bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective relationships between body weight and physical activity: an observational analysis from the NAVIGATOR study
Authors: Preiss David , Thomas Laine E , Wojdyla Daniel M , Haffner Steven M , Gill Jason M R , Yates Thomas , Davies Melanie J , Holman Rury R , McMurray John J , Califf Robert M , Kraus William E
Published: August 2015

Objectives

While bidirectional relationships exist between body weight and physical activity, direction of causality remains uncertain and previous studies have been limited by self-reported activity or weight and small sample size. We investigated the prospective relationships between weight and physical activity.

Design

Observational analysis of data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study, a double-blinded randomised clinical trial of nateglinide and valsartan, respectively.

Setting

Multinational study of 9306 participants.

Participants

Participants with biochemically confirmed impaired glucose tolerance had annual measurements of both weight and step count using research grade pedometers, worn for 7 days consecutively. Along with randomisation to valsartan or placebo plus nateglinide or placebo, participants took part in a lifestyle modification programme.

Outcome measures

Longitudinal regression using weight as response value and physical activity as predictor value was conducted, adjusted for baseline covariates. Analysis was then repeated with physical activity as response value and weight as predictor value. Only participants with a response value preceded by at least three annual response values were included.

Results

Adequate data were available for 2811 (30%) of NAVIGATOR participants. Previous weight (χ2=16.8; p<0.0001), but not change in weight (χ2=0.1; p=0.71) was inversely associated with subsequent step count, indicating lower subsequent levels of physical activity in heavier individuals. Change in step count (χ2=5.9; p=0.02) but not previous step count (χ2=0.9; p=0.34) was inversely associated with subsequent weight. However, in the context of trajectories already established for weight (χ2for previous weight measurements 747.3; p<0.0001) and physical activity (χ2for previous step count 432.6; p<0.0001), these effects were of limited clinical importance.

Conclusions

While a prospective bidirectional relationship was observed between weight and physical activity, the magnitude of any effect was very small in the context of natural trajectories already established for these variables.

Trial registration number

NCT00097786.
The impact of HPV vaccination on future cervical screening: a simulation study of two birth cohorts in Denmark
Authors: Hestbech Mie Sara , Lynge Elsebeth , Kragstrup Jakob , Siersma Volkert , Vazquez-Prada Baillet Miguel , Brodersen John
Published: August 2015

Objectives

To explore the interplay between primary and secondary prevention of cervical cancer by estimating future screening outcomes in women offered human papillomavirus (HPV) vaccination when they were sexually naïve.

Design

Estimation of outcome of liquid-based cytology screening for a post-HPV vaccination cohort using pre-vaccination screening data combined with HPV vaccination efficacy data reported in the literature.

Setting

Denmark.

Data

The number of screening diagnoses at first screen in a pre-vaccination birth cohort was multiplied by reported risk reductions expected for women who were vaccinated for HPV before sexual debut. All identified studies were reviewed by two authors, and weighted pooled estimates of vaccine efficacies were used.

Main outcome measures

Proportions of positive and false-positive cervical cytologies and positive predictive value (PPV) were calculated using cervical intraepithelial neoplasia (CIN) grade 2+ and 3+ as cut-off values.

Results

The proportion of positive screening tests was reduced from 8.7% before vaccination to 6.5% after vaccination, and the proportion of false-positive screening tests using CIN2+ as a cut-off was reduced from 5.5% pre-vaccination to 4.3% post-vaccination, and using CIN3+ as a cut-off from 6.2% to 4.7%. PPVs were reduced from 23% to 19% (cut-off CIN2+), and from 14% to 12% (cut-off CIN3+).

Conclusions

In our calculations, the proportion of positive screening results with liquid-based cytology will be reduced as a consequence of HPV vaccination, but the reduction is small, and the expected decline in PPV is very limited. In this situation, the information general practitioners will have to provide to their patients will be largely unchanged.
What interventions increase commuter cycling? A systematic review
Authors: Stewart Glenn , Anokye Nana Kwame , Pokhrel Subhash
Published: August 2015

Objective

To identify interventions that will increase commuter cycling.

Setting

All settings where commuter cycling might take place.

Participants

Adults (aged 18+) in any country.

Interventions

Individual, group or environmental interventions including policies and infrastructure.

Primary and secondary outcome measures

A wide range of ‘changes in commuter cycling’ indicators, including frequency of cycling, change in workforce commuting mode, change in commuting population transport mode, use of infrastructure by defined populations and population modal shift.

Results

12 studies from 6 countries (6 from the UK, 2 from Australia, 1 each from Sweden, Ireland, New Zealand and the USA) met the inclusion criteria. Of those, 2 studies were randomised control trials and the remainder preintervention and postintervention studies. The majority of studies (n=7) evaluated individual-based or group-based interventions and the rest environmental interventions. Individual-based or group-based interventions in 6/7 studies were found to increase commuter cycling of which the effect was significant in only 3/6 studies. Environmental interventions, however, had small but positive effects in much larger but more difficult to define populations. Almost all studies had substantial loss to follow-up.

