Camilo José Cela University

What is the role played by mechanisms in medical reasoning? In this paper, we provide an inferential study of the use of mechanisms in medical reasoning. Medical reasoning includes clinical reasoning and biomedical research reasoning. It is not conceived in terms of a specific form of inference, but as a complex form of reasoning involving abductions, deductions, and inductions. This methodology sheds a new light on the notion of mechanistic evidence, which has been the object of a regain of interest in recent literature, but which remains unclearly defined. We claim that “mechanistic evidence” is ambiguous: it can mean “evidence of a mechanism” or “mechanism as evidence”. Then, two main groups of medical reasoning can be identified: inference to mechanisms and inference from mechanisms. This serves as a basis to distinguish between factual evidence and the more pragmatic notion of evidence as reasons to accept a claim. In this context, we assess the role of mechanisms in the process of producing evidence.

The prevalence of chronic diseases, including allergies, is increasing in schoolchildren, making school nurses essential in managing students’ health. This study aimed to determine the prevalence of chronic conditions in schoolchildren within a network of Spanish educational centers with school nurses. A descriptive cross-sectional study was conducted in May 2023, covering 25,951 students from these centers. Schoolchildren and educational center data were collected from the school health records to document health information and nursing activities. Mean age of students was 10.11 years (50.20% female). A total of 9.45% had chronic disorders, including disorders of the respiratory (4.14%), neurological (2.94%), digestive (2.28%), musculoskeletal (1.25%), and cardiovascular (1.14%) systems. A total of 12.5% had allergies (6.10% food allergies), and 2.81% had food intolerances. Identifying and recording these diseases are key responsibilities of the school nurse, supporting improved care quality and informing policies to ensure school nurse availability and enhanced health management protocols for students.

Importance Integration of molecular biomarker information into systemic therapy has become standard practice in breast cancer care. However, its implementation in guiding radiotherapy (RT) is slower. Although postoperative RT is recommended for most patients after breast-conserving surgery and, depending on risk factors, following mastectomy, emerging evidence has indicated that patients with low scores on gene expression signatures or selected clinical-pathological features may have very low local recurrence rates. This narrative review explored the potential of biomarker-directed personalized RT approaches, which may optimize treatment strategies and be associated with improved patient outcomes and experiences. Observations Distinctions between prognostic and predictive biomarkers were highlighted, emphasizing the importance of analytical and clinical validity in biomarker-based studies. Findings from studies investigating the prognostic and predictive value of various genomic signatures and immunohistochemical markers for guiding breast RT were presented. These included the Adjuvant Radiotherapy Intensification Classifier and the Profile for the Omission of Local Adjuvant Radiation, which have shown potential in predicting RT benefits. The genomic-adjusted radiation dose and role of tumor-infiltrating lymphocytes were also discussed. Ongoing clinical trials exploring the use of biomarkers in ductal carcinoma in situ and invasive breast cancer to refine RT decision-making were illustrated. Conclusions and Relevance The results of this narrative review suggest that evidence-based shared decision-making is crucial to optimize treatment according to the individual’s predicted benefits and risks along with their personal preferences. Incorporation of biomarker-directed approaches in RT for breast cancer may hold promise for personalized treatment, potentially facilitating omission of RT for patients at low risk of recurrence, while identifying those who may benefit from intensified therapy. This personalized RT approach may be associated with improved clinical outcomes and quality of life and facilitate decision-making for people with breast cancer. However, there remains a need for robust clinical and analytical validation of biomarkers to ensure reliability and clinical utility for RT optimization.

As living organisms, our systems experience constant changes. Over time, the accumulation of small alterations leads to a loss of function across all body subsystems and eventually disease and death. This phenomenon, known as the aging process, occurs in both healthy and pathological conditions and is characterized by significant alterations in the brain oscillatory activity. Magnetoencephalography (MEG) and Electroencephalography (EEG) are noninvasive functional neuroimaging techniques able to measure, respectively, the weak magnetic fields and electric potentials generated by electric currents flowing inside the brain. The notable temporal and spatial resolution of such techniques makes them suitable both for resting state and task-based studies, depending on the experiment goals. This chapter delves into the nature of the neurophysiological signals that can be recorded through M/EEG and how they can aid in the characterization of the hallmarks of healthy and pathological aging, as in the case of Alzheimer’s disease. It also provides an overview of the influence of lifestyle in the promotion of a healthy neurophysiological profile.

