A Novel Protocol for Nasal Decolonization Using Prolonged Application of an Alcohol-Based Nasal Antiseptic Reduces Surgical Site Infections in Total Joint Arthroplasty Patients: A Retrospective Cohort Study.

Background: Current nasal decolonization strategies utilize pre-operative agents without consideration for short-term re-colonization or de novo colonization. Many strategies utilize an antibiotic-based agent, raising concerns of limited gram-negative antimicrobial coverage and the emergence of resistant bacterial strains. This study evaluated the clinical utility of a non-antibiotic, alcohol-based nasal decolonization agent in decreasing surgical site infection (SSI) rates after total joint arthroplasty. Patients and Methods: We retrospectively compared an 18-month cohort of elective primary total joint arthroplasty patients treated peri-operatively with an alcohol-based sanitizer to historical controls. The alcohol-based agent was administered pre-operatively the day of surgery and for two weeks after surgery. Patients were followed for 90 days and assessed for signs or symptoms of SSI. Patient and caregiver compliance was recorded. There were 779 patients included in the experimental group and 647 included in the historical control group. Results: Patients receiving alcohol-based nasal decolonization had a lower rate of SSI compared with controls not receiving nasal decolonization (0.64% [5/779] vs. 1.55% [10/647]; p = 0.048; odds ratio, 2.43). Utilization of an alcohol-based nasal sanitizer in the pre-operative and prolonged post-operative setting decreased infection rates by 41.3% in our elective total joint arthroplasty setting. Conclusions: When used pre- and post-operatively, alcohol-based nasal decolonization of bacteria in patients undergoing total joint arthroplasty led to a substantial decrease in SSIs.

The Patient's perspective: A review of the results from a radiotherapy patient experience survey in the North-West of England.

INTRODUCTION: A patient experience survey was undertaken for patients completing radiotherapy at the three Northwest of England Radiotherapy Providers. METHODS: A previously reported National Radiotherapy Patient Experience Survey was adapted and undertaken in the Northwest of England. Quantitative data was analysed to establish trends. Frequency distribution was applied to appraise the number of participants selecting each of the pre-determined responses. Thematic analysis of free text responses was conducted. RESULTS: The questionnaire received 653 responses from the 3 providers across seven departments. Thematic analysis revealed 3 themes; logistics, information and operational. CONCLUSION: The results indicate that the majority of patients are satisfied with their treatment and care. Patients' responses indicate areas for improvements. Expectancy theory states that an individual's satisfaction is related to the difference between expected service and the service received. Consequently, when reviewing services and developing improvement it is important to understand patients' expectations. This regional survey starts to capture what people receiving radiotherapy expect from the service and the professionals delivering their treatment. IMPLICATIONS FOR PRACTICE: This survey responses make a case for reviewing the information provision pre and post radiotherapy. This includes clarifying the understanding of consent for treatment including the intended benefits and potential late effects. There is an argument to offer information sessions prior to radiotherapy to achieve more relaxed and informed patients. A recommendation from this work is for the radiotherapy community undertake a national radiotherapy patient experience survey, facilitated via the 11 Radiotherapy ODNs. A national radiotherapy survey has multiple benefits to inform improvements in practice. This includes benchmarking services against national averages. This approach is aligned with the principles of the service specification in terms of reducing variation and increasing quality.

Integrating Serum Biomarkers into Prediction Models for Biochemical Recurrence Following Radical Prostatectomy.

This study undertook to predict biochemical recurrence (BCR) in prostate cancer patients after radical prostatectomy using serum biomarkers and clinical features. Three radical prostatectomy cohorts were used to build and validate a model of clinical variables and serum biomarkers to predict BCR. The Cox proportional hazard model with stepwise selection technique was used to develop the model. Model evaluation was quantified by the AUC, calibration, and decision curve analysis. Cross-validation techniques were used to prevent overfitting in the Irish training cohort, and the Austrian and Norwegian independent cohorts were used as validation cohorts. The integration of serum biomarkers with the clinical variables (AUC = 0.695) improved significantly the predictive ability of BCR compared to the clinical variables (AUC = 0.604) or biomarkers alone (AUC = 0.573). This model was well calibrated and demonstrated a significant improvement in the predictive ability in the Austrian and Norwegian validation cohorts (AUC of 0.724 and 0.606), compared to the clinical model (AUC of 0.665 and 0.511). This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict BCR. This model can be employed prior to treatment and could improve clinical decision making, impacting on patients' outcomes and quality of life.

