L/kg for SDZ, 0.62 L/kg for SMX and 3.14 L/kg for TMP). SMX has the highest elimination half-life (2.83 h) followed by SDZ and TMP (2.01 h and 1.49 h, respectively). The oral bioavailability of the 3 molecules was approximately 100%. Bodyweight could explain some of the inter-individual variability in the volume of distribution of SDZ and SMX and the clearance of SDZ and TMP, as heavier broilers have higher typical values. Monte Carlo simulations of a large virtual broiler population (n = 1,000) showed that the targeted plasma ratio of TMP:S of 1:19 was rarely or never reached at the individual level for both combinations at the marketed doses and greatly varies over time and between individuals, questioning the relevance of the 1:5 dose ratio for current formulations of TMP/S.

Cofactor F420 is an electron carrier playing a crucial role in a variety of microorganisms during redox reactions of the primary and secondary metabolism due to its low redox potential and thus arouses increasing interest. In this study, cofactor F420 glutamyl tail length spectra in various habitats like manure, compost, soil, and digester sludge samples and their respective microbial communities were investigated using high performance liquid chromatography and an amplicon sequencing approach A previous in-silico study was used to identify F420 producing microorganisms. The highest concentration of cofactor F420 could be achieved in the horse manure, digester sludge, and mixed manure samples, which was approximately 100-fold higher than in all the other samples. The high content of the cofactor in the samples with high O2 availability pointed to the important role of the cofactor not only in redox reactions of anaerobic but also for aerobic microorganisms and indicated its ubiquitous character. The most abundant derivate was F420-3 comprising the largest part of the cofactor derivates in seven out of ten samples. The high abundance of F420-3 in samples with distinct properties (e.g. O2 and H2O availability) showed its important role in redox reactions of the primary and secondary metabolism among prokaryotes.

Introdução: Desde a descoberta do HIV, na década de 1980, o vírus tornou-se uma preocupação global de saúde pública. Atualmente, estima-se que 38 milhões de pessoas estejam vivendo com o HIV. Desafios persistem, bem como a progressão para a fase AIDS e sua relação com as doenças oportunistas vigentes. Estas surgem no contexto do comprometimento do sistema imunológico do indivíduo, como consequência do HIV não controlado, sendo identificada a fase AIDS. Objetivo: Apresentaremos um relato de caso de coinfecção neurocriptococose, paracoccidioidomise e citomegalovirose em um paciente, portador de HIV em fase AIDS, internado na enfermaria do serviço de infectologia do Hospital Heliópolis-SP. Método: Realizada coleta de dados, revisão de prontuário e pesquisa bibliográfica sobre HIV/AIDS e doenças oportunistas. O estudo foi feito mediante obtenção de Termo de Consentimento Livre e Esclarecido em que o paciente autoriza utilização de dados clínicos. Resultados: Paciente, masculino, 22 anos, natural de Ribeirão Pires (SP). Procurou o pronto atendimento do Hospital Heliópolis devido quadro de emagrecimento não intencional progressivo, há um ano, com perda acentuada de 10 quilos nos últimos quatro meses. Associados, apresentava cefaleia de forte intensidade, febre não aferida no período. No PS, evolui com náuseas, dois episódios de convulsão tônico-clônica generalizada, alteração de comportamento agressivo e rebaixamento do nível de consciência. Realizado rastreio infeccioso com sorologia reagente para HIV. Coleta de liquor realizada em âmbito de internação com antígeno criptocócico positivo. Iniciado tratamento para neurocriptococose, com rastreio para demais infecções oportunistas, evidenciando PCR-CMV sérico positivo com alta carga viral. Instituído tratamento para a citomegalovirose disseminada. Na evolução, há o aparecimento de lesões ulcerosas e vesiculares em dorso com realização de biópsia. Sendo evidenciado Paracoccidioides brasiliensis, em resultado anatomopatológico. Finalizados os tratamentos em regime de internação, com melhora clínica, paciente continua com seguimento clínico e tratamento no ambulatório do serviço de infectologia. Paciente em uso regular de TARV e melhora do status imunológico. Conclusão: O rastreio infeccioso das doenças oportunistas e seus tratamentos, como do próprio HIV, reduzem a morbimortalidade dos pacientes, trazendo aumento da sobrevida e controle da sua doença de base.