Previous research has focused on the possibility of cervical dysfunction in migraine patients, similar to what is observed in patients with tension-type headaches. However, there is no evidence concerning the physical function of other body regions, even though lower levels of physical activity have been reported among migraine patients. The aim of this study was to compare cervical and extra-cervical range of motion, muscular strength, and endurance, as well as overall levels of physical activity, between patients with chronic migraine (CM) and asymptomatic participants. The secondary objective included the analysis of associations between CM-related disability and various physical and psychological variables. A total of 90 participants were included in this cross-sectional study: 30 asymptomatic participants (AG) and 60 patients with CM. Cervical and lumbar range of motion, strength and endurance, as well as handgrip strength were measured. Headache-related disability, kinesiophobia, pain behaviors, physical activity level and headache frequency were assessed through a self-report. Lower values were found in CM vs AG for cervical and lumbar ranges of motion (p < 0.05; effect sizes ranging from 0.57 to 1.44). Also, for neck extension strength (p = 0.013; d = − 0.66), lumbar strength (p < 0.001; d = − 1.91) and handgrip strength (p < 0.001; d = − 0.98), neck endurance (p < 0.001; d = − 1.81) and lumbar endurance (p < 0.001; d = − 2.11). Significant differences were found for physical activity levels (p = 0.01; d = − 0.85) and kinesiophobia (p < 0.001; d = − 0.93) between CM and AG. Headache-related disability was strongly associated with headache frequency, activity avoidance, and rest, which together explained 41% of the variance. The main findings of this study suggest that patients with CM have a generalized fitness deficit and not specifically cervical dysfunction. These findings support the hypothesis that migraine patients have not only neck-related issues but also general body conditions.

Background Human adamantinomatous craniopharyngioma (ACP) is a brain tumor that originates at the base of the skull and shows aggressive local behavior, invading sensitive structures such as the optic pathways and hypothalamus. The conventional treatment of the tumor has been surgery and radiotherapy with the consequent development of serious sequelae. It is well known that Substance P (SP) peptide and Neurokinin-1 receptor (NK-1R) are involved in inflammation and cancer progression and its blockage with NK-1R antagonists has been shown to effectively counteract tumor development in preclinical trials. The oncogenic mechanism underlying ACP is based on a secretory phenotype associated with the production of paracrine biomarkers that establish an inflammatory and angiogenic microenvironment for the progression of ACP. Methods With the aim of describing the existence and distribution of SP/NK-1R in the ACP, we studied by immunohistochemistry the expression of SP and NK-1R in 43 human ACP and compared with healthy pituitary gland samples. Results SP and the NK-1R were overexpressed in all ACP more than in pituitary glands samples. SP expression is found widespread the ACP and is preferentially localized in the nucleus than in cytoplasm of tumor cells. Likewise, areas of glial reaction and endothelial cells also express SP preferentially in the cell nuclei. NK-1R is expressed mainly in the glial reaction, especially in the nuclei and membranes of its inflammatory cells and less prominently in the cytoplasm. In ACP neovessels, NK-1R is expressed in endothelial cells and fibroblasts that constitute their basement membranes. Tumor cells did not show significant NK-1R expression. Conclusions These findings, reported here for the first time, suggest a role for SP and NK-1R in pituitary gland and ACP and opens the door to future clinical trials on treatment with NK-1R antagonist drugs in ACP patients.