Glycosylation in Indolent, Significant and Aggressive Prostate Cancer by Automated High-Throughput N-Glycan Profiling.

The diagnosis and treatment of prostate cancer (PCa) is a major health-care concern worldwide. This cancer can manifest itself in many distinct forms and the transition from clinically indolent PCa to the more invasive aggressive form remains poorly understood. It is now universally accepted that glycan expression patterns change with the cellular modifications that accompany the onset of tumorigenesis. The aim of this study was to investigate if differential glycosylation patterns could distinguish between indolent, significant, and aggressive PCa. Whole serum N-glycan profiling was carried out on 117 prostate cancer patients' serum using our automated, high-throughput analysis platform for glycan-profiling which utilizes ultra-performance liquid chromatography (UPLC) to obtain high resolution separation of N-linked glycans released from the serum glycoproteins. We observed increases in hybrid, oligomannose, and biantennary digalactosylated monosialylated glycans (M5A1G1S1, M8, and A2G2S1), bisecting glycans (A2B, A2(6)BG1) and monoantennary glycans (A1), and decreases in triantennary trigalactosylated trisialylated glycans with and without core fucose (A3G3S3 and FA3G3S3) with PCa progression from indolent through significant and aggressive disease. These changes give us an insight into the disease pathogenesis and identify potential biomarkers for monitoring the PCa progression, however these need further confirmation studies.

A risk calculator to inform the need for a prostate biopsy: a rapid access clinic cohort.

BACKGROUND: Prostate cancer (PCa) represents a significant healthcare problem. The critical clinical question is the need for a biopsy. Accurate risk stratification of patients before a biopsy can allow for individualised risk stratification thus improving clinical decision making. This study aims to build a risk calculator to inform the need for a prostate biopsy. METHODS: Using the clinical information of 4801 patients an Irish Prostate Cancer Risk Calculator (IPRC) for diagnosis of PCa and high grade (Gleason ≥7) was created using a binary regression model including age, digital rectal examination, family history of PCa, negative prior biopsy and Prostate-specific antigen (PSA) level as risk factors. The discrimination ability of the risk calculator is internally validated using cross validation to reduce overfitting, and its performance compared with PSA and the American risk calculator (PCPT), Prostate Biopsy Collaborative Group (PBCG) and European risk calculator (ERSPC) using various performance outcome summaries. In a subgroup of 2970 patients, prostate volume was included. Separate risk calculators including the prostate volume (IPRCv) for the diagnosis of PCa (and high-grade PCa) was created. RESULTS: IPRC area under the curve (AUC) for the prediction of PCa and high-grade PCa was 0.6741 (95% CI, 0.6591 to 0.6890) and 0.7214 (95% CI, 0.7018 to 0.7409) respectively. This significantly outperforms the predictive ability of cancer detection for PSA (0.5948), PCPT (0.6304), PBCG (0.6528) and ERSPC (0.6502) risk calculators; and also, for detecting high-grade cancer for PSA (0.6623) and PCPT (0.6804) but there was no significant improvement for PBCG (0.7185) and ERSPC (0.7140). The inclusion of prostate volume into the risk calculator significantly improved the AUC for cancer detection (AUC = 0.7298; 95% CI, 0.7119 to 0.7478), but not for high-grade cancer (AUC = 0.7256; 95% CI, 0.7017 to 0.7495). The risk calculator also demonstrated an increased net benefit on decision curve analysis. CONCLUSION: The risk calculator developed has advantages over prior risk stratification of prostate cancer patients before the biopsy. It will reduce the number of men requiring a biopsy and their exposure to its side effects. The interactive tools developed are beneficial to translate the risk calculator into practice and allows for clarity in the clinical recommendations.

Impact of the 2020 COVID-19 pandemic on the workload of the orthopaedic service in a busy UK district general hospital.

