A Systematic Review of Clinical Practice Guidelines for Persons With Non-specific Low Back Pain With and Without Radiculopathy: Identification of Best Evidence for Rehabilitation to Develop the WHO's Package of Interventions for Rehabilitation.

OBJECTIVE: To Identify evidence-based rehabilitation interventions for persons with non-specific low back pain (LBP) with and without radiculopathy and to develop recommendations from high-quality clinical practice guidelines (CPGs) to inform the World Health Organization's (WHO) Package of Interventions for Rehabilitation (PIR). DATA SOURCE: We searched MEDLINE, EMBASE, CINAHL, PsycINFO, National Health Services Economic Evaluation Database, Health Technology Assessment Database, PEDro, the Trip Database, the Index to Chiropractic Literature and the gray literature. STUDY SELECTION: Eligible guidelines were (1) published between 2009 and 2019 in English, French, Italian, or Swedish; (2) included adults or children with non-specific LBP with or without radiculopathy; and (3) assessed the benefits of rehabilitation interventions on functioning. Pairs of independent reviewers assessed the quality of the CPGs using AGREE II. DATA SYNTHESIS: We identified 4 high-quality CPGs. Recommended interventions included (1) education about recovery expectations, self-management strategies, and maintenance of usual activities; (2) multimodal approaches incorporating education, exercise, and spinal manipulation; (3) nonsteroidal anti-inflammatory drugs combined with education in the acute stage; and (4) intensive interdisciplinary rehabilitation that includes exercise and cognitive/behavioral interventions for persistent pain. We did not identify high-quality CPGs for people younger than 16 years of age. CONCLUSION: We developed evidence-based recommendations from high-quality CPGs to inform the WHO PIR for people with LBP with and without radiculopathy. These recommendations emphasize the potential benefits of education, exercise, manual therapy, and cognitive/behavioral interventions.

Is impaired lung function related to spinal deformities in patients with adolescent idiopathic scoliosis? A systematic review and meta-analysis-SOSORT 2019 award paper.

PURPOSE: Some teenagers with adolescent idiopathic scoliosis (AIS) display compromised lung function. However, the evidence regarding the relations between pulmonary impairments and various spinal deformity parameters in these patients remains unclear, which affects clinical management. This systematic review and meta-analysis aimed to summarize the associations between various lung function parameters and radiographic features in teenagers with AIS. METHODS: A search of PubMed, Embase, PEDro, SPORTDiscus, CINAHL, Cochrane Library, and PsycINFO (from inception to March 14, 2022) without language restriction. Original studies reporting the associations between lung function and spinal deformity in patients with AIS were selected. Independent reviewers extracted data and evaluated the methodological quality of the included studies according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pearson correlation and 95% confidence intervals were calculated using random-effects meta-analysis. RESULTS: Twenty-seven studies involving 3162 participants were included. Limited-quality evidence supported that several spinal parameters were significantly related to lung function parameters (e.g., absolute value and percent of the predicted forced vital capacity (FVC; %FVC), forced expiratory volume in one second (FEV1; %FEV1), and total lung capacity (TLC; %TLC)) in AIS patients. Specifically, meta-analyses showed that main thoracic Cobb angles in the coronal plane were significantly and negatively related to FVC (r = - 0.245), %FVC (r = - 0.302), FEV1 (r = - 0.232), %FEV1 (r = - 0.348), FEV1/FVC ratio (r = - 0.166), TLC (r = - 0.302), %TLC (r = - 0.183), and percent predicted vital capacity (r = - 0.272) (p < 0.001). Similarly, thoracic apical vertebral rotation was negatively associated with %FVC (r = - 0.215) and %TLC (r = - 0.126) (p < 0.05). Conversely, thoracic kyphosis angles were positively related to %FVC (r = 0.180) and %FEV1 (r = 0.193) (p < 0.05). CONCLUSION: Larger thoracic Cobb angles, greater apical vertebral rotation angle, or hypokyphosis were significantly associated with greater pulmonary impairments in patients with AIS, although the evidence was limited. From a clinical perspective, the results highlight the importance of minimizing the three-dimensional spinal deformity in preserving lung function in these patients. More research is warranted to confirm these results.

