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Abstract Background Deep learning techniques excel at identifying tumor-infiltrating lymphocytes (TILs) and immune phenotypes in hematoxylin and eosin (H&E)-stained slides. However, their ability to elucidate detailed functional characteristics of diverse cellular phenotypes within tumor immune microenvironment (TME) is limited. We aimed to enhance our understanding of cellular composition and functional characteristics across TME regions and improve patient stratification by integrating H&E with adjacent immunohistochemistry (IHC) images. Methods A retrospective study was conducted on patients with Human Papillomavirus-positive oropharyngeal squamous cell carcinoma (OPSCC). Using paired H&E and IHC slides for 11 proteins, a deep learning pipeline was used to quantify tumor, stroma, and TILs in the TME. Patients were classified into immune inflamed (IN), immune excluded (IE), or immune desert (ID) phenotypes. By registering the IHC and H&E slides, we integrated IHC data to capture protein expression in the corresponding tumor regions. We further stratified patients into specific immune subtypes, such as IN, with increased or reduced CD8+ cells, based on the abundance of these proteins. This characterization provided functional insight into the H&E-based subtypes. Results Analysis of 88 primary tumors and 70 involved lymph node tissue images reveals an improved prognosis in patients classified as IN in primary tumors with high CD8 and low CD163 expression (p = 0.007). Multivariate Cox regression analysis confirms a significantly better prognosis for these subtypes. Conclusions Integrating H&E and IHC data enhances the functional characterization of immune phenotypes of the TME with biological interpretability, and improves patient stratification in HPV( + ) OPSCC.

Objective: To assess the performance of the current foundation models in histopathology. Patients and Methods: The assessment involves a comprehensive evaluation of some foundation models, such as the CLIP derivatives, namely PLIP and BiomedCLIP, which were fine-tuned on data scraped from the internet. The comparison is performed against simpler and nonfoundational histology models that are trained on well-curated data, eg, the cancer genome atlas. All models are evaluated on 8 datasets, 4 of which are internal histology datasets collected and curated at Mayo Clinic, and 4 well-known public datasets: PANDA, BRACS, CAMELYON16, and DigestPath. Evaluation metrics include accuracy and macro-averaged F1 score, using a majority vote among top-k (eg, MV@5) at the whole slide image/patch levels. Moreover, all models are evaluated in classification settings. This detailed analysis allows for a deep understanding of each model’s performance across various datasets. Results: In various evaluation tasks, domain-specific (and nonfoundational) models like DinoSSLPath and KimiaNet outperform general-purpose foundation models. The DinoSSLPath excels in whole slide image-level retrieval for internal colorectal cancer and liver datasets with MV@5 macro-averaged F1 scores of 63% and 74%, respectively. The KimiaNet leads in breast and skin cancer tasks with respective Top-1 and MV@5 scores of 56% and 70%, respectively and scores 75% on the public CAMELYON16 dataset. Similar trends are observed in patch-level metrics, highlighting the advantage of using specialized datasets like the cancer genome atlas for histopathological analysis. Conclusion: To enable effective vision-language foundation models in biomedicine, high-quality, multi-modal medical datasets are essential. These datasets serve as the substrate for training models capable of translating research into clinical practice. Of importance, the alignment (correspondence) between textual and visual data—often diagnostic—is critical and requires validation by domain experts. Thus, advancing foundation models in this field necessitates collaborative efforts in data curation and validation.

Abstract Patching whole slide images (WSIs) is an important task in computational pathology. While most of them are designed to classify or detect the presence of pathological lesions in a WSI, the confounding role and redundant nature of normal histology are generally overlooked. In this paper, we propose and validate the concept of an “atlas of normal tissue” solely using samples of WSIs obtained from normal biopsies. Such atlases can be employed to eliminate normal fragments of tissue samples and hence increase the representativeness of the remaining patches. We tested our proposed method by establishing a normal atlas using 107 normal skin WSIs and demonstrated how established search engines like Yottixel can be improved. We used 553 WSIs of cutaneous squamous cell carcinoma to demonstrate the advantage. We also validated our method applied to an external dataset of 451 breast WSIs. The number of selected WSI patches was reduced by 30% to 50% after utilizing the proposed normal atlas while maintaining the same indexing and search performance in leave-one-patient-out validation for both datasets. We show that the proposed concept of establishing and using a normal atlas shows promise for unsupervised selection of the most representative patches of the abnormal WSI patches.

