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Electroacupuncture analgesia is associated with increased serum brain-derived neurotrophic factor in chronic tension-type headache: a randomized, sham controlled, crossover trial
Mônica Chassot1,3,
Jairo Alberto Dussan-Sarria1,2,3,
Francislea Cristina Sehn1,3,
Alícia Deitos1,3,
Andressa de Souza3,4,
Rafael Vercelino1,3,
Iraci LS Torres1,5,
Felipe Fregni6 &
Wolnei Caumo1,2,3,7
Chronic tension-type headache (CTTH) is characterized by almost daily headaches and central sensitization, for which electroacupuncture (EA) might be effective. The central nervous system (CNS) plasticity can be tracked in serum using the brain-derived neurotrophic factor (BDNF), a neuroplasticity mediator. Thus, we tested the hypothesis that EA analgesia in CTTH is related to neuroplasticity indexed by serum BDNF.
We enrolled females aged 18–60 years with CTTH in a randomized, blinded, placebo-controlled crossover trial, comparing ten EA sessions applied for 30 minutes (2–10 Hz, intensity by tolerance) in cervical areas twice per week vs. a sham intervention. Treatment periods were separated by two washout weeks. Pain on the 10-cm visual analog scale (VAS) and serum BDNF were assessed as primary outcomes.
Thirty-four subjects underwent randomization, and twenty-nine completed the protocol. EA was superior to sham to alleviate pain (VAS scores 2.38 ± 1.77 and 3.02 ± 2.49, respectively, P = 0.005). The VAS scores differed according to the intervention sequence, demonstrating a carryover effect (P < 0.05). Using multiple regression, serum BDNF was adjusted for the Hamilton depression rating scale (HDRS) and the VAS scores (r-squared = 0.07, standard β coefficients = −0.2 and −0.14, respectively, P < 0.001). At the end of the first intervention period, the adjusted BDNF was higher in the EA phase (29.31 ± 3.24, 27.53 ± 2.94 ng/mL, Cohen's d = 0.55).
EA analgesia is related to neuroplasticity indexed by the adjusted BDNF. EA modulation of pain and BDNF occurs according to the CNS situation at the moment of its administration, as it was related to depression and the timing of its administration.
According to the International Classification of Headache Disorders, chronic tension type headache (CTTH) is characterized by daily (or almost daily) headaches that last several hours per day [1]. Its prevalence in the general population ranges from 2-5% [2,3], leads to a negative impact on both functionality and quality of life, and increases the risk for excessive analgesic consumption [4]. As with some other chronic pain conditions, patients suffering CTTH present amplification of afferent signals [5], central sensitization phenomena and inadequate descendent inhibitory control [6]. The nervous system changes induced by chronic pain are performed by different actors, including the brain-derived neurotrophic factor (BDNF).
BDNF has been identified as a key player in the sensitization of the system, altering the excitatory/inhibitory balance in the central nervous system (CNS), and in the amplification of pain transmission modulation of the nociceptive sensory inputs in the spinal cord [7,8]. BDNF is secreted by both neurons and neuroglia [9] actively crossing the blood–brain barrier. The CNS contributes to 70-80% of the serum BDNF, allowing for reliable inference of its concentration in the CNS by serum assessments [10]. Having a relevant mediator of the CNS modulation evaluated in a serum sample may open the door for improving the understanding of the neuronal plasticity in clinical scenarios, offering insights into the neuromodulation induced by current therapies, such as electroacupuncture (EA).
Although experimental studies in both animals and humans have suggested that EA effects may go beyond analgesia alone, clinical trials and meta-analyses in CTTH are inconclusive [11,12]. However, such inconclusive evidence for a single therapeutic approach is also shared by pharmacological interventions [13,14]. Nevertheless, anatomical structures analyses have found that EA increases BDNF expression in rat cortexes and hippocampi [15], where long-term depression (LTD) is additionally induced, augmenting BDNF secretion [16]. Moreover, EA has demonstrated its ability to reorganize the somatosensory cortex in patients with neuropathic pain [17], to induce LTD of postsynaptic potentials within the substantia gelatinosa [18], and to modify postsynaptic NMDA (N-methyl-D-aspartic acid) receptor expression [19]. Thus, EA represents a technique for peripheral stimulation with a CNS-modulating effect.
Striving to provide new insights into the neurobiology of CTTH and its neuroplasticity mechanisms, we designed the present cross-over trial involving applying EA and assessing the clinical outcomes and serum BDNF. We hypothesized that EA analgesia is related to changes in neuroplasticity markers as indexed by BDNF.
The methods and results are reported according to CONSORT guidelines. The study protocol was approved by the Research Ethics Committee at the Hospital de Clínicas de Porto Alegre (HCPA) (Institutional Review Board IRB 0000921 - application no.09-259) and was performed in accordance with the Declaration of Helsinki (Resolution 196/96 of the National Health Council). The protocol was registered at clinicaltrials.gov (NCT01954277). The authors confirm that all ongoing and related trials for this drug/intervention are registered.
Design overview, setting, and participants
All patients provided their written informed consent before enrollment into this randomized, single-blinded, placebo-controlled, crossover trial. We included 34 women, aged between 18 and 60 years old, which had a clinical diagnosis of chronic tension-type headache according to the International Headache Society (The International Classification of Headache Disorders, 3rd edition (beta version)) [1]. We excluded patients with any malignancy diagnosis, rheumatoid arthritis, habitual use of anti-inflammatory steroids, decompensated systemic diseases, HIV and pregnancy.
These subjects were recruited from a community cared by a Basic Health Unit linked to the Hospital de Clínicas de Porto Alegre (HCPA) between August 2010 and November 2012. The HCPA is a center of reference for the State of Rio Grande do Sul, receiving patients from different parts of the state. The HCPA Basic Health Unit provides health services that include social services, health prevention and promotion, as well as clinical ambulatory care, serving a population of approximately 6000 habitants. Public media advertisement (journal, radio, and television) was used to recruit patients. They were screened by an initial telephone interview, and if they met inclusion criteria, they were invited for a more in-depth encounter where medical history, and a detailed description of their headaches were determined during a 60-min structured interview. During the same encounter, the baseline biological samples were collected (see Figure 1). CTTH diagnosis was based on criteria from the International Classification of Headache Disorders (The International Classification of Headache Disorders, 3rd edition (beta version)). The participants had to experience headaches with the following characteristics for more than 180 days in the last year: pain lasting hours to days or unremitting; bilateral, pressing or tightening (non-pulsating) quality; mild or moderate intensity; and not aggravated by routine physical activities. The diagnosis was confirmed by a headache treatment specialist.
Randomization and follow-up of the study participants, CONSORT flowchart.
Sample size calculation
The number of subjects in each study group was determined based on previous clinical trials [20]. An a priori estimate indicated that a total sample size of 28 patients divided into two balanced treatment arms (n = 14) was required to detect a reduction in pain intensity with EA at a minimum of 0.8 cm (average SD = 0.5 cm), with a power of 0.8 and an α-level of 0.05. (Cannella KAS, 1998). To account for the multiple outcomes and potential dropouts, we increased the sample size to 17 per group.
Randomization
The patients were randomized into the two groups (electroacupuncture or sham). We used simple randomization to allocate the interventions, using computer software. The simple randomization relies on independent and equal probabilities to receive each intervention, for each subject. Although it is the most basic approach, it preserves unpredictability of the allocation. In our experiment, the computer software generated a random number of 5 digits for each subject, for which one of the interventions was randomly allocated. In this way, it is guaranteed that each subject had the same chance of starting the experiment receiving one or the other intervention, irrespective of the intervention allocated to the other research subjects. The envelopes contained the five digits number that represented the allocated intervention. After the participant agreed to participate in the trial and baseline assessments were performed, the opaque envelope was opened by the investigator responsible for the intervention application. After the washout period (minimum of two weeks), participants returned for completion of the second intervention period (if started with EA, participant would receive sham and vice versa). After each treatment period the baseline assessments were repeated.
To control for possible measurement bias in the present study, the following measures were taken: all treatment sessions were administered by the same trained (F.S.) and experienced (10 years) acupuncturist physician to ensure that the treatment was homogenous among the patients. In addition, none of the patients had undergone previous treatment with acupuncture. One evaluator who was blind to the group assignments was trained to apply the pain scales and conduct psychological tests. To avoid unblinding of the outcomes evaluators, the participants were instructed to discuss all aspects related to their treatment with the treating physician during the treatment sessions.
