Blood cell differential count discretisation modelling to predict survival in adults reporting to the emergency room: a retrospective cohort study.

OBJECTIVES: To assess the survival predictivity of baseline blood cell differential count (BCDC), discretised according to two different methods, in adults visiting an emergency room (ER) for illness or trauma over 1 year. DESIGN: Retrospective cohort study of hospital records. SETTING: Tertiary care public hospital in northern Italy. PARTICIPANTS: 11 052 patients aged >18 years, consecutively admitted to the ER in 1 year, and for whom BCDC collection was indicated by ER medical staff at first presentation. PRIMARY OUTCOME: Survival was the referral outcome for explorative model development. Automated BCDC analysis at baseline assessed haemoglobin, mean cell volume (MCV), red cell distribution width (RDW), platelet distribution width (PDW), platelet haematocrit (PCT), absolute red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets. Discretisation cut-offs were defined by benchmark and tailored methods. Benchmark cut-offs were stated based on laboratory reference values (Clinical and Laboratory Standards Institute). Tailored cut-offs for linear, sigmoid-shaped and U-shaped distributed variables were discretised by maximally selected rank statistics and by optimal-equal HR, respectively. Explanatory variables (age, gender, ER admission during SARS-CoV2 surges and in-hospital admission) were analysed using Cox multivariable regression. Receiver operating curves were drawn by summing the Cox-significant variables for each method. RESULTS: Of 11 052 patients (median age 67 years, IQR 51-81, 48% female), 59% (n=6489) were discharged and 41% (n=4563) were admitted to the hospital. After a 306-day median follow-up (IQR 208-417 days), 9455 (86%) patients were alive and 1597 (14%) deceased. Increased HRs were associated with age >73 years (HR=4.6, 95% CI=4.0 to 5.2), in-hospital admission (HR=2.2, 95% CI=1.9 to 2.4), ER admission during SARS-CoV2 surges (Wave I: HR=1.7, 95% CI=1.5 to 1.9; Wave II: HR=1.2, 95% CI=1.0 to 1.3). Gender, haemoglobin, MCV, RDW, PDW, neutrophils, lymphocytes and eosinophil counts were significant overall. Benchmark-BCDC model included basophils and platelet count (area under the ROC (AUROC) 0.74). Tailored-BCDC model included monocyte counts and PCT (AUROC 0.79). CONCLUSIONS: Baseline discretised BCDC provides meaningful insight regarding ER patients' survival.

The natural history of ALS: Baseline characteristics from a multicenter clinical cohort.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed. METHODS: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal. RESULTS: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database. CONCLUSIONS: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.

Predictors of pain reduction following a program of manual therapies for patients with temporomandibular disorders: A prospective observational study.

BACKGROUND: Clinical guidelines recommend conservative treatment for the management of temporomandibular disorders (TMD), and manual therapy (MT) is commonly applied to reduce pain and improve function. OBJECTIVES: To identify predictors of pain reduction and functional improvement following a program of manual therapies (MTP) in patients with TMD and develop a first screening tool that could be used in clinical practice to facilitate decision-making. DESIGN: A cohort of 102 adults with a diagnosis of TMD were treated with four weekly sessions within a MTP applied to craniomandibular structures. Candidate predictors were demographic variables, general health variables, psychosocial features, TMD characteristics and related clinical tests. A reduction of pain intensity by at least 30% after the MTP was considered a good outcome. Logistic regression was adopted to develop the predictive model and its performance was assessed considering the explained variance, calibration, and discrimination. Internal validation of the prediction models was further evaluated in 500 bootstrapped samples. RESULTS: Patients experiencing pain intensity greater than 2/10 during mouth opening, positive expectations of outcome following a MTP, pain localized in the craniocervical region, and a low Central Sensitization Inventory score obtained a good outcome following the MTP. Predictive performance of the identified physical and psychological variables was characterized by high explained variance (R2 = 58%) and discrimination (AUC = 89%) after internal validation. A preliminary screening clinical tool was developed and presented as a nomogram. CONCLUSIONS: The high discrimination of the prediction model revealed promising findings, although these need to be externally validated in future research. TRIAL REGISTRATION NUMBER: NCT03990662.