Background The fatigue of the inspiratory musculature, particularly the diaphragm, has been demonstrated to exert systemic effects on the body, impacting cardiovascular and performance outcomes. This study aimed to evaluate the influence of an inspiratory muscle fatigue protocol on respiratory muscle strength, functionality, and muscle oxygen saturation in older adults. Methods A single-blinded randomized controlled clinical trial was conducted on twenty-four older adults aged over 60 years, who met inclusion criteria were physically independent in terms of gait and functionality. Participants were randomly assigned to one of three groups: control group, inspiratory muscle fatigue group, or activation group. Diaphragmatic ultrasonography (diaphragmatic thickness, thickening fraction, diaphragm movement curve), maximal inspiratory mouth pressure, muscle oxygen saturation, and functionality (timed up and go test, for five times sit to stand test) were used to measure the study variables at two time points: pre-intervention (T1) and post-intervention (T2). Results In the maximum inspiratory pressure variable in the activation group an increase was found between baseline and post-treatment of 3.00 ± 0.93 cmH2O (P < 0.01), while in the inspiratory muscle fatigue a decrease of -6.75 ± 2.66 cmH2O (P < 0.01) was found. In addition, the inspiratory muscle fatigue group showed lower scores for respiratory and functional variables after performing the diaphragmatic fatigue intervention than the activation and control group (P < 0.05), on the other hand, the activation group showed more positive values for functional and respiratory capacity variables after performing the inspiratory muscle activation training (P < 0.05). Conclusions Fatigue of the inspiratory musculature appears to negatively impact inspiratory muscle strength, peripheral muscle strength, muscular oxygenation, and functionality in older adults. Activation of the inspiratory musculature could contribute to improved respiratory muscle strength and function in these individuals. Trial registration ClinicalTrials.gov ID: NCT06266013.

Objective To evaluate the efficacy of neoadjuvant chemotherapy combination with liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin in patients with locally advanced rectal cancer. Methods This was a phase 2, nonrandomized, multicenter study in adults with stage II or III rectal cancer and an Eastern Cooperative Oncology Group performance status of 0 to 1. Total neoadjuvant therapy (TNT) consisted of neoadjuvant chemotherapy combination with liposomal irinotecan (60 mg/m ² ), oxaliplatin (60 mg/m ² ), leucovorin (400 mg/m ² ), and fluorouracil (2400 mg/m²), followed by chemoradiotherapy [ie, capecitabine (825 mg/m ² ) and radiotherapy according to the standard of care]. The primary efficacy endpoint was the proportion of patients who achieved clinical complete response (cCR), defined as the normalization of pelvic magnetic resonance imaging, rectoscopy, computed tomography scan, and tumor markers. Results The median follow-up was 32.3 months. Of the 30 patients who underwent TNT and were evaluated, 6 (20.0%; 95% CI: 5.2%-34.8%) patients achieved a cCR. There were no deaths. The median disease-free survival (DFS) for patients with cCR was not reached after a follow-up of 32 months; the 1-year DFS rate was 90.0% (95% CI: 71.0%-100%), and the 2-year and 3-year DFS rates were 80.0% (95% CI: 55.0%-100%). No grade ≥4 adverse events (AEs) were observed. Grade 3 AEs occurred in 18 patients (60%), most frequent was diarrhea (n = 9, 30%). Eleven (36.7%) patients experienced serious AEs, with diarrhea being the most frequent (n = 6, 20.0%). Conclusion TNT with 5-fluorouracil, leucovorin, and oxaliplatin and chemoradiation is a safe and effective therapeutic alternative for the management of locally advanced rectal cancer.

García-Sánchez, C, Jiménez-Ormeñ o, E, Lominchar-Ramos, JM, Giráldez-Costas, V, McMahon, JJ, and Soriano, MA. Effects of a short-term detraining period on neuromuscular performance in female handball players. J Strength Cond Res XX(X): 000-000, 2024-The aim of this study was to determine the effects of a 3-week detraining period on lower limbs' neuromuscular performance in female handball players. Fourteen semi-professional players (age: 20.50 6 2.98 years; height: 1.67 6 0.06 m; body mass: 66.89 6 8.75 kg) were evaluated using force plates on 3 separate occasions to assess the maximum and rapid force production by the isometric mid-thigh pull (IMTP) and the ballistic capabilities by countermovement jump (CMJ). The intraclass correlation coefficient, coefficient of variation, standard error of the measurement, and smallest detectable difference were calculated using the first 2 testing sessions. Pre-and postdetraining differences were calculated comparing the first and third testing sessions, using paired t-tests or Wilcoxon test when appropriate and Hedges g effect sizes (ES). The level of significance was set at r # 0.05. There were no significant or meaningful differences in maximum and rapid force production capabilities assessed during the IMTP (p. 0.05). However, there was a significant detriment with small ES in CMJ jump height, modified reactive strength index, peak and mean propulsive force, peak and mean braking force, and braking phase duration (p , 0.05). These findings suggest that although maximum and rapid force production capabilities were not altered among female handball players after a 3-week detraining period, their ballistic capabilities decreased, especially those affecting the eccentric part of a fast dynamic task. They also highlight the importance of testing, planning, and programming in response to the fluctuations in handball players' physical performance over the season.

