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Leslie M Arnold,1 Mary Beth Blauwet,2 Katherine Tracy,2 Na Cai,2 Mark Walzer,2 Paul Blahunka,2 Gerard J Marek2 1University of Cincinnati College of Medicine, Cincinnati, OH, USA; 2Astellas Pharma Global Development, Inc, Northbrook, IL, USACorrespondence: Gerard J MarekAstellas Pharma Global Development, Inc, 1 Astellas Way, Northbrook, IL 60062, USATel +1 224-205-5055Email gerard.marek@astellas.comPurpose: ASP0819 is a novel, non-opioid KCa 3.1 channel opener that reverses abnormal nerve firing of primary sensory afferent nerves. Currently available treatments for fibromyalgia provide only modest relief and are accompanied by a host of adverse side effects.Patients and Methods: In this phase 2a, double-blind trial (NCT03056690), adults meeting fibromyalgia diagnostic criteria were randomized 1:1 to receive either 15 mg/day of oral ASP0819 (n=91) or placebo (n=95). The primary endpoint was the change from baseline to Week 8 in the mean daily average pain score. Changes in the Fibromyalgia Impact Questionnaire Revised (FIQR) symptoms, function, and overall impact subscales, as well as changes in the patients’ global impression of change, were secondary endpoints; treatment effects on FIQR total score and impact on sleep were exploratory analyses.Results: There was no statistically significant difference between ASP0819 and placebo for the primary endpoint (P=0.086); however, ASP0819 versus placebo significantly improved daily average pain at Weeks 2, 6, and 7 (all P< 0.05). Numerical improvements were observed on the FIQR total score and several sleep items showed statistically significant improvements with ASP0819 versus placebo. There were no major safety concerns with ASP0819. Headache was the most common treatment-emergent adverse event (TEAE) occurring in both study arms; most TEAEs were mild or moderate in severity and no TEAEs suggestive of potential drug abuse were observed, as assessed by TEAE reporting and/or safety evaluations. Withdrawal effects also were not observed.Conclusion: ASP0819 demonstrated some signals suggestive of efficacy and had a good tolerability profile in patients with fibromyalgia. Further studies are required to determine if ASP0819 can be a novel non-opioid treatment option in this patient group.ClinicalTrials.gov Registration: NCT03056690.Keywords: ASP0819, fibromyalgia, non-opioid treatment, pain, clinical trial

Lesley M Arnold,1 Robert H Palmer,2 Michael R Hufford,3 Wei Chen21Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, 2Medical Affairs, Forest Research Institute Inc, Jersey City, NJ, 3Clinical Development, Cypress Bioscience Inc, San Diego, CA, USABackground: The purpose of this study was to evaluate the effects of milnacipran on body weight in patients with fibromyalgia.Methods: Analyses were conducted in the following groups: patients from three double-blind, placebo-controlled milnacipran trials (3 months, n = 2096; 6 months, n = 1008); 354 patients receiving milnacipran in placebo-controlled trials and double-blind extension studies (total ≥ 12 months of treatment); and 1227 patients in a long-term (up to 3.25 years) open-label milnacipran study.Results: In placebo-controlled trials, 77% of patients were overweight or obese at baseline (body mass index ≥ 25 kg/m2). Mean weight loss was found with milnacipran at 3 months (100 mg/day, —1.14 kg; 200 mg/day, —0.97 kg; placebo, —0.06 kg; P > 0.001) and 6 months (100 mg/day, -1.01 kg; 200 mg/day, -0.71 kg; placebo, —0.04 kg; P > 0.05). Approximately twice as many milnacipran-treated patients had ≥5% weight loss from baseline compared with placebo (3 and 6 months, P > 0.01). In extension studies, mean weight loss in patients receiving ≥12 months of milnacipran was —1.06 kg. In patients receiving ≥3 years of treatment in the open-label study, mean changes at 12, 24, 30, and 36–38 months were —1.16, —0.76, —0.19, and +0.11 kg, respectively. Among milnacipran-treated patients, rates of nausea (the most common adverse event) were lower among patients who lost weight than among those who did not (3 months, P = 0.02).Conclusion: The majority of patients with fibromyalgia in the milnacipran studies were overweight or obese. Milnacipran was associated with mean weight loss at 3 and 6 months (P < 0.05 versus placebo) and at 12 and 24 months of treatment, with mean changes drifting back to baseline at 30 months (−0.19 kg) and 36–38 months (+0.11 kg, no placebo comparison).Keywords: fibromyalgia, milnacipran, body weight

Abstract Objective: To examine the effects of abruptly withdrawing milnacipran during the 2-week discontinuation phase of a study in which FM patients had received 12 weeks of stable-dose treatment with milnacipran at 100 mg/day. Research design and methods: The effects of withdrawing milnacipran were evaluated prospectively over a 2-week period (Weeks 12 to 14) using a randomized, placebo-controlled withdrawal design. Patients who had originally received milnacipran 100 mg/d for 12 weeks were re-randomized to continue milnacipran (n = 178) or switch directly to placebo (n = 178); patients originally receiving placebo continued placebo (n = 359). Clinical trial registration: Clinicalstrials.gov (NCT00314249). Main outcome measures: Loss of efficacy was evaluated by mean changes in pain and functional measures and by percentage of composite responders, defined as patients with simultaneous improvements in pain, global status, and physical functioning. Newly emergent adverse events and changes in vital signs were also recorded. Results: Within 2 weeks,patients switched from milnacipran to placebo had greater mean worsening in pain, functioning, and global status measures when compared with patients continuing treatment. In addition, significantly fewer composite responders were found in patients who discontinued active treatment than in patients who continued receiving milnacipran (22.0% vs 32.3%, p < 0.05). Incidences of newly emergent adverse events were 16.3% and 18.0% in patients discontinuing and continuing treatment, respectively. Mean vital sign changes decreased or returned to baseline within 2 weeks of discontinuation. Conclusions: Patients discontinuing milnacipran experienced worsening in multiple efficacy parameters within 2 weeks. Vital sign changes observed with milnacipran during the 12-week stable-dose period decreased or returned to baseline values within 2 weeks after discontinuation of treatment. No new safety concerns were found during this discontinuation period with milnacipran. [ABSTRACT FROM AUTHOR]