Introdução: Os Beta-lactâmicos (BL) são amplamente usados contra bactérias, as quais podem ter resistência por meio da produção de Beta-lactamase. Para isso dispõe-se de Beta-lactâmicos + Inibidor da Beta-lactamase: a Piperacilina-Tazobactam, por exemplo, inibe a enzima que degrada o BL. Dentre as reações adversas a esse antimicrobiano, a mielotoxicidade é pouco comum; há relatos de 1-4% de frequência da população geral. Objetivo: Relatar caso de efeito adverso raro do uso da Piperacilina-Tazobactam e contribuir para comunidade científica. Método: Relato de caso realizado no Hospital Heliópolis-SP, após aplicação do Termo de Comprometimento Livre e Esclarecido. Resultados: Masculino, 40 anos, queixa de edema, hiperemia e dor no membro inferior direito (MID), associado a febre e náuseas. Ao exame físico, área hiperemiada, não delimitada, dolorosa, edemaciada, se estendendo da perna até metade da coxa e prejudicando o movimento. Paciente é internado para tratamento de celulite com Oxacilina, apresentando reação de hipersensibilidade e necessidade de troca para Daptomicina. Após 5 dias, evoluiu com piora da infecção, associando-se Piperacilina-Tazobactam para cobertura de germes gram negativos. Após 15 dias, de tratamento com Piperacilina-Tazobactam, inicia febre, sem piora clínica e com neutropenia intensa (80/mm³), anemia (HB:10,9 mg/dl) e plaquetopenia (132 mil cels/mm³). Optado por suspensão das drogas e manutenção da internação hospitalar para avaliar evolução. Paciente evolui com ascensão das linhagens hematológicas para níveis normais, resolução da febre e melhora de lesão em MID, recebendo alta hospitalar. Conclusão: O uso frequente de antimicrobianos, requer conhecimento sobre farmacocinética, farmacodinâmica e farmacovigilância, tal qual dos beta lactâmicos, deve ser acompanhado da ciência das possíveis reações adversas, sendo que até mesmo as mais raras podem estar presentes no uso cotidiano dessa classe. Ao se deparar com uma evolução incomum de mielotoxicidade durante o tratamento de uma infecção, é necessário avaliar a gravidade da doença no momento e os riscos e benefícios da suspensão dos antimicrobianos em uso. No caso relatado, com a interrupção da Piperacilina-Tazobactam, a celulite não se exacerbou e a mielotoxicidade se resolveu, prevenindo um desfecho de maior gravidade que poderia decorrer da intensa pancitopenia.

Introdução: A COVID-19 se tornou um problema mundial em 2020, a ciência necessitou de medidas rápidas, surgindo a vacina, que reduz a morbimortalidade. Com o aumento do volume de informações sobre este assunto e a multiplicação exponencial de falsas notícias, a infodemia se tornou um problema, e a vacinação passou a ser rejeitada pela maioria dos brasileiros. Com o trabalho do Ministério da Saúde (MS), as informações falsas foram aos poucos combatidas. No Brasil, o esquema preconizado pelo MS para pessoas acima de 05 anos, são de 02 doses, com um reforço anual para os grupos prioritários, incorporando em 2024 no calendário vacinal, crianças a partir de 6 meses e 4 anos, tendo uma cobertura vacinal de 84,34%, indo acima das expectativas esperadas. Objetivo: O presente trabalho busca elucidar e analisar os dados da vacinação no Estado de São Paulo. Método: Estudo retrospectivo com base no sistema de Cobertura Vacinal do SUS, disponível gratuitamente de acesso livre, com dados obtidos em 12 de abril de 2024. Resultados: O Estado de São Paulo possui cobertura vacinal monovalente com 2 doses é de 94,16%; 3 doses com 63,86% e 21,16% 4 doses, totalizando 44.059.487 indivíduos imunizados, para uma população total de 44.411.238, abatendo a meta de 90% estabelecida pelo Departamento do Programa Nacional de Imunizações. A única faixa etária abaixo do esperado são as crianças menores de 5 anos. Conclusão: O aumento do bombardeamento de informações na mídia social, impacta negativamente a cobertura vacinal, somado a desinformação e alienação. Apesar do Estado de São Paulo atingir a meta preconizada apenas em 2022, outros estados ainda sofrem com a baixa cobertura vacinal, tornando a imunização de rebanho ineficaz. A desinformação somada à suspeita da eficácia e aflição perante ao novo calendário vacinal, gera um grande impacto em menores de 05 anos, conferindo as doenças reemergentes. Sugere-se continuidade de estudos na área para elucidar fatores biopsicossociais.