Each intervention was applied twice per week during five weeks, for a total of ten sessions. Then, a washout period of at least two weeks was granted for every participant, so they could start the second phase with the complementary intervention after collecting biological samples and performing questionnaires, again.
Electroacupuncture
We used acupuncture needles with guide tubes (Suzhou Huanqiu Acupuncture Medical Appliance Co. Ltd., 218, China) that were 40 mm in length and 0.25 mm in diameter. During the treatment, the patients sat comfortably, and their arms were supported. Needling areas were disinfected and disposable needles inserted at points previously selected as shown in Figure 2. The needles were placed over the anatomical areas as shown in Figure 2. From cephalad to caudal, needles were inserted bilaterally aiming to reach: medial aspect of splenius capitis and semispinalis capitis muscles at the level of C1-C2 vertebrae; lateral aspect of trapezius; semispinalis capitis muscle at the level of C6-T1 vertebrae. Also, at this same level, bilateral needling was performed at level of C6-T1 to reach the levator scapulae muscles. In the hand, the needles were inserted bilaterally to reach the abductor pollicis brevis and dorsal interossei muscles. In the ear, the needles were placed in two points: one in the superior and central area of the tip of the triangular fossa, between the junction of the superior crus and the inferior crus of the antihelix, and the other in the helix root, an area of innervation by the vagus nerve. A total of sixteen needles were used per subject per session. The acupuncture needles were connected to an electro-stimulator device (Model EL 608 NKL, Brusque, SC, Brazil) at an alternating frequency of 2 Hz and 10 Hz (2/10 Hz, 0.3 ms width) for 30 minutes. The intensity of the electrical therapy was adjusted to produce a gentle tapping sensation or up to the tolerance of the patient. The needles on the hand and ear were not electrically stimulated.
Anatomic needling points. Sixteen needles were inserted, from cephalad to caudal, bilaterally: superior and central area of the tip of the triangular fossa in junction of the superior and inferior crus of the antihelix (ear); helix root (ear); medial aspect of splenius capitis and semispinalis capitis muscles (C1-C2 level); lateral aspect of trapezius; semispinalis capitis muscle (C6-T1 level); levator scapulae muscles (C6-T1 level); abductor pollicis brevis and dorsal interossei muscles (hands).
For the sham intervention, we used an electroacupuncture device (Cosmotron, Sao Paulo, Brazil), which was adjusted beforehand to prevent the current from passing through the electrodes. No needling was used at all. The electrical connection between the stimulator and the patient was broken at the output jack plug of the stimulator so that no current could pass to the patient. The patients were informed that this was a high-frequency, low-intensity stimulation and that they would most likely feel no sensation from it. The electrodes were placed in the same areas as the real stimulation. The nerve stimulation unit was left in front of the patient for 30 minutes. This positioning ensured that the flashing diode that simulated the electrical stimulus was both visible and audible. The patients were sitting comfortably, so they could see the device's light sign.
Instruments and assessments
All of the psychological tests used in this study have been validated for the Brazilian population [21,22]. One independent research examiner blinded to the group assignments was trained to administer the pain scales and to conduct the psychological tests. The baseline depressive symptoms of the patients were assessed using the Hamilton Depression Rating Scale. Catastrophic thoughts were assessed using the Brazilian Portuguese version of the Pain Catastrophizing Scale score [21]. The headache impact in daily life was assessed using the Short-Form Headache Impact Test (HIT-6) [22]. Demographic data and medical comorbidities were assessed using a standardized questionnaire. A systematic evaluation of potential complications of the technique, such as pneumothorax or bleeding, was also conducted.
The primary outcomes were pain as assessed by the pain diaries (the maximum pain during the last 24 hours) and serum levels of BDNF. The secondary outcomes were the amount of analgesics used weekly throughout the treatment period.
The intensity of pain was measured by the 10-cm visual analog scale (VAS). The VAS scores ranged from no pain (zero) to the worst possible pain (10). The time of the worst pain during the last 24 hours was recorded daily in the patients' diaries. They were asked to answer the following question: how intense was your worst pain during the last 24 hours? To improve patient compliance, an evaluator checked their pain records weekly.
The analgesic allowed to be used during the treatment period was acetaminophen 750 mg up to four times per day. In case it was not effective as a rescue analgesic, patients were allowed to use ibuprofen 200 mg a maximum of four times per day. If pain persisted, codeine 60 mg was also permitted. If codeine was ineffective, patients could use Dorflex® (Sanofi Aventis, Sao Paulo, Brazil; 35 mg Orfenadrine citrate combined with 300 mg Metamizol (Dypirone) and 50 mg caffeine). These medications could be used a maximum of four times a day. The analgesics used during the treatment period were monitored from diary entries recording analgesic intake, which were assessed in each treatment session. The total analgesic doses taken after starting treatment to the end were considered for the analysis.
The serum levels of BDNF were determined by Enzyme-Linked Immunosorbent Assay (ELISA) using a ChemiKine BDNF Sandwich ELISA Kit, CYT306, Chemicon/Millipore, Billerica, MA, USA. The lower detection limits of the kits are 7.8 pg/mL for BDNF. The data are expressed in ng/mL of blood serum. Blood samples were collected in plastic tubes with separator gel, centrifuged for 10 min at 4500 × g at 4°C, and serum was stored at −80°C for hormone assays. All Biological samples were collected early in the morning.
Continuous and categorical variables were summarized using conventional descriptive statistics. Daily pain on the VAS was averaged per week and used to study pain behavior during the intervention periods. Normality was verified using the Shapiro-Wilk test. Variables were compared between the allocated sequence using independent samples t-tests for continuous variables and Chi-squared or Fisher's exact tests for the categorical variables. Linear mixed models were used to compare outcomes within subjects during each intervention period (EA vs. Sham period) and between subjects according to the allocated phase (EA vs. Sham first). A carryover effect was defined as a significant difference in the pain score on the VAS between the two treatment sequence and was tested with the comparison provided by the linear mixed model. The mean differences between intervention periods according to sequence phase were calculated and presented with their respective standard error of the mean (SEM). The percentage of the change from baseline was calculated as 100-(outcome*100/baseline) and was presented with its respective 95% confidence interval (95%CI). The serum BDNF level was adjusted for severity of depressive symptoms (HDRS) and pain on the VAS using a multiple linear regression.
The standardized mean difference (SMD) was computed in terms of the ratio between the mean change and the pooled standard deviation. The SMD (also known as effect size) was interpreted as follows: small if lower than 0.20, moderate if between 0.50–0.60, and large if larger than 0.80 [21]. We considered all of the randomized patients as part of the analysis using the intention-to-treat method, with the last observation carried forward. A two-sided alpha level (type I error rate) of less than 0.05 was considered to be the statistical significance threshold. The data were analyzed using SSPS version 18.0 (SPSS, Chicago, IL).
Thirty-four patients were randomized (Figure 1). The clinical and demographic characteristics of the subjects according to the sequence allocation were comparable and are shown in Table 1. Seventeen patients were allocated to the phase receiving EA first and seventeen to the phase receiving sham first. Twenty-nine patients completed the study, and two participants in the EA first phase discontinued, one participant because of financial problems and the other participants because of personal problems. In the phase receiving sham first, three patients dropped out for different reasons: one because of lack of time to come to the center, another one because of dissatisfaction with the effect of the treatment and one who gave no justification. No adverse events were observed.
Table 1 Characteristics of the study sample
EA was superior to sham reducing CTTH pain. During the EA period (irrespective of the phase), the mean (±SD) of the pain score on the VAS was 2.38 ± 1.77 (60.17% mean reduction from baseline) compared with 3.02 ± 2.49 during the sham period (38.49% mean reduction from baseline) (P = 0.005) (Figure 3). A significant difference was observed in the primary outcome (pain score on VAS) on the basis of treatment sequence (P < 0.05). Thus, a carryover effect was detected when the EA phase preceded the sham-treatment (Figure 4). The mean pain on the VAS during the EA period was not different than during the sham period (P = 0.29) in the EA-first phase. On the other hand, the mean pain differed between the intervention periods in the phase receiving the sham first (P = 0.003), with the VAS score lowering to 2.49 ± 1.79 during the EA period. Most of the patients (Eleven) had a reduction of 50% or more in the VAS during the EA period. In contrast, only five patients had that level of reduction in the sham-phase.
Mean pain by intervention period. Bars indicate the SEM. Electroacupuncture (EA) was superior to Sham in reducing pain. * P < 0.05.
