This 52-week study evaluated the long-term safety and tolerability of capsaicin 8% w/w (179 mg) patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy (PDPN).
Phase 3, multinational, open-label, randomised, controlled, 52-week safety study, conducted in Europe. Patients were randomised to capsaicin 8% patch repeat treatment (30 or 60 min; 1–7 treatments with ≥ 8-week intervals) to painful areas of the feet plus SOC, or SOC alone. The primary objective was the safety of capsaicin 8% patch repeat treatment (30 min and 60 min applications) plus SOC versus SOC alone over 52 weeks, assessed by changes in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) total score from baseline to end of study (EOS). Secondary safety endpoints included Utah Early Neuropathy Scale (UENS) assessments and standardised testing of sensory perception and reflex function.
Overall, 468 patients were randomised (30 min plus SOC, n = 156; 60 min plus SOC, n = 157; SOC alone, n = 155). By EoS, mean changes in Norfolk QOL-DN total score from baseline [estimated mean difference versus SOC alone; 90% CI for difference] were: 30 min plus SOC, −27.6% [−20.9; −31.7, −10.1]; 60 min plus SOC, −32.8% [−26.1; −36.8, −15.4]; SOC alone, −6.7%. Mean changes [difference versus SOC alone] in UENS total score by EoS versus baseline were: 30 min plus SOC, −2.1 [−0.9; −1.8, 0.1]; 60 min plus SOC, −3.0 [−1.7; −2.7, −0.8]; SOC alone, −1.2. No detrimental deterioration was observed in any of the Norfolk or UENS subscales by EoS with capsaicin. Also, no worsening in sensory perception testing of sharp, warm, cold and vibration stimuli was found with capsaicin by EoS. Capsaicin treatment was well tolerated and the most frequent treatment-emergent adverse events were application site pain (30 min, 28.2%; 60 min, 29.3%), burning sensation (30 min, 9.0%; 60 min, 9.6%) and application site erythema (30 min, 7.7%; 60 min, 8.9%).
In patients with PDPN, capsaicin 8% patch repeat treatment plus SOC over 52 weeks was well tolerated with no negative functional or neurological effects compared with SOC alone.
ClinicalTrials.gov registration: NCT01478607. Date of registration November 21, 2011; retrospectively registered.
Peripheral neuropathic pain (PNP) is widely recognised to have a significant impact on quality of life (QOL) . Painful diabetic peripheral neuropathy (PDPN) has been shown to affect many dimensions of patient QOL, including mood, sleep, work, self-esteem and social relationships, and has a particular impact on individuals with suboptimally managed pain [2, 3]. Approximately one in four people with type 2 diabetes will experience some level of PDPN , which often presents as numbness, tingling, burning, aching, electric shocks, or lancinating pains .
Many patients with PDPN remain undiagnosed or undertreated and few experience complete resolution of pain. There is a clear unmet need for new therapeutic options to improve current standard of care (SOC); available treatments such as antidepressants, antiepileptic drugs and opioids are often limited by contraindications and safety issues, and frequently have insufficient efficacy to achieve adequate pain relief [6–8]. One alternative to these treatments is the capsaicin 8% patch, which contains 179 mg or 8% weight for weight capsaicin and is optimised for rapid delivery of a high concentration of capsaicin directly into the skin . Defunctionalisation of hyperactive nociceptors in the skin induced by the rapid delivery of capsaicin provides fast, targeted, and sustained pain relief after a single treatment. Furthermore, local application of the capsaicin 8% patch provides minimal systemic absorption, without the potential for drug-drug interactions or requirement for dose adjustment in elderly patients or patients with renal or hepatic impairment .
The capsaicin 8% patch is well tolerated and provides effective relief of pain for a variety of types of PNP [11–16]. A single capsaicin 8% patch treatment has demonstrated significant improvements in pain relief versus a placebo patch over 12 weeks, and was well tolerated with no sensory deterioration in patients with PDPN . The present study in patients with PDPN (PACE) was the first evaluation of the long-term safety and tolerability of capsaicin 8% patch repeat treatment plus SOC, compared with SOC alone, over 52 weeks. The study had an open-label design; it primarily assessed the safety of capsaicin 8% patch repeat treatment, with efficacy of the capsaicin 8% patch in PDPN assessed in the double-blind STEP study . In this study, the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire was chosen as the primary endpoint to assess the safety of capsaicin treatment. The Norfolk scale is a validated patient-reported outcome questionnaire, which captures the entire impact of nerve fibre dysfunction on QOL in diabetic neuropathy . The Norfolk tool includes the concentration of symptoms in the extremities and subtle loss of function, such as fine motor impairments, slight sensory changes, unique problems with proprioception and balance and autonomic symptoms. The Norfolk QOL-DN scale was therefore used to assess any functional consequences associated with potentially deleterious effects of capsaicin treatment on peripheral nerve endings in patients with PDPN.
PACE was a Phase 3, multinational, open-label, randomised, controlled, 52-week safety study, conducted in Europe between November 2011 and February 2014 (ClinicalTrials.gov Identifier: NCT01478607). The primary objective assessed the safety of repeat treatment with the capsaicin 8% patch (QUTENZATM 179 mg capsaicin patch, obtained from Astellas Pharma Europe B.V., Leiden, The Netherlands) in patients with PDPN.
Following a screening visit, patients were assigned a six-digit subject number allocated sequentially according to site and randomised to capsaicin 8% patch (30 min) plus SOC or capsaicin 8% patch (60 min) plus SOC or SOC alone in a ratio of 1:1:1 by chronological order of enrolment to receive treatment with the capsaicin 8% patch to painful areas of the feet for either 30 min plus SOC, 60 min plus SOC, or SOC alone. All patients were pretreated with a eutectic mixture of local anaesthetics (EMLA) containing lidocaine 2.5% and prilocaine 2.5%, to limit pain or discomfort during the application period. The 30-min application time was chosen to align with the approved Summary of Product Characteristics . A 60-min application time was also evaluated in order to ensure that the safety objectives of the study were fully covered with respect to possible exposure periods. SOC was optimised for each patient at the discretion of each investigator and was assessed at clinic visits and on days 1 to 5 post-treatment, by completion of a rescue pain medication diary. The treatment area was mapped at screening and baseline visits, and re-mapped before treatment if the treatment area changed. Treatment borders were defined by the most painful areas of the feet, up to a total combined surface area of 1120 cm2 (four patches) for both feet. Assessments were scheduled every two months; clinic visits were scheduled for Month 2, 4, 6, 8, 10, and 12, and telephone contact was scheduled at Month 1, 3, 5, 7, 9, and 11. Capsaicin 8% patch retreatment could occur at both scheduled and unscheduled clinic visits at the investigator's discretion, but only after at least 8 weeks had elapsed since the last treatment (Fig. 1).
Patients could not receive more than seven capsaicin 8% patch treatments during the study. Although patients and investigators were unblinded throughout the study, physicians assessing neurological function were blinded to treatment and not involved in the study in any other manner.
Patients were aged ≥18 years with a diagnosis of PDPN due to type 1 or type 2 diabetes mellitus for ≥1 year prior to the screening visit. Key criteria for inclusion and exclusion are presented in Table 1.
The primary objective was to evaluate the safety of repeat treatment with the capsaicin 8% patch, assessed by the percentage change from baseline to end of study (EoS) in the Norfolk QOL-DN total score. The scale has been shown to correlate with clinical Total Neuropathy Score along with the different features of diabetic neuropathy such as small fibre function (including loss of pain and thermal sensation), large fibre function (including motor function and touch/pressure discrimination) and autonomic nerve function . The Norfolk QOL-DN scale was specifically developed to reliably measure changes in nerve function that translate into changes in QOL, activities of daily living, and health of the individual, where a reduction in score is associated with improved function . In this study, it was used to assess any functional consequences of potential small nerve fibre dysfunction that may have been associated with capsaicin 8% patch repeat treatment and adversely affected QOL.
Secondary safety variables evaluated to support the primary endpoint included Norfolk QOL-DN subscale scores, Utah Early Neuropathy Scale (UENS)  assessments and standardised testing of sensory perception and reflex function. Average pain score, pain severity index, pain interference index, obtained from the Brief Pain Inventory-Diabetic Neuropathy (question 5), response rates and Patient Global Impression of Change were recorded as other secondary endpoints in this study and will be reported separately.
Secondary safety variables related to Norfolk QOL-DN included: percentage change from baseline in Norfolk QOL-DN total score by number of capsaicin treatments; percentage change from baseline in Norfolk QOL-DN subscale scores ('small fibre', 'symptoms', 'autonomic', 'physical functioning', 'activities of daily living'); and absolute Norfolk QOL-DN total score. A reduction in subscale score was associated with improved function.
The UENS, a validated clinical tool developed to detect and quantify signs of early neuropathy and identify modest changes in the severity and spatial distribution of sensation, was used to assess any functional consequences of capsaicin treatment. A reduction in score indicates improvement in sensory function over time. Endpoints related to the UENS included: change from baseline in UENS total score; change from baseline in UENS total score by number of capsaicin treatments; change from baseline in UENS subscale scores ('pinprick sensation', 'motor', 'allodynia/hyperaesthesia', 'large fibre', 'deep tendon reflex'); clinically significant change in UENS total score (defined as a decrease of > 4 points from baseline); and absolute UENS total score.
Sensory examination was performed by neurologists as well as by non-neurologist physician-investigators given study training, and were ideally performed by the same person (Additional file 1). Physicians conducting sensory examinations were blinded to treatment. 'Bedside' sensory and reflex testing was performed on both feet at baseline and EoS to identify any clinically relevant deficits in sensory function. Ratings of evoked sensation were compared with an asymptomatic site and recorded using standardised categorical reporting scales: assessment of warm, cold, and sharp sensations were rated as 'absent', 'diminished', 'normal', or 'painful'. Sensation of vibration on the dorsal surface of the great toe was rated as 'absent', 'markedly diminished', 'mild loss', or 'normal' sensation. Testing areas on the dorsal surface included the great toe, midpoint and medial malleolus and on the plantar surface included the ball and midpoint. Achilles tendon reflex assessment was rated as 'absent', 'diminished', 'normal', 'hyperactive', or 'clonus'. To assess the proportion of patients with changes in sensory perception or reflex category, patients were judged to have improved, stayed the same, or worsened depending on the change in reported category at EoS versus baseline (Fig. 2).
A post-hoc analysis in patients who received the maximum of seven capsaicin 8% patch treatments was performed to determine within-group changes of sensory perception testing over time.
Adverse events (AEs) observed after randomisation (post-randomisation AEs [PRAEs]) were collected for all groups, allowing for comparison of the capsaicin 8% patch arms with the SOC arm. Treatment-emergent AEs (TEAEs) were observed following administration of the capsaicin 8% patch, therefore no TEAEs are reported for the SOC alone group. 'Pain now' Numeric Pain Rating Scale (NPRS) scores, within 15 min and after 60 min following patch removal, were also assessed during the study.
The change in use of concomitant medication was assessed throughout the study; classes of interest were antidepressants, antiepileptic drugs, and opioids.
Regarding sample size, the number of patients planned for the trial were such that safety concerns related to the Norfolk questionnaire would have been picked up. The power calculation for this study used the principle of a non-inferiority study with 90% power and a 95% one sided confidence interval [CI]. The non-inferiority limit was 20%. A clinically meaningful difference in the percentage reduction from baseline on the Norfolk scale was chosen using data from a clinical trial in diabetic peripheral neuropathy with ruboxistaurin , which showed a drug effect of 37.2%, and selecting 20% as the lower margin for clinically meaningful effect. A number of statistical measures were used to describe the data: descriptive statistics for absolute and change from baseline values at each visit and at EoS; 90 or 95% CI for the estimated mean difference between each of the active treatment groups against SOC control for change from baseline; percentage change from baseline at each post-baseline analysis visit and EoS. As the objective of the trial was to assess the safety and tolerability of long-term capsaicin 8% patch treatment, no formal statistical testing was performed to calculate p-values for the difference between both capsaicin groups and SOC alone. At EoS, for each subject, the last available observation was used with the last observation carried forward (LOCF) imputation method. The results were also analysed using the baseline observation carried forward method.
The safety analysis set (SAS) included all patients who received study treatment and was used for all analyses of safety and analgesic effectiveness.
Of the 555 patients screened, a total of 468 patients were randomised at 71 centres across 11 European countries (30 min plus SOC, n = 156; 60 min plus SOC, n = 157; SOC alone, n = 155). A total of 388 patients completed the study (30 min plus SOC, n = 132; 60 min plus SOC, n = 128; SOC alone, n = 128); 80 patients (17.1%) discontinued the study post baseline, most commonly due to withdrawal of consent (n = 44) and adverse events (n = 18; Fig. 3).
Baseline characteristics were similar across treatment groups and specifically, were comparable for age, glycosylated haemoglobin of A1c (HbA1c), average daily pain, Norfolk QOL-DN total score, UENS total score, duration of PDPN and use of prior treatments for PDPN (including pain medications and SOC) (Table 2).
The most commonly prescribed categories of pain medications during the study were analgesics and antiepileptics; the most commonly prescribed drugs for pain during the study were gabapentin and pregabalin (Table 3).
The average interval between each capsaicin retreatment was 68.4 days in the capsaicin 30-min group and 68.3 days in the 60-min group. The mean number of patches used was similar between capsaicin groups (30 min, 1.53; 60 min, 1.42) and the mean duration of patch application was 30.2 min in the 30-min group and 60.2 min in the 60-min group. Over half of patients in the capsaicin 8% patch groups received the maximum seven capsaicin treatments (167/313 [53.4%]) (Additional file 2: Figure S1 and Additional file 3: Figure S2).