Chemotherapy induces hair loss in most cancer patients who undergo treatment, which causes them significant psychosocial trauma. Scalp cooling has demonstrated some efficacy in attenuating chemotherapy-induced alopecia, but response rate varies between patients and chemotherapy class. Here, we showcase in rats a proof-of-concept treatment of using subcutaneous hydrogen peroxide and cumene hydroperoxide injections to provide total protection from hair loss against multiple classes of chemotherapy. We found that subcutaneous peroxides induce cell cycle arrest via P53 activation, thereby protecting hair follicles from the cytotoxic effects of chemotherapy on actively dividing cells. This treatment represents a highly effective and accessible way for cancer patients to maintain quality of life while undergoing treatment for cancer.

The impact of agro-industrial waste can be reduced by using it in crop fertilization. The aim of this study was to evaluate the stomatal density and yield of radish (Raphanus Sativus L.) fertilized with biol at different concentrations, produced from sugar cane residues. A completely randomized blocks design statistical model was used, which consisted of 5 tests with 3 repetitions for each one, being T1 the control trial, and T2, T3, T4 and T5 the treatments using 2, 3, 4 and 5 L of biol in 200 L of water respectively. In terms of crop physical characteristics, the T5 treatment excelled in plant length, equatorial diameter, plant weight, as well as yield with 12.71 t/ha. Likewise, in the chemical analysis of the radish leaves, the T5 treatment showed an increase in K, Ca, Zn and MN, while the T2 did it in N, P and Cu, the T3 in Fe and the T4 in Mg. In terms of stomatal density, T5 stood out with 122 stomatal/mm2. Based on this, it is concluded that the increase in the dose of biol influences the increase in nutrient and stomatal density and hence the yield of the radish crop.

For higher yields in vegetable cultivation, the availability of soil nutrients must be improved. Therefore, the aim of this research was to establish the relationship between stomatal density and the yield of the radish crop fertilized with compost made from organic market waste. A completely randomized block design was used, which consisted of 3 blocks and 5 treatments, which were T1, T2, T3, T4 and T5 with 00, 10, 15, 15, 20 and 25 g compost/plant respectively. The physical characteristics of the plants were evaluated from sowing to harvest and the data obtained were processed by analysis of variance and Duncan's test. Chemical analysis of the compost and soil was carried out, as well as a foliar analysis to determine the nutrient concentration by treatment. The results determined that the treatment (T4) stood out in plant length with 28.96 cm, plant weight with 43.33 g, yield of 10.82 t/ha and bulb diameter of 3.92 cm; likewise, in the concentration of nutrients in the leaves, the treatment (T5) highlighted in N with 5.94%, Ca 4.84%, Mg 1.29%, Zn 64.58 ppm and a stomatal density of 642 stomas/mm2. It is concluded that, at an adequate dose of compost, the concentration of nutrients increases, as well as the stomatal density, resulting in higher yields.

Purpose: Human papillomavirus–associated oropharyngeal squamous cell carcinoma (HPV[+]OPSCC) requires further study to optimize the existing clinical staging system and guide treatment selection. We hypothesize that incorporation of the number of radiographically positive lymph nodes will further stratify patients with clinical N1 (cN1) HPV(+)OPSCC. Methods and Materials: A post hoc analysis from 2 prospective clinical trials at a high-volume referral center was conducted. Patients underwent primary tumor resection and lymphadenectomy, followed by either standard-of-care radiation therapy (60 Gy in 30 fractions) with or without cisplatin (40 mg/m2 weekly) or de-escalated radiation therapy (30 Gy in 20 twice-daily fractions) with concomitant 15 mg/m2 docetaxel once weekly. Imaging studies were independently reviewed by a blinded neuroradiologist classifying radiographic extranodal extension (rENE) and the number and maximal size of involved lymph nodes. Patients without pathologic data available for assessment were excluded. Results: A total of 260 patients were included. Of these, 216 (83%) were cN1. Patients had a median of 2 radiographically positive lymph nodes (range, 0-12), and 107 (41%) had rENE. For cN1 patients, stratifying by radiographically positive lymph nodes (1-2 vs 3-4 vs >4) was predictive of progression-free survival (PFS) (P = .017), with 2-year PFS rates of 96%, 88%, and 81%, respectively. More than 2 radiographically positive lymph nodes was identified as a significant threshold for PFS (P = .0055) and overall survival (P = .029). Radiographic ENE and lymph node size were not predictive of PFS among cN1 patients. Conclusions: The number of radiographically positive lymph nodes is predictive of PFS and overall survival and could be used to meaningfully subcategorize cN1 patients with HPV(+)OPSCC. We recommend further validation of our proposal that cN1 patients with 1 to 2 radiologically positive lymph nodes be categorized as cN1a, patients with 3 to 4 radiologically positive lymph nodes categorized as cN1b, and patients with >4 radiographically positive lymph nodes categorized as cN1c.