Mean pain according to intervention period and sequence phase. Bars indicate the SEM. Bars with the same letter are not significantly different from each other. Both interventions significantly reduced pain when compared to baseline. Electroacupuncture (EA) was superior to Sham in reducing pain.
The serum BDNF was inversely correlated with the level of depressive symptoms and pain intensity, in the sense that more intense symptoms were associated with lower serum BDNF. Thus, the serum BDNF was adjusted for the HDRS and pain (weekly mean pain on the VAS) (r-squared = 0.07, standard β coefficient for the HDRS = −0.2, t = −3.87, standard β coefficient for the pain on the VAS = −0.14, t = −2.74, both P < 0.001). The mean of serum BDNF adjusted for depressive symptoms and pain was 30.01 ± 3.89 ng/mL in the phase receiving the EA first and 28.95 ± 3.45 ng/mL in the phase receiving sham first (Figure 4). At the end of the first EA period, the mean adjusted BDNF was 29.31 ± 3.24 ng/mL and at the end of the first sham period, it was 27.53 ± 2.94 ng/mL. The size of the effect of EA on the adjusted BDNF was moderate (Cohen's d = 0.55).
EA significantly reduced the use of analgesics for CTTH. In the phase beginning with EA, the median number of analgesic doses used weekly (interquartile 25–75 range) was 2 (0–4) during the EA period and 1 (0–4) during the sham period (P = 0.04). In the phase beginning with sham, the median number of analgesic doses used weekly was 3 (0–7.25) during the sham period and 2 (0.5-4) during the EA period (P = 0.04).
In the present study, a relationship between pain and serum BDNF was demonstrated to be influenced by the timing of the EA intervention. In addition, our study demonstrated that the daily pain scores and number of analgesics used were significantly reduced in the phase receiving EA-first. This phenomenon was not observed in the phase starting with sham, confirming the carryover effect (Figure 4). After adjusting for depression and pain, serum BDNF changed in the opposite direction of the clinical outcomes, which suggests that, the elevation of serum BDNF levels after EA is inversely proportional to the perceived pain. In other words, the BDNF increased more after EA in those with greater analgesia (lower VAS) (Figure 5).
Serum BDNF adjusted for pain and depressive symptoms by intervention period and phase. Bars indicate the SEM. Bars with the same letter are not significantly different from each other. In those who received Electroacupuncture (EA) first, the serum BDNF elevation became significant after the Sham intervention, suggesting long-lasting effects of the EA.
EA effects on both pain and BDNF were sustained beyond the real intervention periods. In addition to supporting the effects of EA described in other scenarios, such as neuropathic pain and depression [17,23,24], our findings provide a correlate between the clinical effect and a biological marker, the serum BDNF. The direction of the modulation on pain and BDNF persisted beyond the active intervention period; however, the underlying mechanisms of EA on these outcomes have not been fully elucidated yet. Nevertheless, our findings are in agreement with previous reports indicating that the increase in inhibitory activity and/or the decrease in excitatory synaptic activity may relate to BDNF [25]. In addition, the EA-first phase presented an analgesic effect of moderate magnitude, and the effect had a consistent magnitude with a previous meta-analysis report [26].
In our study, the EA analgesia was associated with the reinstatement of serum BDNF. This finding may be of relevance for clinicians and researchers because it reduces the gap between the apparent inconsistency of EA clinical effects reported in some meta-analysis [12], which has been questioned by experienced clinicians [27]. Furthermore, it extends additional neurobiological support for the sustained effect of EA on pain. This effect is biologically plausible considering the modulatory role of BDNF in the physiopathology of pain, as well as its involvement in neurogenesis and synapsis strengthening [28]. Such properties of the BDNF have been reported in other neuropathological conditions, such as brain ischemia [29] and after the partial dorsal rhizotomy [30]. In both conditions, the EA increased BDNF, which is similar to the effect observed after antidepressant administration in humans [31]. BDNF has been extensively studied in patients with major depression, and has been demonstrated that patients with the acute disorder have lower serum BDNF than when euthymic and than controls. Further, antidepressant treatment increases serum BDNF in those who respond to this pharmacological intervention [32]. Consistent with these reports, in our experiment we detected that serum BDNF was inversely correlated with depressive symptoms, maintaining the same direction of the observations in major depression: lower serum BDNF was associated with more intense depressive symptoms. Because of this, we adjusted for the effect of depressive symptoms on the serum BDNF in order to perceive better the effect of our intervention on the desired outcomes. After this adjustment, it was evident that the changes in BDNF were related to the EA intervention. To improve the understanding of the relationship between EA-induced analgesia and serum BDNF, different processes could be considered: BDNF can down-regulate the functions of NMDA receptors and inhibit the glutamate excitotoxicity [32], and it attenuates down-regulation of superoxide dismutase expression thereby decreasing free radical injuries [33] In addition, it regulates the expression of the calcium channel proteins on the cell membrane and may maintain the homeostasis of intracellular calcium [34]. In addition, BDNF regulates the expression of neuronal genes through upstream element-like transcriptional factors, including c-fos and c-jun, which are involved in the central sensitization process [35].
Even though a carryover effect was observed, these findings permitted us to highlight important points related to the acupuncture effect in the clinical setting. To the best of our knowledge, this is the first clinical study to extend the effect of EA in neuroplasticity markers indexed by the BDNF. In addition to the insights regarding neuroplasticity related to pain, our results also indicate that BDNF is a possible tool to improve the understanding of the disagreement between the clinical effect observed by clinicians and the failure of these techniques over placebo interventions in clinical trials. Although in general the carryover effect is interpreted as disadvantageous, in this study it was convenient, as it helped to reveal the serum BDNF as a possible marker to differentiate the effect of active treatment from those induced by the placebo.
In this study, the placebo effect reduced the pain 38.49%, a rate that is in agreement with previous studies that have reported a reduction in pain as high as 40% when using self-reported outcomes [36]. These findings are also in agreement with a meta-analysis that demonstrated that placebo effects are larger with more sustained pain and in the presence of hyperalgesia [37]. The placebo effect in pain studies may be explained by several patient-related reasons, such as: i) an established lower cognitive anchor point for pain and failure to sufficiently override prior beliefs when making reporting decisions; ii) over-weighting moments with lower pain experience when judging overall pain due to increased cognitive availability of experiences that match expectations; iii) desire to report what they believe the experimenter expectation is, in part because they believe this conforms to 'correct' or normative behavior; iv) desire to be consistent with prior behavior, which could include decreased reports of pain during prior treatment; and v) biasing of their reports towards what they would like to happen [38]. In fact, all these findings encourage us to promote the use markers of neuroplasticity, such as the BDNF, in future clinical studies to characterize the placebo effect.
Some considerations are relevant for a proper interpretation of our results. It is worth highlighting that in our trial a single experienced acupuncturist performed all the interventions. Although it could have reduced the intervention bias, it could also at the same time limit the ability of undertrained practitioners to reproduce the experiment, because slight variations in the technique could hypothetically induce different clinical responses. Nevertheless, because our research question focused on the neuroplasticity underlying the analgesic effect of electroacupuncture in chronic tension type headache, having an experienced acupuncturist providing an intervention of high quality reduced the risk of missing the signal of interest because of an inappropriately applied technique. Further, it is important to consider that because of the experimental design, even with an appropriate technique, it is impossible to determine whether the observed effect are purely due to the effect of the needle alone, electrical current alone, or due to both together.
The use of a crossover design in a small study population helped us to prevent overestimation of the benefits of the therapy being tested [39], making it likely that our results reflect a conservative assessment of the benefits of EA. The two-week washout period between study interventions was insufficient to prevent a carryover effect. The particular strength of this design is that the interventions under investigation were evaluated within the same patients and thus eliminates between-subject variability [40]. Given that patients act as their own controls, the analyses could be based on paired data (using paired tests) [41,42]. Also, because of this within-subject comparison, the cross-over design allows us to reduce the potential confounding effect that antidepressants and analgesics might have on the outcomes assessed. The carryover effect across intervention periods may distort the results obtained during the second intervention periods [43-45]. The number of patients who completed both treatment periods provided sufficient power (80%) to reach statistical significance (P < 0.05), despite 17.64% (3/17) of patients dropping out after the first intervention period and thus not receiving a second intervention. Although the outcome assessor, the care provider, and the patient were blinded (as recommended in the Delphi List for the quality of clinical trials), the attending acupuncturist was not because that was impossible. Finally, although several strategies were used to prevent patients and evaluator team from being unblinded, formal assessment for the awareness of the allocation (either active or placebo) was not performed. However, our objective surrogates are less prone to bias (i.e., serum BDNF and analgesic requirements) were consistent with the pain scores. Thus, unblinding is unlikely to have influenced the direction of our conclusions.
