The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.

A detailed understanding of molecular responses to a hypertrophic stimulus in skeletal muscle leads to therapeutic advances aimed at promoting muscle mass. To decode the molecular factors regulating skeletal muscle mass, we utilized a 24-h time course of human muscle biopsies after a bout of resistance exercise. Our findings indicate: (1) the DNA methylome response at 30 min corresponds to upregulated genes at 3 h, (2) a burst of translation- and transcription-initiation factor-coding transcripts occurs between 3 and 8 h, (3) changes to global protein-coding gene expression peaks at 8 h, (4) ribosome-related genes dominate the mRNA landscape between 8 and 24 h, (5) methylation-regulated MYC is a highly influential transcription factor throughout recovery. To test whether MYC is sufficient for hypertrophy, we periodically pulse MYC in skeletal muscle over 4 weeks. Transient MYC increases muscle mass and fiber size in the soleus of adult mice. We present a temporally resolved resource for understanding molecular adaptations to resistance exercise in muscle ( http://data.myoanalytics.com ) and suggest that controlled MYC doses influence the exercise-related hypertrophic transcriptional landscape.

Scaling and periorificial crusts in a pediatric patient.

This case reports a 14-month-old child with Staphylococcal Scalded Skin Syndrome (SSSS). The child presented generalized scaling erythema accompanied by skin pain, and perioral crusts and fissures and she required hospital admission for antibiotic treatment with intravenous cloxacillin and hidroelectrolyte replacement.SSSS is a blistering skin disorder, mainly affecting children, caused by specific Staphylococcus aureus strains producing exfoliative toxins. It shows erythema in skin folds progressing to blisters within 48 h, often with perioral crusts and fissures. Its diagnosis relies on clinical assessment and it often requires intravenous antibiotics for its treatment.

Gianotti-Crosti syndrome mimicking scabies.

This case report highlights a case of a 65-year-old woman who presented to our clinic with suspicion of refractory scabies. She had undergone multiple treatments without improvement. However, the clinical condition was not scabies but rather Gianotti-Crosti Syndrome (GCS), leading to rapid clinical improvement and avoiding the need for further unnecessary tests and treatments. GCS is a postviral exanthem characterized by symmetrical, red papules on the extremities and buttocks, typically occurring in children but can also affect adults. It is crucial for every physician to distinguish it from other causes of rash, including scabies, to ensure an accurate diagnosis and appropriate management.

Flow starvation during square-flow assisted ventilation detected by supervised deep learning techniques.

BACKGROUND: Flow starvation is a type of patient-ventilator asynchrony that occurs when gas delivery does not fully meet the patients' ventilatory demand due to an insufficient airflow and/or a high inspiratory effort, and it is usually identified by visual inspection of airway pressure waveform. Clinical diagnosis is cumbersome and prone to underdiagnosis, being an opportunity for artificial intelligence. Our objective is to develop a supervised artificial intelligence algorithm for identifying airway pressure deformation during square-flow assisted ventilation and patient-triggered breaths. METHODS: Multicenter, observational study. Adult critically ill patients under mechanical ventilation > 24 h on square-flow assisted ventilation were included. As the reference, 5 intensive care experts classified airway pressure deformation severity. Convolutional neural network and recurrent neural network models were trained and evaluated using accuracy, precision, recall and F1 score. In a subgroup of patients with esophageal pressure measurement (ΔPes), we analyzed the association between the intensity of the inspiratory effort and the airway pressure deformation. RESULTS: 6428 breaths from 28 patients were analyzed, 42% were classified as having normal-mild, 23% moderate, and 34% severe airway pressure deformation. The accuracy of recurrent neural network algorithm and convolutional neural network were 87.9% [87.6-88.3], and 86.8% [86.6-87.4], respectively. Double triggering appeared in 8.8% of breaths, always in the presence of severe airway pressure deformation. The subgroup analysis demonstrated that 74.4% of breaths classified as severe airway pressure deformation had a ΔPes > 10 cmH2O and 37.2% a ΔPes > 15 cmH2O. CONCLUSIONS: Recurrent neural network model appears excellent to identify airway pressure deformation due to flow starvation. It could be used as a real-time, 24-h bedside monitoring tool to minimize unrecognized periods of inappropriate patient-ventilator interaction.