Predicting final results of brace treatment of adolescents with idiopathic scoliosis: first out-of-brace radiograph is better than in-brace radiograph-SOSORT 2020 award winner.

PURPOSE: In-brace radiograph of adolescents with idiopathic scoliosis (AIS) has been shown to reflect brace efficacy and the possibility of achieving curve correction. Conversely, the first out-of-brace radiograph could demonstrate the patient's ability to maintain the correction. We aimed to determine which of the two radiographs is the best predictor of the Cobb angle at the end of treatment (final radiograph). DESIGN: Retrospective cohort study of a prospective dataset. METHODS: The population was selected based on the following inclusion criteria: AIS, age 10-18 years; Risser score 0-2; Cobb angle 25-40°; brace treatment; availability of all radiographs. STATISTICS: Pearson correlations provide a first exploration of data. The univariate and multivariate logistic regression model tested the predictors. Finally ROC curve provided a check of model accuracy. RESULTS: A total of 131 patients were included (mean age 13.0 ± 1.3, Cobb angle 33.2 ± 5.5°; 78% females). At the end of treatment, 56% had stabilised, 9% had progressed, and 44% had improved. The difference between the in-brace and final radiographs was 8.0 ± 6.0°, while the difference between the first out-of-brace and final radiographs was 1.8 ± 5.2°. The best predictor of final outcome was the first out-of-brace radiograph (0.80), compared to in-brace (0.68) and baseline (0.59) radiographs. The best cut-offs to predict avoidance of progression were 30% and 10% of the correction rates for the in-brace and first out-of-brace radiographs, respectively. CONCLUSION: The first out-of-brace radiograph predicts end results better than the in-brace radiograph. It offers an excellent clinical reference for clinicians and patients. The first out-of-brace radiograph should be considered an essential element of future predictive models. LEVEL OF EVIDENCE 1: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.

GCN5 enables HSP12 induction promoting chromatin remodeling, not histone acetylation.

Regulation of stress-responsive genes represent one of the best examples of gene induction, and the relevance and involvement of different regulators may change for a given gene depending on the challenging stimulus. The HSP12 gene is induced by very different stimuli; however, the molecular response to stress has been characterized in detail only for heat shock treatments. In this study, we aimed to verify whether the regulation of transcription induced by oxidative stress utilizes the same epigenetic solutions as those employed in the heat shock response. We also monitored HSP12 induction by employing spermidine, a known acetyltransferase inhibitor, and observed an oxidative stress that synergizes with spermidine treatment. Our data show that during transcriptional response to H2O2, histone acetylation and chromatin remodeling occur. However, when the relevance of Gcn5p to these processes was studied, we observed that induction of transcription is GCN5-dependent, and this does not rely on histone acetylation by Gcn5p despite its HAT activity. Chromatin remodeling accompanying gene activation is GCN5 dependent. Thus, GCN5 controls HSP12 transcription after H2O2 treatment by allowing chromatin remodeling, and it is only partially involved in HSP12 histone acetylation regardless of its HAT activity.

Why Should DNA Topoisomerase I Have a Scaffold Activity?

Since the early 1990s, in vitro studies have demonstrated that DNA topoisomerase I promotes RNA polymerase II transcription, acting as a cofactor, regardless of its catalytic activity. Recent studies, carried in vivo, using yeast as a model system, also demonstrate that DNA topoisomerase I is able to recruit, without the involvement of its catalytic activity, the Sir2p deacetylase on ribosomal genes thus contributes to achieve their silencing. In this review, the DNA topoisomerase I capability, acting as a scaffold protein, as well as its involvement and role in several macromolecular complexes, will be discussed, in light of several observations reported in the literature, pointing out how its role goes far beyond its well-known ability to relax DNA.

Saccharomyces cerevisiae rDNA as super-hub: the region where replication, transcription and recombination meet.