In conclusion, these findings revealed that in patients with CTTH, the relationship between pain and serum BDNF was influenced by the timing of the EA intervention. The EA administered first increased the serum BDNF and facilitated a carryover effect that was associated with the pain scores and the number of analgesics used during the second intervention period. In addition, EA changed the serum BDNF in the opposite direction of depression and pain. Overall, these findings suggest that BDNF may be a serum marker of the neuroplasticity induced by EA.
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Ball S, Marangell LB, Lipsius S, Russell JM. Brain-derived neurotrophic factor in generalized anxiety disorder: results from a duloxetine clinical trial. Prog psychopharmacol Biol Psychiatry. 2013;43:217–21.
Polyakova M, Stuke K, Schuemberg K, Mueller K, Schoenknecht P, Schroeter ML. BDNF as a biomarker for successful treatment of mood disorders: a systematic & quantitative meta-analysis. J Affect Disord. 2015;174C:432–40.
Tremblay R, Hewitt K, Lesiuk H, Mealing G, Morley P, Durkin JP. Evidence that brain-derived neurotrophic factor neuroprotection is linked to its ability to reverse the NMDA-induced inactivation of protein kinase C in cortical neurons. J Neurochem. 1999;72:102–11.
Ikeda O, Murakami M, Ino H, Yamazaki M, Koda M, Nakayama C. Effects of brain-derived neurotrophic factor (BDNF) on compression-induced spinal cord injury: BDNF attenuates down-regulation of superoxide dismutase expression and promotes up-regulation of myelin basic protein expression. J Neuropathol Exp Neurol. 2002;61:142–53.
Blanquet PR, Mariani J, Derer P. A calcium/calmodulin kinase pathway connects brain-derived neurotrophic factor to the cyclic AMP-responsive transcription factor in the rat hippocampus. Neuroscience. 2003;118:477–90.
Schäbitz WR, Sommer C, Zoder W, Kiessling M, Schwaninger M, Schwab S. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke. 2000;31:2212–7.
Lui F, Colloca L, Duzzi D, Anchisi D, Benedetti F, Porro CA. Neural bases of conditioned placebo analgesia. Pain. 2010;151:816–24.
Vase L, Robinson ME, Verne GN, Price DD. Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms. Pain. 2005;115:338–47.
Metcalfe J. Cognitive optimism: self-deception or memory-based processing heuristics? Pers Soc Psychol Rev. 1998;2:100–10.
Grizzle JE. The two-period change-over design an its use in clinical trials. Biometrics. 1965;21:467–80.
Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol. 1991;133:144–53.
Brown BW. The crossover experiment for clinical trials. Biometrics. 1980;36:69–79.
Cleophas TJ, de Vogel EM. Crossover studies are a better format for comparing equivalent treatments than parallel-group studies. Pharm World Sci. 1998;20:113–7.
Cleophas TJ. A simple method for the estimation of interaction bias in crossover studies. J Clin Pharmacol. 1990;30:1036–40.
Wallenstein S, Fisher AC. The analysis of the two-period repeated measurements crossover design with application to clinical trials. Biometrics. 1977;33:261–9.
This research was supported by grants from the following Brazilian agencies: Brazilian Innovation Agency (FINEP) process number - 1245/13 (Caumo W); the Committee for the Development of Higher Education Personnel – CAPES - PNPD/CAPES (for Prof. Wolnei Caumo, Alicia Deitos, Andressa de Souza, Rafael Vercelino), DOCFIX Program CAPES-FAPERGS for Rafael Vercelino, National Council for Scientific and Technological Development - CNPq (Prof. Iraci L.S. Torres, Prof. Wolnei Caumo, and Jairo Alberto Dussan-Sarria), the Postgraduate Program in Medical Sciences at the School of Medicine of the Federal University of Rio Grande do Sul, Postgraduate Research Group at the Hospital de Clínicas de Porto Alegre, and the Foundation of Support of Research at Rio Grande do Sul (FAPERGS) for Prof. Wolnei Caumo.
Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
Mônica Chassot, Jairo Alberto Dussan-Sarria, Francislea Cristina Sehn, Alícia Deitos, Rafael Vercelino, Iraci LS Torres & Wolnei Caumo
Pain and Palliative Care Service at Hospital de Clínicas de Porto Alegre (HCPA), UFRGS, Porto Alegre, Brazil
Jairo Alberto Dussan-Sarria & Wolnei Caumo
Laboratory of Pain and Neuromodulation, Hospital de Clínicas de Porto Alegre at UFRGS, Rua Ramiro Barcelos, 2350 - CEP 90035-003 Bairro Rio Branco, Porto, Brazil
Mônica Chassot, Jairo Alberto Dussan-Sarria, Francislea Cristina Sehn, Alícia Deitos, Andressa de Souza, Rafael Vercelino & Wolnei Caumo
Post-Graduate Program in Health and Human Development, Unilasalle Universitary Center, Canoas, Brazil
Andressa de Souza
Pharmacology Department, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, Brazil
Iraci LS Torres
Spaulding Center of Neuromodulation, Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts, USA
Felipe Fregni
Surgery Department, School of Medicine at UFRGS, Porto Alegre, Brazil
Wolnei Caumo
Mônica Chassot
Jairo Alberto Dussan-Sarria
Francislea Cristina Sehn
Alícia Deitos
Rafael Vercelino
Correspondence to Wolnei Caumo.
MC, FCS, AD, AS, RV participated in the sequence alignment, patients' recruitment, interventions and assessments. JADS, RV, WC drafted the manuscript. ILST, FF, WC participated in the design of the study. WC; JADS performed the statistical analysis. MC, FCS, ILST, FF, WC conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
Chassot, M., Dussan-Sarria, J.A., Sehn, F.C. et al. Electroacupuncture analgesia is associated with increased serum brain-derived neurotrophic factor in chronic tension-type headache: a randomized, sham controlled, crossover trial. BMC Complement Altern Med 15, 144 (2015). https://doi.org/10.1186/s12906-015-0664-x
DOI: https://doi.org/10.1186/s12906-015-0664-x
Brain derived neurotrophic factor
Chronic tension type headache


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Ahmed Omar (ur. 1933 w Casablance) – marokański kolarz szosowy, uczestnik letnich igrzysk olimpijskich.

Omar reprezentował Maroko na letnich igrzyskach olimpijskich podczas igrzysk 1960 w Rzymie. Wystartował w jeździe drużynowej na czas razem z Mohamedem El Gourchem, Mohamedem Ghandorą i Abdallahem Lahoucinem. Marokańczycy zajęli wówczas 19. miejsce spośród 32 reprezentacji. Omar brał także udział w wyścigu indywidualnym ze startu wspólnego, którego nie ukończył.

Przypisy

Urodzeni w 1933
Ludzie urodzeni w Casablance
Marokańscy kolarze szosowi
Marokańscy olimpijczycy
Uczestnicy Letnich Igrzysk Olimpijskich 1960

redpajama_set_name: RedPajamaWikipedia


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The War on Drugs Is Too Harsh For White Users
In a plea that smacks of hypocrisy, Governor Chris Christie is asking us to go easy on a certain kind of person struggling with addiction: affluent White suburbanites.
Stacey Patton Nov 9, 2015
Last Wednesday, New Jersey Governor Chris Christie released a video making an emotional plea for better treatment of drug users. It may have seemed shocking to see a member of the GOP showing an ounce of compassion, common sense, and critical thought about the disastrous war on drugs, and indeed it earned Christie tons of praise.
Brothers and sisters, don't let your eyes and ears deceive you.
The New Jersey governor, like many in the GOP, is expressing compassion for some drug users, demanding leniency for a few, and alternatives for parts of America. Not coincidentally, he is asking for a new approach to deal with drugs at a moment when White suburbanites are becoming the new face of today's heroin "epidemic."
In his video, Christie compares drug addiction to his mother's addition to cigarettes. He speaks movingly about her battle with lung cancer, and how hard she tried to quit smoking.
"We know the lung cancer was caused by the smoking," Christie said. "But no one came to me and said: 'Hey, listen, your mother was dumb. She started smoking when she was 16, then after we told her it was bad for her, she kept doing it. We're not going to give her radiation. We're not going to give her any of that stuff. You know why? Because she's getting what she deserves.' No one said that."
Despite their similarities, drug users are viewed differently. "We say: 'Well, they decided. They're getting what they deserved,'" said Christie.
