Influence of the COVID-19 pandemic on the defined daily dose of antimicrobials in patients requiring elective and emergency surgical procedures.

BACKGROUND: The COVID-19 pandemic has resulted in great incertitude and overwhelming changes in healthcare that have had a direct impact on antibiotic prescription. However, the influence of this pandemic on antibiotic consumption in patients undergoing surgery has not yet been analysed. The goal of this study was to analyse antimicrobial consumption and prescription in the same period of 2019 (pre-COVID-19), 2020 (beginning of the COVID-19 pandemic) and 2021 (established COVID-19) according to the DDD system in surgical patients at a tertiary-level hospital. METHODS: A prospectively maintained database was analysed. All patients who underwent elective or emergency gastrointestinal surgery during the same period (2019, 2020 and 2021) were included. Those who received at least 1 of the 10 most frequently prescribed antimicrobials during those periods were analysed. RESULTS: A total of 2975 patients were included in this study. In 2020, the number of procedures performed decreased significantly (653 versus 1154 and 1168 in 2020 versus 2019 and 2021, respectively; P = 0.005). Of all patients who underwent surgery during these periods, 45.08% received at least one of the antimicrobials studied (45.8% in 2020 versus 22.9% and 22.97% in 2019 and 2021, respectively; P = 0.005). Of these, 22.97% of the patients received a combination of these antimicrobials, with ceftriaxone/metronidazole being the most frequent. Hepato-Pancreato-Biliary and Liver Transplant, Emergency Surgery and Colorectal Surgery units had higher antibiotic consumption. CONCLUSIONS: The COVID-19 pandemic has resulted in a significant decrease in surgical activity and higher post-operative antimicrobial prescription compared with previous and subsequent years.

Switchable CAR T cell strategy against osteosarcoma.

Immunotherapy with chimeric antigen receptor T (CAR T) cells has changed the treatment of hematological malignances, but they are still a challenge for solid tumors, including pediatric sarcomas. Here, we report a switchable CAR T cell strategy based on anti-FITC CAR T cells and a switch molecule conjugated with FITC for targeting osteosarcoma (OS) tumors. As a potential target, we analyzed the expression of B7-H3, an immune checkpoint inhibitor, in OS cell lines. In addition, we evaluate the capacity of an anti-B7-H3 monoclonal antibody conjugated with FITC (anti-B7-H3-FITC mAb) to control the antitumor activity of anti-FITC CAR T cells. The effector functions of anti-FITC CAR T cells against OS, measured in vitro by tumor cell killing activity and cytokine production, are dependent on the presence of the anti-B7-H3-FITC mAb switch. Moreover, OS cells stimulate anti-FITC CAR T cells migration. In vivo, anti-B7-H3 mAb penetrates in the tumor and binds 143B OS tumor cells. Furthermore, anti-FITC CAR T cells reach tumor region and exert antitumor effect in an OS NSG mouse model only in the presence of the switch molecule. We demonstrate that anti-B7-H3-FITC mAb redirects the cytotoxic activity of anti-FITC CAR T cells against OS tumors suggesting that switchable CAR T cell platforms might be a plausible strategy against OS.

Stability of temocillin in outpatient parenteral antimicrobial therapy: is it a real option?

