RESUMEN

Our current understanding of human gait is mostly based on studies using hard, level surfaces in a laboratory environment. However, humans navigate a wide range of different substrates every day, which incur varied demands on stability and efficiency. Several studies have shown that when walking on natural compliant substrates there is an increase in energy expenditure. However, these studies report variable changes to other aspects of gait such as muscle activity. Discrepancies between studies exist even within substrate types (e.g. sand), which suggests that relatively 'fine-scale' differences in substrate properties exert quantifiable influences on gait mechanics. In this study, we compare human walking mechanics on a range of sand substrates that vary in overall foot sinking depth. We demonstrate that variation in the overall sinking depth in sand is associated with statistically significant changes in joint angles and spatiotemporal variables in human walking but exerts relatively little influence on pendular energy recovery and muscle activations. Significant correlated changes between gait metrics are frequently recovered, suggesting a degree of coupled or mechanistic interaction in their variation within and across substrates. However, only walking speed (and its associated spatiotemporal variables) correlate frequently with absolute foot sinkage depth within individual sand substrates, but not across them. This suggests a causative relationship between walking speed and foot sinkage depth within individual sand substates is not coupled with systematic changes in joint kinematics and muscle activity in the same way as is observed across sand substrates.

RESUMEN

OBJECTIVES: Canada has one of the highest age-adjusted incidence and prevalence rates of inflammatory bowel disease (IBD). Large patient volumes and limited resources have created challenges concerning the quality of IBD care, but little is known about patients' experiences. This paper aimed to better understand patient-perceived barriers to IBD care. METHODS: An exploratory qualitative approach was used for this study. Fourteen focus groups (with 63 total participants) were co-facilitated by a researcher and patient research partner across eight Canadian provinces in 2018. Patients diagnosed with IBD (>18 years of age) and their caregivers were purposefully recruited through Crohn's and Colitis Canada, gastroenterology clinics and communities, and national social media campaigns. Focus group sessions were recorded, transcribed, and analyzed using thematic analysis. RESULTS: Most participants self-identified as being white and women. The analysis generated four key themes regarding patient-perceived barriers and gaps in access to IBD care: (1) gatekeepers and their lack of IBD knowledge, (2) expenses and time, (3) lack of holistic care, and (4) care that is not patient-centered. An additional four themes were generated on the topic of patient-perceived areas of health system improvement for IBD care: (1) direct access to care, (2) good care providers, (3) electronic records and passports, and (4) multidisciplinary care or an 'IBD dream team'. CONCLUSIONS: This research contributes to the limited global knowledge on patients' experiences accessing IBD care. It is valuable for the development of care plans and policies to target gaps in care. Patients have identified system-level barriers and ideas for improvement, which should be taken into consideration when implementing system redesign and policy change.

RESUMEN

In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts.

RESUMEN

Background: Transplant centers have traditionally relied upon procurement teams from their own programs (transplant program procurement team [TPT]) to recover donation after circulatory death (DCD) livers and rarely use surgical procurement teams not affiliated with the recipient center (nontransplant program procurement team [NTPT]). However, in the era of wider geographic organ sharing, greater reliance on NTPTs is often necessary. Methods: We used national data to study the association between the origin of the donor procurement team (NTPT versus TPT) and the risk of DCD liver allograft failure. Results: Five hundred NTPT and 2257 TPT DCD transplants were identified: 1-y graft survival was 88.9 and 88.6%, respectively (P = 0.962). In a multivariable model, the origin of the procurement team was not associated with graft failure NTPT versus TPT (hazard ratio, 0.92; 95% confidence interval, 0.71-1.22; P = 0.57) but rather with known risks for DCD graft loss including donor age, degree of recipient illness, cold ischemic time, and retransplantation. The overall incidence of retransplantation and ischemic cholangiopathy as an indication for retransplantation were similar between NTPT and TPT. Conclusions: This data suggests that transplant centers may be able to safely use DCD livers recovered by local surgical teams.