No deterioration (denoted by a reduction in score) in mean (estimated mean difference versus SOC alone; 90% CI for difference) Norfolk QOL-DN total score from baseline to EoS was observed in the capsaicin 8% patch plus SOC groups (30 min, −27.6% [−20.9; −31.7, −10.1]; 60 min, −32.8% [−26.1; −36.8, −15.4]) compared with SOC alone (−6.7%) (Fig. 4). By EoS, patients who received the maximum seven capsaicin treatments plus SOC also had no deterioration in Norfolk QOL-DN when compared with the overall SAS population (Fig. 4).
The mean difference [90% CI] from baseline in Norfolk QOL-DN total score between groups increased throughout the study (Fig. 5).
In addition, no deterioration in any of the Norfolk QOL-DN subscale scores from baseline to EoS was observed in both capsaicin plus SOC groups versus SOC alone (Fig. 4).
The mean change [SD] from baseline to EoS in absolute UENS total score was −2.1 [5.0] with capsaicin 30 min and −3.0 [5.1] with capsaicin 60 min, compared with −1.2 [4.2] in SOC alone group (least squares mean difference [90% CI]: 30 min, −0.9 [−1.8, 0.1]; 60 min: −1.7 [−2.7, −0.8]) (Fig. 6).
No deterioration in UENS total score was noted in patients who received the maximum seven capsaicin treatments plus SOC compared with the overall SAS population (Fig. 6). A clinically significant improvement in UENS total score (defined as a decrease of > 4 points from baseline) was observed in 35.6 and 37.9% of patients in the capsaicin 30-min and capsaicin 60-min groups, respectively, compared with 22.5% of patients in the SOC alone group.
Regarding UENS subscales, no deterioration in mean [SD] 'pinprick sensation' score was observed in the capsaicin plus SOC groups compared with SOC alone (30 min, −1.4 [3.84]; 60 min, −2.2 [3.99]; SOC, −0.7 [3.14]). There were no noticeable differences or only minimal changes across treatment groups in the other UENS subscale scores (Fig. 6).
No differences were observed between treatment groups (data not show) using the baseline observation carried forward method.
The capsaicin 8% patch had no negative impact on sensory perception and reflex testing and the majority of patients had no change from baseline to EoS (Fig. 7, Additional file 4: Table S1). In patients who received the maximum seven capsaicin treatments, there was also no negative impact from baseline to EoS (Additional file 5: Figure S3). A shift to worsened sensation was reported by a lower proportion of patients in both the overall population and the capsaicin 8% patch seven treatment cohort (Fig. 7, Additional file 5: Figure S3).
By EoS, the proportion of patients reporting 'normal' sensation increased for the majority of tests in all three groups; however, reporting of 'normal' sharp (on ball of foot), warm, and cold sensation was greater for capsaicin groups plus SOC versus SOC alone (Fig. 8a). The proportion of patients reporting 'absent' sharp (on plantar midpoint), warm, cold and vibration sensation decreased in all groups by EoS, with the greatest change in warm, cold and vibration seen in the capsaicin 60 min plus SOC group (Fig. 8b). There was also a decrease in the proportion of patients, in all groups, reporting 'absent' or 'markedly diminished' vibration sensation by EoS, and this was accompanied by a corresponding increase in 'mild loss' vibration in all groups (Fig. 8b). These findings were mirrored in the subset of patients who received the maximum seven capsaicin treatments plus SOC, with more patients in the capsaicin groups reporting 'normal' sensation for sharp, warm, and cold tests compared with the SOC alone group (Additional file 6: Figure S4, Additional file 7: Table S2). Also in the seven treatments subset, the proportion of patients reporting 'absent' sharp (on plantar midpoint), warm, cold and vibration sensation decreased in all groups by EoS, with the greatest change in warm and cold seen in the capsaicin 60 min plus SOC group (Additional file 8: Figure S5). In addition, fewer patients in the seven treatment subset reported 'absent' vibration sensation by EoS, accompanied by a corresponding increase in 'mild loss' vibration (Additional file 8: Figure S5).
Mean 'pain now' NPRS scores after patch application were low (≤3.5); peak mean pain scores were observed within 15 min after the first patch removal (3.5; median 3.0, interquartile range 2.0–5.0) to 60 min after the first patch removal (3.3; median 3.0, interquartile range 1.0–5.0). However, 'pain now' NPRS scores decreased after the second patch removal and were stable from the fifth to the last patch removal. More patients in the capsaicin 8% patch 60-min group used concomitant analgesics for application site-related pain (29.9%) compared with the 30-min group (22.4%).
The proportion of patients reporting any PRAE was 67.3% (30 min plus SOC), 69.4% (60 min plus SOC) and 48.4% (SOC alone) (Table 4), and the majority of PRAEs were of mild or moderate severity.
Severe PRAEs were reported by 12.2, 7.6 and 6.5% in the patients in the capsaicin 30 min, capsaicin 60 min, and SOC alone, groups, respectively; overall, these severe PRAEs were most commonly categorised as cardiac disorders, infections and infestations, and musculoskeletal and connective tissue disorders. The difference in PRAEs between the capsaicin plus SOC groups and SOC alone was primarily due to the reporting of application site pain or erythema in the capsaicin groups, which were predominately mild or moderate in severity (Table 4).
TEAEs were similar in the capsaicin 8% patch 30-min and 60-min plus SOC treatment groups (66.7 and 67.5%, respectively) and were generally mild or moderate in severity (Table 4). Over one-third of TEAEs in the capsaicin groups were application site reactions; the type and frequency of these reactions were comparable between both capsaicin groups. The proportion of patients with application site reactions decreased throughout the study, from between the first and second to between the sixth and seventh treatments (application site pain: 30 min, −6.9%; 60 min, −7.9%, burning sensation: 30 min, −2.8%; 60 min −2.2%). Four patients in the 60-min group discontinued due to drug-related TEAEs (four events: muscle spasms, rectal adenocarcinoma, neuralgia, and psoriasis); no drug-related discontinuations were reported in the 30-min group. Severe TEAEs were reported by 12.2% in the 30-min group and 7.6% in the 60-min group; severe TEAEs considered as drug related were reported by 2.6% in the 30-min group and 1.9% in the 60-min group. Serious TEAEs considered as drug related were reported by two patients in the 60-min group (three events: angina pectoris, rectal adenocarcinoma and accelerated hypertension), and by no patients in the 30-min group. These events were officially classified as drug-related by the investigator because causation could not be excluded; however, the sponsor considered it unlikely that repeat treatment with capsaicin 8% patch was the cause of these events. Four deaths were reported during the study: capsaicin 30 min, multiple injuries and brain death (n = 1); capsaicin 60 min, hypotension (n = 1); SOC alone, pneumonia (n = 1), atrial fibrillation (n = 1). None of the deaths were considered to be drug related by the investigator. The only finding of note from vital sign and laboratory analyses was that the change in HbA1c from screening to EoS was marginally greater in the SOC alone arm (0.24%), compared with the capsaicin 30 min (0.06%) and 60 min (0.06%) arms, although HbA1c levels were generally controlled throughout the study.
Overall, there was no decrease in the use of concomitant medications in any of the treatment groups throughout the study; use of concomitant medications was comparable from baseline to EoS in both capsaicin groups (Additional file 9: Table S3). The proportion of patients using antiepileptics at the end of the study was comparable with the proportion reported at baseline for both capsaicin groups. However, the proportion of patients using antiepileptic drugs had increased by > 10% in the SOC alone group at the end of the study. Small increases were also observed in antidepressant and opioid use in the SOC alone group from baseline to the EoS.
In patients with PDPN, capsaicin 8% patch repeat treatment plus SOC over 52 weeks was well tolerated, had no negative functional or neurological effects and raised no new safety concerns compared with SOC therapy.
While the efficacy and safety of a single capsaicin 8% treatment has been previously characterised in patients with PDPN in the double-blind STEP study , the open-label PACE study was the first to assess the long-term safety and tolerability of repeated treatment over 52 weeks in PDPN. Capsaicin 8% patch repeat treatment plus SOC was not associated with any deterioration in Norfolk QOL-DN total or subscale scores compared with SOC alone. For the safety endpoints, few differences were observed in results between the 30-min and 60-min capsaicin groups.
Regarding the UENS total score and 'pinprick sensation' subscale, and sharp, cold, warm and vibration sensation on standardised neurological tests, no deterioration was observed with capsaicin 8% patch repeat treatment. By EoS, the majority of patients showed no change in sensation category, indicating that the changes observed in Figs. 8a and b and Additional file 6: Figure S4 and Additional file 8: Figure S5 were predominantly in patients who transitioned from 'absent' to 'diminished' or to 'normal' during the study. Taken together, these findings indicate that there was no small fibre mediated sensory loss with capsaicin 8% patch repeat treatment. The sensory testing observations in the subset of patients who received seven consecutive capsaicin treatments demonstrated that regular, repeat treatment with the capsaicin 8% patch was also not associated with deterioration in sensory function.
Alongside the double-blind STEP study, the PACE study formed part of a successful regulatory submission to remove the restriction of treatment with capsaicin 8% patch in patients with diabetes in Europe. The capsaicin 8% patch is now indicated for the treatment of peripheral neuropathic pain in adults either alone or in combination with other medicinal products for pain in Europe .
Although the open-label design of this study may be perceived as more representative of capsaicin 8% patch repeat treatment in clinical practice than in a double-blind design, the observed safety evaluations may have been biased by the open-label design. Although the physicians assessing neurological function were blinded to treatment, patients and investigators were unblinded, which may have impacted on the findings. As the primary objective of this open-label study was to assess the safety and tolerability of capsaicin 8% patch repeat treatment, p-values were not calculated to supplement the 90% CIs for the between-group differences each month. Furthermore, differences between treatment groups in an open-label study may be caused by the fact that patients know which treatment they are receiving. The LOCF imputation method is a conservative method to estimate the treatment effect. The underlying assumption is that subjects that withdraw have worse efficacy than those that stay in the trial. The LOCF imputation method did use the data of withdrawn subjects and therefore, theoretically, gave worse results in this study than from a non-imputed analysis. As the limitations of the LOCF for missing data methodology are recognised, the results were also analysed using the baseline observation carried forward method, and no differences in the results were observed. Quantitative Sensory Testing (QST) was not performed in this multicenter study and instead, 'bedside' sensory testing was used. Although it was not feasible in this multicenter study to provide adequate QST training across all centres, or standardise all assessments in all study centres, potential advantages of QST such as quantification of sensory deficits and allodynia/hyperalgesia, and standardisations of values for several painful sites [22, 23] may have provided greater sensitivity in detecting small variations of thermal or mechanical deficits, and reduced possible variability in testing within and between centres. Other limitations include the impact of concomitant opioid use on the results and that the patient population was 99% Caucasian, and therefore the findings may not be widely applicable to patients of other ethnicity.
Repeat treatment with the capsaicin 8% patch plus SOC versus SOC alone over 52 weeks in patients with PDPN was well tolerated and consistent with the established safety profile of the capsaicin 8% patch. Capsaicin plus SOC had no negative functional or neurologic effects compared with SOC alone.
The Coordinating Investigator of this study was Dr. Ladislav Pazdera. The authors would like to thank all study investigators (for full list see Additional file 4: Table S1) and Faysal Riaz of Astellas Pharma Europe Ltd., Chertsey, UK for critical review and his valuable comments.
This study was funded by Astellas Pharma Europe B.V., Leiden, The Netherlands. Astellas Pharma Europe B.V. developed the study design and protocol in conjunction with the clinical investigators, were responsible for collection and statistical analysis of the data and provided the study drug. The authors received editorial support for manuscript preparation from Sarah Reynolds of NexGen Healthcare Communications, London, UK, and this assistance was supported by Astellas Pharma Europe Ltd.
The study synopsis, including the actual results of the study, can be found at www.astellasclinicalstudyresults.com.
Access to anonymized individual patient level data has been organized using the system of CSDR at www.clinicalstudydatarequest.com. Requests will be reviewed by an independent panel and if approved access will be granted after a data sharing agreement has been signed. This study will be listed on the site.
The authors directed and are fully responsible for all interpretation of the data and editorial decisions for this manuscript. All authors listed have contributed sufficiently to the manuscript to be included as authors, and all those who are qualified to be authors are listed in the author by line in line with ICMJE requirements. HJ, MS, SL, RS and MvS contributed to study design and data collection, analysis and interpretation. AV and NK contributed to study design and data analysis and interpretation. EV contributed to data analysis and interpretation. SP, LP and EO contributed to data collection, analysis and interpretation. All authors listed were involved in drafting the manuscript and have read and approved the final version.
A.V. has received research funding from Astellas Pharma, Pfizer, and Daiichi Sankyo; Astellas Pharma has licensed the Norfolk QOL-DN from Eastern Virginia Medical School; A.V. and E.V. have received royalties from the licensing. N.K. was a paid consultant for Astellas Pharma to support the design of this study and received a research grant from Astellas Pharma. M.S., H.J., R.S., and M.v.d.S. are employed by Astellas Pharma Europe B.V. Stephen Long was employed by Astellas Pharma Europe B.V. at the time of the study. Serge Perrot, Ladislav Pazdera and Enrique Ortega have no disclosures.
The study was approved by independent ethics committees and conducted in accordance with the Declaration of Helsinki and other applicable guidelines, laws, and regulations. Written informed consent was obtained for all patients. The design and instruments used to evaluate the endpoints were approved by the European Medicines Agency prior to initiation of the study.
Astellas Pharma Ltd. QUTENZA™ 179 mg cutaneous patch SPC (2015). Available at https://www.medicines.org.uk/emc/medicine/23156. Accessed 4 Apr 2016.