Introdução: A febre oropouche é uma arbovirose causada pelo vírus Oropouche (OROV) que é transmitida, principalmente, pela picada do mosquito Culicoides paraenses, conhecido como maruim ou mosquito-pólvora. No ciclo urbano, o mosquito Culex quinquefasciatus também pode atuar como vetor da doença. Os primeiros casos no país foram notificados durante a construção da rodovia Belém-Brasília, nos anos de 1950 e desde então, surtos esporádicos foram relatados em alguns estados da região amazônica. A doença manifesta-se como um quadro febril agudo, similar ao causado pela dengue, associado a sintomas como cefaleia, mialgia, artralgia, mal-estar, tontura, náuseas e vômitos, sendo um desafio distinguir a febre oropouche de outras arboviroses comuns no Brasil. Dessa forma, o diagnóstico deve considerar o uso de exames laboratoriais específicos, sejam eles sorológicos ou moleculares, como o RT-PCR. Geralmente a doença é autolimitada e seu tratamento baseia-se no uso de sintomáticos. Objetivo: Analisar e identificar o perfil epidemiológico da febre oropouche no Brasil e compreender o aumento do número de casos no ano de 2024. Método: O estudo foi desenvolvido com base na análise do Informe Semanal sobre Arboviroses do Centro de Operações de Emergências do Ministério da Saúde (MS) publicado em 25 de abril de 2024. Resultados: Em 2023, 835 amostras tiveram diagnóstico laboratorial detectável para o vírus Oropouche no Brasil. Em 2024, foram notificados 3.861 casos confirmados entre as semanas epidemiológicas 01 e 16, sendo 2.791 no Amazonas, 734 em Rondônia, 154 na Bahia, 139 no Acre, 28 no Pará, 10 no Piauí e 05 em Roraima. A maioria dos casos tiveram como local provável de infecção os estados localizados na região amazônica, inclusive aqueles notificados em outras regiões, em pessoas que visitaram esses estados. No entanto, a transmissão em estados extra-amazônicos, como Bahia e Piauí, foi notificada pelo MS em 2024. Conclusão: Os casos de febre oropouche concentram-se, ainda hoje, nos estados da região amazônica, apesar do potencial crescente em expandir sua distribuição no país. Dessa forma, o aumento do número de casos em relação aos anos anteriores pode refletir o impacto das mudanças climáticas e do desmatamento nessas regiões, assim como a melhora nos sistemas de vigilância e diagnóstico das arboviroses no Brasil.

Introdução: A tuberculose é uma doença que pode se apresentar com diversidade clínica, mimetizando outras patologias, a depender do órgão acometido. Dentre os casos, 90% apresentam a forma pulmonar, manifestando-se com tosse prolongada, astenia, fadiga, e perda de peso, raramente apresentaram manifestações endócrino metabólicas, porém são descritas: insuficiência adrenal, secreção inapropriada do hormônio antidiurético (SIHAD), hipercalcemia, tireoidopatias e hipopituitarismo. A SIHAD, ocorre por mecanismos patológicos em que o aumento do hormônio vasopressina, acarreta em inibição da diurese e consequentemente diluição do sódio. Objetivo: O presente trabalho busca contribuir com a comunidade científica, relatando manifestação incomum da tuberculose pulmonar. Método: Relato de caso realizado no Instituto de Assistência Médica ao Servidor Público Estadual de São Paulo - IAMSPE, aplicado o Termo de Comprometimento Livre e Esclarecido. Resultados: Masculino, 67 anos, hipertenso, diabético tipo 2, em uso de losartana e metformina, interna em enfermaria de Doenças do Aparelho Respiratório para tratamento de Tuberculose Pulmonar, em uso do esquema RIPE, dose otimizada. Evolui com hiponatremia de 118 mg/dl, assintomático, de forma crônica. Exames laboratoriais revelam hiponatremia hiposmolar, osmolaridade sérica de 258 mOsm/L, osmolaridade urinária 344 mOsm/Kg, paciente euvolêmico, com perda urinária de sódio, ACTH, função tireoideana e cortisol, dentro dos valores de referência, marcadores tumorais dentro da normalidade e sorologias negativas. Exames de imagem revelam tomografia de tórax com árvore em brotamento e caverna, tomografia de abdome sem alterações, após descartar outras causas, diagnosticando SIADH. Paciente sendo assistido por equipe multidisciplinar de nefrologia, endocrinologia e nutrição. Iniciou reposição com salina hipertônica, restrição hídrica, diuréticos e continuidade do tratamento para tuberculose pulmonar. Conclusão: As manifestações endócrino-metabólicas da tuberculose não são levadas em consideração pela maioria dos profissionais. A SIHAD, um distúrbio metabólico que pode ser fatal, merece atenção e individualização. Após tratamento para causa base, paciente apresenta melhora de natremia.