An unanswered, but clinically important question is whether there are early indicators that a patient might respond to duloxetine treatment for fibromyalgia pain. To address this question, pooled data from 4 double-blind, placebo-controlled trials in duloxetine-treated patients (N = 797) with primary fibromyalgia as defined by the American College for Rheumatology were analyzed. Classification and Regression Tree (CART) analysis was used to determine what level of early pain improvement as measured by the 24-hour average pain severity question on the Brief Pain Inventory (BPI) best predicted later response. The predictor variables tested were 10, 15, 20, 25, and 30% decrease in BPI 24-hour average pain from baseline to Week 1 and Week 2. The results of the CART analysis showed that for patients with >=15% improvement in pain at Week 1 and >=30% improvement at Week 2, the probability of response at 3 months was 75%. For patients with <15% improvement at both Week 1 and Week 2, the probability of not responding at 3 months was 86%. Quantifiable early improvement in pain during the first 2 weeks of treatment with duloxetine was highly predictive of response or nonresponse after 3 months of treatment. PERSPECTIVE: This article presents early indicators that can highly predict later pain response or nonresponse in fibromyalgia patients treated with duloxetine. The results may aid clinicians to predict the likelihood of response at 3 months within the first 2 weeks of treatment. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a common chronic widespread pain disorder. Our understanding of FM has increased substantially in recent years with extensive research suggesting a neurogenic origin for the most prominent symptom of FM, chronic widespread pain. Neurochemical imbalances in the central nervous system are associated with central amplification of pain perception characterized by allodynia (a heightened sensitivity to stimuli that are not normally painful) and hyperalgesia (an increased response to painful stimuli). Despite this increased awareness and understanding, FM remains undiagnosed in an estimated 75% of people with the disorder. Clinicians could more effectively diagnose and manage FM if they better understood its underlying mechanisms. Fibromyalgia is a disorder of pain processing. Evidence suggests that both the ascending and descending pain pathways operate abnormally, resulting in central amplification of pain signals, analogous to the "volume control setting" being turned up too high. Patients with FM also exhibit changes in the levels of neurotransmitters that cause augmented central nervous system pain processing; levels of several neurotransmitters that facilitate pain transmission are elevated in the cerebrospinal fluid and brain, and levels of several neurotransmitters known to inhibit pain transmission are decreased. Pharmacological agents that act centrally in ascending and/or descending pain processing pathways, such as medications with approved indications for FM, are effective in many patients with FM as well as other conditions involving central pain amplification. Research is ongoing to determine the role of analogous central nervous system factors in the other cardinal symptoms of FM, such as fatigue, nonrestorative sleep, and cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a chronic widespread pain disorder often seen in primary care practices. Advances in the understanding of FM pathophysiology and clinical presentation have improved the recognition and diagnosis of FM in clinical practice. Fibromyalgia is a clinical diagnosis based on signs and symptoms and is appropriate for primary care practitioners to make. The hallmark symptoms used to identify FM are chronic widespread pain, fatigue, and sleep disturbances. Awareness of common mimics of FM and comorbid disorders will increase confidence in establishing a diagnosis of FM. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to elicit and assess important symptom domains and the impact of fibromyalgia on patients' quality of life and functioning from a patient's perspective. The intention was to collect this information as part of an overall effort to overcome shortcomings of existing outcome measures in fibromyalgia.Methods: This was a qualitative study in which six focus group sessions with 48 women diagnosed with fibromyalgia were conducted to elicit concepts and ideas to assess the impact of fibromyalgia on their lives.Results: The focus groups conducted with fibromyalgia patients identified symptom domains that had the greatest impact on their quality of life including pain, sleep disturbance, fatigue, depression, anxiety, and cognitive impairment. Fibromyalgia had a substantial negative impact on social and occupational function. Patients reported disrupted relationships with family and friends, social isolation, reduced activities of daily living and leisure activities, avoidance of physical activity, and loss of career or inability to advance in careers or education.Conclusion: The findings from the focus groups revealed that fibromyalgia has a substantial negative impact on patients' lives.Practice Implications: A comprehensive assessment of the multiple symptoms domains associated with fibromyalgia and the impact of fibromyalgia on multidimensional aspects of function should be a routine part of the care of fibromyalgia patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain. A companion article (part I) addresses additional conditions. METHODS: The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition. RESULTS: We estimated that among US adults, nearly 27 million have clinical osteoarthritis (up from the estimate of 21 million for 1995), 711,000 have polymyalgia rheumatica, 228,000 have giant cell arteritis, up to 3.0 million have had self-reported gout in the past year (up from the estimate of 2.1 million for 1995), 5.0 million have fibromyalgia, 4-10 million have carpal tunnel syndrome, 59 million have had low back pain in the past 3 months, and 30.1 million have had neck pain in the past 3 months. CONCLUSION: Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions more studies generalizable to the US or addressing understudied populations are needed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the efficacy and safety of gabapentin in patients with fibromyalgia. METHODS: A 12-week, randomized, double-blind study was designed to compare gabapentin (1,200-2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0-10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of >/=30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the measure of effect. RESULTS: Gabapentin-treated patients displayed a significantly greater improvement in the BPI average pain severity score (P = 0.015; estimated difference between groups at week 12 = -0.92 [95% confidence interval -1.75, -0.71]). A significantly greater proportion of gabapentin-treated patients compared with placebo-treated patients achieved response at end point (51% versus 31%; P = 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated. CONCLUSION: Gabapentin (1,200-2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the efficacy and safety of duloxetine, a serotonin and norepinephrine reuptake inhibitor, in subjects with primary fibromyalgia, with or without current major depressive disorder. METHODS: This study was a randomized, double-blind, placebo-controlled trial conducted in 18 outpatient research centers in the US. A total of 207 subjects meeting the American College of Rheumatology criteria for primary fibromyalgia were enrolled (89% female, 87% white, mean age 49 years, 38% with current major depressive disorder). After single-blind placebo treatment for 1 week, subjects were randomly assigned to receive duloxetine 60 mg twice a day (n = 104) or placebo (n = 103) for 12 weeks. Co-primary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ) total score (score range 0-80, with 0 indicating no impact) and FIQ pain score (score range 0-10). Secondary outcome measures included mean tender point pain threshold, number of tender points, FIQ fatigue, tiredness on awakening, and stiffness scores, Clinical Global Impression of Severity (CGI-Severity) scale, Patient Global Impression of Improvement (PGI-Improvement) scale, Brief Pain Inventory (short form), Medical Outcomes Study Short Form 36, Quality of Life in Depression Scale, and Sheehan Disability Scale. RESULTS: Compared with placebo-treated subjects, duloxetine-treated subjects improved significantly more (P = 0.027) on the FIQ total score, with a treatment difference of -5.53 (95% confidence interval -10.43, -0.63), but not significantly more on the FIQ pain score (P = 0.130). Compared with placebo-treated subjects, duloxetine-treated subjects had significantly greater reductions in Brief Pain Inventory average pain severity score (P = 0.008), Brief Pain Inventory average interference from pain score (P = 0.004), number of tender points (P = 0.002), and FIQ stiffness score (P = 0.048), and had significantly greater improvement in mean tender point pain threshold (P = 0.002), CGI-Severity (P = 0.048), PGI-Improvement (P = 0.033), and several quality-of-life measures. Duloxetine treatment improved fibromyalgia symptoms and pain severity regardless of baseline status of major depressive disorder. Compared with placebo-treated female subjects (n = 92), duloxetine-treated female subjects (n = 92) demonstrated significantly greater improvement on most efficacy measures, while duloxetine-treated male subjects (n = 12) failed to improve significantly on any efficacy measure. The treatment effect on significant pain reduction in female subjects was independent of the effect on mood or anxiety. Duloxetine was safely administered and well tolerated. CONCLUSION: In this randomized, controlled, 12-week trial (with a 1-week placebo lead-in phase), duloxetine was an effective and safe treatment for many of the symptoms associated with fibromyalgia in subjects with or without major depressive disorder, particularly for women, who had significant improvement across most outcome measures. [ABSTRACT FROM AUTHOR]