Soil acidification is a major problem in the inland Pacific Northwest. A potential solution is the application of lime to neutralize acidity and raise pH. As lime is an expensive input, precision variable rate application is necessary. However, high-resolution mapping of pH and buffer pH for lime prescription requires costly sampling and analysis. To reduce the amount of sampling needed, remote sensing, which correlates with soil pH and buffer pH, can be used to determine optimal sampling locations and allow optimal interpolation. We used soil and crop data from the Washington State University R.J. Cook Agronomy Farm to develop an optimal sampling plan for a farmer’s property, followed that sampling design, and used the measured pH and buffer pH to fit a Bayesian hierarchical model using remote sensing variables specific to that farmer’s land. Following this, a new model was developed for the research farm with similar covariates. Ultimately, on the farmer’s field, we observed a root mean square error (RMSE) of 0.2487 for soil pH at a depth of 0–10 cm and 0.1221 for modified Mehlich buffer at 0–10 cm of depth. For the research farm, where buffer pH was not measured, we saw an RMSE of 0.3272 for soil pH at 0–10 cm of depth and 0.3381 for soil pH at 10–20 cm of depth. The ability make predictions of soil acidity with uncertainty using this technique allows for prescription lime application while optimizing soil sampling and testing. Further, this paper serves as a case study of on-farm research.

The last decade has witnessed a remarkable progress in our understanding of the brain. This has mainly been based on the scrutiny and modeling of the transmission of activity among neurons across lively synapses. A main conclusion, thus far, is that essential features of the mind rely on collective phenomena that emerge from a willful interaction of many neurons that, mediating other cells, form a complex network whose details keep constantly adapting to their activity and surroundings. In parallel, theoretical and computational studies developed to understand many natural and artificial complex systems, which have truthfully explained their amazing emergent features and precise the role of the interaction dynamics and other conditions behind the different collective phenomena they happen to display. Focusing on promising ideas that arise when comparing these neurobiology and physics studies, the present perspective article shortly reviews such fascinating scenarios looking for clues about how high-level cognitive processes such as consciousness, intelligence, and identity can emerge. We, thus, show that basic concepts of physics, such as dynamical phases and non-equilibrium phase transitions, become quite relevant to the brain activity while determined by factors at the subcellular, cellular, and network levels. We also show how these transitions depend on details of the processing mechanism of stimuli in a noisy background and, most important, that one may detect them in familiar electroencephalogram (EEG) recordings. Thus, we associate the existence of such phases, which reveal a brain operating at (non-equilibrium) criticality, with the emergence of most interesting phenomena during memory tasks.

Androgenetic alopecia (“AGA”) is the most prevalent type of progressive hair loss, causing tremendous psychological and social stress in patients. However, AGA treatment remains limited in scope. The pathogenesis of androgenetic alopecia is not completely understood but is known to involve a hair follicle miniaturization process in which terminal hair is transformed into thinner, softer vellus-like hair. This process is related to the dysregulation of the Wnt/β-catenin signaling pathway, which causes premature termination of the anagen growth phase in hair follicles. Historically used for wound healing, platelet rich plasma (“PRP”) has recently been at the forefront of potential AGA treatment. PRP is an autologous preparation of plasma that contains a high number of platelets and their associated growth factors such as EGF, IGF-1, and VEGF. These factors are known to individually play important roles in regulating hair follicle growth. However, the clinical effectiveness of PRP is often difficult to characterize and summarize as there are wide variabilities in the PRP preparation and administration protocols with no consensus on which protocol provides the best results. This study follows the previous review from our group in 2018 by Cervantes et al. to analyze and discuss recent clinical trials using PRP for the treatment of AGA. In contrast to our previous publication, we include recent clinical trials that assessed PRP in combination or in direct comparison with standard of care procedures for AGA such as topical minoxidil and/or oral finasteride. Overall, this study aims to provide an in-depth analysis of PRP in the treatment of AGA based on the evaluation of 17 recent clinical trials published between 2018 and October 2021. By closely examining the methodologies of each clinical trial included in our study, we additionally aim to provide an overall consensus on how PRP can be best utilized for the treatment of AGA.