Objetivos: A trombofilia é uma condição onde se tem maior propensão a eventos tromboembólicos, seja genética ou adquirida, de formar trombos. Isso se deve a uma anormalidade no sistema de coagulação sanguínea. Nas gestantes é uma das principais causas de aborto de repetição e há risco de morte materna, sendo durante a gestação o risco de tromboembolismo venoso aumenta de 5 a 10 vezes e no puerpério, aumentam 20 vezes. Trata-se de uma condição que pode ser silenciosa, dificultando o diagnóstico precoce e, portanto, o acompanhamento gestacional de forma contínua desde o início da gestação é fundamental. A perda fetal pode ser explicada pela formação de trombos venosos intraplacentários e infartos placentários, que podem levar a insuficiência placentária. Além disso, essa condição aumenta os riscos de AVC, pré-eclâmpsia, embolia pulmonar, trombose e IAM. Diante disso, a elaboração de materiais de orientação sobre essa doença é estratégica, sendo o farmacêutico essencial para a confecção de materiais, orientação ao paciente e no acompanhamento durante o tratamento utilizando sua formação, minimizando riscos para a mãe e o bebê. Este trabalho visa apresentar as estratégias criadas para melhorar a adesão e orientações para acompanhamento de pacientes gestantes, diante dessa fase que requer mais cuidado e atenção à saúde e onde podem surgir algumas intercorrências, como é o caso da tromboembolismo. Material e métodos: Utilizou-se uma revisão bibliográfica, utilizando fontes como, Scielo e Pubmed, como descritores: trombofilia relacionada a gestação e ou pré-natal. Foram criados formulários com perguntas estruturadas para identificar fatores de risco, orientações sobre exames laboratoriais, e estratégias de prevenção e tratamento da trombofilia. Resultados: Os formulários foram desenvolvidos para fornecer orientações claras e práticas para gestantes em risco de trombofilia, considerando variáveis como histórico familiar, sintomas, e resultados de testes laboratoriais. Os documentos focaram na necessidade de personalização das orientações, considerando a diversidade de perfis clínicos e a importância da comunicação eficaz incluindo a atenção ambulatorial, hospitalar e domiciliar. Discussão: Tendo em vista que ainda existem pessoas que não realizam o pré-natal por diversos motivos, falta de conhecimento, socioeconômico, idade, falta de apoio familiar ou de um parceiro, entre outros. Com isso, fica nítido a importância da difusão de informação e a implementação de lembretes e alertas para monitoramento contínuo foi destacada como uma estratégia para garantir a adesão ao pré-natal e a eficácia das medidas preventivas no período gestacional. Conclusão: Os formulários mostraram-se ferramentas úteis para padronizar a orientação de pacientes gestantes e garantir a consistência no manejo da trombofilia. A utilização de formulários contribui para uma melhor organização do atendimento e pode melhorar a detecção precoce de riscos. A integração desses formulários nas práticas clínicas e outras medidas como explicação de como usar corretamente o medicamento deve ser priorizada pelo farmacêutico a fim melhorar a adesão, somada às estratégias mencionadas. pode potencialmente reduzir complicações associadas à trombofilia e melhorar os desfechos para as gestantes.

Prior studies suggest that the reductions in physical activity during Covid-19-related lockdowns impacted physical and mental health. Whether reductions in physical activity that occurred during lockdowns also relate to cognitive functions such as memory and attention is less explored. Here, we investigated whether changes in physical activity (PA) that occurred during and following Covid-19-related lockdowns could predict a variety of measures of cognitive performance in 318 young adults. Participants were assessed on their engagement in PA before, during, and after lockdowns. They also completed tests of cognitive control, working memory, and short-term memory following lockdown(s). As expected, engagement in PA decreased during lockdown and returned to near baseline levels thereafter. Decreases in PA during lockdown predicted individual differences in cognitive performance following lockdown. Greater reductions in PA during lockdown were associated with lower scores on the go/no-go task, a measure of cognitive control ability, and the n-back task, a measure of working memory performance. Larger post-lockdown increases in PA were associated with higher scores on the same tasks. Individual differences in pandemic-related stress and insomnia also predicted cognitive outcomes. These findings suggest that reductions of PA can predict cognitive performance, and underscore the importance of maintaining PA for cognitive health, especially in situations such as lockdowns.

