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Mild endurance exercise has been shown to compensate for declined muscle quality and may positively affect the brain under conditions of energy restriction. Whether this involves brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) activation in relation to central and peripheral tissue levels of associated factors such as beta hydroxy butyrate (BHB), branched-chain amino acids (BCAA) and thyroid hormone (T3) has not been studied. Thus, a subset of male Wistar rats housed at thermoneutrality that were fed or fasted was submitted to 30-min-mild treadmill exercise bouts (five in total, twice daily, 15 m/min, 0° inclination) over a period of 66 h. Prefrontal cortex and gastrocnemius muscle BHB, BCAA, and thyroid hormone were measured by LC-MS/MS analysis and were related to BDNF and mammalian target of rapamycin (mTOR) signaling. In gastrocnemius muscle, mild endurance exercise during fasting maintained the fasting-induced elevated BHB levels and BDNF-CREB activity and unlocked the downstream Akt-mTORC1 pathway associated with increased tissue BCAA. Consequently, deiodinase 3 mRNA levels decreased whereas increased phosphorylation of the mTORC2 target FOXO1 was associated with increased deiodinase 2 mRNA levels, accounting for the increased T3 tissue levels. These events were related to increased expression of CREB and T3 target genes beneficial for muscle quality previously observed in this condition. In rat L6 myoblasts, BHB directly induced BDNF transcription and maturation. Mild endurance exercise during fasting did not increase prefrontal cortex BHB levels nor was BDNF activated, whereas increased leucine levels were associated with Akt-independent increased phosphorylation of the mTORC1 target P70S6K. The associated increased T3 levels modulated the expression of known T3-target genes involved in brain tissue maintenance. Our observation that mild endurance exercise modulates BDNF, mTOR and T3 during fasting provides molecular clues to explain the observed beneficial effects of mild endurance exercise in settings of energy restriction.

A Mediterranean-style healthy eating pattern (MED-HEP) supports metabolic health, but the utility of including low-glycemic index (GI) foods to minimize postprandial glucose excursions remain unclear. Therefore, we investigated the relative contribution of GI towards improvements in postprandial glycemia and glycemic variability after adopting a MED-HEP. We conducted a randomized, controlled dietary intervention, comparing high- versus low-GI diets in a multi-national (Italy, Sweden, and the United States) sample of adults at risk for type 2 diabetes. For 12 weeks, participants consumed either a low-GI or high-GI MED-HEP. We assessed postprandial plasma glucose and insulin responses to high- or low-GI meals, and daily glycemic variability via continuous glucose monitoring at baseline and post-intervention. One hundred sixty adults (86 females, 74 males; aged 55 ± 11 y, BMI 31 ± 3 kg/m2, mean ± SD) with ≥two metabolic syndrome traits completed the intervention. Postprandial insulin concentrations were greater after the high-GI versus the low-GI test meals at baseline (p = 0.004), but not post-intervention (p = 0.17). Postprandial glucose after the high-GI test meal increased post-intervention, being significantly higher than that after the low-GI test meal (35%, p < 0.001). Average daily glucose concentrations decreased in both groups post-intervention. Indices of 24-h glycemic variability were reduced in the low-GI group as compared to baseline and the high-GI intervention group. These findings suggest that low-GI foods may be an important feature within a MED-HEP.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined as the presence of hepatic steatosis in addition to one of three metabolic conditions: overweight/obesity, type 2 diabetes mellitus, or metabolic dysregulation. Chronic exposure to excess dietary fatty acids may cause hepatic steatosis and metabolic disturbances. The alteration of the quality of mitochondria is one of the factors that could contribute to the metabolic dysregulation of MAFDL. This study was designed to determine, in a rodent model of MAFLD, the effects of a long-term high-fat diet (HFD) on some hepatic processes that characterize mitochondrial quality control, such as biogenesis, dynamics, and mitophagy. To mimic the human manifestation of MAFLD, the rats were exposed to both an HFD and a housing temperature within the rat thermoneutral zone (28–30 °C). After 14 weeks of the HFD, the rats showed significant fat deposition and liver steatosis. Concomitantly, some important factors related to the hepatic mitochondrial quality were markedly affected, such as increased mitochondrial reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) damage; reduced mitochondrial biogenesis, mtDNA copy numbers, mtDNA repair, and mitochondrial fusion. HFD-fed rats also showed an impaired mitophagy. Overall, the obtained data shed new light on the network of different processes contributing to the failure of mitochondrial quality control as a central event for mitochondrial dysregulation in MAFLD.