When you visit a Tempe Smile Design dentist, you can be confident that you are receiving care from someone who is passionate about the health of your teeth. Dr. Stacy Tracy and Dr. Roxane Huber are both dedicated to making sure your experience is as comfortable and relaxing as possible, all while providing the highest standards of dental patient care.
The Tempe Smile Design practice is committed to the idea that an informed patient is a confident patient, so they will work with you to ensure you understand all potential procedures and plans of care before any work is completed.
The best leaders or specialists in any profession often stem from personal experiences formed in childhood. Dr. Tracy's path to dentistry is no exception. After her teeth were damaged in a childhood incident, she spent a great deal of time experiencing the many facets of the dental profession; particularly reconstructive dentistry. The confidence Dr. Tracy gained after completing the reconstructive process combined with a newfound curiosity in the profession led to her lifelong passion for the field of dentistry. Dr. Tracy's goal is to give all patients the care they need in order to restore the confidence they deserve.
In addition to post-graduate training, Dr. Tracy is an active member of numerous dental associations, including the Academy of General Dentistry (AGD), the ADA (American Dental Association) and the AzDA (Arizona Dental Association). Her membership is an effective way to ensure she is always equipped with the most current dental practice information and can pass modern plans of care to her patients. Through continuing education, as well as philanthropic work for organizations such as AZ Mission of Mercy (AZMOM), Dr. Tracy's passion for dentistry is evident in all aspects of her life.
A native of the Midwest, Dr. Roxane Huber grew up in Bismarck, North Dakota and attended the University of Minnesota for her undergraduate studies and dental school training. Dr. Huber graduated from the University of Minnesota School of Dentistry in 2004. Shortly after graduation, she relocated to Arizona and joined Dr. Tracy at Tempe Smile Design eight years after the practice first opened. Since 2006, Dr. Tracy and Dr. Huber have worked together to build a practice that was designed to put patient care at the forefront.
Dr. Roxane Huber also participates in several dental-related charity events each year including the AZ Mission of Mercy (AZMOM).
The Tempe Smile Design dentist team of Dr. Stacy Tracy and Dr. Roxane Huber brings a level of excellence in patient care that most patients are not accustomed to experiencing. There mutual commitment to patient best practices, ongoing technological, technique updates, and relationship building with every patient sets them apart in the field. If you are ready to experience the difference a team of dentists truly committed to customized patient care can bring, contact the Tempe Smile Design office today to schedule a consultation or to ask any questions you have about your smile. The entire staff values privacy and collaboration and is looking forward to helping you regain a healthy, lifelong smile.