Saccharomyces cerevisiae ribosomal DNA, the repeated region where rRNAs are synthesized by about 150 encoding units, hosts all the protein machineries responsible for the main DNA transactions such as replication, transcription and recombination. This and its repetitive nature make rDNA a unique and complex genetic locus compared to any other. All the different molecular machineries acting in this locus need to be accurately and finely controlled and coordinated and for this reason rDNA is one of the most impressive examples of highly complex molecular regulated loci. The region in which the large molecular complexes involved in rDNA activity and/or regulation are recruited is extremely small: that is, the 2.5 kb long intergenic spacer, interrupting each 35S RNA coding unit from the next. All S. cerevisiae RNA polymerases (I, II and III) transcribing the different genetic rDNA elements are recruited here; a sequence responsible for each rDNA unit replication, which needs its molecular apparatus, also localizes here; moreover, it is noteworthy that the rDNA replication proceeds almost unidirectionally because each replication fork is stopped in the so-called replication fork barrier. These localized fork blocking events induce, with a given frequency, the homologous recombination process by which cells maintain a high identity among the rDNA repeated units. Here, we describe the different processes involving the rDNA locus, how they influence each other and how these mutual interferences are highly regulated and coordinated. We propose that an rDNA conformation as a super-hub could help in optimizing the micro-environment for all basic DNA transactions.

Histone acetylation landscape in S. cerevisiae nhp6ab mutants reflects altered glucose metabolism.

BACKGROUND: The execution of many genetic programs, influenced by environmental conditions, is epigenetically controlled. Thus, small molecules of the intermediate metabolism being precursors of most of nutrition-deriving epigenetic modifications, sense the cell surrounding environment. METHODS: Here we describe histone H4K16 acetylation distribution in S. cerevisiae nhp6ab mutant, using ChIP-seq analysis; its transcription profile by RNA-seq and its metabolic features by studying the metabolome. We then intersected these three -omic approaches to unveil common crosspoints (if any). RESULTS: In the nhp6ab mutant, the glucose metabolism is switched to pathways leading to Acetyl-CoA synthesis. These enhanced pathways could lead to histone hyperacetylation altering RNA transcription, particularly of those metabolic genes that maintain high Acetyl-CoA availability. CONCLUSIONS: Thus, the absence of chromatin regulators like Nhp6 A and B, interferes with a regulative circular mechanism where histone modification, transcription and metabolism influence each other and contribute to clarify the more general phenomenon in which gene regulation feeds metabolic alterations on epigenetic basis. GENERAL SIGNIFICANCE: This study allowed us to identify, in these two factors, a common element of regulation in metabolism and chromatin acetylation state that could represent a powerful tool to find out relationships existing between metabolism and gene expression in more complex systems.

Construct validity of the Trunk Aesthetic Clinical Evaluation (TRACE) in young people with idiopathic scoliosis.

BACKGROUND: Aesthetics is recognized as a main outcome in idiopathic scoliosis (IS) treatment, but to date, there is no criterion standard for physicians' evaluation. Trunk Aesthetic Clinical Evaluation (TRACE) is a simple 12-point ordinal scale to quantify symmetry as a proxy of aesthetics. TRACE is already diffused worldwide and has been used in clinical research. OBJECTIVE: We aimed to validate TRACE and improve it with Rasch analysis. MATERIAL AND METHODS: This study involved an observational Rasch analysis validation of an evaluation tool in outpatient rehabilitation centres. From a clinical database, we randomly selected patients who had IS, were age 10 to 18, had brace prescription at first evaluation, and had at least 2 consultations. Rasch analysis (partial credit model) was used. Differential item functioning (DIF) was assessed for age, sex, disease severity, bracing and treatment. The median was chosen to dichotomize disease severity and bracing. We removed 64 outlier participants (4%). RESULTS: We included 1553 participants (1334 females; mean [SD] age 13 [1.7] years old). TRACE items showed ordered thresholds and proper fit to the Rasch model. The score-to-measure conversion table showed proper length (range -4.55 to 4.79 logit) with a mean (SE) measure of -0.52 (0.04) logit. The principal component analysis supported the TRACE unidimensionality. The TRACE was free from DIF for age, sex and bracing. CONCLUSIONS: The TRACE ordinal scale has been converted into a Rasch-consistent, interval-level measure of trunk aesthetics in IS patients and can be used to compare different populations. Its main flaw is low reliability, likely because of the small number of items. TRACE can be used as an outcome measure and in everyday clinical evaluation of IS, even if new developments of the scale are advised.