The impact of Covid-19-related distress on general health, oral behaviour, psychosocial features, disability and pain intensity in a cohort of Italian patients with temporomandibular disorders.

This study aimed to understand the impact of COVID-19 distress on psychological status, features of central sensitization and facial pain severity in people with temporomandibular disorders (TMDs). In this prospective cohort study, 45 adults (19 chronic, 26 acute/subacute TMD) were recruited prior to the COVID-19 outbreak. Baseline assessment took place before the outbreak while a follow-up was performed immediately after the lockdown period. Multiple variables were investigated including age, gender, perceived life quality, sleep quality, anxiety and depression, coping strategies, central sensitization, pain intensity, pain-related disability and oral behaviour. COVID Stress Scales (CSS) were applied at follow-up to measure the extent of COVID-related distress. CSS were significantly higher in those with chronic TMDs compared to those with acute/subacute TMDs (p<0.05). In people with chronic TMD, the variation in anxiety and depression from baseline to follow-up was significantly correlated with scores on the CSS (r = 0.72; p = 0.002). Variations of the central sensitization inventory (r = 0.57; p = 0.020) and graded chronic pain scale (r = 0.59; p = 0.017) were significantly correlated with scores on the CSS. These initial findings indicate that people with chronic TMD were more susceptible to COVID-19 distress with deterioration of psychological status, worsening features of central sensitization and increased chronic facial pain severity. These findings reinforce the role of stress as a possible amplifier of central sensitization, anxiety, depression, chronic pain and pain-related disability in people with TMDs. Trial Registration: ClinicalTrials.gov ID: NCT03990662.

Predictors of pain reduction following manual therapy in patients with temporomandibular disorders: a protocol for a prospective observational study.

INTRODUCTION: Temporomandibular disorders (TMDs) are principally characterised by pain in the craniomandibular area and probable limitations of jaw opening. Manual therapy, like other recommended conservative treatments included in clinical guidelines, is commonly used to treat patients with TMD to reduce pain and improve function. However, outcomes may be variable. The aim of this study is to identify predictors associated with pain reduction in patients with TMD following manual therapy by analysing a combination of patient-reported outcome measures and clinical tests. Such knowledge will support a more personalised management approach by facilitating clinical decision-making. METHODS/ANALYSIS: An observational prospective design will recruit a cohort of 100 adults with a diagnosis of TMD (according to Axis I of the Diagnostic Criteria for TMD) at a Dental Hospital in Italy. Patients will be treated with four weekly sessions of manual therapy applied to craniomandibular structures. An array of predictors has been chosen based on previous research on prognostic factors for TMD and altered pain modulation in musculoskeletal disorders. Candidate predictors including demographic variables, general health variables, psychosocial features, TMD characteristics and clinical tests of the temporomandibular joint and masticatory muscles will be collected at baseline. Definition of good outcome is a clinically significant reduction of pain intensity over the last week (≥30% reduction Visual Analogue Scale) immediately following the four week intervention. Exploratory factor analysis will be applied to analyse factor loading of candidate predictors for good outcome at four weeks. Subsequently, a logistic multivariable regression model will be performed to calculate low and high risk of good outcome. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the 'Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico' and University of Birmingham Ethics Committee. The results will be submitted for publication in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: NCT03990662; Pre-results.

Efficacy of virtual reality to reduce chronic low back pain: Proof-of-concept of a non-pharmacological approach on pain, quality of life, neuropsychological and functional outcome.