BACKGROUND: Temocillin is an interesting alternative to carbapenems for susceptible Enterobacteriaceae. Although its use in outpatient parenteral antimicrobial therapy (OPAT) programmes has generated interest, this has been hampered by the lack of stability data. OBJECTIVES: The purpose of the present study was to evaluate the physical and chemical stability of temocillin at the recommended dose for its use in OPAT programmes, contained in polypropylene infusion bags or polyisoprene elastomeric devices at different temperatures, and to describe a novel LC-MS/MS developed for the quantification of temocillin. METHODS: Temocillin daily dose (6 g) was diluted in 500 mL of 0.9% sodium chloride to obtain a final concentration of 12 g/L. This solution was stored at 4°C, 25°C, 32°C and 37°C for 72 h, both in polypropylene infusion bags and in polyisoprene elastomeric pumps. Physical and chemical stability were evaluated during 72 h after manufacturing. Solutions were considered stable if colour, clearness and pH remained unchanged and if the percentage of intact drug was ≥90%. RESULTS: Temocillin attained the chemical stability criterion of ≥90% of the original concentration for the whole experiment in both devices at 4°C, 25°C and 32°C. At 37°C, temocillin was stable for 24 h but its concentration dropped below 90% from that timepoint. No precipitation occurred and minor colour changes were observed. CONCLUSIONS: Temocillin is stable under OPAT conditions and it would be an appropriate candidate for the treatment of patients who can be discharged to complete therapy in an OPAT programme. For this study, an LC-MS/MS method was developed.

Public Health-Led Insights on Electric Micro-mobility Adoption and Use: a Scoping Review.

The advent of electric micro-mobility (EMM) has transformed the urban mobility landscape, with projections indicating a 5-10% increase in its modal share in European cities by 2030. In this scoping review, we aimed to comprehensively examine the key determinants of EMM adoption and usage from a public health perspective. Sixty-seven articles were included in the analysis, primarily covering e-bikes and e-scooters. The determinants were categorised into two broad categories: (1) contextual determinants that encompass enabling and hindering factors related to legal frameworks, transportation systems and infrastructure, and technology, and (2) individual-level determinants that pertain to intrinsic motivations and deterrents of individuals. Our findings reveal that EMM vehicles are widely perceived as a cost-effective, flexible, ad hoc, and fast mode of transportation within urban areas, augmenting accessibility and connectivity. Additionally, the lightweight, foldable, and transportable nature of these vehicles is highly appreciated by users. However, several barriers have also been identified, including inadequate infrastructure and end-of-trip facilities, limited capability to traverse diverse terrains and trip scenarios, acquisition and maintenance costs, limited carrying capacities, technical failures, and accident risks. Our results suggest that the interplay of contextual enablers and barriers and personal motivations and deterrents drive the emergence, adoption, and usage of EMM. Hence, a comprehensive understanding of both contextual and individual-level determinants is crucial for ensuring a sustainable and healthy uptake of EMM.

Personal strategies to mitigate the effects of air pollution exposure during sport and exercise: a narrative review and position statement by the Canadian Academy of Sport and Exercise Medicine and the Canadian Society for Exercise Physiology.

Air pollution is among the leading environmental threats to health around the world today, particularly in the context of sports and exercise. With the effects of air pollution, pollution episodes (eg, wildfire conflagrations) and climate change becoming increasingly apparent to the general population, so have their impacts on sport and exercise. As such, there has been growing interest in the sporting community (ie, athletes, coaches, and sports science and medicine team members) in practical personal-level actions to reduce the exposure to and risk of air pollution. Limited evidence suggests the following strategies may be employed: minimising all exposures by time and distance, monitoring air pollution conditions for locations of interest, limiting outdoor exercise, using acclimation protocols, wearing N95 face masks and using antioxidant supplementation. The overarching purpose of this position statement by the Canadian Academy of Sport and Exercise Medicine and the Canadian Society for Exercise Physiology is to detail the current state of evidence and provide recommendations on implementing these personal strategies in preventing and mitigating the adverse health and performance effects of air pollution exposure during exercise while recognising the limited evidence base.

Association between Vancomycin Pharmacokinetic Parameters and Clinical and Microbiological Efficacy in a Cohort of Neonatal Patients.