The subthalamic nucleus (STN) modulates basal ganglia output and plays a fundamental role in the pathophysiology of Parkinson’s disease (PD). Blockade/ablation of the STN improves motor signs in PD. We assessed the topography of focused ultrasound subthalamotomy ( n = 39) by voxel-based lesion-symptom mapping to identify statistically validated brain voxels with the optimal effect against each cardinal feature and their respective cortical connectivity patterns by diffusion-weighted tractography. Bradykinesia and rigidity amelioration were associated with ablation of the rostral motor STN subregion connected to the supplementary motor and premotor cortices, whereas antitremor effect was explained by lesioning the posterolateral STN projection to the primary motor cortex. These findings were corroborated prospectively in another PD cohort ( n = 12). This work concurs with recent deep brain stimulation findings that suggest different corticosubthalamic circuits underlying each PD cardinal feature. Our results provide sound evidence in humans of segregated anatomy of subthalamic-cortical connections and their distinct role in PD pathophysiology and normal motor control.

FOXO transcription factors belong to the forkhead protein family and are distinguished by their unique forkhead (FKH) DNA-binding domain. In the realm of mammals, four FOXO paralogs are recognized: FOXO1, FOXO3, FOXO4, and FOXO6. These paralogs are evolutionary counterparts of the daf-16 gene discovered in the nematode C. elegans. A key feature shared by these paralogs is a consensus binding site known as the DAF-16 family protein-binding site (DBE: 5′-TTGTTTAC-3′). The functional outcome of FOXO transcription factors primarily hinges on their affinity for these specific binding sites within the promoters of their target genes. Nevertheless, it is worth noting that many of these target genes exhibit tissue-specific expression patterns. Consequently, there is not a single FOXO target gene whose expression can reliably serve as a universal indicator of FOXO activity across all cell types and tissues or in response to all stimuli. In light of these considerations, we present a collection of target genes that, when collectively assessed, can accurately gauge FOXO activation. In this chapter, we outline a specific protocol for utilizing quantitative reverse transcription polymerase chain reaction (qRT-PCR) to measure the expression levels of these genes.

FOXO3 is a transcription factor that mainly exerts its functions in the cell nucleus. The amino acid sequence of FOXO3 contains a nuclear localization sequence (NLS) and a nuclear export sequence (NES) allowing for nuclear/cytoplasmic shuttling that plays an important role in regulating FOXO3 activity. Nuclear accumulation of FOXO3 proteins can be the result of translocation to the nucleus triggered by upstream regulatory input or trapping of FOXO3 within the nucleus through the inhibition of its nuclear export via the receptor CRM1. In order to distinguish these two modes of FOXO3 activation, we have generated a multiplexed assay. The development of this platform includes a reporter cell line that monitors CRM1 activity by using RFP-labeled HIV-1 Rev. protein with a strong heterologous NES. Simultaneously, the intracellular localization of FOXO3 can be monitored by a second cell line stably expressing GFP-FOXO3. Here we describe a detailed protocol on how to co-culture these reporter cell lines and use them to interrogate compound-induced FOXO3 activation in order to understand the mode of action.

The forkhead box O (FOXO) family of transcription factors translates environmental cues into precise gene expression patterns maintaining cellular equilibrium while influencing critical determinations of cell destiny and differentiation. FOXO proteins exert their effects through specific consensus binding to promoter sites within target genes. Notably, among the array of techniques available for assessing the transcriptional activity of FOXO factors, the utilization of luciferase-based reporters emerges as particularly distinctive. Luciferase, an enzyme sourced from bioluminescent organisms, instigates the oxidation of luciferin, culminating in the generation of oxyluciferin accompanied by discernible luminescence, a quantifiable event readily gauged using a luminometer. The adoption of luciferase activity as a measure in transcriptional assays is widespread due to its numerous advantages including simplicity, remarkable reproducibility, and high sensitivity. Moreover, the continuous advancements witnessed in luciferase-based vectors and measurement reagents bestow notable flexibility upon this methodology. Luciferase-based reporters offer a powerful tool for uncovering constituents within the signaling pathways governing FOXO factor function. Furthermore, these assays are also suitable for evaluating the efficacy of FOXO-targeting agents, whether they be inhibitors or activators. Here, we present a comprehensive, step-by-step elucidation of a commonly employed assay, adeptly quantifying the potential of small molecular compounds to amplify FOXO-specific transcriptional activity in U2OS cells.