OBJECTIVES: Chronic pain, such as low-back pain, can be a highly disabling condition degrading people's quality of life (QoL). Not every patient responds to pharmacological therapies, thus alternative treatments have to be developed. The chronicity of pain can lead to a somatic dysperception, meaning a mismatch between patients' own body perception and its actual physical state. Since clinical evaluation of pain relies on patients' subjective reports, a body image disruption can be associated with an incorrect pain rating inducing incorrect treatment and a possible risk of drug abuse. Our aim was to reduce chronic low-back pain through a multimodal neurorehabilitative strategy using innovative technologies to help patients regain a correct body image. METHODS: Twenty patients with chronic low-back pain were included. Before and after treatment, patients underwent: a neurological exam; a neuro-psychological evaluation testing cognitive functions (memory, attention, executive functions) and personality traits, QoL and mood; pain ratings; sensorimotor functional abilities' testing. Patients underwent a 6 week-neurorehabilitative treatment (total 12 sessions) using virtual reality (VRRS system, Khymeia, Italy). Treatment consisted on teaching patients to execute correct movements with the painful body parts to regain a correct body image, based on the augmented multisensory feedback (auditory, visual) provided by the VRRS. RESULTS: Our data showed significant reductions in all pain rating scale scores (p<0.05); significant improvements of QoL in the domains of physical functioning, physical role functioning, bodily pain, vitality, and social role functioning; improvements in cognitive functions (p<0.05); improvements in functional scales (p<0.05) and mood (p = 0.04). CONCLUSION: This non-pharmacological approach was able to act on the multi-dimensional aspects of pain and improved patients' QoL, pain intensity, mood and patient's functional abilities.

Cognitive training with action-related verbs induces neural plasticity in the action representation system as assessed by gray matter brain morphometry.

Embodied cognition theories of semantic memory still face the need for multiple sources of converging evidence in support of the involvement of sensory-motor systems in action-related knowledge. Previous studies showed that training manual actions improves semantic processing of verbs referring to the trained actions. The present work aimed to provide complementary evidence by measuring the brain plasticity effects of a cognitive training requiring sustained lexical-semantic processing of action-related verbs. We included two groups of participants, namely the Proximal Group (PG) and the Distal Group (DG), which underwent a 3-week training with verbs referring to actions involving the proximal and the distal upper limb musculature, respectively. Before and after training, we measured gray matter voxel brain morphometry based on T1 structural magnetic resonance imaging. By means of this 2 (Group: PG, DG) × 2 (Time: pre-, post-training) factorial design, we tested whether sustained cognitive experience with specific action-related verbs induces congruent brain plasticity modifications in target regions of interest pertaining to the action representation system. We found significant post- versus pre-training gray matter volume increases, specifically for PG in the left dorsal precentral gyrus, and for DG in the right cerebellar lobule VIIa. These preliminary results suggest that a cognitive training can induce structural plasticity modifications in brain regions specifically coding for the distal and proximal motor actions the trained verbs refer to.

Training of manual actions improves language understanding of semantically related action sentences.

Conceptual knowledge accessed by language may involve the reactivation of the associated primary sensory-motor processes. Whether these embodied representations are indeed constitutive to conceptual knowledge is hotly debated, particularly since direct evidence that sensory-motor expertise can improve conceptual processing is scarce. In this study, we sought for this crucial piece of evidence, by training naive healthy subjects to perform complex manual actions and by measuring, before and after training, their performance in a semantic language task. Nineteen participants engaged in 3 weeks of motor training. Each participant was trained in three complex manual actions (e.g., origami). Before and after the training period, each subject underwent a series of manual dexterity tests and a semantic language task. The latter consisted of a sentence-picture semantic congruency judgment task, with 6 target congruent sentence-picture pairs (semantically related to the trained manual actions), 6 non-target congruent pairs (semantically unrelated), and 12 filler incongruent pairs. Manual action training induced a significant improvement in all manual dexterity tests, demonstrating the successful acquisition of sensory-motor expertise. In the semantic language task, the reaction times (RTs) to both target and non-target congruent sentence-picture pairs decreased after action training, indicating a more efficient conceptual-semantic processing. Noteworthy, the RTs for target pairs decreased more than those for non-target pairs, as indicated by the 2 × 2 interaction. These results were confirmed when controlling for the potential bias of increased frequency of use of target lexical items during manual training. The results of the present study suggest that sensory-motor expertise gained by training of specific manual actions can lead to an improvement of cognitive-linguistic skills related to the specific conceptual-semantic domain associated to the trained actions.