Sport teaches girls so much more than how to play; it is about teamwork, leadership, determination, and courage.
We strongly believe in access to sport for all and encourage everybody to join in, recreationally or competitively, fostering a positive attitude towards health, fitness and physical recreation.
We focus on you as an individual helping you to excel in your chosen field, whether that is team sports such as hockey, netball, volleyball, handball, cricket, rugby or football, or individual sports such as badminton, tennis, athletics, gymnastics, dance, or swimming. Everyone has access to our fitness suite and a personalised fitness programme and as girls progress through the school, they get the chance to try a broader and broader range of activities, such as boxfit and spin through to ultimate Frisbee and trampolining.
A varied and diverse fixture programme includes mid-week and Saturday fixtures plus opportunities to take part in Girls' Day School Trust National Sports Rallies, as well as achieving a regional standard or higher in a range of competitions and participating in regular sports tours and tour weekends. Wonderful facilities include a swimming pool, astro-turf, large playing fields, netball and tennis courts, a large sports hall, squash courts and a superb state-of- the-art fitness suite and studio.


Espresso is a testing framework which provides the facility to write the tests for user interactions and unitary tests. Since the release of its version 2 it is now a part of Android Testing Support Library.
The android apps we build at FOSSASIA follow rigorous testing methods. See this simple UI test in the Phimp.me app using espresso to check if button and bottom navigation are displayed in an activity. You can also find our other tests related to API and databases in the Open Event Android App.
In this blog we learn how to add this facility to your app and write a test for a simple app that takes the name of from the user and prints it on the other screen on button click.
Before we begin with writing our tests knowing some basic components will help in understanding the code better. Writing tests with espresso is easy as its construction is similar to English language.
ViewAssertions : Allows you to assert the state of a view.
ViewMatchers : Allows you to locate a view in the current view hierarchy.
Consider an app which takes a name from the user and displays it on the next screen on clicking the button.
//Locate the view with id "name" and type the text "Natalie"
//Locate the view with id "new_name" and check its text is equal with "Natalie"
You can run tests by right clicking on the class and selecting the "run test" option. If the interaction is not as expected then the message will be displayed.
Up until now unit test were in main focus but as we move towards the more complex apps where user interaction plays an essential role, UI testing becomes equally necessary.


text:
Use Trauma Strategically To Create An Emotional Arc
By Lisa Hall-Wilson
Many authors give their characters past trauma that makes life more difficult and at the very least adds internal conflict. But are you strategic with the kind of trauma you choose—the severity, the onset, the symptoms and coping mechanisms? What's the character's emotional arc and how does the trauma shape that arc?
Trauma is anything that leaves a person feeling overwhelmed.
That's it. There's no threshold of "bad" that needs to be reached. We tend to think of trauma as huge horrifying events, such as combat/war, displacement, a natural disaster, car/plane/train accidents, rape, kidnapping, a near-death encounter, etc. These kinds of events change you, sometimes in only the span of minutes.
However, what's more common is the everyday kind of trauma that every one of us has suffered to varying degrees. Some common examples might be divorce, forced relocation, public ridicule, loss of a loved one (even to natural causes), job loss, relationship loss, betrayal, poor response to a personal disclosure, sibling rivalry, emotional neglect, a health crisis or a sudden medical procedure, etc. This kind of backstory influences characters' decisions, motivations, priorities, likes and dislikes, prejudices, and blind spots just as much as the big trauma events.
I really love the character Tyrion in the Game of Thrones series (books and TV). Tyrion is shaped by the fact that he has dwarfism. Having dwarfism is not a peripheral detail to differentiate him from the other characters. The specific and unique kinds of trauma he suffered growing up because of his stature influences every future decision and is subtly woven into every emotion he expresses, numbs, and holds back. His past trauma equipped him to survive, even though that same trauma was also a handicap and an anchor. The trauma wasn't just a detail added to create sympathy in readers for a hard-to-like character.
Strategic Use Of Trauma
Before randomly choosing a trauma from the past, think about who your character is and how this trauma could make their story journey more difficult for them. Get really curious about this.
As an example, let's take a look at Bilbo Baggins. Bilbo is a perfectly respectable hobbit until a wizard shows up with 13 loud, strong, obstinate, opinionated dwarves. Knowing what sort of challenges are ahead of him, what kind of trauma background could an author give a character like Bilbo that would make solving his story problem even more challenging (and definitely feel impossible)?
Bilbo is a homebody and an introvert, and living with so many boisterous individuals with strong personalities is a challenge. But imagine a Bilbo with a past of abuse that comes out in his adult life as extreme people-pleasing and conflict avoidance? How would this anxiety have made life even more difficult and bring additional challenges during his encounter with Gollum, facing off with Smaug, or negotiating with a walled-up Thorin to honor his promises to the people of Lake Town?
The past trauma you choose to include should be more than emotion-theatre. It should make your character's journey more difficult and be specific to the journey ahead of them. I know this is hard if you're a pantser, but it may be something to consider for a rewrite or editing phase.
Trauma Memories Are Often Avoided
Part of being strategic with trauma backstory is knowing when and how much to share. My personal preference is to drip in backstory. What does the reader need to know to make sense of what's going on right now? It's often far less than what you think the reader needs. This slow peeling back of emotional layers can increase the tension for readers.
Because the reality is that most people will do almost anything to avoid being reminded of the worst moment of their life. These are not the sorts of things people navel gaze over.
"Trauma comes back as a reaction, not a memory."
~Bessel Van Der Kolk
Consistent use of coping mechanisms can show a past trauma early on without having to delve into the backstory before it's necessary. A great example of this are the opening scenes from the movie Sleeping With The Enemy—Laura's obsessive straightening of cans in cupboards, of adjusting towels on towel rods to precision, etc. It all pointed to this frantic need to appease someone else, someone she was afraid of. The specifics of the trauma weren't necessary in those opening scenes to create tension.
There have been studies done on young men who suffered abuse by priests as young boys. Those who struggle with anxiety (of any sort) often become gym rats. They work out, they are health nuts, because they don't ever want to be overpowered again. This obsessive need to be strong, stronger than most everyone else, is the reaction.
So ask yourself: How can you be strategic with the reaction to the emotions your character suppresses or tries to avoid?
Trauma Is Like A Spider's Web
Trauma is not just something the character thinks about. Emotions are the key to making trauma reactions believable and visceral for readers, so be strategic with specific and unique ways those emotions affect the character's body. Where do they hold or carry the tension? Do they clench their teeth? Does their neck ache? Do they have stomach problems? Do they have trouble sleeping? Do they startle easily? Do they get angry easily?
The way they carry the past in their body will also affect their behavior and choices. Some people become angry when one of those old emotions are triggered. Some people become compliant and seek to please everyone around them. My point? It's all connected. One symptom or coping mechanism or trauma memory doesn't exist in isolation from the character's thinking, feeling, reacting, and decision-making. Avoid the temptation to use past trauma as emotion-theatre.
You can't tear a hole in a spider's web and not create reverberations felt throughout the entire structure. How could you use those reverberations to create more inner or external conflict? Maybe a woman who's been raped obsessively uses exercise to regain a sense of control. But then she breaks her leg and is stuck on the sofa for two months. There's a tear in the web. How would removing that coping mechanism affect her thinking, her emotions, her ability to cope with all of it?
PSSSST! Lisa's got two courses on writing in deep POV that you might want to check out. Writing in Emotional Layers and Deep Point Of View Foundations can help you learn the effects the tools used in deep POV aim to create, so you can use those tools to best serve your story and your voice.
Lisa Hall-Wilson
Resident Writing Coach
If Lisa had a super-power it would be breaking down complicated concepts into digestible practical steps. Lisa loves helping writers "go deeper" and create emotional connections with readers using deep point of view! Hang out with Lisa on Facebook at Confident Writers where she talks deep point of view.
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Filed Under: Backstory, Character Wound, Characters, Emotion, Resident Writing Coach, Writing Craft
Vivienne says
A wonderful post. Many thanks. The trouble is, that it's made me want to go back and check through all my other books to see how I've included this tension, and make revisions!
Lisa Hall-Wilson says
I would find it overwhelming to go back and update everything I'd ever written with the new things I've learned. Within reason. Just make the next one even better 😀 Glad you enjoyed the post.
Irish Roots Author: Rethinking a Character's Past says:
[…] read a blog post today on Writers Helping Writers that contained this […]

redpajama_set_name: RedPajamaCommonCrawl


11.7 acres in Downtown Murfreesboro! This tract is literally the largest available tract of land left inside the old city limits of Downtown Murfreesboro. Western boundary runs along a creek that borders Oaklands Park. Frontage on E Clark & N Highland.


text:
Sobre

O Sistema:
                        O iCombH5 é um sistema interativo gratuito na web, que fortalece o aprendizado do aluno na resolução
                        de problemas de Análise Combinatória por meio de exercícios de correção automática.
                        Para resolver o que é pedido em um determinado exercício, o aluno deve dividir o problema em subproblemas
                        -- aplicar a estratégia "dividir para conquistar".
                        Cada subproblema é considerado um estágio, onde deve-se seguir passos que envolvem raciocínio, ações e
                        modelagem para descobrir a quantidade de elementos que são solicitados.

