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Abstract Background The influenza A virus is an important infectious cause of morbidity and mortality in humans and was responsible for 3 pandemics in the 20th century. As the replication of the influenza virus is based on its host's machinery, codon usage of its viral genes might be subject to host selection pressures, especially after interspecies transmission. A better understanding of viral evolution and host adaptive responses might help control this disease. Results Relative Synonymous Codon Usage (RSCU) values of the genes from segment 1 to segment 6 of avian and human influenza viruses, including pandemic H1N1, were studied via Correspondence Analysis (CA). The codon usage patterns of seasonal human influenza viruses were distinct among their subtypes and different from those of avian viruses. Newly isolated viruses could be added to the CA results, creating a tool to investigate the host origin and evolution of viral genes. It was found that the 1918 pandemic H1N1 virus contained genes with mammalian-like viral codon usage patterns, indicating that the introduction of this virus to humans was not through in toto transfer of an avian influenza virus. Many human viral genes had directional changes in codon usage over time of viral isolation, indicating the effect of host selection pressures. These changes reduced the overall GC content and the usage of G at the third codon position in the viral genome. Limited evidence of translational selection pressure was found in a few viral genes. Conclusions Codon usage patterns from CA allowed identification of host origin and evolutionary trends in influenza viruses, providing an alternative method and a tool to understand the evolution of influenza viruses. Human influenza viruses are subject to selection pressure on codon usage which might assist in understanding the characteristics of newly emerging viruses.

Abstract Background Next-generation sequencing produces high-throughput data, albeit with greater error and shorter reads than traditional Sanger sequencing methods. This complicates the detection of genomic variations, especially, small insertions and deletions. Findings Here we describe ParMap, a statistical algorithm for the identification of complex genetic variants, such as small insertion and deletions, using partially mapped reads in nextgen sequencing data. Conclusions We report ParMap's successful application to the mutation analysis of chromosome X exome-captured leukemia DNA samples.

Background: Homeless shelters have emerged as components of the social services network, playing an important role in providing health care to the homeless population. The aim of this study was to evaluate an individualized physical therapy intervention for people experiencing homelessness and to determine the relationship between self-perceived variables., Methods: Pre and post study, setting at the "Santa y Real Hermandad de Nuestra Señora del Refugio y Piedad" homeless shelter in Zaragoza, Spain. Participants were people experiencing homelessness with musculoskeletal disorders who attended a physical therapy service at shelter facilities. A physical therapy program was implemented including health education, exercise and manual therapy, electrotherapy, thermotherapy and bandaging. Demographic variables (age and gender), nationality, employment situation, educational level, pain location, number of painful areas, feeling of loneliness (3-Item Loneliness Scale; values from 3 to 9), pain intensity (Numerical Pain Rating Scale [NPRS]; from 0 to 10) and self-perceived health (Clinical Global Impression [CGI]; from 1 to 7)., Results: Sixty-four homeless people (age of 46.4 ± 10.9 years) participated in the study. Musculoskeletal pain was reported by 98.4% of subjects, with moderate pain intensities (6.1), and 48.4% presenting with pain at multiple sites. Perceptions of loneliness were low (3.7 ± 2.5) and self-perceived health status was moderately ill (3.5 ± 1.7). Positive significant correlations were identified between pain intensity and self-perceived health. The average number of sessions was 1.5 (± 0.8), with manual therapy (35.6%) followed by health education (23.5%) being the most frequently used techniques. Both pain and self-perceived health improved after treatment, even following a brief intervention., Conclusions: This study demonstrates the potentially negative impact of untreated pain on the self-perceived health of homeless individuals with musculoskeletal disorders that should be targeted for consideration. The findings suggest that a paradigm shift in pain management, including a physical therapy service in shelters, is needed to address the rehabilitation demands of these individuals in a real-life context. This study was approved by the Aragon Ethics Committee (PI19/438) and performed according to the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) statement., (© 2024. The Author(s).)