Conclusions

Despite commuter cycling prevalence varying widely between countries, robust evidence of what interventions will increase commuter cycling in low cycling prevalence nations is sparse. Wider environmental interventions that make cycling conducive appear to reach out to hard to define but larger populations. This could mean that environmental interventions, despite their small positive effects, have greater public health significance than individual-based or group-based measures because those interventions encourage a larger number of people to integrate physical activity into their everyday lives.
Cohort profile: systemic lupus erythematosus in Sweden: the Swedish Lupus Linkage (SLINK) cohort
Authors: Arkema Elizabeth V , Simard Julia F
Published: August 2015

Purpose

A cohort of individuals with systemic lupus erythematosus (SLE) was identified through linkage of several national registers to investigate important epidemiological questions using not only population-based data to minimise selection bias, but also to identify matched comparators from the general population to serve as controls. This cohort was established to overcome the general dearth of data in SLE epidemiology.

Participants

All individuals registered in Sweden with a personal identity number and who have obtained medical care at any hospital or public non-primary outpatient specialist care with suspected SLE were identified. Inpatient register data date back to the 1960s, although complete national coverage of the inpatient register was achieved in 1987. In 2001, the outpatient component was also added to the register, representing the entire country of Sweden. For each suspected individual with SLE, up to five individuals from the general population were identified and matched on sex, birth year and county of residence.

Findings to date

We have linked this study population to a number of national and quality registers in Sweden to identify first-degree relatives, deaths, births, dispensed prescriptions, comorbidities and disease end points, such as stroke and cancer, as well as basic health economic data. We found geographic variability in the prevalence of SLE by county. We have also shown that being first-born confers a reduced odds of having SLE in childhood and early adulthood.

Future plans

In addition to updating the national register linkage with several more years of follow-up data, we are adding several quality registers in Sweden, including the Tuberculosis register and the Social Insurance Office database. While these updates are ongoing and additional follow-up accumulates, we are studying a number of outcomes in SLE, including stroke, pregnancy and death. We will continue to present findings at scientific conferences and in the peer-reviewed literature.
Improving the documentation of nasogastric tube insertion and adherence to local enteral nutrition guidelines
Authors: Cole Esther
Published: August 2015

Fine bore nasogastric (NG) tubes are often required for patients who have insufficient nutrition to meet their daily requirements, as well as for feeding or medications when there are difficulties with swallowing. “Death or severe harm as a result of a naso […] gastric tubes being misplaced in the respiratory tract” is one of the Department of Health’s list of "never events". Noble’s Hospital, Isle of Man, has local guidelines based on the National Patient Safety Agency’s 2005 guidelines and 2011 update, regarding the initial insertion and confirmation of placement of NG tubes.

Retrospective baseline data looking at 13 case notes across 10 hospital wards showed that the majority of NG tube insertions took place on the stroke unit. A three-point quality of guidelines score showed that 8/13 (62%) cases were following guidelines appropriately. A seven-point quality of documentation score showed no case notes had full documentation.

A teaching intervention for junior doctors and nurses was devised. However, there was no significant improvement in quality scores after 90 days (49 NG tube insertions). Therefore, an NG tube bundle, which included a pro forma for the case notes, information poster, and sticker for the nurse notes, was trialled on the stroke unit for six weeks. This showed that 10/12 (83%) cases were following guidelines appropriately. While only 2/12 (16%) of case notes had full documentation, this represented the two occasions when the pro forma was filled in and filed correctly. It is hoped that there could be a roll out of the intervention hospital-wide with identification of ways to improve usage of the NG tube bundle.
ImERSE (Improving Experience through Regular Shadowing Events)
Authors: Calvert William , Minford Joanne , Platt Carol , Chatfield Catriona
Published: August 2015

Systematic operational quality improvement strategies within the NHS are hard to find, although there are numerous published reports of sporadic departmental models and methods resulting in improvements in clinical care. We describe the experience of devising a tool to provide large data collection of patient care experiences by using medical students to shadow patient journeys. This combines patient and family centred care (PFCC) and quality improvement approaches to create a systematic organisational strategy for improving care.

The ImERSE (improving experience through regular shadowing events) approach could be applied to any area of health care to generate population specific improvement priorities. It can be used to promote patient and family centred care and provide a unique medical education experience.

We describe its evolution in its first year of use and suggest that using the ImERSE approach delivers beneficial characteristics to patients and their families, those undergoing a shadowing experience, and provider organisations.
Improving VTE risk assessment at point of admission to a tertiary centre cardiology ward
Authors: Wilson Rachel
Published: August 2015

