Multiple models for outbreak decision support in the face of uncertainty.

Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.

Low anterior resection with transanal transection and single-stapled anastomosis: technical aspects and initial results.

BACKGROUND: Rectal cancer (RC) is a surgical challenge due to its technical complexity. The double-stapled (DS) technique, a standard for colorectal anastomosis, has been associated with notable drawbacks, including a high incidence of anastomotic leak (AL). Low anterior resection with transanal transection and single-stapled (TTSS) anastomosis has emerged to mitigate those drawbacks. METHODS: Observational study in which it described the technical aspects and results of the initial group of patients with medium-low RC undergoing elective laparoscopic total mesorectal excision (TME) and TTSS. RESULTS: Twenty-two patients were included in the series. Favourable postoperative outcomes with a median length of stay of 5 days and an AL incidence of 9.1%. Importantly, all patients achieved complete mesorectal excision with tumour-free margins, and no mortalities were reported. CONCLUSION: TTSS emerges as a promising alternative for patients with middle and lower rectal tumours, offering potential benefits in terms of morbidity reduction and oncological integrity compared with other techniques.

Analytical Solution to a Third-Order Rational Difference Equation.

Inspired by some open conjectures in a rational dynamical system by G. Ladas and Palladino, in this paper, we consider the problem of solving a third-order difference equation. We comment the conjecture by Ladas. A third-order rational difference equation is solved analytically. The solution is compared with the solution to the linearized equation. We show that the solution to the linearized equation is not good, in general. The methods employed here may be used to solve other rational difference equations. The period of the solution is calculated. We illustrate the accuracy of the obtained solutions in concrete examples.

Realism and the point at infinity: The end of the line?

Philosophers of mathematics often rely on the historical progress of mathematics in support of mathematical realism. These histories typically build on formal semantic tools to evaluate the changes in mathematics, and on these bases present later mathematical concepts as refined versions of earlier concepts which are taken to be vague. Claiming that this view does not apply to mathematical concepts in general, we present a case-study concerning projective geometry, for which we apply the tools of cognitive linguistics to analyse the developmental trajectory of the domain. On the basis of this analysis, we argue for the existence of two conceptually incompatible inferential structures, occurring at distinct moments in history, both of which yield the same projective geometric theorems; the first invoked by the French mathematicians Girard Desargues (1591-1661) and Jean-Victor Poncelet (1788-1867), and the second characterising a specific modern mode. We demonstrate that neither of these inferential structures can be considered as a refinement of the other. This case of conceptual development presents an issue to the standard account of progress and its bearing on mathematical realism. Our analysis suggests that the features that distinguish the underlying conceptually incompatible inferential structures are invisible to the standard application of the tools of formal semantics. Thus this case-study stands as an example of the manner and necessity of linguistics-specifically cognitive linguistics-to inform the philosophy of mathematics.

Covasim: An agent-based model of COVID-19 dynamics and interventions.

The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.

Efficacy and safety of lurbinectedin and doxorubicin in relapsed small cell lung cancer. Results from an expansion cohort of a phase I study.

Background A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI <90 days; including six with refractory disease [CTFI ≤30 days]). Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; median overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, decreased appetite, vomiting, alopecia) were mostly mild or moderate. Conclusion Doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2 on Day 1 q3wk has shown noteworthy activity in relapsed SCLC and a manageable safety profile. The combination is being evaluated as second-line therapy for SCLC in an ongoing, randomized phase III trial. Clinical trial registration www.ClinicalTrials.gov code: NCT01970540. Date of registration: 22 October, 2013.

The perception of quantity ain't number: Missing the primacy of symbolic reference.

Clarke and Beck's defense of the theoretical construct "approximate number system" (ANS) is flawed in serious ways - from biological misconceptions to mathematical naïveté. The authors misunderstand behavioral/psychological technical concepts, such as numerosity and quantical cognition, which they disdain as "exotic." Additionally, their characterization of rational numbers is blind to the essential role of symbolic reference in the emergence of number.

Biofeedback Systems for Gait Rehabilitation of Individuals with Lower-Limb Amputation: A Systematic Review.

