p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response.

Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science.

Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor BI-3231. Through high-throughput screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45 for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD+ dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231 will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.

Delay discounting in Parkinson's disease: A systematic review and meta-analysis.

Delay discounting refers to the depreciation of the value of a reward as a function of the time it takes to obtain it. Growing evidence shows altered delay discounting in several pathological conditions, including neurological disorders. Here, we conducted a systematic review and meta-analysis of the published literature on delay discounting (DD) in Parkinson's Disease (PD). We found steeper DD in patients with PD, compared to healthy controls, both in "on" and "off" dopaminergic medication. These results confirm altered DD in PD and suggest an independent influence of the dopaminergic medication and the clinical condition itself on it. Also the effect of impulse control disorder and of pharmacological treatments are analysed.

Sleep disturbances and sleep disorders as risk factors for chronic postsurgical pain: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed at evaluating the role of sleep disturbances and sleep disorders in influencing presence and intensity of chronic postsurgical pain (CPSP). We included cohort studies which enrolled adults, assessed sleep disturbances or disorders before surgery, measured pain intensity, presence of pain, or opioid use at least three months after surgery. Eighteen studies were included in a narrative synthesis and 12 in a meta-analysis. Sleep disturbances and disorders were significantly related to CPSP, with a small effect size, r = 0.13 (95% CI 0.06-0.20). The certainty of evidence was rated low due to risk of bias and heterogeneity. In subgroup analyses the above association was significant in studies that used pain intensity as the outcome, but not in those that used presence of pain; in studies on patients who underwent total knee arthroplasty or other surgeries, but not in those on patients who had breast cancer surgery or total hip arthroplasty; in the single study that assessed insomnia and in studies that assessed sleep disturbances as predictors. A meta-regression showed that the follow-up length was positively associated with the overall estimate. Our findings suggest that presurgical sleep disturbances and disorders should be evaluated to detect patients at risk for CPSP. Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=272654.

Psychological factors and trajectories of post-surgical pain: A longitudinal prospective study.

A significant proportion of patients do not experience relief from pain during the early postsurgical period after joint arthroplasty and are at risk for developing chronic pain. The objectives of this study were to identify biopsychosocial factors associated with acute postsurgical pain trajectories and with pain intensity and interference after 1, 3, and 12 months. Two hundred ten patients listed for joint arthroplasty filled a presurgical battery of questionnaires assessing presurgical pain intensity, catastrophizing, emotional distress, state anxiety and depression, self-efficacy, central sensitization, and executive functions. From the day after surgery, they were asked to fill a 7-day diary, including questions about postsurgical pain and postsurgical state catastrophizing. Finally, they provided data about pain intensity and interference after 1, 3, and 12 months. Predictors of acute pain trajectories were investigated using multilevel growth curve analysis. Results showed that central sensitization was a predictor of the intercept of pain trajectories and daily postsurgical catastrophizing was a significant covariate of pain intensity in the acute phase. Analyses of follow-up data showed that central sensitization was a predictor of pain intensity and pain interference at 3 and 12 months, that emotional distress was related with pain intensity and interference at 1 month, and with pain interference at 3 months, and that cognitive flexibility was associated with pain interference at 1 month. Assessment of these factors could enable to identify patients at risk for worse outcomes and to plan targeted treatments to be implemented during the patient's inward stay.

17ß-Hydroxysteroid Dehydrogenase Type 1 Inhibition: A Potential Treatment Option for Non-Small Cell Lung Cancer.

In the face of the clinical challenge posed by non-small cell lung cancer (NSCLC), the present need for new therapeutic approaches is genuine. Up to now, no proof existed that 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is a viable target for treating this disease. Synthesis of a rationally designed library of 2,5-disubstituted furan derivatives followed by biological screening led to the discovery of 17ß-HSD1 inhibitor 1, capable of fully inhibiting human NSCLC Calu-1 cell proliferation. Its pharmacological profile renders it eligible for further in vivo studies. The very high selectivity of 1 over 17ß-HSD2 was investigated, revealing a rational approach for the design of selective inhibitors. 17ß-HSD1 and 1 hold promise in fighting NSCLC.

Psychological Support Interventions for Healthcare Providers and Informal Caregivers during the COVID-19 Pandemic: A Systematic Review of the Literature.