Circulating immune cell populations at rest and in response to acute endurance exercise in young adults with cerebral palsy.

AIM: The aim of this observational study was to determine the immune status and function in young adults with cerebral palsy (CP) in comparison to typically developing individuals. METHOD: Blood samples from 12 individuals with CP (five males, seven females; mean age: 25 years 1 month (5 years 9 months); age range: 19-38 years) and 17 typically developing individuals (eight males, nine females; mean age: 31 years 4 months (6 years 2 months); age range: 20-40 years) were collected before, immediately after, and 1 hour after 45 minutes of frame running or running respectively. Independent t-tests were used to compare heart rate, level of exertion, and baseline cell proportions between groups. Mixed model analysis of variance was utilized to investigate immune cell responses to exercise across groups. RESULTS: Baseline levels of gamma delta (TCRγδ+) T-cells were significantly higher (absolute percentage: +2.65, p = 0.028) in the individuals with CP. Several cell populations showed similar significant changes after exercise in both CP and typically developing groups. Cytotoxic (CD8+) T-cells were only significantly elevated immediately after exercise in the typically developing participants (p < 0.01). Individuals with CP exhibited significantly lower heart rates (-11.1%, p < 0.01), despite similar ratings of perceived exertion. INTERPRETATION: Elevated baseline TCRγδ+ T-cells may indicate low-grade inflammation in adults with CP. Although most of the cell populations showed typical responses to endurance exercise, the absence of response in CD8+ T-cells in individuals with CP may indicate the need for higher intensity during exercise. WHAT THIS PAPER ADDS: TCRγδ+ T-cell baseline levels are elevated in adults with cerebral palsy (CP). The CD8+ T-cell response to exercise was blunted in adults with CP. Exercise intensity is decisive for CD8+ T-cell responses in individuals with CP.

Personality and gender prototypes for predicting health: a multilevel and cluster analysis.

Prior studies have identified that mentally healthy people tend to share common characteristics and common ways of coping with stressful life events; they show similar patterns of behavior and more flexible and adaptive social roles. The objectives of the study are to assess the influence of personality factors on gender roles and mental health, to identify personality patterns along with gender roles, and to assess the influence of the patterns identified on mental health. Data collection from a sample of 795 university students was carried out during 2019. Multilevel analyses tested the associations between gender (BSRI) and personality (TIPI) and between personality and health -mental health (GHQ12) and wellbeing (MHC-SF). Cluster analysis explored tendencies of gender and personality, and each cluster showed different health patterns. Individuals with high scores in extraversion, conscientiousness, emotional stability, openness to experience, and very high agreeableness score, as well as high femininity and masculinity scores, presented a decreased psychological morbidity (ß= -3.62, 0.57 (SE), p<0.001) and an increased well-being (ß=7.68, 1.15 (SE), p<0.001). The most relevant indicators of mental health were identified in androgynous individuals, those individuals with high scores in masculinity and femininity, as well as high scores in extraversion, openness to experience, emotional stability, agreeableness, and conscientiousness.

Characterization of postintensive care syndrome in a prospective cohort of survivors of COVID-19 critical illness: a 12-month follow-up study.