While the significance of obtaining restful sleep at night and maintaining daytime alertness is well recognized for human performance and overall well-being, substantial variations exist in the development of sleepiness during diurnal waking periods. Despite the established roles of the hypothalamus and striatum in sleep-wake regulation, the specific contributions of this neural circuit in regulating individual sleep homeostasis remain elusive. This study utilized resting-state functional magnetic resonance imaging (fMRI) and mathematical modeling to investigate the role of hypothalamus-striatum connectivity in subjective sleepiness variation in a cohort of 71 healthy adults under strictly controlled in-laboratory conditions. Mathematical modeling results revealed remarkable individual differences in subjective sleepiness accumulation patterns measured by the Karolinska Sleepiness Scale (KSS). Brain imaging data demonstrated that morning hypothalamic connectivity to the dorsal striatum significantly predicts the individual accumulation of subjective sleepiness from morning to evening, while no such correlation was observed for the hypothalamus-ventral striatum connectivity. These findings underscore the distinct roles of hypothalamic connectivity to the dorsal and ventral striatum in individual sleep homeostasis, suggesting that hypothalamus-dorsal striatum circuit may be a promising target for interventions mitigating excessive sleepiness and promoting alertness.

Objectives: This study assesses exposure to malaria vector mosquitos that is nonpreventable through use of nets, the contribution of outdoor and indoor biting towards residual vector exposure, and the risk factors for being bitten and for being infected with malaria parasites on Bioko Island, Equatorial Guinea. Methods: Human behavior and malaria infection data were collected from 13,735 randomly selected residents during cross-sectional surveys, concomitantly with entomological human landing catches, indoors and outdoors, in 20 locations on the Island. Self-reported time of going indoors, going to bed and whether using a net were analyzed to impute for each respondent the number of bites received outdoors and indoors during the night before the survey. Results: On average, each person received 2.7 (95% CI: 2.6-2.8) bites per night outdoors, 8.5 (8.3 to 8.7) bites indoors if not using a net, and 4.7 (4.5 to 4.8) bites indoors if using a net. Malaria infection was associated with more bites, regardless of whether received indoors or outdoors. Older age, male gender, not using a net, rural location, and going indoors later increased the risk of being bitten. The proportion of bites not averted by using a net was estimated as 66% (61 to 71). Conclusions: A large proportion of biting, mostly indoors, may not be preventable by bednets. Tools targeting indoor biting should be prioritized in Bioko. Novel vector control tools are urgently needed to reduce overall exposure to mosquito bites.

Background & Aims: Although most hepatocellular carcinoma (HCC) cases are driven by hepatitis and cirrhosis, a subset of patients with chronic hepatitis B develop HCC in the absence of advanced liver disease, indicating the oncogenic potential of hepatitis B virus (HBV). We investigated the role of HBV transcripts and proteins on HCC development in the absence of inflammation in HBV-transgenic mice. Methods: HBV-transgenic mice replicating HBV and expressing all HBV proteins from a single integrated 1.3-fold HBV genome in the presence or absence of wild-type HBx (HBV1.3/HBVxfs) were analyzed. Flow cytometry, molecular, histological and in vitro analyses using human cell lines were performed. Hepatocyte-specific Stat3- and Socs3-knockout was analyzed in HBV1.3 mice. Results: Approximately 38% of HBV1.3 mice developed liver tumors. Protein expression patterns, histology, and mutational landscape analyses indicated that tumors resembled human HCC. HBV1.3 mice showed no signs of active hepatitis, except STAT3 activation, up to the time point of HCC development. HBV-RNAs covering HBx sequence, 3.5-kb HBV RNA and HBx-protein were detected in HCC tissue. Interestingly, HBVxfs mice expressing all HBV proteins except a C-terminally truncated HBx (without the ability to bind DNA damage binding protein 1) showed reduced signs of DNA damage response and had a significantly reduced HCC incidence. Importantly, intercrossing HBV1.3 mice with a hepatocyte-specific STAT3-knockout abrogated HCC development. Conclusions: Expression of HBV-proteins is sufficient to cause HCC in the absence of detectable inflammation. This indicates the oncogenic potential of HBV and in particular HBx. In our model, HBV-driven HCC was STAT3 dependent. Our study highlights the immediate oncogenic potential of HBV, challenging the idea of a benign highly replicative phase of HBV infection and indicating the necessity for an HBV ‘cure’. Impact and implications: Although most HCC cases in patients with chronic HBV infection occur after a sequence of liver damage and fibrosis, a subset of patients develops HCC without any signs of advanced liver damage. We demonstrate that the expression of all viral transcripts in HBV-transgenic mice suffices to induce HCC development independent of inflammation and fibrosis. These data indicate the direct oncogenic effects of HBV and emphasize the idea of early antiviral treatment in the ‘immune-tolerant’ phase (HBeAg-positive chronic HBV infection).