INTRODUCTION: The COVID -19 outbreak has had a profound effect on the management of healthcare service provision in the UK. Orthopaedic departments have been no exception to this and have needed to adapt to the changing circumstances by releasing resources and focusing on 'essential' activity. The aim of this study is to quantify the reduction in trauma and, in addition, describe any changes in the type of referrals to the trust which may have been affected by the pandemic itself and the social distancing measures employed by the UK government. METHODS: The study was performed in a UK District Hospital which is also a Trauma Unit providing trauma and orthopaedic care to a population of 625,000 people. The trust based electronic database of trauma referrals was used to compare the numbers of, and types of referral to our trauma service during the COVID-19 pandemic and the corresponding time periods in the previous 3 years. RESULTS: The mean number of referrals per week to the service reduced by 33% in the time period following the confirmation of the outbreak as a pandemic (p<0.0001). Number of operations performed per week reduced by 26% (p = 0.001). There was no change in the number of referrals relating to domestic abuse or non-accidental injury. In addition, numbers of hip fractures, periprosthetic fractures and prosthetic joint dislocations were unchanged. There was a significant reduction in the number of referrals for simple fractures, native joint dislocations, wounds and soft tissue injuries. Within the paediatric population, similarly, a reduction in simple fracture referrals was demonstrated. DISCUSSION: An association between the outbreak of the pandemic and a reduction in referral numbers to our department has been demonstrated. The direct cause of this may be multifactorial but proposing that it is, in part, due to the social distancing measures introduced by the government is certainly conceivable. The patterns of injury would reflect this also with low energy and fragility trauma persisting whilst injuries associated with younger people have reduced. We would suggest that information such as this could be useful in healthcare planning and resource allocation in future pandemic situations.

Discovery and Contribution of Nontypeable Haemophilus influenzae NTHI1441 to Human Respiratory Epithelial Cell Invasion.

Nontypeable Haemophilus influenzae (NTHi) is the primary cause of bacterially induced acute exacerbations of chronic obstructive pulmonary disease (COPD). NTHi adheres to and invades host respiratory epithelial cells as a means to persist in the lower airways of adults with COPD. Therefore, we mined the genomes of NTHi strains isolated from the airways of adults with COPD to identify novel proteins to investigate their role in adherence and invasion of human respiratory epithelial cells. An isogenic knockout mutant of the open reading frame NTHI1441 showed a 76.6% ± 5.5% reduction in invasion of human bronchial and alveolar epithelial cells at 1, 3, and 6 h postinfection. Decreased invasion of the NTHI1441 mutant was independent of either intracellular survival or adherence to cells. NTHI1441 is conserved among NTHi genomes. Results of whole-bacterial-cell enzyme-linked immunosorbent assay (ELISA) and flow cytometry experiments identified that NTHI1441 has epitopes expressed on the bacterial cell surface. Adults with COPD develop increased serum IgG against NTHI1441 after experiencing an exacerbation with NTHi. This study reveals NTHI1441 as a novel NTHi virulence factor expressed during infection of the COPD lower airways that contributes to invasion of host respiratory epithelial cells. The role in host cell invasion, conservation among strains, and expression of surface-exposed epitopes suggest that NTHI1441 is a potential target for preventative and therapeutic interventions for disease caused by NTHi.

Investigation of thermally induced damage to surrounding nerve tissue when using curettage and cementation of long bone tumours, modelled in cadaveric porcine femurs.

INTRODUCTION: Curettage with cement augmentation is a technique used in the treatment of bone tumours. Thermal energy released during the cement polymerisation process can damage surrounding tissues. This study aims to record temperature changes at various sites on and around bone during the cementing process. We hypothesised that adjacent structures, such as the radial nerve, may be threatened by this process in the clinical setting. MATERIALS AND METHODS: Using 18 porcine femurs as a model of the human humerus, we used thermocouples and a thermal imaging camera to measure changes in temperature during the cementing process. Fractures were created in nine samples to establish whether a discontinuity of the cortex had an effect on thermal conduction. RESULTS: Significantly higher temperatures were recorded in samples with a fracture compared to those without a fracture. The site overlying the centre of the cement bolus (hypothetical site of the radial nerve) demonstrated higher temperatures than all other sites on the same cortex. When considering the radial nerve site, over half the samples demonstrated temperatures exceeding 47 °C for over a minute. When a threshold of 50 °C for more than 30 s was considered, three samples without a fracture exceeded this value compared to two with a fracture. CONCLUSION: The temperatures recorded were sufficient to cause damage to neural tissue. Limiting thermal exposure to soft tissues is recommended. Increased attention is required when using larger cement boluses, or where bone quality is poor or a fracture, iatrogenic or preexisting, is present.

A radio counterpart to a neutron star merger.

Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultrarelativistic jet, viewed off-axis, or a cocoon of mildly relativistic ejecta. Within 100 days of the merger, the radio light curves will enable observers to distinguish between these models, and the angular velocity and geometry of the debris will be directly measurable by very long baseline interferometry.

