Intermittent preventive treatment in pregnancy with sulfadoxine/pyrimethamine is contra-indicated in HIV-positive pregnant women receiving sulfamethoxazole/trimethoprim prophylaxis. Since mefloquine is being considered as a replacement for sulfadoxine/pyrimethamine in this vulnerable population, an investigation on the pharmacokinetic interactions of mefloquine, sulfamethoxazole and trimethoprim in pregnant, HIV-infected women was performed.A double-blinded, placebo-controlled study was conducted with 124 HIV-infected, pregnant women on a standard regimen of sulfamethoxazole/trimethoprim prophylaxis. Seventy-two subjects received three doses of mefloquine (15 mg/kg) at monthly intervals. Dried blood spots were collected from both placebo and mefloquine arms four to 672 h post-administration and on day 7 following a second monthly dose of mefloquine. A novel high-performance liquid chromatographic method was developed to simultaneously measure mefloquine, sulfamethoxazole and trimethoprim from each blood spot. Non-compartmental methods using a naïve-pooled data approach were used to determine mefloquine pharmacokinetic parameters.f), and area-under-the-curve (AUC0→∞) were 12.0 days, 0.035 l/h/kg and 431 µg-h/ml, respectively. Although trimethoprim steady-state levels were not significantly different between arms, sulfamethoxazole levels showed a significant 53 % decrease after mefloquine administration relative to the placebo group and returning to pre-dose levels at 28 days.Sulfamethoxazole/trimethoprim prophylaxis did not noticeably influence mefloquine pharmacokinetics relative to reported values. The mefloquine half-life, observed clearance (CL/Although a transient decrease in sulfamethoxazole levels was observed, there was no change in hospital admissions due to secondary bacterial infections, implying that mefloquine may have provided antimicrobial protection. In many parts of Africa, pregnancy is complicated by co-infection with malaria and human immunodeficiency virus (HIV). Maternal malaria was associated with a two-fold higher HIV-1 viral concentration, and in areas where HIV prevalence is greater than 10 % of the population, the proportional increase of malaria during pregnancy can be from 5.5 to 18.8 % . In addiPlasmodium falciparum infections since the 1960s, there have been few MQ pharmacokinetic studies involving pregnant women. Pharmacokinetic parameters of many drugs are altered in pregnant women due to the differences in the physiological functions relative to non-pregnant women. For example, a controlled study of pregnant and non-pregnant women infected with P. falciparum showed a significantly lower maximum blood concentration (Cmax) and a larger volume of distribution (Vd/F) of MQ in the pregnant group  that occurs during steady state. Therefore, the averages of these values were used to determine the steady-state [Css (min)] values for TMP and SMX , where ‘b’ is the rate constant.Pharmacokinetic parameters for MQ were calculated based on the use of non-compartmental methods of analysis of naïve-pooled data (NPD) using PK Solutions Vers. 2.0 Pharmacokinetic Data Analysis software . The software uses a method based on curve stripping, which resolves the concentration–time curve into a series of exponential terms used to calculate the various PK parameters. A tri-exponential equation  was similar to the mean half-life of 11.6 days for whole blood MQ in pregnant women given 125 or 250 mg per week during the third trimester of pregnancy  for TMP (2.23 µg/ml in placebo arm vs 1.86 µg/ml in MQ arm) ] for SMX showed as much as a 53 % decrease in the MQ arm relative to the placebo arm. An ANOVA analysis reveals significant changes in the SMX concentration–time profile in the MQ arm (p < 0.0002) while no significant changes (p > 0.05) were observed for SMX in the placebo arm. It was observed that as MQ is being eliminated, SMX concentrations gradually increase back to original levels ] for SMX in the placebo arm (23.8 µg/ml) is less than that reported in healthy adults taking the same dose (Table The presence of MQ did not significantly affect the steady-state minimum concentrations [Cmax = 9 ± 3 days) for the carboxymefloquine metabolite [bx) to SMX concentrations from seven to 28 days. The growth constant (b) of 0.0015 h−1 is equal to a doubling time of 19 days. The half-life for carboxymefloquine of 21 days [Drug interactions can occur as a result of competitive or non-competitive inhibition of the Cytochrome p450 enzyme. The Cytochrome p450 isoform, CYP3A4, has been implicated in MQ metabolism since the co-administration of ketoconazole, a potent inhibitor of CYP3A4 was shown to significantly increase plasma MQ levels in humans . Since Stabolite . The rat 21 days  correspo 21 days .max, Cmax, as well as the absorption rate constant (ka). Obtaining multiple blood samples in a short period of time required for absorption phase kinetics is difficult under the conditions encountered in developing countries. Drug metabolites were not quantified using the described analytical technique, therefore any associations with metabolite levels could not be made directly. Although no significant differences were seen for TMP between the MQ and placebo arm, low levels and high variability may have masked any changes. Over 95 % of the subjects in the study were taking an antiretroviral medication  concomitant with MQ and CTX. Possible interactions with these antiretrovirals cannot be ruled out.Limitations of this study include the lack of sufficient blood samples collected during the MQ absorption phase to obtain accurate tThis is the first study assessing the pharmacokinetic inter-relationship of MQ and CTX. In this study, prophylactic levels of CTX did not significantly alter MQ pharmacokinetics in HIV-infected pregnant women relative to reported parameters in pregnant women not receiving CTX. While exposure to MQ did not affect TMP levels, there is concern that the transient decline in SMX levels would result in an increase in hospital admissions from secondary bacterial infections. However, this was not the case. Results from the multi-site clinical trial from which this study is derived do not support this assertion . This im


Genetic details are added by a nominated neuromuscular specialist. In addition questionnaires about pain, quality of life and scapular fixation are included.The United Kingdom (UK) Facioscapulohumeral Dystrophy (FSHD) Patient Registry launched in May 2013. Funded by the Muscular Dystrophy Campaign and supported by the TREAT-NMD Alliance. This patient driven registry collects the internationally agreed core dataset, an outcome of an ENMC Workshop held in 2010 [In the 12 months between May 2013 and May 2014 over 400 people registered, 92% with a diagnosis of FSHD1. Similar proportions of patients registered from both sexes and 59% of patients were between 40 and 70 years old (mean 47.39). Muscle weakness was widely reported with periscapular shoulder weakness occurring most frequently (89%) followed by weakness of the hip girdle (73%), facial muscles (72%) and foot dorsiflexor (71%). The onset of facial weakness was reported significantly earlier than weakness in other areas with 66% experiencing facial weakness before 20 years old.Full time wheelchair use was reported in 18% of cases, 62% having lost ambulation between 31 and 60 years old (mean 41.61). Use of a wheelchair or other assistive device part time was reported in 44% of cases. A small proportion of patients report hearing loss (18%), retinal vascular disease (2%) and using ventilation (7%).Additional questionnaires on pain were completed by 350 patients during this time and the majority reporting at least some pain, most often described as tiring or aching. Persistent pain (experienced for at least 3 months in a year) was reported by 92% with 53% of people describing this pain as distressing, horrible or excruciating. The location of the pain is variable but most often reported in the shoulder.A broad spectrum of patients has registered providing a new insight into the FSHD population in the UK. The Registry aims to help facilitate and accelerate clinical research and trials, sharing a common dataset with a growing number of FSHD registries around the world will allow the registry to achieve this locally and internationally. The registry is well placed to inform future clinical research and help develop of standards of care.