Restriction enzymes and their use in molecular biology: An overview.

Restriction enzymes have been identified in the early 1950s of the past century and have quickly become key players in the molecular biology of DNA. Forty years ago, the scientists whose pioneering work had explored the activity and sequence specificity of these enzymes, contributing to the definition of their enormous potential as tools for DNA characterization, mapping and manipulation, were awarded the Nobel Prize. In this short review, we celebrate the history of these enzymes in the light of their many different uses, as these proteins have accompanied the history of DNA for over 50 years representing active witnesses of major steps in the field.

Fob1p recruits DNA topoisomerase I to ribosomal genes locus and contributes to its transcriptional silencing maintenance.

S. cerevisiae ribosomal DNA (rDNA) locus hosts a series of highly complex regulatory machineries for RNA polymerase I, II and III transcription, DNA replication and units recombination, all acting in the Non Transcribed Spacers (NTSs) interposed between the repeated units by which it is composed. DNA topoisomerase I (Top1p) contributes, recruiting Sir2p, to the maintenance of transcriptional silencing occurring at the RNA Polymerase II cryptic promoters, located in the NTS region. In this paper we found that Fob1p presence is crucial for Top1p recruitment at NTS, allowing transcriptional silencing to be established and maintained. We also showed the role of Nsr1p in Top1p recruitment to rDNA locus. Our work allows to hypothesize that Nsr1p targets Top1p into the nucleolus while Fob1p is responsible for its preferential distribution at RFB.

The Natural History of Idiopathic Scoliosis During Growth: A Meta-Analysis.

OBJECTIVE: The aim of the study was to provide a meta-analysis of current literature concerning the natural history of idiopathic scoliosis during growth. DESIGN: A comprehensive search of Medline, Embase, And Scopus databases was conducted up to November 2016. Eligible works were prospective or retrospective studies that enrolled patients with infantile idiopathic scoliosis, juvenile idiopathic scoliosis, or adolescent idiopathic scoliosis, followed up without any treatment from the time of detection. A meta-analysis for proportion was performed. The following studies were grouped per diagnosis: infantile idiopathic scoliosis, juvenile idiopathic scoliosis, and adolescent idiopathic scoliosis. RESULTS: Of the 1797 citations screened, we assessed 61 full-text articles and included 13 of these (2301 participants). Three studies included infantile idiopathic scoliosis patients (347 participants), five studies included a mixed population of juvenile idiopathic scoliosis and adolescent idiopathic scoliosis (1330 participants), and five studies included adolescent idiopathic scoliosis patients only (624 participants). The random pooled estimated progression rate was 49% (95% confidence interval = 1%-97%) for infantile idiopathic scoliosis, 49% in a mixed group of patients affected by juvenile idiopathic scoliosis or adolescent idiopathic scoliosis (95% confidence interval = 19%-79%), and 42% in adolescent idiopathic scoliosis (95% confidence interval = 11%-73%). CONCLUSIONS: During growth, idiopathic scoliosis tends to progress in a high percentage of cases. The progression rate varies according to the age at diagnosis, with infantile scoliosis being the most unpredictable. There are many confounders, such as age, Risser sign and baseline Cobb angles that were not consistent among studies, making the data very heterogeneous.

Spontaneous and complete regeneration of a vertebra plana after surgical curettage of an eosinophilic granuloma.