Cardiology wards are generally high turnover units, which may receive primary PCI, high-risk NSTEMI patients, and other general cardiac admissions from a large geographical area. Many centres also provide national specialist services for rarer cardiac conditions for which admissions may be lengthy. Cardiac patients have significant risk factors for venous thromboembolism (VTE) as immobility may be due to systolic dysfunction, attachment to continuous monitoring and predisposition to chest pain, or cardiac syncope. It is recommended by NICE that an initial VTE risk assessment is undertaken at the time of patient admission, with reassessment within 24 hours. For this purpose a risk assessment tool is featured on the front of many Trust drug charts. It is noted that this risk assessment is electronic in other trusts. We undertook an audit into the drug chart documentation of VTE risk assessment on the cardiology ward and the Coronary Care Unit (CCU) at The Royal Free Hospital. It was evident that documentation of VTE risk assessment was poor. The audit interventions were; a teaching presentation to the cardiology department, an educational poster, several update emails to the department and the identification of a ‘VTE risk assessment champion’ to audit ongoing compliance. Following these measures the second audit round demonstrated that documentation of initial risk assessment was slightly improved, but significant improvement was seen in documentation of risk assessment at 24 hours post admission. Results from a third audit cycle indicated that the improvement in initial VTE risk assessment was sustained, and that there was a significant sustained improvement in risk assessment at 24 hours (p <0.05).

Recommendations for sustained improvement included: redesigning the drug chart so that the VTE risk assessment tool was linked to the VTE prophylaxis prescription box, and designating the responsibility of the initial VTE risk assessment to the on call junior doctor who receives admissions on to the ward.
Immunohistochemistry should undergo robust validation equivalent to that of molecular diagnostics
Authors: Elliott Kelly , McQuaid Stephen , Salto-Tellez Manuel , Maxwell Perry
Published: August 2015

Immunohistochemistry (IHC) is a widely available and highly utilised tool in diagnostic histopathology and is used to guide treatment options as well as provide prognostic information. IHC is subjected to qualitative and subjective assessment, which has been criticised for a lack of stringency, while PCR-based molecular diagnostic validations by comparison are regarded as very rigorous. It is essential that IHC tests are validated through evidence-based procedures. With the move to ISO15189 (2012), not just of the accuracy, specificity and reproducibility of each test need to be determined and managed, but also the degree of uncertainty and the delivery of such tests. The recent update to ISO 15189 (2012) states that it is appropriate to consider the potential uncertainty of measurement of the value obtained in the laboratory and how that may impact on prognostic or predictive thresholds. In order to highlight the problems surrounding IHC validity, we reviewed the measurement of Ki67and p53 in the literature. Both of these biomarkers have been incorporated into clinical care by pathology laboratories worldwide. The variation seen appears excessive even when measuring centrally stained slides from the same cases. We therefore propose in this paper to establish the basis on which IHC laboratories can bring the same level of robust validation seen in the molecular pathology laboratories and the principles applied to all routine IHC tests.
The efficacy and risks of preoperative embolization of spinal tumors
Authors: Awad Al-Wala , Almefty Kaith K , Ducruet Andrew F , Turner Jay D , Theodore Nicholas , McDougall Cameron G , Albuquerque Felipe C
Published: August 2015

Background

The goal of preoperative embolization of spinal tumors is to improve surgical outcomes by diminishing the vascular supply to the tumor to reduce intraoperative blood loss and operative time.

Objective

To report our institutional experience with spinal tumor embolization and review the present literature.

Methods

Clinical records from January 1, 2001 to December 31, 2012 were reviewed and analyzed. Angiograms were used to calculate the percentage reduction in tumor vascularity, and relevant clinical and operative data were collected and analyzed.

Results

Thirty-seven patients underwent preoperative spinal tumor embolization (24 metastatic and 13 primary lesions) and were included in the study. One complication resulted in transient lower extremity weakness and was attributed to post-embolization swelling, which fully resolved after surgical resection. The transient neurological complication rate was 1/37 (3%) and the permanent rate was 0/37 (0%). The average surgical estimated blood loss (EBL) was 1946 mL (100–7000 mL) and the average operative time was 330 min (range 164–841 min). After embolization, tumor blush was reduced by 83% on average. Average pre- and postoperative modified Rankin Scale scores were 2.10 and 1.36, respectively (p=0.03). Cases in which tumor blush was decreased by ≥90% (classes 1 or 2) after embolization had significantly less operative blood loss than those cases in which <90% (classes 3 or 4) was achieved (mean EBL 1391 vs 2296 mL, respectively, p=0.05).

Conclusions

Spinal tumor embolization is a safe procedure, is associated with few complications, and may improve surgical outcomes by limiting intraoperative blood loss and reducing operative time.
Mechanical thrombectomy with the Trevo ProVue device in ischemic stroke patients: does improved visibility translate into a clinical benefit?
Authors: Kabbasch Christoph , Mpotsaris Anastasios , Chang De-Hua , Hiß Sonja , Dorn Franziska , Behme Daniel , Onur Oezguer , Liebig Thomas
Published: August 2015

Purpose

To investigate the efficacy and safety of the Trevo ProVue (TPV) stent retriever in stroke patients with large artery occlusions, with particular attention to the full structural radiopacity of the TPV.

Materials and methods

Case files and images of TPV treatments were reviewed for clinical and technical outcome data, including revascularization rates, device and procedure related complications, and outcome at discharge and after 90 days.