Background Previous studies correlated Sensititre YeastOne and gradient diffusion plastic strips with standard procedures for the detection of echinocandin‐resistant C. glabrata isolates. However, these studies were limited by the low number of resistant isolates studied; the inclusion of sufficient numbers of mutant isolates is essential to test the procedures' capacity to detect resistance. Objective We assessed the performance of Sensititre YeastOne and Etest strips to detect echinocandin resistance in susceptible or resistant C. glabrata isolates ( n = 80) in which the FKS genes were sequenced, and MICs interpreted using EUCAST and CLSI breakpoints. Patients/Methods Isolates were echinocandin‐susceptible ( n = 50) or echinocandin‐resistant according to EUCAST 7.4 methodology. Echinocandin susceptibility using Sensititre YeastOne and Etest strips and categorical agreement were assessed. Results All except one anidulafungin‐resistant isolate had an anidulafungin Sensititre YeastOne MIC ≥ 0.25 mg/L, while most micafungin‐resistant isolates had a MIC ≥ 0.25 mg/L. Likewise, all anidulafungin‐resistant isolates had an anidulafungin Etest strip‐obtained MIC ≥ 0.03 mg/L, whereas micafungin‐resistant isolates were ≥ 0.125 mg/L. Overall, these commercial methods correctly classified > 90% of isolates by using any breakpoint. Despite the low number of errors detected, these were mostly false resistance (major errors) with EUCAST breakpoints and false susceptibility (very major errors) with CLSI breakpoints. Conclusions Sensititre YeastOne and Etest strips were suitable procedures to detect echinocandin resistance in C. glabrata . The high number of FKS mutants included reinforces our study and opens the door for multicentre validations.

Background Although psychological factors play a significant role in the onset and prognosis of acute coronary syndrome (ACS), psychological interventions (PIs) are rarely included in cardiac rehabilitation (CR) programs due to inconclusive evidence regarding specific intervention components and effect sizes. This study aimed to assess the efficacy of a PI based on cognitive-behavioral treatment (CBT) and positive psychology therapy (PPT) in improving psychological and clinical outcomes in patients with ACS. Methods This PsicoCare trial was an open-label randomized controlled trial that compared a combined CBT and PPT-based PI (the PsicoCare program) with a standard CR program (control group). We recruited 87 ACS patients, and psychological outcomes, functional capacity, biochemical and anthropometric measures, and clinical outcomes were assessed at baseline, 2 months, and 9 months after the ACS event. Results The PsicoCare group showed significant improvements in depression, anger traits, anger-in, and anger control-out compared to the control group. Additionally, the PsicoCare intervention was associated with the improved maintenance of cognitive function, social support, and spiritual coping styles, while the control group showed deterioration in these areas. Patients experiencing severe ACS showed significant improvement in personal strength and meaning as a result of the PsicoCare intervention. However, no significant effects were observed on anxiety, anger-out, emotion regulation skills, dispositional optimism, other personal strengths, or quality of life. Both groups demonstrated similar improvements in functional capacity and clinical outcomes. Conclusion The study suggests that CBT and PPT-based PIs may offer additional benefits for ACS patients, particularly regarding their psychological health. Further larger trials are required to confirm these findings. Clinical trial registration identifier, NCT05287061.