Dysmenorrhea (DYS), or recurrent menstrual pain, is a highly prevalent pain condition among otherwise healthy women. However, the progression of DYS over time and the influence of the menstrual cycle phases need to be better understood. While the location and distribution of pain have been used to assess pain mechanisms in other conditions, they are unexplored in DYS. Thirty otherwise healthy women with severe DYS and 30 healthy control women were recruited into 3 subgroups (n = 10) according to the length of their menstrual history (<5, 5-15, or>15 years since menarche). The intensity and distribution of menstrual pain were recorded. Pressure pain thresholds at abdominal, hip, and arm sites, pressure-induced pain distribution, temporal summation of pain, and pain intensity after pressure cessation over the gluteus medius were assessed at 3 menstrual cycle phases. Compared with the healthy control women, those with DYS showed lower pressure pain thresholds in every site and menstrual cycle phase (P < .05), enlarged pressure-induced pain areas during menstruations (P < .01), and increased temporal summation and pain intensity after pressure cessation in the overall menstrual cycle (P < .05). Additionally, these manifestations were enhanced during the menstrual and premenstrual phases compared to ovulation in women with DYS (P < .01). Women with long-term DYS demonstrated enlarged pressure-induced pain distribution, enlarged menstrual pain areas, and more days with severe menstrual pain compared to the short-term DYS subgroup (P < .01). Pressure-induced and menstrual pain distributions were strongly correlated (P < .001). These findings suggest that severe DYS is a progressive condition underscored by facilitated central pain mechanisms associated with pain recurrence and exacerbation. PERSPECTIVE: Enlarged pressure-induced pain areas occur in DYS, associated with the length of the condition and the distribution of menstrual pain. Generalized hyperalgesia is present throughout the entire menstrual cycle and intensifies during premenstrual and menstrual phases., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Motivation: Here, we performed a benchmarking analysis of five tools for microbe sequence detection using transcriptomics data (Kraken2, MetaPhlAn2, PathSeq, DRAC and Pandora). We built a synthetic database mimicking real-world structure with tuned conditions accounting for microbe species prevalence, base calling quality and sequence length. Sensitivity and positive predictive value (PPV) parameters, as well as computational requirements, were used for tool ranking., Results: GATK PathSeq showed the highest sensitivity on average and across all scenarios considered. However, the main drawback of this tool was its slowness. Kraken2 was the fastest tool and displayed the second-best sensitivity, though with large variance depending on the species to be classified. There was no significant difference for the other three algorithms sensitivity. The sensitivity of MetaPhlAn2 and Pandora was affected by sequence number and DRAC by sequence quality and length. Results from this study support the use of Kraken2 for routine microbiome profiling based on its competitive sensitivity and runtime performance. Nonetheless, we strongly endorse to complement it by combining with MetaPhlAn2 for thorough taxonomic analyses., Availability and Implementation: https://github.com/fjuradorueda/MIME/ and https://github.com/lola4/DRAC/., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2023. Published by Oxford University Press.)

Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3 + T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3 + CD8 + cytotoxic T cells (CTLs, p = .0079), CD3 + CD4 + FOXP3 - T helper cells (T h , p = .0010), and CD3 + CD4 + FOXP3 + regulatory T cells (Tregs, p = .0089) with no difference in CD68 + macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor., Competing Interests: YMS has recieved funding from Regeneron. BTF has financial interests in both Regeneron and Thermo Fisher Scientific. GAM is a consultant for CEND Biopharma and Synthekine, and has recieved funding from MERCK, Roche, BioLine, and Regeneron. None of the disclosures listed are related to this work., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell nonautonomous pathways may help overcome resistance to targeted therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor 1B (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a proinflammatory state in osteoblasts that, through the acute-phase protein serum amyloid A (SAA), acts in a positive feedback loop on leukemia cells by increasing expression of IDO1-the rate-limiting enzyme for kynurenine synthesis-thereby enabling AML progression. This leukemia-osteoblast cross-talk, conferred by the kynurenine-HTR1B-SAA-IDO1 axis, could be exploited as a niche-focused therapeutic approach against AML, opening new avenues for cancer treatment., Significance: AML remains recalcitrant to treatments due to the emergence of resistant clones. We show a leukemia-cell nonautonomous progression mechanism that involves activation of a kynurenine-HTR1B-SAA-IDO1 axis between AML cells and osteoblasts. Targeting the niche by interrupting this axis can be pharmacologically harnessed to hamper AML progression and overcome therapy resistance. This article is highlighted in the In This Issue feature, p. 873., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: and Purpose: Endometriosis-associated pain is the main cause of chronic pelvic pain in women. Endometriosis has a significant negative impact across different domains of patients' quality of life. This study aimed to evaluate the efficacy of an intracavitary application of monopolar dielectric radiofrequency in women with endometriosis-associated pain., Patient Presentation: Five women with endometriosis received 25 sessions of an intracavitary application of monopolar dielectric radiofrequency within three months. Outcomes, including quality of life, sex interference (Endometriosis Health Profile [EHP]-30 + section C), myofascial pain syndrome (myofascial trigger points), pain intensity (Visual Analogue Scale), frequency and referral pattern, pressure pain thresholds, allodynia and neuropathic pain (modified DN4), were examined both during and outside menses, after intervention and six months later., Results: Clinically meaningful improvements were achieved by most participants regarding pelvic pain intensity, abdominal sensitivity, and myofascial pain of the pelvic floor., Conclusion: This study lays the foundation for future in-depth research, suggesting that monopolar dielectric radiofrequency could be helpful in improving the symptomatology and quality of life of women with endometriosis, also in patients who are unresponsive to medical and/or surgical treatments, or who cannot undergo them in the short term., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Musculoskeletal pain is highly prevalent among office workers and causes high costs to the public health system. Strategies including education and exercise are recommended, with major benefits when conducted by physical therapists in the occupational environment. However, the required investment is uncommon among companies. This study aimed to evaluate the efficacy of a multimodal physiotherapy intervention to relieve musculoskeletal pain in office workers., Materials and Methods: The study employed a single group study with a pre-post study design and was conducted at Universidad San Jorge in 2018. Outcome variables were: workplace ergonomics (INSHT Guide), existence and severity of musculoskeletal disorders (Nordic Musculoskeletal Questionnaire), musculoskeletal pain intensity (Numeric Rating Scale), and Clinical Global Impression Scale. Office workers in a university setting ( n = 24, 19 females) were assessed at baseline, after 4 weeks of in-person sessions and following 3 weeks of autonomous performance. The physiotherapy program included education, ergonomic supervision, self-treatment, strengthening, and stretching exercises. A repeated-measures ANOVA or Friedman test (with post hoc comparisons) and Chi-squared test were used to compare the study variables., Results: At baseline, cervical spine (54%), shoulder (42%), and lumbar regions (37.5%) were the most symptomatic regions according to the Nordic Musculoskeletal Questionnaire. Even if the proportion of symptomatic areas did not decrease significantly after the intervention, a great reduction of musculoskeletal pain intensity was observed after the program in the cervical ( P < 0.001), lower back ( P = 0.005), shoulder ( P = 0.006) regions, and in the overall pain level ( P < 0.001)., Conclusions: These results support that a multimodal physiotherapy program can relieve work-related musculoskeletal pain in office workers and serve as a basis for future controlled trials., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Education and Health Promotion.)