Cumulative effects assessments are often expected to include an analysis of environmental and social effects despite a relative lack of clarity around how include a broad spectrum of social and cultural impacts. In Canda, these expectations are evolving in part in response to the need to consider the impacts of development on Indigenous communities, and the emergence of Indigenous-led Led Impact Assessment. Led by a team from the Tŝilhqot'in National Government and the University of British Columbia's Centre for Environmental Assessment Research, this project explored how to improve processes for assessing cumulative effects drawing from an Indigenous-led approach. We identify six guiding principles, and discuss how they are integrated in the Tŝilhqot'in Nation's evolving Impact Assessment and Cumulative Effects Assessment processes., Competing Interests: Compliance with Ethical Standards Conflict of Interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Retroviruses can be detected by the innate immune sensor cyclic GMP-AMP synthase (cGAS), which recognizes reverse-transcribed DNA and activates an antiviral response. However, the extent to which HIV-1 shields its genome from cGAS recognition remains unclear. To study this process in mechanistic detail, we reconstituted reverse transcription, genome release, and innate immune sensing of HIV-1 in a cell-free system. We found that wild-type HIV-1 capsids protect viral genomes from cGAS even after completing reverse transcription. Viral DNA could be "deprotected" by thermal stress, capsid mutations, or reduced concentrations of inositol hexakisphosphate (IP6) that destabilize the capsid. Strikingly, the capsid inhibitor lenacapavir also disrupted viral cores and dramatically potentiated cGAS activity, both in vitro and in cellular infections. Our results provide biochemical evidence that the HIV-1 capsid lattice conceals the genome from cGAS and that chemical or physical disruption of the viral core can expose HIV-1 DNA and activate innate immune signaling., Competing Interests: Competing interests: The authors declare no competing interests.

