Physiopathologie, diagnostic et traitements des maladies musculo-squelettiques

Importance: Patient-reported outcome (PRO) data from clinical trials can provide valuable evidence to inform shared decision making, labeling claims, clinical guidelines, and health policy; however, the PRO content of clinical trial protocols is often suboptimal. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was published in 2013 and aims to improve the completeness of trial protocols by providing evidence-based recommendations for the minimum set of items to be addressed, but it does not provide PRO-specific guidance. Objective: To develop international, consensus-based, PRO-specific protocol guidance (the SPIRIT-PRO Extension). Design, Setting, and Participants: The SPIRIT-PRO Extension was developed following the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework for guideline development. This included (1) a systematic review of existing PRO-specific protocol guidance to generate a list of potential PRO-specific protocol items (published in 2014); (2) refinements to the list and removal of duplicate items by the International Society for Quality of Life Research (ISOQOL) Protocol Checklist Taskforce; (3) an international stakeholder survey of clinical trial research personnel, PRO methodologists, health economists, psychometricians, patient advocates, funders, industry representatives, journal editors, policy makers, ethicists, and researchers responsible for evidence synthesis (distributed by 38 international partner organizations in October 2016); (4) an international Delphi exercise (n = 137 invited; October 2016 to February 2017); and (5) consensus meeting (n = 30 invited; May 2017). Prior to voting, consensus meeting participants were informed of the results of the Delphi exercise and given data from structured reviews evaluating the PRO protocol content of 3 defined samples of trial protocols. Results: The systematic review identified 162 PRO-specific protocol recommendations from 54 sources. The ISOQOL Taskforce (n = 21) reduced this to 56 items, which were considered by 138 international stakeholder survey participants and 99 Delphi panelists. The final wording of the SPIRIT-PRO Extension was agreed on at a consensus meeting (n = 29 participants) and reviewed by external group of experts during a consultation period. Eleven extensions and 5 elaborations to the SPIRIT 2013 checklist were recommended for inclusion in clinical trial protocols in which PROs are a primary or key secondary outcome. Extension items focused on PRO-specific issues relating to the trial rationale, objectives, eligibility criteria, concepts used to evaluate the intervention, time points for assessment, PRO instrument selection and measurement properties, data collection plan, translation to other languages, proxy completion, strategies to minimize missing data, and whether PRO data will be monitored during the study to inform clinical care. Conclusions and Relevance: The SPIRIT-PRO guidelines provide recommendations for items that should be addressed and included in clinical trial protocols in which PROs are a primary or key secondary outcome. Improved design of clinical trials including PROs could help ensure high-quality data that may inform patient-centered care.

RATIONALE: The 2002 American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias identified nonspecific interstitial pneumonia (NSIP) as a provisional diagnosis. Concern was expressed that NSIP was a "wastebasket" category, difficult to distinguish from other idiopathic interstitial pneumonias. OBJECTIVES: The following questions were addressed: (1) Is idiopathic NSIP a distinct entity? 2) If so, what are its clinical, radiologic and pathologic characteristics? (3) What is the role of radiology and pathology in establishing the diagnosis? (4) To make a diagnosis of idiopathic NSIP, what other disorders need to be excluded and how should this be done? METHODS: Investigators who had previously reported cases of idiopathic NSIP were invited to submit cases for review (n = 305). After initial review, cases with complete clinical, radiologic, and pathologic information (n = 193) were reviewed in a series of workshops. MEASUREMENTS AND MAIN RESULTS: Sixty-seven cases were identified as NSIP. Mean age was 52 years, 67% were women, 69% were never-smokers, and 46% were from Asian countries. The most common symptoms were dyspnea (96%) and cough (87%); 69% had restriction. By high-resolution computed tomography, the lower lung zones were predominantly involved in 92% of cases; 46% had a peripheral distribution; 47% were diffuse. Most showed a reticular pattern (87%) with traction bronchiectasis (82%) and volume loss (77%). Lung biopsies showed uniform thickening of alveolar walls with a spectrum of cellular to fibrosing patterns. Five-year survival was 82.3%. CONCLUSIONS: Idiopathic NSIP is a distinct clinical entity that occurs mostly in middle-aged women who are never-smokers. The prognosis of NSIP is very good.