According to the data derived from several national and international registries, including SANI (Severe Asthma Network Italy), and considering the strong impact that frequent or regular use of oral corticosteroid has on quality of life (QoL) of severe asthmatics, as well as on the costs for managing corticosteroid-related diseases, oral corticosteroid sparing up to withdrawal should be considered a primary outcome in the management of severe asthma. New biologics have clearly demonstrated that this effect is possible, with concomitant reduction in the rate of exacerbations and in symptom control. Then, there is no reason for using so frequently oral corticosteroid before having explored all alternatives currently available for a large part of severe asthmatics.

BackgroundThe value of carer involvement has been extensively researched and promoted. However, the field lacks exploration of conceptual issues, which might help to explain why there are widespread difficulties in putting policy into practice in this area, as implementation rates remain low internationally.AimsThis qualitative study explored patients’, carers’ and clinicians’ perspectives on the role of carers in mental healthcare, particularly with regards to in-patient settings.MethodSixteen focus groups were conducted with patients, carers and clinicians who have current or previous experience of in-patient settings. A thematic analysis was conducted on the transcripts, exploring two key domains: (a) what a ‘carer’ is, and (b) how the ‘carer’ role is described within the context of the hospital environment.ResultsParticipants diverged in their opinions of what the ‘carer’ role entails, and the perceived helpfulness of it. Issues unique to the in-patient setting were identified, such as the role of the hospital environment in enabling or being a barrier to carer involvement. These differing perspectives and contextual factors had an impact on the position of carers in the hospital setting, as they could be viewed as helpful, a hindrance or as passive visitors, depending on the perspectives of clinicians.ConclusionsMore clarity and agreement is needed between patients, carers and clinicians in terms of how the ‘carer’ role is defined. This has the potential to improve carers’ experience of involvement in hospital settings.

Adults with central adiposity and other features of the metabolic syndrome have a markedly elevated risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD). A Mediterranean-style healthy eating pattern (MED-HEP) and consumption of foods with a lower glycemic index (GI) are potential dietary approaches to curb the T2D and CVD epidemic. However, experimental evidence of the effectiveness of MED-HEP and of the contribution of GI towards improving indices of glucose homeostasis, especially among non-diabetic people, are lacking. Therefore, we developed the MedGI-Carb trial, a multi-center (Italy, Sweden, and United States) intervention in adults with at least two components of the metabolic syndrome (elevated waist circumference + one other component) that aims to improve markers of glucose homeostasis through dietary modification. All participants were randomized to consume an isocaloric high- or low-GI MED-HEP for 12 weeks. We hypothesized that indexes of insulinemia (primary outcome: postprandial insulin and glucose after standardized breakfast and lunch; secondary outcomes: fasting plasma glucose and insulin, HbA1c, 24-h continuous glucose monitoring) would be improved more with the low-GI versus the high-GI MED-HEP. Additionally, we hypothesized that consumption of a MED-HEP would improve other markers of cardiometabolic health and well-being (fasting blood pressure, fasting lipid profile, sleep quality, satiety, global metabolic alterations in the plasma metabolome, changes in the gut microbiota, subjective health and well-being), with no difference between groups. Collectively, the design of MEDGI-Carb allows several different research questions to be explored. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03410719.

Dietary (poly)phenol intake has been associated with a lower risk of cardiovascular mortality and new events. However, no conclusive data can be drawn from clinical trials evaluating the effects of (poly)phenols on cardiovascular risk factors. In addition, the mechanisms of action behind the beneficial association of (poly)phenol intake with cardiovascular health are not completely understood. Therefore, this perspective aimed to highlight the main methodological limitations that might explain the conflicting results obtained so far. In addition, novel insights on local and systemic effects of (poly)phenols were discussed. Finally, some critical issues to take into consideration in future studies were reported.This more comprehensive approach could represent a strategy to deeply understand the effects of (poly)phenols on human health.

