Classification of Adventitious Sounds Combining Cochleogram and Vision Transformers.

Early identification of respiratory irregularities is critical for improving lung health and reducing global mortality rates. The analysis of respiratory sounds plays a significant role in characterizing the respiratory system's condition and identifying abnormalities. The main contribution of this study is to investigate the performance when the input data, represented by cochleogram, is used to feed the Vision Transformer (ViT) architecture, since this input-classifier combination is the first time it has been applied to adventitious sound classification to our knowledge. Although ViT has shown promising results in audio classification tasks by applying self-attention to spectrogram patches, we extend this approach by applying the cochleogram, which captures specific spectro-temporal features of adventitious sounds. The proposed methodology is evaluated on the ICBHI dataset. We compare the classification performance of ViT with other state-of-the-art CNN approaches using spectrogram, Mel frequency cepstral coefficients, constant-Q transform, and cochleogram as input data. Our results confirm the superior classification performance combining cochleogram and ViT, highlighting the potential of ViT for reliable respiratory sound classification. This study contributes to the ongoing efforts in developing automatic intelligent techniques with the aim to significantly augment the speed and effectiveness of respiratory disease detection, thereby addressing a critical need in the medical field.

ACKR1 favors transcellular over paracellular T-cell diapedesis across the blood-brain barrier in neuroinflammation in vitro.

The migration of CD4+ effector/memory T cells across the blood-brain barrier (BBB) is a critical step in MS or its animal model, EAE. T-cell diapedesis across the BBB can occur paracellular, via the complex BBB tight junctions or transcellular via a pore through the brain endothelial cell body. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB, we here directly compared the transcriptome profile of pMBMECs favoring transcellular or paracellular T-cell diapedesis by RNA sequencing (RNA-seq). We identified the atypical chemokine receptor 1 (Ackr1) as one of the main candidate genes upregulated in pMBMECs favoring transcellular T-cell diapedesis. We confirmed upregulation of ACKR1 protein in pMBMECs promoting transcellular T-cell diapedesis and in venular endothelial cells in the CNS during EAE. Lack of endothelial ACKR1 reduced transcellular T-cell diapedesis across pMBMECs under physiological flow in vitro. Combining our previous observation that endothelial ACKR1 contributes to EAE pathogenesis by shuttling chemokines across the BBB, the present data support that ACKR1 mediated chemokine shuttling enhances transcellular T-cell diapedesis across the BBB during autoimmune neuroinflammation.

Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing.

OBJECTIVES: The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap. METHODS: Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis. RESULTS: Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1, emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4, RNF145, IL12B, IL5, IRF1, IFNGR1, PTK2B, TRIM35, EGR2 and ETS2, each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides. CONCLUSIONS: We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis.

EOG Signal Classification with Wavelet and Supervised Learning Algorithms KNN, SVM and DT.

The work carried out in this paper consists of the classification of the physiological signal generated by eye movement called Electrooculography (EOG). The human eye performs simultaneous movements, when focusing on an object, generating a potential change in origin between the retinal epithelium and the cornea and modeling the eyeball as a dipole with a positive and negative hemisphere. Supervised learning algorithms were implemented to classify five eye movements; left, right, down, up and blink. Wavelet Transform was used to obtain information in the frequency domain characterizing the EOG signal with a bandwidth of 0.5 to 50 Hz; training results were obtained with the implementation of K-Nearest Neighbor (KNN) 69.4%, a Support Vector Machine (SVM) of 76.9% and Decision Tree (DT) 60.5%, checking the accuracy through the Jaccard index and other metrics such as the confusion matrix and ROC (Receiver Operating Characteristic) curve. As a result, the best classifier for this application was the SVM with Jaccard Index.

Celiac Disease Is a Risk Factor for Mature T and NK Cell Lymphoma: A Mendelian Randomization Study.