The primary hyperoxalurias are a group of autosomal recessive disorders of endogenous oxalate overproduction. This review discusses the major biochemical, genetic, and therapeutic advances that have led to a better understanding of the disease.

Many efforts have been devoted to the description of the prognosis of multiple sclerosis and its possible influential factors in terms of time to reach disability milestones. By contrast, the age at which patients with multiple sclerosis reach these milestones has not yet stirred much interest. We have tested the hypothesis whether the prognosis of multiple sclerosis depends on the current age of patients and the initial course of the disease. We have assessed disease onset and course, and assignment of scores of irreversible disability in 1844 patients with multiple sclerosis. We have used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: DSS 4 (limited walking but without aid), DSS 6 (walking with unilateral aid) and DSS 7 (wheelchair-bound). We used Kaplan-Meier analyses to estimate the age of the patients at assignment of disability milestones. The possible influence of the initial course of multiple sclerosis and of other clinical variables early assessable in the disease on these outcome measures was also studied, using the Kaplan-Meier curves for univariate analyses and Cox models for multivariate analyses. For the 1844 patients, median ages at time of assignment of irreversible disability were 44.3 years (95% CI 43.3-45.2) for a score of DSS 4, 54.7 years (95% CI 53.5-55.8) for DSS 6 and 63.1 years (95% CI 61.0-65.1) for DSS 7. These results were essentially similar whether the initial course of multiple sclerosis was exacerbating-remitting or progressive, and whatever the initial symptomatology. Females reached disability milestones at an older age than males. The most influential clinical factor was age at clinical onset of multiple sclerosis: the younger the onset, the younger the age at assignment of disability milestones. Therefore, prognosis in multiple sclerosis appears, at least to some extent, as age-dependent and not substantially affected by the initial course, be it exacerbating-remitting or progressive. Aside acute focal recurrent inflammation and diffuse chronic neurodegeneration, accelerated ageing-related mechanisms may operate in the central nervous system of multiple sclerosis patients.

Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulation of renal sodium excretion results in disorders of altered intravascular volume, such as hypertension. The amiloride-sensitive epithelial sodium channel (ENaC) is thought to be the only mechanism for sodium transport in the cortical collecting duct (CCD) of the kidney. However, it has been found that much of the sodium absorption in the CCD is actually amiloride insensitive and sensitive to thiazide diuretics, which also block the Na-Cl cotransporter (NCC) located in the distal convoluted tubule. In this study, we have demonstrated the presence of electroneutral, amiloride-resistant, thiazide-sensitive, transepithelial NaCl absorption in mouse CCDs, which persists even with genetic disruption of ENaC. Furthermore, hydrochlorothiazide (HCTZ) increased excretion of Na+ and Cl- in mice devoid of the thiazide target NCC, suggesting that an additional mechanism might account for this effect. Studies on isolated CCDs suggested that the parallel action of the Na+-driven Cl-/HCO3- exchanger (NDCBE/SLC4A8) and the Na+-independent Cl-/HCO3- exchanger (pendrin/SLC26A4) accounted for the electroneutral thiazide-sensitive sodium transport. Furthermore, genetic ablation of SLC4A8 abolished thiazide-sensitive NaCl transport in the CCD. These studies establish what we believe to be a novel role for NDCBE in mediating substantial Na+ reabsorption in the CCD and suggest a role for this transporter in the regulation of fluid homeostasis in mice.