Minimal clinically important difference (MCID) can be defined as the smallest change or difference in an outcome measure that is perceived as beneficial and would lead to a change in the patient's medical management. The aim of the current expert consensus report is to provide a “state-of-the-art” review of the currently available literature evidence about MCID for end-points to monitor asthma control, in order to facilitate optimal disease management and identify unmet needs in the field to guide future research. A series of MCID cut-offs are currently available in literature and validated among populations of asthmatic patients, with most of the evidence focusing on outcomes as patient reported outcomes, lung function and exercise tolerance. On the contrary, only scant and partial data are available for inflammatory biomarkers. These clearly represent the most interesting target for future development in diagnosis and clinical management of asthma, particularly in view of the several biologic drugs in the pipeline, for which regulatory agencies will soon require personalised proof of efficacy and treatment response predictors.

The present investigation was undertaken to increase our insight into the molecular basis of the physiological changes in rat testis induced by food withdrawal, and to clarify whether reduced testicular function can be ameliorated by mild exercise. Male rats were selected for four separate experiments. The first of each group was chow-fed, the second was chow-fed and submitted to exercise (5 bouts in total for 30 min at 15 m/min, and 0° inclination), the third was submitted to food withdrawal (66 h) and the fourth was submitted to food withdrawal and to exercise. At the end of experiments, we investigated (i) serum and testicular sex hormone levels; (ii) protein levels of StAR, 3β-Hydroxysteroid dehydrogenase (3β-HSD) and P450 aromatase, which play a key role in steroid hormone biosynthesis; and (iii) protein levels of mitotic and meiotic markers of spermatogenesis in rats, in relation to testis morphology and morphometry. We found that mild exercise or food withdrawal alone induced a significant increase or decrease in both serum and testis testosterone levels, respectively. Interestingly, we found that these levels were brought back to basal levels when food withdrawal was combined with mild exercise. The changes in testosterone levels observed in our experimental groups correlated well with the expression of steroidogenic enzymes as well as with spermatogenic activity. With mild exercise the increased testosterone/17β-estradiol (T/E2) ratio in the testis correlated with an increased spermatogenic activity. The T/E2 ratio dropped in fasted rats and was significantly reversed when food withdrawal was combined with exercise. Histological and morphometric analyses confirmed that spermatogenic activity varied in concomitance with each experimental condition. Importantly, the testis and serum T/E2 ratios correlated, confirming that exercise rescues the decline in food withdrawal-induced spermatogenesis. In conclusion, this study highlights that mild exercise normalizes the reduced spermatogenic activity caused by food withdrawal through the modulation of the steroidogenic pathway and restoring the T/E2 ratio, underlining the beneficial effects of mild exercise on the prevention and/or amelioration of reduced testis function caused by restricted caloric intake.

Abstract Exercise under fasting conditions induces a switch to lipid metabolism, eliciting beneficial metabolic effects. Knowledge of signaling responses underlying metabolic adjustments in such conditions may help to identify therapeutic strategies. Therefore, we studied the effect of mild exercise on rats submitted to food withdrawal at thermoneutrality (28°C) for 3 days. Animals were housed at thermoneutrality rather than the standard housing temperature (22°C) to avoid beta‐adrenergic signaling responses that themselves affect metabolism and well‐being. Quantitative analysis of multi‐organ mRNA levels, myofibers, and serum metabolites shows that this protocol (a) boosts fat oxidation in muscle and liver, (b) reduces lipogenesis and increases gluconeogenesis in liver, (c) increases serum acylcarnitines (especially C4OH) and ketone bodies and the use of the latter as fuel in muscle, (d) increases Type I myofibers, and (e) is associated with an increased thyroid hormone uptake and metabolism in muscle. In addition, stool microbiome DNA analysis revealed that food withdrawal dramatically alters the presence of bacterial genera associated with ketone metabolism. Taken together, this protocol induces a drastic switch toward increased lipid and ketone metabolism compared to exercise or food withdrawal alone, which may prove beneficial and may involve local thyroid hormones, which may be regarded as exercise mimetics.