An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8 + T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.

Large-scale cancer genomic studies enable the systematic identification of mutations that lead to the genesis and progression of tumors, uncovering the underlying molecular mechanisms and potential therapies. While some such mutations are recurrently found in many tumors, many others exist solely within a few samples, precluding detection by conventional recurrence-based statistical approaches. Integrated analysis of somatic mutations and RNA expression data across 12 tumor types reveals that mutations of cancer genes are usually accompanied by substantial changes in expression. We use topological data analysis to leverage this observation and uncover 38 elusive candidate cancer-associated genes, including inactivating mutations of the metalloproteinase ADAMTS12 in lung adenocarcinoma. We show that ADAMTS12 -/- mice have a five-fold increase in the susceptibility to develop lung tumors, confirming the role of ADAMTS12 as a tumor suppressor gene. Our results demonstrate that data integration through topological techniques can increase our ability to identify previously unreported cancer-related alterations.

Patients who, during admission, begin to use enteral nutrition (EN) and do not recover adequate oral intake need proper planning prior to discharge. The present study is a descriptive analysis of patients discharged with EN from our hospital in 2018. In all, the study included 141 patients (50.3% male) with an average age of 76.18 ± 14 years with the most frequent reasons for enteral support being neurological disease (71.3%) and ear, nose, and throat (ENT) and maxillofacial surgery (17.02%) (others accounted for 11.68%). In these two groups, differences were observed in both the average age (77 vs. 70.5 years) and sex of patients-mostly women (58%) in the first group and men (70%) in the second. Overall, the access routes used were nasogastric tube (76.4%), and percutaneous endoscopic gastrostomy (18.4%); 67.1% of the episodes ended by 30 June, 60.6% of patients died (47% of neurological patients), and 39.3% patients recovered function of the oral passage (85% of surgical/head and neck tumor). The duration of support was as follows: 1-3 months, 32%; 6-12 months, 26.9%; more than 12 months, 18.5%. This indicated some frequent and clearly differentiated profiles in the patients studied, which may contribute to better care and support in order to maintain long-term treatment.

Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Enriched environments and exercise provide complex environmental stimulation that can induce emotional and cognitive changes; however, few studies have evaluated the effects of these two components on other behaviours, such as novelty seeking or pain sensitivity. The aim of the present study was to investigate the influence of voluntary physical activity provided through different housing conditions on anxiety, locomotor activity, pain sensitivity, and exploration. Male mice at postnatal day (PND) 21 and were randomly assigned to one of four different conditions on PND 28: Marlau cages (MC), a standardized cage designed to provide a complex environment; physical exercise in large groups (PE‑8); physical exercise in small groups (PE‑4); or a standard environment (SE). After seven weeks, animals were evaluated in the hole‑board task, the elevated zero maze, actimeter, and hot plate test. In the hole‑board task, MC animals displayed more exploration than animals in the PE‑8 and PE‑4 groups, but no significant differences were observed between groups in the actimeter. In the elevated zero maze, MC and PE‑8 animals exhibited an anxiogenic‑like profile as compared to the SE group. When pain sensitivity was evaluated, the PE‑8 group displayed a higher sensitivity to noxious thermal stimuli than the SE group. These data suggest that the complexity of the environment in which physical activity and environmental stimulation are provided can influence animal behaviours such as novelty seeking, emotional response, and pain sensitivity. These animal models could be useful for designing more personalized interventions that include physical, social, and cognitive stimulation to promote a more active lifestyle in humans. Such interventions could be useful in the prevention and treatment of aging‑related decline or neurodegenerative diseases.