OBJECTIVE: Because the optimal cyclophosphamide (CY) treatment duration for severe polyarteritis nodosa (PAN) without virus infection and microscopic polyangiitis (MPA) has not been established, we conducted a trial to compare the effectiveness of 6 versus 12 CY pulses given in combination with corticosteroids (CS). METHODS: Sixty-five (18 PAN, 47 MPA) previously untreated patients were randomized to receive 12 (n = 34) or 6 (n = 31) CY pulses combined with CS. PAN and MPA were histologically proven or met ACR criteria. All patients presented >or=1 factor of severity according to the five factor score (FFS). CY pulses were administered every 2 weeks for 1 month, then every 4 weeks. The end point of the study was the number of events (relapses and/or deaths) occurring in each group, analyzed according to an intention-to-treat strategy. The outcome was evaluated by Cox proportional hazards analysis. RESULTS: The baseline characteristics were similar for both groups. The mean (+/- SD) followup was 32 +/- 21 months. Survival analysis showed a significantly lower relapse probability (P = 0.02; hazards ratio [HR] = 0.34) and higher event-free survival (P = 0.02, HR = 0.44) for the 12 CY-pulse group while the mortality rates were not significantly different (P = 0.47). CONCLUSION: These results suggest that 6 CY pulses are less effective than 12 CY pulses to treat severe PAN and MPA, particularly with respect to the risk of relapses.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) are common diseases that frequently co-exist, along with overweight/obesity. While the mechanical impact of excess body weight on joints may explain lower limb OA, we sought to explore whether T2DM is linked to OA outside of excess weight and whether T2DM may play a role in OA pathophysiology. The consequence of T2DM on OA outcomes is a question of research interest. METHODS: We conducted a critical review of the literature to explore the association between T2DM and OA, whether any association is site-specific for OA, and whether the presence of T2DM impacts on OA outcomes. We also reviewed the literature to assess the safety of anti-OA treatments in patients with T2DM. RESULTS: T2DM has a pathogenic effect on OA through 2 major pathways involving oxidative stress and low-grade chronic inflammation resulting from chronic hyperglycemia and insulin resistance. T2DM is a risk factor for OA progression and has a negative impact on arthroplasty outcomes. Evidence is mounting for safety concerns with some of the most frequently prescribed anti-OA medications, including paracetamol, non-steroidal anti-inflammatory drugs, and corticosteroid injections, while other anti-OA medications may be safely prescribed in OA patients with T2DM, such as glucosamine and intra-articular hyaluronic acid. CONCLUSIONS: Future research is needed to better understand whether diabetes control and prevention can modulate OA occurrence and progression. The selection of therapy to treat OA symptoms in patients with T2DM may require careful consideration of the evidence based to avoid untoward safety issues.

BACKGROUND AND OBJECTIVES: Sclerostin, a bone antianabolic peptide involved in osteoporosis, is elevated in patients undergoing maintenance dialysis. However, there are no data for patients with early CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between January and July 2010, serum sclerostin and GFR (calculated by inulin clearance) were measured in 90 patients with CKD. Fasting blood samples were also drawn for determination of calcium, phosphorus, parathyroid hormone, bone alkaline phosphatase, and 25-OH vitamin D. RESULTS: Median GFR was 66.5 (interquartile range, 40.0-88.3) ml/min per 1.73 m(2). Median sclerostin level was 53.5 (interquartile range, 37.5-77.2) pmol/L, was higher in patients with a GFR <60 ml/min per 1.73 m(2), and was highest in those with ESRD. Sclerostin levels were significantly more elevated in men than women (P<0.05). An inverse relationship was found between sclerostin and GFR (r=-0.58; P<0.001), and a positive correlation was seen with age (r=0.34; P<0.01) and serum phosphate (r=0.26; P=0.02). In multiple regression analyses, GFR, sex, and serum phosphate were the only variables associated with serum sclerostin (P<0.001). Age lost its relationship with sclerostin level. CONCLUSIONS: This is the first study reporting higher serum sclerostin levels starting at CKD stage III. GFR, sex, and serum phosphate were the only measures associated with sclerostin level, suggesting that the effect of age reported in the literature might instead be attributable to the altered renal function in the elderly. Correcting the serum phosphorus level may be associated with lower sclerostin levels.