Origens:
                        O iComb foi inspirado na experiência do software Combien?, sistema desenvolvido pela Université Pierre et Marie Curie - LIP6 - França.

redpajama_set_name: RedPajamaGithub


With improvements in industrial production workflow and process equipment, automation control systems are becoming more widely used. Since HollySys was established, it accumulated a lot of experience in food & beverage (F&B) industry projects. It is also used in food industries such as sugar, oil processing, starch, and deep processing, and beverage industries such as fermentation and extraction for producing alcoholic drinks for consumption, the manufacturing of different types of alcoholic drinks, and the processing of different types of soft drinks such as carbonated drinks, juices, protein drinks, and tea.
HollySys is able to provide sugar manufacturing clients with DCS control system and full plant integrated DCS control solutions that contain functions such as monitoring processes by process segment, user, region, and user authority. HollySys is able to provide users with services such as electrical instrument design, selection, full-package equipment preparation, installation, testing, and maintenance. For the sugar manufacturing industry, it had developed a series of cost-effective and established electrical instrument full-package solutions.
Starch is an important renewable industrial ingredient, mainly used in food,textiles, pulp and paper, feed, pharmaceuticals, and chemical industries. Take corn starch for example, the solutions provided by HollySys included automation solutions for processes such as the cleaning process, soaking process, corn crushing and germ separation process, refining and fibre cleaning process, starch and skin separation process, and starch drying process.
Automation solutions for oil pre-treatment include solutions for processes such as measurement, cleaning, crushing, softening, flaking, and baking.
Automation solutions for oil extraction include solutions for processes such as soaking, wet bean steaming, mixed oil treatment, and solvent recovery.
Automation solutions for oil refining include solutions for processes such as degumming, de-acidification, bleaching, and deodorisation.
For alcohol processing, the automation solutions provided by HollySys cover all processes involved in alcohol production – liquid saccharification, fermentation, and distillation.


text:
When Galaxies Collide: A Q&A on Our Milky Way's Future
By Clara Moskowitz 2011-08-16T12:40:28Z Science & Astronomy
Artist's conception of the Milkomeda galaxy a trillion years from now.
(Image: © David A. Aguilar (CfA))
After about 5 billion years, the Milky Way will be no more. Our galaxy is set to collide with our neighbor Andromeda to create the so-called Milkomeda galaxy.
Astronomer Lauranne Lanz of the Harvard-Smithsonian Center for Astrophysics in Cambridge, Mass., is part of a team that has assembled an atlas of colliding galaxies to better understand how these cosmic train wrecks occur.
SPACE.com talked to Lanz about what's in store for the Milky Way and whether the Earth is doomed.
SPACE.com: A collision of galaxies sounds violent. Is it?
Lauranne Lanz: When two galaxies collide, the stars don't collide into each other — that's the first thing to keep in mind.
What really happens is that the stars pass through each other kind of like a mesh, but their gases do collide, and in that process, that sparks the creation of new stars because when gas becomes dense it likes to form stars.So from that point of view, it is pretty violent, and it does look quite messy, but in a very pretty way. [Stunning Photos of Galaxy Collisions]
The Andromeda Galaxy photographed with a 12.5-inch telescope by amateur astronomer Robert Gendler.
(Image credit: © 2002 R. Gendler, Photo by R. Gendler)
SPACE.com: So is the Milky Way definitely on a collision course?
Lanz: Oh, definitely. We know that Andromeda and the Milky Way are going to come together in about 5 billion years, which is roughly around the time that the sun will be puffing up into a red giant, so we'll have other problems at that point.
SPACE.com: Is the Earth doomed?
Lanz: When the sun expands, the Earth is going to get quite warm. So from the point of view of the sun, we're going to have problems.
From the point of view of Andromeda, we're not going to hit any other solar system. When new stars are created, since they live relatively shortly from the point of view of stars, and when you get massive stars you get supernovae, and you don't really want all that many in your neighborhood, so that's not good for us either.
But other than that not too many bad things will happen from colliding galaxies.
SPACE.com: How do you feel about the word Milkomeda?
Lanz: It's not that bad.
SPACE.com: What is the Milkomeda system going to look like?
Lanz: Very often they'll go through a messy phase where they've got arms everywhere. But if you give them long enough they settle into an elliptical, typically.
A near galactic-collision between NGC 2207 (left) and IC 2163 captured by the Hubble Space Telescope. Scientists predict the Milky Way will merge with its neighbor Andromeda in about 5 billion years.
(Image credit: NASA and The Hubble Heritage Team (STScI))
Are there usually signs of the galactic train wreck afterward?
SPACE.com: Lanz: If you look long enough after the collision, you're not going to see any traces.
One of the earlier projects that I did is looking at a system that had had a collision. It had a lot more dust than it should, which told us that it ate a spiral that had dust. So that's one way that you can potentially tell if a system has had a collision — if it's got stuff that you don't expect that type of galaxy to have.
SPACE.com: How common are galaxy collisions?
Lanz: As we understand the growth of galaxies over the entire age of the universe, we really think that small ones form and then clump together to form bigger ones. So really any large galaxy will have had multiple of these events.
Whether it's events with other large ones is unclear, but they've definitely had [collisions] themselves with tiny little ones that they eat up.
You can follow SPACE.com Senior Writer Clara Moskowitz on Twitter @ClaraMoskowitz. Visit SPACE.com for the latest in space science and exploration news on Twitter @Spacedotcom and on Facebook.
India to Launch Chandrayaan-2 Moon Lander Mission July 22
For All Humankind: The National Space Society and ISDC 2019


text:
Pierre Rivalz, le chevalier Rivalz, parfois appelé Jean-Pierre Rivalz le jeune, est un peintre, graveur, collectionneur d'art et professeur de dessin français, né à Toulouse le , et mort dans la même ville le .

Biographie
Pierre Rivalz est le fils d'Antoine Rivalz, peintre de l'hôtel de ville de Toulouse, et de Louise Rivalz, le beau-frère de Jean-Baptiste Despax.

Il a hérité de son père, Antoine Rivalz, son « cabinet, à savoir livres, estampes, dessins originaux, modèles, instruments de mathématiques et généralement tout ce qui peut avoir du rapport avec ces professions ».

Il a d'abord été formé au dessin et à la peinture par son père. Il a séjourné à Rome entre 1735 et 1746 où il est l'élève de Pierre Subleyras. Ayant fait le portrait du pape Benoît XIV qui l'a nommé comte du Sacré palais et chevalier de l'Éperon d'Or. Il est présent à la première assemblée de la Société des beaux-arts de Toulouse, le .

Il s'est marié par contrat du 12 janvier 1752 avec Magdelaine de Poussoy, fille d'Antoine de Poussoy, écuyer, et de Marianne de Carratié. Ils se sont mariés dans l'église Saint-Jean-de-Jérusalem le 18 janvier 1752. De son mariage sont nés :
 Louise-Françoise Rivalz, née le 7 novembre 1755,
 Aymonde Rivalz, née le 4 mars 1757,
 Maurice-Jérôme Rivalz, né le 22 septembre 1758, décédé le 15 août 1758.

Il succède à Guillaume Cammas comme peintre de l'hôtel de ville de Toulouse, en 1756. Il est remplacé, en 1779, comme peintre et architecte du Capitole par son ancien élève François Cammas, en 1779. Comme peintre de l'hôtel de ville, il est professeur de peinture dans le cours donné par l'Académie royale de peinture, sculpture et d'architecture. Il doit aussi restaurer les peintures qui sont exposées dans l'hôtel de ville en 1762. En 1763, il peint, pour le prix de , la nouvelle salle de bal ouverte dans le prolongement de la salle des Illustres, exécutée sous la direction de l'architecte Hardy.

Grand collectionneur d'œuvres antiques, une partie de sa collection est entrée au musée de Toulouse, aujourd'hui, au musée Saint-Raymond, comme le Relief des Amazones ou la réplique antique du Discobole de Myron (Chevalier Rivalz, Différents morceaux antiques que l'on voit à Toulouse chez M. Rivalz, professeur de l'Académie royale des arts).

Élèves
Professeur de peinture de l'académie de peinture, sculpture et architecture, il a eu pour élèves :
 Jacques Gamelin,
 Jean Suau
 François Cammas

Tableaux
 Saint Albert, aux Carmes Déchaussés ;
 Baptême de Jésus-Christ, à l'église Saint-Jean de Jérusalem ;
 Immaculée Conception, à l'église Saint-Jean de Jérusalem ;
 Jésus-Christ en croix, à l'église Saint-Jean de Jérusalem ;
 La Prédication de saint Jean-Baptiste
 Naissance du Sauveur, aux Orphelines ;
 Portrait d'Antoine Rivalz
 Prédication de saint Jean, à l'église Saint-Jean de Jérusalem.
 Apothéose de saint Saturnin
 Naissance de saint Jean-Baptiste, signé 1778, tableau commandé par le Grand-Prieur de Toulouse pour l'église de Reignès qui en dépendait, puis au couvent des Dames Maltaise, à Saint-Cyprien, ensuite au musée des Augustins avant d'être exposé à l'église Saint-Pierre des Chartreux de Toulouse.

Le 9 juin 1753, il a reçu la commande du Grand Prieur de Toulouse de cinq tableaux pour la décoration de la salle de l'Hôtel de Malte pour le prix de  :
 La prise de Rhodes par le grand Maître Fr. Folco de Villareto en 1309,
 Le siège de Rhodes soutenu par le Fr. Pietro Abussone en 1479,
 L'Armée de la Religion combat et prend celle du Sultan d'Egypte en 1510,
 André Roi de Hongrie reçoit par dévotion la semi-croix du Fr. Guerrino di Montecorto,
 La Prise du Grand Gallion.
Le quatrième de ces tableaux se trouvait au musée des Augustins en 1818, mais a ensuite disparu. Aucun de ces tableaux ne semblent subsister.

Certains tableaux qui sont cités dans les premiers catalogues du Museum provisoire rédigés par Jean Paul Lucas ont ensuite disparu.

Publication
 Analyse des différens ouvrages de peinture, sculpture et architecture qui sont dans l'hôtel de ville de Toulouse dédiée à Mademoiselle de Vaudeuil, Toulouse, imprimerie de Joseph Dalles, 1770.