Vancomycin pharmacokinetic/pharmacodynamic (PK/PD) targets have not been validated in the neonatal population as no specifically designed studies are available. The main goal of this study was to analyze the therapeutic vancomycin regimen, the 24-h area under the curve (AUC24), and the trough plasma concentration (Ct) obtained that achieved clinical and microbiological effectiveness in a cohort of neonates. This was an observational, prospective, single-center study covering a period of 2 years. Eligible patients were neonates and young infants who were undergoing treatment with intravenous vancomycin for ≥72 h with ≥1 Ct available. The primary outcome was the association of Ct and AUC24 with clinical and microbiological efficacy at the beginning (early clinical evolution [ECE]) and the end (late clinical evolution [LCE]) of treatment with vancomycin. A total of 43 patients were included, 88.4% of whom were cured. In ECE, the cutoff points of the receiver operating characteristic (ROC) curve were 238 mg · h/L (sensitivity of 61% and specificity of 88%) for AUC24 and 6.8 µg/mL (sensitivity of 61% and specificity of 92%) for Ct. In LCE, the Ct value was 11 µg/mL, with a sensitivity of 80% and a specificity of 92%. In this analysis, AUC24 was not considered a good predictor. Logistic regression showed that a vancomycin Ct of ≤6.8 µg/mL was associated with an unfavorable ECE (P = 0.001), being 18 times more likely to progress poorly compared to those with higher levels. AUC24 and Ct are good predictors of ECE in this population. Concentrations close to 7 µg/mL and an AUC24 of around 240 mg · h/L 48 h after antibiotic initiation seem to be sufficient to achieve clinical cure in most cases.

Is Once-Daily High-Dose Ceftriaxone plus Ampicillin an Alternative for Enterococcus faecalis Infective Endocarditis in Outpatient Parenteral Antibiotic Therapy Programs?

Ceftriaxone administered as once-daily high-dose short infusion combined with ampicillin has been proposed for the treatment of Enterococcus faecalis infective endocarditis in outpatient parenteral antibiotic therapy programs (OPAT). This combination requires synergistic activity, but the attainment of ceftriaxone synergic concentration (Cs) with the regimen proposed for OPAT has not been studied. This phase II pharmacokinetic study enrolled healthy adult volunteers who underwent two sequential treatment phases. During phase A, volunteers received 2 g of ceftriaxone each 12 h during 24 h followed by a 7-day wash-out. Then the participants received phase B, which consisted of a single dose of 4 g of ceftriaxone. Throughout both phases, each volunteer underwent intensive pharmacokinetic (PK) sampling over 24 h. Ceftriaxone total and unbound concentrations were measured. Twelve participants were enrolled and completed both phases. Mean ceftriaxone total and free concentrations 24 h after the administration of 2 g each 12 h were 86.44 ± 25.90 mg/liter and 3.59 ± 1.35 mg/liter, respectively, and after the 4-g single dose were 34.60 ± 11.16 mg/liter and 1.40 ± 0.62 mg/liter, respectively. Only 3 (25%) patients in phase A maintained unbound plasma concentrations superior to the suggested Cs = 5 mg/liter during 24 h, and none (0%) in phase B. No grade 3 to 4 adverse events or laboratory abnormalities were observed. Ceftriaxone optimal exposure combined with ampicillin to achieve maximal synergistic activity against E. faecalis required for the treatment of infective endocarditis remains unknown. However, the administration of a single daily dose of 4 g of ceftriaxone implies a reduction in the time of exposure to the proposed Cs. (This study has been registered in the European Union Drug Regulating Authorities Clinical Trials [EudraCT] database under identifier 2017-003127-29.).

Sequence-based epidemiology of an OXA-48 plasmid during a hospital outbreak.

