Competing effects in fourth‐order aggregation–diffusion equations

We give sharp conditions for global in time existence of gradient flow solutions to a Cahn–Hilliard‐type equation, with backwards second‐order degenerate diffusion, in any dimension and for general initial data. Our equation is the 2‐Wasserstein gradient flow of a free energy with two competing effects: the Dirichlet energy and the power‐law internal energy. Homogeneity of the functionals reveals critical regimes that we analyse. Sharp conditions for global in time solutions, constructed via the minimising movement scheme, also known as JKO scheme, are obtained. Furthermore, we study a system of two Cahn–Hilliard‐type equations exhibiting an analogous gradient flow structure

Quantifying tissue growth, shape and collision via continuum models and Bayesian inference

Although tissues are usually studied in isolation, this situation rarely occurs in biology, as cells, tissues, and organs, coexist and interact across scales to determine both shape and function. Here, we take a quantitative approach combining data from recent experiments, mathematical modelling, and Bayesian parameter inference, to describe the self-assembly of multiple epithelial sheets by growth and collision. We use two simple and well-studied continuum models, where cells move either randomly or following population pressure gradients. After suitable calibration, both models prove to be practically identifiable, and can reproduce the main features of single tissue expansions. However, our findings reveal that whenever tissue-tissue interactions become relevant, the random motion assumption can lead to unrealistic behaviour. Under this setting, a model accounting for population pressure from different cell populations is more appropriate and shows a better agreement with experimental measurements. Finally, we discuss how tissue shape and pressure affect multi-tissue collisions. Our work thus provides a systematic approach to quantify and predict complex tissue configurations with applications in the design of tissue composites and more generally in tissue engineering

Quantifying cell cycle regulation by tissue crowding

The spatiotemporal coordination and regulation of cell proliferation is fundamental in many aspects of development and tissue maintenance. Cells have the ability to adapt their division rates in response to mechanical constraints, yet we do not fully understand how cell proliferation regulation impacts cell migration phenomena. Here, we present a minimal continuum model of cell migration with cell cycle dynamics, which includes density-dependent effects and hence can account for cell proliferation regulation. By combining minimal mathematical modelling, Bayesian inference, and recent experimental data, we quantify the impact of tissue crowding across different cell cycle stages in epithelial tissue expansion experiments. Our model suggests that cells sense local density and adapt cell cycle progression in response, during G1 and the combined S/G2/M phases, providing an explicit relationship between each cell cycle stage duration and local tissue density, which is consistent with several experimental observations. Finally, we compare our mathematical model predictions to different experiments studying cell cycle regulation and present a quantitative analysis on the impact of density-dependent regulation on cell migration patterns. Our work presents a systematic approach for investigating and analysing cell cycle data, providing mechanistic insights into how individual cells regulate proliferation, based on population-based experimental measurements

Oral fosfomycin for treatment of acute bacterial prostatitis caused by multidrug-resistant Enterobacterales

Acute prostatitis; Fosfomycin-tromethamine; Multidrug resistanceProstatitis aguda; Fosfomicina-trometamina; Resistència a múltiples medicamentsProstatitis aguda; Fosfomicina-trometamina; Resistencia a múltiples medicamentosTo assess the feasibility of oral fosfomycin-tromethamine (FT) for the management of acute bacterial prostatitis (ABP) caused by multidrug-resistant (MDR) Enterobacterales. An observational study of adult patients diagnosed with ABP from Vall d’Hebron University Hospital (Barcelona, Spain), treated with oral FT. The primary outcome was clinical cure defined as symptom relief at the control visit, 2–4 weeks post-end of treatment. Secondary outcomes included microbiological cure, relapse, and adverse events related to the treatment. Eighteen patients with ABP caused by Enterobacterales (15 Escherichia coli and three Klebsiella pneumoniae) were included. Microorganisms were MDR bacteria [14 extended-spectrum beta-lactamase (ESBL) producers and two carbapenemase producing K. pneumoniae]. Patients received treatment with FT 3 g/48 hours during a median of 14 days (Q25–Q75, 12–17.75). Fifteen patients received a lead-in phase of intravenous suitable antimicrobial during a median of 7 days (Q25–Q75, 3.75–8). No patient had to stop treatment due to adverse events, and the only side effect reported in two patients was diarrhea. Clinical cure was achieved in all (18/18) patients and microbiological cure in 11/12 patients. After a median of follow-up of 5 months (Q25–Q75, 2–11), 2/18 patients relapsed with an orchitis and a new episode of ABP. FT is an attractive step-down therapy for ABP in patients with resistance or side effects to first-line drugs. The availability of oral treatment could reduce the use of the carbapenems, with a benefit in the quality of life of the patient, health costs, and an ecological impact

The effect of a live music therapy intervention on critically ill paediatric patients in the intensive care unit: A quasi-experimental pretest-posttest study

Background: Music therapy as a nonpharmacological means of managing patient pain, anxiety, and discomfort is a recognised technique, although it is not widely used in the paediatric intensive care unit (PICU). Aim: The aim of this study was to assess the clinical effect of a live music therapy intervention on vital signs and levels of discomfort and pain for paediatric patients in the PICU. Methods: This was a quasi-experimental pretesteposttest study. The music therapy intervention was carried out by two music therapists who were specifically trained, each possessing a master's degree in the field of hospital music therapy. Ten minutes before the start of the music therapy session, the investigators recorded the vital signs of the patients and assessed their levels of discomfort and pain. The procedure was repeated at the start of the intervention; at 2, 5, and 10 min during the intervention; and at 10 min following the conclusion of the intervention. Results: Two hundred fifty-nine patients were included; 55.2% were male, with a median age of 1 year (0 e21). A total of 96 (37.1%) patients suffered a chronic illness. The main reason for PICU admission was respiratory illness, at 50.2% (n ¼ 130). Significantly lower values were observed for heart rate (p ¼ 0.002), breathing rate (p < 0.001), and degree of discomfort (p < 0.001) during the music therapy session. Conclusions: Live music therapy results in reduced heart rates, breathing rates, and paediatric patient discomfort levels. Although music therapy is not widely used in the PICU, our results suggest that using interventions such as that used in this study could help reduce patient discomfor