Background: The well-established connection between oral bacteria and infective endocarditis (IE) has prompted discussions about using antibiotic prophylaxis (AP) before invasive dental procedures. In 2007/2008, guidelines restricted AP from moderate and high-risk to exclusively high-risk patients. Objectives: The authors aimed to assess whether the proportion of oral streptococcal IE increased in moderate-risk patients using University Hospital Zurich data from 2000 to 2022. Methods: Adult IE patients were categorized into risk groups based on European Society of Cardiology and Swiss guidelines. The investigation focused on analyzing the proportion of oral streptococcal IE across different risk groups in two distinct periods (1: 2000-2008; 2: 2009-2022). Logistic regression models, adjusted for various factors, were employed. Results: Of 752 IE cases, 163 occurred in period 1, and 589 in period 2. Oral streptococci caused 22% of cases. Proportions of streptococcal IE in period 1 versus period 2 were 24% versus 16% in high-risk, 24% versus 39% in moderate-risk, 33% versus 7% in low-/unknown-risk, and 18% versus 14% in no-risk patients. Compared to the other risk groups, the moderate-risk group had a 22% higher chance of oral streptococcal IE in period 2. After multivariable adjustment, moderate-risk patients had twice the risk of oral streptococcal IE compared to period 1 (OR: 2.59 [95% CI: 1.16-5.81]). Among moderate-risk conditions, congenital valve anomalies were associated with oral streptococcal IE (unadjusted OR: 2.52 [95% CI: 1.71-3.71]). Conclusions: Oral streptococcal IEs increased in the moderate-risk group of patients after the AP guideline change. Exploring the potential necessity for expanding AP indications to certain patient groups with congenital valve anomalies may be warranted.

Human papillomaviruses (HPV) cause 99% of all cervical cancer cases globally, with the high-risk genotypes 16 and 18 causing at least 70% of these cases. An estimated 90% of the global cervical cancer burden occurs in low-to-middle-income countries (LMICs), particularly in sub-Saharan Africa (SSA). Primary prevention through the administration of efficacious HPV vaccines is key to the World Health Organization’s global strategy for accelerating the elimination of cervical cancer as a disease of public health concern. The rollout of HPV vaccination in SSA is faced with several challenges, such as the high cost of vaccine procurement, a lack of funding and political will from the central governments of countries, and inadequate infrastructure for vaccine cold chain storage and transport. Stigma, misinformation, lack of education and awareness, and vaccine hesitancy constitute the social factors that affect the successful rollout or implementation of vaccination programs in SSA. Based on the challenges SSA faces in rolling out HPV vaccination, we recommend using strategies that address both the demand-side and supply-side obstacles to HPV vaccination uptake. These include costs and availability, fighting vaccine hesitancy, and increasing vaccine confidence.

Objectives: Postoperative atrial fibrillation (POAF) is the most common perioperative arrhythmia. The association of POAF with negative short-term outcomes after cardiac surgery is well understood; however, the association of POAF with long-term morbidity and mortality is not well described. We compared the risk of long-term clinical outcomes (up to 9 years postdischarge) in patients with and without POAF following open-chest cardiac surgery. Methods: This observational, retrospective cohort study used data from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) Swedish Cardiac Surgery Registry and National Board of Health and Welfare. Patients aged 55 to 90 years who underwent open-chest coronary artery bypass and/or valvular surgery between 2010 and 2019 were included. Clinical outcomes were adjusted for differences in baseline demographics and clinical history using multivariable Cox regression. Results: A total of 30,870 patients with a mean age of 69.2 years were included in the study (no POAF, n = 20,734; POAF, n = 10,136). The median follow-up was 4.6 years. After adjustment, POAF was associated with a significantly higher risk of recurrent atrial fibrillation (hazard ratio [HR], 2.30; 95% CI, 2.21-2.41), heart failure (HR, 1.17; 95% CI, 1.10-1.25), chronic kidney disease (HR, 1.15; 95% CI, 1.07-1.24), all-cause mortality (HR, 1.11; 95% CI, 1.04-1.18), and cardiovascular mortality (HR, 1.16; 95% CI, 1.06-1.26). POAF was also associated with a numerically higher risk of ischemic stroke and major bleed, but these findings were not statistically significant after adjustment. Conclusions: These data provide further insight into the long-term clinical outcomes associated with POAF in patients undergoing cardiac surgery.