"I'm pro-life," Christie declared, as he wound up for another opportunity to tighten his embrace of the #WhiteLivesMatterMore platform and assault a women's right to choose. "And I think that if you're pro-life, that means you've got to be pro-life for the whole life, not just for the nine months they're in the womb. It's easy to be pro-life for the nine months they're in the womb – they haven't done anything to disappoint us yet. They're perfect in there. But when they get out, that's when it gets tough. The 16-year-old teenage girl on the floor of the county lockup, addicted to heroin, I'm pro-life for her too. Her life is just as much a precious gift from God as the one in the womb."
If only Christie's pro-life stance extended to Black and Latinos living in Camden, Newark, and Trenton, where he has slashed aid to local school districts and cut social services to the poor while coddling the wealthiest residents. Never mind his support for the death penalty. Or the fact that his push for drug courts furthers the criminalization process, particularly for communities of color because these courts penalize relapse with incarceration and eject people who are unable to abstain from drug use for a period of time. Not to mention, there are racial disparities in completion rates due to greater unemployment rates and housing instability for Black and Latino users in recovery.
Christie's critiques of the war on drugs may be longstanding, as he has pushed for treatment for first-time offenders in New Jersey, but like his GOP compatriots, the only thing consistent about him is his hypocrisy and inconsistencies. In a recent interview with conservative talk radio host, Hugh Hewitt, he expressed his opposition to legalization efforts in Colorado and Washington.
"Marijuana is a gateway drug. We have an enormous addiction problem in this country. And we need to send very clear leadership from the White House on down through the federal law enforcement. Marijuana is an illegal drug under federal law. And the states should not be permitted to sell it and profit from it," he said.
Similarly, he has dragged his feet to implement the 2010 medical marijuana law in New Jersey, although recently claiming that he supports it. He calls for compassion even as he "vows to 'crack down' on marijuana as president."
Despite the hypocrisy and contradictions, he is being lauded by the left and the right: MSNBC host Rachel Maddow touted the video, which the Huffington Post posted to Facebook on October 30. "Whether you like Chris Christie as a politician or not, whether you like him as a candidate or not, his kind of skill at communicating the way you saw him communicate there, on an issue like this, that's why he still seems like he could be a contender," Maddow said.
The National Review's Jonah Goldberg wrote, "Whatever you think of the issues involved, you can see how this would leave a lasting impression, particularly in a state struggling with a major heroin problem. It's also a good example of why I think he's got a shot."
He received a complimentary tweet from Vanity Fair writer Peter Sagal and NPR reporter Scott Simon called the moment "candid, moving," and "utterly human."
Now he wants compassion when the new face of America's drug problem is a White, affluent suburban heroin user? And be clear, they have always been the face of drug use and drug distribution. Where was Christie's "humanity" when these decades-old draconian drug war policies were destroying countless Black families, and eroding any economic gains in Black communities? Now those zero-tolerance and three-strikes-you're-out and sentencing juveniles as adults policies are NOW too extreme and inhumane? GTFOHWTBS!
Having locked up so many people of color, and having ignored illegal drug use and drug dealing within white, affluent, and suburban communities for three decades, the GOP is now looking in the mirror only to see drugs as a White public health "problem," one that deserves sympathy and kindness.
Days before Christie made his plea to be more empathetic to drug users, the New York Times published a story about how, now that 90 percent of new heroin users over the last decade are White, race and class are driving a different reaction to the opioid epidemic compared with previous drug crises. White parents are using their power and resources to lobby for the decriminalization of drugs even though those laws have rarely been applied to Whites, whose overdoses in "cocaine apartments" are covered in the media, whose drug dealing is neither policed nor punished, and where and how drug courts are available. The Times interviewed a White former undercover narcotics detective who said he is finding new ways to respond to drug users.. His job now is to reach out to people who have overdosed and help them get treatment.
"The way I look at addiction now is completely different," he said. "I can't tell you what changed inside of me, but these are people and they have a purpose in life and we can't as law enforcement look at them any other way. They are committing crimes to feed their addiction, plain and simple. They need help."
Marc Mauer, executive director of the criminal justice reform group the Sentencing Project, points to the power of White privilege because of how anti-Black racism and the Jim Crow nature of the war on drugs has concealed who indeed is getting high and selling drugs.
"Both the image and reality is that this is a White and often middle-class problem," Mauer said.
Yet, ironically and further revealing the entrenched racism of the war on drugs and the systemic privileges of whiteness, Mauer celebrates how whiteness is fostering a conversation.
"We're having a much broader conversation about prevention and treatment, and trying to be constructive in responding to this problem. This is good. I don't think we should lock up White kids to show we're being equal," he said.
Indeed, but if compassion is necessary now, what about for those locked up in America's prison cells? Where is the demand for second chances and sympathy for those on probation, who have to check "the box," who can find themselves locked up for testing positive for alcohol or drugs? Is Christie and others going to fight for some retroactive compassion because there are millions of people, mostly black and Latino, who could use reparations for decades of tough-on-crime a.k.a. "tough on people of color" policies.
Data tells us that rates of drug use and selling are comparable across racial lines. However, people of color are far more likely to be stopped, searched, arrested, prosecuted, convicted, and incarcerated for drug law violations than are Whites. Arrest and incarceration rates for African Americans and Latinos are not higher because drug use or sales in these communities are higher, but rather because law enforcement focuses on urban areas, lower-income communities, and on communities of color as well as inequitable treatment by the biased criminal justice system which has led to the mass criminalization of people of color, particularly young Black men who have been suffering life-long penalties and exclusions that follow a drug conviction have created a permanent second-class status for millions of them. They can't vote, get licensed, access public assistance, find employment, live in public housing, etc. The drug war has succeeded not in curbing drug use, abuse or sales, but in its REAL goal of supporting the lucrative criminal justice system and maintaining society's racist dynamics.
The hypocrisy of these White parents, law-enforcement officers, drug-policy experts, and elected officials is breathtaking. They're trying to frame this as a desire to help states save money after decades of expensive tough-on-crime policies. Don't believe the hype! THIS is what White supremacy looks like, and it requires that White drug userss be decriminalized and viewed as flawed humans who simply need help, rather than as inherently bad, criminal, dangerous deviants who need to be locked up and held down in order for society to function.
Now that we are focused on the White girl or guy in the suburbs doing heroin, Percocet, oxycontin, and meth, it's suddenly a national tragedy and health crisis, versus a societal scourge and crime issue like the crack epidemic that launched the war on drugs. Now that folks are paying attention to Becky and Conner shooting up, everybody wants to talk about prevention and treatment, and suddenly drug addiction is a disease instead of a crime, and the response must be understanding and empathy, not locking up and disenfranchising.
Wouldn't it have been something if these folks who are now coming out to change the harsh penalizing policies of zero tolerance (at least in their Zip codes), had taken the same sympathetic, understanding, and pro-human approach when it was all about Black people abusing drugs? Black and Latino communities have been devastated by the harsh drug laws and policies designed to send them directly to jail, do not pass Go.
When people of color are using illicit drugs, it's a character flaw, a lack of integrity, and maybe even an inherent criminality that simply requires the right substance and circumstance to become addiction. Where was the call for leniency then?
Even now, the racial scripts are clear in that the "criminals"—the drug dealers—are poisoning otherwise law-abiding White communities. For example, the emergent narrative around New Hampshire has been that heroin is coming from New York. In other words, those thugs and criminals from New York (read Black youth) are bringing drugs to those quiet suburban residential communities. Reframing the war on drugs—more police and harsher sentences—as one to protect White innocence from Black criminality is on full display here. Drug treatment and more police are about protecting White humanity.
Whether using or selling, there was no recognition of the humanity of people of color; no concern for their well-being. Instead, families and communities of color have been destroyed to feed the prison pipeline. Folks haven't been addressing the issue of addiction and dependency until they migrated to the suburbs.
I wish the GOP would just be honest and own the fact that they only care about White people from politically important states going to prisons. And I wish the media would stop acting like White folks are actually going to prison en masse for drugs. That shit ain't never happened and it ain't never gonna happen. The real truth is that the laws need to be changed because they've already locked up so much of the Black and Latino population—you know, all those "disposable populations."
Listen, don't be naïve. This is racial bigotry unmasked. White drug users will get the help they need, but that same courtesy of sympathy and a more gentle touch will not be extended to users of color. The war on Black lives will continue because racial control of Black bodies and lives, contrasted with help, exoneration and redemption for Whites, is what White supremacy requires. And let's be clear: The real drug here is White supremacy and America's addiction is growing.