Notes et références

Annexes

Bibliographie

Articles connexes
 Peintre de l'hôtel de ville de Toulouse

Liens externes

  Neil Jeffares, Dictionay of pastellists before 1800 : Rivalz, Jean-Pierre, chevalier de

Peintre français du XVIIIe siècle
Peintre classique français
Peintre toulousain
Peintre de l'hôtel de ville de Toulouse
Professeur de l'Académie royale de peinture, sculpture et architecture de Toulouse
Personnalité liée à Toulouse
Culture à Toulouse
Naissance en septembre 1720
Naissance à Toulouse
Décès en juillet 1785
Décès à Toulouse
Décès à 64 ans

redpajama_set_name: RedPajamaWikipedia


text:
Q: How to exclude elements inside a child-element from a selection without using children()? I have an element like so:

  click me

     click me too

and I need to select the a elements that are not inside bar. Problem is I can't use children(), because my foo is much more complex than above.
Question:
Is there a way to select "some" elements from a foo and explicitly excluding "some" elements from bar?

A: If the anchor elements may not always be a direct child of foo you can use the filter() method.
var anchors = $("#foo a").filter(function(){
    return !$("#bar").find(this).length;
});

Working Example http://jsfiddle.net/v63tC/

A: You can use .filter() along with $.contains() to solve this
var $bar = $('#bar');
var items = $('#foo a.some').filter(function() {
    return !$.contains($bar[0], this)
})

Demo: Fiddle

A: May be with a > direct child notation:
$('#foo > a')

You can omit some elem with .not():
$("#foo a").not('#bar a').length;

Fiddle

A: Since you mentioned that your #foo element is considerably more complex than the example, is it safe to assume that it's not just direct descendants that you'll need to be selecting? If that is the case, I'd suggest the following:
$('#foo a.some').filter(function() {
    return $(this).parents('#bar').length === 0;
});

That selects all  elements inside of #foo, then filters them down so that only those that don't have an ancestor with the id of bar on them are kept.

A: You can do that (assuming the variable foo is your #foo)
var a = foo.find('> a');

A: You can use child selectors for accomplishing your first task (getting all  elements from foo):
$('#foo > a'). ...

redpajama_set_name: RedPajamaStackExchange


60° diamonds are extremely versatile and quilts made with them are great for hand-piecing projects.
Jinny likes to assemble the diamonds into a base unit, decide where to put lights, and go from there. The unit for Red Fort is one of the simplest, as it has only four diamonds—two lights and two darks.
Decide what size diamond you want. So many people nowadays are collecting 2½" strips and like to cut their diamonds from those strips. That is the size that was used for Red Fort. The 60° degree Perfect Cut Diamond Ruler makes cutting the diamonds a breeze. Click here to learn about using the 60° ruler.
Start off by making stacks of units. For a scrappy effect, when making the units, use different fabrics in each of the four diamonds. For the darks, Jinny usually make one of them darker than the other, and does the same for the lights. Sometimes she will mix it up, using a medium fabric as a light in one unit and as a dark in the other. As long as there is contrast between light and dark in each of the units it will work out. Jinny's advice? Don't try to think ahead. Just make the units!
Once you have a lot of units, lay them out into larger sections. Each of these large units will have 12 of the smaller ones. Start by making a star using six of the diamond units and then fill in with the remaining six around the edge.
The side, top/bottom and corner units use additional shapes (partial diamonds) to finish off the edges. Those shapes, for 2 ¼" or 2 ½ diamonds, are included in the free download, Red Fort Templates.
A quilt of this size, including the border shown, is 66" x 78". A smaller quilt with five large units (two in the top row, one in the middle and two at the bottom) with the border will finish at 49" x 64".
For the border, Jinny used a border print fabric and an accent fabric. The narrow stripe from the border is first, then an accent border, then the wider stripe from the border fabric to finish it off.
She used the Golden Gauge Calipers to determine the width of that middle, accent border.
And when it comes to putting the borders on the quilt, see our tip for achieving perfectly mitered corners — without math — when working with a rectangular quilt.
Many people ask, "what is a tessellation?" A tessellation is a shape or combination of shapes which will indefinitely cover an area without any gaps or overlaps. Even though we tend to think of tessellations only as interlocking motifs, any quilt block that repeats itself can be considered a tessellation. But it is interlocking patterns that are intriguing, and once you know how to create them, a whole world of design will open up.
Jinny has made several quilts based on tessellating designs.
Squares, triangles and hexagons are tessellations since, when placed side by side, they will cover an area without any gaps or overlaps.
If you take a chunk away from any of these shapes, they are no longer a tessellation because the shapes will not fit perfectly next to each other — there will be gaps where the pieces were taken away.
The secret to creating tessellations is this: if you take away a piece of a shape, give the piece back to a another part of the shape. You will once again have tessellation because the piece you give back will fit into the hole where it was taken away.
Jinny's book, Designing Tessellations: The Secrets of Interlocking Patterns (now out of print but often available used on amazon.com or ebay), describes this simple process of creating tessellating shapes. It covers how to create geometric-style interlocking patterns suitable for patchwork, as well as more realistic-type tessellations which would be suitable for all types of surface design.
In traditional patchwork designs, fabric is cut to fit within the various shapes of the block pieces. As a result, we often cut into a beautiful portion of the fabric, "forcing" it to fit within that shape, and possibly spoiling the design of the fabric. Jinny began to wonder what would happen if we let the design of the fabric dictate the boundaries of the shape.
Jinny's quilt, Renaissance Garden, uses this technique. (The pattern includes an instruction sheet on soft-edge piecing.) Watch the video to learn how to create the soft-edge pieces and get some great ideas for using the technique in your quilts.
Download the free Renaissance Garden pattern.
Jinny is renowned for a sophisticated use of color in her quilts. Although she has no formal training in color theory or background in art, she has developed a terrific eye and a short list of color "secrets".
Watch as Jinny shares with you her four secrets to beautiful quilt color schemes.
I often use fragmenting when designing quilts. The concept of fragmenting a traditional patchwork block is not new. It has been used for centuries with the traditional Lone Star design.
In the Lone Star design, each of the diamonds of a traditional eight-pointed star has been broken up into the same number of smaller diamonds.
The diamond units in a traditional eight-pointed star block (left) can be fragmented (center). We know this "fragmented" design as the Lone Star quilt. You can fragment the background squares and triangles, too. That's what I did for my Stained Glass Star quilt!
Traditionally, each round of diamonds from the center outwards is the same fabric. I used this same idea to create the quilt, Star Sapphire. Each of the diamonds has been broken into eight divisions per side, but the coloring is different from that of a traditional Lone Star. I treated each large diamond unit as being made up of four smaller diamonds, and then shaded the patches within each of those four diamonds to create a non-traditional effect.
In the traditional lone star design (right) the colors radiate out from the center with each round of color the same in each diamond unit. In Star Sapphire (right), I switched up the color shading to get a design with a more faceted look.
When I developed the idea of fragmenting an entire design, I still started with a traditional quilt block. However, then I broke all the shapes in the design into smaller versions of that same shape. Each shape had the same number of divisions. In addition, when coloring the fragmented shapes, I shaded each of them from light to dark. Let's look at a recent example.
The Rajasthan wall-sized quilt is really just one big block!
The larger version of Rajasthan is four blocks sewn together. A border print triangle is used in one corner so that when the quilt is assembled, you get a center medallion.
Fragmenting is fun. It gives you the opportunity to really play with color and shading, or simply to use lots more fabrics. When selecting a design, a simpler one will best.
Divide each side of each shape into the same number of equal divisions.
Draw parallel lines from the sides of the shape to one of the other sides.
Draw the second set of lines.
With a triangle, you need a third set of lines. Sometimes I find this last set makes the shape too busy and I opt to eliminate it.
Because a triangle has three outside lines, none of which are parallel, to fully fragment the shape you need to draw three sets of lines (Triangle 3). However, you could decide to just stop at two sets of lines as in Triangle 2 and use diamond-shaped patches to fill the unit. You might also decide to remove a different set of lines as in Triangle 4: in this example, you'll fill the shape with square and half-square triangle patches.
Shade the units from light to dark. Try shading in various directions until you find the one you like best.
Different light-to-dark progressions can make a big difference in how your quilt will look. Having the lightest fabric in one unit against the darkest in another unit can create a nice glow. Take another look at Star Sapphire to see how this can work.
For more detailed information on fragmenting, coloring fragmented designs and creating templates for each of the shapes, see pages 45 to 48 of my book, The Quilters Album of Patchwork Patterns.
For other examples of my fragmented quilt designs, take a look at Mayflowers, Summer Lily, and Fabergé. All of them are free pattern downloads!
While working on my first book, Patchwork Patterns, I kept finding designs that were based on a 5 x 5 grid. Since I did not know how to fold a piece of paper to get five equal divisions I set them aside and was not going to use them. But before long there was a stack of those designs. Someone had shown me how to fold a square and get a five pointed star, so it seemed logical to me that there must be a way to fold a square and get five equal divisions. I sat down with a stack of squares and started experimenting and finally found a way!
The following day I was leaving on a trip and figured the airplane ride would give me a good opportunity to write down what I had discovered. Working with a paper napkin, I folded and wrote, folded again and wrote some more until all the steps were explained.
If I want to divide a 7¾" square into five equal divisions, it would be hard to do the math and count off all the tick marks. If my square were 10 inches then it would be very easy to do. I would simply mark a division every two inches. Well, all you have to do is to pretend that the square is 10 inches.
Step 1. Angle the ruler across the square so that zero is on the left side of the square and 10 inches falls on the opposite parallel side.
Step 2. Make a mark every two inches and you will have five equal divisions.
Step 4. Turn the paper 90 degrees and repeat steps 1-3 to get the lines going in the other direction. It is best to use a different colored pencil for the dots so that you do not get the first set of dots mixed up with the second.
For a more detailed explanation of this technique see The Quilter's Album of Patchwork Patterns, pages 29-32.
Often we see a photograph, a flower, leaf or other image that has breathtaking colors. We may want to try to recreate those colors, but never seem to quite get it right. The two images shown here are of the American flag. The first image is the regular photograph. The second one has the individual colors in the photo selected.
We would say there are three colors in the flag — red, white and blue. Yet, when you see an American flag blowing in the wind, your eye perceives so many more than just three discrete colors. The play of light and shadow and the transparency of the flag translates our glorious red, white and blue into dozens of shades and hues.
I often use my computer to find the colors in an image such as this and then work with those colors in a quilt project. This is how I do it using Adobe Photoshop. Other image editing software will work in a similar way.
First, if I'm not using a digital image, I scan the picture or object at a very low resolution (the dpi or pixel setting). When I want to see individual squares of colors, I set the dpi to a very low number.
If you already have an electronic image, open it in your photo editing software and set the resolution to a very low number such as 8 or 10 dpi.
Next, use the eye-dropper tool to select a color from one of the squares.
Then, make a selection box below the image and use the paint bucket tool to fill that selection with the color. I continue making boxes and filling them with the colors in the image.
Finally, I rearrange the boxes in a shaded order and I have a palette of colors to refer to when selecting fabrics for my project!
During a Jinny Beyer seminar session on color shading, participants created full-sized quilt mock-ups from strips of fabric pasted to paper foundations.
Each mock-up is a variation of a single, original Jinny Beyer quilt design called Stony Creek. Each mock-up uses the same fabrics and the same quilt design. However, the fabric placement varies in each version.
Jinny explored this color exercise, and how shading creates special effects, in the May/June 2010 issue of Fons & Porter's Love of Quilting magazine.
Jinny's Portable Palette is an indispensable tool for choosing colors for your quilts.
It's very similar to a painter's fan deck of colors. The Palette includes a 1¾" x 7″ swatch of each of the 150 fabrics in Jinny's Palette Collection. The fabrics shade beautifully from one color to the next, making it easy to find a range of colors that will work with your focus fabric, inspiration photo or color scheme.
Watch as Jinny shows you how to use the Portable Palette in variety of ways that are sure to help you choose the colors for your next quilt. And get more details on the Portable Palette below.