Background/Objective: Immune checkpoint inhibitors (ICI), including Programmed Cell Death 1, Programmed Cell Death Ligand 1, and Cytotoxic T-lymphocyte Associated Antigen 4 inhibitors, upregulate T-cell responses against tumor cells and are becoming a cornerstone in the treatment of various advanced solid and hematological cancers. Mulvihill-Smith Syndrome (MSS) is a rare genetic syndrome that has been associated with metabolic abnormalities and early-onset tumors, including malignancies. We report the first known case of ICI-induced hyponatremia attributable to syndrome of inappropriate antidiuretic hormone ADH release (SIADH) in a patient with MSS. Case Report: A 23-year-old female patient with MSS and hepatocellular carcinoma presented with recurrent hyponatremia. Assessment of fluid status and electrolytes revealed a euvolemic, hypotonic process consistent with SIADH shortly after initiating adjuvant therapy with atezolizumab, a Programmed Cell Death Ligand 1 inhibitor. Discussion: Endocrine etiologies for euvolemic hypotonic hyponatremia, including adrenal insufficiency and hypothyroidism, were excluded. The diagnosis of SIADH was confirmed based on electrolyte and osmolality studies. Sodium levels normalized with fluid restriction. Given the onset of hyponatremia 30 days after atezolizumab initiation, we posit that atezolizumab triggered severe hyponatremia due to SIADH. Conclusion: With the expanding utilization of ICIs, including in patients predisposed to malignancies such as MSS, vigilant monitoring for ICI-mediated electrolyte imbalances is crucial. Monitoring for hyponatremia and SIADH in the setting of ICI therapy is recommended.

Background: Restoring a functional dermis following extensive, deep wounds, such as those caused by severe burns, presents a significant reconstructive challenge. Although split thickness skin graft (STSG) and full thickness skin graft (FTSG) can provide adequate coverage, dermal templates are becoming increasingly important in restoring function. The purpose of this systematic review is to assess the efficacy, advantages and limitations of employing NovoSorb® Biodegradable Temporizing Matrix (BTM) in the treatment of complex wounds. Methods: The systematic review was carried out in accordance with PRISMA and MOOSE guidelines when appropriate. All studies until April 2024 involving patients treated with NovoSorb® BTM were considered. Infection, adverse events, and BTM loss were among the outcomes evaluated. Results: We identified 725 studies, and 69 were included after screening. The included studies involved 880 participants and were mostly concerned with the management of burns, but other difficult wounds were also addressed. The infection rate was 10%, yet only few reported losing their BTM as a result of this consequence. The incidence of adverse events was low, with the majority of trials reporting no adverse events related to BTM. Conclusion: Our systematic review focused primarily on case series and case reports that demonstrated the efficacy of Novosorp BTM and the rarity of side effects. However, there were very few comparison research. More research is needed to fully analyze the efficacy, limitations, and downsides of using Novosorb (BTM).

Therapeutic Area: ASCVD/CVD Risk Factors Background: The American Heart Association (AHA) recently updated its Life's Simple 7 (LS7) cardiovascular health metric to Life's Essential 8 (LE8) by including sleep health and recognition of psychosocial influences on cardiovascular health. African American adults face psychosocial and structural factors affecting sleep and the achievement of optimal cardiovascular health; thus, we examined the correlation between LS7 and LE8 scores in a community sample of African American adults. Methods: Demographic, behavioral (e.g., diet), and clinical (e.g., lipids) measures were collected from African American adults at 16 churches in Minnesota as part of a randomized controlled trial (FAITH! Trial) and an accompanying ancillary study (Heart Health+). We computed LS7 (range: 0-14) and LE8 scores (range: 0-100), indicating low to high cardiovascular health, as per AHA recommendations. Pearson correlation was used to assess the linear correlation between the two cardiovascular health scores. Results: Participants (N=58) were predominantly female (67%), with a mean age of 54 (SD 12) years and high cardiometabolic risk (93% had overweight/obesity) (Table 1). Mean composite LS7 and LE8 scores were 6.7 [1.9] and 56.9 [11.6], respectively. Mean LE8 scores were highest for tobacco/nicotine exposure (84.1 [24.2]) and lowest for diet (30.3 [12.4]). LE8 was strongly correlated with LS7 (r=0.84, p

Background and purpose: In a relevant number of primary breast cancer patients, lymphatic drainage to the contralateral internal mammary nodes (cIMN) is being observed. Nevertheless, so far lymphatic drainage pathway to the cIMN is largely neglected during adjuvant radiotherapy. Materials and methods: This study evaluated the incidental dose to the cIMN for 120 volumetric modulated arc therapy (VMAT) treatment plans for node positive breast in dependence of internal mammary node irradiation (IMNI) and deep inspiration breath hold (DIBH). Additionally, incidental dose distribution to the cIMN based on the field design in the MA20, EORTC22922/10925 and AMAROS trials was assessed. Results: The incidental dose (Dmean ± SD) to the cIMN-CTV was 13.0 (±4.7) Gy with a maximum dose of