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5: Prognostic signature of immune recovery status in treated HIV-positive patients

Background: The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4+ T-cell turnover. Methods: We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-β/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery. Findings: The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response. Interpretation: SDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance. Funding: This work was supported by Fondo de Investigacion Sanitaria and SPANISH AIDS Research Network (ISCIII-FEDER); AGAUR and Gilead Fellowship. FV and YMP are supported by grants from the Programa de Intensificación (ISCIII) and Servicio Andaluz de Salud, respectively. JVG,EY and LR are supported by the Instituto de Salud Carlos III (ISCIII). AR is supported by Departament de Salut, Generalitat de Catalunya and by the Instituto de Salud Carlos III (ISCIII)

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5 : Prognostic signature of immune recovery status in treated HIV-positive patients

The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4 T-cell turnover. We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-β/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery. The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response. SDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance. This work was supported by Fondo de Investigacion Sanitaria and SPANISH AIDS Research Network (ISCIII-FEDER); AGAUR and Gilead Fellowship. FV and YMP are supported by grants from the Programa de Intensificación (ISCIII) and Servicio Andaluz de Salud, respectively. JVG,EY and LR are supported by the Instituto de Salud Carlos III (ISCIII). AR is supported by Departament de Salut, Generalitat de Catalunya and by the Instituto de Salud Carlos III (ISCIII)

Correlation of recist, computed tomography morphological response, and pathological regression in hepatic metastasis secondary to colorectal cancer : The avamet study

The prospective phase IV AVAMET study was undertaken to correlate response evaluation criteria in solid tumors (RECIST)-defined response rates with computed tomography-based morphological criteria (CTMC) and pathological response after liver resection of colorectal cancer metastases. Eligible patients were aged ≥18 years, with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and histologically-confirmed colon or rectal adenocarcinoma with measurable liver metastases. Preoperative treatment was bevacizumab (7.5 mg on day 1) + XELOX (oxaliplatin 130 mg/m, capecitabine 1000 mg/m bid on days 1-14 q3w). After three cycles, response was evaluated by a multidisciplinary team. Patients who were progression-free and metastasectomy candidates received one cycle of XELOX before undergoing surgery 3-5 weeks later, followed by four cycles of bevacizumab + XELOX. A total of 83 patients entered the study; 68 were eligible for RECIST, 67 for CTMC, and 51 for pathological response evaluation. Of these patients, 49% had a complete or partial RECIST response, 91% had an optimal or incomplete CTMC response, and 81% had a complete or major pathological response. CTMC response predicted 37 of 41 pathological responses versus 23 of 41 responses predicted using RECIST (p = 0.008). Kappa coefficients indicated a lack of correlation between the results of RECIST and morphological responses and between morphological and pathological response rates. CTMC may represent a better marker of pathological response to bevacizumab + XELOX than RECIST in patients with potentially-resectable CRC liver metastases

Correlation of RECIST, Computed Tomography Morphological Response, and Pathological Regression in Hepatic Metastasis Secondary to Colorectal Cancer: The AVAMET Study.

Background: The prospective phase IV AVAMET study was undertaken to correlate response evaluation criteria in solid tumors (RECIST)-defined response rates with computed tomography-based morphological criteria (CTMC) and pathological response after liver resection of colorectal cancer metastases. Methods: Eligible patients were aged >/=18 years, with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and histologically-confirmed colon or rectal adenocarcinoma with measurable liver metastases. Preoperative treatment was bevacizumab (7.5 mg on day 1) + XELOX (oxaliplatin 130 mg/m(2), capecitabine 1000 mg/m(2) bid on days 1-14 q3w). After three cycles, response was evaluated by a multidisciplinary team. Patients who were progression-free and metastasectomy candidates received one cycle of XELOX before undergoing surgery 3-5 weeks later, followed by four cycles of bevacizumab + XELOX. Results: A total of 83 patients entered the study; 68 were eligible for RECIST, 67 for CTMC, and 51 for pathological response evaluation. Of these patients, 49% had a complete or partial RECIST response, 91% had an optimal or incomplete CTMC response, and 81% had a complete or major pathological response. CTMC response predicted 37 of 41 pathological responses versus 23 of 41 responses predicted using RECIST (p = 0.008). Kappa coefficients indicated a lack of correlation between the results of RECIST and morphological responses and between morphological and pathological response rates. Conclusion: CTMC may represent a better marker of pathological response to bevacizumab + XELOX than RECIST in patients with potentially-resectable CRC liver metastases

Travelling waves in a minimal go-or-grow model of cell invasion

We consider a minimal go-or-grow model of cell invasion, whereby cells can either proliferate, following logistic growth, or move, via linear diffusion, and phenotypic switching between these two states is densitydependent. Formal analysis in the fast switching regime shows that the total cell density in the twopopulation go-or-grow model can be described in terms of a single reaction-diffusion equation with densitydependent diffusion and proliferation. Using the connection to single-population models, we study travelling wave solutions, showing that the wave speed in the go-or-grow model is always bounded by the wave speed corresponding to the well-known Fisher-KPP equation