PURPOSE: Studies integrating an exhaustive longitudinal long-term follow-up of postintensive care syndrome (PICS) in critically ill COVID-19 survivors are scarce. We aimed to 1) describe PICS-related sequelae over a 12-month period after intensive care unit (ICU) discharge, 2) identify relevant demographic and clinical factors related to PICS, and 3) explore how PICS-related sequelae may influence health-related quality of life (HRQoL) in critically ill COVID-19 survivors. METHODS: We conducted a prospective cohort study in adult critically ill survivors of SARS-CoV-2 infection that did or did not need invasive mechanical ventilation (IMV) during the COVID-19 pandemic in Spain (March 2020 to January 2021). We performed a telemedicine follow-up of PICS-related sequelae (physical/functional, cognitive, and mental health) and HRQoL with five data collection points. We retrospectively collected demographic and clinical data. We used multivariable mixed-effects models for data analysis. RESULTS: We included 142 study participants in the final analysis, with a median [interquartile range] age of 61 [53-68] yr; 35% were female and 59% needed IMV. Fatigue/dyspnea, pain, impaired muscle function, psychiatric symptomatology and reduced physical HRQoL were prominent sequelae early after ICU discharge. Over the 12-month follow-up, functionality and fatigue/dyspnea improved progressively, while pain remained stable. We observed slight fluctuations in anxiety symptoms and perception of cognitive deficit, whereas posttraumatic stress disorder (PTSD) and depressive symptoms improved, with a mild rebound at the end of the follow-up. Female sex, younger age, and the need for IMV were risk factors for PICS, while having higher cognitive reserve was a potential protective factor. Physical HRQoL scores showed a general improvement over time, whereas mental HRQoL remained stable. Shorter ICU stay, better functionality, and lower scores for fatigue/dyspnea and pain were associated with better physical HRQoL, while lower scores for anxiety, depression, and PTSD were associated with better mental HRQoL. CONCLUSIONS: Postintensive care syndrome was common in COVID-19 critical illness survivors and persisted in a significant proportion of patients one year after ICU discharge, impacting HRQoL. The presence of risk factors for PICS may identify patients who are more likely to develop the condition and who would benefit from more specific and closer follow-up after ICU admission. STUDY REGISTRATION: ClinicalTrials.gov ( NCT04422444 ); first submitted 9 June 2020.

RéSUMé: OBJECTIF: Les études intégrant un suivi longitudinal exhaustif à long terme des syndromes post-soins intensifs (SPSI) chez les survivant·es gravement malades de la COVID-19 sont rares. Notre objectif était 1) de décrire les séquelles liées au SPSI sur une période de 12 mois après la sortie de l'unité de soins intensifs (USI), 2) d'identifier les facteurs démographiques et cliniques pertinents liés au SPSI, et 3) d'explorer comment les séquelles liées au SPSI peuvent influencer la qualité de vie liée à la santé (QVLS) chez les survivant·es gravement malades de la COVID-19. MéTHODE: Nous avons mené une étude de cohorte prospective chez des adultes gravement malades survivant·es d'une infection par le SRAS-CoV-2 qui ont eu ou non besoin d'une ventilation mécanique invasive (VMI) pendant la pandémie de COVID-19 en Espagne (mars 2020 à janvier 2021). Nous avons effectué un suivi par télémédecine des séquelles liées au SPSI (santé physique/fonctionnelle, cognitive et mentale) et à la QVLS avec cinq points de collecte de données. Nous avons rétrospectivement colligé des données démographiques et cliniques. Des modèles multivariés à effets mixtes ont été utilisés pour l'analyse des données. RéSULTATS: Nous avons inclus 142 participant·es à l'étude dans l'analyse finale, avec un âge médian [intervalle interquartile] de 61 [53-68] ans; 35 % étaient des femmes et 59 % avaient besoin de VMI. La fatigue/dyspnée, la douleur, l'altération de la fonction musculaire, la symptomatologie psychiatrique et la réduction de la QVLS physique étaient des séquelles importantes peu après la sortie de l'USI. Au cours du suivi de 12 mois, la fonctionnalité et la fatigue/dyspnée se sont améliorées progressivement, tandis que la douleur est restée stable. Nous avons observé de légères fluctuations des symptômes d'anxiété et de perception du déficit cognitif, tandis que le trouble de stress post-traumatique (ESPT) et les symptômes dépressifs se sont améliorés, avec un léger rebond à la fin du suivi. Le sexe féminin, un jeune âge et le besoin de VMI étaient des facteurs de risque de SPSI, tandis qu'une réserve cognitive plus élevée était un facteur potentiel de protection. Les scores physiques de la QVLS ont montré une amélioration générale au fil du temps, tandis que la QVLS mentale est restée stable. Un séjour plus court aux soins intensifs, une meilleure fonctionnalité et des scores plus faibles pour la fatigue/dyspnée et la douleur étaient associés à une meilleure QVLS physique, tandis que des scores plus faibles pour l'anxiété, la dépression et le ESPT étaient associés à une meilleure QVLS mentale. CONCLUSION: Le syndrome post-soins intensifs était fréquent chez les survivant·es d'une maladie grave de la COVID-19 et a persisté chez une proportion importante de patient·es un an après leur sortie de l'unité de soins intensifs, ce qui a eu un impact sur la QVLS. La présence de facteurs de risque de SPSI peut identifier les patient·es qui sont plus susceptibles de développer la maladie et qui bénéficieraient d'un suivi plus spécifique et plus étroit après leur admission aux soins intensifs. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov ( NCT04422444 ); première soumission le 9 juin 2020.

Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage.

OBJECTIVES: To identify the arthritogenic B cell epitopes of glucose-6-phosphate isomerase (GPI) and their association with rheumatoid arthritis (RA). METHODS: IgG response towards a library of GPI peptides in patients with early RA, pre-symptomatic individuals and population controls, as well as in mice, were tested by bead-based multiplex immunoassays and ELISA. Monoclonal IgG were generated, and the binding specificity and affinity were determined by ELISA, gel size exclusion chromatography, surface plasma resonance and X-ray crystallography. Arthritogenicity was investigated by passive transfer experiments. Antigen-specific B cells were identified by peptide tetramer staining. RESULTS: Peptide GPI293-307 was the dominant B cell epitope in K/BxN and GPI-immunised mice. We could detect B cells and low levels of IgM antibodies binding the GPI293-307 epitopes, and high affinity anti-GPI293-307 IgG antibodies already 7 days after GPI immunisation, immediately before arthritis onset. Transfer of anti-GPI293-307 IgG antibodies induced arthritis in mice. Moreover, anti-GPI293-307 IgG antibodies were more frequent in individuals prior to RA onset (19%) than in controls (7.5%). GPI293-307-specific antibodies were associated with radiographic joint damage. Crystal structures of the Fab-peptide complex revealed that this epitope is not exposed in native GPI but requires conformational change of the protein in inflamed joint for effective recognition by anti-GPI293-307 antibodies. CONCLUSIONS: We have identified the major pathogenic B cell epitope of the RA-associated autoantigen GPI, at position 293-307, exposed only on structurally modified GPI on the cartilage surface. B cells to this neo-epitope escape tolerance and could potentially play a role in the pathogenesis of RA.

Delirium-related psychiatric and neurocognitive impairment and the association with post-intensive care syndrome-A narrative review.

INTRODUCTION: Delirium is common among patients admitted to the intensive care unit (ICU) and its impact on the neurocognitive and psychiatric state of survivors is of great interest. These new-onset or worsening conditions, together with physical alterations, are called post-intensive care syndrome (PICS). Our aim is to update on the latest screening and follow-up options for psychological and cognitive sequelae of PICS. METHOD: This narrative review discusses the occurrence of delirium in ICU settings and the relatively new concept of PICS. Psychiatric and neurocognitive morbidities that may occur in survivors of critical illness following delirium are addressed. Future perspectives for practice and research are discussed. RESULTS: There is no "gold standard" for diagnosing delirium in the ICU, but two extensively validated tools, the confusion assessment method for the ICU and the intensive care delirium screening checklist, are often used. PICS complaints are frequent in ICU survivors who have suffered delirium and have been recognized as an important public health and socio-economic problem worldwide. Depression, anxiety, post-traumatic stress disorder, and long-term cognitive impairment are recurrently exhibited. Screening tools for these deficits are discussed, as well as the suggestion of early assessment after discharge and at 3 and 12 months. CONCLUSIONS: Delirium is a complex but common phenomenon in the ICU and a risk factor for PICS. Its diagnosis is challenging with potential long-term adverse outcomes, including psychiatric and cognitive difficulties. The implementation of screening and follow-up protocols for PICS sequelae is warranted to ensure early detection and appropriate management.