RESUMEN

Objectives: Patients with non-small cell lung cancer treated with immunotherapy and modern chemoradiation regimens show improved progression-free and overall survival. However, patients with limited oligo-progression represent a potential population in which local therapy such as surgery may have a potential role as salvage treatment. The objectives of our study were to evaluate the feasibility and safety of salvage lung resection after immunotherapy in patients with non-small cell lung cancer. Methods: The National Cancer Database was queried for patients diagnosed and treated for non-small cell lung cancer stage I to IV, from 2013 to 2020. Patients who underwent surgery as salvage after immunotherapy were defined as undergoing surgery >5 months from the initiation of immunotherapy. As a sensitivity analysis, patients who underwent surgery as salvage after chemoradiation were also analyzed in a similar fashion. Surgical outcomes such as type of surgery, complete resection (R0) rates, and complete pathologic response rates were determined for feasibility. Length of stay, 30-day readmission rates, and 30-day mortality rates were determined and overall survivals were estimated with Kaplan-Meier analysis to evaluate for safety. Results: Of the 934,093 patients diagnosed with non-small cell lung cancer stage I to IV from 2013 to 2020, 164 patients received immunotherapy and after 5 months underwent surgery. Lobectomy was the most commonly performed operation (74%) and pneumonectomy was required in 9% (n = 15). R0 resection was achieved in 89% (n = 146) and of these patients, 23% (n = 37) had complete pathologic response. Median length of stay was 4 days, 30-day readmission was 5%, and 30-day mortality was 0.6%. In our sensitivity analysis of chemoradiation patients (n = 445), the above data were similar to previously reported cohort studies of patients undergoing chemoradiation and subsequently salvage surgery. Conclusions: Lung resection after immunotherapy appears to be a feasible salvage treatment option, with lobectomy being most common and with high R0 resection rates. Low patient morbidity and mortality rates also suggest the safety of this approach. Salvage surgery may be considered in patients who have oligo-progression after immunotherapy within the context of a comprehensive multidisciplinary treatment plan.

RESUMEN

BACKGROUND: Transaminase and creatinine elevations have been well described in adults treated with remdesivir for COVID-19. It is hypothesized that a similar safety profile exists in children with COVID-19 treated with remdesivir, but available data are limited, especially in children < 12 months. The primary aim of this study was to determine the prevalence and timing of elevations in transaminases and creatinine in children with COVID-19 who were treated with remdesivir. METHODS: This was a retrospective, observational cohort study including all pediatric patients admitted to a single, freestanding children's hospital who were positive for COVID-19 and received at least 1 dose of remdesivir between 1/1/2020 and 5/31/2022. Available baseline and peak transaminase and creatinine concentrations were evaluated. Multivariable logistic regression analysis was performed to identify risk factors for transaminase elevation. RESULTS: A total of 180 patients met inclusion criteria. Creatinine elevation of any grade was noted in 16% and remained elevated only in those with underlying chronic kidney disease. Transaminase elevation of any grade was noted in 58% of patients and remained elevated in only 1%. Older age and critical respiratory disease were associated with higher risk of significant transaminase elevation, whereas non-Hispanic ethnicity was strongly associated with protection against significant transaminase elevation. CONCLUSIONS: In our cohort of hospitalized children with COVID-19 who were treated with remdesivir, most patients experienced only mild transaminitis and normal creatinine concentrations. A limited number of patients experienced laboratory abnormalities which were transient, suggesting a favorable safety profile for remdesivir use in pediatrics.