The adult greyhound was found to be similar to adult man with respect to kinetic and histomorphometric indices of calcium metabolism. The relationship between trabecular bone tissue balance and the pattern of human PTH fragment 1-34 (hPTH 1-34) administration by daily injections or continuous sc infusions was investigated in this model and the results compared to those from a clinical trial of hPTH 1-34 in involutional osteoporosis (peptide administration by single daily injections). In the dogs, the daily injection regime elevated plasma levels of immunoreactive hPTH 1-34 for no more than 4 h/day. The greyhounds so treated showed significantly increased indices of bone formation (surface osteoid, plasma alkaline phosphatase activity, and skeletal accretion rate of calcium) and resorption (number of osteoclasts, resorption surfaces). Iliac trabecular bone volume increased significantly, as it did in the patients. The infusions did not significantly increase the trabecular bone volume or the 47Ca accretion rate, two parameters which increased in parallel in dogs and patients treated successfully by daily injections. The osteoclastic surfaces, however, were clearly increased by continuous infusions, while the increases in the osteoblastic surfaces were less statistically significant. Since hPTH 1-34 may inhibit osteogenesis in Friedenstein chambers, it is possible that the increased osteoblastic activity induced by the daily injection regime in trabecular bone is dependent on the noncontinuous nature of the PTH stimulus.

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is a genetic disorder with autosomal dominance and variable penetrance, characterized by epistaxis, telangiectasia and visceral manifestations of the disease. The estimated minimal prevalence is 1/10,000 inhabitants. The diagnosis is established on clinical criteria, and may be further confirmed by the identification of causative mutations in either the ENG or the ACVRL1 gene coding for endoglin and ALK1, respectively. Pulmonary vascular manifestations of HHT include pulmonary arteriovenous malformations (PAVMs; especially in patients with ENG mutations) and less frequently pulmonary hypertension (especially in patients with ACVRL1 mutations). In 15-33% of patients with HHT, PAVMs consist of abnormal communications between pulmonary arteries and pulmonary veins, causing right-to-left shunting, and thus, frequently hypoxemia and dyspnea on exertion, although PAVMs may remain asymptomatic and frequently undiagnosed unless complications occur. PAVMs result in severe and frequent complications often at a young age, which may reveal the diagnosis, e.g. transient ischemic attack and cerebral stroke (10-19% of patients), systemic severe infections and abscesses (including cerebral abscess in 5-19% of patients), and rarely massive hemoptysis or hemothorax. Infections in HHT are related to the right-to-left shunting that bypasses the pulmonary capillaries and facilitates the passage of septic or aseptic emboli into the systemic and especially cerebral circulation, and potentially to minor defects in innate immunity. Treatment of PAVMs based on transcatheter coil vaso-occlusion of the feeding artery significantly decreases right-to-left shunting, hypoxemia and dyspnea on exertion, and reduces the risk of systemic complications. Long-term follow-up is warranted after transcatheter vaso-occlusion of PAVMs due to frequent recanalization of treated PAVMs and development or growth of untreated PAVMs. Patients with HHT should be informed of the risk of PAVM and potentially severe complications occurring in heretofore asymptomatic subjects. All adult patients with HHT should be proposed systematic screening for PAVM, by contrast echocardiography (preceded by anteroposterior chest radiograph) or computed tomography of the chest. Pulmonary hypertension is rare in HHT, and may be due either to systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension. Pulmonary hypertension is detected by systematic examination of right cardiac cavities and tricuspid regurgitation flow at echocardiography, and the diagnosis is established by right heart catheterization.

The aim of the study was to investigate whether interleukin-10 (IL-10) genetic polymorphisms influence this cytokine production as well as the incidence and outcome of diffuse large B-cell lymphoma (DLBCL). The frequency of IL-10(-1082G) allele was found to be higher in 199 patients with DLBCL as compared with 112 control subjects (0.47 versus 0.39, P =.043). Increased serum levels of IL-10 were associated with adverse prognostic factors and poor DLBCL outcome. The frequencies of IL-10(-819T) and IL-10(-592A) alleles were lower in patients with elevated IL-10 serum levels (0.155 versus 0.32, P =.14). As compared with patients carrying the IL-10(-1082AA) genotype, patients with the IL-10(-1082G) allele (IL-10(-1082GG/GA) genotypes) had higher complete remission rate (78% [confidence interval (CI), 71%-85%] versus 65% [CI, 52%-78%], P =.07), 5-year freedom from progression (FFP) (60% [CI, 52%-68%] versus 40% [CI, 27%-53%], P =.013), and overall survival (OS) (63% [CI, 55%-71%] versus 33% [CI, 20%-45%], P =.0009). Among factors of the International Prognostic Index, IL-10(-1082G) allele remained an independent variable, predicting longer freedom from progression (FFP) (RR [relative risk] =.76, P =.00035) and OS (RR =.78, P =.0015). These results indicate that IL-10 production contributes to the clinical course of DLBCL and that this phenomenon involves a substantial genetic component.