Objective and subjective cognition in survivors of COVID-19 one year after ICU discharge: the role of demographic, clinical, and emotional factors.

BACKGROUND: Intensive Care Unit (ICU) COVID-19 survivors may present long-term cognitive and emotional difficulties after hospital discharge. This study aims to characterize the neuropsychological dysfunction of COVID-19 survivors 12 months after ICU discharge, and to study whether the use of a measure of perceived cognitive deficit allows the detection of objective cognitive impairment. We also explore the relationship between demographic, clinical and emotional factors, and both objective and subjective cognitive deficits. METHODS: Critically ill COVID-19 survivors from two medical ICUs underwent cognitive and emotional assessment one year after discharge. The perception of cognitive deficit and emotional state was screened through self-rated questionnaires (Perceived Deficits Questionnaire, Hospital Anxiety and Depression Scale and Davidson Trauma Scale), and a comprehensive neuropsychological evaluation was carried out. Demographic and clinical data from ICU admission were collected retrospectively. RESULTS: Out of eighty participants included in the final analysis, 31.3% were women, 61.3% received mechanical ventilation and the median age of patients was 60.73 years. Objective cognitive impairment was observed in 30% of COVID-19 survivors. The worst performance was detected in executive functions, processing speed and recognition memory. Almost one in three patients manifested cognitive complaints, and 22.5%, 26.3% and 27.5% reported anxiety, depression and post-traumatic stress disorder (PTSD) symptoms, respectively. No significant differences were found in the perception of cognitive deficit between patients with and without objective cognitive impairment. Gender and PTSD symptomatology were significantly associated with perceived cognitive deficit, and cognitive reserve with objective cognitive impairment. CONCLUSIONS: One-third of COVID-19 survivors suffered objective cognitive impairment with a frontal-subcortical dysfunction 12 months after ICU discharge. Emotional disturbances and perceived cognitive deficits were common. Female gender and PTSD symptoms emerged as predictive factors for perceiving worse cognitive performance. Cognitive reserve emerged as a protective factor for objective cognitive functioning. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422444; June 9, 2021.

The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity.

BACKGROUND: Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. METHODS: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. RESULTS: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. CONCLUSIONS: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.

The Effect of Clusters of Double Triggering and Ineffective Efforts in Critically Ill Patients.

OBJECTIVES: To characterize clusters of double triggering and ineffective inspiratory efforts throughout mechanical ventilation and investigate their associations with mortality and duration of ICU stay and mechanical ventilation. DESIGN: Registry-based, real-world study. BACKGROUND: Asynchronies during invasive mechanical ventilation can occur as isolated events or in clusters and might be related to clinical outcomes. SUBJECTS: Adults requiring mechanical ventilation greater than 24 hours for whom greater than or equal to 70% of ventilator waveforms were available. INTERVENTIONS: We identified clusters of double triggering and ineffective inspiratory efforts and determined their power and duration. We used Fine-Gray's competing risk model to analyze their effects on mortality and generalized linear models to analyze their effects on duration of mechanical ventilation and ICU stay. MEASUREMENTS AND MAIN RESULTS: We analyzed 58,625,796 breaths from 180 patients. All patients had clusters (mean/d, 8.2 [5.4-10.6]; mean power, 54.5 [29.6-111.4]; mean duration, 20.3 min [12.2-34.9 min]). Clusters were less frequent during the first 48 hours (5.5 [2.5-10] vs 7.6 [4.4-9.9] in the remaining period [p = 0.027]). Total number of clusters/d was positively associated with the probability of being discharged alive considering the total period of mechanical ventilation (p = 0.001). Power and duration were similar in the two periods. Power was associated with the probability of being discharged dead (p = 0.03), longer mechanical ventilation (p < 0.001), and longer ICU stay (p = 0.035); cluster duration was associated with longer ICU stay (p = 0.027). CONCLUSIONS: Clusters of double triggering and ineffective inspiratory efforts are common. Although higher numbers of clusters might indicate better chances of survival, clusters with greater power and duration indicate a risk of worse clinical outcomes.