Celiac disease (CeD) is an immune-mediated disorder triggered by gluten ingestion that damages the small intestine. Although CeD has been associated with a higher risk for cancer, the role of CeD as a risk factor for specific malignancies, such as enteropathy-associated T-cell lymphoma (EATL), remains controversial. Using two-sample Mendelian randomization (2SMR) methods and the summarized results of large genome-wide association studies from public repositories, we addressed the causal relationship between CeD and eight different malignancies. Eleven non-HLA SNPs were selected as instrumental variables (IVs), and causality estimates were obtained using four 2SMR methods: random-effects inverse variance-weighted, weighted median estimation, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). We identified a significant causal relationship between CeD and mature T/NK cell lymphomas. Under a multivariate Mendelian randomization model, we observed that the causal effect of CeD was not dependent on other known lymphoma risk factors. We found that the most instrumental IV was located in the TAGAP locus, suggesting that aberrant T cell activation might be relevant in the T/NK cell malignization process. Our findings provide new insights into the connection between immune imbalance and the development of severe comorbidities, such as EATL, in patients with CeD.

Mucosal Immune Defence Gene Polymorphisms as Relevant Players in the Pathogenesis of IgA Vasculitis?

ITGAM-ITGAX (rs11150612, rs11574637), VAV3 rs17019602, CARD9 rs4077515, DEFA (rs2738048, rs10086568), and HORMAD2 rs2412971 are mucosal immune defence polymorphisms, that have an impact on IgA production, described as risk loci for IgA nephropathy (IgAN). Since IgAN and Immunoglobulin-A vasculitis (IgAV) share molecular mechanisms, with the aberrant deposit of IgA1 being the main pathophysiologic feature of both entities, we assessed the potential influence of the seven abovementioned polymorphisms on IgAV pathogenesis. These seven variants were genotyped in 381 Caucasian IgAV patients and 997 matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of these seven polymorphisms when the whole cohort of IgAV patients and those with nephritis were compared to controls. Similar genotype and allele frequencies of all polymorphisms were disclosed when IgAV patients were stratified according to the age at disease onset or the presence/absence of gastrointestinal or renal manifestations. Likewise, no ITGAM-ITGAX and DEFA haplotype differences were observed when the whole cohort of IgAV patients, along with those with nephritis and controls, as well as IgAV patients, stratified according to the abovementioned clinical characteristics, were compared. Our results suggest that mucosal immune defence polymorphisms do not represent novel genetic risk factors for IgAV pathogenesis.

Comparative study of the lipid profile of tears and plasma enriched in growth factors.

The Tear Film Lipid Layer (TFLL) acts primarily as an interface between the aqueous layer and air. Tear film lipid is composed of a thin layer of polar lipids that interact with the secretory layer of the underlying mucosa and a thicker layer of non-polar lipids at the air interface. The tear film has a complex structure and composition that protects the cornea, promotes wound healing, and maintains high-quality vision. Plasma Rich in Growth Factor (PRGF) eye drops emerged as an exciting new treatment for corneal epitheliopathies, including aqueous deficient dry eye. The purpose of this study was to compare the lipidomic profile of eye drops obtained from PRGF with tear lipidome to determine whether PRGF drops could be an adequate complement to tears in patients with impaired TFLL. To address this study, tears and blood was collected and processed from healthy donors to obtain PRGF eye drops. Samples were aliquoted and stored at -80 °C until use. The lipid profiles of these samples were analysed by Ultrahigh Performance Liquid Chromatography (UHPLC) using a Vanquish UHPLC system to obtain untargeted lipidome profiles on a Q-Exactive HF-X hybrid quadrupole-Orbitrap mass spectrometer. In PRGF eye drops, 408 lipids were identified in ESI+ mode and 183 in ESI- mode, and they were grouped into 15 different lipid classes from four distinct categories. By contrast, 112 lipid species were identified from tear samples in ESI+ mode and 36 in ESI- mode, belonging to 12 lipid classes from six different categories. The relative abundance of most lipid species was much greater in the PRGF eye drops than in the tear, although there were some lipids present in tears that were not found in the PRGF, such as wax esters and (O-acyl)-ω-hydroxy fatty acids. In summary, these results suggest that the lipids present in PRGF eye drops could serve as a tear supplement in individuals in whom tear lipid composition is altered, although there are differences in the lipid profile of these two fluids.