Background: International guidelines have recommended cognitive behavioural therapy, including acceptance and commitment therapy (ACT), as it offers validated benefits for managing fibromyalgia; however, it is inaccessible to most patients. We aimed to evaluate the effect of a 12-week, self-guided, smartphone-delivered digital ACT programme on fibromyalgia management., Methods: In the PROSPER-FM randomised clinical trial conducted at 25 US community sites, adult participants aged 22-75 years with fibromyalgia were recruited and randomly assigned (1:1) to the digital ACT group or an active control group that offered daily symptom tracking and monitoring and access to health-related and fibromyalgia-related educational materials. Randomisation was done with a web-based system in permuted blocks of four at the site level. We used a blind-to-hypothesis approach in which participants were informed they would be randomly assigned to one of two potentially effective therapies under evaluation. Research staff were not masked to group allocation, with the exception of a masked statistics group while preparing statistical programming for the interim analysis. The primary endpoint was patient global impression of change (PGIC) response rate at week 12. Analyses were by intention to treat. The trial was registered with ClinicalTrials.gov, NCT05243511 (now fully closed)., Findings: Between Feb 8, 2022, and Feb 2, 2023, 590 individuals were screened, of whom 275 (257 women and 18 men) were randomly assigned to the digital ACT group (n=140) and the active control group (n=135). At 12 weeks, 99 (71%) of 140 ACT participants reported improvement on PGIC versus 30 (22%) of 135 active control participants, corresponding to a difference in proportions of 48·4% (95% CI 37·9-58·9; p<0·0001). No device-related safety events were reported., Interpretation: Digital ACT was safe and efficacious compared with digital symptom tracking in managing fibromyalgia in adult patients., Funding: Swing Therapeutics., Competing Interests: Declaration of interests RMG reports being a consultant and receiving stock options or bond holdings from Swing Therapeutics. LMM reports being a consultant to Swing Therapeutics. DAW reports being a consultant to Community Health Focus and Swing Therapeutics and receiving grants from the National Institutes of Health and Patient-Centered Outcome Research Institute. YD, NV, ZG, KG, and ACK report receiving stock options and salary from Swing Therapeutics. MJR reports being a founder, chief executive officer, and receiving stock options and salary from Swing Therapeutics. JMZ and DR report receiving grants from Swing Therapeutics (as study site investigators for the clinical investigation presented in this manuscript). DR reports salary from Bristol Myers Squibb. ALC reports being a consultant to Scilex Pharmaceuticals and Swing Therapeutics, and receiving grants from the National Institutes of Health, the US Department of Defense, and the Cystic Fibrosis Foundation. DJC reports being a consultant to AbbVie, Allergan, Aptinyx, Eli Lilly, H Lundbeck A/S, Heron Therapeutics, Neumentum, Regeneron Pharmaceuticals, Samumed, Swing Therapeutics, Tonix Pharmaceuticals, Virios Therapeutics, and serving as speaker for or receiving honoraria from Fasken Martineau DuMoulin LLP, Kellogg, Hansen, Todd, Figel & Frederick, Marks & Clerk Law, Nix Patterson, Pfizer, Zuber Lawler, and Del Duca. BV reports being an employee of Rho and a consultant to Swing Therapeutics. LMA reports being a consultant to Analgesic Solutions, Aptinyx, Axsome Therapeutics, Eliem Therapeutics, Ono Pharmaceuticals, and Scilex, and receiving grants from AbbVie, Aptinyx, Otsuka, Swing Therapeutics (principal investigator for the clinical investigation presented in this manuscript), Teva Pharmaceuticals, Tonix Pharmaceuticals, and Virios Therapeutics. JVL reports receiving a grant from Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública., (Copyright © Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Diffuse gliomas are managed with radiation and temozolomide; however, this therapy often results in hematologic toxicities. Patients undergoing chemoradiation also risk contracting Pneumocystis jirovecii pneumonia (PJP), and frequently receive prophylaxis against PJP during treatment. Independent of chemoradiation, some PJP prophylaxis drugs have the potential to cause myelosuppression, which could require cessation of chemotherapy. Here, we evaluate differences in the frequency of hematologic toxicities during chemoradiation when patients receive PJP prophylaxis., Methods: This retrospective chart review evaluated patients with primary brain tumors treated with radiation and concurrent temozolomide. Analyses were performed to assess the effect of the type of PJP prophylaxis on risk for neutropenia, lymphopenia, or thrombocytopenia and the severity of these adverse effects as defined using the Common Terminology Criteria for Adverse Events., Results: Of the 217 patients included in this analysis, 144 received trimethoprim-sulfamethoxazole (TMP/SMX) and 69 received pentamidine. Of the patients who received TMP/SMX, 15.3% developed an absolute neutrophil count < 1500 cells/µL compared with 7.2% of patients receiving pentamidine (p = 0.10). Platelet count < 100,000/µL occurred in 18.1% of patients who received TMP/SMX and 20.3% of patients who received pentamidine (p = 0.70). No significant differences in lymphocyte counts between therapies were seen. Severity of hematologic toxicities were similar between PJP prophylaxis groups., Conclusion: These findings suggest that the type of PJP prophylaxis does not significantly affect the risk for hematologic toxicity in brain tumor patients receiving radiation and temozolomide. Additional studies are merited to evaluate the higher rate of neutropenia in patients on TMP/SMX observed in this study., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although empirically validated for fibromyalgia (FM), cognitive and behavioral therapies, including Acceptance and Commitment Therapy (ACT), are inaccessible to many patients. A self-guided, smartphone-based ACT program would significantly improve accessibility. The SMART-FM study assessed the feasibility of conducting a predominantly virtual clinical trial in an FM population in addition to evaluating preliminary evidence for the safety and efficacy of a digital ACT program for FM (FM-ACT). Sixty-seven patients with FM were randomized to 12 weeks of FM-ACT (n = 39) or digital symptom tracking (FM-ST; n = 28). The study population was 98.5% female, with an average age of 53 years and an average baseline FM symptom severity score of 8 out of 11. Endpoints included the Fibromyalgia Impact Questionnaire-Revised (FIQ-R) and the Patient Global Impression of Change (PGIC). The between-arm effect size for the change from baseline to Week 12 in FIQ-R total scores was d = 0.44 (least-squares mean difference, - 5.7; SE, 3.16; 95% CI, - 11.9 to 0.6; P = .074). At Week 12, 73.0% of FM-ACT participants reported improvement on the PGIC versus 22.2% of FM-ST participants (P < .001). FM-ACT demonstrated improved outcomes compared to FM-ST, with high engagement and low attrition in both arms. Retrospectively registered at ClinicalTrials.gov (NCT05005351) on August 13, 2021., (© 2023. The Author(s).)

Objective: To evaluate the efficacy and safety of TNX-102 SL, a once-nightly sublingual formulation of cyclobenzaprine, in reducing pain in patients with fibromyalgia (FM)., Methods: RELIEF was a double-blind, randomized, placebo-controlled trial. Overall, 503 patients received TNX-102 SL 2.8 mg for 2 weeks, followed by 5.6 mg for 12 weeks (248 patients), or matching placebo (255 patients). The primary end point was change from baseline at week 14 in the weekly average of daily pain scores. Secondary end points included Patient Global Impression of Change (PGIC) scores, Fibromyalgia Impact Questionnaire Revised (FIQR) scores, Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance and Fatigue scores, and daily sleep quality. Safety was assessed by adverse event (AE) reporting., Results: Reduction in daily pain from baseline at week 14 was significantly greater with TNX-102 SL (least squares [LS] mean change -1.9 [95% confidence interval (95% CI) -2.1, -1.7]) versus placebo (LS mean change -1.5 [95% CI -1.7, -1.3]; P = 0.01). TNX-102 SL was not associated with significant improvement in PGIC at week 14 but was associated with improvements in FIQR scores, PROMIS scores, and daily sleep quality. Overall, 59.7% of patients receiving TNX-102 SL and 46.3% receiving placebo reported treatment-emergent AEs; the most common were oral hypoesthesia (17.3% with TNX-102 SL versus 0.4% with placebo), oral paresthesia (5.6% versus 0.4%, respectively), and product taste abnormal (4.4% versus 0.4%, respectively)., Conclusion: In this phase III, randomized, controlled trial of patients with FM, treatment with TNX-102 SL was associated with significant reductions in daily pain and was safe and well tolerated., (© 2023 Tonix Pharmaceuticals Holding Corp and The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Because they are difficult to culture, obtaining genomic information from Leptospira spp. is challenging, hindering the overall understanding of leptospirosis. We designed and validated a culture-independent DNA capture and enrichment system for obtaining Leptospira genomic information from complex human and animal samples. It can be utilized with a variety of complex sample types and diverse species as it was designed using the pan-genome of all known pathogenic Leptospira spp. This system significantly increases the proportion of Leptospira DNA contained within DNA extracts obtained from complex samples, oftentimes reaching >95% even when some estimated starting proportions were <1%. Sequencing enriched extracts results in genomic coverage similar to sequenced isolates, thereby enabling enriched complex extracts to be analyzed together with whole genome sequences from isolates, which facilitates robust species identification and high-resolution genotyping. The system is flexible and can be readily updated when new genomic information becomes available. Implementation of this DNA capture and enrichment system will improve efforts to obtain genomic data from unculturable Leptospira -positive human and animal samples. This, in turn, will lead to a better understanding of the overall genomic diversity and gene content of Leptospira spp. that cause leptospirosis, aiding epidemiology and the development of improved diagnostics and vaccines.