Psychophysical testing in chronic migraine and chronic tension type headache: An observational study.

BACKGROUND: Clinical presentation is the key to the diagnosis of patients with migraine and tension-type headache, but features may overlap when both become chronic. Psychophysical parameters may distinguish both conditions. We aimed to compare psychophysical aspects of patients with chronic migraine, chronic tension-type headache and headache-free controls, and to determine whether these can predict headache frequency. METHODS: An examiner blinded to the diagnosis assessed 100 participants (chronic migraine (n = 38), chronic tension-type headache (n = 31) and controls (n = 31)). Assessed variables included painful area, pressure pain thresholds, temporal summation, cervical range of motion, neck posture, headache and neck impact, quality of life, and kinesiophobia. Comparison between groups was performed with one-way ANOVA and multiple linear regression was used to assess the headache frequency predictors. RESULTS: We found differences of both headache groups compared to controls (p < 0.01), but not between headache groups. Neck disability was a significant predictor of headache frequency for chronic tension-type headache (adjusted R2 = 0.14; ß = 0.43; p = 0.03) and chronic migraine (adjusted R2 = 0.18; ß = 0.51; p < 0.01). CONCLUSIONS: Chronic tension-type headache and chronic migraine showed similar psychophysical results, but were significantly worse when compared to controls. The psychophysical examination did not discriminate between headache types. The variable best explaining headache frequency for both headache types was neck disability.

Higher order theory of mind in patients with bipolar disorder and schizophrenia/schizoaffective disorder.

Some evidence suggests that patients with bipolar disorder (BD) have better Theory of Mind (ToM) skills than patients with schizophrenia/schizoaffective disorder (SCH). However, this difference is not consistently reported across studies, so rather than being global, it may be restricted to specific aspects of ToM. Our primary objective was to compare higher order ToM performance between BD and SCH patients using the Hinting Task (HT). Ninety-four remitted patients were recruited (BD = 47, SCH = 47). Intelligence quotient (IQ), attention, memory, executive functions, and processing speed were also assessed. Patients with BD performed better on the HT than patients with SCH, even when the analysis was adjusted for IQ and neurocognition (p < 0.001, [Formula: see text] = 0.144). Regression analysis in the total sample showed that a diagnosis of SCH and lower IQ were associated with lower HT scores (R2 = 0.316, p < 0.001). In the BD group, verbal memory and processing speed were the main predictors of HT performance (R2 = 0.344, p < 0.001). In the SCH group, no variable was significant in explaining HT performance. In the context of previous studies that found no significant differences in the most basic aspects of ToM (e.g., understand other people's thoughts/beliefs), our results suggest that differences between the two disorders might be limited to the more challenging aspects (e.g., understand the intended meaning of indirect requests). No causal inferences can be made in this cross-sectional study. However, regression analyses show that whereas in BD patients, ToM functioning would be partially modulated by neurocognitive performance, in SCH patients, it could be largely independent of the well-known neurocognitive impairment.

Physiological Response to the 6-Minute Frame Running Test in Children and Adults With Cerebral Palsy.