Results

76 patients were treated with TPV. Mean National Institutes of Health Stroke Scale (NIHSS) score was 18 and 68% had additional intravenous thrombolysis. 63 occlusions were in the anterior circulation: 44 M1 (58%), 8 M2 (11%), 8 internal carotid artery-terminus (11%), 2 internal carotid artery- left (3%), 1 A2 (1%), and 13 vertebrobasilar (17%). 58 of 76 (76%) were solely treated with TPV; the remainder were treated with additional stent retrievers. Mean number of passes in TPV only cases was 2.2 (SD 1.2). In rescue cases, 3.2 (SD 2.2) passes were attempted with the TPV followed by 2.6 rescue device passes (SD 2). TPV related adverse events occurred in 4/76 cases (5%) and procedural events in 6/76 cases (8%). Mean procedural duration was 64 min (SD 42). Thrombolysis in Cerebral Infarction (TICI) 2b/3 recanalization was achieved in 69/76 patients (91%), including 50% TICI 3. Of 56 survivors (74%), 37 (49%) showed a favorable outcome at 90 days (Solitaire With the Intention for Thrombectomy trial criteria), statistically associated with age, baseline NIHSS, onset to revascularization time, and TICI 2b–3 reperfusion. TPV radiopacity allowed for visual feedback, changing the methodology of stent retriever use in 44/76 cases (58%).

Conclusions

Neurothrombectomy with TPV is feasible, effective, and safe. The recanalization rate compares favorably with reported data in the literature. Improved structural radiopacity may facilitate neurothrombectomy or influence the course of action during retrieval.
Quantitative analysis of hemorrhage clearance and delayed cerebral ischemia after subarachnoid hemorrhage
Authors: Ko Sang-Bae , Choi H Alex , Helbok Raimund , Schmidt J Michael , Badjatia Neeraj , Claassen Jan , Connolly E Sander , Mayer Stephan A , Lee Kiwon
Published: August 2015

Objective

Initial hemorrhage burden is an independent predictor for delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the association between clot clearance and DCI still remains to be elucidated.

Methods

Quantitative analysis of hemorrhage volume and clot clearance was made in 116 consecutive patients who were scanned within 24 h from onset. Cisternal plus intraventricular hemorrhage volume (CIHV) was calculated as clot volume from the initial scans and scans performed up to 7 days after onset. Clot clearance was calculated as a percentage of residual clot volume compared with the clot volume on the initial scan. Initial clot volume and clot clearance were dichotomized to evaluate the association with DCI.

Results

Included patients were aged 55.5±15.2 years with a female preponderance (65.5%, (76/116)). The group with higher initial clot volume (≥17.2 mL) had higher odds for DCI (OR 4.3, 95% CI 1.3 to 14.0, p=0.015). However, the rate of DCI was not different between high and low clot clearance groups (26.7% vs 31.0%, p=0.66). Clot clearance rate was similar in patients with and without DCI up to day 7 after onset.

Conclusions

The quantitative clot clearance rate is not an independent predictor for DCI.
Severe hemiparesis as a prehospital tool to triage stroke severity: a pilot study to assess diagnostic accuracy and treatment times
Authors: Gupta Rishi , Manuel Marissa , Owada Kumiko , Dhungana Samish , Busby Leslie , Glenn Brenda A , Brown Debbie , Zimmermann Susan A , Horn Christopher , Rochestie Dustin , Hormes Joseph T , Johnson Andrew K , Khaldi Ahmad
Published: August 2015

Introduction

With the publication of the recent trials showing the tremendous benefits of mechanical thrombectomy, opportunities exist to refine prehospital processes to identify patients with larger stroke syndromes.

Materials and methods

We retrospectively reviewed consecutive patients who were brought via scene flight from rural parts of the region to our institution, from December 1, 2014 to June 5, 2015, with severe hemiparesis or hemiplegia. We assessed the accuracy of the diagnosis of stroke and the number of patients requiring endovascular therapy. Moreover, we reviewed the times along the pathway of patients who were treated with endovascular therapy.

Results

45 patients were brought via helicopter from the field to our institution. 27 (60%) patients were diagnosed with an ischemic stroke. Of these, 12 (26.7%) were treated with mechanical thrombectomy and 6 (13.3%) with intravenous tissue plasminogen activator alone. An additional three patients required embolization procedures for either a dural arteriovenous fistula or cerebral aneurysm. Thus a total of 15 (33%) patients received an endovascular procedure and 21/45 (46.7%) received an acute treatment. For patients treated with thrombectomy, the median time from first medical contact to groin puncture was 101 min, with 8 of the 12 patients (66.7%) being discharged to home.

Conclusions

We have presented a pilot study showing that severe hemiparesis or hemiplegia may be a reasonable prehospital tool in recognizing patients requiring endovascular treatment. Patients being identified earlier may be treated faster and potentially improve outcomes. Further prospective controlled studies are required to assess the impact on outcomes and cost effectiveness using this methodology.
Quality indicators for blogs and podcasts used in medical education: modified Delphi consensus recommendations by an international cohort of health professions educators
Authors: Lin Michelle , Thoma Brent , Trueger N Seth , Ankel Felix , Sherbino Jonathan , Chan Teresa
Published: August 2015

Background

Quality assurance concerns about social media platforms used for education have arisen within the medical education community. As more trainees and clinicians use resources such as blogs and podcasts for learning, we aimed to identify quality indicators for these resources. A previous study identified 151 potentially relevant quality indicators for these social media resources.