Gaucher disease, an autosomal recessive condition due to deficiency of lysosomal glucocerebrosidase, is a multisystemic disease, with variable age of onset, severity and progression. It is classified into subtypes delineated by the absence (type 1) or presence (type 2 and 3) of primary nervous system involvement.The ethnically diverse, largely immigrant population in South Florida has a spectrum of Gaucher disease phenotypes, creating a challenge for optimization of disease management and an opportunity to explore treatment patterns.Ninety-three records from patients with Gaucher type I in South Florida were retrieved from the International Collaborative Gaucher Group (ICGG) Registry. Individual genotypes were correlated with severity scores and success at achieving published therapeutic goals for haemoglobin concentration, platelet count, spleen volume, liver volume and amelioration of bone pain and bone crises.The majority of patients were diagnosed during the fifth decade of life. Almost two-thirds were homozygous for the N370S mutation, reflecting the large Ashkenazi Jewish population in South Florida. The majority received imiglucerase (62.8%) at various intervals. 24.5% of patients underwent splenectomy before starting enzyme replacement therapy. After a median 12 treatment years, South Florida patients matched or exceeded the ICCG 4 year therapeutic goal achievement for platelet count (85.4% vs. 79.6% success), spleen volume (93.3% vs. 78.0% success), liver volume (93.4% vs. 90.6% success), and bone crises (100% vs. 99% success). Nevertheless, fewer patients with intact spleens had sustained achievement of all 6 therapeutic goals (30.4% versus 41.4%) and only 40% of the splenectomy patients sustained achievement of 5/5 possible goals. 54.7% of the intact spleen patients continued to have bone pain vs. 29.8% in ICCG. Significantly, only 37% of the ICGG patient cohort had bone pain prior to initiation of treatment compared to 73.4% of the South Florida patients (moderate or severe pain in 59.6%).Demographic characteristics are a significant determinant of the differences in response to treatment observed in South Florida Gaucher patients compared to those described in the international population enrolled in the ICGG Gaucher Registry. Individual genotypes and ethnic background are important considerations for optimizing patient care for Gaucher disease. GBA1[Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder that, with the exception of rare patients with saposin C deficiency, is caused by mutations in the glucocerebrosidase gene, GBA1,3 and unGBA1.GBA1 variant alleles that are associated with GD, 6 mutations account for 98% of those found in the Ashkenazi Jewish population in which GD1 is especially prevalent[GBA1 mutation projecting a disease incidence of 1/600 live births[The incidence of GD1is estimated at 1/50,000-75,000 live births in non-Jewish populations in North America, Europe and Australia. Of moree births,11. The e births. Among we births,14. It ie births.Here, we present a demographic and genotypic profile for 93 GD1 patients who live in South Florida and are enrolled in the ICGG Gaucher Registry and correlate genotype with validated severity scores and hematologic, visceral and skeletal therapeutic outcomes.The ICGG Gaucher Registry was launched in 1991 to track the clinical, demographic, genetic, biochemical and therapeutic characteristics of patients with GD throughout the world, irrespective of disease severity, treatment status or treatment choice. GovernaGenotype was obtained for most patients by PCR specific oligonucleotide screening for 5 common mutations prevalent in the Ashkenazi Jewish population . Samples from some patients with unidentified alleles were referred to the ICGG Registry Genotyping Service at the laboratory of H. Ronald Scott, MD, PhD at the University of Washington, Seattle, WA, USA for whole gene sequencing.Patients were categorized based on a validated DS3 disease severity scoring system, performIn 2008, an ICGG Registry benchmark analysis evaluated the attainment of six previously suggested therapeutic goals  in 195 non-splenectomized patients with type I GD after 4 years of imiglucerase treatment. Here, wT test .Demographic analyses used standard descriptive statistics (frequencies and percentages). DS3 scores are summarized using means and standard deviations. ANOVA testing was performed using a 2 tailed 93 individuals  were initially eligible. 57 (61.2%) were women. The mean (SD) age at first assessment was 49.9 years . 75 patients (80.6%) reported Ashkenazi Jewish ethnicity. Five lacked genotype information. There were 4 sibling pairs. Of 84 unrelated patients with genotype data, 52 (61.9%) were homozygous for the N370S allele and 29 (34.5%) carried one N370S allele  were highly variable but generally in the mild to moderate range  indicated a clinically mild phenotype. ERT access was not problematical. One patient with symptomatic bone disease declined ERT and SRT. Until the imiglucerase shortage/interruption beginning in June 2009, virtually all patients who required treatment received imiglucerase. Two patients of unknown genotype who died prior to 1995 received alglucerase 60 U/kg every 2 weeks. They are excluded from the genotype and response analyses . At last evaluation through June 2011, 49 patients were receiving imiglucerase of whom 1 was infused weekly, 33 every two weeks, 2 every three weeks and 13 every four weeks . Fifteen patients (24.5%) had splenectomy prior to treatment initiation.17 patients are deceased of whom 4 had undergone splenectomy. The mean age (SD) at death was 71.9 15.4) years; median age at death (range): 71.5 years (28y-92y); interquartile range: 64.5y-83.8y. The genotypes of deceased patients were 13 - N370S/N370S, 2 N370S/L444P and 1 N370S/V394L. The causes of death are shown in Table .4 years;As shown in Table After a median 12 treatment years, South Florida patients matched or exceeded the ICCG 4 year therapeutic goal achievement for platelet count (85.4% vs. 79.6% success), spleen volume (93.3% vs. 78.0% success), liver volume (93.4% vs. 90.6% success), and bone crises (100% vs. 99% success). Nevertheless, fewer patients with intact spleens had sustained achievement of all 6 therapeutic goals (30.4% versus 41.4%) and only 40% of the splenectomy patients sustained achievement of 5/5 possible goals  continued to have bone pain vs. 29.8% in ICCG. On average, there was no age difference between patients with residual bone pain and those free of pain. Of note, only 37% of the ICGG patient cohort had bone pain prior to initiation of treatment compared to 73.4% of the South Florida patients (moderate or severe pain in 59.6%). Of 28 patients with baseline bone pain scaled as moderate or worse, 20 (71.4%) failed to realize the therapeutic goal for bone pain at their most recent evaluation. Of 35 patients who initially reported either no bone pain or pain no worse than mild, 15 (42.8%) had bone pain at their most recent evaluation. Age at inception of ERT was not significantly associated either with severity of pre-treatment bone pain or with therapeutic goal “failure” due to persistent bone pain. However, of the 61 patients included in the therapeutic goal analysis, only 9 patients were younger than 30 years of age when ERT was begun and only 4 were younger than 18 years. Regardless of age at inception of treatment, severity of pre-treatment bone pain was a key predictor for persistent bone pain. Age at commencement of ERT also did not appear to be a significant determinant of failure to achieve therapeutic goals other than bone pain. Among our patients, poor compliance with treatment schedules was not a contributory factor to poor therapeutic responses.The initial total DS3 bone domain score, although including heavily weighted information about avascular necrosis, lytic lesions, fractures, bone marrow infiltration and bone density, was less likely to predict pain outcomes than the bone pain score itself. There also was no significant association between the baseline DS3 bone domain score and composite attainment of therapeutic goals in either patients with intact spleens or in those with splenectomy Table . LikewisTo our best estimate, the 93 patients included in this report constitute at least 75% of known GD1 patients living in South Florida during a 22 year period. During that time, a 1990 population of 3.5 million in which 57% were non-Hispanic White has grown to 5.5 million with only 41% being non-Hispanic White[Compared to the GD1 patients from the Northeast United States described by Taddei et al., somewha2+1 , we elected to evaluate our patients in terms of achievement of therapeutic goals for hemoglobin concentration, platelet count, spleen and liver enlargement, bone pain and bone crises. These short term goals are not necessarily disease specific over an extended period of observation and they are an incomplete representation of all the elements that are integral to capturing the essence of clinical response to treatment for life long chronic illnesses such as GD1. Nevertheless, regulatory approvals of new therapy for GD1 and most reports of 4–10 year treatment outcomes have relied heavily, and sometimes exclusively on these six parameters,27, and Although assessment of achievement of multiple therapeutic goals is very useful for individualized case management, our results demonstrate the limitations and pitfalls of such applications to studies of patient populations that are not matched in terms of pre-treatment characteristics and potentially confounding concurrent or emerging medical events. Although the percentages of our patients completely at therapeutic goal after a median 12 years of GD1 treatment was less than that reported by ICCG after 4 years of treatment, the clinical circumstances suggested that many “failures” were probably not attributable to “breakthrough” manifestations of GD1. In fact, with the longer duration of treatment, as predicted by the 10 year imiglucerase experience, improveThe clinical outcomes research field is increasingly emphasizing the centrality of patient-reported input and value-based medicine  as a necessary accompaniment to classical efficacy and safety studies with physician-conceived endpoints (evidence-based medicine),30. RareNeal J Weinreb receives honoraria and expense reimbursement for serving on a Board of Advisors of the ICGG Gaucher Registry; travel reimbursements and/or honoraria and/or research support from Genzyme-a Sanofi Company, Shire, Pfizer Corporation, and Actelion Corporation. Olaf A Bodamer is member of the Speaker Bureau for Shire and Genzyme-Sanofi, receives research support from Shire and is on the US Advisory Board for Gaucher Disease for Shire.MO participated in data analysis and helped to draft and to revise the manuscript. DB participated in the study design and data analysis and helped revise the manuscript. OAF helped to review and revise the manuscript. NJW conceived of the study, participated in the study design, data analysis and statistical analysis, and helped to draft and to revise the manuscript. All the authors read and approved the final manuscript.