Asunto(s)

RESUMEN

Accurate quantification of von Willebrand factor ristocetin cofactor activity (VWF:RCo) is critical for the diagnosis and classification of von Willebrand disease, the most common hereditary and acquired bleeding disorder in humans. Moreover, it is important to accurately assess the function of von Willebrand factor (VWF) concentrates within the pharmaceutical industry to provide consistent and high-quality biopharmaceuticals. Although the performance of VWF:RCo assay has been improved by using coagulation analyzers, which are specialized devices for blood and blood plasma samples, scientists still report a high degree of intra- and inter-assay variation in clinical laboratories. Moreover, high, manual sample dilutions are required for VWF:RCo determination of VWF concentrates within the pharmaceutical industry, which are a major source for assay imprecision. For the first time, we present a precise and accurate method to determine VWF:RCo, where all critical pipetting and mixing steps are automated. A pre-dilution setup was established on CyBio FeliX (Analytik-Jena) liquid handling system, and an adapted VWF:RCo method on BCS-XP analyzer (Siemens) is used. The automated pre-dilution method was executed on three different, most frequently used coagulation analyzers and compared to manual pre-dilutions performed by an experienced operator. Comparative sample testing revealed a similar assay precision (coefficient of variation = 5.9% automated, 3.1% manual pre-dilution) and no significant differences between the automated approach and manual dilutions of an expert in this method. While no outliers were generated with the automated procedure, the manual pre-dilution resulted in an error rate of 8.3%. Overall, this operator-independent protocol enables standardization and offers an efficient way of fully automating VWF activity assays, while maintaining the precision and accuracy of an expert analyst. Key features • Automated pre-dilution setup for von Willebrand factor concentrates of various natures. • Combination of a liquid handling system (CyBio FeliX) with a coagulation analyzer (BCS-XP). • Simplifies method transfer to other laboratories. • Basic training for CyBio FeliX and BCS-XP is required. Graphical overview VWF:RCo assay principle and measurement setup. Platelets (yellow ellipsoids) with negative surface charge (- - -) are treated with formaldehyde, which partly denatures the cell surface and thus stabilizes platelets for use as assay reagents. Stabilized platelets (dark-yellow-framed yellow ellipsoids) are then brought in contact with ristocetin A (chemical structure shown; black dots), which binds to the platelet surface and facilitates binding of VWF (green circles). The graphs show an example of quantitative determination of platelet agglutination by measurement of light transmission, where increasing amounts of VWF increase light transmission over time. The photo in the left-bottom corner shows the CyBio FeliX setup for VWF sample dilution and the photo in the right-bottom corner displays the BCS-XP system, which is used for VWF:RCo measurements.

RESUMEN

Antimicrobial resistance (AMR) emerges when disease-causing microorganisms develop the ability to withstand the effects of antimicrobial therapy. This phenomenon is often fueled by the human-to-human transmission of pathogens and the overuse of antibiotics. Over the past 50 years, increased computational power has facilitated the application of Bayesian inference algorithms. In this comprehensive review, the basic theory of Markov Chain Monte Carlo (MCMC) and Sequential Monte Carlo (SMC) methods are explained. These inference algorithms are instrumental in calibrating complex statistical models to the vast amounts of AMR-related data. Popular statistical models include hierarchical and mixture models as well as discrete and stochastic epidemiological compartmental and agent based models. Studies encompassed multi-drug resistance, economic implications of vaccines, and modeling AMR in vitro as well as within specific populations. We describe how combining these topics in a coherent framework can result in an effective antimicrobial stewardship. We also outline recent advancements in the methodology of Bayesian inference algorithms and provide insights into their prospective applicability for modeling AMR in the future.