PURPOSE: To determine the physiological response and association to peak oxygen uptake of the 6-minute Frame Running test (6-MFRT) in persons with cerebral palsy (CP). METHODS: Twenty-four participants with CP, Gross Motor Function Classification System II/III/IV, performed the 6-MFRT. Distance, peak heart rate (HR peak ), peak respiratory exchange ratio (RER peak ), and peak oxygen uptake ( O 2peak ) were measured. RESULTS: HR peak ranged from 146 to 201 beats per minute, RER peak from 0.94 to 1.49, 6-MFRT distance from 179 to 1220 m and O 2peak from 0.62 to 2.18 L/min. HR peak was achieved in 63%, RER peak in 71%. A strong correlation was observed between 6-MFRT and O 2peak . CONCLUSIONS: The 6-MFRT represented a (near) maximum effort for 75% of the participants and the 6-MFRT can be used to estimate oxygen consumption on an individual basis.

Genetic and epigenetic regulation of skeletal muscle ribosome biogenesis with exercise.

KEY POINTS: Ribosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery. A PCR-based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE. Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non-canonical MYC-associated regions, but not the promoter. Myonuclear-specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans. A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage. ABSTRACT: Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, although the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise-induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 ± 8 years, 25 ± 4 kg m-2 ) at rest and 30 min, 3 h, 8 h and 24 h after acute endurance (n = 10, 45 min cycling, 70% V̇O2max ) or resistance exercise (n = 10, 4 × 7 × 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using quantitative PCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER and global rDNA CpG methylation was assessed using reduced-representation bisulphite sequencing. Ribosome biogenesis and MYC transcription were associated primarily with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated with rDNA gene dosage, as well as epigenetic changes in enhancer and non-canonical MYC-associated areas in rDNA, but not the promoter. A mouse model of in vivo metabolic RNA labelling and genetic myonuclear fluorescence labelling validated the effects of an acute hypertrophic stimulus on ribosome biogenesis and Myc transcription, and also corroborated rDNA enhancer and Myc-associated methylation alterations specifically in myonuclei. The present study provides the first information on skeletal muscle genetic and rDNA gene-wide epigenetic regulation of ribosome biogenesis in response to exercise, revealing novel roles for rDNA dosage and CpG methylation.

Molecular characterization of group A rotavirus strains detected in alpacas (Vicugna pacos) from Peru.

The alpaca is a very important social and economic resource for the production of fibre and meat for Andean communities. Peru is the main producer of alpacas. Group A rotavirus (RVA) has been sporadically detected in alpacas. In this study, a total of 1423 faecal samples from alpacas from different locations of the Puno department in Peru were collected and analysed by an antigen-capture ELISA in order to detect RVA. Four per cent of the samples were RVA-positive (57/1423). The genotype constellation of three selected alpaca RVA strains were G3/8 P[1/14]-I2-R2/5-C2/3-M2/3-A17-N2/3-T6-E3-H3. Two of the analysed strains presented a bovine-like genotype constellation, whereas the third strain presented six segments belonging to the AU-1-like genogroup (G3, M3, C3, N3, T3 and E3), suggesting reassorting events. Monitoring of the sanitary health of juvenile alpacas is essential to reduce the rates of neonatal mortality and for the development of preventive health strategies.

Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures.

This study explored the muscle genome-wide response to long-term unloading (84-day bed rest) in 21 men. We hypothesized that a part of the bed rest-induced gene expression signature would be resilient to a concurrent flywheel resistance exercise (RE) countermeasure. Using DNA microarray technology analyzing 35 345 gene-level probe-sets, we identified 335 annotated probe-sets that were downregulated, and 315 that were upregulated after bed rest (P < .01). Besides a predictable differential expression of genes and pathways related to mitochondria (downregulation; false-discovery rates (FDR) <1E-04), ubiquitin system (upregulation; FDR = 3E-02), and skeletal muscle energy metabolism and structure (downregulation; FDR ≤ 3E-03), 84-day bed rest also altered circadian rhythm regulation (upregulation; FDR = 3E-02). While most of the bed rest-induced changes were counteracted by RE, 209 transcripts were resilient to the exercise countermeasure. Genes upregulated after bed rest were particularly resistant to training (P < .001 vs downregulated, non-reversed genes). Specifically, "Translation Factors," "Proteasome Degradation," "Cell Cycle," and "Nucleotide Metabolism" pathways were not normalized by RE. This study provides an unbiased high-throughput transcriptomic signature of one of the longest unloading periods in humans to date. Classical disuse-related changes in structural and metabolic genes/pathways were identified, together with a novel upregulation of circadian rhythm transcripts. In the context of previous bed rest campaigns, the latter seemed to be related to the duration of unloading, suggesting the transcriptomic machinery continues to adapt throughout extended disuse periods. Despite that the RE training offset most of the bed rest-induced muscle-phenotypic and transcriptomic alterations, we contend that the human skeletal muscle also displays a residual transcriptomic signature of unloading that is resistant to an established exercise countermeasure.