Individuals with lower-limb amputation often have gait deficits and diminished mobility function. Biofeedback systems have the potential to improve gait rehabilitation outcomes. Research on biofeedback has steadily increased in recent decades, representing the growing interest toward this topic. This systematic review highlights the methodological designs, main technical and clinical challenges, and evidence relating to the effectiveness of biofeedback systems for gait rehabilitation. This review provides insights for developing an effective, robust, and user-friendly wearable biofeedback system. The literature search was conducted on six databases and 31 full-text articles were included in this review. Most studies found biofeedback to be effective in improving gait. Biofeedback was most commonly concurrently provided and related to limb loading and symmetry ratios for stance or step time. Visual feedback was the most used modality, followed by auditory and haptic. Biofeedback must not be obtrusive and ideally provide a level of enjoyment to the user. Biofeedback appears to be most effective during the early stages of rehabilitation but presents some usability challenges when applied to the elderly. More research is needed on younger populations and higher amputation levels, understanding retention as well as the relationship between training intensity and performance.

ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line.

Lurbinectedin is an inhibitor of active transcription of protein-coding genes, causing DNA-break accumulation, apoptosis and modulation of the tumor microenvironment. Early-phase clinical trials indicate promising activity of lurbinectedin in small-cell lung cancer. Here, we describe the rationale and design of ATLANTIS (NCT02566993), an open-label, randomized, multicenter Phase III study to compare the efficacy of lurbinectedin and doxorubicin combination with standard-of-care chemotherapy, investigator's choice of cyclophosphamide/doxorubicin/vincristine or topotecan, in patients with small-cell lung cancer that has progressed following one line of platinum-based chemotherapy. Patients are randomized in a 1:1 ratio. The primary end point is overall survival and key secondary end points include progression-free survival, best tumor response and duration of response, each assessed by independent review committee.

Where Does the Ordered Line Come From? Evidence From a Culture of Papua New Guinea.

Number lines, calendars, and measuring sticks all represent order along some dimension (e.g., magnitude) as position on a line. In high-literacy, industrialized societies, this principle of spatial organization- linear order-is a fixture of visual culture and everyday cognition. But what are the principle's origins, and how did it become such a fixture? Three studies investigated intuitions about linear order in the Yupno, members of a culture of Papua New Guinea that lacks conventional representations involving ordered lines, and in U.S. undergraduates. Presented with cards representing differing sizes and numerosities, both groups arranged them using linear order or sometimes spatial grouping, a competing principle. But whereas the U.S. participants produced ordered lines in all tasks, strongly favoring a left-to-right format, the Yupno produced them less consistently, and with variable orientations. Conventional linear representations are thus not necessary to spark the intuition of linear order-which may have other experiential sources-but they nonetheless regiment when and how the principle is used.

Tomato ethylene sensitivity determines interaction with plant growth-promoting bacteria.

Background and Aims: Plant growth-promoting bacteria (PGPB) are soil micro-organisms able to interact with plants and stimulate their growth, positively affecting plant physiology and development. Although ethylene plays a key role in plant growth, little is known about the involvement of ethylene sensitivity in bacterial inoculation effects on plant physiology. Thus, the present study was pursued to establish whether ethylene perception is critical for plant-bacteria interaction and growth induction by two different PGPB strains, and to assess the physiological effects of these strains in juvenile and mature tomato ( Solanum lycopersicum ) plants. Methods: An experiment was performed with the ethylene-insensitive tomato never ripe and its isogenic wild-type line in which these two strains were inoculated with either Bacillus megaterium or Enterobacter sp. C7. Plants were grown until juvenile and mature stages, when biomass, stomatal conductance, photosynthesis as well as nutritional, hormonal and metabolic statuses were analysed. Key Results: Bacillus megaterium promoted growth only in mature wild type plants. However, Enterobacter C7 PGPB activity affected both wild-type and never ripe plants. Furthermore, PGPB inoculation affected physiological parameters and root metabolite levels in juvenile plants; meanwhile plant nutrition was highly dependent on ethylene sensitivity and was altered at the mature stage. Bacillus megaterium inoculation improved carbon assimilation in wild-type plants. However, insensitivity to ethylene compromised B. megaterium PGPB activity, affecting photosynthetic efficiency, plant nutrition and the root sugar content. Nevertheless, Enterobacter C7 inoculation modified the root amino acid content in addition to stomatal conductance and plant nutrition. Conclusions: Insensitivity to ethylene severely impaired B. megaterium interaction with tomato plants, resulting in physiological modifications and loss of PGPB activity. In contrast, Enterobacter C7 inoculation stimulated growth independently of ethylene perception and improved nitrogen assimilation in ethylene-insensitive plants. Thus, ethylene sensitivity is a determinant for B. megaterium , but is not involved in Enterobacter C7 PGPB activity.