Transcriptome of microglia reveals a species-specific expression profile in bovines with conserved and new signature genes.

Evidence is growing that microglia adopt different roles than monocyte-derived macrophages (MDM) during CNS injury. However, knowledge about their function in the pathogenesis of neuroinfections is only rudimentary. Cattle are frequently affected by neuroinfections that are either zoonotic or related to diseases in humans, and, hence, studies of bovine neuroinfections as a natural disease model may generate fundamental data on their pathogenesis potentially translatable to humans. We investigated the transcriptomic landscape and lineage markers of bovine microglia and MDM. Although bovine microglia expressed most microglial signature genes known from humans and mice, they exhibited a species-specific transcriptomic profile, including strikingly low expression of TMEM119 and enrichment of the two scavenger receptors MEGF10 and LY75. P2RY12 was amongst the most enriched genes in bovine microglia, and antibodies against P2RY12 labeled specifically resting microglia, but also reactive microglia within neuroinfection foci in-situ. On the other hand, F13A1 was amongst the most enriched genes in bovine monocytes and MDM and, additionally, the encoded protein was expressed in-situ in monocytes and MDM in the inflamed brain but not in microglia, making it a promising marker for infiltrating MDM in the brain. In culture, primary bovine microglia downregulated signature genes, expressed markers of activation, and converged their transcriptome to MDM. However, they retained several microglia signature genes that clearly distinguished them from bovine MDM, making them a promising in-vitro tool to study mechanisms of microglia-pathogen interactions.

Safety and Effectiveness of a Single Multiallergen Subcutaneous Immunotherapy in Polyallergic Patients.

BACKGROUND: As the number of allergic sensitizations increases the severity of allergic respiratory diseases worsens. Multiple monoallergen immunotherapy can be accompanied by poor treatment adherence and high costs, single multiallergen immunotherapy needs to prove efficacy whilst maintaining a good safety profile. METHODS: Observational, retrospective, multicenter study using a 2-pollen single undiluted multiallergen subcutaneous immunotherapy (SCIT) in routine clinical practice in Spain. Patients with rhinoconjunctivitis, with/without controlled asthma, sensitized to grass, olive, Parietaria, Cupressus, plane tree and/or Salsola pollen were included. Primary and secondary clinical efficacy endpoints were quality of life (mini Rhinitis Quality of Life Questionnaire (miniRQLQ)) and visual analogue scale (VAS) respectively. All adverse events were documented. RESULTS: Ten centers included 97 patients, median age 32 years. SCIT treatment included combinations of grass mix with olive, Parietaria, Cupressus, plane tree or Salsola or olive with Parietaria, Cupressus or Salsola. The mean duration of SCIT was 1.8 years with a high treatment adherence (73%). Significant improvement in quality of life, nasal and ocular symptoms, activity limitations and practical problems (p< 0.0001) and other symptoms (p= 0.024) was observed. Most patients did not develop asthma-like symptoms and a significant improvement of all allergic symptom severity was perceived. VAS showed a significant improvement in rhinoconjunctivitis and asthma by patients and physicians. Twenty-nine patients experienced adverse reactions, 25 had local and 6 had systemic reactions. CONCLUSIONS: Single undiluted multiallergen SCIT treatment of two different pollens is efficacious and safe in both children and adults, showing that it is a suitable option for the treatment of polyallergic patients.

Human-Machine Interface: Multiclass Classification by Machine Learning on 1D EOG Signals for the Control of an Omnidirectional Robot.

People with severe disabilities require assistance to perform their routine activities; a Human-Machine Interface (HMI) will allow them to activate devices that respond according to their needs. In this work, an HMI based on electrooculography (EOG) is presented, the instrumentation is placed on portable glasses that have the task of acquiring both horizontal and vertical EOG signals. The registration of each eye movement is identified by a class and categorized using the one hot encoding technique to test precision and sensitivity of different machine learning classification algorithms capable of identifying new data from the eye registration; the algorithm allows to discriminate blinks in order not to disturb the acquisition of the eyeball position commands. The implementation of the classifier consists of the control of a three-wheeled omnidirectional robot to validate the response of the interface. This work proposes the classification of signals in real time and the customization of the interface, minimizing the user's learning curve. Preliminary results showed that it is possible to generate trajectories to control an omnidirectional robot to implement in the future assistance system to control position through gaze orientation.

Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis.

OBJETIVE: Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis. METHODS: Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu's arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data. RESULTS: The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression. CONCLUSIONS: Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Genetics of vasculitis.

PURPOSE OF REVIEW: We aim to give an overview of the recent progress in the knowledge of the genetic component of vasculitides. RECENT FINDINGS: Using a state-of-the-art imputation method to analyse the major histocompatibility complex (MHC) region, Ombrello and colleagues narrowed down the association between human leukocyte antigen (HLA)-B51 and Behçet's disease to a model of five amino acids of the HLA-B molecule involved in the binding of the antigen, the interactions with receptors on CD8 T cells and natural killer cells, and the signal peptide of HLA-B, suggesting a crucial role of the cellular cytotoxicity on this disease. Other recent genetic studies have identified several loci with strong effects on vasculitis predisposition, most of them representing important players in the immune and inflammatory response. These associations include ERAP1, CCR1-CCR3, STAT4, KLRC4, GIMAP4, and TNFAIP3 in Behçet's disease; BLK and CD40 in Kawasaki disease; SERPINA1 and SEMA6A in antineutrophil cytoplasmic antibody associated vasculitides; IL12B and FCGR2A/ FCGR2A in Takayasu arteritis; and CECR1 in a newly defined vascular inflammatory syndrome associated with adenosine deaminase (ADA2) deficiency. Although other vasculitides, such as giant cell arteritis (GCA) or immunoglobulin A vasculitis, have not benefitted by the great advantage of the large-scale genetic analyses yet, some interesting associations have been recently suggested, such as the classical functional PTPN22 allele rs2476601 (R620W) with GCA. SUMMARY: The analysis of high-throughput genotyping and exome-sequencing data has produced a considerable advance in the identification of consistent genetic risk factors in vasculitides during the last 3 years. Further collaborative efforts, which will increase the sample size, and the use of custom arrays like the immunochip, will definitively help to better understand the genetic basis of vasculitides and to identify the common and specific molecular pathways underlying their pathophysiology.

Influence of prior use of the same or different effectors in a reaching action.

Use of different effectors in two consecutive actions could generate an attentional shift between the effectors with shorter latencies in the second action of reaching. 18 participants (10 men; M age = 21.3 yr.) participated in an experiment with two main variables: (1) effector switching with two levels (Switching and No Switching), where the participants use or do not use a different motor effector for each action; (2) lifting muscles, i.e., the muscles involved in the first phase of the reaching, with two levels (finger-lifting muscle and palm-lifting muscle). Premotor time, Motor time, Reaction time, Movement time, and Total time were measured. For Premotor, Movement, and Total times, faster responses were observed when there was no switching of the effector. This delay could be due to an attentional shift between motor effectors and its relations with motor processes. Possible applications include the ergonomic design of device controls, considering that the use of the same effector is beneficial when fast reaction times are sought.

A Collaborative Platform for Advancing Automatic Interpretation in ECG Signals.

Numerous papers report the efficiency of the automatic interpretation capabilities of commercial algorithms. Unfortunately, these algorithms are proprietary, and academia has no means of directly contributing to these results. In fact, nothing at the same stage of development exists in academia. Despite the extensive research in ECG signal processing, from signal conditioning to expert systems, a cohesive single application for clinical use is not ready yet. This is due to a serious lack of coordination in the academic efforts, which involve not only algorithms for signal processing, but also the signal acquisition equipment itself. For instance, the different sampling rates and the different noise levels frequently found in the available signal databases can cause severe incompatibility problems when the integration of different algorithms is desired. Therefore, this work aims to solve this incompatibility problem by providing the academic community with a diagnostic-grade electrocardiograph. The intention is to create a new standardized ECG signals database in order to address the automatic interpretation problem and create an electrocardiography system that can fully assist clinical practitioners, as the proprietary systems do. Achieving this objective is expected through an open and coordinated collaboration platform for which a webpage has already been created.