Abstract Background The limb center of pressure (COP) path measures and quantifies the load distribution within a limb in a still or moving subject. Under this premise, the aim of this study was to test whether data derived from this parameter could detect the differences between sound and lame limbs in unilaterally lame dogs with elbow dysplasia. To accomplish this purpose, ten unilaterally lame dogs of similar conformation were walked over a pressure platform. Next, the COP path, in relation to the position of sound and lame limbs, was measured in a coordinate system over a standard paw template obtained by pedobarography during the whole support phase. To compare variables, force platform data (peak vertical force and vertical impulse) from the same animals were obtained. Sound and lame limb statokinesiograms were also obtained while the animals stood still. Results The statistical analysis clearly showed that COP in lame limbs start cranially and were shorter than sound limbs. In addition, the value of the COP excursion index was lower in lame limbs. Finally, the area of statokinesiograms was greater in lame limbs. Conclusion This methodology based in limb COP characteristics serves to discriminate between sound and lame limbs in dogs with elbow dysplasia.

Objectives: There is a lack of effective therapy for recurrent or metastatic salivary gland carcinoma. Androgen deprivation therapy has demonstrated efficacy in cases of salivary duct carcinoma (SDC) and high-grade adenocarcinoma not otherwise specified (NOS) that express androgen receptor.Materials and Methods: We conducted a single institution retrospective cohort study examining patients treated for recurrent/metastatic SDC or high-grade adenocarcinoma NOS of the salivary gland. Survival analyses were performed to assess for efficacy of first-line androgen deprivation therapy (ADT) vs. first-line conventional cytotoxic chemotherapy. Efficacy of salvage ADT was also assessed.Results: Fifty-eight patients were reviewed. Thirty-five patients had recurrent/metastatic disease of which 28 had SDC (80%) and 7 had high-grade adenocarcinoma NOS (20%). Median overall survival for first-line ADT was 25 months compared to 25 months for first-line chemotherapy [RR 0.54 (0.23–1.28, p = 0.16)]. Patients treated with first-line ADT had a response rate of 45% (9/20) and patients treated with first-line chemotherapy had a response rate of 14% (2/14). Six patients received salvage ADT with 1 patient demonstrating complete response and 3 with stable disease as best response (clinical benefit rate 67%).Conclusion: Overall survival for first line ADT and first line cytotoxic chemotherapy was comparable but response rates to first-line ADT were higher than those with first-line chemotherapy. Salvage ADT is active in recurrent/metastatic salivary gland carcinoma.

Inverse Stochastic Resonance (ISR) is a phenomenon in which the average spiking rate of a neuron exhibits a minimum with respect to noise. ISR has been studied in individual neurons, but here, we investigate ISR in scale-free networks, where the average spiking rate is calculated over the neuronal population. We use Hodgkin-Huxley model neurons with channel noise (i.e., stochastic gating variable dynamics), and the network connectivity is implemented via electrical or chemical connections (i.e., gap junctions or excitatory/inhibitory synapses). We find that the emergence of ISR depends on the interplay between each neuron's intrinsic dynamical structure, channel noise, and network inputs, where the latter in turn depend on network structure parameters. We observe that with weak gap junction or excitatory synaptic coupling, network heterogeneity and sparseness tend to favor the emergence of ISR. With inhibitory coupling, ISR is quite robust. We also identify dynamical mechanisms that underlie various features of this ISR behavior. Our results suggest possible ways of experimentally observing ISR in actual neuronal systems.