Objective

To identify quality markers for blogs and podcasts using an international cohort of health professions educators.

Methods

A self-selected group of 44 health professions educators at the 2014 International Conference on Residency Education participated in a Social Media Summit during which a modified Delphi consensus study was conducted to determine which of the 151 quality indicators met the a priori ≥90% inclusion threshold.

Results

Thirteen quality indicators classified into the domains of credibility (n=8), content (n=4) and design (n=1) met the inclusion threshold.

Conclusions

The quality indicators that were identified may serve as a foundation for further research on quality indicators of social media-based medical education resources and prompt discussion of their legitimacy as a form of educational scholarship.
Criteria for social media-based scholarship in health professions education
Authors: Sherbino Jonathan , Arora Vineet M , Van Melle Elaine , Rogers Robert , Frank Jason R , Holmboe Eric S
Published: August 2015

Background

Social media are increasingly used in health professions education. How can innovations and research that incorporate social media applications be adjudicated as scholarship?

Objective

To define the criteria for social media-based scholarship in health professions education.

Method

In 2014 the International Conference on Residency Education hosted a consensus conference of health professions educators with expertise in social media. An expert working group drafted consensus statements based on a literature review. Draft consensus statements were posted on an open interactive online platform 2 weeks prior to the conference. In-person and virtual (via Twitter) participants modified, added or deleted draft consensus statements in an iterative fashion during a facilitated 2 h session. Final consensus statements were unanimously endorsed.

Results

A review of the literature demonstrated no existing criteria for social media-based scholarship. The consensus of 52 health professions educators from 20 organisations in four countries defined four key features of social media-based scholarship. It must (1) be original; (2) advance the field of health professions education by building on theory, research or best practice; (3) be archived and disseminated; and (4) provide the health professions education community with the ability to comment on and provide feedback in a transparent fashion that informs wider discussion.

Conclusions

Not all social media activities meet the standard of education scholarship. This paper clarifies the criteria, championing social media-based scholarship as a legitimate academic activity in health professions education.
Learning theory and its application to the use of social media in medical education
Authors: Flynn Leslie , Jalali Alireza , Moreau Katherine A
Published: August 2015

Background

There is rapidly increasing pressure to employ social media in medical education, but a review of the literature demonstrates that its value and role are uncertain.

Objective

To determine if medical educators have a conceptual framework that informs their use of social media and whether this framework can be mapped to learning theory.

Methods

Thirty-six participants engaged in an iterative, consensus building process that identified their conceptual framework and determined if it aligned with one or more learning theories.

Results

The results show that the use of social media by the participants could be traced to two dominant theories—Connectivism and Constructivism. They also suggest that many medical educators may not be fully informed of these theories.

Conclusions

Medical educators’ use of social media can be traced to learning theories, but these theories may not be explicitly utilised in instructional design. It is recommended that formal education (faculty development) around learning theory would further enhance the use of social media in medical education.
Why does the gout attack stop? A roadmap for the immune pathogenesis of gout
Authors: Schett Georg , Schauer Christine , Hoffmann Markus , Herrmann Martin
Published: August 2015

Gout is one of the most severe and frequent rheumatic diseases. Clinical manifestations of gout arise from uric acid crystal deposition in the musculoskeletal tissue. At high concentrations of uric acid in the body (hyperuricaemia), needle-shaped monosodium urate (MSU) crystals are formed. The structures are ingested by neutrophils and monocytes and thereby trigger robust activation of the inflammasome, an intracellular protein complex mounting an inflammatory response. Inflammasome activation builds interleukin-1, which acts as a proinflammatory mediator and induces vasodilation, recruitment of additional leucocytes and the expression of proinflammatory cytokines and chemokines. This process is associated with the clinical manifestation of an acute gout attack. Such attacks, however, stop rather rapidly and the process of resolution of inflammation in gout is now better defined. Neutrophils having ingested MSU crystals undergo a specific form of cell death called NETosis, which is characterised by the formation of neutrophil extracellular traps (NETs). During this process, DNA is extruded, allowing the dense packaging of MSU crystals as well as the degradation of proinflammatory cytokines, thereby allowing the stopping of the inflammatory process. Reactive oxygen species are essential for forming NETs and for allowing the resolution of inflammation in gout. This process of NETosis is critical for understanding tophaceous gout, since tophi are composed of NETs and densely packed MSU crystals.
Antirheumatic drugs and reproduction in women and men with chronic arthritis
Authors: Bazzani Chiara , Andreoli Laura , Agosti Michele , Nalli Cecilia , Tincani Angela
Published: August 2015