Objectives. A large OXA-48 outbreak in the Netherlands involved the spread of OXA-48producing Enterobacteriaceae among at least 118 patients, suggesting horizontal transfer of this resistance gene through one or more plasmids. Elucidating transmission dynamics of resistance plasmids is hampered by the low resolution of classic typing methods. This study aimed to investigate the molecular epidemiology of plasmids carrying OXA-48 carbapenemase using a next-generation sequencing approach.Methods. A total of 68 OXA-48-producing Enterobacteriaceae isolated from the hospital outbreak, as well as 22 non-outbreak related OXA-48-producing Enterobacteriaceae from the Netherlands, Libya and Turkey were selected. Plasmids were sequenced using the Illumina Miseq platform, and read sets were assembled and analysed.Results. In all plasmids bla OXA-48 was embedded in transposon Tn1999.2 and located on a ca. 62 kb IncL/M conjugative plasmid in 14 different species. There were a maximum of 2 SNPs (single nucleotide polymorphisms) between the core sequence alignment of all plasmids. Closely related sequence variants of this plasmid were detected in non-outbreak isolates from the Netherlands and other countries. Thirty-one of 89 OXA-48-producing isolates also harboured bla CTX-M-15, which was not located on the bla OXA-48-carrying plasmid. Sequencing of four plasmids harbouring bla CTX-M15 revealed extensive plasmid heterogeneity.Conclusions. A ca 62 kb plasmid was responsible for the OXA-48 outbreak in a Dutch hospital. Our findings provide strong evidence for both within-host inter-species and between host dissemination of plasmid-based OXA-48 during a nosocomial outbreak. These findings exemplify the complex epidemiology of carbapenemase producing Enterobacteriaceae (CPE).

Evaluation of risk factors associated to detection of Blastocystis sp. in fecal samples in population from Barcelona, Spain: a case-control study.

Blastocystis sp. is the most common intestinal parasite isolated in humans. The aim of the study was to describe the risk factors associated to Blastocystis sp. detection. A case-control retrospective study was carried out at Vall d'Hebron University Hospital (Barcelona, Spain), which receives all fecal samples collected in Barcelona at primary care level. Eligible patients were patients older than 18 years in whom three consecutive stool samples were examined for parasitic diagnosis from January to December 2017. Positive patients for Blastocystis sp. were assigned as cases whereas negative patients were assigned as controls. Overall, 4174 patients were eligible for the study, from whom 724 (17.3%) had Blastocystis sp. detection. From these, 170 cases (Blastocystis sp. positive) and 170 controls (Blastocystis sp. negative) were randomly selected for inclusion. One hundred and twenty-six (37.1%) of them were immigrants, and 171 (50.3%) patients had traveled out of Spain the year before. The majority of individuals had jobs with no direct contact with other people (health personnel, teachers, and caregivers) (85.6%), and 29.4% were in usual contact with animals. Regarding clinical information, 68.2% of patients presented digestive symptoms, 3.5% presented an immunosuppressant condition, and 6.5% were infected by other intestinal parasites. Variables associated to Blastocystis sp. detection were being born in Africa, having traveled abroad, and working in direct contact with other people. Having other intestinal parasitic infections had a protective value. Our study provides new insights into the epidemiology of Blastocystis sp. in industrialized countries.

Prevalence, risk factors and genetic characterisation of extended-spectrum beta-lactamase and carbapenemase-producing Enterobacteriaceae (ESBL-E and CPE): a community-based cross-sectional study, the Netherlands, 2014 to 2016.

BackgroundThe epidemiology of carriage of extended-spectrum beta-lactamase-producing (ESBL-E) and carbapenemase-producing Enterobacteriaceae (CPE) in the general population is unknown.AimIn this observational study, the prevalence and risk factors for intestinal ESBL-E and CPE carriage in the Dutch general population were determined. ESBL-E were characterised.MethodsFrom 2014 to 2016, ca 2,000 residents were invited monthly to complete a questionnaire and provide a faecal sample, which was tested for ESBL-E. The first 1,758 samples were also tested for CPE. Risk factors for ESBL-E carriage were identified by multivariable logistic regression analysis. ESBL-E isolates underwent whole genome sequencing.ResultsOf 47,957 individuals invited, 4,177 (8.7%) completed the questionnaire and provided a faecal sample. ESBL-E were detected in 186 (4.5%) individuals, resulting in an adjusted prevalence of 5.0% (95% confidence interval (CI):3.4-6.6%). Risk factors were: born outside the Netherlands (odds ratio (OR): 1.99; 95% CI: 1.16-4.54), eating in restaurants > 20 times/year (OR: 1.70; 95% CI: 1.04-2.76), antibiotic use < 6 months ago (OR: 2.05; 95% CI: 1.05-4.03), swimming in sea/ocean < 12 months ago (OR: 1.63; 95% CI: 1.11-2.39), travelling to Africa (OR: 3.03; 95% CI: 1.23-7.46) or Asia (OR: 2.00; 95% CI: 1.02-3.90) < 12 months ago, and not changing kitchen towels daily (OR: 2.19; 95% CI: 1.24-3.87). The last had the largest population attributable risk (PAR) (47.5%). Eighty-four of 189 (44.4%) ESBL-E isolates carried bla CTX-M-15. Escherichia coli isolates belonged to 70 different sequence types (ST)s, of which ST131 (42/178 isolates; 23.6%) was most prevalent. Associations were observed between IncFIA plasmids and ST131 and bla CTX-M-27, and between IncI1 and ST88 and bla CTX-M-1. No CPE were detected.ConclusionsThe prevalence of ESBL-E carriage in the Netherlands' community-dwelling population is 5.0%. Identified risk factors were mostly travelling (particularly to Asia and Africa) and kitchen hygiene. CPE were not detected.

