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Felicia Forma,1 Tyler G Knight,2 Frances P Thorndike,1 Xiaorui Xiong,1 Rebecca Baik,2 Fulton F Velez,1 Yuri A Maricich,1 Daniel C Malone3 1Pear Therapeutics, Inc., Medical Affairs Department, Boston, MA, USA; 2Labcorp Drug Development, Market Access Consulting Department, Gaithersburg, MD, USA; 3Strategic Therapeutics, LLC, Oro Valley, AZ, USACorrespondence: Felicia Forma, Pear Therapeutics, Medical Affairs Department, 200 State St, Boston, MA, 02109, USA, Email felicia.forma@peartherapeutics.comBackground and Objectives: This analysis evaluated insomnia severity and long-term impact on healthcare resource utilization (HCRU) and costs after treatment with Somryst® (previously called SHUTi), a digital therapeutic delivering cognitive behavioral therapy for insomnia (CBT-I).Methods: Change from baseline in insomnia severity index (ISI) score was assessed using last observed ISI score. A pre/post analysis of claims data was conducted, comparing HCRU in patients with self-identified sleep problems who successfully initiated the therapeutic (index date) between June 1, 2016 and December 31, 2018.Results: A total of 248 patients were analyzed (median age 56.5 years, 57.3% female, mean ISI score 19.13, 52.4% treated with sleep aid medications pre-index). After 9 weeks, mean ISI score declined by 37.2% from baseline (19.1 vs 12.0), 58.8% of patients achieved ISI responder status (ISI score improved by => 7; NNT: 1.7), and 26.6% of patients achieved insomnia remission (ISI score < 8; NNT for remission: 3.8). After two-year follow-up, post-index events were reduced (compared to 2 years pre-index) for emergency department visits (− 53%; IRR: 0.47; 95% CI 0.27, 0.82; P=0.008), hospiatizations (-21%; IRR: 0.79; 95% CI 0.46, 1.35; P=0.389) and hospital outpatient visits (− 13%; IRR: 0.87; 95% CI 0.66, 1.14; P=0.315). Slightly increased rates were observed for ambulatory surgical center visits (2%; IRR: 1.02; 95% CI 0.73, 1.44; P=0.903) and office visits (2%; IRR: 1.02; 95% CI 0.92, 1.14; P=0.672). The number of patients treated with sleep aid medications dropped 18.5% (52.4% pre-index vs 42.7% post-index). Average number of prescriptions decreased from 3.98 pre-index to 3.73 post-index (P= 0.552). Total two-year cost reduction post-index vs pre-index was $510,678, or -$2059 per patient.Conclusion: In a real-world cohort of patients with chronic insomnia, treatment with a digital therapeutic delivering CBT-I was associated with reductions in insomnia severity, emergency department visits, and net costs.Keywords: CBT-I, cognitive behavioral therapy for insomnia, chronic insomnia, prescription digital therapeutic, SHUTi, Somryst

Alesia Sadosky,1 Caroline Schaefer,2 Rachael Mann,3 Felicia Bergstrom,2 Rebecca Baik,2 Bruce Parsons,1 Srinivas Nalamachu,4 Edward Nieshoff,5 Brett R Stacey,6 Alan Anschel,7 Michael Tuchman81Pfizer Inc, New York, NY, 2Covance Market Access Services Inc, Gaithersburg, MD, 3Covance Market Access Services Inc, San Diego, CA, 4International Clinical Research Institute, Overland Park, KS, 5Rehabilitation Institute of Michigan/Wayne State University, Detroit, MI, 6Oregon Health and Science University, Portland, OR, 7Rehabilitation Institute of Chicago, Chicago, IL, 8Palm Beach Neurological Center, Palm Beach Gardens, FL, USABackground: The purpose of this study was to characterize the burden of illness among adult subjects with painful diabetic peripheral neuropathy (pDPN) seeking treatment in the US.Methods: This observational study recruited 112 subjects with pDPN during routine visits from general practitioner and specialist sites. Subjects completed a one-time questionnaire, which included demographics, symptom duration, health care resource use, out-of-pocket costs, employment status, and validated measures that assessed pain, functioning, sleep, anxiety and depression, health status, and productivity. Investigators completed a case report form based on a 6-month retrospective chart review to capture clinical information, pDPN-related treatments, and other pDPN-related health care resource use over the past 6 months. Annualized costs were extrapolated based on reported 6-month health care resource use.Results: The mean age of the subjects was 61.1 years, 52.7% were female, and 17.9% were in paid employment. The most common comorbid conditions were sleep disturbance/insomnia (43.8%), depressive symptoms (41.1%), and anxiety (35.7%). The mean pain severity score was 5.2 (0–10 scale), and 79.5% reported moderate or severe pain. The mean pain interference with function score was 5.0 (0–10 scale) overall, with 2.0 among mild, 5.1 among moderate, and 7.0 among severe. The mean Medical Outcomes Study sleep problems index score was 48.5 (0–100 scale). The mean health state utility score was 0.61. Among subjects employed for pay, mean overall work impairment was 43.6%. Across all subjects, mean overall activity impairment was 52.3%. In total, 81.3% were prescribed at least one medication for their pDPN; 50.9% reported taking at least one nonprescription medication. Adjusted mean annualized total direct and indirect costs per subject were $4841 and $9730, respectively. Outcomes related to pain interference with function, sleep, health status, activity impairment, prescription medication use, and direct and indirect costs were significantly worse among subjects with more severe pain (P < 0.0020).Conclusion: Subjects with pDPN exhibited high pain levels, which were associated with poor sleep, function, and productivity. Health care resource utilization in pDPN was prevalent and costs increased with greater pain severity. The burden of pDPN was greater among subjects with greater pain severity.Keywords: painful diabetic peripheral neuropathy, pain assessment, burden of illness, quality of life, treatment patterns, health care resource use, costs, productivity