The impact of rheumatic disease on fertility and reproduction can be remarkable. Many disease-related factors can influence patients’ sexual functioning, perturb fertility and limit family planning. Antirheumatic pharmacological treatment can also have a crucial role in this field. Proper counselling, preferably provided by a multidisciplinary team of rheumatologists, obstetricians, gynaecologists and neonatologists, is recommended for patients taking antirheumatic drugs, not only at the beginning, but also during the course of treatment. Paternal exposure to antirheumatic drugs was not found to be specifically associated with congenital malformation and adverse pregnancy outcome, therefore discontinuation of these drugs while planning for conception should be weighed against the risk of disease flare. Drugs in Food and Drug Administration (FDA) category ‘X’ should be withdrawn in a timely manner in women who desire a pregnancy. Meanwhile, disease control can be achieved with anti-tumour necrosis factor (TNF)-α agents, which are not teratogenic drugs. If maternal disease control is permissive, they can be stopped as soon as the pregnancy test turns positive and be resumed during pregnancy in case of a flare.
The osteocyte: key player in regulating bone turnover
Authors: Goldring Steven R
Published: August 2015

Osteocytes are the most abundant cell type in bone and are distributed throughout the mineralised bone matrix forming an interconnected network that ideally positions them to sense and to respond to local biomechanical and systemic stimuli to regulate bone remodelling and adaptation. The adaptive process is dependent on the coordinated activity of osteoclasts and osteoblasts that form a so called bone multicellular unit that remodels cortical and trabecular bone through a process of osteoclast-mediated bone resorption, followed by a phase of bone formation mediated by osteoblasts. Osteocytes mediate their effects on bone remodelling via both cell–cell interactions with osteoclasts and osteoblasts, but also via signaling through the release of soluble mediators. The remodelling process provides a mechanism for adapting the skeleton to local biomechanical factors and systemic hormonal influences and for replacing bone that has undergone damage from repetitive mechanical loading.
Glucocorticoids: bad or safe for the bones?
Authors: Lems Willem F
Published: August 2015

Until recently, patients with rheumatoid arthritis (RA) were treated with monotherapy using conventional drugs such as sulfasalazine, antimalarials, intramuscular gold and methotrexate, which often leads to persistent arthritis, loss of functional capacity and decreased quality of life. The use of high-dose glucocorticoids (GCs) and active RA are both associated with generalised bone loss and fractures, while GCs have a strong immunosuppressive effect. With the introduction of very effective tumour-necrosis factor-blockers and other biologics, clinical remission is a realistic target in around half of the early patients with RA; the same appears true for the use of methotrexate with chronic low dose or initially high-dose GCs. With the use of a treat-to-target strategy focusing on clinical remission or low disease activity in early patients with RA, the negative effects of systemic inflammation on bone can be inhibited and local bone loss (in the joints), and generalised bone loss at the spine and hips, can be limited or prevented. Whether this also leads to a reduction in vertebral and non-vertebral fractures remains to be demonstrated. Another issue is, in other systemic rheumatic diseases in which treatment options are smaller and less effective than in RA, local and systemic bone loss may still occur.
New insights into treatment of osteoporosis in postmenopausal women
Authors: Geusens Piet
Published: August 2015

For the prevention of fractures, antiresorptive drugs (bisphosphonates and denosumab) that decrease high bone resorption and, secondarily, also bone formation, are the mainstream of therapy. Osteoanabolic drugs, such as teriparatide, increase bone formation more than bone resorption, and are used in severe osteoporosis, including patients treated with antiresorptive drugs who still lose bone and have recurrent fractures. New potential drugs for fracture prevention that uncouple bone resorption from bone formation include odanacatib, a specific inhibitor of cathepsin-K, the enzyme that degrades bone collagen type I, that inhibits bone resorption and only temporarily bone formation, and monoclonal antibodies against sclerostin (romosozumab, blosozumab), that stimulate bone formation and decrease bone resorption.
Non-radiographic axial spondyloarthritis and ankylosing spondylitis: what are the similarities and differences?
Authors: Baraliakos X , Braun J
Published: August 2015

The development of the axial spondyloarthritis and ankylosing spondylitis (ASAS) classification criteria has had several implications for our understanding of the entire spectrum of spondyloarthritides (SpA). Going beyond the modified New York criteria, which concentrate on conventional radiographs of the sacroiliac joints (SIJ) for the classification of ankylosing spondylitis, the ASAS criteria add active inflammation of the SIJ as obtained by MRI and human leucocyte antigen (HLA) B27 to classify patients with chronic back pain starting at a young age as axial SpA (axSpA). AxSpA should be considered as one disease that includes AS, the radiographic form, as well as the non-radiographic (nr-axSpA) form. Similarities and differences between these subgroups have been described in 3 studies: 1 local study, 1 national study (German SpA Inception Cohort) and 1 international study mainly conducted to test the efficacy of a tumour necrosis factor α blocker. Most clinical features and assessments of axSpA showed the same prevalence in patients with and without radiographic changes. However, some differences have been observed: the male:female ratio, the proportion of patients with objective signs of inflammation such as bone marrow oedema as detected by MRI, and the proportion of patients with increased levels of C reactive protein were higher in patients with AS. Importantly, these factors have also been identified as prognostic factors for more severe disease in terms of new bone formation. Thus, nr-axSpA may represent an early stage of AS but may also just be an abortive form of a disease which does cause much pain but which may also never lead to structural changes of the axial skeleton. Since the cut-off between nr-axSpA and AS is artificial and unreliable, we think that the term nr-axSpA should not be used for diagnosis but only for classification for historical reasons.
Old and new treatment targets in axial spondyloarthritis
Authors: Rios Rodriguez Valeria , Poddubnyy Denis
Published: August 2015