#BlackLivesMatter Addiction Chris Christie GOP heroin How It Is Media Race systemic racism viral videos War on Drugs
Stacey Patton is an assistant professor of multimedia journalism at Morgan State University and is the author of the forthcoming book, SPARE THE KIDS: WHY WHUPPING CHILDREN WON'T SAVE BLACK AMERICA. Follow her: @DrStaceyPatton.
More by Stacey Patton
It's OK to Question White Evangelicals Adopting Black Kids
The Other Church Abuse Story
Can Pediatricians Convince Black Parents To Stop Spanking?
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redpajama_set_name: RedPajamaCommonCrawl


This project was created in the course of the university lecture "Open Games Workshop" directed by Dr.-Ing. Wolfgang Höhl at Ludwig-Maximilians-Universität (LMU) Munich | Media Informatics Groups . Summer term 2016. Kindly supported by Daniel Volk, Ravensburger Digital, Munich / Germany.


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Legendary physicist Stephen Hawking once said, "It's also important not to become angry, no matter how difficult life is because you can lose all hope if you can't laugh at yourself and at life in general." And it has become the motto of this 27-year-old wheelchair warrior from Siliguri, West Bengal.
What makes this man a multitalented wheelchair warrior? He is a well-known graphic designer, composer, singer, entrepreneur, motivational speaker, happiness coach and there is definitely a lot more he is yet to explore.
Sai's first fracture happened when he was just 3 and half months old and the number of fractures kept on increasing since then. Failing to understand the situation, his parents took him to Kolkata where doctors told them that he was suffering from a rare disease called Osteogenesis Imperfecta, which is an extremely rare condition and is also known as Brittle Bone Disease.
When he was a child, there was no trace of the disease but suddenly everything was different for him. "When you are that young, it is difficult for a child to understand that he is not normal but a special child. You don't know what to feel. It is not an easy feeling to cope up with. 3-4 fractures a year was normal for me. I had numerous fractures till date, but after 50, I have stopped counting," says Sai.
His mother Shila Dasgupta used to teach at the same school he was enrolled in so that she can also take care of him. Whenever Sai had to change school, she had to leave her job too.
There is a mindset that prevails in our society that disabled people are less productive and therefore private sectors and few government sectors as well are skeptical about hiring them. "When people see a person confined to a wheelchair, they feel that I won't be able to live up to their expectations," says Sai.
Sai's life is like the magic life of Butterfly- a caterpillar goes through the transformation, becomes a pupa and then when life seems to end, it changes into something so beautiful as a butterfly.
Similarly, when hope was diluted with fear and despair in Sai's life, he thought to pen down his incredible story and in 2015, his book- My Life, My Love, My Dear Swami was published, which he wrote in 2 months and consists of 52 pages. It will surely make a difference when we say, he wrote this book with his only functioning index finder, a virtual keyboard, and a mouse. Isn't this just extraordinary?
The book has also received appreciation from PM Narendra Modi and a thank you letter was sent from Prime Minister's office, New Delhi. Now the book is published in 9 languages and a teacher from Jadavpur University has translated it into Bengali– "Amar Praan, Amar Prem, Amar Priyo Bhagoban".
Sai has traveled to 6 foreign countries virtually and people love to listen to his speeches. Through Skype, he was able to join millions of people in the US, New Jersey, Malaysia, Thailand, Singapore, and Nepal.
"Be it a heart patient in a wheelchair going to a post-office or a visually-impaired person using the lift in a shopping mall, they cannot travel without assistance. I have seen places, where it is mentioned 'wheelchair area'. At times, I feel so humiliating because like others, I also like to be a part of the crowd when someone picks you up from there to show you are different, it is cruel." Sai says.
"Same with the movie theatres. Don't disabled people love to watch movies? They do! But, a brand which spends millions to perfect the screens and seating space and looks after all the needs of a fully abled person, can't they build a ramp too? So that people like us can go and enjoy?", asks Sai.
Consider yourself a blessing and not blunder. Happiness should be the limelight of our lives, there can be nothing more important than this and we should start by looking at ourselves. You have to greet the problems and beat it in the best possible manner.
Till date, Sai has received 44 awards and that includes Winner of All India Wheelchair Wanderlust Competition 2016 and Limca Book of Records 2018. He has also etched his name in Asia Book of Records 2018 for Fastest Typing Speed (24 words per minute) with one finger of left hand. Currently, he is doing a research on how to make India disabled-friendly and more accessible to happiness.
If this man with 90% disability has 100% ability to live life to the fullest, think positive and inspire others to choose happiness over pain, then what's holding you back?


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As the research manager for the Creation team I oversee research about how people create content and share it with friends and family through Facebook. I received my BA and MSc degrees from Stanford University where I studied applied anthropology – my emphasis was on ecotourism and sustainable development, and I spent several field seasons in the Peruvian Amazon studying tour group composition and its impact on the wildlife viewing experience. In 2013 I transitioned to the education technology space as a user researcher for digital products. Immediately prior to joining Facebook I spent several years building the UX research team at Udemy, an online teaching and learning platform. When not at work I'm an avid crafter, cook, baker and traveler.


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Posts by Jim Henson
Micro-Budget Filmmaking – Gareth Edwards: From 'Monsters' to 'Rogue One'
By Jim Henson | October 15, 2020
Micro-Budget Filmmaking – Gareth Edwards: From 'Monsters' to 'Rogue One' Rogue One: A Star Wars Story was a breath of fresh air into the somewhat stale Star Wars franchise, especially after the painfully derivative, completely uninspired, by-the-numbers The Force Awakens. New characters took center stage, including yet another female protagonist, and with some support from some legacy…
Film Movements in Cinema: Soviet Montage
By Jim Henson | July 6, 2020
Soviet Montage Film Movement (1924-1935) Everyone who has ever seen a movie has at some point in time, seen a section of films were a series of shots that indicate actions over a span of time, usually without dialogue. This is what is referred to as a Montage, which is French for assembly or editing.…
Film Movements in Cinema: French Impressionism
By Jim Henson | June 29, 2020
Film Movements in Cinema: French Impressionism The horrors and the atrocities of the First World War provided existential fodder for the rise of the French Impressionist movement, which focused on silent film and spanned a time period of approximately 1918 to 1930. The movement was unequivocally and unapologetically rooted in French nationalism. The production houses…
Film Movements in Cinema: German Expressionism
German Expressionism (1919-1926) German life in the 1920s wasn't exactly all sunshine and rainbows and dancing until the cows came home. It was more like War was Hell, we lost, life really sucks, and we're just going to wallow in it for the next seven years or so. German Expressionism pulled out all of the…
Film Movements in Cinema: Australian New Wave
Australian New Wave (1975-1985) The Australian New Wave Film Movement, starting in mid-1970 and ending about a decade later, is unabashedly and completely Australian and doesn't shy away from poking fun at their colloquialisms and the Australian way of life, otherwise known as Ozploitation. Australian film was pretty much dormant from World War II until about…
Film Movements in Cinema: L.A. Rebellion
How Filmmakers Fought Racism with the L.A. Rebellion Film Movement (1967–1991) Decades before Black Lives Matter existed there was another movement, which was heavily influenced by the Civil Rights Movement and the L.A. Watts Riots. The period between 1967-1991 served as a reaction against the 1970's blaxploitation movies and helped usher in the work of…
Film Movements in Cinema: The Movie Brats
By Jim Henson | June 8, 2020
Film Movements in Cinema: The Movie Brats (1960s – 1980s) Oh boy, here we go. The death of the Hollywood studio system in the 1960s gave way to possibly the most prolific filmmakers in movie history; the likes of Robert Altman, Hal Ashby, and Peter Bogdonovich were falling stars and a new group of directors…
Nora Ephron Screenplays (Download PDF)
Nora Ephron Screenplays (Download) Nora Ephron (1941-2012) was the preeminent female screenwriters and directors in the business. From Silkwood Julie & Julia, her work was second to none. Coincidentally, Meryl Streep appeared in her first and last films. Listen to one of Nora's final talks about screenwriting and the directing process here. <span data-mce-type="bookmark" style="display:…
Ridley Scott Film's Screenplay PDF Collection (Download)
Ridley Scott's Screenplays (Download) Take a listen to the legendary Ridley Scott as he discusses his screenwriting and filmmaking process. The screenplays below are the only ones that are available online. If you find any of his missing screenplays please leave the link in the comment section.  (NOTE: For educational and research purposes only). Take a listen…
Steven Spielberg Film's Screenplay Collection (Download PDF)
By Jim Henson | April 11, 2019
Steven Spielberg Screenplays (Download) Take a listen to the legendary Steven Spielberg as he discusses his screenwriting and filmmaking process. The screenplays below are the only ones that are available online. If you find any of his missing screenplays please leave the link in the comment section. When you are done reading take a listen to…
Tim Burton Film's Screenplay Collection (Download PDF)
By Jim Henson | April 2, 2019
Tim Burton's Screenplays (Download) Before you see Tim Burton's Dumbo take a listen to the legendary director as he discusses his screenwriting and filmmaking process here. Afterward, you can download Tim Burton Film's Screenplay collection and learn how the masterworks from page to screen.  The screenplays…


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AI 4 Scientific Discovery
About AI3SD
Network Themes
Network Vision
AI3SD Team
Network Executive Group
AI3SD Members
AI3SD Intern Cohort 2021
ML4MC Summer School Students
AI3SD Events
AI3SD Online Seminar Series
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Data Seminar Series 2020
Winter Seminar Series 2020/21
AI 4 Proteins Seminar Series 2021
Skills 4 Scientists Seminar Series 2021
Machine Learning for Materials & Chemicals Seminar Series 2021
Autumn Seminar Series 2021
ECR Funding
Funding FAQs (Internship Funding Call)
Funding Calls
16/02/2021 – AI3SD Summer Internship Call
Workshop Funding
All aspects of the Network will be developed through co-creation from amongst the members. Experience in running networks has shown us that finding the right language and approach to communication is essential for true co-creative and meaningful collaborations. For the proposed network this will be facilitated by making use of the philosophical underpinnings of AI & Discovery to provide a common language that enables the AI and Physical Science communities to engage in joint endeavours. The output of these endeavours will impact directly on the nature of what discovery & theory will mean in the next decades and on the skills set that the AI generation of researchers will need to develop.