Abstract Background Fibromyalgia (FM) is characterized by chronic, widespread pain, fatigue, and other symptoms; yet few studies have comprehensively assessed its humanistic burden. This observational study evaluates the impact of FM severity on patients' symptoms, health-related quality of life (HRQoL), and productivity in the United States. Methods 203 FM subjects were recruited from 20 physician offices. Subjects completed a questionnaire including the EuroQol 5D (EQ-5D), Fibromyalgia Impact Questionnaire (FIQ), Multidimensional Assessment of Fatigue (MAF), Medical Outcomes Study Sleep Scale (MOS-SS), and Hospital Anxiety and Depression Scale (HADS) and questions about demographics, pain and other symptoms, HRQoL and productivity. FIQ total scores were used to define FM severity, with 0- < 39, 39- < 59, and 59-100, representing mild, moderate, and severe FM, respectively. Sites recorded subjects' clinical characteristics and FM treatment on case report forms using medical records. Summary statistics were calculated for continuous variables and frequency distributions for categorical variables. Differences across FM severity groups were evaluated using the Kruskal-Wallis or Chi-square tests. Statistical significance was evaluated at the 0.05 level. Results Mean (SD) age was 47.9 (10.9); 95% were female. Most (92%) were prescribed medication for FM; 24% and 66% reported moderate and severe FM, respectively. Mean (SD) scores were: 6.3 (2.1) for pain intensity; 0.35 (0.35) for EQ-5D; 30.7 (14.2) for MAF; 57.5 (18.4) for MOS-SS Sleep Problems Index; 10.2 (4.8) for HADS anxiety and 9.4 (4.4) for HADS depression. Subjects with worse FM severity reported significantly increased pain severity, HRQoL, fatigue, sleep disturbance, anxiety and depression (p < 0.001). Overall, 50% of subjects reported some disruption in their employment due to FM; this differed across severity levels (p < 0.001). Employed subjects missed a mean (SD) of 1.8 (3.9) workdays during the past 4 weeks; this also differed across severity levels (p = 0.03). Conclusions FM imposes a substantial humanistic burden on patients in the United States, and leads to substantial productivity loss, despite treatment. This burden is higher among subjects with worse FM severity.

Genome editing by homology directed repair (HDR) is leveraged to precisely modify the genome of therapeutically relevant hematopoietic stem and progenitor cells (HSPCs). Here, we present a new approach to increasing the frequency of HDR in human HSPCs by the delivery of an inhibitor of 53BP1 (named "i53") as a recombinant peptide. We show that the use of i53 peptide effectively increases the frequency of HDR-mediated genome editing at a variety of therapeutically relevant loci in HSPCs as well as other primary human cell types. We show that incorporating the use of i53 recombinant protein allows high frequencies of HDR while lowering the amounts of AAV6 needed by 8-fold. HDR edited HSPCs were capable of long-term and bi-lineage hematopoietic reconstitution in NSG mice, suggesting that i53 recombinant protein might be safely integrated into the standard CRISPR/AAV6-mediated genome editing protocol to gain greater numbers of edited cells for transplantation of clinically meaningful cell populations., (© 2024. The Author(s).)

Background: Vitiligo is an autoimmune disorder that causes patchy loss of skin pigmentation. Up to 2.16% of pediatric patients may have vitiligo. This study estimated vitiligo point prevalence in children and adolescents (ages: 4-11 and 12-17 years) in the United States (US)., Methods: An online, population-based survey of a nationally representative sample of individuals based on 2017 US Census Bureau estimates for age, race, Hispanic origin, income, and geographic region was conducted from December 2019 to March 2020. Parent/legal guardian proxies responded on behalf of their children or adolescents to vitiligo screening questions. Proxy-reported vitiligo status was adjudicated by expert dermatologists who reviewed photographs of vitiligo lesions uploaded by proxies using a teledermatology application. Estimated point prevalence (including diagnosed and undiagnosed vitiligo and its subtypes) was calculated for proxy-reported and clinician-adjudicated vitiligo., Results: There were 9,118 eligible proxy responses (5,209 children, mean age 7.7 years; 3,909 adolescents, mean age 14.4 years). The proxy-reported vitiligo prevalence (95% confidence interval) for children and adolescents was 1.52% (1.11-1.93) and 2.16% (1.66-2.65), respectively. The clinician-adjudicated prevalence (sensitivity analysis bounds) was 0.84% (0.83-1.23) and 1.19% (1.18-1.74), respectively. Approximately 69% of children and 65% of adolescents had nonsegmental vitiligo (clinician adjudicated) and up to 50% may be undiagnosed., Conclusion: Based on the clinician-adjudicated prevalence estimates, there were more than 591,000 cases of vitiligo in children and adolescents in the US in 2020. More than two-thirds had nonsegmental vitiligo and nearly half may be undiagnosed. Future studies should confirm these findings., (© 2023 S. Karger AG, Basel.)