Two main treatment targets in axial spondyloarthritis (axSpA) could be currently defined: (1) reduction of inflammation resulting in control of signs and symptoms such as pain and stiffness and (2) prevention or retardation of structural damage progression in the spine resulting in preservation of functional status and improvement in the long-term outcome. A good control of signs and symptoms could be successfully achieved nowadays in the majority of patients treated with non-steroidal anti-inflammatory drugs (NSAIDs—the first-line therapy in axSpA) and with tumour necrosis factor (TNF) α blockers (the second-line therapy, if NSAIDs fail). Several pipeline drugs including interleukin (IL) 17 and IL-23 antagonists might be helpful in the immediate future in achievement of this treatment target in case of inefficacy of NSAIDs and TNFα blockers. Retardation of radiographical spinal progression in axSpA—disease modification—is currently a much more challenging task than a good symptom control. In this review, we discuss symptomatic and possible disease-modifying properties of current and forthcoming treatment options for axSpA.
Treatment of complex regional pain syndrome type I with bisphosphonates
Authors: Giusti Andrea , Bianchi Gerolamo
Published: August 2015

Complex regional pain syndrome type I (CRPS-I) is a common and disabling disorder affecting a peripheral limb, usually developing after a trauma to an extremity. CRPS-I is characterised by presence of spontaneous pain, allodynia and hyperalgesia, disproportionate to the inciting event and by a variety of autonomic disturbances and trophic abnormalities. The pathophysiology of CRPS-I has not been fully understood. Experimental models have suggested that an initial triggering event may produce the release of proinflammatory neuropeptides and cytokines, generating a sort of neurogenic inflammation. Thereafter, increased microvascular permeability and intramedullary pressure, reduced oxygen extraction and cellular hypoxia maintain and make the disease worse, producing metabolic tissue acidosis. In this context, it is probable that, far from being a key player, the sympathetic nervous system contributes interacting with these mechanisms and producing vasomotor disturbances. Bisphosphonates (BPs) are potent inhibitors of osteoclastic activity widely used for the management of osteoporosis and other metabolic bone diseases. Their primary pharmacological action is the reduction of bone turnover. An enhanced osteoclastic activity has never been clearly demonstrated in CRPS-I. Therefore, it is likely that the positive effects of BPs in this condition are not related to their antiresorptive properties, but to a more complex interaction between these pharmacological agents and the pathophysiological mechanisms underlying CRPS-I. Results of several clinical trials have suggested the potential beneficial effects of BPs in CRPS-I. In five randomised controlled trials, oral and intravenous alendronate and intravenous clodronate, pamidronate and neridronate demonstrated to be effective in reducing pain and improving physical function in patients presenting with CRPS-I, with a good profile of safety and tolerability. Although these trials have a number of limitations, including the small samples enrolled, there is sufficient evidence to support the use of BPs as agents of choice in the management of CRPS-I.
Rheumatoid arthritis treatment: the earlier the better to prevent joint damage
Authors: Monti Sara , Montecucco Carlomaurizio , Bugatti Serena , Caporali Roberto
Published: August 2015

The management of rheumatoid arthritis has undergone major advances in recent years, both in terms of the drugs armamentarium and therapeutic strategy. Treating disease to target, aiming at remission, through a tight control protocol is regarded as the standard of care. Reaching clinical and radiographic disease remission has therefore become an achievable goal. Increasing evidence has demonstrated that early diagnosis, prompt treatment initiation and early achievement of remission are the major predictors of long-term clinical, functional and radiographic outcomes. Concentrating efforts in controlling disease activity in a very early window of opportunity offers unique sustained benefits. In this short review, we analysed the available evidence supporting the value of treating rheumatoid arthritis early and the impact on disease outcomes, with particular focus on radiographic progression.
Pathophysiology of osteoarthritis: canonical NF-κB/IKKβ-dependent and kinase-independent effects of IKKα in cartilage degradation and chondrocyte differentiation
Authors: Olivotto Eleonora , Otero Miguel , Marcu Kenneth B , Goldring Mary B
Published: August 2015