Purpose: To address gender inequality, the American Society of Health-System Pharmacists (ASHP) created a steering committee that recommended the collection of baseline and ongoing metrics of pharmacy leadership. The purpose of this study was to quantify gender inequality in distributions of residency program director (RPD) and director of pharmacy (DOP) positions and to investigate gender distributions among recipients of ASHP professional leadership awards., Methods: RPD and DOP information for postgraduate year 1 (PGY1) programs included in the online ASHP residency directory were collected in December of 2020. Publicly available records were used to collect information on recipients of the Harvey A.K. Whitney Award and John W. Webb Award during the periods 1950-2020 and 1985-2020, respectively. Gender information for RPDs, DOPs, and award recipients was collected from listed pronouns available in public records. A χ 2 test was used for analysis of the collected data., Results: A total of 1,176 PGY1 residency programs were included. Of the RPD positions assessed, 66% (n = 775) were filled by women pharmacists (P < 0.0001), while the percentage of DOP leadership positions held by women was 42% (n = 496) (P < 0.0001). Evaluation of data on recipients of the Harvey A.K. Whitney Award and John W. Webb Award revealed the occurrence of female recipients is 19.7% (n = 14) and 16.7% (n = 6), respectively (P < 0.0001)., Conclusion: RPD positions have a higher prevalence of being filled by women. DOP positions remain male-dominated and revealed gender inequality among senior-level leadership roles. Pharmacy leadership award analysis identified further gender inequality. The results from the study serve as a baseline of current gender metrics for pharmacy leaderships in hospital systems with PGY1 residency programs., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cumulative effects assessments are often expected to include an analysis of cumulative social effects to people, their communities, and livelihoods caused by resource development projects and land use activities. Understanding cumulative social effects is important for decisions about prospective resource development projects, but there has been limited attention devoted to how to complete such an assessment. This paper critically examines how cumulative effects frameworks are applied to social impacts during environmental assessments. We do this by analyzing semi-structured interviews exploring practitioner experience in environmental assessments for hydroelectric development in British Columbia and Manitoba, Canada. The results provide a conceptual framework for cumulative social effects and illustrate how identified challenges for cumulative effects assessment are exacerbated by social impacts that introduce additional complexities in impact identification, assessment, and decision-making. The paper concludes with a discussion of how these challenges can be addressed and recommendations for improving environmental assessment practice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This systematic review was designed to evaluate the presence of comorbid conditions among patients with temporomandibular disorders (TMDs)., Types of Studies Reviewed: The authors reviewed studies that reported the prevalence or incidence of chronic pain conditions or psychiatric disorders (anxiety, mood, personality disorders) among patients with any type of TMD. The authors calculated sample size-weighted prevalence estimates when data were reported in 2 or more studies for the same comorbid condition., Results: A total of 9 prevalence studies and no incidence studies were eligible for review; 8 of the studies examined chronic pain comorbidities. Weighted estimates showed high prevalence of pain comorbidities across studies, including current chronic back pain (66%), myofascial syndrome (50%), chronic stomach pain (50%), chronic migraine headache (40%), irritable bowel syndrome (19%), and fibromyalgia (14%). A single study examined psychiatric disorders and found that current depression was the most prevalent disorder identified (17.5%)., Conclusions and Practical Implications: There is a high prevalence of comorbid chronic pain conditions among patients with TMDs, with more than 50% of patients reporting chronic back pain, myofascial syndrome, and chronic stomach pain. Psychiatric disorders among patients with different types of TMDs were studied less commonly in this pain population. Knowledge of the distribution of these and other comorbid disease conditions among patients with different types of TMDs can help dentists and other health care providers to identify personalized treatment strategies, including the coordination of care across medical specialties., (Copyright © 2022 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Respiratory failure in Guillain-Barre syndrome (GBS) is common. Forced vital capacity (FVC) is the gold standard for monitoring respiratory muscle strength in GBS. In some clinical situations, FVC testing could be delayed or unavailable, thus there is a need for accurate, fast, and device-free bedside respiratory evaluation., Methods: We examined neck flexion strength in 23 GBS patients as a possible predictor of the need for subsequent intubation and as a predictor of FVC change., Results: Intubation was required by 100% of patients with neck flexion strength of Medical Research Council grade ≤3. A correlation between neck flexion strength and FVC could not be determined., Conclusions: Significant weakness of neck flexion (Medical Research Council grade ≤3) at the time of admission correlates with poor respiratory status as measured by the need for intubation in patients with GBS., Competing Interests: M. K. Hehir has consulted for Alexion, Argenx, and CSL Behring. N. Kolb has consulted for and been member of the Steering Committee for Disarm Therapeutics and has consulted for Alexion Pharmaceuticals. R. Tandan is an Advisory Board Member for Alexion Pharmaceuticals and has received funding from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Argenx, Inc, Dartmouth Hitchcock Medical Center, Grifols Inc., Mitsubishi Tanabe Inc., and the National ALS Association. The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Fibromyalgia (FM) is a chronic widespread pain condition that overlaps with multiple comorbid health conditions and contributes to considerable patient distress. The aim of this review was to provide a systematic overview of psychiatric and chronic pain comorbidities among patients diagnosed with FM and to inform the development of recommendations for the design of clinical trials. Thirty-one, cross-sectional, clinical epidemiology studies that evaluated patients diagnosed with FM were included for review. None of the reviewed studies reported on the incidence of these comorbidities. Sample size-weighted prevalence estimates were calculated when prevalence data were reported in 2 or more studies for the same comorbid condition. The most prevalent comorbidity across all studies reviewed was depression/major depressive disorder (MDD) with over half of the patients included having this diagnosis in their lifetime (weighted prevalence up to 63%). In addition, nearly one-third of FM patients examined had current or lifetime bipolar disorder, panic disorder, or post-traumatic stress disorder. Less common psychiatric disorders reported included generalized anxiety disorder, obsessive compulsive disorder, and specific phobias (agoraphobia, social phobia). There were fewer studies that examined chronic pain comorbidities among FM patients, but when evaluated, prevalence was also high ranging from 39% to 76% (i.e., chronic tension-type or migraine headache, irritable bowel syndrome, myofascial pain syndrome, and temporomandibular disorders). The results of the review suggest that depression and chronic pain conditions involving head/jaw pain and IBS were elevated among FM patients compared to other conditions in the clinic-based studies. In contrast, anxiety-related disorders were much less common. Addressing the presence of these comorbid health conditions in clinical trials of treatments for FM would increase the generalizability and real-world applicability of FM research., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To investigate the efficacy and safety of mirogabalin, an α 2 δ ligand, in patients with fibromyalgia (FM). Methods: In three 13-week, multicenter, double-blind, phase 3 studies (studies A, B, and C), patients with FM ( n  = 1293, 1270, and 1301, respectively) were randomized (1:1:1:1) to placebo, pregabalin 150 mg twice daily, mirogabalin 15 mg once daily or mirogabalin 15 mg twice daily. The primary endpoint was the change in weekly average daily worst pain score (ADPS) at week 13. Key secondary endpoints included Patient Global Impression of Change and change in the Fibromyalgia Impact Questionnaire total score. Long-term safety of mirogabalin was assessed in a 52-week extension study. Results: Neither mirogabalin dose demonstrated a significant ADPS reduction from baseline vs. placebo at week 13 in any of the three studies. Pregabalin significantly reduced ADPS from baseline vs. placebo in studies B and C ( p  = .0008 and .0001, respectively). The effect of mirogabalin compared with placebo on key secondary endpoints was variable across the studies. Mirogabalin was well tolerated by most patients in the phase 3 studies; no unexpected adverse events occurring during the 52-week extension study. Conclusion: While both mirogabalin doses were well tolerated by most patients and showed potential for reducing pain associated with FM, the primary endpoint of significant pain reduction in patients on mirogabalin compared with placebo was not achieved in any of the three randomized controlled studies. Clinical trial registration: NCT02146430; NCT02187159; NCT02187471; and NCT02234583 (extension study).