Purpose: This study sought to describe patient characteristics and treatment patterns among patients with insomnia prescribed trazodone in the United States., Methods: This real-world, retrospective, descriptive cohort study used US commercial insurance claims from July 1, 2009, through June 30, 2019. The index date was the first prescription for trazodone between January 1, 2010, and December 31, 2018, with 6 months for the preindex period and ≥6 months for the postindex period., Findings: Among 5.8 million patients with insomnia, 17.7% were prescribed trazodone, and 357,380 adults (6.2%) and 7564 children (0.1%) met the study eligibility criteria. The mean (SD) age was 48.8 (15.8) years for adults and 14.8 (2.7) years for pediatrics. Most patients were female (229,280 adults [64.2%] and 4481 children [59.2%]). Insomnia due to mental disorder was the most common specific diagnosis. The most common (>25%) comorbid conditions were anxiety, depression, and hypertensive disease, and 1 of 10 had a history of substance abuse. Zolpidem was previously prescribed (73,342 adults [20.5%] and 233 children [3.1%]) and continued to be prescribed. Concomitant antidepressants were most common (216,893 adults [60.7%] and 5414 children [71.6%]), but benzodiazepines (132,740 adults [37.1%] and 1188 children [15.7%]), antiepileptics (115,064 adults [32.2%] and 2103 children [27.8%]), nonbenzodiazepines (90,946 adults [25.4%] and 542 children [7.2%]), and antipsychotics (40,490 adults [11.3%] and 2063 children [27.3%]) were also prescribed., Implications: This study provides current evidence that trazodone use is widespread among patients with insomnia and is often associated with other specific comorbidities, such as psychiatric conditions. A deeper knowledge of the real-world management of patients with insomnia may facilitate steps toward improving sleep quality, daytime functioning, and clinical outcomes for patients., Competing Interests: Declaration of Competing Interest All authors have seen and approved the manuscript. This study was sponsored by Angelini Pharma S.p.A., of which I. Pochiero, M. Gorini, A. Comandini, F. Calisti, G. Di Loreto, and A. Cattaneo are employees. The study was conducted by Labcorp Drug Development, of which T. Knight, K.P. Anastassopoulos, R. Patel, and R. Baik are employees. O. Bruni is a consultant for Fidia Pharma., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: This study aimed to characterize current treatment patterns and healthcare resource utilization (HRU) observed among patients with hepatocellular carcinoma (HCC) after the failure of sorafenib in real-world setting in Taiwan., Methods: A chart review was conducted in 130 patients; the inclusion criteria were patients with HCC who were aged 20 years or older and had received systemic therapy or best supportive care after failure of first-line systemic treatment with sorafenib between 2016 and 2018. Anonymized data on patient characteristics, treatment pathways, and survival were abstracted., Results: The mean age of patients was 61.7 years (range 27-84); of these 130 patients, 103 (79%) were male, 81 (62%) had high alpha-fetoprotein (AFP) levels (≥400 ng/mL), and 96 (78.0%) were deceased at the time of data abstraction. After sorafenib therapy, 60 patients (46%) received systemic therapy, including nivolumab monotherapy (42%) and chemotherapy (25%). Oncologist visits at a semiannual per-patient rate of 3.7 (95% confidence interval [CI] 3.4-4.0) and hospitalizations at rate of 1.1 (95% CI 1.0-1.3) were the key contributors to HRU. Semiannual per-patient hospitalization rate was 1.3 (95% CI 1.1-1.5) in the high-AFP group. Median survival from discontinuation of sorafenib was 6.9 months (95% CI 5.9-9.0)., Conclusions: This real-world evidence research on treatment patterns reflected substantial HRU consistent with the severity of HCC, particularly in the high-AFP group. Findings highlighted continuing high mortality in HCC, underlying a need for new treatments that can lengthen survival. Results can inform future evaluations of new HCC treatments that estimate the health economic impact of their adoption in Taiwan., (Copyright © 2022 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Cystic fibrosis (CF) is a monogenic disease caused by impaired production and/or function of the CF transmembrane conductance regulator (CFTR) protein. Although we have previously shown correction of the most common pathogenic mutation, there are many other pathogenic mutations throughout the CF gene. An autologous airway stem cell therapy in which the CFTR cDNA is precisely inserted into the CFTR locus may enable the development of a durable cure for almost all CF patients, irrespective of the causal mutation. Here, we use CRISPR-Cas9 and two adeno-associated viruses (AAVs) carrying the two halves of the CFTR cDNA to sequentially insert the full CFTR cDNA along with a truncated CD19 (tCD19) enrichment tag in upper airway basal stem cells (UABCs) and human bronchial epithelial cells (HBECs). The modified cells were enriched to obtain 60%-80% tCD19 + UABCs and HBECs from 11 different CF donors with a variety of mutations. Differentiated epithelial monolayers cultured at air-liquid interface showed restored CFTR function that was >70% of the CFTR function in non-CF controls. Thus, our study enables the development of a therapy for almost all CF patients, including patients who cannot be treated using recently approved modulator therapies., Competing Interests: Declaration of interests M.H.P. has equity and serves on the Scientific Advisory Board of CRISPR Therapeutics and Graphite Bio. J.V.N. is a consultant with COOK Medical, which manufactures the pSIS graft. Neither company had any input on the design, execution, interpretation, or publication of the work in this manuscript., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Importance: Vitiligo can have profound effects on patients and is often associated with other autoimmune comorbid conditions. It is important to understand the current prevalence of vitiligo, including diagnosed, undiagnosed, and subtypes (nonsegmental and segmental)., Objective: To estimate the point prevalence of vitiligo in the US., Design, Setting, and Participants: For this population-based study of adults in the US, a cross-sectional online survey was administered between December 2019 and March 2020 to obtain participant self-reported vitiligo status. A representative sample of the US adult general population, aged 18 to 85 years, was recruited using a stratified proportional, sampling design from general population research panels. Additionally, 3 expert dermatologists adjudicated participants' self-reported vitiligo diagnosis by reviewing photographs uploaded by the participants using a teledermatology app designed and tested specifically for this study., Main Outcomes and Measures: The main outcomes were the point prevalence estimates of overall vitiligo, as well as diagnosed, undiagnosed, nonsegmental, and segmental vitiligo., Results: Among the 40 888 eligible adult participants, the mean (SD) age was 44.9 (17.4) years, 23 170 (56.7%) were female, 30 428 (74.4%) were White, and 4225 (10.3%) were of Hispanic, Latino, or Spanish origin. Self-reported vitiligo prevalence was 1.38% (95% CI, 1.26%-1.49%), with 0.77% (95% CI, 0.68%-0.85%) for diagnosed and 0.61% (95% CI, 0.54%-0.69%) for undiagnosed. Based on expert dermatologist review of 113 photographs of participants with self-reported vitiligo, clinician-adjudicated vitiligo prevalence (sensitivity bounds) was 0.76% (0.76%-1.11%), with 0.46% (0.46%-0.61%) for diagnosed and 0.29% (0.29%-0.50%) for undiagnosed. Self-reported nonsegmental vitiligo prevalence was 0.77% (95% CI, 0.68%-0.85%), with 0.48% (95% CI, 0.41%-0.55%) for diagnosed and 0.29% (95% CI, 0.23%-0.34%) for undiagnosed. Clinician-adjudicated nonsegmental vitiligo prevalence (sensitivity bounds) was 0.58% (0.57%-0.84%), with 0.37% (0.37%-0.49%) for diagnosed and 0.21% (0.20%-0.36%) for undiagnosed. Self-reported segmental vitiligo prevalence was 0.61% (95% CI, 0.53%-0.69%), with 0.28% (95% CI, 0.23%-0.33%) for diagnosed and 0.33% (95% CI, 0.27%-0.38%) for undiagnosed. Clinician-adjudicated segmental vitiligo prevalence (sensitivity bounds) was 0.18% (0.18%-0.27%), with 0.09% (0.09%-0.12%) for diagnosed and 0.08% (0.08%-0.15%) for undiagnosed., Conclusions and Relevance: Results of this survey study demonstrated that the current US population-based prevalence estimate of overall (diagnosed and undiagnosed combined) vitiligo in adults is between 0.76% (1.9 million cases in 2020) and 1.11% (2.8 million cases in 2020). Additionally, this study suggests that approximately 40% of adult vitiligo in the US may be undiagnosed. Future studies should be performed to confirm these findings.