Areas of Chemical, Physical and Material Sciences
Chemicals and Materials Discovery: We will be pushing the limits of synthesis, properties and engineering of molecules and materials, enabling the discovery and exploitation of unseen and un-imagined parts of chemical and material space.
Areas of AI
Types of AI: We will investigate the impact of different types of AI modalities (e.g. pattern recognition vs reasoning AI, narrow vs broad AI) on scientific discovery. We will also explore what limits might exist in probing machine learning (AI) models to derive the rationale and reasons for the outputs of the models. This will enable us to map AI properties or transient states onto the more traditional approach to theory. As machine learning moves from addressing small scale text-book problems in statistical pattern recognition to being parts of deployable systems that can be integrated into discovery science roles, two important challenges, Privacy and Provenance, need to be addressed. (a) Privacy preserving learning, whereby the owners of data from domains in which privacy matters may be unwilling to share data. In such scenarios, algorithmic advances that can work with minimal statistical information about data, rather than working with raw data, will need to be developed (b) Provenance: Learning systems that are embedded in a discovery setting will need to be cognisant of the provenance of data used for their training. As multiple sources of data become available, particularly when experimental data are archived in public repositories, uncertainty about them is bound to increase. The frontiers of machine learning need to be pushed to cope with varying reliability of the available data.
Agents & Swarms: How much can AI for Scientific Discovery make use of, and learn, from the expert game players? We will push the frontiers of Deep Reinforcement Learning whereby agent-based modelling at a "high level" can take advantage of data-driven models at a lower level. These two topics have developed largely separately in the literature, and bringing them together is crucial for discovery science in that reinforcement learning is suitable for planning and experiment design whereas data-driven modelling is needed to extract useful information from large and complex experimental data. Inducing strong coupling between the two is an open-ended challenge that needs to be addressed.
Evolutionary approaches & Understanding the AI results: Conventional applications of AI tend to work in well-defined problem domains (clear objective functions, supervised learning methods, data-driven deduction) but scientific discovery is often ad hoc and opportunistic, with discoveries that can arise in unexpected ways and in 'problems' that are ill-defined at the outset. The human capability for discovery in such domains is surpassed only by natural evolutionary processes. Operating in a purely non-teleological way, biological evolution is the epitome of such an ad hoc and opportunistic process. Recent breakthroughs in two specific areas provide an opportunity to exploit artificial evolutionary processes for scientific discovery in a new way: (a) 'distilling natural laws from experimental data'; (b) Exploiting the formal equivalence of natural evolution and machine learning. In general, what is the impact of the understanding the results and therefore the ethical basis for using the resulting models.
This Network is funded by EPSRC under Grant Number: EP/S000356/1
1-3/03/2022 – AI3SD Network+ Conference 2022 – Chilworth Manor Hotel
March 1 @ 11:00 am - March 3 @ 3:30 pm
01/12/2021 – AI3SD Autumn Seminar VIII: Molecules, Graphs & Networks
24/11/2021 – AI3SD Autumn Seminar VII: Digital Twins
17/11/2021 – AI3SD Autumn Seminar VI – Medicinal Chemistry
10/11/2021 – AI3SD Autumn Seminar V: Quantum Machine Learning
03/11/2021 – AI3SD Autumn Seminar IV: AI & ML 4 Drugs & Materials


Check out a fantastically eerie video for the You're Dead! highlight.
Be warned - it's pretty graphic and definitely NSFW.
"It spotlights death. It's about death. It's deathy. It reeks of death."
In case you missed it this weekend.
His score includes material from six unreleased songs.
Hear a jazzy, Herbie Hancock-featuring new number from You're Dead!
Watch a crazy, intense video that includes some snippets of new music.
We have some news about the follow-up to Until the Quiet Comes.


text:
ENCADEMS - 2020 (Volume 8 - Issue 10)
A Study on Technical Advancements in Construction Industry
Amarender Kadian, 2020, A Study on Technical Advancements in Construction Industry, INTERNATIONAL JOURNAL OF ENGINEERING RESEARCH & TECHNOLOGY (IJERT) ENCADEMS – 2020 (Volume 8 – Issue 10),
Authors : Amarender Kadian
Paper ID : IJERTCONV8IS10040
Volume & Issue : ENCADEMS – 2020 (Volume 8 – Issue 10)
Amarender kadian
Asssitant Professor, Dept. of Civil Engg.
BMIET, Sonipat, Haryana
Abstract: From ancient times to current modern era, the construction industry is among those very few businesses which not only affects the daily lives of humans but also affects the economy as well as the environment throughout the globe. As human quality of life is directly related to the build-up environment surrounding us, not only it is the quality of life but construction industry also offers basic requirements such as shelters, spaces and infrastructures for doing business to other industries resulting in employment of millions of people around the globe. According to the World Economic Forum the construction industry alone accounts for over 6% of the global GDP and with an average of over 2,00,000 people moving towards worlds urban areas daily, the construction industry has revolutionized itself for the modern world as per its requirements through the adoption of latest trends and techniques such as the Drone Surveying, 3-D printing and other eco-friendly techniques like the use of Recycled plastics etc. for the betterment of the society.
This study discuss an overview of various innovative advancements through which the construction sector has gone with time, as these advancements and technological developments are mainly compiled on the basis of previous researches and reports.
As the technologies developed in all the fields in engineering, it is essential to develop new tendencies to researches and innovations in civil engineering area additionally, so that we can minimize the time of construction and price of creation and effort of humans. Civil engineering has usually readily adopted new technologies, the usage of improvements like GPS to devise new roads and suspension structures to construct bridges. And as generation continues to evolve, we are able to assume that the civil engineering area will best hold incorporating this current technology in an increasing number of innovative ways. In fact, it already is. New technologies the ones that have been released in the final 5 years are about to revolutionize the civil engineering area and allow innovations previously no longer possible.
NECESSITIES OF IMPLEMENTING RECENT TRENDS IN CONSTRUCTION INDUSTRY
Basically all the conventional code books, creation exercise are prepared with view of safety and durability best. Thats why we are able to attain so many challenging constructions. But once we break monotony and start exploring new developments we can achieve any difficulties arising in production and when we start imagination into
implementation we can alternate the world Safety in creation Less time ,Less effort & cost, Aesthetic appearance.