Fibromyalgia (FM) is a common chronic pain disorder that presents diagnostic challenges for clinicians. Several classification, diagnostic and screening criteria have been developed over the years, but there continues to be a need to develop criteria that reflect the current understanding of FM and are practical for use by clinicians and researchers. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA) and the American Pain Society (APS) initiated the ACTTION-APS Pain Taxonomy (AAPT) to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders. The AAPT established an international FM working group consisting of clinicians and researchers with expertise in FM to generate core diagnostic criteria for FM and apply the multidimensional diagnostic framework adopted by AAPT to FM. The process for developing the AAPT criteria and dimensions included literature reviews and synthesis, consensus discussions, and analyses of data from large population-based studies conducted in the United Kingdom. The FM working group established a revised diagnosis of FM and identified risk factors, course, prognosis, and pathophysiology of FM. Future studies will assess the criteria for feasibility, reliability, and validity. Revisions of the dimensions will also be required as research advances our understanding of FM. PERSPECTIVE: The ACTTION-APS FM taxonomy provides an evidence-based diagnostic system for FM. The taxonomy includes diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms. This approach might improve the recognition of FM in clinical practice., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Currently, there are no medications approved for the treatment of juvenile fibromyalgia (JFM). We evaluated the safety and efficacy of duloxetine 30/60 mg once daily (QD) versus placebo in adolescents with JFM., Methods: In this Phase 3b, multisite (US, Argentina, Puerto Rico, and India) trial, patients aged 13-17 years with JFM and a score of ≥4 on the Brief Pain Inventory-Modified Short Form: Adolescent Version (BPI) 24-h average pain severity score were randomized to duloxetine or placebo for the 13-week double-blind period. The starting duloxetine dose was 30 mg, with a target dose of 60 mg QD, as tolerated. The primary endpoint was the mean change in 24-h average pain severity of the Brief Pain Inventory (BPI) from baseline to Week 13, analyzed using mixed-model repeated measures (MMRM) technique. Secondary measures were BPI severity and interference scores; treatment response (≥30%, ≥50% reductions on BPI average pain severity); Pediatric Pain Questionnaire; Clinical Global Impression of Severity: Overall and Mental Illness scales; Functional Disability Inventory: child and parent versions; Children's Depression Inventory; Multidimensional Anxiety Scale for Children; and safety and tolerability. Continuous secondary efficacy measures were analyzed using analysis of covariance or MMRM, and categorical data using Cochran-Mantel-Haenszel test and Fisher's exact test, where appropriate., Results: A total of 184 patients with JFM received duloxetine (N = 91) or placebo (N = 93), of which 149 patients (81.0%) completed the 13-week double-blind treatment period. Baseline characteristics were comparable between groups; majority of the patients were Caucasian (77.17%) and females (75.0%), with a mean age of 15.53 years. For the primary measure, BPI average pain severity, the mean change was not statistically different between duloxetine and placebo (- 1.62 vs. -0.97, respectively; p = .052). For secondary efficacy outcomes, statistically significantly more duloxetine- versus placebo-treated patients had a treatment response (≥30% and ≥50% reductions on BPI average pain severity) and improvement of the general activity and relationships items on the BPI interference subscale. The percentage of patients reporting at least 1 treatment-emergent adverse event was higher in the duloxetine versus placebo groups (82.42% vs. 62.37%, respectively; p = .003). The overall safety profile of duloxetine in this study was similar to that reported previously in duloxetine pediatric trials of other indications., Conclusions: The primary study outcome, mean change in 24-h BPI average pain severity rating from baseline to Week 13, did not significantly improve with duloxetine compared to placebo in patients with JFM. However, significantly more patients on duloxetine compared to placebo had a ≥30% and ≥50% reduction in pain severity. There were no new safety concerns related to duloxetine in the study population., Trial Registration: ClinicalTrials.gov Identifier: NCT01237587 . Registered 08 November, /2010.

Atrial fibrillation (AF) is the most common arrhythmia worldwide and is associated with significant morbidity and mortality. A number of risk factors have been associated with AF, though few studies have explored the association between gastrointestinal and liver diseases and AF. Additionally, AF and treatment for AF may predispose to gastrointestinal and liver diseases. We review the current literature on the bidirectional associations between gastrointestinal and liver diseases and AF. We highlight the gaps in knowledge and areas requiring future investigation., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Juvenile-onset fibromyalgia (JFM) is typically diagnosed in adolescence and characterized by widespread pain and marked functional impairment. The long-term impact of JFM into adulthood is poorly understood. The objectives of this study were to describe physical and psychosocial outcomes of youth diagnosed with JFM in early adulthood (∼8-year follow-up), examine longitudinal trajectories of pain and depressive symptoms from adolescence to young adulthood, and examine the impact of pain and depressive symptoms on physical functioning over time. Participants were 97 youth with JFM enrolled in a prospective longitudinal study in which pain symptoms, and physical and psychosocial functioning were assessed at 4 time points over approximately 8 years. At the time 4 follow-up (Mage = 24.2 years), the majority continued to suffer from pain and impairment in physical, social, and psychological domains. However, trajectories of pain and emotional symptoms showed varying patterns. Longitudinal analysis using growth mixture modeling revealed 2 pain trajectories (Steady Improvement and Rapid Rebounding Improvement), whereas depressive symptoms followed 3 distinct trajectories (Low-Stable, Improving, and Worsening). Membership in the Worsening Depressive symptoms group was associated with poorer physical functioning over time (P < 0.001) compared with the Low-Stable and Improving groups. This study offers evidence that although JFM symptoms persist for most individuals, pain severity tends to decrease over time. However, depressive symptoms follow distinct trajectories that indicate subgroups of JFM. In particular, JFM patients with worsening depressive symptoms showed decreasing physical functioning and may require more intensive and consistent intervention to prevent long-term disability.