Myeloproliferative neoplasms (MPNs) cause the over-production of blood cells such as erythrocytes (polycythemia vera) or platelets (essential thrombocytosis). JAK2 V617F is the most prevalent somatic mutation in many MPNs, but previous modeling of this mutation in mice relied on transgenic overexpression and resulted in diverse phenotypes that were in some cases attributed to expression level. CRISPR-Cas9 engineering offers new possibilities to model and potentially cure genetically encoded disorders via precise modification of the endogenous locus in primary cells. Here we develop "scarless" Cas9-based reagents to create and reverse the JAK2 V617F mutation in an immortalized human erythroid progenitor cell line (HUDEP-2), CD34+ adult human hematopoietic stem and progenitor cells (HSPCs), and immunophenotypic long-term hematopoietic stem cells (LT-HSCs). We find no overt in vitro increase in proliferation associated with an endogenous JAK2 V617F allele, but co-culture with wild type cells unmasks a competitive growth advantage provided by the mutation. Acquisition of the V617F allele also promotes terminal differentiation of erythroid progenitors, even in the absence of hematopoietic cytokine signaling. Taken together, these data are consistent with the gradually progressive manifestation of MPNs and reveals that endogenously acquired JAK2 V617F mutations may yield more subtle phenotypes as compared to transgenic overexpression models., Competing Interests: The authors would also like to declare that no competing interests exist.