This study evaluated the effects of inhalation of lavender essential oil on the pain of open-heart surgery. The main complaint of patients after open-heart surgery is chest pain. Due to the side effects of opioids, it is important to use a non-invasive way to effectively relieve pain including aromatherapy with analgesics. This study was a clinical single-blind trial and was conducted on 40 patients who had open-heart surgery in the cardiac ICU of 2 Hospitals of Tehran University of Medical Sciences, 2012. Criteria included: full consciousness, spontaneous breathing ability and not using synthetic opioids within 2 hours before extubation. After extubation, the patients were asked to mark the intensity of their pain using the visual analogue scale. Then, a cotton swab which was impregnated with 2 drops of lavender essential oil 2% was placed in their oxygen mask, and they got breath for 10 minutes. 30 minutes after aromatherapy, they were asked to re-mark their pain intensity. The level of patient’s pain before and after aroma therapy were compared. The pain mean level before and after inhaling lavender essential oil was 5.60 (SD = 2.262) and 4.98 (SD = 2.293), respectively . Therefore, there is no significant difference and the result of study proves that lavender essential oil inhalation has no effect on reducing the pain of open-heart surgery. Nowadays, heart surgery is one of the most common surgeries and has its own side effects . A problDeveloping the blood clot will increase the risk of pulmonary embolism . Also, aet al. also wrote that although the pain of incision was inevitable, it was controllable and in the absence of rapid and appropriate controls, it could become severe and lead to chronic pain  from labiatae family with some therapeutic properties is vastly used in the variety of aromatherapy methods  and linalyl acetate (35%). Other components include α-pinene, limonene, 1,8-cineole, cis- and trans-ocimene, 3-octanone, camphor, caryophyllene, terpinen-4-ol and avandulyl acetate   . In 2011cesarean .It is the first assessment report of the effect of lavender essential oil on open-heart surgery pain. The researcher studied on the effectiveness of aromatherapy with Lavender essential oil on pain of open-heart surgery with fewer side effects.MethodsLavandula officinalis (L. vera) collected from botanical garden of School of Pharmacy in Jan. 2013, and was identified  in Pharmacognosy Lab. in School of Pharmacy, 2% solution was prepared by sesame oil (Saman Co. Iran). Patients’ age was in the range of 18-65. Characteristic subjects of patients under investigation included: full consciousness and being aware of time and place, extubated and having spontaneous breathing, no addiction to opioids or strong analgesics, not receiving analgesics within 2 hours before intervention, not having asthma, allergies, chronic obstructive pulmonary and other lung diseases, contact dermatitis to aromatic substances. Also, some exclusion criteria were set in this research. The patients that needed medical intervention during the inhalation, or in case of allergies, respiratory problems and emergencies, were excluded from this research.This study is a single-blind clinical trial, which has the ethical approval from Ethics Committee of Islamic Azad University of Tehran Medical Branch, and was conducted on 40 patients who had undergone open-heart surgery, cardiac ICU departments in Moheb Hospital and Tehran Heart Center. The lavender oil was prepared by hydrodistillation from etc.) and the second part was a visual analogue scale to determine the pain intensity on a 10 cm ruler including 10 numbers begin form 0 indicates "no pain" and ends in 10 that indicates "most severe pain".Gradual sampling was used in this study. A two-part questionnaire was used in this study for the data collection. The first part included demographic characteristics subjects under investigation  were 50 to 59 years and average age was 50 years old (SD=15.16). 37.5% of patients had hypertension, 30% had hyperlipidemia disease and 20% had diabetes. 57.5% had an experience of previous surgery and only 10 % had an experience of aromatherapy. None of the subjects had experience of using lavender essential oil, previously.Comparison of pain average before and after aromatherapy showed that the pain mean level before inhaling lavender essential oil was 5.60 (SD= 2.262), and after inhaling lavender was 4.98 (SD=2.293). Since the p-value=0.1>0.05, there is no statistically significant difference and the result of study proves that lavender essential oil inhalation has no effect on reducing the pain of open-heart surgery .Among the demographic variables using Chi-square statistical test, only age and marital status had a significant effect on pain. The elder people and married people felt less pain. There were no lavender essential oil related adverse effects hemodynamic, respiratory, gastrointestinal or allergic reaction observed during the study.One of the factors affecting the pain is age; Potter and Perry have studied on “relation of developmental differences and how adults reaction to pain are more effective” . In our et al. studied on the "Evaluation of aromatherapy in treating postoperative pain in New York”  than patients in the lavender group  (P=0.007). Moreover, the Lavender group patients required significantly less morphine postoperatively than placebo group patients (In 2006, Kim ew York” . Similarew York” , But in ive pain .27, 82% patients .Essential oils have both physiological and psychological effects . When la


Eighty-two percent of graduates reported being “very much improved” or “much improved”. A second analyses provided evidence that treatment effects were robust across sites with no differences (<0.001) found on five of seven selected outcome measures. A third analysis found that number of days of treatment was correlated on three of seven measures at the <0.01 level. However, the amount of variance explained by days of treatment was under 5% on even the most highly correlated measure. These finding are consistent with previous research and explore short-term effectiveness of treatment across treatment sites and with variable duration of treatment.Chronic low back pain is one of the major health problems in the U.S., resulting in a large number of years of disability. To address the biopsychosocial nature of pain, interdisciplinary pain programs provide integrated interventions by an interdisciplinary team in a unified setting with unified goals. This study examined outcomes of an interdisciplinary program located at two sites with different staff, yet with a unified model of treatment and documentation. Efficacy at the combined sites was examined by comparing standard measures obtained upon admission to the program with measures at completion of a 3–4 week long program for 393 patients with chronic low back pain (CLBP). Repeated measures included pain severity, pain interference, efficacy of self-management strategies, hours of activity, depression, ability to do ADLs, and physical endurance. All repeated measures differed at the  Patient with chronic pain.This patient’s (probably accurate) perception captures the frustration of both healthcare providers and patients facing chronic low back pain (CLBP). This subjective impression of being “stuck” is reflected in the continued suffering and disability despite the high cost of ongoing healthcare. As evidenced by recent reports by the Institute of Medicine ,2, betweIn an effort to better understand the problem of CLBP, some have suggested that the problem is more accurately understood and more effectively treated by use of a biopsychosocial model . The bioThe role of psychosocial factors has been well documented in both the development of CLBP and the resulting disability. These factors have been found to increase risk for acute low back pain developing into chronic pain, and for increased risk of disability associated with low back pain ,8,9. In A variety of psychosocial factors have been found to be of relevance ,14. ClinIn light of data indicating the impact of a biopsychosocial model, interventions based on these factors are used with varying degrees of frequency and have become commonly recommended ,16. The In light of the interactive nature of many factors using the biopsychosocial model, one response has been the development of the interdisciplinary pain management program . To addrThese programs include multiple types of providers  offering coordinated services “under one roof”, with frequent communication through team meetings around a unified vision and goals. They utilize standardized measurement of functioning of physical ability, pain and suffering, emotional distress, utilization of medical resources, and functional activities of living. The model emphasizes the use of structured supervised physical activation with treatment to change behavioral and social patterns which have evolved from, and have changed, the patients’ experience of pain as well as their life functioning. Treatment is designed to address the array of factors impacting patients’ pain, distress, and subsequent disability. It is interesting that some of these factors are ones found by Pincus , which pet al. [et al. [et al. [Over the last 30 years, the effectiveness of these programs has been extensively examined for both treatment efficacy and cost-effectiveness ,24,25,26et al.  documentet al. , in the et al. . When clet al. ,30, the  [et al.  document [et al. , Smith e [et al.  repeatedet al. [i.e., greater number of hours resting a day and high levels of pain) profited more with high intensity treatment, whereas persons with lower dysfunction did not respond differentially to levels of intensity of treatment.Several issues warrant further exploration. First, few studies have examined the impact of providing similar programs at multiple sites to see if effectiveness is similar in various treatment settings. Second, the role of the duration of treatment has been explored in a limited fashion ,35,36 wiIn order to further evaluate these issues, the present study utilized a large data set collected over 14 years from two programs with similar models but different locations to address three questions. First, prior to analyzing site and duration, did the program as a whole produce clinically significant change at the completion of treatment across a broad range of outcomes in a large sample of persons with low back pain? Second, were outcomes at the two sites of the program similar or significantly different? Third, did a range of intensity (days of treatment) create differences in outcomes? Data were collected from a larger data set accumulated for quality control purposes of patients attending the comprehensive interdisciplinary program (Baylor Center for Pain Management) from 2000 to 2014. Four hundred eighty five patients (40%) had a primary diagnosis of back pain according to the Pain Region, as defined by the International Association for the Study of Pain . Of thesThe comprehensive outpatient program at the Baylor Center for Pain Management in Dallas, Texas, has provided interdisciplinary treatment since 1995. This program was carried at two sites—in Dallas and Richardson—with the same treatment protocol, staffing patterns, program direction, and standard outcomes measures and procedures. Each site utilized a psychologist, a licensed professional counselor providing biofeedback, an occupational therapist, a physical therapist, and a case manager. Both sites were under the direction of the same program director over the 15 years providing broad stability in treatment and data collection. Program size would range from 2–12 patients at a time. Patients were included if pain was chronic (over 6 months), it interfered with functional activities and/or demonstrated elevated emotional distress, and patients reported desire for improvement and functional goals. Patients were excluded if their level of psychiatric problems or cognitive functions would interfere with participation and understanding in a group-oriented program. As an outpatient program, patients were required to be safe and independent for all self-care, ambulation, and transfers. Patients were also required to set goals and to commit to regular participation in the programs.Initially, the program consisted of 20 days of treatment (approximately 100 h) but, over time, has been reduced to 12 days of treatment (approximately 60 h) to adapt to scheduling needs of patients and insurance carriers. Daily patients participated in one hour of physical therapy, one hour of aquatics therapy, one hour of counseling or biofeedback, one hour CBT group, one hour occupational therapy group, one mind/body technique for pain control, and one hour occupational therapy with focus on lifestyle management for adaptive living including return to work. Training in meditative practice, biofeedback, as well as consultation with chaplain services and nutrition services were included.Data were gathered