Transglutaminase type 2-dependent selective recruitment of proteins into exosomes under stressful cellular conditions.

Numerous studies are revealing a role of exosomes in intercellular communication, and growing evidence indicates an important function for these vesicles in the progression and pathogenesis of cancer and neurodegenerative diseases. However, the biogenesis process of exosomes is still unclear. Tissue transglutaminase (TG2) is a multifunctional enzyme with different subcellular localizations. Particularly, under stressful conditions, the enzyme has been also detected in the extracellular matrix, but the mechanism(s) by which TG2 is released outside the cells requires further investigation. Therefore, the goal of the present study was to determine whether exosomes might be a vehicle for TG2 to reach the extracellular space, and whether TG2 could be involved in exosomes biogenesis. To address this issue, we isolated and characterized exosomes derived from cells either expressing or not TG2, under stressful conditions (i.e. proteasome impairment or expressing a mutated form of huntingtin (mHtt) containing 84 polyglutamine repeats). Our results show that TG2 is present in the exosomes only upon proteasome blockade, a condition in which TG2 interacts with TSG101 and ALIX, two key proteins involved in exosome biogenesis. Interestingly, we found that TG2 favours the assembly of a protein complex including mHtt, ALIX, TSG101 and BAG3, a co-chaperone involved in the clearance of mHtt. The formation of this complex is paralleled by the selective recruitment of mHtt and BAG3 in the exosomes derived from TG2 proficient cells only. Overall, our data indicate that TG2 is an important player in the biogenesis of exosomes controlling the selectivity of their cargo under stressful cellular conditions. In addition, these vesicles represent the way by which cells can release TG2 into the extracellular space under proteostasis impairment.

Regulation of human immunodeficiency virus type 1 (HIV-1) mRNA translation.

Human immunodeficiency virus type 1 (HIV-1) mRNA translation is a complex process that uses the host translation machinery to synthesise viral proteins. Several mechanisms for HIV-1 mRNA translation initiation have been proposed including (1) cap-dependent, eIF4E-dependent, (2) cap-dependent, cap-binding complex-dependent, (3) internal ribosome entry sites, and (4) ribosome shunting. While these mechanisms promote HIV-1 mRNA translation in the context of in vitro systems and subgenomic constructs, there are substantial knowledge gaps in understanding how they regulate viral protein production in the context of full-length virus infection. In this review, we will summarise the different translation mechanisms used by HIV-1 mRNAs and the challenges in understanding how they regulate protein synthesis during viral infection.

Characterization of human fibroblastic reticular cells as potential immunotherapeutic tools.