CRISPR/Cas9-mediated beta-globin (HBB) gene correction of sickle cell disease (SCD) patient-derived hematopoietic stem cells (HSCs) in combination with autologous transplantation represents a recent paradigm in gene therapy. Although several Cas9-based HBB-correction approaches have been proposed, functional correction of in vivo erythropoiesis has not been investigated previously. Here, we use a humanized globin-cluster SCD mouse model to study Cas9-AAV6-mediated HBB-correction in functional HSCs within the context of autologous transplantation. We discover that long-term multipotent HSCs can be gene corrected ex vivo and stable hemoglobin-A production can be achieved in vivo from HBB-corrected HSCs following autologous transplantation. We observe a direct correlation between increased HBB-corrected myeloid chimerism and normalized in vivo red blood cell (RBC) features, but even low levels of chimerism resulted in robust hemoglobin-A levels. Moreover, this study offers a platform for gene editing of mouse HSCs for both basic and translational research.

Cystic fibrosis (CF) is a monogenic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Mortality in CF patients is mostly due to respiratory sequelae. Challenges with gene delivery have limited attempts to treat CF using in vivo gene therapy, and low correction levels have hindered ex vivo gene therapy efforts. We have used Cas9 and adeno-associated virus 6 to correct the ΔF508 mutation in readily accessible upper-airway basal stem cells (UABCs) obtained from CF patients. On average, we achieved 30%-50% allelic correction in UABCs and bronchial epithelial cells (HBECs) from 10 CF patients and observed 20%-50% CFTR function relative to non-CF controls in differentiated epithelia. Furthermore, we successfully embedded the corrected UABCs on an FDA-approved porcine small intestinal submucosal membrane (pSIS), and they retained differentiation capacity. This study supports further development of genetically corrected autologous airway stem cell transplant as a treatment for CF., Competing Interests: Declaration of Interests M.H.P. has equity and serves on the scientific advisory board of CRISPR Therapeutics. J.V.N. is a consultant with COOK Medical, which manufactures the pSIS graft. Neither company had any input on the design, execution, interpretation, or publication of the work in this manuscript., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To compare (1) complication and (2) conversion rates to open surgery (OS) from laparoscopic surgery (LS) and robotic-assisted surgery (RA) for rectal cancer patients who underwent rectal resection. (3) To identify patient, physician, and hospital predictors of conversion., Materials and Methods: A US-based database study was conducted utilizing the 2012-2014 Premier Healthcare Data, including rectal cancer patients ≥18 with rectal resection. ICD-9-CM diagnosis and procedural codes were utilized to identify surgical approaches, conversions to OS, and surgical complications. Propensity score matching on patient, surgeon, and hospital level characteristics was used to create comparable groups of RA\LS patients (n = 533 per group). Predictors of conversion from LS and RA to OS were identified with stepwise logistic regression in the unmatched sample., Results: Post-match results suggested comparable perioperative complication rates (RA 29% vs LS 29%; p = .7784); whereas conversion rates to OS were 12% for RA vs 29% for LS (p < .0001). Colorectal surgeons (RA 9% vs LS 23%), general surgeons (RA 13% vs LS 35%), and smaller bed-size hospitals (RA 14% vs LS 33%) have reduced conversion rates for RA vs LS (p < .0001). Statistically significant predictors of conversion included LS, non-colorectal surgeon, and smaller bed-size hospitals., Limitations: Retrospective observational study limitations apply. Analysis of the hospital administrative database was subject to the data captured in the database and the accuracy of coding. Propensity score matching limitations apply. RA and LS groups were balanced with respect to measured patient, surgeon, and hospital characteristics., Conclusions: Compared to LS, RA offers a higher probability of completing a successful minimally invasive surgery for rectal cancer patients undergoing rectal resection without exacerbating complications. Male, obese, or moderately-to-severely ill patients had higher conversion rates. While colorectal surgeons had lower conversion rates from RA than LS, the reduction was magnified for general surgeons and smaller bed-size hospitals.

Background: HIV-related neuropathic pain (HIV-NeP) is common; however, the burden of HIV-NeP is not well-understood., Methods: The cross-sectional study aimed to characterize the HIV-NeP burden. A total of 103 patients with HIV-NeP recruited during routine office visits completed a questionnaire to assess patient-reported outcomes, including pain severity, health status, sleep, mood, and lost productivity. Physicians completed a 6-month retrospective chart review., Results: The sample was predominantly male and not employed for pay. A majority (75.7%) of patients experienced moderate or severe pain. Pain interference, general health, physical health, and depression were worse among patients with more severe pain (all Ps < .006). Most (87.4%) patients were prescribed at least 1 medication for NeP. HIV-related neuropathic pain was associated with 36.1% work impairment. Adjusted annualized costs increased with increasing pain severity (P < .0001)., Conclusion: The impact of HIV-NeP on health status, physical function, and depression increases with severity, resulting in substantial clinical and economic burden., (© The Author(s) 2015.)