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.

Probiotics, including Lactobacilli, have been postulated to alleviate allergic and inflammatory diseases, but evidence that they exert an anti-inflammatory effect by immune modulation of pathogenic T cell effectors is still lacking. The aim of this study was to examine whether L. casei could affect antigen-specific T cell-mediated skin inflammation. To this end, we used contact hypersensitivity to the hapten 2,4-dinitrofluorobenzene, a model of allergic contact dermatitis mediated by CD8+ CTL and controlled by CD4+ regulatory T cells. Daily oral administration of fermented milk containing L. casei or L. casei alone decreased skin inflammation by inhibiting the priming/expansion of hapten-specific IFN-gamma-producing CD8+ effector T cells. The down-regulatory effect of the probiotics required the presence of CD4+ T cells, which control the size of the hapten-specific CD8+ T cell pool primed by skin sensitization. L. casei cell wall was as efficient as live L. casei to regulate both the CHS response and the hapten-specific CD8+ T cell response, suggesting that cell wall components contribute to the immunomodulatory effect of L. casei. This study provides the first evidence that oral administration of L. casei can reduce antigen-specific skin inflammation by controlling the size of the CD8+ effector pool.

BACKGROUND: The aim of this study was to examine trends of Down syndrome (DS) in relation to maternal age and termination of pregnancies (ToP) in 20 registries of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). METHODS: Trends of births with DS (live-born and stillborn), ToP with DS, and maternal age (percentage of mothers older than 35 years) were examined by year over a 12-year period (1993-2004). The total mean number of births covered was 1550,000 annually. RESULTS: The mean percentage of mothers older than 35 years of age increased from 10.9% in 1993 to 18.8% in 2004. However, a variation among the different registers from 4-8% to 20-25% of mothers >35 years of age was found. The total mean prevalence of DS (still births, live births, and ToP) increased from 13.1 to 18.2/10,000 births between 1993 and 2004. The total mean prevalence of DS births remained stable at 8.3/10,000 births, balanced by a great increase of ToP. In the registers from France, Italy, and the Czech Republic, a decrease of DS births and a great increase of ToP was observed. The number of DS births remained high or even increased in Canada Alberta, and Norway during the study period. CONCLUSIONS: Although an increase in older mothers was observed in most registers, the prevalence of DS births remained stable in most registers as a result of increasing use of prenatal diagnostic procedures and ToP with DS.

Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

Infectious diseases caused by viral agents kill millions of people every year. The improvement of prevention and treatment of viral infections and their associated diseases remains one of the main public health challenges. Towards this goal, deciphering virus-host molecular interactions opens new perspectives to understand the biology of infection and for the design of new antiviral strategies. Indeed, modelling of an infection network between viral and cellular proteins will provide a conceptual and analytic framework to efficiently formulate new biological hypothesis at the proteome scale and to rationalize drug discovery. Therefore, we present the first release of VirHostNet (Virus-Host Network), a public knowledge base specialized in the management and analysis of integrated virus-virus, virus-host and host-host interaction networks coupled to their functional annotations. VirHostNet integrates an extensive and original literature-curated dataset of virus-virus and virus-host interactions (2671 non-redundant interactions) representing more than 180 distinct viral species and one of the largest human interactome (10,672 proteins and 68,252 non-redundant interactions) reconstructed from publicly available data. The VirHostNet Web interface provides appropriate tools that allow efficient query and visualization of this infected cellular network. Public access to the VirHostNet knowledge-based system is available at http://pbildb1.univ-lyon1.fr/virhostnet.