Biological and clinical consequences of NPM1 mutations in AML.

Acute myeloid leukemia (AML) is characterized by accumulation of myeloid cells in the bone marrow because of impaired differentiation and proliferation, resulting in hematopoietic insufficiency. NPM1 is one of the most commonly mutated genes in AML, present in 20-30% of cases. Mutations in NPM1 represent a distinct entity in the World Health Organization (WHO) classification and commonly indicate a better risk prognosis. In this review, we discuss the many functions of NPM1, the consequence of mutations in NPM1 and possible mechanisms through which mutations lead to leukemogenesis. We also discuss clinical consequences of mutations, associated gene expression patterns and the role of NPM1 mutations in informing prognosis and therapeutic decisions and predicting relapse in AML.

The neonatal preventable harm index: a high reliability tool.

OBJECTIVE: The aim of this study is to identify, quantify and disseminate a novel set of safety indicators for monitoring the occurrence of preventable harm in the neonatal intensive care unit (NICU). STUDY DESIGN: Literature review and experiences in an academic, level IV NICU identified prevalent, preventable safety events: hospital-acquired infections (catheter-associated bloodstream infection, ventilator-associated pneumonia), unscheduled extubations, intravenous infiltrates requiring intervention, first week readmissions, serious adverse drug events and miscellaneous events (unanticipated harm or serious near misses). Negative binominal regression evaluated the event incidence trends. RESULTS: Of 226 preventable harm events occurring between March 2013 and January 2015, the most common were unscheduled extubations (98; 2/100 ventilator days) and intravenous infiltrates (62; 2.7/100 admissions). No trends were detected (rate ratio: 0.99; confidence limits: 0.96 to 1.01; P=0.38). CONCLUSION: The Neonatal Preventable Harm Index represents a novel and transparent means to monitor serious safety events and direct harm prevention strategies in the NICU.

European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators significantly outperform the Prostate Cancer Prevention Trial (PCPT) 2.0 in the prediction of prostate cancer: a multi-institutional study.

OBJECTIVE: To analyse the performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) and two iterations of the European Randomised Study of Screening for Prostate Cancer (ERSPC) Risk Calculator, one of which incorporates prostate volume (ERSPC-RC) and the other of which incorporates prostate volume and the prostate health index (PHI) in a referral population (ERSPC-PHI). PATIENTS AND METHODS: The risk of prostate cancer (PCa) and significant PCa (Gleason score ≥7) in 2001 patients from six tertiary referral centres was calculated according to the PCPT-RC and ERSPC-RC formulae. The calculators' predictions were analysed using the area under the receiver-operating characteristic curve (AUC), calibration plots, Hosmer-Lemeshow test for goodness of fit and decision-curve analysis. In a subset of 222 patients for whom the PHI score was available, each patient's risk was calculated as per the ERSPC-RC and ERSPC-PHI risk calculators. RESULTS: The ERSPC-RC outperformed the PCPT-RC in the prediction of PCa, with an AUC of 0.71 compared with 0.64, and also outperformed the PCPT-RC in the prediction of significant PCa (P<0.001), with an AUC of 0.74 compared with 0.69. The ERSPC-RC was found to have improved calibration in this cohort and was associated with a greater net benefit on decision-curve analysis for both PCa and significant PCa. The performance of the ERSPC-RC was further improved through the addition of the PHI score in a subset of 222 patients. The AUCs of the ERSPC-PHI were 0.76 and 0.78 for PCa and significant PCa prediction, respectively, in comparison with AUC values of 0.72 in the prediction of both PCa and significant PCa for the ERSPC-RC (P = 0.12 and P = 0.04, respectively). The ERSPC-PHI risk calculator was well calibrated in this cohort and had an increase in net benefit over that of the ERSPC-RC. CONCLUSIONS: The performance of the risk calculators in the present cohort shows that the ERSPC-RC is a superior tool in the prediction of PCa; however the performance of the ERSPC-RC in this population does not yet warrant its use in clinical practice. The incorporation of the PHI score into the ERSPC-PHI risk calculator allowed each patient's risk to be more accurately quantified. Individual patient risk calculation using the ERSPC-PHI risk calculator can be undertaken in order to allow a systematic approach to patient risk stratification and to aid in the diagnosis of PCa.

Improving multivariable prostate cancer risk assessment using the Prostate Health Index.