Perioperative blood loss during total hip arthroplasty (THA) increases patient morbidity, length of stay (LOS), medical resource use (MRU), and costs. Minimizing blood loss may reduce postoperative anemia, the need for blood transfusions, and the increased risk of infections and longer hospital stays associated with blood transfusions. Pharmacologic agents and bipolar sealer devices can minimize perioperative bleeding. A retrospective, comparative cohort study in the US hospital setting was conducted to assess MRU and associated costs and the incidence of transfusion and complications among patients undergoing THA with or without the use of a bipolar sealer. Using a nationwide all-payer hospital administrative database, THA procedures from January 1, 2008, to March 31, 2011, were identified using International Classification of Diseases, Ninth Revision, Clinical Modification procedure code 81.51. The bipolar sealer cohort (n=2683) and matched control cohort (n=2683) had a mean age of 65 years from 38 hospitals. The 2 groups had similar incidences of pre-operative anemia and medical comorbidities. Patients in the bipolar sealer group required significantly fewer blood transfusions (21.3% vs 23.8%; P=.0286) and had significantly lower incidence of hematomas (0.2% vs 0.9%; P=.0015) and significantly shorter LOS (2.90 vs 3.31 days; P<.0001) overall. The bipolar sealer group had higher supply costs, which were offset by reduced hospital inpatient room and board and operating room costs; there was no significant difference in total hospital costs between the 2 groups ($18,937 vs $18,734; P=.56). A bipolar sealer decreases postoperative blood transfusions and LOS during primary THA without increasing total hospital costs., (Copyright 2014, SLACK Incorporated.)

Objective: Pain is a prevalent condition that often involves a neuropathic component. Hydrocodone is one of the most widely used opioids for pain but is often associated with side effects (SEs). This study sought to characterize the experience of patients taking hydrocodone for non-cancer pain., Methods: A nationwide survey of adults in the United States taking hydrocodone for non-cancer pain was conducted. The survey included questions to characterize these patients and their experience with hydrocodone-related SEs. A neuropathic pain subgroup also was examined., Results: Among 630 respondents, the average age was 50.1 years (14.25). Most (90.6 percent) were Caucasian and 72.5 percent were female. Back pain or low back pain was the most common (42.1 percent) type of pain. Almost three-fourths (73.3 percent) experienced at least one SE, and 67.3 percent reported being bothered. More than three-fourths (78.3 percent) reported being satisfied with hydrocodone relieving pain; however, less (74.8 percent) reported being satisfied with it overall. More than one-fourth (27.6 percent) reported taking hydrocodone less than instructed with 41.4 percent of them reporting that SEs were bothersome as a reason. A greater percent of the neuropathic pain subgroup (266 respondents) experienced at least one SE (80.8 percent) and were bothered by them (75.6 percent). Overall satisfaction was slightly lower (71.1 percent) among these respondents, and among the 24.8 percent taking less than instructed, more than half (54.5 percent) reported that SEs were bothersome as a reason., Conclusions: This study demonstrates an unmet need for better therapeutic options to manage pain, including neuropathic pain. Therapies that offer improved tolerability also may increase adherence, which could affect overall satisfaction and response to pain management.

Aims: We evaluated echocardiography and electrocardiography (ECG) results in children with non-specific mitochondrial disease (MD) in order to study early cardiac involvement, a well-known complication of the disease., Methods: Among non-specific MD children whose isolated mitochondrial respiratory chain complex I defect was confirmed by muscle biopsy and satisfied the criteria of MD, 27 who had no cardiac symptoms were evaluated by echocardiography and ECG., Results: Three (11.1%) out of the 27 non-specific MD patients had left ventricular ejection fraction of less than 55% and two of them (7.4%) had fractional shortening of less than 26%. ECG abnormalities were observed in 16 of the non-specific MD patients (59.3%). Prolongation of heart rate-corrected QT interval was seen in 11 (40.7%) and widening of the QRS interval in eight (29.6%). Left ventricular ejection fraction and fractional shortening of the patients were significantly decreased compared with those in the control group while heart rate-corrected QT interval was prolonged in the former group. QRS interval was more widened in non-specific MD patients, but without statistical significance., Conclusion: The potentially severe cardiac involvement observed in our subjects suggests that early cardiac evaluation after confirming the diagnosis of MD and regular follow-up tests should be strongly recommended in children even in cases without typical cardiac manifestations., (© 2012 The Authors. Journal of Paediatrics and Child Health © 2012 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Background: Chronic pain is a prevalent condition in the United States. Musculoskeletal pain, including joint and back pain, is the most common type of chronic pain, and many patients with back pain have a neuropathic component. Pain has direct economic consequences. While oxycodone controlled-release (CR) is one of the most widely used oral long-acting opioids for pain, including pain with a neuropathic component, it is often associated with bothersome side effects, resulting in additional medical resource use (MRU) and costs., Objective: To examine the impact on MRU and costs to payers of side effects in patients taking oxycodone CR alone or in combination with other pain medications for noncancer pain (including those with neuropathic pain symptoms)., Methods: A nationwide convenience sample of adults in the United States, who participated in a survey research panel and reported current use of oxycodone CR for noncancer pain, completed an online survey between November 2, 2010, and December 13, 2010. Respondents were excluded if they reported current use of other extended-release or long-acting opioid prescription medications. The survey consisted of questions on demographics, clinical characteristics, pain characteristics, experience with pain medication, and MRU associated with side effects. Payer costs were calculated based on the MRU reported by the respondents multiplied by Medicare reimbursement rates for hospitalizations and outpatient visits and average wholesale price (AWP) minus 20% for medications. A subgroup of patients who reported neuropathic pain symptoms also was examined., Results: After applying the exclusion criteria, 432 respondents completed the survey. Approximately half of the respondents (n = 219; 50.7%) reported neuropathic pain symptoms. The majority of respondents were Caucasian (88.4%) and female (63.7%) with an average age of 41.8 years (14.89). Respondents most frequently reported low back pain (41.2%), followed by osteoarthritis/rheumatoid arthritis (20.4%), neuropathic pain (10.6%), and fibromyalgia (9.0%). Respondents reported having their pain condition for an average of 5.4 (7.42) years. On days when taken, respondents reported a mean oxycodone CR daily dose of 83.3 mg (126.93) taken in an average of 2 doses. Most respondents (82.4%) reported experiencing at least 1 side effect with 77.5% being bothered by at least 1 side effect. The most frequently reported side effects ( greater than 25%) were drowsiness (41.4%), constipation (37.0%), fatigue or daytime sleepiness (36.6%), and dizziness (27.1%). Among respondents who reported being bothered by one or more side effects in the previous month, MRU associated with side effects was reported by 39.1% of respondents and significantly increased as the level of side-effect bother increased from 19.8% among those "A little bit bothered" to 38.4% among those "Bothered" to 61.0% among those "Extremely bothered" (P less than 0.001). Additionally, total average payer costs (in 2010 dollars) per respondent in the previous month associated with side effects were $238 ($1,159) and also significantly increased as the level of side-effect bother increased from $61 ($512) among those "A little bit bothered" to $238 ($1,160) among those "Bothered" to $425 ($1,561) among those "Extremely bothered" (P less than 0.001). Results reported in the neuropathic pain subgroup were similar to results reported in the total study sample., Conclusions: Among adults taking oxycodone CR for chronic noncancer pain (with or without a neuropathic pain component), over three-fourths reported being bothered by side effects. Respondents who reported higher levels of side-effect bother also reported greater MRU, resulting in increased payer costs. The results of this study provide further support of the econo-mic burden to payers associated with opioid-related side effects in patients with chronic noncancer pain, with and without neuropathic pain.