Osteoarthritis (OA), a whole-joint disease driven by abnormal biomechanics and attendant cell-derived and tissue-derived factors, is a rheumatic disease with the highest prevalence, representing a severe health burden with a tremendous economic impact. Members of the nuclear factor κB (NF-κB) family orchestrate mechanical, inflammatory and oxidative stress-activated processes, thus representing a potential therapeutic target in OA disease. The two pivotal kinases, IκB kinase (IKK) α and IKKβ, activate NF-κB dimers that might translocate to the nucleus and regulate the expression of specific target genes involved in extracellular matrix remodelling and terminal differentiation of chondrocytes. IKKα, required for the activation of the so-called non-canonical pathway, has a number of NF-κB-independent and kinase-independent functions in vivo and in vitro, including controlling chondrocyte hypertrophic differentiation and collagenase activity. In this short review, we will discuss the role of NF-κB signalling in OA pathology, with emphasis on the functional effects of IKKα that are independent of its kinase activity and NF-κB activation.
Early knee osteoarthritis
Authors: Favero Marta , Ramonda Roberta , Goldring Mary B , Goldring Steven R , Punzi Leonardo
Published: August 2015

Concepts regarding osteoarthritis, the most common joint disease, have dramatically changed in the past decade thanks to the development of new imaging techniques and the widespread use of arthroscopy that permits direct visualisation of intra-articular tissues and structure. MRI and ultrasound allow the early detection of pre-radiographic structural changes not only in the peri-articular bone but also in the cartilage, menisci, synovial membrane, ligaments and fat pad. The significance of MRI findings such as cartilage defects, bone marrow lesions, synovial inflammation/effusions and meniscal tears in patients without radiographic signs of osteoarthritis is not fully understood. Nevertheless, early joint tissue changes are associated with symptoms and, in some cases, with progression of disease. In this short review, we discuss the emerging concept of early osteoarthritis localised to the knee based on recently updated knowledge. We highlight the need for a new definition of early osteoarthritis that will permit the identification of patients at high risk of osteoarthritis progression and to initiate early treatment interventions.
Structural integrity versus radiographic progression in rheumatoid arthritis
Authors: Favalli Ennio Giulio , Becciolini Andrea , Biggioggero Martina
Published: August 2015

Rheumatoid arthritis (RA) is a chronic, progressive and inflammatory disease often leading to irreversible destruction of articular structures and consequent disability. The key steps of RA pathogenetic mechanisms are the break of immune tolerance and the production of autoantibodies, followed by systemic and local inflammation resulting in damage of both subchondral bone (erosion) and cartilage (joint space narrowing (JSN)). Evidences from clinical trials suggest that erosions and JSN are the result of inter-related but partly independent pathogenetic pathways, in both cases mediated by pro-inflammatory cytokines, even if a direct effect of cyclic citrullinated peptides (anticitrullinated protein antibodies, ACPAs) on bone damage had been postulated. As a consequence, the suppression of inflammation provided by synthetic and biological disease-modifying antirheumatic drugs results in a decreased progression of bone and cartilage damage, supporting the effectiveness of the treat-to-target strategy. Nevertheless, radiographic progression may also be detected in patients achieving a sustained clinical remission. Two main reasons for this apparent uncoupling between clinical synovitis and damage progression should be considered. First, in some cases, the use of composite indices to define remission may not be completely adequate to identify residual disease activity, requiring the concomitant introduction of more sensible tools such as imaging. Second, the direct effect of biological drugs on bone destruction inducers, such as pro-inflammatory cytokines, may explain the suppression of radiographic progression despite the persistence of clinical synovitis. In this review, we discuss the link between autoimmunity, inflammation, joint damage and disability, focusing on how radiographic progression may predict functional disability.
Bone and TNF in rheumatoid arthritis: clinical implications
Authors: Manara Maria , Sinigaglia Luigi
Published: August 2015

Experimental data have demonstrated that tumour necrosis factor (TNF) plays a significant role in systemic and local bone loss related to rheumatoid arthritis (RA). In clinical studies on patients with RA, treatment with TNF inhibitors was able to arrest systemic bone loss assessed by bone mineral density and bone turnover markers, but there is scarce evidence of a clinically meaningful effect of TNF inhibition in preventing fractures. TNF inhibitors showed a higher efficacy in reducing radiographic progression related to the disease compared to methotrexate in randomised clinical trials. Data from observational studies seem to confirm the effectiveness of anti-TNF therapy in reducing joint damage evolution.
OsteoRheumatology: a new discipline?
Authors: Favero Marta , Giusti Andrea , Geusens Piet , Goldring Steven R , Lems Willem , Schett Georg , Bianchi Gerolamo
Published: August 2015

This review summarises recent evidence about the interaction between bone, the immune system and cartilage in disabling conditions such as osteoarthritis, rheumatoid arthritis and spondyloarthritis. These topics have been recently discussed at the ‘OsteoRheumatology’ conference held in Genoa in October 2014. The meeting, at its 10th edition, has been conceived to bring together distinguished international experts in the fields of rheumatic and metabolic bone diseases with the aim of discussing emerging knowledge regarding the role of the bone tissue in rheumatic diseases. Moreover, this review focuses on new treatments based on underlying the pathophysiological processes in rheumatic diseases. Although, a number of issues still remain to be clarified, it seems quite clear that in clinical practice, as well as in basic and translational research, there is a need for more knowledge of the interactions between the cartilage, the immune system and the bone. In this context, ‘OsteoRheumatology’ represents a potential new discipline providing a greater insight into this interplay, in order to face the multifactorial and complex issues underlying common and disabling rheumatic diseases.