OBJECTIVES: To analyse the clinical utility of a prediction model incorporating both clinical information and a novel biomarker, p2PSA, in order to inform the decision for prostate biopsy in an Irish cohort of men referred for prostate cancer assessment. PATIENTS AND METHODS: Serum isolated from 250 men from three tertiary referral centres with pre-biopsy blood draws was analysed for total prostate-specific antigen (PSA), free PSA (fPSA) and p2PSA. From this, the Prostate Health Index (PHI) score was calculated (PHI = (p2PSA/fPSA)*√tPSA). The men's clinical information was used to derive their risk according to the Prostate Cancer Prevention Trial (PCPT) risk model. Two clinical prediction models were created via multivariable regression consisting of age, family history, abnormality on digital rectal examination, previous negative biopsy and either PSA or PHI score, respectively. Calibration plots, receiver-operating characteristic (ROC) curves and decision curves were generated to assess the performance of the three models. RESULTS: The PSA model and PHI model were both well calibrated in this cohort, with the PHI model showing the best correlation between predicted probabilities and actual outcome. The areas under the ROC curve for the PHI model, PSA model and PCPT model were 0.77, 0.71 and 0.69, respectively, for the prediction of prostate cancer (PCa) and 0.79, 0.72 and 0.72, respectively, for the prediction of high grade PCa. Decision-curve analysis showed a superior net benefit of the PHI model over both the PSA model and the PCPT risk model in the diagnosis of PCa and high grade PCa over the entire range of risk probabilities. CONCLUSION: A logical and standardized approach to the use of clinical risk factors can allow more accurate risk stratification of men under investigation for PCa. The measurement of p2PSA and the integration of this biomarker into a clinical prediction model can further increase the accuracy of risk stratification, helping to better inform the decision for prostate biopsy in a referral population.

Predicting prostate cancer: analysing the clinical efficacy of prostate cancer risk calculators in a referral population.

BACKGROUND: The decision to proceed to biopsy for the diagnosis of prostate cancer in clinical practice is a difficult one. Prostate cancer risk calculators allow for a systematic approach to the use of patient information to predict a patient's likelihood of prostate cancer. AIMS: In this paper, we validate the two leading prostate cancer risk calculators, the prostate cancer prevention trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) in an Irish population. METHODS: Data were collected for 337 men referred to one tertiary referral center in Ireland. Calibration analysis, ROC analysis and decision curve analysis were undertaken to ascertain the performance of the PCPT and the ERSPC risk calculators in this cohort. RESULTS: Of 337 consecutive biopsies, cancer was subsequently diagnosed in 146 men (43 %), 98 (67 %) of which were high grade. The AUC for the PCPT and ERSPC risk calculators were 0.68 and 0.66, respectively for the prediction of prostate cancer. Each calculator was sufficiently calibrated in this cohort. Decision curve analysis demonstrated a net benefit via the use of the PCPT and ERSPC risk calculators in the diagnosis of prostate cancer. CONCLUSIONS: The PCPT and ERSPC risk calculators achieve a statistically significant prediction of prostate cancer in this Irish population. This study provides external validation for these calculators, and therefore these tools can be used to aid in clinical decision making.

Surgical management of complex multiloculated hydrocephalus in infants and children.

OBJECTIVE: Multiloculated hydrocephalus may occur as a consequence of intraventricular hemorrhage or infection and is characterized by enlargement of multiple noncommunicating intraventricular and/or periventricular cysts. In this study, we report the outcomes of open and endoscopic fenestration for multiloculated hydrocephalus at our institution. METHODS: Records of children who underwent endoscopic or open fenestration at St. Louis Children's Hospital from 1999 to 2011 were analyzed. The cause of MLH, operative parameters, length of hospital stay, and subsequent shunt intervention rate were recorded. RESULTS: Twenty-five subjects were identified for study. Twelve subjects underwent open craniotomy and 13 underwent endoscopic fenestration. Endoscopic fenestration was associated with decreased blood loss, operative time, and length of stay (p = 0.003, 0.002, 0.02, respectively). Subjects undergoing craniotomy had an average of 5.1 ± 4.5 subsequent shunt-related interventions versus 3.1 ± 4.0 in the endoscopy group (p = 0.25). The craniotomy group's median subsequent shunt revision rate was 0.74 interventions per year versus 0.50 interventions per year in the endoscopy group (p = 0.51). Fifty percent of subjects in the open fenestration group required additional fenestration surgery compared to 38.5% in the endoscopic group (p = 0.70). CONCLUSION: Both open and endoscopic fenestration appeared effective at improving shunt management. The endoscopic technique may offer advantages in operative time, blood loss, and length of hospital stay. These data suggest that endoscopic fenestration may be used as the initial approach for treatment of multiloculated hydrocephalus, with craniotomy and open fenestration used for more severe or refractory cases.