In psychodynamic psychotherapy, verbal (structures and intents) and non-verbal (voice and interruptions) dimensions of communication intertwine conveying information and determining the mutual regulation between therapist and patient through conversational sequences. The communication components interplay is the foundation for building the therapeutic alliance, a relational dimension that predicts a psychotherapy outcome and change, influenced by patient-therapist exchanges from the initial stages of their encounter. Depressed patients present specific verbal and non-verbal communication and show difficulties in developing and maintaining the therapeutic alliance. Based on the reviewed literature, the main aim of this study was to analyze how the action of specific communicative modes, implemented by the therapist and depressed patients, affect the reciprocal construction of the early therapeutic alliance by each participant during the mutual regulation processes. We employed a mixed methods approach based on a systematic observation of communication and alliance ruptures and repairs within the audio recordings and verbatim transcripts of 20 psychotherapy sessions (6,232 speaking turns) with seven depressed patients. The observational design was nomothetic, follow-up, and multidimensional. The choice of methodology is justified because we developed a comprehensive procedure that integrates an ad hoc indirect observation system (the Communicative Modes Analysis System in Psychotherapy), analyzing verbal and non-verbal communication, and an observational tool with deductive categories (the Collaborative Interactions Scale-Revised), assessing the therapeutic alliance construction. Once we confirmed the intra-and inter-observer reliability for the ad hoc system and the inter-rater reliability for the tool with deductive (or theoretical) categories, we performed descriptive statistics (to describe quantitatively communicative modes and alliance ruptures and repairs), lag sequential analysis (to detect stable patterns in communication-alliance interactions), and polar coordinate analysis (to identify significant relationships between communicative modes and alliance ruptures and repairs). Results confirm that the therapist's verbal (asking and exploring) and non-verbal (elaborating and cooperatively interrupting) modes and the depressed patients' verbal (asserting and exploring) and non-verbal (expressing emotions and cooperatively interrupting) modes determine stable patterns and significant associations with collaborative behaviors connected to the reciprocal construction of alliance by each participant. All this may provide professionals with useful information to increase the psychotherapy effectiveness with depressed patients.

We here describe the case of a 43-year-old White woman who was diagnosed with rheumatoid arthritis treated with anti-tumour necrosis factor drugs that caused an adverse drug reaction. The objective of this study was to describe the outcome of a pregnancy under baricitinib, a JAK-inhibitor drug, in a woman affected by rheumatoid arthritis. Scant data are available about the safety of JAK inhibitors during pregnancy. A case report and review of literature about JAK-inhibitor exposure during pregnancy were conducted. After the failure of biologic disease-modifying antirheumatic drugs due to a loss of efficacy and adverse drug reaction, the patient was started on baricitinib when it was marketed. During the fifth month of this treatment, she reported missing her period and a pregnancy was confirmed, despite a previous recommendation of adequate contraception. Thus, she had been exposed to baricitinib for several weeks before conception and during the whole first-trimester until the 17th week of gestation. The treatment with baricitinib was promptly discontinued and she was regularly examined. Foetal growth was normal throughout pregnancy and ultrasound examination did not detect any macroscopic abnormality. This is the first report of exposure to baricitinib during pregnancy outside the drug registration study program. We report the positive pregnancy outcome of a continuous exposure to baricitinib during the first 17 weeks of pregnancy. Small molecules, such as JAK inhibitors, are increasingly being used in clinical practice in rheumatoid arthritis and in other diseases. Hence, more broad and focused studies are required to have an insight of safety for this drug class in the case of accidental exposure before or during pregnancy.

BackgroundLast year, there were more than 63 622 involuntary admissions to psychiatric hospitals in England. One of the core principles stipulated in the code of practice for care under the Mental Health Act is involving involuntary patients in care decisions.AimsIdentifying barriers and facilitators to shared decision-making with involuntary patients.MethodFocus groups and individual interviews with patients and clinicians who have experience with involuntary hospital treatment were carried out. Data were subjected to thematic analysis.ResultsTwenty-two patients and 16 clinicians participated. Barriers identified included challenges in communication, and noisy and busy wards making one-to-one meetings difficult. Patient involvement was identified as easier if initiated early after admission and if the whole clinical team was on board. Carers' presence helped decision-making through providing additional information and comfort.ConclusionsThe barriers and facilitators identified can inform changes in the practice of involuntary care to increase patient involvement.Declaration of interestNone.