Wound healing is a complex process regulated by various cell types and a plethora of mediators. While interactions between wounded skin and the hair follicles (HFs) could induce HF neogenesis or promote wound healing, it remains unknown whether the wound healing-associated signaling milieu can be manipulated to protect against alopecia, such as chemotherapy-induced alopecia (CIA). Utilizing a well-established neonatal rat model of CIA, we show here that skin wounding protects from alopecia caused by several clinically relevant chemotherapeutic regimens, and that protection is dependent on the time of wounding and hair cycle stage. Gene expression profiling unveiled a significant increase in interleukin-1 beta (IL-1β) mediated signaling by skin wounding. Subsequently, we showed that IL-1β is sufficient and indispensable for mediating the CIA-protective effect. Administration of IL-1β alone to unwounded rats exhibited local CIA protection while IL-1β neutralization abrogated CIA protection by wounding. Mechanistically, IL-1β retarded postnatal HF morphogenesis, making HFs at the wound sites or IL-1β treated areas damage-resistant while the rats developed total alopecia elsewhere. We conclude that wound healing switches the cutaneous cytokine milieu to an IL-1β-dominated state thus retarding HF growth progression and rendering the HFs resistant to chemotherapy agents. In the future, manipulation of HF progression through interfering with the IL-1β signaling milieu may provide therapeutic benefits to a variety of conditions, from prevention of CIA to inhibition of hair growth and treatment of hirsutism.

Knowledge of crop abiotic and biotic stress is important for optimal irrigation management. While spectral reflectance and infrared thermometry provide a means to quantify crop stress remotely, these measurements can be cumbersome. Computer vision offers an inexpensive way to remotely detect crop stress independent of vegetation cover. This paper presents a technique using computer vision to detect disease stress in wheat. Digital images of differentially stressed wheat were segmented into soil and vegetation pixels using expectation maximization (EM). In the first season, the algorithm to segment vegetation from soil and distinguish between healthy and stressed wheat was developed and tested using digital images taken in the field and later processed on a desktop computer. In the second season, a wireless camera with near real-time computer vision capabilities was tested in conjunction with the conventional camera and desktop computer. For wheat irrigated at different levels and inoculated with wheat streak mosaic virus (WSMV), vegetation hue determined by the EM algorithm showed significant effects from irrigation level and infection. Unstressed wheat had a higher hue (118.32) than stressed wheat (111.34). In the second season, the hue and cover measured by the wireless computer vision sensor showed significant effects from infection (p = 0.0014), as did the conventional camera (p < 0.0001). Vegetation hue obtained through a wireless computer vision system in this study is a viable option for determining biotic crop stress in irrigation scheduling. Such a low-cost system could be suitable for use in the field in automated irrigation scheduling applications.

We investigate the efficient transmission and processing of weak, subthreshold signals in a realistic neural medium in the presence of different levels of the underlying noise. Assuming Hebbian weights for maximal synaptic conductances--that naturally balances the network with excitatory and inhibitory synapses--and considering short-term synaptic plasticity affecting such conductances, we found different dynamic phases in the system. This includes a memory phase where population of neurons remain synchronized, an oscillatory phase where transitions between different synchronized populations of neurons appears and an asynchronous or noisy phase. When a weak stimulus input is applied to each neuron, increasing the level of noise in the medium we found an efficient transmission of such stimuli around the transition and critical points separating different phases for well-defined different levels of stochasticity in the system. We proved that this intriguing phenomenon is quite robust, as it occurs in different situations including several types of synaptic plasticity, different type and number of stored patterns and diverse network topologies, namely, diluted networks and complex topologies such as scale-free and small-world networks. We conclude that the robustness of the phenomenon in different realistic scenarios, including spiking neurons, short-term synaptic plasticity and complex networks topologies, make very likely that it could also occur in actual neural systems as recent psycho-physical experiments suggest.

In this paper we review our research on the effect and computational role of dynamical synapses on feed-forward and recurrent neural networks. Among others, we report on the appearance of a new class of dynamical memories which result from the destabilisation of learned memory attractors. This has important consequences for dynamic information processing allowing the system to sequentially access the information stored in the memories under changing stimuli. Although storage capacity of stable memories also decreases, our study demonstrated the positive effect of synaptic facilitation to recover maximum storage capacity and to enlarge the capacity of the system for memory recall in noisy conditions. Possibly, the new dynamical behaviour can be associated with the voltage transitions between up and down states observed in cortical areas in the brain. We investigated the conditions for which the permanence times in the up state are power-law distributed, which is a sign for criticality, and concluded that the experimentally observed large variability of permanence times could be explained as the result of noisy dynamic synapses with large recovery times. Finally, we report how short-term synaptic processes can transmit weak signals throughout more than one frequency range in noisy neural networks, displaying a kind of stochastic multi-resonance. This effect is due to competition between activity-dependent synaptic fluctuations (due to dynamic synapses) and the existence of neuron firing threshold which adapts to the incoming mean synaptic input.