BACKGROUND: During the COVID-19 pandemic, healthcare providers and informal caregivers were at an increased risk of adverse mental health effects. This systematic review provides a summary of the available evidence on the content and efficacy of the psychological support interventions in increasing mental health among healthcare providers and informal caregivers during the COVID-19 pandemic. METHODS: PubMed, Google Scholar, PsychINFO, and Scopus databases were systematically searched for relevant articles, and the methodological quality of selected articles was assessed using the Quality Assessment Tool for Quantitative Studies. RESULTS: A search of electronic databases identified five reports based on inclusion and exclusion criteria. All psychological support interventions for caregivers were delivered digitally. Despite the large heterogeneity of the selected studies, the findings support the efficacy of mental health interventions in reducing distress and burnout, while promoting self-efficacy and well-being in both healthcare providers and informal caregivers. CONCLUSION: Since mental health problems are expected to increase during, and as a result of, the COVID-19 pandemic, and digital tools might offer a range of mental health treatments to meet the unique and immediate needs of people, further research is needed to test the cost-effectiveness of digital psychological interventions.

Motor synergies: Evidence for a novel motor signature in autism spectrum disorder.

In autism spectrum disorder (ASD), socio-communicative impairments and stereotypical behaviours are paralleled by sensorimotor deficits. Individuals with ASD show an altered selection of motor parameters, resulting in clumsy and fragmented actions. Here, we investigated inter-joint coordination and motor synergies as a potential substrate of motor control problems in ASD. Synergies enable co-controlling redundant motor degrees of freedom (DoF, e.g. joint angles, muscles) by mapping behavioural goals into a flexible and low-dimensional set of variables. This mechanism simplifies motor control and helps to find unambiguous solutions for motor tasks. In a reaching-grasping paradigm, children with ASD showed reduced coupling between DoF, which correlated with socio-communicative symptoms severity. Impaired synergies may help to frame well-established motor problems in ASD, including impaired motor sequencing and abnormal trial-to-trial motor variability. On the other hand, synergies also provide an effective and compact coding system of observed actions. Impaired synergies may thus jeopardize motor interaction by initiating bottom-up cascade effects, leading to pervasive impairments of social behaviour. Finally, we trained an automatic classification algorithm to distinguish between ASD and typically developing (TD) participants based on reaching-grasping kinematics. Classification accuracy reached up to 0.947. This result corroborates and expands previous accounts claiming that motor-based early recognition is feasible and effective in ASD.

Uric acid, impaired fasting glucose and impaired glucose tolerance in youth with overweight and obesity.

BACKGROUND AND AIM: The relationships between uric acid (UA) and prediabetes is poorly explored in youth. We investigated the association between UA, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), insulin resistance (IR) and low insulin sensitivity (IS) in youth with overweight/obesity (OW/OB). METHODS AND RESULTS: A cross-sectional study was performed in 2248 youths with OW/OB (age 5-17 years). The sample was stratified in sex-specific quintiles (Q1 to Q5) of UA and the associations with fasting (FG), 2-h post-load glucose (2H-PG), IR and low IS were investigated. IR and low IS were estimated by assessment model of insulin resistance (HOMA-IR) and whole-body IS index (WBISI), respectively. IFG was defined as FG ≥ 100 < 126 mg/dL, IGT as 2H-PG ≥140 < 200 mg/dL, IR as HOMA-IR ≥75th percentile and low IS as WBISI ≤25th percentile by sex. Age, body mass index z-score, 2H-PG, HOMA-IR and WBISI, increased across sex-quintiles of UA while FG did not. The prevalence of IFG and IR were significantly increased in Q5 vs Q1 (reference quartile, P < 0.025). The prevalence of IGT increased from Q3 to Q5 vs Q1 (P < 0.025-0.0001) and that of low IS from Q2 to Q5 vs Q1 (P < 0.005-0.0001). CONCLUSIONS: In youth with OW/OB, rates of IGT and low IS increased progressively across quintiles of UA. On the contrary, IFG and IR were associated only with the highest quintile of UA. Our data suggest that UA is a biomarker of impaired glucose metabolism prevalently in post-challenge condition rather than in fasting state.

Psychological and psychosocial predictors of chronic postsurgical pain: a systematic review and meta-analysis.