Background: Patients with fibromyalgia report persistent widespread pain, fatigue, and substantial functional limitations, which may lead to high health resource use (HRU) and lost productivity. Previous analyses of the U.S. population have not examined the direct and indirect costs of fibromyalgia by severity level., Objectives: To assess (a) HRU, direct and indirect costs associated with fibromyalgia in routine clinical practice in the United States using a patient-centric approach, and (b) the relationship of fibromyalgia severity level to HRU and costs., Methods: This study recruited a nonprobability convenience sample of 203 subjects aged 18 through 65 years between August 2008 and February 2009 from 20 U.S. community-based physician offices. Subjects had a prior diagnosis of fibromyalgia by a rheumatologist, neurologist, or pain specialist; received treatment at the enrolling physician's practice for at least 3 months; experienced widespread pain for at least 3 months; and experienced pain in the previous 24 hours. Subjects completed a 106-item patient questionnaire that included 5 validated health-related quality-of-life instruments and study-specific questions about demographics; clinical history; overall health; treatment satisfaction; and impact of fibromyalgia on cognitive function, daily activities, and employment status. Subjects also self-reported hours of unpaid informal caregiver time because of inability to perform daily activities (e.g., housework, child care), out-of-pocket expenses for medical and nonmedical services, and lost productivity related to fibromyalgia for the previous 4 weeks. The 20-item Fibromyalgia Impact Questionnaire total score was used to stratify subjects into fibromyalgia severity groups (0 to less than 39 = mild, 39 to less than 59 = moderate, 59 to 100 = severe). Staff at each site recorded clinical characteristics, HRU, and medication use attributable to fibromyalgia on a paper clinical case report form (CRF) based on a 3-month retrospective medical chart review. Unit costs for 2009 were assigned to the 3-month HRU data reported on the CRF and 4-week subject-reported lost productivity. Costs were then annualized and reported in the following categories: direct medical, direct nonmedical, and indirect. Differences across severity levels were evaluated using the Kruskal-Wallis test (continuous measures) and Pearson chi-square or Fisher's exact tests (categorical measures) at the 0.05 alpha level., Results: Of the 203 subjects, 21 (10.3%) had mild, 49 (24.1%) had moderate, and 133 (65.5%) had severe fibromyalgia. For subjects with mild, moderate, and severe fibromyalgia, respectively, the number of fibromyalgia-related medications (3-month means: 1.8, 2.3, and 2.8, P = 0.011) and office visits to health care providers (3-month means: 2.7, 5.2, and 6.9, P < 0.001) significantly differed across severity levels. Across severity levels, total medical and nonmedical out-of-pocket costs also differed (P = 0.025). Mean [median] 3-month total direct costs (including payer costs for HRU and out-of-pocket costs for medical and nonmedical services) were $1,213 [$1,150], $1,415 [$1,215], and $2,329 [$1,760] for subjects with mild, moderate, and severe fibromyalgia, respectively (P = 0.002); and mean [median] 3-month indirect costs (including subject-reported absenteeism, unemployment, disability, and the estimated value of unpaid informal care) were $1,341 [$0], $5,139 [$1,680], and $8,285 [$7,030] (P < 0.001). Mean total indirect costs accounted for 52.5%, 78.4%, and 78.1% of mean total costs for subjects with mild, moderate, and severe fibromyalgia, respectively., Conclusions: Direct and indirect costs related to fibromyalgia are higher among subjects with worse fibromyalgia severity. Indirect costs account for a majority of fibromyalgia-related costs at all fibromyalgia severity levels.