Fibroblastic reticular cells (FRCs) are essential players during adaptive immune responses not only as a structural support for the encounter of antigen-presenting cells and naive T lymphocytes but also as a source of modulatory signals. However, little is known about this cell population in humans. To address the phenotypical and functional analysis of human FRCs here we established splenic (SP) and mesenteric lymph node (LN) CD45-CD31-CD90+podoplanin+ myofibroblastic cell cultures. They shared the phenotypical characteristics distinctive of FRCs, including the expression of immunomodulatory factors and peripheral tissue antigens. Nevertheless, human FRCs also showed particular features, some differing from mouse FRCs, like the lack of nitric oxide synthase (NOS2) expression after interferon (IFN)γstimulation. Interestingly, SP-FRCs expressed higher levels of interleukin (IL)-6, BMP4, CCL2, CXCL12 and Notch molecules, and strongly adapted their functional profile to lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (Poly I:C) and IFNγ stimulation. In contrast, we found higher expression of transforming growth factor (TGF)ß and Activin A in LN-FRCs that barely responded via Toll-Like Receptor (TLR)3 and constitutively expressed retinaldehyde dehydrogenase 1 enzyme, absent in SP-FRCs. This study reveals human FRCs can be valuable models to increase our knowledge about the physiology of human secondary lymphoid organs in health and disease and to explore the therapeutic options of FRCs.

Autocrine activation of canonical BMP signaling regulates PD-L1 and PD-L2 expression in human dendritic cells.

Bone morphogenetic proteins (BMPs) are multifunctional growth factors regulating differentiation and proliferation in numerous systems including the immune system. Previously, we described that the BMP signaling pathway is functional in human monocyte-derived dendritic cells (MoDCs), which were found to express both the specific receptors and the Smad proteins required for signal transduction. In this study, we provide evidence that human MoDCs produce BMP-4 and that this production is increased over the maturation process as is BMP signal transduction. When DCs are matured in the presence of an inhibitor of the BMP pathway, the expression of the maturation markers PD-L1 and PD-L2 is reduced, while cytokine production is not affected. As a result, these mature DCs present an augmented ability to stimulate both T cells and NK cells. Eventually, the inhibition of BMP signaling during maturation causes a reduced expression of IRF-1, a transcription factor that positively regulates the expression of PD-L1 and PD-L2. The present study indicates that the BMP signaling pathway regulates PD-L1 and PD-L2 expression in human MoDCs during the maturation process, probably through the IRF-1 transcription factor, and also points out that the manipulation of BMP signaling might considerably improve the immunogenicity of MoDCs used in immunotherapy.

A discrete population of IFN λ-expressing BDCA3hi dendritic cells is present in human thymus.

Human thymus contains two major subpopulations of dendritic cells (DCs), conventional DCs (cDCs) and plasmacytoid DCs (pDCs), which are mainly involved in central tolerance and also in protecting the thymus against infections. In blood and peripheral organs cDCs include the subpopulation of BDCA3(hi) DCs, considered as equivalents to mouse CD8α(+) DCs. In this study we describe in human thymus the presence of a discrete population of BDCA3(hi) DCs that, like their peripheral counterparts, express CD13, low-intermediate levels of CD11c, CLEC9A, high levels of XCR1, IRF8 and TLR3, and mostly lack the expression of CD11b, CD14 and TLR7. Thymic BDCA3(hi) DCs display immature features with a low expression of costimulatory molecules and HLA-DR, and a low allostimulatory capacity. Also, BDCA3(hi) DCs exhibit a strong response to TLR3 stimulation, producing high levels of interferon (IFN)-λ1 and CXCL10, which indicates that, similarly to thymic pDCs, BDCA3(hi) DCs can have an important role in thymus protection against viral infections.

Expression of BMPRIA on human thymic NK cell precursors: role of BMP signaling in intrathymic NK cell development.