Safety and feasibility of concomitant surgery during holmium laser enucleation of the prostate (HoLEP).

PURPOSE: To determine the feasibility and outcomes associated with performing simultaneous surgical procedures during holmium laser enucleation of the prostate (HoLEP) in patients with benign prostatic hyperplasia and concomitant urologic conditions. METHODS: A retrospective review of patients that underwent a HoLEP was performed. Patients undergoing a concomitant procedure at the time of HoLEP were selected and stratified based on complexity of the secondary procedure (simple, intermediate, and complex) and matched based on age and prostate volume to patients undergoing only a HoLEP. Baseline characteristics, preoperative, operative, and postoperative outcomes were collected. RESULTS: A total of 372 HoLEPs were performed. Thirty-eight (10.2 %) patients underwent concomitant procedures at the time of HoLEP. Compared to the simple and intermediate secondary surgical procedures, the matched control group that underwent a HoLEP alone did not demonstrate statistically significant differences in the preoperative, operative, or postoperative outcomes. Patients with a complex secondary surgical procedure at the time of HoLEP had statistically significant differences in operative time (221 vs. 65 min, p = 0.007), estimated blood loss (92 vs. 33 mL, p = 0.012), catheter time (8.5 vs. 1 day, p = 0.041), and length of hospitalization (2 vs. 1 day, p = 0.032) compared to the control group. CONCLUSIONS: Obstructive voiding symptoms secondary to BPH are common in older patients and may coincide with other concomitant lower urinary tract pathology that may require surgical intervention. Rather than staging surgical interventions, it appears that definitive treatment for BPH with HoLEP is safe and efficacious in those patients that also require secondary procedures.

Is it healthy urban agriculture? Human exposure to potentially toxic elements in urban gardens from Andalusia, Spain.

Different vegetable species and topsoils were collected from different urban gardens of Seville, Cordoba, and Huelva (South Spain) and from two small towns in a mining area (Riotinto), together with topsoil close to the plants. The concentration of potentially toxic elements (PTEs) (As, B, Ba, Cd, Co, Cr, Cu, Mo, Ni, Pb, and Zn) was evaluated in edible plant parts and in the soils. The same species were also purchased from Seville local markets and from a peri-urban area (domestic garden in a rural area) and also analyzed. Plant/soil pollution relation was studied and human health risk was assessed by different parameters. Soils of urban gardens from the mining area were more contaminated with As, Cr, Cu, Pb, and Zn in comparison with other locations, and generally, soils from cities showed higher values of As, Pb, and Zn than the peri-urban ones. The mean concentration of almost all potentially toxic elements was higher in leafy than in fruiting and bulbous species. Arsenic, Cd, and Pb concentrations were below health-based guidance values in all vegetables except Cd in one sample in the peri-urban area. In general, PTEs concentration in vegetables from city urban gardens did not exceed the one found in market vegetables for almost all studied elements, except in lettuce for almost elements. The hazard quotient (HQ) values were lower than the unit for all PTEs in plant species from the studied gardens, as well as the hazard index (HI), indicating that consumption of these vegetables can be considered safe and without risk to human health. Also, cancer risk values for As were below the established limits in all vegetables from the studied urban gardens, including those from the As-contaminated soils in the mining area.

Predictive models and applicability of artificial intelligence-based approaches in drug allergy.

PURPOSE OF REVIEW: Drug allergy is responsible for a huge burden on public healthcare systems, representing in some instances a threat for patient's life. Diagnosis is complex due to the heterogeneity of clinical phenotypes and mechanisms involved, the limitations of in vitro tests, and the associated risk to in vivo tests. Predictive models, including those using recent advances in artificial intelligence, may circumvent these drawbacks, leading to an appropriate classification of patients and improving their management in clinical settings. RECENT FINDINGS: Scores and predictive models to assess drug allergy development, including patient risk stratification, are scarce and usually apply logistic regression analysis. Over recent years, different methods encompassed under the general umbrella of artificial intelligence, including machine and deep learning, and artificial neural networks, are emerging as powerful tools to provide reliable and optimal models for clinical diagnosis, prediction, and precision medicine in different types of drug allergy. SUMMARY: This review provides general concepts and current evidence supporting the potential utility of predictive models and artificial intelligence branches in drug allergy diagnosis.