Knowledge about psychological and psychosocial predictors of chronic postsurgical pain is important to identify patients at risk for poor outcomes. The objective of this systematic review with meta-analysis was to assess the effect of such predictors. A comprehensive search of the available literature on this topic was performed using the electronic databases PubMed, Scopus, Embase, and PsycInfo. Estimates of the effect of each predictor were extracted, and both a narrative synthesis and a quantitative synthesis of these estimates were performed. Multiple imputation was used to take into account the effect of nonsignificant estimates in case they were not reported by original studies. From a sample of 8322 records, 83 articles were included in the narrative synthesis and 41 studies were used to perform the meta-analyses. The narrative synthesis showed that evidence about the effect of psychological predictors is heterogeneous, with few expected predictors, such as optimism, state anxiety and psychological distress, consistently associated with chronic postsurgical pain. By contrast, the meta-analyses showed that state anxiety, trait anxiety, mental health, depression, catastrophizing and, to a lesser extent, kinesiophobia and self-efficacy have a weak but significant association with chronic postsurgical pain. In conclusion, this study showed that psychological predictors have a significant association with chronic postsurgical pain and that state anxiety is the most explicative one.

ISPRM/ESPRM guidelines on Physical and Rehabilitation Medicine professional practice for adults with obesity and related comorbidities.

BACKGROUND: The World Health Organization (WHO) has declared obesity as the largest global chronic health problem in adults. In the last years, attention has been drawn to rehabilitative interventions for patients with obesity. AIM: The aim of this manuscript is to provide Physical and Rehabilitation Medicine (PRM) physicians with evidence-based recommendations for the rehabilitation of patients with overweight or obesity and related comorbidities. DESIGN: Evidence-based guidelines. POPULATION: Adults with overweight or obesity. METHODS: Guidelines were based on GRADE and WHO recommendations. A comprehensive search of the available evidence about rehabilitation treatments for obesity was performed, and 17 separate systematic literature reviews were conducted. For each outcome, estimates of the effects of rehabilitation treatments were computed and employed along with an assessment of quality of evidence, desirable and undesirable effects, values and preferences to formulate the recommendations. Recommendations were reviewed by a consensus expert panel using a modified Delphi process. RESULTS: We strongly recommend providing comprehensive multiprofessional and multidisciplinary interventions including exercise, diet and behavioral or cognitive-behavioral therapy. The nutritional component of these treatments should include diets with either a high-protein or a low-fat content. It is strongly recommended to prescribe frequent moderate aerobic exercise. We strongly recommend providing cognitive-behavioral interventions as the behavioral component of rehabilitation programs. CONCLUSIONS: PRM physicians should lead multidisciplinary teams providing comprehensive and individualized rehabilitation programs for patients with overweight or obesity. These guidelines were endorsed by the International Society of Physical and Rehabilitation Medicine (ISPRM) and by the European Society of Physical and Rehabilitation Medicine (ESPRM).

Persulfate Reaction in a Hair-Bleaching Formula: Unveiling the Unconventional Reactivity of 1,13-Diamino-4,7,10-Trioxatridecane.

The stability and unconventional reactivity of 1,13-diamino-4,7,10-trioxatridecane in the presence of NH3, H2O2, and (NH4)2S2O8 are described. The ether-diamine is an ingredient marketed to hair salons and consumers for so-called "plex" services to compensate for hair damage during bleaching. The main reaction product identified is an unexpected azanyl ester derivative. This is considered relevant for the safety evaluation when used in cosmetic products. The mechanism of reaction was explored through DFT calculations. This study represents the first attempt to assess the stability of a plex active in an oxidative environment.

Experimental investigation on the mechanical behavior of polyurethane PICCs after long-term conservation in in vivo-like conditions.

INTRODUCTION: In a previous paper, the authors investigated the mechanical behavior of several commercial polyurethane peripherally inserted central venous catheters (PICCs) in their 'brand new' condition. The present study represents a second step of the research activity and aims to investigate possible modifications of the PICC mechanical response, induced by long-term conservation in in vivo-like conditions, particularly when used to introduce oncologic drugs. METHODS: Eight 5 Fr single-lumen catheters from as many different vendors, were examined. Several specimens were cut from each of them and kept in a bath at 37°C for 1, 2, 3 and 6 months. Two fluids were used to simulate in vivo-like conditions, i.e. ethanol and Ringer-lactate solutions, the first being chosen in order to reproduce a typical chemical environment of oncologic drugs. The test plan included swelling analyses, uniaxial tensile tests and dynamic mechanical thermal analysis (DMTA). RESULTS AND CONCLUSIONS: All tested samples were chemically and mechanically stable in the studied conditions, as no significant weight variation was observed even after six months of immersion in ethanol solution. Uniaxial tensile tests confirmed such a response. For each PICC, very similar curves were obtained from samples tested after different immersion durations in the two fluid solutions, particularly for strains lower than 10%.