upon admission to the program (Day 1) and at the final day of treatment. Outcomes included changes in pain, emotional distress, activity levels, medical utilization, physical abilities, instrumental activities of living, and patients’ perception of change. These data are used to measure primary outcomes indicated by the IMPACCT group ,38.Upon admission, patients completed a questionnaire which included demographic data, duration of pain (in months), and estimate of utilization of medical resources in the year prior.Abbreviations are as follows: the Multidimensional Pain Inventory (MPI) ; Beck DeIn addition, at graduation, patients completed the Patients’ Global Impression of Change (PGIC) scale  and a raInitial analysis was made by combining data from graduates from the two sites. Descriptive analysis was conducted for the program’s primary descriptors of the participants, including frequency of categorical variables and means and standard deviations for continuous variables with the exception of duration for which median and range were chosen due to the extreme variability. Shapiro-Wilk tests for normality of distribution were carried out on variables. Because distributions did not meet assumptions of normality, a series of Wilcoxon signed rank tests were used to measure the effects of treatment. Effect size was measured using the value of r, which is appropriate for Wilcoxon tests.Second, outcome variables from the two sites were carried out using repeated-measures ANOVAs, with treatment site as one variable and individual patient’s change in scores from pre to post as the second variable. It should be noted that, although some measures were not normally distributed, ANOVAs are robust to minor deviations from normality. Chi-square tests were used for categorical variables, such as the Patient’s Global Impression of Change.Third, the relationship between the numbers of days of treatment and the amount of change was calculated using a series of correlation coefficients.t(392)= −2.78, p = 0.004) younger  than those at Site 2 . The duration of pain in months was also significantly shorter (t(354)= 3.0, p = 0.002) in Site 1  than in Site 2 , although the distribution was so broad as to undermine meaningfulness of central tendency. Gender distribution was not different . Payer source was also significantly different .Analysis of descriptive statistics see  found sit-tests found that changes for all variables were significant at the 0.001 level using Wilcoxon signed rank t-tests.Seven standard measures see  were usep = 0.001.These changes were found for both self-report repeated measures—self-reported perception of clinical progress and objective measures obtained by a physical therapist . Changes were large as evidenced by effect sizes (ES’s), ranging from 0.66–0.85. All changes were at Although only 36% of patients see  achievedProminent changes in function were also found. Interference by pain was reduced by at least 30% for 47% of patients (ES = 0.77), 70% of patients increased hours of activity by 30% (ES = 0.78), and 91% of patients increased by at least 30% in their ability to carry out primary desired activities of living as measured by the COPM (ES = 0.85).These self-reported changes in activity and functional ADLs were mirrored by changes in physical functioning. Distance walked in a 5-min timed task improved by at least 30% in 61% of patients (ES = 0.85).Ratings of emotional distress markedly improved. Using standard interpretation of scores, depression decreased by at least 30% in 78% of patients (ES = 0.82) with mean scores changing from moderate (pre-treatment mean = 21.5) to minimal (post-treatment mean = 10.2) range of depression using standard interpretation of the scores.Due to the challenges in quantifying medication usage in this clinical setting, data were not collected on specific types or dosages of medication used by each patient. However, patients were asked at graduation to report any change in the use of pain medication. Of the 344 patients in this group: 13 (9%) reported taking no medications; 162 (47%) reported taking fewer; 138 (40%) were unchanged in the use of medication; and 31 (9%) reported taking more medication.a priori goal of either “much improved”  or “very much improved ”. Forty-four (15%) reported “minimal improvement”, and only 3 (1%) reported “no change”. No patients reported being “minimally worse,” “much worse”, or “very much worse”.Patients reported positive changes on global impression of change. Eighty-two percent of 281 patients reporting met the p = 0.002) and distance walked in five minutes . Second, as reviewed above in p < 0.05 level and, in fact, were at the p = 0.001 level.It should be noted that, although some measures were not normally distributed, it was decided that parametric tests would be conducted because of the clarity of presentation, as well as the fact that ANOVAs are quite robust to minor deviations from normality. Therefore, repeated-measures ANOVAs see  were conp = 0.05 level. Hours of activity and distance walked each demonstrate an interaction effect of Site × Change and an amount of change . Chi-square tests of patient ratings of five ratings of improvement by pain site revealed no significant difference between sites .Some variability was found between measures in the interaction of the site and outcome measures. For four of the seven measures , the interaction of Site × Change was not significant at the p = 0.01 level  and at the p = 0.001 level , these correlations were quite low. For example, although significant, the number of days of treatment completed only accounted for 4% of the variance (r2 = 0.41) in the change in hours active per day.Finally, the amount of change for selected variables was evaluated to determine correlation with the number of days of treatment completed. Although several change scores were correlated at the This study explored three aspects of interdisciplinary programs for treatment of chronic pain. In the first analysis, results were consistent with previous literature indicating that interdisciplinary pain management programs can provide broad-based change, even for patients with entrenched CLBP associated with high pain, emotional distress, functional disability, and excessive use of medications and medical resources. Consistent with recommendations by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group and others for research with chronic low back pain ,44, it iAlthough this study was confirmatory of previous studies, a number of potential limitations should be noted. First, this was not a randomized controlled trial, but data were collected on a prospective basis as part of a quality assurance assessment. As such, there was no control group, so a potential placebo effect could not be measured or ruled out. Second, 20% of patients discontinued treatment for a variety of reasons, and, due to the focus of this study, no analysis was made of factors predicting non-completion or the degree of change during the program. A previous study of these programs, however, with all diagnostic groups included, found predictors for non-completion and identified factors predicting a response to treatment .p > 0.001 level, both six months and one year following treatment. However, six months later, some measures had regressed towards the pre-treatment scores, yet others had remained stable, and some had even continued to improve. All measures had regressed somewhat one year following treatment.In addition, these changes reflect immediate effects of treatment at program completion. Additional literature ,32,33 suIn the second analysis, this study also documented that interdisciplinary programs were effective across treatment sites. Patient populations were somewhat different based on descriptive data, such as age and duration of pain. Despite this, groups did not differ globally on a variety of measures selected to represent an array of domains. In addition, there were no differences in change at the two sites on six of seven measures, although difference in response was noted on one measure: change in distance walked in five minutes. This study suggests that, even with somewhat different populations, interdisciplinary programs were robust in the change they produced.In the third analysis, this study also provided evidence that change was only minimally correlated with the number of days of treatment. Despite statistically significant correlations between the numbers of days of treatment, days of treatment only accounted for 4% of variance at most. This finding is consistent with the results of a previous review .et al. [As Gatchel et al.  noted in


Multiple mechanisms are involved in pain associated with osteoarthritis (OA). The painDETECT and Self‐Report Leeds Assessment of Neuropathic Symptoms and Signs (S‐LANSS) questionnaires screen for neuropathic pain and may also identify individuals with musculoskeletal pain who exhibit abnormal central pain processing. The aim of this cross‐sectional study was to evaluate painDETECT and S‐LANSS for classification agreement and fit to the Rasch model, and to explore their relationship to pain severity and pain mechanisms in OA.A total of 192 patients with knee OA completed questionnaires covering different aspects of pain. Another group of 77 patients with knee OA completed questionnaires and underwent quantitative sensory testing for pressure–pain thresholds (PPTs). Agreement between painDETECT and S‐LANSS was evaluated using kappa coefficients and receiver operator characteristic (ROC) curves. Rasch analysis of both questionnaires was conducted. Relationships between screening questionnaires and measures of pain severity or PPTs were calculated using correlations.PainDETECT and S‐LANSS shared a stronger correlation with each other than with measures of pain severity. ROC curves identified optimal cutoff scores for painDETECT and S‐LANSS to maximize agreement, but the kappa coefficient was low (κ = 0.33–0.46). Rasch analysis supported the measurement properties of painDETECT but not those of S‐LANSS. Higher painDETECT scores were associated with widespread reductions in PPTs.The data suggest that painDETECT assesses pain quality associated with augmented central pain processing in patients with OA. Although developed as a screening questionnaire, painDETECT may also function as a measure of characteristics that indicate augmented central pain processing. Agreement between painDETECT and S‐LANSS for pain classification was low, and it is currently unknown which tool may best predict treatment outcome. Pain is a major symptom of patients with osteoarthritis (OA) and has a variety of characteristics suggesting differing underlying mechanisms Although OA is traditionally considered to be nociceptive, some patients describe aspects of their pain as burning or shooting. Such characteristics suggest mechanisms that are shared with neuropathic pain P < 0.0001). However, those investigators did not control for pain intensity and did not examine agreement between classifications.S‐LANSS uses a binary response system requiring subjects to confirm whether or not they have experienced a symptom. It uses a summative score for 7 items to classify subjects into 2 groups: pain is not of a predominantly neuropathic origin (score <12) and pain is of a predominantly neuropathic origin (score ≥12). S‐LANSS exhibited good sensitivity 74%) and specificity (76%) when compared with clinical assessment of pain type across groups of individuals with primarily nociceptive conditions  or neuropathic conditions  % and speAlthough painDETECT and S‐LANSS were developed to classify neuropathic pain, these instruments have also been used to measure neuropathic pain–like symptoms It is important to examine the measurement properties of the questionnaires, because both have been used as measurement scales. This can be achieved with Rasch analysis, which has several statistical advantages, including (given fit to the model) transformation of raw scores into interval‐level data, thereby facilitating, for example, valid analysis of changes in data following an intervention The aim of this study was to optimize and compare properties of painDETECT and S‐LANSS as classification and measurement questionnaires in patients with knee OA. Relationships between these questionnaires and measures of pain intensity were investigated to explore possible confounding by pain severity and their potential for use in phenotyping. Associations between painDETECT scores and PPTs were assessed to examine the extent to which this questionnaire measures augmented central pain processing.Box 1Although painDETECT and the Self‐Report Leeds Assessment of Neuropathic Symptoms and Sign may classify people with knee osteoarthritis (OA) according to a pain phenotype, potentially representing augmented central pain processing, the level of agreement between the classifications made by these questionnaires is low. Further work is required to establish the accuracy of these