In cancer molecular imaging, selecting binders with high specificity and affinity for biomarkers is paramount for achieving high-contrast imaging within clinical time frames. Nanobodies have emerged as potent candidates, surpassing antibodies in pre-clinical imaging due to their convenient production, rapid renal clearance, and deeper tissue penetration. Multimerization of nanobodies is a popular strategy to enhance their affinity and pharmacokinetics; however, traditional methods are laborious and may yield heterogeneous products. In this study, we employ a Holliday junction (HJ)-like nucleic acid-based scaffold to create homogeneous nanostructures with precise multivalent and multiparatopic nanobody displays. The plug-and-play assembly allowed the screening of several nanobody multimer configurations for the detection of the breast cancer biomarker, human epidermal growth factor receptor 2 (HER2). In vitro studies demonstrated significant improvements in binding avidity, particularly with the biparatopic construct exhibiting high sensitivity, surpassing that of traditional antibody-based cell binding. Furthermore, our HJ platform allowed for adaptation from fluorescence-based to nuclear imaging, as demonstrated in xenografted mice, thereby allowing for future in vivo applications. This work highlights the potential of nucleic acid-mediated multimerization to markedly enhance nanobody binding, by exploring synergistic combinations and offering versatility for both in vitro diagnostics and cancer molecular imaging with prospects for future theranostic applications.

Summary: Background: Female mice are more resistant to obesogenic effects of a high-fat diet (HFD), compared to male mice. Although the underlying mechanisms are poorly understood, sex hormones seem to play an important role. Interestingly, the activity of the oestrogen receptor-α (ERα) is affected by the calcium-sensing-receptor (CaSR). Therefore, we investigated sex-differences upon diet-induced obesity and the role of adipocyte-specific CaSR herein. Methods: Adipocyte-specific Casr deficient mice (AdipoqCre+Casrflox) and control mice (Casrflox) were injected with AAV8-PCSK9 to make them prone to develop atherosclerosis and fed an obesity-inducing diet for 12 weeks. Findings: Female mice have lower visceral white adipose tissue (vWAT) mass compared to male mice, while this sex-difference is abolished upon adipocyte-specific Casr deficiency. Furthermore, while females showed elevated levels of inflammatory cytokines and CD3+CD8+ T cell accumulation in vWAT, compared to males, adipocyte-specific Casr deficiency abrogated this sex-phenotype and demonstrated an inhibition of inflammatory signalling pathways. The expression of Erα, as well as associated genes involved in adipocyte differentiation, was increased in female mice in a mostly adipocyte-specific Casr dependent manner. Interestingly, circulating lipid levels were reduced in female compared to male mice, which correlated with decreased atherosclerotic plaque formation. These systemic effects were abrogated upon adipocyte-specific Casr deficiency. Interpretation: Our findings indicate that female mice show a more pronounced vWAT dysfunction compared to males upon obesity. This sex effect is abolished upon adipocyte-specific Casr deficiency. In contrast, females show diminished atherosclerotic plaque formation compared to males, an effect that was abrogated by adipocyte-specific Casr deficiency. Funding: This work was supported by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University, by the Corona Foundation, by the Deutsche Forschungsgemeinschaft (DFG), the BMBF and Free State of Bavaria and the DZHK.

Urban mobility planning is increasingly characterized by the pressure to establish low-emission, space-efficient, and socially inclusive transport services. One such planning task for decision-makers in public institutions is the efficient design of bicycle-sharing networks. This study examines the factors that influence decision-making in this process, both among practitioners and within the research literature on decision support systems (DSS). Employing a dual approach of academic literature review and 16 qualitative interviews with public sector planners, we identify and compare different dimensions of key factors affecting location choice. The results reveal significant contrasts, for instance, between the emphasis placed by academic researchers on ensemble optimization of quantifiable factors and the more target-complex, intuitive approaches pursued by public planning practitioners. We blend core characteristics from both perspectives in a synthesis analysis. We argue that future efforts should aim for more vertical planning assistance, citizen involvement for diversified demand indications, integration of local factors into DSS, and standardized data formats to enable better DSS integration. Our study offers a rare qualitative insight into a complex choice problem faced by public decision-makers, linked with predominantly quantitative research.