RESUMEN

Background: Patients with alcohol use disorder (AUD) and high-risk opioid use are at risk of serious complications. The purpose of this study was to estimate the prevalence of and factors associated with high-risk opioid use in patients with an alcohol use problem from 2005 to 2018. Methods: This repeated cross-sectional study analyzed data from first admissions for alcohol treatment (2005-2018) to the NYS Office of Addiction Services and Supports merged with Medicaid Claims Data. High-risk opioid use was defined as opioid dose ≥50 morphine mg equivalents (MME) per day; opioid prescriptions overlapping ≥7 days; opioids for chronic pain >90 days or opioids for acute pain >7 days. Results: Patients receiving ≥50 MME increased from 690 to 3226 from 2005 to 2010; then decreased to 2330 in 2018. From 2005-2011, patients with opioid prescriptions overlapping ≥7 days increased from 226 to 1594 then decreased to 892 in 2018. From 2005-2010, opioid use >7 days for acute pain increased from 133 to 970 and plateaued after 2010. From 2005-2018, patients who received opioids >90 days for chronic pain trended from 186 to 1655. White patients, females, age 36-55, patients with chronic and acute pain diagnoses had the highest rates of high-risk use. Conclusions: The prevalence of high-risk opioid use in patients with alcohol use problems increased from 2005 to 2011, and generally decreased after 2010. However, prevalence of opioids >90 days for chronic pain trended up from 2005 to 2018. High-risk opioid use among patients with AUD emphasizes the need to develop interventional strategies to improve patient care.

RESUMEN

Severe congenital protein C deficiency (SCPCD) is a rare disorder associated with life-threatening purpura fulminans and disseminated intravascular coagulation that typically present within hours after birth. Treatment options for patients with SCPCD include replacement therapy with a plasma-derived protein C concentrate. In this targeted literature review, we summarize information on the use of protein C concentrate as long-term prophylaxis (>1 week of treatment) for patients with SCPCD. In total, 18 publications were included in the review, of which 15 were case studies. Treatment with protein C concentrate (Ceprotin; Baxalta US Inc, a Takeda company; Takeda Manufacturing Austria AG) was reported in 11 publications, and treatment with protein C concentrate (Protexel; LFB Biomedicaments) was reported in 2 publications. One publication reported on both Ceprotin and Protexel. Details of protein C concentrate treatment regimens, including the dose, administration frequency, and route of administration, were reported in 11 publications. Dosing regimens varied across all 11 publications, possibly due to different protein C trough levels among patients or the administration of concomitant medications. Seven of the 11 publications reported on patients who initially received intravenous protein C concentrate and subsequently switched to subcutaneous administration. Treatment outcomes with protein C concentrate were generally favorable, including the prevention of coagulopathy and thrombosis and the healing of cutaneous lesions. Three adverse events in 1 publication were identified as being possibly related to Ceprotin administration. Although published data are limited, this review provides valuable insights into the treatment of patients with SCPCD in clinical practice, including protein C concentrate dosing regimens, administration routes, and associated clinical outcomes.

RESUMEN

The activation of the NLRP3 inflammasome has been linked to several inflammatory and autoinflammatory diseases. Despite cases of potential hearing improvement in immune-mediated diseases, direct evidence of the efficacy of targeting this mechanism in the inner ear is still lacking. Previously, we discovered that macrophages are associated with Sensorineural Hearing loss (SNHL) in Chronic Suppurative Otitis Media (CSOM), the leading cause of this permanent hearing loss in the developing world and incurring costs of $4 to $11 billion dollars in the United States. However, the underlying mechanism remained unknown. Here, we investigate how macrophages drive permanent hearing loss in CSOM. We first confirmed the occurrence of NLRP3 inflammasome activation in cochlear macrophages in CSOM. We then revealed that Outer Hair Cells (OHCs) were protected in CSOM by macrophage depletion and subsequently confirmed the same protection in the NLRP3 knockout condition. Furthermore, we showed that therapeutic inhibition of NLRP3 inflammasome activation and downstream inhibition of IL-1ß protects OHCs in CSOM. Collectively, our data demonstrates that the main driver for hearing loss in CSOM is NLRP3 inflammasome activation in cochlear macrophages and this is therapeutically targetable, leading the way for the development of interventions to prevent the leading cause of permanent hearing loss and a costly disease in the developed world.