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Q: How can I use following javascript statement of openerp 7.0 to odoo 11? In the following piece of code , I am getting error on line no 2 . I want to convert line no 2 as per new syntax suitable for odoo 11. Please help in this.
var ShowTaskBoard = Widget.extend({
model_iteration: new instance.web.Model('my_module.iteration'),

self.model_iteration.query()
            .filter([["is_active","=","true"]])
            .order_by("project_id")
            .all().done(function (records) {
                _(records).each(display);

                // create board for first entry
                self.initBoard();
            }
)};

A: That widget will be failing even on OpenERP 7.0 because of errors with the syntax. Maybe will be better if you provide the original code. For example you are defining the property model_iteration as new instance.web.Model('my_module.iteration') which will work without issues but as long a you put a comma you are saying that next you will be defining another property. Maybe you wanna define model_iteration as a function to be able to define the code like:
var ShowTaskBoard = Widget.extend({
    model_iteration: function() {
        var self = this;
        new instance.web.Model('my_module.iteration').query()
            .filter([["is_active","=","true"]])
            .order_by("project_id")
            .all().done(function (records) {
                _(records).each(display);
                // create board for first entry
                self.initBoard();
            }
    }
)};

You will need to find a way to call the function model_iteration and I assume that there will be functions named display and initBoard to complete the usage defined in your code


text:
"You'd better watch out for the boss today. She seems to be in a bad mood. I just saw her go into her office and her face is like .........," Lilly said to Mary.
"I know we're supposed to think all babies are cute, but Pete and Paula's is not. Their baby is one that only a mother could .........," Wilson said to his wife.
"Don't accept that car at ......... value, Lewis. Take it to a mechanic and see what he thinks. There may be a lot of problems you don't know about," his brother said.
The time had come to face his ......... and climb the telephone pole. He had been afraid of heights for years, but that fear was holding him back from advancement in the cable company.
His daughter was turning twelve and he would have to talk to her about the facts of ......... soon. She was going to have a sex education class in school, but he thought she should hear about sex from her parents first.
Don't give up on your business even if it hasn't made you any money yet. Failure is the ......... of success. Thomas Edison failed many times before inventing the light bulb.
"You have to ask her to the dance if you want to go with her. Stop being so shy. Faint ......... never won fair lady, Keenan," Wes told him.
"We had a bet that whoever lost the race would pay the other ten dollars. So pay up, because I beat you fair and .........," Pauline told her.
They'd spent a lot of time together in the past, but as soon as she told Maxie thatshe really needed a friend to talk to, Max said that he felt tired and wanted to go see a movie instead. She didn't need ......... friends like Max.
She wanted to improve high school education in America. Too many kids fell by the ......... and ended up without a diploma or a fair chance of success in society.


The review by privacy regulators of Internet of Things (IoT) technologies together with the joint initiative on connected cars and self-driving cars might be an essential step towards IoT rules.
As part of an initiative launched by the Global Privacy Enforcement Network, the privacy authorities of 29 countries worldwide started an investigation on the compliance with privacy regulations of IoT technologies. The investigation could not have a better timing since the European Parliament has just approved the Data Protection Regulation which sets stricter privacy compliance obligations, especially for technologies performing profiling activities such as IoT technologies, and higher sanctions.
The Italian privacy regulator had launched in 2015 a consultation on the Internet of Things, but this new initiative has the purpose to better understand the status quo.
Inevatibly operators that are running IoT technologies and overlooked privacy compliance might be the target of investigations and such initiative might be a further warning for them.
During the same days when the Privacy Sweep 2016 has been launched, EU policy makers and European vehicle manufacturers have reached their first agreement on the future of self-driving cars and their place on the continent's roads committing, through the so called "Declaration of Amsterdam" to cooperate in setting the rules that might foster their growth.
Such initiatives shall be considered to be part of the Internet of Things plan announced by the European Commission at the end of 2015 that shall lead to specific rules for the sector.


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text:
Homesite Insurance Receiv...
Homesite Insurance Receives E-Fusion Award for Business Geographics Underwriting System Powered by Pitney Bowes Group 1 Software
- Group 1 Software's advanced geocoding technology enables faster, more accurate, and more efficient underwriting for home insurance policies -
LANHAM, Md., Nov. 29 /PRNewswire/ -- Group 1 Software, Inc., a Pitney Bowes Company (NYSE: PBI), today announced that Homesite Insurance Group has received a 2006 E-Fusion award for its Business Geographics Underwriting system, which uses Group 1 Software's GeoStan™ geocoding technology to enable faster, more accurate, and more efficient underwriting. The E-Fusion award is designated by a panel of judges at A.M. Best's annual E-Fusion conference, held this year in Boston.
With GeoStan, Homesite is able to determine immediately whether a given home, apartment or condominium is within a risk area for natural disasters, such as floods, brushfire, hurricanes, high winds, and hail, as well as other relevant underwriting criteria, including accurately determining rating territories, among other factors. This information allows Homesite to better manage exposure, make underwriting decisions, and respond promptly to new policy applications.
"Our judges were impressed by this project," said Lee McDonald, vice president of communications with the A.M. Best Company. "We had many extremely sophisticated entries, so receiving the 2006 E-Fusion award in the Underwriting and Pricing category is quite an accomplishment."
"Managing exposure concentration is one of the biggest challenges facing underwriters in the homeowner insurance industry," said Manuel Rios, vice president and chief underwriter for Homesite Group. "By using Group 1 Software's geocoding technology, we are able to assess risk factors much faster and more accurately. For our customers, this means real-time decisions on policy applications, rather than waits of up to 30 days. For Homesite, it means significantly improved business efficiency and better-informed underwriting decisions."
Group 1 Software's geocoding process begins by standardizing and correcting address information, which is then translated into longitude and latitude coordinates and combined with other geospatial data for assessing risk with far greater ease and accuracy as compared to ZIP code or other assessment methods. GeoStan technology combines USPS® postal data with spatial data files from the world's leading data providers to deliver the most comprehensive set of address-level geocodes available.
"Congratulations to Homesite on this prestigious E-Fusion award," said Steve Walden, vice president of Business Geographics for Pitney Bowes Group 1 Software. "Homesite is a perfect example of an industry leader that is leveraging technology to drive their business strategy and growth. We're proud to be a dedicated partner in support of Homesite's drive for underwriting precision and excellence."
In addition to the insurance industry, GeoStan's high-definition data is also used by telecommunications, transportation, finance, routing and mapping companies, among others, for a variety of marketing and operational applications, including identifying customers eligible for location-based services and providing starting and ending locations for optimizing delivery routes.
Group 1 Software (http://www.g1.com/) turns data into results, providing innovative software solutions that enable our clients to better understand and connect with their millions of customers, prospects, and partners. Group 1 Software helps over 3,000 organizations maximize the value of customer data to improve profitability, increase effectiveness, and strengthen customer relationships, through consolidating, cleansing and enriching corporate data, and generating personalized business documents for multi-channel delivery, customer care and efficient business processing. Our comprehensive Customer Communications Management (CCM) solutions span from database to delivery, adding value to every aspect of communication and allowing clients to integrate intelligence throughout their mailstream. As part of Pitney Bowes (NYSE: PBI), a $5.6 billion company, Group 1 Software's solutions are utilized by leaders in the insurance, financial services/banking, GIS/mapping, government, mail services, retail, telecommunications, utility, and other industries, including Entergy, ING, L.L. Bean, MapQuest, Microsoft, Safeco Insurance, Wal-Mart and Wells Fargo.
GeoStan, Group 1, Group 1 Software, and the Group 1 logo are trademarks or registered trademarks of Group 1 Software, Inc. Pitney Bowes and the Pitney Bowes Process Bar Design are trademarks or registered trademarks of Pitney Bowes, Inc. All other brand names and trademarks are the property of their respective owners.
SOURCE: Pitney Bowes Group 1 Software
CONTACT: Doug Gunster of Pitney Bowes Group 1 Software, +1-301-918-0864,
douglas_gunster@g1.com
Web site: http://www.g1.com/
http://www.pb.com/