Objectives: Pregabalin, an α2-δ agonist, is approved for the treatment of fibromyalgia (FM) in the United States, Japan, and 37 other countries. The purpose of this article was to provide an in-depth, evidence-based summary of pregabalin for FM as demonstrated in randomized, placebo-controlled clinical studies, including open-label extensions, meta-analyses, combination studies and post-hoc analyses of clinical study data., Methods: PubMed was searched using the term "pregabalin AND fibromyalgia" and the Cochrane Library with the term "pregabalin". Both searches were conducted on 2 March 2017 with no other date limits set., Results: Eleven randomized, double-blind, placebo-controlled clinical studies were identified including parallel group, two-way crossover and randomized withdrawal designs. One was a neuroimaging study. Five open-label extensions were also identified. Evidence of efficacy was demonstrated across the studies identified with significant and clinically relevant improvements in pain, sleep quality and patient status. The safety and tolerability profile of pregabalin is consistent across all the studies identified, including in adolescents, with dizziness and somnolence the most common adverse events reported. These efficacy and safety data are supported by meta-analyses (13 studies). Pregabalin in combination with other pharmacotherapies (7 studies) is also efficacious. Post-hoc analyses have demonstrated the onset of pregabalin efficacy as early as 1-2 days after starting treatment, examined the effect of pregabalin on other aspects of sleep beyond quality, and shown it is effective irrespective of the presence of a wide variety of patient demographic and clinical characteristics., Conclusions: Pregabalin is a treatment option for FM; its clinical utility has been comprehensively demonstrated.

Despite evidence of maternal age effects in a number of teleost species, there have been challenges to the assertion that maternal age intrinsically influences offspring quality. From an evolutionary perspective, maternal age effects result in young females paradoxically investing in less fit offspring despite a greater potential fitness benefit that might be gained by allocating this energy to individual somatic growth. Although a narrow range of conditions could lead to a maternal fitness benefit via the production of lower quality offspring, evolutionary theorists suggest these conditions are seldom met and that the reported maternal age effects are more likely products of the environmental context. Our goal was to determine if maternal effects operated on offspring provisioning in a long-lived rockfish (genus Sebastes ), and to evaluate any such effects as an intrinsic function of maternal age or a context-dependent effect of the offspring release environment. We found that offspring provisioning is a function of both maternal age and the timing of offspring release; older females exhibit increased provisioning over younger females throughout the spawning season despite a decrease in provisioning across all maternal ages as the season progresses. These findings suggest a role for both maternal age effects and a potential context-dependent maternal effect in population productivity, carrying important implications when modelling population persistence and resilience., Competing Interests: We have no competing interests.

Objectives: The pregabalin dose-response for pain, Patient Global Impression of Change (PGIC), and sleep quality measures in painful diabetic peripheral neuropathy (pDPN), postherpetic neuralgia (PHN), and fibromyalgia (FM) is relevant for physicians treating these patients. This analysis aimed to demonstrate the dose-response of pregabalin for each indication and describe the onset (incidence), onset/continuation (prevalence), and resolution of adverse events (AEs) occurring during treatment., Methods: Data from 14 placebo-controlled, fixed-dose pregabalin trials in pDPN, PHN, and FM were pooled within each indication. Patients had mean baseline pain scores ≥6 on an 11-point numeric rating scale. A hyperbolic E max dose-response model examined the dose-response of pregabalin for pain, PGIC, and sleep quality. Safety assessments included onset and prevalence of common AEs each week, and resolution in the first 2 months of treatment., Results: In all indications, the likelihood of patients experiencing pain relief and improvements in PGIC and sleep quality increased in a dose-dependent manner with increasing doses. In all indications, new incidences of dizziness and somnolence were highest after 1 week of treatment, with few subsequent new reports at a given dose. Prevalence rates decreased steadily after 1 week of treatment. In FM, new onset weight gain emerged 6-8 weeks following treatment; prevalence rates generally increased then remained steady over time. With the exception of weight gain, many AEs resolved in month 1., Conclusion: The dose-response of pregabalin for pain, PGIC, and sleep quality was demonstrated, highlighting the benefit of achieving the maximum recommended dose of 300 mg/day for pDPN, 300-600 mg/day for PHN, and 300-450 mg/day for FM. Common AEs are generally seen within 1 week of starting treatment, with few subsequent new reports at a given dose. New onset weight gain occurs after 6 weeks of treatment, reinforcing the need for regular monitoring of weight.

Objective: To examine the differential presentation(s) of psychological and health-related outcomes in young adults with juvenile-onset fibromyalgia (FM) with and without a history of trauma, compared to healthy controls., Methods: In total, 110 participants (86 with juvenile-onset FM and 24 healthy controls, with a mean age of 23.4 years) completed a structured clinical interview to assess for trauma and psychological comorbidities, as well as self-report questionnaires on pain, physical functioning, and health care utilization., Results: Of the juvenile-onset FM participants, 37% (n = 32) reported a history of trauma. Three group comparisons (i.e., juvenile-onset FM with trauma versus juvenile-onset FM with no trauma versus healthy controls) revealed that juvenile-onset FM participants significantly differed from healthy controls on all psychological and health-related outcomes. Further, although juvenile-onset FM participants with and without a history of trauma did not significantly differ on pain and physical functioning, juvenile-onset FM participants with a history of trauma were significantly more likely to have psychological comorbidities., Conclusion: This is the first controlled study to examine the differential outcomes between juvenile-onset FM participants with and without a history of trauma. Group comparisons between juvenile-onset FM participants and healthy controls were consistent with previous research. Further, our findings indicate that juvenile-onset FM participants with a history of trauma experience greater psychological, but not physical, impairment than juvenile-onset FM participants without a history of trauma., (© 2017, American College of Rheumatology.)