PURPOSE: The eosinophilic granuloma is a unifocal or multifocal Langerhans cell histiocytosis characterized by an expanding proliferation of Langerhans cells in bones. Skeletal LCH is a rare condition, and vertebral regeneration in cases of vertebral body collapse is even rarer. We report the case of a girl with spontaneous complete healing. METHODS AD RESULTS: A 3-year-old girl was referred for nighttime back pain, with no fever and no neurologic signs. Within a few days, she developed sudden painful restriction of all spine movements. X-ray and computed tomography (CT) of the spine showed reduced T7 vertebral body height (vertebra plana).The patient underwent T7 curettage and the histopathological exam was suggestive of LCH. Two additional skull lesions were found and therefore she underwent chemotherapy. After 7 years of follow-up, total vertebral reconstruction was observed. CONCLUSIONS: Despite the rarity of the condition and despite the rarity of vertebral body lesion resolution, total vertebral body reconstruction was observed over a 7-year period. Long-term follow-up is necessary for a better understanding of the final outcome of patients with EG.

Adolescents with idiopathic scoliosis and their parents have a positive attitude towards the Thermobrace monitor: results from a survey.

BACKGROUND: A temperature monitor is used to objectively measure brace wear time in adolescent idiopathic scoliosis. The reliability of this device have been demonstrated, and some specialists introduced the use of a compliance monitor as a standard of care in everyday clinical practice, as we did since 2010 with the Thermobrace (TB). The attitude towards these objective monitors has never been investigated. The present study aims to investigate the attitude of parents and patients towards the use of temperature sensors for measuring brace wear compliance. METHODS: Three hundred one consecutive girls and 63 boys and their parents have been interviewed. The inclusion criteria were as follows: brace wear full-time prescription at first visit and at least one visit with download and discussion of TB data. Usefulness, acceptability, reliability, and feeling related to data download were the investigated domains. Patients were invited by the administrative staff to complete anonymously the questionnaire. The European Commission was informed about the present survey and approved it (ICT-37-2015-1). Descriptive statistic was used to present the results. RESULTS: Among the 364 invited patients and parents, 336 adhered by completing it (rate of responders was 93.2%). The mean age was 14.65 (SD 2.36), the mean Cobb angle was 34.18 (SD 13.57), and the average brace wear prescription was 21.76 h per day (SD 2.53). We did not ask parents about their age, profession, nor other personal data. Globally, the interviewed patients and parents showed a very positive attitude towards the TB monitor: the mean rate of parents stating a completely or at least partially positive attitude towards this electronic device was 94.0% while among patients, it was 85.6%. CONCLUSIONS: This is the first study investigating the attitude of parents and patients towards a brace wear compliance monitor. People who experienced this objective monitoring are aware of the advantages related to it and support its usefulness not only for clinicians but also for patients and parents to respect the hours prescribed without any affection on the children and parents or the patient-physician relationship. The present results should encourage the spread of these tools in daily clinical practice.

A novel role for Nhp6 proteins in histone gene regulation in Saccharomyces cerevisiae.

Maintaining a stable and balanced histone pool is of paramount importance for genome stability and fine regulation of DNA replication and transcription. This involves a complex regulatory machinery, exploiting transcription factors as well as histone chaperones, chromatin remodelers and modifiers. The functional details of this machinery are as yet unclear. Previous studies report histone decrease in mammalian and yeast HMGB family mutants. In this study we find that Nhp6 proteins, the S. cerevisiae HMGB1 homologues, control histone gene expression by affecting nucleosome stability at regulative regions of the histone clusters. In addition, we observe that histone gene overexpression in the nhp6ab mutant is accompanied by downregulated translation, which in turn is responsible for the histone decrease phenotype. Our observations allow us to incorporate Nhp6 proteins into the large group of chromatin factors that tightly regulate histone gene expression.

Molecular Mechanism of DNA Topoisomerase I-Dependent rDNA Silencing: Sir2p Recruitment at Ribosomal Genes.