Approach to the care process by nurse case managers in a breast unit.

OBJECTIVE: Breast units led by nurse case managers are being implemented to provide comprehensive care in the detection and treatment of breast cancer. However, their implementation is heterogeneous and the results of the care process with this professional have not been studied. The aim of the study is to describe the management in time and the approach of the process by a nurse case manager in the breast unit of women with suspected breast cancer pathology, derived from the breast cancer screening program. METHODS: Descriptive, cross-sectional, retrospective study carried out in 2021. Women treated in a breast unit managed by a nurse case manager in a hospital in southern Spain were included. Sociodemographic, clinical and care process characteristics were analysed RESULTS: A total of 118 women of Spanish nationality (92%) participated, with a mean age of 59 years. The diagnosis of malignancy was made in 74.6% of them. Seventy-nine percent of the women had their first visit within 3 days. The mean time to diagnosis was 3.98 days (SD: ±3.93), 4.2 weeks (SD: ±1.84) to initiate treatment and a total in-hospital time of 33 days (SD: ±13.45). CONCLUSIONS: The management of nurse case managers in breast units contributes to improving or speeding up times, in accordance with international guidelines, helping this approach in the continuity of the care process for women referred after screening for breast cancer detection.

Association of Neurokinin-1 Receptor Signaling Pathways with Cancer.

BACKGROUND: Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity. METHOD: This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed. CONCLUSION: NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.

Impact of COVID-19 Restrictions in Childbirth and Puerperium: A Cross-Sectional Study.

Introduction (1): The COVID-19 pandemic led to changes in healthcare during pregnancy, childbirth and puerperium. The objective of this study was to know the impact of visit restrictions, PCR performance and use of masks on delivery and puerperium care. Methods (2): A descriptive cross-sectional study was carried out. A survey was used to assess the impact of COVID-19-related measures on women who had given birth in hospitals in the Region of Murcia, Spain, between March 2020 and February 2022. Results (3): The final sample size was 434 women. The average scores were 4.27 for dimension 1 (Visit restrictions), 4.15 for dimension 2 (PCR testing) and 3.98 for dimension 3 (Mask use). More specifically, we found that the restriction of visits was considered a positive measure for the establishment of the mother-newborn bond (mean score 4.37) and that the use of masks at the time of delivery should have been made more flexible (mean score 4.7). Conclusions (4): The policy of restricting hospital visits during the pandemic caused by COVID-19 has been considered beneficial by mothers, who expressed that they did not feel lonely during their hospital stay.

Microbial uptake in oral mucosa-draining lymph nodes leads to rapid release of cytotoxic CD8+ T cells lacking a gut-homing phenotype.

The gastrointestinal (GI) tract constitutes an essential barrier against ingested microbes, including potential pathogens. Although immune reactions are well studied in the lower GI tract, it remains unclear how adaptive immune responses are initiated during microbial challenge of the oral mucosa (OM), the primary site of microbial encounter in the upper GI tract. Here, we identify mandibular lymph nodes (mandLNs) as sentinel lymphoid organs that intercept ingested Listeria monocytogenes (Lm). Oral Lm uptake led to local activation and release of antigen-specific CD8+ T cells that constituted most of the early circulating effector T cell (TEFF) pool. MandLN-primed TEFF disseminated to lymphoid organs, lung, and OM and contributed substantially to rapid elimination of target cells. In contrast to CD8+ TEFF generated in mesenteric LN (MLN) during intragastric infection, mandLN-primed TEFF lacked a gut-seeking phenotype, which correlated with low expression of enzymes required for gut-homing imprinting by mandLN stromal and dendritic cells. Accordingly, mandLN-primed TEFF decreased Lm burden in spleen but not MLN after intestinal infection. Our findings extend the concept of regional specialization of immune responses along the length of the GI tract, with CD8+ TEFF generated in the upper GI tract displaying homing profiles that differ from those imprinted by lymphoid tissue of the lower GI tract.