Abstract Multiple sclerosis is characterized by tissue atrophy involving the brain and the spinal cord, where reactive inflammation contributes to the neurodegenerative processes. Recently, the presence of synapse alterations induced by the inflammatory responses was suggested by experimental and clinical observations, in experimental autoimmune encephalomyelitis mouse model and in patients, respectively. Further knowledge on the interplay between pro-inflammatory agents, neuroglia and synaptic dysfunction is crucial to the design of unconventional protective molecules. Here we report the effects, on spinal cord circuits, of a cytokine cocktail that partly mimics the signature of T lymphocytes sub population Th1. In embryonic mouse spinal organ-cultures, containing neuronal cells and neuroglia, cytokines induced inflammatory responses accompanied by a significant increase in spontaneous synaptic activity. We suggest that cytokines specifically altered signal integration in spinal networks by speeding the decay of GABAA responses. This hypothesis is supported by the finding that synapse protection by a non-peptidic NGF mimetic molecule prevented both the changes in the time course of GABA events and in network activity that were left unchanged by the cytokine production from astrocytes and microglia present in the cultured tissue. In conclusion, we developed an important tool for the study of synaptic alterations induced by inflammation, that takes into account the role of neuronal and not neuronal resident cells.

In several countries, thrombotic events after vaccination with ChAdOx1 nCoV-19 have led to heterologous messenger RNA (mRNA) boosting. We tested the antibody response to SARS-CoV-2 spike protein four weeks after heterologous priming with the ChAdOx1 (ChAd) vector vaccine followed by boosting with BNT162b2(ChAd/BNT), comparing data of homologous regimen (BNT/BNT, ChAd/ChAd) subjects positive for SARS-CoV-2 after the first dose of BNT162b2 (BNT1dose/CoV2) and convalescent COVID-19. Methods: healthy subjects naïve for SARS-CoV-2 infection were assessed for serum IgG anti-S-RBD response 21 days after priming (T1), 4 (TFULL) and 15 (T15W) weeks after booster dose. Results: The median IgG anti-S-RBD levels at TFULL of Chad/BNT group were significantly higher than the BNT/BNT group and ChAd/ChAd. Those of BNT/BNT group were significantly higher than ChAd/ChAd. IgG anti-S-RBD of BNT1dose/CoV2 group were similar to BNT/BNT, ChAd/BNT and ChAd/Chad group. The levels among COVID-19 convalescents were significantly lower than ChAd/BNT, BNT/BNT, ChAd/Chad and BNT1dose/CoV2. The proportion of subjects reaching an anti-S-RBD titer >75 AU/mL, correlated with high neutralizing titer, was 94% in ChAd/BNT and BNT/BNT, 60% in BNT1dose/CoV2, 25% in ChAd/ChAd and 4.2% in convalescents. At T15W the titer of ChAd/BNT was still significantly higher than other vaccine schedules, while the anti-S-RBD decline was reduced for ChAd/ChAd and similar for other combinations. Conclusion: Our data highlight the magnitude of IgG anti-S-RBD response in ChAd/BNT dosing, supporting the current national guidelines for heterologous boosting

Background: We here describe the case of a 71-year-old Caucasian woman previously diagnosed with Eosinophilic Granulomatosis with Polyangiitis (EGPA) that had been treated with Mepolizumab, an anti-IL5 monoclonal antibody, since 2019 with a good clinical response. Methods: She had a mild COVID-19 in December 2020 and she tested negative for SARS-CoV-2 infection in only late January 2021. In April 2021 she received the first dose of mRNA BNT162b2 vaccine. Ten days later she developed myalgia, dyspnea and numbness of the limbs due to a relapse of EGPA that occurred during Mepolizumab treatment.