The bone morphogenetic protein (BMP) signaling pathway regulates survival, proliferation, and differentiation of several cell types in multiple tissues, including the thymus. Previous reports have shown that BMP signaling negatively regulates T-cell development. Here, we study the subpopulation of early human intrathymic progenitors expressing the type IA BMP receptor (BMPRIA) and provide evidence that CD34(+)CD1a(-)BMPRIA(+) precursor cells mostly express surface cell markers and transcription factors typically associated with NK cell lineage. These CD34(+) cells mostly differentiate into functional CD56(+) natural killer (NK) cells when they are cocultured with thymic stromal cells in chimeric human-mouse fetal thymic organ cultures and also in the presence of SCF and IL-15. Moreover, autocrine BMP signaling can promote the differentiation of thymic NK cells by regulating the expression of key transcription factors required for NK cell lineage (eg, Id3 and Nfil3) as well as one of the components of IL-15 receptor, CD122. Subsequently, the resulting population of IL-15-responsive NK cell precursors can be expanded by IL-15, whose action is mediated by BMP signaling during the last steps of thymic NK cell differentiation. Our results strongly suggest that BMPRIA expression identifies human thymic NK cell precursors and that BMP signaling is relevant for NK cell differentiation in the human thymus.

Newer generations of multi-target CAR and STAb-T immunotherapeutics: NEXT CART Consortium as a cooperative effort to overcome current limitations.

Adoptive T cellular immunotherapies have emerged as relevant approaches for treating cancer patients who have relapsed or become refractory (R/R) to traditional cancer treatments. Chimeric antigen receptor (CAR) T-cell therapy has improved survival in various hematological malignancies. However, significant limitations still impede the widespread adoption of these therapies in most cancers. To advance in this field, six research groups have created the "NEXT Generation CART MAD Consortium" (NEXT CART) in Madrid's Community, which aims to develop novel cell-based immunotherapies for R/R and poor prognosis cancers. At NEXT CART, various basic and translational research groups and hospitals in Madrid concur to share and synergize their basic expertise in immunotherapy, gene therapy, and immunological synapse, and clinical expertise in pediatric and adult oncology. NEXT CART goal is to develop new cell engineering approaches and treatments for R/R adult and pediatric neoplasms to evaluate in multicenter clinical trials. Here, we discuss the current limitations of T cell-based therapies and introduce our perspective on future developments. Advancement opportunities include developing allogeneic products, optimizing CAR signaling domains, combining cellular immunotherapies, multi-targeting strategies, and improving tumor-infiltrating lymphocytes (TILs)/T cell receptor (TCR) therapy. Furthermore, basic studies aim to identify novel tumor targets, tumor molecules in the tumor microenvironment that impact CAR efficacy, and strategies to enhance the efficiency of the immunological synapse between immune and tumor cells. Our perspective of current cellular immunotherapy underscores the potential of these treatments while acknowledging the existing hurdles that demand innovative solutions to develop their potential for cancer treatment fully.

Correction: Del Valle-Moreno et al. Model-Informed Precision Dosing Software Tools for Dosage Regimen Individualization: A Scoping Review. Pharmaceutics 2023, 15, 1859.

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FiCRoN, a deep learning-based algorithm for the automatic determination of intracellular parasite burden from fluorescence microscopy images.

Protozoan parasites are responsible for dramatic, neglected diseases. The automatic determination of intracellular parasite burden from fluorescence microscopy images is a challenging problem. Recent advances in deep learning are transforming this process, however, high-performance algorithms have not been developed. The limitations in image acquisition, especially for intracellular parasites, make this process complex. For this reason, traditional image-processing methods are not easily transferred between different datasets and segmentation-based strategies do not have a high performance. Here, we propose a novel method FiCRoN, based on fully convolutional regression networks (FCRNs), as a promising new tool for estimating intracellular parasite burden. This estimation requires three values, intracellular parasites, infected cells and uninfected cells. FiCRoN solves this problem as multi-task learning: counting by regression at two scales, a smaller one for intracellular parasites and a larger one for host cells. It does not use segmentation or detection, resulting in a higher generalization of counting tasks and, therefore, a decrease in error propagation. Linear regression reveals an excellent correlation coefficient between manual and automatic methods. FiCRoN is an innovative freedom-respecting image analysis software based on deep learning, designed to provide a fast and accurate quantification of parasite burden, also potentially useful as a single-cell counter.