questionnaires as stratification tools in this condition.Rasch‐converted painDETECT scores may function as a measurement scale for the extent of augmented pain processing in people with knee OA.Questionnaires that classify pain mechanisms in people with OA could help target treatments to those who are most likely to benefit, and identify subgroups of patients suitable for recruitment to clinical trials.Patients with radiographic evidence of knee OA and accompanying pain on most days for the past month were recruited to participate in a cross‐sectional questionnaire study between December 2010 and July 2011  pain rating index and present pain intensity scale A separate sample of patients with clinically diagnosed OA and accompanying knee pain was recruited from primary and secondary care services through another questionnaire study, in order to measure PPTs; radiographs were not scored for these patients. As part of the questionnaire study, these patients were provided an information sheet that included a section on PPT testing and were invited to indicate on their consent form if they were interested in participating. Those interested were telephoned to confirm eligibility and to arrange a time for the test. The same exclusion criteria applied, but patients were also required to be able and willing to travel and undergo PPT testing. In addition to the larger questionnaire, the patients also completed painDETECT, a pain body map, and the ICOAP scale; all of these questionnaires were completed at home. On the day of testing (an average of 34 days after the questionnaires were administered), the patients rated their worst knee pain over the last week on a scale from 0 (no pain) to 10 (pain as severe as it could be) PPTs were measured by 1 of 2 female researchers, using an electronic pressure algometer . The algometer had a 1‐cm–diameter probe, which was applied with increasing pressure at a rate of 50 kPa/second. When patients pressed a switch to indicate that the application was experienced as pain, the probe was immediately retracted, and stimulation ceased. Patients were familiarized with the testing procedure by application of the stimulus to their fingernail. PPTs were recorded at 3 sites in reference to their more painful knee Kappa coefficients Rasch analysis http://onlinelibrary.wiley.com/doi/10.1002/acr22431/abstract). These patients were not, however, included in the other analyses  or used with the other questionnaire scores.An arithmetic average was calculated for PPTs at each site and compared using Friedman's ANOVA by ranks, with pairwise comparisons. Associations between PPTs and Rasch‐transformed painDETECT scores used Spearman's correlation coefficients and partial correlations, controlling for constant and intermittent ICOAP scores. Demographics and pain scores were compared between the questionnaire study and the PPT substudy using Mann‐Whitney U and chi‐square tests. These tests were also conducted to compare patients included in the ROC curve analysis and those who were not, and to compare patients for whom there was agreement between painDETECT and S‐LANSS pain classifications and patients for whom there was no agreement. Patients with missing questionnaire data were included in the Rasch analyses of painDETECT and S‐LANSS and therefore Rasch‐based correlations with these questionnaires, because the Rasch model can handle missing data Sample size calculations for the questionnaire study were based on Rasch analysis. Approximately 150 patients were required in order to have at least 95% confidence that item calibrations were within ±0.5 logits P < 0.05).Of the 474 patients invited to take part in the questionnaire study, 192 were eligible and agreed to participate. Of the 171 patients who responded, 83 (49%) self‐reported pain localized to their knee(s) on the MPQ body map , and 88 (51%) also reported pain in other areas. Additional characteristics of the patients are shown in Table P < 0.001) using painDETECT and S‐LANSS cutoffs of ≥19 and ≥12, respectively. Although the questionnaires showed agreement for pain classifications in 100 patients (74%), they showed disagreement in 35 patients (26%). In 21 of these 35 patients, pain was classified by S‐LANSS as primarily neuropathic and by painDETECT as unlikely neuropathic or as an ambiguous result; for the remaining 14 participants, the opposite was observed. No significant differences were observed for demographic characteristics and the majority of pain scores between patients whose classifications were agreed upon and those whose classifications were not agreed upon. However, summary median painDETECT and S‐LANSS scores were significantly higher (both P < 0.001) in the group in which classifications were disagreed upon than in the group in which classifications were agreed upon, despite producing different pain classifications on an individual patient level in the former group.Fair agreement P < 0.001 and κ = 0.46 , P < 0.001, respectively) but the new cutoffs for S‐LANSS resulted in negligible change .ROC curves were constructed Figure  to deterThe item about the “course” of the patient's pain uses a negative scoring weight that cannot be entered into RUMM2020. Therefore, 1 was added to each of the scoring weights for this item. However, because this approach resulted in misfit ; however, because rescoring did not substantially affect fit, these items were left unaltered. Summary fit statistics indicated adequate fit and a unidimensional scale Table . None ofP = 0.007) following removal of item 4 . The correlations between the questionnaires were very similar when the standard scoring systems were used instead of the Rasch‐converted scores.Rasch‐transformed painDETECT and S‐LANSS scores shared a stronger correlation with each other than with measures of pain severity Table . The assP < 0.05). The sternum and anterior tibia had significantly lower PPTs (more sensitive) compared with the medial joint line (P < 0.01). Higher painDETECT scores were associated with lower PPTs at each site, both in univariate analyses , and after controlling for ICOAP scores . Correlations between the PPT sites and the ICOAP  and NRS  scores indicated that the associations were stronger between PPTs and painDETECT than between PPTs and measures of pain severity. Standard scores for painDETECT and ICOAP produced similar correlations.Of the 114 patients contacted by telephone, 77 were included in the PPT substudy. Those who were not included either were not eligible or were unwilling to participate. Of the 76 patients who responded, 34 (45%) self‐reported pain only in their knee(s) , and 42 (55%) also reported pain in other areas. Demographic characteristics are shown in Table The characteristics of OA‐related pain are diverse, and the quality of this pain suggests mechanisms overlapping with neuropathic pain. In this study, we showed that painDETECT (with 1 item removed) may function as a measure of neuropathic pain–like symptoms in OA, but that S‐LANSS does not function well as a measurement scale. The pain characteristics measured by painDETECT were associated with widespread reductions in PPTs.The mechanisms of OA pain remain incompletely understood but may include changes in the joint and changes in central pain processing PainDETECT, with removal of 1 item, displayed good fit to the Rasch model and was relatively well targeted to the sample, supporting its measurement properties. Although additional items that assess lower trait levels would be useful to fully capture the trait range, precision at this end of the scale is perhaps of reduced importance. Instead, focus should be on individuals with higher trait levels who may benefit from interventions addressing neuropathic pain–like symptoms.S‐LANSS performed less well as a measurement scale. Misfitting items were observed, and the PSI was low, raising concerns about the reliability of the fit statistics and the ability of the scale to discern distinct strata within the sample Although some characteristics distinguish painDETECT and S‐LANSS, they shared a stronger association with each other than with measures of pain severity. The correlation between painDETECT and S‐LANSS remained strong when controlling for pain severity. Both questionnaires appear to address a coherent phenotype in patients with knee OA, despite the aforementioned differences in pain classifications. MPQ PRI scores exhibited similar associations with painDETECT, S‐LANSS, and measures of pain severity, possibly because the MPQ considers neuropathic‐like as well as nociceptive‐like characteristics PainDETECT scores are increased in patients with fibromyalgia, a condition characterized by widespread pain and tenderness associated with abnormal central pain processing but without demonstrable neuropathology Another limitation of the study is that non‐OA knee pain may have confounded the results. Individuals with central pain augmentation frequently report widespread pain, and 53% of the patients in this study reported pain at another site(s) in addition to the knee. Patients with known fibromyalgia (based on self report or case note review) were excluded, but the patients were not classified as having or not having fibromyalgia. Pain mechanisms in fibromyalgia may overlap with those in OA Neuropathic pain is classified as pain caused by a lesion or disease of the somatosensory nervous system In conclusion, ∼30% of the study sample had scores above the cutoff on painDETECT or S‐LANSS, potentially representing a phenotype within knee OA. This phenotype shares characteristics with neuropathic pain and is associated with augmented central pain processing, as indicated by widespread reductions in PPTs. The data suggest that painDETECT and S‐LANSS target a discrete phenotype in knee OA, reflecting pain quality as distinct from pain severity. In addition, Rasch analysis showed that painDETECT may be used as a measurement scale for these phenotypic characteristics. However, agreement between painDETECT and S‐LANSS for pain classification was only fair, and it is currently uncertain which tool is more accurate. Further work with a larger sample size is required to develop these questionnaires as stratification and outcome tools for testing treatments directed at central processing in patients with knee OA.All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Moreton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Study conception and design. Moreton, das Nair, Walsh, Lincoln.Acquisition of data. Moreton, Tew, Wheeler.Analysis and interpretation of data. Moreton, das Nair, Walsh, Lincoln.Supplementary Table 1Click here for additional data file.Supplementary Table 2Click here for additional data file.


DPD deficiency is the result of loss-of-function mutations within the dihydropyrimidine dehydrogenase (DPD) gene. The IVS14+1G>A variant is associated with DPD deficiency as a result of a 165-bp deletion in the DPD mRNA. A rare mutation, c.2846A>T, is characterized by a change of the acidic aspartic acid to the aliphatic valine with potential impairment of enzyme activity [In this study, we describe the spectrum of toxicities of fluoropyrimidines in patients carrying the IVS14+1G>A and 2846A>T variants.®) and IVS14+1G>A and 2846T>C DPD variants were screened on a Real-Time Life Sciences® 7900 HT platform. The study was approved by the local Ethics Committee.Data were collected from 550 patients with gastrointestinal, breast, head-neck and pancreatic cancers. They were evaluated for DPD genotype upon development of grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v.4) following standard fluoropyrimidine-containing regimens in combination with other cytotoxic agents and/or anti-EGFR and VEGF antibodies. DNA was extracted from blood by the Qiamp DNA Blood Mini Kit , G3/4 mucositis (48%), febrile neutropenia (45%), G3/4 thrombocytopenia (38%), G3/4 anemia (24%), G2/3 hand-foot syndrome (14%), G3 dermatitis (7%) and G2/4 alopecia (7%). The IVS14+1AA patient showed diarrhea G2, mucositis G3, anemia G1, pistrinopenia G3, febrile neutropenia G4, complete alopecia and Staphylococcus aureus sepsis. This patient required 20 days of hospitalization and was managed with antibiotics, platelet transfusion, port removal, G-CSF administration and parenteral nutrition. The patient survived because she was given a reduced 5-FU 250 mg/sqm test dose without folates, while the 2846TT patient deceased after the first cycle of FOLFOX4 treatment because of a diarrhea G3, mucositis G4, febrile neutropenia and piastrinopenia G4.Patients carrying the deleterious IVS14+1G>A and 2846T>C variant alleles display severe toxicities which are fatal in homozygous variant subjects. Although the frequence of DPYD*2A allele is low, the screening for DPD mutation is clinically relevant to avoid the severe toxicities or death in patients treated with fluoropyrimidine-containing regimens. This finding suggests the usefulness of pre-treatment screening of DPD in patients candidates to fluoropyrimidine treatment.