Group 2 innate lymphoid cells are key in lipid transfer protein allergy pathogenesis.

Background: Immunopathology in food allergy is characterized by an uncontrolled type 2 immune response and specific-IgE production. Recent studies have determined that group 2 innate lymphoid cells (ILC2) participate in the food allergy pathogenic mechanism and their severity. Our objective was to investigate the role of ILC2 in peach-allergic patients due to non-specific lipid transfer protein (Pru p 3) sensitization. Methods: The immune response in peripheral blood mononuclear cells was characterized in lipid transfer protein-allergic patients and healthy controls. We have analyzed the Pru p 3 uptake on ILC2, the expression of costimulatory molecules, and their involvement on the T-cell proliferative response and cytokine production under different experimental conditions: cytokines involved in group 2 innate lymphoid cell activation (IL-33 and IL-25), Pru p 3 as main food allergen, and the combination of both components (IL-33/IL-25+Pru p 3) using cell sorting, EliSpot, flow cytometry, and confocal microscopy. Results: Our results show that Pru p 3 allergen is taken up by group 2 innate lymphoid cells, regulating their costimulatory molecule expression (CD83 and HLA-DR) depending on the presence of Pru p 3 and its combination with IL-33/IL-25. The Pru p 3-stimulated ILC2 induced specific GATA3+Th2 proliferation and cytokine (IL-4, IL-5, and IL-13) production in lipid transfer protein-allergic patients in a cell contact-dependent manner with no changes in Tbet+Th1- and FOXP3+Treg cell differentiation. Conclusions: The results indicate that in lipid transfer protein-allergic patients, the responsible allergen, Pru p 3, interacts with group 2 innate lymphoid cells, promoting a Th2 cell response. Our results might be of interest in vivo, as they show a role of group 2 innate lymphoid cells as antigen-presenting cells, contributing to the development of food allergy. Consequently, group 2 innate lymphoid cells may be considered as potential therapeutic targets.

A synthetic glycodendropeptide induces methylation changes on regulatory T cells linked to tolerant responses in anaphylactic-mice.

Introduction: Lipid transfer proteins (LTPs) are allergens found in a wide range of plant-foods. Specifically, Pru p 3, the major allergen of peach, is commonly responsible for severe allergic reactions. The need for new alternatives to conventional food allergy treatments, like restrictive diets, suggests allergen immunotherapy as a promising option. It has been demonstrated that sublingual immunotherapy (SLIT) with synthetic glycodendropeptides, such as D1ManPrup3, containing mannose and Pru p 3 peptides induced tolerance in mice and that the persistence of this effect depends on treatment dose (2nM or 5nM). Moreover, it produces changes associated with differential gene expression and methylation profile of dendritic cells, as well as phenotypical changes in regulatory T cells (Treg). However, there are no works addressing the study of epigenetic changes in terms of methylation in the cell subsets that sustain tolerant responses, Treg. Therefore, in this work, DNA methylation changes in splenic-Treg from Pru p 3 anaphylactic mice were evaluated. Methods: It was performed by whole genome bisulphite sequencing comparing SLIT-D1ManPrup3 treated mice: tolerant (2nM D1ManPrup3), desensitized (5nM D1ManPrup3), and sensitized but not treated (antigen-only), with anaphylactic mice. Results: Most of the methylation changes were found in the gene promoters from both SLIT-treated groups, desensitized (1,580) and tolerant (1,576), followed by the antigen-only (1,151) group. Although tolerant and desensitized mice showed a similar number of methylation changes, only 445 genes were shared in both. Remarkably, interesting methylation changes were observed on the promoter regions of critical transcription factors for Treg function like Stat4, Stat5a, Stat5b, Foxp3, and Gata3. In fact, Foxp3 was observed exclusively as hypomethylated in tolerant group, whereas Gata3 was only hypomethylated in the desensitized mice. Discussion: In conclusion, diverse D1ManPrup3 doses induce different responses (tolerance or desensitization) in mice, which are reflected by differential methylation changes in Tregs.