Reduced mitochondrial DNA and OXPHOS protein content in skeletal muscle of children with cerebral palsy.

AIM: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP). METHOD: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were analyzed with a focused query investigating metabolism- and mitochondria-related gene networks. RESULTS: The mtDNA to genomic DNA ratio was lower in the children with CP compared to the typically developing group (-23%, p=0.002). Out of five investigated complexes in the mitochondrial respiratory chain, we observed lower protein levels of all complexes (I, III, IV, V, -20% to -37%; p<0.05) except complex II. Total peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) messenger RNA (p<0.004), isoforms PGC1α1 (p=0.05), and PGC1α4 (p<0.001) were reduced in CP. Transcriptional similarities were observed between CP, aging, and 90 days' bed rest. INTERPRETATION: Mitochondrial biogenesis, mtDNA, and oxidative phosphorylation protein content are reduced in CP muscle compared with typically developing muscle. Transcriptional pathways shared between aging and long-term unloading suggests metabolic dysregulation in CP, which may guide therapeutic strategies for combatting CP muscle pathology. What this paper adds Cerebral palsy (CP) muscle contains fewer energy-generating organelles than typically developing muscle. Gene expression in CP muscle is similar to aging and long-term bed rest.

Postoperative Psychosocial Factors in Health Functioning and Health-Related Quality of Life After Knee Arthroplasty: A 6-Month Follow up Prospective Observational Study.

OBJECTIVE: Knee arthroplasty (KA) is an effective and cost-effective treatment for end-stage knee osteoarthritis. Despite high surgical success rates, as many as 25% of patients report compromised postoperative functioning, persistent pain, and reduced quality of life. The purpose of this study was to assess the predictive value of psychological factors in health functioning and quality of life, during a 6-month period after KA. DESIGN: A prospective observational study. SETTING: Surgery at two hospitals and follow-up was carried out through the domiciliary rehabilitation service. SUBJECTS: In total, 89 patients (age 70.27 ± 7.99 years) met the inclusion criteria. METHOD: A test battery composed of Health functioning associated with osteoarthritis (WOMAC), Health-related quality of life (EQ-5D-5L), Anxiety and Depression (HADS), Pain attitudes (SOPA-B), Pain catastrophizing (PCS), and Fear of Movement (TSK-11) was assessed at 1 week, and 1, 3, and 6 months after surgery. A mixed effects linear model was used to estimate the effect of time and covariates. An exploratory factor analysis was used to identify the number of dimensions underlying the group of psychological measurements. RESULTS: In WOMAC model, anxiety level (F = 120.8), PCS (F = 103.9), depression level (F = 93.6) and pain score (F = 72.8) were the most influential variables. Regarding EQ-5D-5L model, anxiety level (F = 98.5), PCS (F = 79.8), depression level (F = 78.3) and pain score (F = 45) were the most influential variables. Pain score and the psychosocial variables of PCS, TSK, HADS-A, HADS-D, SOPA-B Emotion, SOPA-B Harm and SOPA-B Disability loaded in one single dimension. CONCLUSIONS: Postoperative acute pain and psychosocial factors of pain catastrophizing, anxiety, depression, and pain attitudes might influence health functioning and quality of life during KA rehabilitation. Such factors could be gathered into one single dimension defined as pain-related psychologic distress.