This research aims to discover how much the older adults in Central Los Angele have benefitted from an intergenerational community program. In addition, how intergenerational learning has successfully addressed various needs of these older adults because of the COVID-19 pandemic. The need for intergenerational programs has grown significantly over the past two years, with many older adults experiencing loneliness, anxiety, and depression. Intergenerational Programs provide a sense of comfort, relief, and a place where they can feel needed. They also help the older generations think a part of society and give them a sense of purpose and feelings of value. Through various intergenerational activities, the younger generation takes in information that will help them develop their levels of resilience and social identities.

In this work we study the detection of weak stimuli by spiking (integrate-and-fire) neurons in the presence of certain level of noisy background neural activity. Our study has focused in the realistic assumption that the synapses in the network present activity-dependent processes, such as short-term synaptic depression and facilitation. Employing mean-field techniques as well as numerical simulations, we found that there are two possible noise levels which optimize signal transmission. This new finding is in contrast with the classical theory of stochastic resonance which is able to predict only one optimal level of noise. We found that the complex interplay between adaptive neuron threshold and activity-dependent synaptic mechanisms is responsible for this new phenomenology. Our main results are confirmed by employing a more realistic FitzHugh-Nagumo neuron model, which displays threshold variability, as well as by considering more realistic stochastic synaptic models and realistic signals such as poissonian spike trains.

Complex coherent dynamics is present in a wide variety of neural systems. A typical example is the voltage transitions between up and down states observed in cortical areas in the brain. In this work, we study this phenomenon via a biologically motivated stochastic model of up and down transitions. The model is constituted by a simple bistable rate dynamics, where the synaptic current is modulated by short-term synaptic processes which introduce stochasticity and temporal correlations. A complete analysis of our model, both with mean-field approaches and numerical simulations, shows the appearance of complex transitions between high (up) and low (down) neural activity states, driven by the synaptic noise, with permanence times in the up state distributed according to a power-law. We show that the experimentally observed large fluctuation in up and down permanence times can be explained as the result of sufficiently noisy dynamical synapses with sufficiently large recovery times. Static synapses cannot account for this behavior, nor can dynamical synapses in the absence of noise.

Superior mesenteric artery (SMA) syndrome is an uncommon but well-recognized clinical entity. It can lead to proximal small bowel obstruction and severe morbidity and mortality in lieu of late diagnosis and concomitant existing comorbidities. We report a 54-year-old female, with SMA syndrome which manifested itself after Nissen fundoplication along with two major complications. The diagnosis of SMA was established by clinical symptoms and radiological findings.

The presenting pattern and natural progression of biochemical markers of biliary tract obstruction in patients with gallstone pancreatitis have not been elucidated. We analyzed serial values of bilirubin levels following admission to discharge in 143 patients. Ninety-four of patients demonstrated a Decrescendo (falling) pattern of bilirubin levels from admission until normalization at 21 hours (median). Forty-nine patients demonstrated a Crescendo-Decrescendo (initially rising) pattern with peak levels of bilirubin occurring at 39 hours after admission followed by a subsequent normalization after a median of 119 hours. Patients in the Decrescendo group were significantly younger (33 versus 41 years, P=.02) and more patients had experienced symptoms for greater than 48 hours (65% versus 47%, P=.05). Ten percent of patients in the Decrescendo group and 29% of patients in the Crescendo-Decrescendo group underwent ERCP (P=.02). Normalization of biochemical markers after ERCP was significantly delayed in both groups compared to no ERCP. Older patients present earlier, with higher bilirubin levels and normalize slower than younger patients, perhaps due to fibrosis of the ampulla and decreased compliance of the common bile duct. Patients who disobstruct spontaneously (90%) normalize quicker than patients undergoing ERCP.