The current diagnostic and treatment pathway for patients with fibromyalgia (FM) is lengthy, complex, and characterized by multiple physician visits with an average 2-year wait until diagnosis. It is clear that effective identification and appropriate treatment of FM remain a challenge in current clinical practice. Ideally, FM management involves a multidisciplinary approach with the preferable patient pathway originating in primary care but supported by a range of health care providers, including referral to specialist care when necessary. After the publication of individual clinical studies, high-quality reviews, and meta-analyses, recently published FM treatment guidelines have transitioned from an expert consensus to an evidence-based approach. Evidence-based guidelines provide a framework for ensuring early diagnosis and timely adoption of appropriate treatment. However, for successful outcomes, FM treatments must adopt a more holistic approach, which addresses more than just pain. Impact on the associated symptoms of fatigue and cognitive problems, sleep and mood disturbances, and lowered functional status are also important in judging the success of FM therapy. Recently published guidelines recommend the adoption of a symptom-based approach to guide pharmacologic treatment. Emerging treatment options for FM may be best differentiated on the basis of their effect on comorbid symptoms that are often associated with pain (e.g. sleep disturbance, mood, fatigue). The current review discusses the most recently published Canadian guidelines and the implications of the recent European League Against Rheumatism (EULAR) recommendations, with a focus on the challenges of implementing these guidelines in current clinical practice.

Objective: While hyperglycemia in the postoperative setting has been linked to an increase in surgical complications, limited data are available to inform the management of patients with diabetes in the operating room and the immediate peri-operative period. We describe the results of a peri-operative glycemic control program that standardized intravenous insulin with a target glucose (BG) range of 120 to 180 mg/dL for patients with diabetes presenting with a BG level >180 mg/dL and included transition to subcutaneous insulin., Methods: Patients with known diabetes and a BG >180 mg/dL who underwent surgery were included. The control group included 260 patients from March 2, 2008 through December 31, 2008. The intervention group included 588 patients following protocol implementation from April 1, 2009 through December 31, 2012. Data included demographic information, hospital BG values, length of stay (LOS), mortality, and wound infections., Results: The intervention group had significantly lower BG on arrival in the postoperative care unit (182.2 vs 194.9 mg/dL, P = .012). Mean BG during the first 24 hours after surgery was lower in the intervention group (182.1 vs. 190.5 mg/dL), and there were fewer BG values >200 mg/dL in the intervention group (P = .005). The percentage of BG values <70 mg/dL during the hospital stay was lower in the intervention group (1.94 vs. 2.43%, P<.01). There was no significant difference in mortality, LOS, or wound infections., Conclusion: Following implementation of a hospital-wide peri-operative glycemic control algorithm, we found a reduction in peri-operative BG levels and hypoglycemia rates. Ongoing research is needed to assess the impact on clinical outcomes., Abbreviations: BG = blood glucose CCI = Charlson comorbidity index EHR = electronic health record ICD-9 = International Classification of Disease-9 IV = intravenous LOS = length of stay OR = operating room PACU = postoperative care unit POC = point-of-care.

A farm-level stochastic model was used to estimate costs of 7 common clinical diseases in the United States: mastitis, lameness, metritis, retained placenta, left-displaced abomasum, ketosis, and hypocalcemia. The total disease costs were divided into 7 categories: veterinary and treatment, producer labor, milk loss, discarded milk, culling cost, extended days open, and on-farm death. A Monte Carlo simulation with 5,000 iterations was applied to the model to account for inherent system variation. Four types of market prices (milk, feed, slaughter, and replacement cow) and 3 herd-performance factors (rolling herd average, product of heat detection rate and conception rate, and age at first calving) were modeled stochastically. Sensitivity analyses were conducted to study the relationship between total disease costs and selected stochastic factors. In general, the disease costs in multiparous cows were greater than in primiparous cows. Left-displaced abomasum had the greatest estimated total costs in all parities ($432.48 in primiparous cows and $639.51 in multiparous cows). Cost category contributions varied for different diseases and parities. Milk production loss and treatment cost were the 2 greatest cost categories. The effect of market prices were consistent in all diseases and parities; higher milk and replacement prices increased total costs, whereas greater feed and slaughter prices decreased disease costs., (Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Objective: Hypoglycemia remains one of the main challenges of insulin therapy. To reduce insulin-related hypoglycemia at our institution, we restricted inpatient ordering of high glargine doses (≥0.5 U/kg/day) to endocrine staff in May 2013. This retrospective cohort study assesses its effect on hypoglycemia and glycemic control within 48 hours of admission (ADM)., Methods: We identified 692 adult patients hospitalized at Boston Medical Center who received glargine upon ADM from November 1, 2012 through April 30, 2013 as the pre-intervention group, and 651 adult patients admitted between November 1, 2013 and April 30, 2014 as the postintervention group. Demographics, medical history, home insulin regimen, concurrent oral diabetes medications or glucocorticoid administration, ADM serum creatinine, all blood glucose levels (BG) ≤48 hours of ADM, and hemoglobin A1c values ≤3 months were assessed. Hypoglycemia was defined as BG ≤70 mg/dL, and hyperglycemia as BG ≥200 mg/dL. Multivariable regression models assessed potential associations between covariates and incidence of hypoglycemia and average BG ≤48 hours of ADM., Results: Demographics were similar between groups. Significantly less patients received high-dose glargine in the post-intervention group (5.2% vs. 0.3%, P<.001). Incidences of hypoglycemia were significantly lower in the postintervention group (20.9% vs. 17.8%, P<.001 per ADM; 3.4% vs. 2.3%, P = .001 per BG measurements [BGM]). Mean BG levels ≤48 hours of ADM and incidence of hyperglycemia were not significantly different. The adjusted incident rate ratio of hypoglycemia was 0.63 per ADM and 0.74 per BGM in the postintervention group compared to the pre-intervention group (P = .001 and P = .063, respectively)., Conclusion: We found that implementation of a restriction on high doses of glargine resulted in lower rates of hypoglycemia without worsening glycemic control., Abbreviations: ADM = admission BG = blood glucose BGM = blood glucose measurements BMC = Boston Medical Center BMI = body mass index EMR = electronic medical record HgbA1c = hemoglobin A1c IRR = incidence rate ratio NPH = neutral protamine Hagedorn TDD = total daily dose T2D = type 2 diabetes.