Background: Fibromyalgia (FM) is characterized by chronic, widespread pain, fatigue, and other symptoms; yet few studies have comprehensively assessed its humanistic burden. This observational study evaluates the impact of FM severity on patients' symptoms, health-related quality of life (HRQoL), and productivity in the United States., Methods: 203 FM subjects were recruited from 20 physician offices. Subjects completed a questionnaire including the EuroQol 5D (EQ-5D), Fibromyalgia Impact Questionnaire (FIQ), Multidimensional Assessment of Fatigue (MAF), Medical Outcomes Study Sleep Scale (MOS-SS), and Hospital Anxiety and Depression Scale (HADS) and questions about demographics, pain and other symptoms, HRQoL and productivity. FIQ total scores were used to define FM severity, with 0- < 39, 39- < 59, and 59-100, representing mild, moderate, and severe FM, respectively. Sites recorded subjects' clinical characteristics and FM treatment on case report forms using medical records. Summary statistics were calculated for continuous variables and frequency distributions for categorical variables. Differences across FM severity groups were evaluated using the Kruskal-Wallis or Chi-square tests. Statistical significance was evaluated at the 0.05 level., Results: Mean (SD) age was 47.9 (10.9); 95% were female. Most (92%) were prescribed medication for FM; 24% and 66% reported moderate and severe FM, respectively. Mean (SD) scores were: 6.3 (2.1) for pain intensity; 0.35 (0.35) for EQ-5D; 30.7 (14.2) for MAF; 57.5 (18.4) for MOS-SS Sleep Problems Index; 10.2 (4.8) for HADS anxiety and 9.4 (4.4) for HADS depression. Subjects with worse FM severity reported significantly increased pain severity, HRQoL, fatigue, sleep disturbance, anxiety and depression (p < 0.001). Overall, 50% of subjects reported some disruption in their employment due to FM; this differed across severity levels (p < 0.001). Employed subjects missed a mean (SD) of 1.8 (3.9) workdays during the past 4 weeks; this also differed across severity levels (p = 0.03)., Conclusions: FM imposes a substantial humanistic burden on patients in the United States, and leads to substantial productivity loss, despite treatment. This burden is higher among subjects with worse FM severity.

Background: Fibromyalgia (FM) is characterized by persistent and widespread pain and often associated with other symptoms and comorbidities. Thus, FM patients seek care from multiple physician specialties. This study compared prescribing patterns, patient-reported outcomes (PROs), healthcare resource use (HRU), and direct costs related to FM in routine clinical practice across physician specialties., Methods: This cross-sectional, observational study recruited 203 FM subjects from 20 community-based physician offices (eight primary care, six rheumatology, three neurology, three psychiatry). Subjects completed questions about pain, other symptoms, quality of life, productivity, treatment effectiveness and satisfaction, and out-of-pocket expenses related to FM; site staff recorded subjects' treatment and HRU based on medical chart review. Results were compared across specialties. Statistical significance was evaluated at the 0.05 level. Annual direct costs associated with FM were calculated in 2009 US dollars., Results: Subject demographic and clinical characteristics were not significantly different across physician specialties, except psychiatry subjects had the highest mean number of co-morbid conditions; p < 0.001. PROs were similar across physician specialties except fatigue; neurology subjects reported the highest levels. There were no significant differences in subject-reported outcomes of medication effectiveness (p = 0.782) and medication satisfaction (p = 0.338) for FM. Psychiatry subjects had more FM-related physician visits compared to other specialties (p = 0.013) and a higher proportion received diagnostic tests related to FM (p = 0.013). The mean (SD) number of FM prescription medications prescribed per subject was highest in the primary care and lowest in the neurology group; p = 0.024. The proportion of hypnotic (p = 0.001), muscle relaxant (p = 0.005), anxiolytic (p = 0.005), anti-epileptic (p = 0.007), and other medications (p = 0.044) prescribed for FM were significantly different across specialties. Overall direct medical costs did not differ significantly (p = 0.284) across specialties., Conclusions: Patient characteristics were similar across specialties, except with regards to comorbidity burden. This study noted significant differences among physician specialties in HRU and treatment patterns among medications, diagnostics, and outpatient visits. Consistent with other studies, this study did not identify a dominant strategy for FM management across physician specialties as overall per patient medical costs and subject-reported treatment satisfaction were similar. Future research to better characterize differences among physician specialties in FM management, as well as the reasons for these differences, would be useful.

Purpose: To evaluate myocardial conductivity to understand cardiac involvement in patients with mitochondrial disease., Methods: We performed retrospective study on fifty-seven nonspecific mitochondrial encephalopathy patients with no clinical cardiac manifestations. The patients were diagnosed with mitochondrial respiratory chain complex defects through biochemical enzyme assays of muscle tissue. We performed standard 12-lead electrocardiography (ECG) on all patients., Results: ECG abnormalities were observed in 30 patients (52.6%). Prolongation of the QTc interval (>440 ms) was seen in 19 patients (33.3%), widening of the corrected QRS interval in 15 (26.3%), and bundle branch block in four (7.0%). Atrioventricular block, premature atrial contraction and premature ventricular contraction were seen in two patients each (3.5%) and Wolff-Parkinson-White syndrome in one patient (1.8%)., Conclusion: Given this finding, we recommend active screening with ECG in patients with mitochondrial disease even in patients without obvious cardiac manifestation.