Saccharomyces cerevisiae sir2Δ or top1Δ mutants exhibit similar phenotypes involving ribosomal DNA, including (i) loss of transcriptional silencing, resulting in non-coding RNA hyperproduction from cryptic RNA polymerase II promoters; (ii) alterations in recombination; and (iii) a general increase in histone acetylation. Given the distinct enzymatic activities of Sir2 and Top1 proteins, a histone deacetylase and a DNA topoisomerase, respectively, we investigated whether genetic and/or physical interactions between the two proteins could explain the shared ribosomal RNA genes (rDNA) phenotypes. We employed an approach of complementing top1Δ cells with yeast, human, truncated, and chimeric yeast/human TOP1 constructs and of assessing the extent of non-coding RNA silencing and histone H4K16 deacetylation. Our findings demonstrate that residues 115-125 within the yeast Top1p N-terminal domain are required for the complementation of the top1∆ rDNA phenotypes. In chromatin immunoprecipitation and co-immunoprecipitation experiments, we further demonstrate the physical interaction between Top1p and Sir2p. Our genetic and biochemical studies support a model whereby Top1p recruits Sir2p to the rDNA and clarifies a structural role of DNA topoisomerase I in the epigenetic regulation of rDNA, independent of its known catalytic activity.

LBP and lower limb discrepancy: 3D evaluation of postural rebalancing via underfoot wedge correction.

Leg Length Discrepancy (LLD) is very often associated to Low Back Pain (LBP), but still controversial is the use of underfoot wedge correction (heel rise) to re-balance pelvis and trunk posture. In a review of our last 5 years clinical activity we observed that more than 70% out of 300 LBP patients presented a LLD. In more than 80 % we ascertained, via Baropodography, the presence of underfoot asymmetric load, during standing. More durable therapy recovery effect has been observed when LLD correction had been adopted. These reasons led us to start a study to assess if a Full 3D multifactorial Posture evaluation approach, by means of Opto-electronic device associated to foot pressure maps recording, was able to quantitatively discriminate the clinically observed phenomena. On a 94 LBP (av. age 46.3±16 Y range 15-82 Y) patients sample, 83 (88%) have been found to improve posture when LLD was corrected. The 94 patients showed a mean lower limb discrepancy of µ=8±3.2mm associated to a mean scoliotic lumbar curve µ=10.5°±5.1° Cobb (frontal plane), mean Spinal offset µ=6.6±4.9mm and mean Global offset 10.7±8.8mm. The applied paired t-test comparison (indifferent vs. corrected orthostasis) showed significant (p < 0.05) postural improvements could be obtained in the whole or in a part of the considered parameters, both in rebalancing and in spine deformities reduction after the application of suitable under-foot wedge. The joint 3D opto-electronic and foot pressure map approach proved to be effective to control several clinical parameters with statistical significance.

Leg length discrepancy in scoliotic patients.

The aetiological aspects as well as postural attitude implications represent an open question in scoliosis evaluation and treatment. Leg length discrepancy (LLD) is often recognised in scoliotic patients, but surprisingly still controversial is the use of underfoot wedge corrections in order to compensate pelvis tilt. In fact, literature reports conflicting results on the efficacy of LLD equalization also given the argued uncertainty of LLD clinical assessment and limitations related to X-ray measurements. Moreover concern is about anatomic and functional LLD and associated estimation of the pelvic torsion. In such a topic, a significant helpful tool has been demonstrated to be 3D kinematic optoelectronic measurements and other useful data obtained from force platforms and/or baropodographic systems. 135 (94.4%) out of 143 Scoliotic patients sample (av. age 16.4±10.2 Y range 4-66 Y), have been found to improve posture when LLD was corrected. The 143 patients showed a mean lower limb discrepancy of µ=10.2±5.2mm associated to a mean main scoliotic curve µ=16.4°±9.4° Cobb (frontal plane), mean Spinal offset µ=7.5±5.5mm and mean Global offset µ=10.1±7.1mm. The applied paired t-test comparison (indifferent vs. corrected orthostasis) showed significant (p < 0.05) postural improvements could be obtained in the whole or in a part of the considered postural parameters, after the application of suitable under-foot wedge. The present investigation confirm results of a previous study demonstrating the efficacy of under-foot wedge use in leg asymmetry correction, posture re-balancing and spine deformities reduction, pointing out the significant contribution of the 3D opto-electronic measurement approach in the critical process of assessing the correct under-foot wedge size, therapy planning and monitoring.