The purpose of this study was to evaluate prospectively the evolution of femoral and vertebral bone mineral density (BMD) in hypothyroid subjects treated with replacement doses (mean +/- SD dose of L-thyroxine = 135 +/- 32 micrograms/day) as compared to an untreated group. Vertebral bone density was also measured in other patients who had been treated for at least 2 years with either suppressive (mean dose = 154 +/- 36 micrograms/day, n = 28) or replacement doses (mean dose = 104 +/- 52 micrograms/day, n = 21) according to the thyrotrophin response (TSH) to the thyrotrophin releasing hormone (TRH) administration. In primary hypothyroid patients, a mean decrease of 5.4% (P less than 0.01) for vertebral BMD, 7.3% (P less than 0.01) for trochanter and 7% (P less than 0.001) for femoral neck was observed after 1 year of treatment. This loss was unrelated either to age or to menopausal status (ANOVA). A clinical and hormonal state of euthyroidism was reached since the 3rd month of treatment. Fasting urinary calcium/creatinine excretion was increased significantly (P less than 0.05) at the 3rd month, and plasma osteocalcin (OC) increased significantly from the 3rd month onwards (P less than 0.05) up to the 12th month (P less than 0.025). In the cross-sectional study, vertebral BMD was not significantly different from age-matched normal values in patients receiving either substitutive or suppressive doses of LT4. These results suggest that in the case of primary hypothyroidism even appropriate thyroid replacement therapy could lead during the first year of treatment to a significant reduction in vertebral and femoral BMD. However, the fact that an increased fracture rate has not been documented in long-term treated patients, and the results of our cross-sectional study, suggest that this bone mass reduction could be transient and reversible due to new bone formation at the end of the resorptive sequence.

Mollicutes is a class of parasitic bacteria that have evolved from a common Firmicutes ancestor mostly by massive genome reduction. With genomes under 1 Mbp in size, most Mollicutes species retain the capacity to replicate and grow autonomously. The major goal of this work was to identify the minimal set of proteins that can sustain ribosome biogenesis and translation of the genetic code in these bacteria. Using the experimentally validated genes from the model bacteria Escherichia coli and Bacillus subtilis as input, genes encoding proteins of the core translation machinery were predicted in 39 distinct Mollicutes species, 33 of which are culturable. The set of 260 input genes encodes proteins involved in ribosome biogenesis, tRNA maturation and aminoacylation, as well as proteins cofactors required for mRNA translation and RNA decay. A core set of 104 of these proteins is found in all species analyzed. Genes encoding proteins involved in post-translational modifications of ribosomal proteins and translation cofactors, post-transcriptional modifications of t+rRNA, in ribosome assembly and RNA degradation are the most frequently lost. As expected, genes coding for aminoacyl-tRNA synthetases, ribosomal proteins and initiation, elongation and termination factors are the most persistent (i.e. conserved in a majority of genomes). Enzymes introducing nucleotides modifications in the anticodon loop of tRNA, in helix 44 of 16S rRNA and in helices 69 and 80 of 23S rRNA, all essential for decoding and facilitating peptidyl transfer, are maintained in all species. Reconstruction of genome evolution in Mollicutes revealed that, beside many gene losses, occasional gains by horizontal gene transfer also occurred. This analysis not only showed that slightly different solutions for preserving a functional, albeit minimal, protein synthetizing machinery have emerged in these successive rounds of reductive evolution but also has broad implications in guiding the reconstruction of a minimal cell by synthetic biology approaches.

Patient-reported outcomes (PROs) are used in clinical trials to provide valuable evidence on the impact of disease and treatment on patients' symptoms, function and quality of life. High-quality PRO data from trials can inform shared decision-making, regulatory and economic analyses and health policy. Recent evidence suggests the PRO content of past trial protocols was often incomplete or unclear, leading to research waste. To address this issue, international, consensus-based, PRO-specific guidelines were developed: the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-PRO Extension. The SPIRIT-PRO Extension is a 16-item checklist which aims to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection to minimise research waste, and ultimately better inform patient-centred care. This SPIRIT-PRO explanation and elaboration (E&E) paper provides information to promote understanding and facilitate uptake of the recommended checklist items, including a comprehensive protocol template. For each SPIRIT-PRO item, we provide a detailed description, one or more examples from existing trial protocols and supporting empirical evidence of the item's importance. We recommend this paper and protocol template be used alongside the SPIRIT 2013 and SPIRIT-PRO Extension paper to optimise the transparent development and review of trial protocols with PROs.