The role of gender, psycho-social factors and anthropological-cultural dimensions on pain in neurorehabilitation. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

Pain is frequent in patients undergoing neurorehabilitation, but there is a number of still unanswered questions on this topic. The Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) was constituted with the purpose to identify the best practices that can be used in this context. In this article we summarize the existing evidence and recommendations provided by the ICCPN about the role of gender, psycho-social factors and anthropological-cultural dimensions on pain in neurorehabilitation. Sex, gender, psycho-social variables, anthropological and cultural features may influence pain expression, and its pharmacological and non-pharmacological outcome, but the role of these factors has not been consistently explored in neurorehabilitation. There is a number of psychological factors that can be correlated with or represent a predictor for pain, or may influence the treatment and outcome of neurorehabilitation programs. All these factors should be considered when designing these programs, and future studies should incorporate them as potential covariates that may influence outcome.

Pharmacological and non-pharmacological strategies in the integrated treatment of pain in neurorehabilitation. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

The interplay between pain and neurorehabilitation is very complex, in that pain may be a target for treatment, but can also have negative effects on neurorehabilitation procedures. Moreover, side effects of drugs, which are currently used to treat pain, may negatively influence rehabilitation outcomes. Because of the lack of guidelines or consensus, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) was aimed to answer some open questions on the treatment of pain in this setting. To this aim, we collected evidence on the pharmacological and non-pharmacological strategies and their role in the integrated approach to pain. Despite the lack of studies in patients undergoing neurorehabilitation, current guidelines on the pharmacological treatment of nociceptive and neuropathic pain may be applied in this setting. Non-pharmacological strategies include physical therapy, invasive procedures, psychological treatments and psychotherapy, which together with pharmacological therapies play a key role in the integrated approach to pain. The ICCPN recommendations offer information to ameliorate the current treatment of pain in neurorehabilitation, and to design future studies to answer the still open questions on this topic.

Psychological Considerations in the Assessment and Treatment of Pain in Neurorehabilitation and Psychological Factors Predictive of Therapeutic Response: Evidence and Recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

BACKGROUND: In order to provide effective care to patients suffering from chronic pain secondary to neurological diseases, health professionals must appraise the role of the psychosocial factors in the genesis and maintenance of this condition whilst considering how emotions and cognitions influence the course of treatment. Furthermore, it is important not only to recognize the psychological reactions to pain that are common to the various conditions, but also to evaluate how these syndromes differ with regards to the psychological factors that may be involved. As an extensive evaluation of these factors is still lacking, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) aimed to collate the evidence available across these topics. OBJECTIVES: To determine the psychological factors which are associated with or predictive of pain secondary to neurological conditions and to assess the influence of these aspects on the outcome of neurorehabilitation. METHODS: Two reviews were performed. In the first, a PUBMED search of the studies assessing the association between psychological factors and pain or the predictive value of these aspects with respect to chronic pain was conducted. The included papers were then rated with regards to their methodological quality and recommendations were made accordingly. In the second study, the same methodology was used to collect the available evidence on the predictive role of psychological factors on the therapeutic response to pain treatments in the setting of neurorehabilitation. RESULTS: The first literature search identified 1170 results and the final database included 189 articles. Factors such as depression, anxiety, pain catastrophizing, coping strategies, and cognitive functions were found to be associated with pain across the various conditions. However, there are differences between chronic musculoskeletal pain, migraine, neuropathy, and conditions associated with complex disability with regards to the psychological aspects that are involved. The second PUBMED search yielded 252 studies, which were all evaluated. Anxiety, depression, pain catastrophizing, coping strategies, and pain beliefs were found to be associated to different degrees with the outcomes of multidisciplinary programs, surgery, physical therapies, and psychological interventions. Finally, sense of presence was found to be related to the effectiveness of virtual reality as a distraction tool. CONCLUSIONS: Several psychological factors are associated with pain secondary to neurological conditions and should be acknowledged and addressed in order to effectively treat this condition. These factors also predict the therapeutic response to the neurorehabilitative interventions.