text:
Andy Shauf's Foxwarren Plot Tour, Share Video for "Sunset Canyon"
The clip stars Busy Philipps
After sharing a video for "To Be" late last year, Andy Shauf's full-band project Foxwarren have now released a clip for "Sunset Canyon" alongside plans for their first-ever tour.
Directed by Laura-Lynn Petrick, the video stars actor and talk show host Busy Philipps, who is surrounded by nature in the sunny clip.
"The video was my ethereal gaze on a female seeking serenity in the nature that surrounds her," Petrick explained in a statement. "Inspired by Italian neorealism, Busy and I spent the day exploring the forests of the canyons and enjoying the winter sun reflecting with nature."
Philipps added, "'Sunset Canyon' is one of my favourite songs from the Foxwarren album and I basically have been making my own music videos to the song since it came out. Working with Laura-Lynn on the video was so amazing. She is such a talent and I loved the easy going vibe of the day, wandering through the canyon with her in my mom's dress from the sixties."
Foxwarren will tour their self-titled LP throughout late May, June and July, beginning with a date in their hometown of Regina on May 29. Further Canadian stops have been set for Saskatoon, Edmonton, Calgary, Vancouver and Toronto, with support from Hannah Cohen.
Foxwarren is out now via Arts & Crafts/Anti-. Find the band's tour itinerary below.
05/29 Regina, SK – The Exchange*
05/30 Saskatoon, SK – Broadway Theatre*
05/31 Edmonton, AB – The Starlite Room*
06/01 Calgary, AB – Commonwealth*
06/04 Vancouver, BC – The Biltmore Cabaret*
06/05 Seattle, WA – Crocodile*
06/06 Portland, OR – Doug Fir Lounge*
06/08 Sonoma, CA – Huichica Festival
06/11 Los Angeles, CA – Teragram Ballroom*
06/24 Baltimore, MD – Metro Gallery*
06/25 Philadelphia, PA – Johnny Brenda's*
06/28 Portsmouth, NH – 3S Artspace*
06/29 North Adams, MA – Solid Sound Festival
07/02 Detroit, MI – El Club*
07/05 Minneapolis, MN – 7th Street Entry*
07/06 Chicago, IL – Empty Bottle*
07/12 Toronto, ON – Lee's Palace*
* with Hannah Cohen
More Foxwarren
More Busy Philipps
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Foxwarren
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Western Canadian Music Awards Reveal 2019 Nominees
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Pinegrove Announce Feature Film and Soundtrack 'Amperland, NY'
Pinegrove have announced a feature film, as well as a 21-song accompanying soundtrack — both titled Amperland, NY after the band's longtime...
Busy Philipps Joins Cameo to Record "Stay the Fuck Home" Messages for Coronavirus
Experts agree that the best way to slow the spread of coronavirus is through social distancing and, when possible, staying home. Now, Busy P...
Busy Philipps' Late-Night Show 'Busy Tonight' Gets Cancelled
Busy Philipps revealed earlier today that her late-night talk show Busy Tonight will be dropped from the E! network after May 16. "Busy...
Busy Philipps Accuses James Franco of Physically Attacking Her on Set of 'Freaks and Geeks'
Busy Philipps has accused James Franco of physically attacking her on the set of Freaks and Geeks. This comes from an excerpt of her upcomin...
Busy Philipps and Ellen DeGeneres Discuss Being Survivors of Sexual Assault
Busy Philipps bravely spoke out about being raped at the age of 14, after watching the Kavanaugh hearings last week. Today, she appeared on...
Exclaim!'s 50 Best Albums of 2020
This was a year of solitude and introspection, whether we wanted it or not. It was a year that forced everyone to confront their deepest, da...
Barack Obama Is an Andy Shauf Fan
Barack Obama is known for sharing his surprisingly cool playlists, which span genres and include plenty of contemporary artists. He just del...
Listen to Two New Songs from Andy Shauf
Continuing with his Neon Skyline vignette, Andy Shauf has shared two new songs narrating more of the album's love story. The new 7-inch rele...
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We've all heard it a million times before: six months ago, at the start of the calendar year, who could have predicted what 2020 had in stor...
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Andy Shauf took listeners to The Neon Skyline earlier this year, and the LP was named one of Exclaim!'s Must-Hear Canadian Albums from Winte...


The number of measles cases in the United States has soared to more than 460, the highest number since 1991. More than half of the cases are in New York, where 21 people had to be hospitalized, five of them in intensive care. Last week, New York City Mayor Bill de Blasio declared measles a public health emergency, and has ordered mandatory vaccination in parts of the city. VOA Zlatica Hoke reports measles cases are up 300 percent worldwide this year, according to the World Health Organization.


Like a little cream in your coffee? Or perhaps you just dig a good cup of "strong coffee." This coffee is the answer for you. Our darkest roast, the Blue Ridge Blend is here to make sure there's a Hatchet Coffee for everyone.


"My first attempt came out pretty yummy. It doesn't look quite as appetizing as your meal because I cut the meat pretty horribly. I just made due with what I had, which was rib-eye steak. The kimchi fried rice I added egg too and cut out the seaweed, since I didn't have any. But end result was delicious, I made it for me and my grandmother and she really really liked the meal. The meat came out nice and tender and she even ate some of the kimchi fried rice and she's not a big fan of kimchi. Thanks so much for sharing your recipes "
"What side dishes would you pair with the soup, beside rice?"


text:
TheHill
Opinion | International
December 03, 2021 - 09:01 AM EST
To counter China, the Senate must confirm US ambassadors
By Jenna Ben-Yehuda, opinion contributor
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We've achieved a rare moment of consensus in Washington: the bipartisan recognition that a revanchist China poses a threat to U.S. interests. While there's less agreement on what precise cocktail of cooperation and competition might best help the U.S. to avoid this already Cold War becoming a hot one, there's broad agreement that China's influence ought to be countered.
To do so, we would be foolish to seek only those strategies that check China militarily. We must also pursue the full range of diplomatic and development tools available. Anything less ties one arm behind our back as China presses ahead. But pushing back needn't be complicated and one concrete path is staring the Senate in the face: It's time to confirm President Biden's ambassadors-designate to ensure the full complement of diplomatic presence, especially in those countries most lured by and vulnerable to China's unchecked rise.
The need to confirm Biden's pick for China, Ambassador Nicholas Burns, is obvious and critical (though no less politically charged), but a range of other unconfirmed nominees outside of Asia also merit attention. Consider Latin America, a region in which China's economic and diplomatic gains offer an especially sobering perspective on the scope of its ambitions. From 2002 to 2019, China's investment in the region increased 18-fold, making it the area's second-leading trading partner, right behind the United States.
China's grip over Latin America is vast and diverse, ranging from economic, diplomatic and educational influences, to technological, security and environmental ones. As a result, it's no exaggeration to say that the People's Republic of China (PRC) has a powerful and sustained impact on the decisions of leaders across the region.
The fact that many Chinese companies do not adhere to international environmental, labor and safety standards is just the start. The reality is that the PRC's actions greatly harm U.S interests in the region, from propping up anti-democratic leaders, undermining U.S. security relationships and worsening the already-growing scourge of corruption.
Take Paraguay. This small country of some 7 million people is far from the largest, wealthiest or most powerful country in the region; but, as the only remaining South American nation that still recognizes Taiwan (and one of only 15 countries in the world), Paraguay is on the front lines of the losing struggle to counter China's influence in Latin America - a fact that has drawn the attention of Senate Republicans. Just last month, Sen. Marco Rubio (R-Fla.) highlighted China's troubling pressure on Paraguay as his key point in illustrating U.S. disadvantages in the region.
Despite this, Republican Sens. Ted Cruz (Texas) and Josh Hawley (Mo.) - both vocal proponents of getting tough on China - have placed unprecedented holds on essentially all State Department ambassadorial and other nominees, including on President Biden's nominee to Paraguay, Marc Ostfield. Ostfield, currently the State Department's ombudsman, is a career civil servant and member of the senior executive service, making him amongst the least "political" of Biden's nominees, having served under Republican and Democratic administrations alike.
Yet Ostfield, like the 79 other ambassadorial nominees on which Cruz has also placed holds, is being blocked not for questions surrounding his record or qualifications, but rather as part of the blanket hold Cruz has placed on nominees to signal his opposition to Biden's mid-May waiving of congressionally-imposed sanctions on the Nord Stream 2 pipeline project stretching from Russia to Germany. Hawley added his own holds on nominees as a means of demanding the resignation of several senior administration officials for their handling of the Afghanistan withdrawal.
The result is that, for reasons having nothing to do with Paraguay or Ostfield, the U.S. Embassy in Asunción continues to have no ambassador, an ignominious status it has maintained since September 2020. Meanwhile, China continues to dangle the promise of hard-to-get COVID vaccines in front of this strapped nation that earlier this year had one of the highest COVID death rates in the world. Other Taiwan-affirming holdouts in the region, Honduras, Haiti and Belize, are also ambassador-less with the former awaiting an initial hearing and the latter two without nominations from the White House.
Make no mistake, having a U.S. ambassador in Paraguay alone is not a bulwark against Chinese influence. But the absence of one certainly sends a clear signal about our weakened commitment to countering Beijing's ambitions around the world. Rectifying this is simple, free, and could happen in a matter of days, making it the lowest possible hanging fruit in U.S. efforts to counter Chinese influence. That's why it's time for Cruz and Hawley to set differences over Nord Stream 2 and Afghanistan aside so that we can bring all assets to bear as we counter China's influence around the world. To do so, they need only to lift their holds. Our diplomats will do the rest.
Jenna Ben-Yehuda is the president and CEO of the Truman Center for National Policy and a former State Department official.
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