In the Danish Emergency Process Triage (DEPT) pain is used as an independent contributor for triaging patients and is validated by the Numerical Pain Rating scale, NRS-11. Prior studies have assessed the congruence between nurse's assessment of their patients' pain intensity and the patients' own pain perception with mixed results. The aim of this study was to examine the correlation in pain score between nurse and patient and the inter-rater agreement between nurses when the pain score is used in a triage system in an Emergency Department.The patients were asked to score themselves on the NRS scale and a final NRS score was then given by the nurses based on their objective findings. We asked two nurses to independently validate the same patients according to the DEPT triage instructions. The two nurses did not have access to each other's pain score of the patient. Data were analysed by Wilcoxon signed rank test and Kappa statistics.A total of 326 independent patient-nurse pairs of observations were analysed. The nurses scored the patient significantly lower on the NRS scale than the patients did themselves . The overall inter-rater agreement between nurses and patient was moderate  but lower for younger patients and patients with an orthopaedic pain complaint. In 163 patients, pain score was assessed by two nurses and the inter-rater agreement moderate , lower for younger patients and female patients.Nurses score patient pain lower than the patients on the NRS scale, especially young and orthopaedic patients. The inter-rater agreement between the nurses was also moderate and lower for young and female patients. These findings weaken the usage of pain in triage systems.


Background: Slowing of the electroencephalogram (EEG) is frequent in Parkinson’s (PD) and Alzheimer’s disease (AD) and correlates with cognitive decline. As overlap pathology plays a role in the pathogenesis of dementia, it is likely that demented patients in PD show similar physiological alterations as in AD.Objective: To analyze distinctive quantitative EEG characteristics in early cognitive dysfunction in PD and AD.Methods: Forty patients (20 PD- and 20 AD patients with early cognitive impairment) and 20 normal controls (NC) were matched for gender, age, and education. Resting state EEG was recorded from 256 electrodes. Relative power spectra, median frequency (4–14 Hz), and neuropsychological outcome were compared between groups.Results: Relative theta power in left temporal region and median frequency separated the three groups significantly (p = 0.002 and p < 0.001). Relative theta power was increased and median frequency reduced in patients with both diseases compared to NC. Median frequency was higher in AD than in PD and classified groups significantly (p = 0.02).Conclusion: Increase of theta power in the left temporal region and a reduction of median frequency were associated with presence of AD or PD. PD patients are characterized by a pronounced slowing as compared to AD patients. Therefore, in both disorders EEG slowing might be a useful biomarker for beginning cognitive decline. Mild cognitive impairment (MCI) is a prodromal syndrome of neurodegenerative dementia without significant impairment in activities of daily living (ADL); however, it is unspecific as it can be caused by various pathologies  has increasingly been used to characterize cognitive impairment in different disorders  was based on Litvan et al. (N = 5) was made according to Emre et al.  or mild dementia due to probable AD (N = 8) were recruited from the Memory Clinic, University Center for Medicine of Aging, Basel. Thereof 20 patients were matched to the PD group for gender, age, and education. MCI due to probable AD was diagnosed according to Winblad et al.  were matched to both patient groups according to gender, age, and education Table . Inclusiz-scores . They were instructed to relax, but to stay awake and to minimize eye and body movements. A continuous EEG with closed eyes was recorded for 12 min. During data acquisition, a subset of electrodes was monitored online by a technician to check for vigilance and artifacts. For patients taking benzodiazepines for sleep deprivation (one patient per group), medication was discontinued before EEG recording for at least 48 h. Only benzodiazepines with short half-life were allowed. One patient of the PD group was taking low-dose quetiapine for sleep deprivation, three patients were taking acetylcholinesterase inhibitors.t(x) = log(x/(1 − x)] to achieve an approximate normal distribution  without artifacts or signs of sleep and drowsiness were visually selected, filtered  and down-sampled (500 Hz). Data from 214 electrodes (excluding cheek and neck electrodes) were subjected to automated artifact detection  were used .No significant differences between the patient groups regarding age, education, the combined MMSE/CDT, and gender were found , NC > PD (p < 0.001), and AD > PD (p < 0.05).Occipital median frequency differed significantly between groups with the following pattern found in the p = 0.02) was achieved. After backwards elimination, the resulting model included only median frequency as predictor (p = 0.03). ROC analysis yielded an AUC of 0.72 with a sensitivity and specificity at the best index of Youden (0.45) of 60 and 85%, respectively. The positive predictive and negative predictive values were 80 and 68%, respectively.As the median frequency was significantly different between AD and PD, it was chosen as independent variable for a logistic regression model to classify the two groups. A significant classification of both groups (We checked for a confounding influence of the variables MMSE, LED, alertness, age, and gender on the power values, by entering the variables into linear models with stepwise backwards elimination. No significant effects of the potentially confounding variables on the qEEG parameters were found. We conducted sensitivity analysis by running the statistics on all but one PD patient taking neuroleptics and on all but three patients taking AChE-inhibitors. The outcome was not affected as similar results and significances were obtained with and without those patients.The main alteration of EEG in patients with subtle cognitive deficits due to AD or PD consists in an increase of relative theta power, predominantly in the temporal regions and in a slowing of the occipital median frequency. The slowing is more pronounced in PD than in AD patients.Bi-temporal increase of relative theta power in demented PD and AD patients is a known finding (Babiloni et al., Dysfunction of the cholinergic system is common in both, AD and PD (Mesulam et al., The advantage of the present study is the comparison of demographically well balanced groups of patients with AD or PD at incipient cognitive decline with a group of NCs. Limitations include the relatively small sample sizes and the inherent failure of AD-MCI patients to formally fulfill the diagnostic criteria of AD. Longitudinal assessment of these patients is warranted.Nina Benz: none; Florian Hatz: none; Habib Bousleiman: none; Michael M. Ehrensperger: none; Ute Gschwandtner: Support from Mach-Gaensslen-Foundation, Gossweiler Foundation, Parkinson Schweiz, Synapsis Foundation, Botnar Foundation; Martin Hardmeier: none; Stephan Ruegg: Swiss National Science Foundation; Christian Schindler: Swiss National Science Foundation; Ronan Zimmermann: none; Andreas Urs Monsch: Swiss National Science Foundation, Parkinson Schweiz, Gossweiler Foundation, Synapsis Foundation, Novartis, Novartis Research Foundation; Peter Fuhr: Support of research from Swiss National Science Foundation, Mach-Gaensslen-Foundation, Gossweiler Foundation, Parkinson Schweiz, Synapsis Foundation, Botnar Foundation, Freiwillige Akademische Gesellschaft Basel, Novartis Research Foundation, Novartis, Roche, AbbVie.