Variations in radiotherapy delivery in England - evidence from the national radiotherapy dataset.

AIMS, MATERIALS AND METHOD: Data in the national radiotherapy dataset for England for 2009-2011 is based upon downloads of activity from every linear accelerator in the country through its oncology management system linked to the local patient administration system to give a full overview of each patient episode. RESULTS: An analysis of this dataset shows that there is still a considerable variation in radiotherapy activity across the country, with a two-fold variation between the most and least active networks. Lower activity is seen in London and the southeast compared with the rest of the country, but when the data are split between the north and south of the country, no such variation is seen. Activity is higher in smaller centres and non-teaching centres. About half of all treatment is palliative and this proportion does not vary with geography, although there is considerable variation between individual centres in the proportion of radical radiotherapy given. There is a trend towards less use of radiotherapy, both radical and palliative, in the more deprived population groups, although no change in the relative use of palliative and radical treatment. CONCLUSION: It is important to emphasise that these data currently reflect activity patterns only and do not reflect quality of care or treatment outcomes, which will be achieved by linkage with cancer registry data in the future.

PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation.

Recent observations indicate prostatic diseases are comorbidities of systemic metabolic dysfunction. These discoveries revealed fundamental questions regarding the nature of prostate metabolism. We previously showed that prostate-specific ablation of PPARγ in mice resulted in tumorigenesis and active autophagy. Here, we demonstrate control of overlapping and distinct aspects of prostate epithelial metabolism by ectopic expression of individual PPARγ isoforms in PPARγ knockout prostate epithelial cells. Expression and activation of either PPARγ 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36. Differential effects of PPARγ isoforms included decreased basal cell differentiation, Scd1 expression and triglyceride fatty acid desaturation and increased tumorigenicity by PPARγ1. In contrast, PPARγ2 expression significantly increased basal cell differentiation, Scd1 expression and AR expression and responsiveness. Finally, in confirmation of in vitro data, a PPARγ agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARγ agonization increased prostatic differentiation markers, whereas HFD downregulated PPARγ-regulated genes and decreased prostate differentiation. These data provide a rationale for pursuing a fundamental metabolic understanding of changes to glucose and fatty acid metabolism in benign and malignant prostatic diseases associated with systemic metabolic stress.

Long-term maintenance of response across multiple fibromyalgia symptom domains in a randomized withdrawal study of pregabalin.

OBJECTIVE: To determine the incidence and duration of response of clinically meaningful improvements with pregabalin across several key symptoms of fibromyalgia (FM). METHODS: This was a post hoc analysis of data from a multicenter, double-blind, placebo-controlled, randomized, withdrawal study, originally designed to evaluate the efficacy of pregabalin monotherapy for durability of effect on FM pain based on pain and Patient Global Impression of Change (PGIC) criteria. Responder criteria for Fibromyalgia Impact Questionnaire total score (≥16-point change), Medical Outcomes Study Sleep Scale Sleep Disturbance subscale (≥15.8-point change), and the 36-item Short-Form Health Survey Vitality scale (≥10-point change) were used to evaluate the incidence and duration of improvements in function, sleep, and fatigue for pregabalin versus placebo among pain and PGIC responders. A composite responder index consisting of pain, PGIC, function, and sleep endpoints was used to explore multidimensional response. RESULTS: Approximately 80% of patients meeting pain and PGIC improvement criteria at randomization had clinically meaningful improvement in fatigue, sleep, or function. Higher proportions of patients in the pregabalin group maintained a clinically meaningful response, and pregabalin-treated patients had a significantly longer time to loss of therapeutic response compared with the placebo group. Composite responder Kaplan-Meier analysis, performed with patients demonstrating clinically meaningful improvements in pain, PGIC, function, and sleep at randomization showed a significantly longer median time to loss of therapeutic response for pregabalin-treated patients. DISCUSSION: The results from this post hoc analysis indicate that pregabalin provides long-term effects across multiple domains of FM (ClinicalTrials.gov registry ID: NCT00151489).