Asunto(s)

RESUMEN

OBJECTIVE: We propose a selection process to identify a small molecule inhibitor to treat NLRP3-associated sensory hearing loss. BACKGROUND: The NLRP3 inflammasome is an innate immune sensor and present in monocytes and macrophages. Once the inflammasome is activated, a cleavage cascade is initiated leading to the release of proinflammatory cytokines IL-1ß and IL-18. The NLRP3 inflammasome has been implicated in many causes of hearing loss, including autoimmune disease, tumors, and chronic suppurative otitis media. Although the target has been identified, there is a lack of available therapeutics to treat NLRP3-associated hearing loss. METHODS: We created a target product profile with specific characteristics that are required for a compound to treat sensory hearing loss. We then looked at available small molecule NLRP3 inhibitors at different stages of development and selected compounds that fit that profile best. Those compounds were then tested for cell toxicity in MTT assays to determine the dosage to be used for efficacy testing. We tested efficacy of a known NLRP3 inhibitor, MCC950, in a proof-of-concept screen on reporter monocytes. RESULTS: Six compounds were selected that fulfilled our selection criteria for further testing. We found the maximum tolerated dose for each of those compounds that will be used for further efficacy testing. The proof-of-concept efficacy screen on reporter monocytes confirmed that those cells can be used for further efficacy testing. CONCLUSION: Our selection process and preliminary results provide a promising concept to develop small molecule NLRP3 inhibitors to treat sensory hearing loss.

RESUMEN

Chronic suppurative otitis media (CSOM) is a neglected disease that afflicts 330 million people worldwide and is the most common cause of permanent hearing loss among children in the developing world. Previously, we discovered that outer hair cell (OHC) loss occurred in the basal turn of the cochlea and that macrophages are the major immune cells associated with OHC loss in CSOM. Macrophage-associated cytokines are upregulated. Specifically, CCL-2, an important member of the MCP family, is elevated over time following middle ear infection. CCR2 is a common receptor of the MCP family and the unique receptor of CCL2. CCR2 knockout mice (CCR2-/-) have been used extensively in studies of monocyte activation in neurodegenerative diseases. In the present study, we investigated the effect of CCR2 deletion on the cochlear immune response and OHC survival in CSOM. The OHC survival rate was 84 ± 12.5% in the basal turn of CCR2+/+ CSOM cochleae, compared with was 63 ± 19.9% in the basal turn of CCR2-/- CSOM cochleae (p ≤ 0.05). Macrophage numbers were significantly reduced in CCR2-/- CSOM cochleae compared with CCR2+/+ CSOM cochleae (p ≤ 0.001). In addition, CCL7 was upregulated, whereas IL-33 was downregulated, in CCR2-/- CSOM cochleae. Finally, the permeability of the blood-labyrinth barrier in the stria vascularis remained unchanged in CCR2-/- CSOM compared with CCR2+/+ CSOM. Taken together, the data suggest that CCR2 plays a protective role through cochlear macrophages in the CSOM cochlea.

Asunto(s)

Asunto(s)

RESUMEN

Loss of proper T-cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG-1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age-related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro-inflammatory factors. To develop therapies against pathologies caused by defective T-cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age-related diseases.

RESUMEN

Individual-based simulation has become an increasingly crucial tool for many fields of population biology. However, implementing realistic and stable simulations in continuous space presents a variety of difficulties, from modeling choices to computational efficiency. This paper aims to be a practical guide to spatial simulation, helping researchers to implement realistic and efficient spatial, individual-based simulations and avoid common pitfalls. To do this, we delve into mechanisms of mating, reproduction, density-dependent feedback, and dispersal, all of which may vary across the landscape, discuss how these affect population dynamics, and describe how to parameterize simulations in convenient ways (for instance, to achieve a desired population density). We also demonstrate how to implement these models using the current version of the individual-based simulator, SLiM. Since SLiM has the capacity to simulate genomes, we also discuss natural selection - in particular, how genetic variation can affect demographic processes. Finally, we provide four short vignettes: simulations of pikas that shift their range up a mountain as temperatures rise; mosquitoes that live in rivers as juveniles and experience seasonally changing habitat; cane toads that expand across Australia, reaching 120 million individuals; and monarch butterflies whose populations are regulated by an explicitly modeled resource (milkweed).