The objective of this study was to evaluate pain in women with breast cancer-related lymphedema and the characteristics of aggravating factors and coping mechanisms. The study was conducted in the Clinica Godoy, São Jose do Rio Preto, with a group of 46 women who had undergone surgery for the treatment of breast cancer. The following variables were evaluated: type and length of surgery; number of radiotherapy and chemotherapy sessions; continued feeling of the removed breast (phantom limb), infection, intensity of pain, and factors that improve and worsen the pain. The percentage of events was used for statistical analysis. About half the participants (52.1%) performed modified radical surgery, with 91.3% removing only one breast; 82.6% of the participants did not perform breast reconstruction surgery. Insignificant pain was reported by 32.60% of the women and 67.3% said they suffered pain; it was mild in 28.8% of the cases , moderate in 34.8% , and severe in 4.3%. The main mechanisms used to cope with pain were painkillers in 41.30% of participants, rest in 21.73%, religious ceremonies in 17.39%, and chatting with friends in 8.69%. In conclusion, many mastectomized patients with lymphedema complain of pain, but pain is often underrecognized and undertreated. Chronic pain affects from 25% to 60% of patients submitted to breast cancer treatment, and thus this is an important clinical problem which involves intra- and postoperative factors . ChemothThe objective of this study was to evaluate pain in women with breast cancer treatment-related lymphedema and the characteristics of aggravating factors and coping mechanisms.Descriptive, qualitative study assessing pain reported after treatment of breast cancer surgery in a group of 46 women.All patients who had been subjected to breast cancer treatment and who were in rehabilitation due to lymphedema in the Clinica Godoy in São Jose do Rio Preto, SP, in 2010 were considered for participation in this study.The following variables were investigated using a questionnaire: type and length of surgery, number of radiotherapy and chemotherapy sessions, infection, pain (at removed breast or at another site of the body), intensity of pain, and factors that improved and worsened the pain. The intensity of the pain was evaluated using a visual scale of 0 to 10 . The body weight and height were measured to calculate the BMI. The responses to each item were analyzed as a frequency of events (%) and mean or median for age.All patients who accepted to participate in the study signed informed consent forms and the study was approved by the Research Ethics Committee of FAMERP (Protocol number 85923).About half (52.1%) of the participants performed modified radical surgery  and only 17.37% underwent breast reconstruction surgery; the surgery was performed after more than 19 months in almost 74% of cases. Six to ten sessions of chemotherapy were used in 63.04% of the cases and more than 30 sessions of radiotherapy in 71.3% in a period from 1 to 120 months were used .Insignificant pain was reported by 32.61% of the women and 67.3% said they suffered pain; it was mild in 28.26% of the cases , moderate in 34.78% , and severe in 4.35% .The main coping mechanisms were painkillers for 41.30%, rest for 21.74%, participating in religious services for 17.39%, and chatting with friends for 8.70% .Another characteristic was that 39.1% of the women reported that they had pain outside the region of the surgery  within 6 to 12 months after the surgery which reduced after two years. At the site of the breast, 39.13% reported that the pain persisted for up to one year and 4.34% for up to two years . WorseniThis study shows the prevalence of pain, the coping mechanisms, and the aggravation factors in women treated for breast cancer and subsequently for lymphedema. Pain was reported by 67% of the study sample, with varying intensities of pain and using different mechanisms for its control. This prevalence is similar to that reported in the literature .The use of painkillers was the most cited mechanism, followed by resting. However, unconventional options were also reported as a mechanism of coping with pain such as participating in religious services as described by 17.3% of the patients. Thus, a search for something higher and spiritual constituted a protective mechanism against physical pain. Another aspect that calls the attention is that more than 52% of these patients were college graduates and that the level of education did not interfere in their pursuit for faith as a mechanism of pain control. Several factors are cited that can affect pain such as psychological aspects, infection, immunotherapy, type of surgery, nerve injuries, and bursitis;  an assocAnother way of controlling pain was chatting with friends as mentioned by 8.6% of the women; thus, a mechanism for pain control that involved spiritual or psychological acts was used by more than 25% of the cases.An important differential that caught the attention was in relation to pain and its location either at the site of surgery or in other parts of the body. The reports of pain in other locations were associated with emotional aspects associated with treatment and sometimes with the type of surgery used. However, the reduction of pain over time was important in the evolution of patients.Worsening of pain on physical exertion was reported by 50% of the patients, with stress being the second most common factor in 34.7% of patients. Environmental factors, such as heat and cold, also influenced the symptoms.Thus, several factors that interfere in the pain were identified by participants as were the mechanisms  they used to control it. These methods of coping with the pain help patients to alleviate their suffering. In addition to the physical and psychological aspects, a broad approach to these patients involves an investigation of difficulties experienced in their day-to-day lives, coping mechanisms, nutritional aspects, and the adaption to their reality; this approach must be individualized –12.In respect to the occupation of participants in this study, many reported that the surgery took place after they had retired; a second group requested retirement due to illness. The retired individuals had activities in their homes and remained with their families and those who had requested sick leave, even after two years, did not return to their normal activities as they reported feeling a loss of the physical functioning of the arm on the operated side.The majority of individuals who continued in their jobs were self-employed in informal activities and without the necessary documentation to claim sick allowance and thus could not stop working. The majority of participants had completed college education, but this did not change their psychological, social, and physical difficulties. Most did not receive psychological support or any type of physical therapy after surgery.These data highlight the multifactorial consequences of breast cancer treatment, which often are associated and are difficult to detect and so it is difficult to give the required support.In this study, it was found that most of the participants did not receive any kind of psychological and physical support from different health services during treatment. Treatment programs that involve a multidisciplinary team and that more broadly address the problems of these patients are thus recommended –15 and pThe results of this study show the need for rehabilitation programs immediately after breast cancer surgery. It is being recognized by more and more health care professionals that morbidity after breast cancer treatment causes functional sequelae that interfere in the daily life of patients , 14.In conclusion, many mastectomized patients with lymphedema complain of pain, but pain is often underrecognized and undertreated.


We investigated the long-term effects and safety of botulinum toxin-A (BTX-A) for treating trigeminal neuralgia (TN). We also studied long-term maintenance of this therapeutic effect.A visual analog scale (VAS) score, pain attack frequency per day, patient’s overall response to treatment and side effects during 14-month follow-up were evaluated in 88 patients with TN receiving BTX-A. The primary endpoints were pain severity (assessed by VAS) and pain attack frequency per day. The secondary endpoint was the patient’s overall response to treatment, assessed using the Patient Global Impression of Change. The influence of different doses  on the therapeutic effect was evaluated.Treatment was deemed “effective” within 1 month in 81 patients and at 2 months in 88 patients (100%). The shortest period of effective treatment was 3 months, and complete control of pain was observed in a maximum of 46 patients. The therapeutic effect decreased gradually after 3 months, and the prevalence of effective treatment at 14 months was 38.6%, with complete control of pain seen in 22 patients (25%). There was no significant difference in the prevalence of effective treatment between different dose groups at identical time points (p > 0.05). Three patients showed swelling at injection sites and 10 patients showed facial asymmetry, both of which disappeared spontaneously without special treatment.Local subcutaneous injection of BTX-A for TN treatment has considerable therapeutic effects lasting several months and is safe for this indication. At least one-quarter of patients maintained complete analgesia. The maintenance period of the therapeutic effect may be related to the reduction in the VAS score after the first injection of BTX-A. Trigeminal neuralgia (TN) is characterized by sudden , severe, brief, stabbing, recurrent pain in the distribution of one or more branches of the trigeminal nerve. TN is usually evoked by the stimulation of facial “trigger points”, such as teeth-brushing, face-washing, drinking, or shaving. Because the pain is long-term and severe, the quality of life of patients is severely affected .Clostridium botulinum. It relaxes muscles through the release of acetylcholine at nerve–muscle junctions. Therefore, BTX-A is used widely in cosmetology and treating dysmyotonia [Botulinum toxin A (BTX-A) is a type of exotoxin produced by myotonia . BTX-A cmyotonia . It is uRecently, the use of BTX-A for pain management has received considerable attention. In 2002, Micheli et al. were the first to report that BTX-A can relieve TN . SubsequThe study protocol was approved by the Ethics Committee of Zhengzhou University . All patients provided written informed consent to participate in the study.We conducted an open study. Eighty-eight subjects with primary one-branch classical TN treated with BTX-A were recruited as outpatients or inpatients from the Neurology Department of the First Affiliated Hospital, Zhengzhou University from January 2009 to June 2012. The goal, procedure and safety aspects of the study were explained to each of the patients and Informed consent was included in the documents of each patient. The medications which were used to alleviate their pain were asked to remain unchanged during the course of the study. All patients showed symptom improvement after 8 weeks of treatment, and were followed up for 12 months. And for some patients who didn’t show symptom improvement within 2–4 weeks,we gave an additional dose, and plus the additional dose for the first dose as the treatment dose. The patients who showed improvement after 8 weeks of re-injection were followed up for 12 months too. Before hospital admission, all patients underwent laboratory examinations to exclude coagulation disorders and severe dysfunction of the heart, liver or kidneys. Detailed physical examinations as well as CT and MRI of the cranium were conducted to exclude secondary TN.