Background: Motor impairments limit the functional abilities of patients after stroke; it is important to identify low-cost rehabilitation avenues. The aim of this study is to determine the effectiveness of thermal stimulation in addition to conventional therapy for functional recovery in post-stroke patients. Methods: An electronic search was performed in the MEDLINE, Scopus, Web of Science, EMBASE, CINAHL, SPORTDiscus, Epistemonikos, LILACS, and PEDro databases. The eligibility criterion was randomized clinical trials that analyzed the clinical effects of thermal stimulation plus conventional therapy. Two authors independently performed the search, study selection, data extraction, and risk of bias assessment. Results: Eight studies met the eligibility criteria, and six studies were included in the quantitative synthesis. For thermal stimulation plus conventional therapy versus conventional therapy alone, the mean difference (MD) for function was 6.92 points (95% CI = 4.36–9.48; p < 0.01), for motor function was 6.31 points (95% CI = 5.18–7.44; p < 0.01), for balance was 4.41 points (95% CI = −2.59–11.4; p = 0.22), and for walking was 1.01 points (95% CI = 0.33–1.69; p < 0.01). For noxious thermal stimulation versus innocuous thermal stimulation, the MD for activities of daily living was 1.19 points (95% CI = −0.46–2.84; p = 0.16). Conclusions: In the short term, adding thermal stimulation to conventional therapy showed statistically significant differences in functional recovery in post-stroke patients. The quality of evidence was high to very low according to GRADE rating. The studies included varied in the frequency and dosage of thermal stimulation, which may affect the consistency and generalizability of the results. A larger quantity and a better quality of clinical studies are needed to confirm our findings. PROSPERO registration: CRD42023423207.

Background Current research relates jaw clenching to athletic performance, in terms of force and agility. However, the impact of jaw clenching on sports accuracy is unclear. Objectives To analyse the impact of jaw position and chewing type on free‐throw accuracy and electromyographic (EMG) activity of masticatory muscles during free‐throws. Methods Cross‐sectional study with 25 female basketball players aged 18–44. Each participant executed 18 free‐throws under three different jaw conditions: mandibular rest, maximum intercuspation, and with interdental cotton rolls, in randomised order. Results Chewing type and jaw position were not associated with shooting accuracy ( p = 0.106; p = 0.778). There was a positive correlation between EMG activity of the right masseter and free‐throw accuracy at maximum intercuspation ( r s = 0.402; p = 0.046). In contrast, negative correlations were found with other muscles when the occlusal vertical dimension was altered ( r s = −0.619, p = 0.001; r s = −0.490; p = 0.013; r s = −0.534; p = 0.006). The chewing type affected the EMG of the left masseter in the altered occlusal vertical dimension ( H = 6.969; p = 0.031). Significant differences in EMG recordings were observed across different mandibular positions during free‐throws ( p < 0.001). Conclusions While jaw positioning and chewing type do not impact free‐throw accuracy in amateur female basketball players, the EMG activity of masticatory muscles is linked to shooting performance. This highlights the need for further research on motor behaviour of masticatory muscles in precision sports, especially for athletes using intraoral devices.

Background: Caffeine is a widely recognized ergogenic aid for enhancing exercise performance. However, its effect on throwing performance has been less studied, yielding contradictory results. Objectives: The main aim of the study was to analyze the potential ergogenic effects of a moderate dose of caffeine (3 mg·kg⁻¹ body mass) on vertical jump performance and throwing distance during a simulated competition in trained discus and hammer throwers. Methods: In a randomized, counterbalanced, and repeated measures design, 14 well-trained throwers (9 hammer throwers and 5 discus throwers; age 24.8 ± 6.3 years old, training 14.9 ± 5.0 h per week, competing experience 10.5 ± 6.1 years) performed a countermovement jump (CMJ) test, a modified throw, and a complete throw after the ingestion of 3 mg·kg⁻¹ body mass of caffeine or a placebo. Each participant performed three maximal-effort valid modified throws of his/her respective event (i.e., hammer or discus throw), plus three maximal-effort valid official throws (up to five tries, respectively, in case any attempt was called as foul). Throwing distance was measured according to World Athletics regulations using a metal tape, while release speed was assessed with a radar device. After the performance measurements, participants completed a form about side effects prevalence. Results: Caffeine, compared to placebo, increased throw distance (3.0 ± 5.1%, p = 0.048) and speed release (5.7 ± 8.7%, p = 0.03) for the complete throw, and distance (3.6 ± 4.4%, p = 0.01) and speed release (4.8 ± 7.4 %, p = 0.01) for the modified throw. Caffeine ingestion did not significantly improve jump height (1.1 ± 4.3%, p = 0.28), although it improved force and power on braking and the propulsive phases of the CMJ (p < 0.05). Caffeine only increased the prevalence of activeness (p < 0.05). Conclusions: An acute moderate dose of caffeine enhanced hammer and discus throw performance in well-trained throwers during a simulated competitive setting, with minimal adverse side effects.