RESUMEN

OBJECTIVES: Rumination syndrome (RS) is challenging to diagnose, which can lead to diagnostic delays. Our objective was to evaluate the length of time from RS symptom onset to diagnosis in patients referred to our institution and to examine whether this duration predicts treatment outcomes. METHODS: We conducted a review of patients with RS evaluated at our institution. Data were collected from chart review and patient/family reported questionnaires. We evaluated the time from symptom onset to diagnosis over time and whether it was associated with symptom resolution. RESULTS: We included 247 patients with RS (60% female, median age of 14 years, interquartile range [IQR]: 9-16 years). The median age at symptom onset was 11 years (IQR: 5-14 years) and median age at diagnosis was 13 years (IQR: 9-15 years) for a median duration of 1 year (IQR: 0-3 years) between symptom onset and diagnosis. Length of time between symptom onset and diagnosis did not change significantly at our institution from 2016 to 2022. Among the 164 children with outcome data, 47 (29%) met criteria for symptom resolution after treatment. A longer time to diagnosis was associated with a lower likelihood of symptom resolution after treatment (p = 0.01). CONCLUSION: In our experience, the time to RS diagnosis after symptom onset is shorter than previously described. A longer delay in diagnosis is associated with lower likelihood of symptom resolution after treatment, emphasizing the importance of a prompt recognition of rumination symptoms and a timely diagnosis.

RESUMEN

The formation of molecular-based functional materials is a key step towards the development of technologies at the nanoscale. Recently, it has been shown that after oxidation of closo-[B10H10]2- anions, an induced aggregation of two cluster units is achieved, retaining their parent B10 backbones as persistent building blocks. Such characterization provides an interesting scenario to further understand relevant factors leading to aggregation in a minimal structure involving two units. Here, we explore the interaction between closo-[B10H10]2- units in two isomers, namely, iso- and trans-[B20H18]2-, involving different intercluster contacts based on B-B and B-H interactions, respectively. Our results show that the inherent spherical aromatic characteristics of the parent closo-[B10H10]2- cluster are persistent in both iso- and trans-[B20H18]2- isomers as an interplay between the spherical aromatic properties from both B10 motifs, leading to an overlap of the shielding regions from shielding cone properties, ascribed as a dual spherical-spherical aromatic cluster. From 11B-NMR features, it came out that trans-[B20H18]2- involves larger differences in comparison to closo-[B10H10]2-, owing to the variation of the B10-B10 backbone provided by the intercluster B-interaction, thus resulting in a more effective aggregation connecting such building units, towards boron-based cluster materials.

RESUMEN

A fundamental goal in population genetics is to understand how variation is arrayed over natural landscapes. From first principles we know that common features such as heterogeneous population densities and barriers to dispersal should shape genetic variation over space, however there are few tools currently available that can deal with these ubiquitous complexities. Geographically referenced single nucleotide polymorphism (SNP) data are increasingly accessible, presenting an opportunity to study genetic variation across geographic space in myriad species. We present a new inference method that uses geo-referenced SNPs and a deep neural network to estimate spatially heterogeneous maps of population density and dispersal rate. Our neural network trains on simulated input and output pairings, where the input consists of genotypes and sampling locations generated from a continuous space population genetic simulator, and the output is a map of the true demographic parameters. We benchmark our tool against existing methods and discuss qualitative differences between the different approaches; in particular, our program is unique because it infers the magnitude of both dispersal and density as well as their variation over the landscape, and it does so using SNP data. Similar methods are constrained to estimating relative migration rates, or require identity-by-descent blocks as input. We applied our tool to empirical data from North American grey wolves, for which it estimated mostly reasonable demographic parameters, but was affected by incomplete spatial sampling. Genetic based methods like ours complement other, direct methods for estimating past and present demography, and we believe will serve as valuable tools for applications in conservation, ecology and evolutionary biology. An open source software package implementing our method is available from https://github.com/kr-colab/mapNN.