®; 100 U/bottle; Lanzhou Bioproduction Institute, Lanzhou, China) was diluted with 0.9% saline (2 mL) to 50 U/mL before use. The BTX-A solution was injected in the facial area and the trigger point of pain at a depth of 0.5 cm, 2.5-5 IU per point, separation of 15 mm and at 15–20 injection points. And for some patients the pain within one side of gum, the injection points were 4–10,and because the gingival mucosa is thinner than skin, the dosage were fewer than facial area in each point.BTX-A crystals  was recorded in detail each day by patients before and after therapy. Clinic visits or telephone follow-up were undertaken by the same person every week for 2 months and every month thereafter. The patient’s overall response to treatment was followed up each month after therapy. The extent of pain was evaluated through a visual analog scale (VAS) with 11 points on a ruler of length 10 cm where 0 denoted “no pain” and 10 denoted “most severe pain”. Patients pointed to the representive point of pain on the panel without reading it but instead according to their feelings, and the corresponding pain scores were recorded. We adopted the classification that a reduction in the VAS score of <50% after treatment meant that treatment was classified as being “ineffective”, 50–70% as “effective”, >75% as “significantly effective” and “0” meant that pain was “completely controlled”. The total effective value was defined as the percentage of patients with a reduction in the VAS score of ≥50%. The patient’s overall response to treatment assessed using the Patient Global Impression of Change. PCIC is a single-item rating by patients of their improvement with treatment during the therapy on a 7-point scale that ranges from ‘very much improved’ to ‘very much worse’ with ‘no change’ as the mid-point.Information regarding side effects  was recorded in detail.2 test. p < 0.05 was considered significant.Data are the mean ± SD and were analyzed using SPSS ver20.0 . The effective value was analyzed using the χThe patient cohort comprised 38 males (43.2%) and 50 females (56.8%). The age range was 33–89 years . Disease progression was 14–150 months with mean of 52 months and SD of 50.17. All 88 patients showed symptom improvement within 2 weeks. The percentage of patients in whom treatment was effective at 2 months reached 100%.The pain area was in the first branch of the trigeminal nerve in 19 cases, in the second branch in 42 cases, and in the third branch in 27 cases.Maximal and minimal doses were 170 U and 25 U, respectively. The dose was ≤50 U in 43 cases, 50–100 U in 32 cases, and ≥100 U in 13 cases.Treatment was classified as being effective within 1 month in 81 cases, and was effective at 2 months in 88 cases . All the patients who showed symptoms improvement significantly reduced pain attack frequency. TN was classified as being completely controlled at 3 months in 46 cases. The number of cases in whom treatment was classified as being effective at 3 months decreased to 76, and the number of cases with a reduction in the VAS score of 50–75% decreased from 30 to 17 at 2 months. After 3 months, the effect of BTX-A decreased gradually, with a prevalence of effective treatment of 38.6% at 14 months, and of TN being completely controlled in 22 cases (25%)  Table .There was no significant difference in the prevalence of pain attack frequency between different dose groups at identical time points between 1 month and 14 months (p > 0.05) , of which 14 cases showed no pain at 14 months. These results suggest that the factor influencing the long-term effect of BTX-A is not dose but the extent of the reduction of the VAS score. That is, the more the VAS score decreases, the longer the therapeutic effect is maintained. Therefore, to reach complete control of symptoms and limit the minimal effective dose, we recommend a small dose for the first injection and increase the dose after 2–4 weeks for those in whom complete control of symptoms after the first injection is not observed.The mechanism of action of BTX-A in pain therapy is not clear. Recent studies suggest that BTX-A can relieve pain through inhibition of the release of cytokines from sensory terminals and by reducing neurogenic inflammation . This efWe observed only mild local side effects. Local swelling at injection sites occurred in 3 patients and disappeared within 7 days . Muscle relaxation and facial asymmetry at injection sites occurred in 10 patients and disappeared within 6–8 weeks , which may have been due to the diffusion of BTX-A into deeper layers of facial muscles as well as the induction of transient muscle paralysis. All side effects were mild and disappeared without the requirement for special treatment.During the study, we observed more than 90% patients with effective treatment reported that they were “much improved” or “very much improved” each month. That means the treatment not only improved the TN symptoms, but also showed an improvement in the quality of life, emotional function, side effect burden. So, we think the subcutaneous injection of BTX-A for treating TN is a clinical trial achieved a good satisfaction out of participants’ aggregation all of the components of their experience—pain relief, improvement in physical and emotional functioning, side effects and so on.And for those patients who have lost the injection efficacy, 10 patients choose the surgical treatment, 4 patients received the medical treatment, and 40 patients received re-injection.In conclusion, we found that local subcutaneous injection of BTX-A for treating TN had considerable beneficial effects lasting for several months and was safe to use for this indication. One-quarter of patients could reach complete control of pain for >14 months, and maintenance of the therapeutic effect was related to a reduction in the extent of the VAS score after the first injection.The authors declare that they have no competing interest.YJL study concept and design. SL acquisition of data. HFZ carried out the treatment and studies, drafted the manuscript. YC participated in the sequence alignment, analysis and interpretation. YQM, CHH, CJW revise the manuscript. NCX, YKZ, YC study supervision. All authors read and approved the final manuscript.


Background. Two prophylactic papillomavirus (HPV) vaccines have been available for primary prevention of cervical cancer. Although serious adverse effects (AE) were rare, more than 230 women have been suffering from severe AEs such as persistent pain and headache in Japan. Our research group started to treat adolescent females suffering from the AEs. Objective. To survey the characteristics of and the effects of cognitive behavioral therapy on adolescent female suffering from the AEs in Japanese multidisciplinary pain centers. Methods. One hundred and forty-five patients suffering from the AEs were reviewed retrospectively and 105 patients of them were provided guidance on home exercise and activities of daily living based partially on a cognitive-behavioral approach. The intensity of pain was rated by the patients using a numerical rating scale (NRS). Furthermore, the Hospital Anxiety and Depression Scale (HADS) and the Pain Catastrophizing Scale (PCS) were used. Results. Eighty out of the 105 patients who received the guidance were followed up, 10 displayed a marked improvement, and 43 showed some improvement. Conclusions. Guidance on home exercise and activities of daily living based on a cognitive-behavioral approach alleviated the AEs that women suffered from after HPV vaccination in Japan. Cervical cancer is the fourth most common cancer in women in the world . GenitalBoth vaccines were introduced in Japan in 2010 and Japanese women were required to receive one of these vaccines from April 2013. The introduction of the vaccines has generated great controversy over its safety in Japan . In JapaChronic pain of adolescents interferes with their daily lives and is associated with functional disability and distress , 7. In tRetrospective analysis from July 2013 to July 2014 was performed on women who visited multidisciplinary pain centers (Pain Centers) in Japan. All patients were referred from other hospitals to the Pain Centers because of AEs after HPV vaccination. Treatment protocols used in the present report were based on institutional policy and clinical guidelines approved by the IRB of each institution. After obtaining approval from the IRB , we routinely explain to all patients that we record and store demographics, symptoms, course of pain, and medical records of all patients for future possible use in our research. After we explained these details, we obtained written informed consent upon their initial visit to the Pain Centers.n = 40). Three-quarters of the women who presented (n = 105) accepted this, to whom we proposed the provision of guidance on home exercise and ADL based partially on a cognitive-behavioral approach.We saw the patients and checked their clinical and laboratory data which they brought to the center. We sometimes performed additional medical examinations if the data they provided were insufficient. Based on their symptoms, signs, physical condition, and medical data, we confirmed and explained to these women that in almost all cases there was no clinical or laboratory evidence of relevant pathology in their pain and its associated symptoms. Some patients and family members declined to accept this  where 0 indicated no pain and 10 the greatest pain possible. Furthermore, we used the Hospital Anxiety and Depression Scale (HADS) to determine the levels of anxiety and depression and the Pain Catastrophizing Scale (PCS) to determine the levels of physical and emotional distress associated with their current pain problems that they and family members associated with their HPV vaccination. The HADS consists of 14 items; the anxiety (HADS-A) and depression (HADS-D) subscales each include 7 items –11. A 4-We gave them and family members some explanations as follows: prolonged pain can result in sleep disorders, decreased desire, anxiety, depression, and decreased routine activity, occasionally causes withdrawal from school or society, and otherwise disrupts daily activities , 9, 14. Furthermore, the guidance was designed to inform the patients and family members about how to correct or eliminate excessive fear of pain, improper thinking for treating pain, and anxiety caused by distorted cognition as well as how to control activity levels by appropriate pacing by a doctor (anesthesiologist or orthopedic surgeon) for engagement with normal daily activities and the patients and family members were asked to do these matters at home. The guidance was arranged according to their daily activities at each visit. Frequency of visits ranged from once a month to once every two months. For stretching, a doctor (orthopedic surgeon) or physiotherapist instructed the patients to stretch the muscle groups in their shoulder girdles, lumbar area, hips, thighs, and lower legs tailored to each female. Stretching consisted of self-performed static stretching with the muscle groups extended for 20 seconds each twice a day. Also, they were instructed in muscular strengthening exercises to strengthen the trunk and leg muscle groups in the supine, sitting, and standing positions, performing 10 repetitions under their own body weight tailored to each female twice a day. In 9 cases, psychotherapists provided the females and their family members with counseling as needed.Patients were categorized as showing marked signs of improvement  for pain compared to initial visit), some improvement , no improvement , and deterioration  depending on the state of pain 6 months after the initial visit. Moreover, patients who did not visit the hospital again even with an appointment for a follow-up visit and those who visited the Pain Centers to receive a second opinion were categorized separately.p = 0.1443). There was no significant difference between the two groups in the vaccine doses . There was no statistically significant difference between the two groups in the median (range) duration of symptoms . The median (range) of anxiety subscale of pretreatment HADS was 5 (0–17) in the accept group and 6 (0–15) in the decline group . The median (range) of depression subscale of pretreatment HADS was 4 (0–16) in the accept group and 5 (0–16) in the decline group . The median (range) of pretreatment PCS was 27.5 (0–51) in the accept group and 30 (0–52) in the decline group . NRS showed a statistically significant difference but the difference was not clinically significant.The characteristics of the patients are described in p = 0.1807). Pain improvement in the accept group was described for each age in p = 0.5521). There were no significant differences in treatment outcomes for each different type of symptom  ( 0.6826) . There w 0.6826) .n = 40), three-quarters of the women who presented (n = 105) accepted this. In Japan, some researchers regard the symptoms as a consequence of psychosomatic reactions, so we had expected that psychological issues of the decline group might have been worse than those of the accept group. Although we compared the background between these two groups, we did not identify any significant differences in the type and dose of vaccine, the duration of symptoms, and psychological issues of HADS and PCS. However, we think that we need further studies in these points. NRS showed a statistically significant difference but we considered that the difference was not clinically significant.Two prophylactic HPV vaccines  were introduced in Japan. The cause of serious symptoms among teenage girls vaccinated with the HPV vaccines and their safety have yet to be verified. In the present survey, we confirmed and explained to these women that in almost all cases there was no clinical or laboratory evidence of relevant pathology in their pain and its associated symptoms, based on their symptoms, signs, physical condition, and medical data. While some patients and family members declined to accept this  vaccines  have been available for primary prevention of cervical cancer. More than 230 women have been suffering from severe adverse effects (AEs) such as persistent pain and headache after vaccination in Japan, so Japan has stopped recommending the HPV vaccines. Our research group started to treat women suffering from AEs after HPV vaccination. Guidance on home exercise and activities of daily living based on a cognitive-behavioral approach alleviated, to some extent, the AEs that adolescent females suffered from after HPV vaccination in Japan.