SAFETY IN CONSTRUCTION
In olden days the protection and precaution level is just too low in production discipline thats why so many lives were lost during construction. For an example, in the course of time creation of Panama Canal it's miles expected that over 25,000 labors lost their lives all through the massive and dangerous project, with most are demise from disease and landslides. So that with the aid of implementing new tendencies can provide protection to the workers
LESS TIME, EFFORTS & COST
Following the old tendencies in creation effects in delaying or long term of production, which increases the price of production, substanceswastage, nice reduction etc., however by way of adopting the few recent traits can minimize the above drawbacks and helps in constructing the systems within the time. In traditional or antique creation practices there's no use of gadgets which increases the effort of the workers , however incurrent traits by means of use of current devices which includes computerized rendering machines for plastering, portray reduces each time and effort.
By imposing contemporary traits in creation enterprise, we will lessen the fee of creation ex: – with the aid of the use of of modern-daydevices, ideas we will limit the number employees and working days there by way of it proves that low-cost
AESTHATIC APPEARANCE
Most of the structures constructed now days are in view of aesthetic point of view, some of the skyscrapers, are built without the restriction of price, for achieving this component the construction industry has to adopt current traits, substances, system. Some of the systems enlisted right here to prove, the ones are Burj Khalifa, Petronas Twin Towers, Empire State Building, World Trade Centre, Shanghai Tower and Abraj Al Bait Towers etc
LATEST ADVANCEMENTS IN CONSTRUCTION INDUSTRY
SURVEYING WITH DRONES:
Civil engineering has developed to the point of readiness with applications for unmanned aerial vehicles, which
could help in scanning and mapping creation sites as nicely as capturing photos and motion pictures for surveying purposes. UAVs often proves that a cheap measure for aerial mapping, as a drone does not require a pilot, however rather, a technician. UAVs are useful to behavior the aerial surveying for several times around the same construction discipline, which way in the destiny, UAVs can capture a style of pictures and motion pictures at the same time as the task is being finished and that will allows to better manage task progress and maintain document UAVs will additionally transforms civil engineering through using photo scanning, an photograph capture technique that uses photos (rather than lasers) to capture photographs. Photo scanning captures not just the ground surface, but additionally buildings, plants, benches, and other nearby structures and represents them in 3dimensions. With those advanced capabilities, drones will allow for extra correct and extrainter active realistic representations of civil engineering initiatives there are also potential troubles regarding federal aviation administration (FAA) regulations, citizens right to privacy, and how liability insurance could deal with drone usage.
3-D PRINTING IN MARRYING DESIGN AND CONSTRUCTION
printing is gaining lots of scope in creation industry not simply creating a model, however also in business and with 3-d printers coming down in rate each year, it's now not long before we will see them used in civil engineering. 3-D printing offers benefits for each layout and
creation, with 3-d printing, it is smooth to design custom and innovative creation resources and then construct them the usage of nearly any kind of material imaginable. In fact, 3-D printers are already in use in production initiatives in Europe. Dutch construction enterprise Heymans
maximum famous for its "clever highway" and its sparkling bicycle paths, which use luminescent paint to really mark street lanes at night has created the world's first 3-d- revealed bridge. The bridge, which was first designed in October 2015, will span across the Oudezijds Achterburgwal canal when it's miles completed in 2017. MX3D's 3D printer, though, isn't like those that we've traditionally seen. Rather than a desktop 3-D printer, MX3D's era is composed of a fixed of large mechanical arms that hold a torch-like tool for welding. These robotic arms build 3-dobjects in an open warehouse space in place of inner a container as most 3-D printers do. The arms can also print in all directions, unlike standard three-D printers, which lets in for an awful lot extra creativity and variability in the design stage. Heymans Innovation Manager Jarred van der Venn says that 3-d printing jons design and production into a single procedure, rather than two separate processes as has traditionally been seen in creation. Van der Venn notes that this alteration will require web site managers and designers to start
searching at the design technique in a new manner. However, 3-d printers do pose numerous challenges for civil engineering. First and foremost, three-D printers are limited in the types of materials they can print as an example, 3D printers that could print circuit boards are nevertheless in improvement and won't be ready for commercial use for several years. 3D printers also pose a danger to production jobs, and schooling staff to apply three-D printers may also require a enormous capital investment.
USE OF RECYCLED PLASTIC IN CONSTRUCTION
Plastic is one of the maximum commonly recycled merchandise in now days, with plastic substances maximum often being recycled into bottles, bags, toys, containers, and lots greater. But now, a Dutch enterprise is attempting to recycle plastic into some thing plenty larger: Roads and constructing materials. VolkerWessels is a Dutch construction organization that is preparing to construct a Plastic Road in Rotterdam. While VolkwerWessels' Plastic Road is nevertheless most effective a concept, it's becoming quite famous in Holland, where 96 million lots of carbon dioxide are released into the air through road constructing and maintenance alone. VolkerWessels expects that its Plastic Road will reduce greenhouse fuel emissions at the same time as making roads stronger and increasing their lifespan Holland's infrastructure industry expects that those new roads will slowly trade the way, thus development occurs. Relative to laying an asphalt street, building the plastic roads is extensively faster, and will take only a few weeks to construct. These Plastic Roads are also useful in the upgrading of infrastructure. As the street is hollow, which allows town planners to run pipes and wires inside the road itself. By the diverse researches and scientifically it's been proved that the street's hollow cavities are useful in draining floodwater throughout heavy rainfall. If Hollands plan succeed, it might forever change the manner of civil engineers all over the arena approaching the street building. There are issues about the plastic roads that Netherland plans to construct. Environmentally, there are concerns that the plastic may additionally integrate with the soil and harmful to the local flora. The street's additives are also quite volatile, and exposure to chlorine will cause the street to release hydrogen chloride a color less fuel that, when exposed to atmospheric humidity turns into hydrochloric acid. When it turns into sufficiently concentrated, hydrochloric acid forms an acidic mist which can cause irreversible harm to human tissue and if it's far mixed with an oxidizing agent, hydrochloric acid synthesizes into toxic chlorine fuel. That means the engineering method would require strict safety measures a good way to protect the on- web page crew, and the substances engineers responsible for the plastic street has to take the remedial measures to create a protect or additional water-proof layer
that stops leaching and exposure to chemicals.
USE OF HOLOGRAPHIC COMPUTERS
Giving More Accurate Information to Engineers in Real Time, Holographic computers The next revolution in civil engineering is here, and it's going to be a forever change in the facts management and communication processes. Microsoft has been promoting its new Hollers for over a year, guiding the world's most respected era journalists to a secret underground bunker at the enterprise's Redmond campus for tightly controlled product demonstrations. Hollers is a mixed truth headset that layers 3-d holograms over physical world photos in order to convey beneficial records to the wearer. Using the Hollers, civil engineers can see virtual input drawn over physical items, share that enter with collaborators thru Skype, fine-tune designs in three-D, and discover designs in actual time. A style of businesses are currently the use of Microsoft Hollers to modify the manner manufacturing happens. Volvo, for example is the usage of. Hollers generation to design and configure its vehicles in completely new ways now a days. Meanwhile, NASA's Jet Propulsion Laboratory is planning to use the Hollers to make holographic representations of the Mars landscape based on Mars Rover snap shots. Currently, businesses in the architecture and production industries are piloting the Hollers and growing progressive new processes that leverage 3-D holographic models to enhance the layout phase. However, the Hollers additionally having a few of the disadvantages. The headset could serve as a workplace distraction that impede productivity. The prototype model also has a completely limited discipline of view, allowing boom in truth imaginative and prescient of simplest certain items.
USE OF RFID CARDS FOR ADDIFIONAL SECURITY
RFID protection cards Site protection is usually a priority, and with technology evolving, website managers need more and more safety features at their disposal. The subsequent big aspect in web site security is contactless safety cards. These cards assist in identifying precise cardholder, and can deliver users get admission to to stable offices, secure parking, and even pc networks. The excellent benefit that these clever cards offer is that security turns into plenty less difficult to manage. Employees can take a look at themselves into and out of the worksite with just a swiping of a card. However, security cards also having certain disadvantages. Firstly, safety cards can be lost or stolen. That method safety cards that are said as stolen or misplaced will need to be right away deactivated. Card- based totally web page get entry to structures are also vulnerable to hacking website. Workers won't even recognize their card has been hacked.
ADVANCED SOFTWARES RESHAPING THE FUTURE OF CONSTRUCTION INDUSTRY:
Modern softwares being the tools to predict the structural parameters in modern construction industry, helps in
getting the realistic image of the project even in the 3D view, Apart from that such softwares also let designers and contractors to know about the structural behavior, age of deception etc. along with the weak zones of the project that they have to deal with during the construction process in the future.
Based on the functions and uses, such softwares are classified as follows:
MODELLING SOFTWARES:
SP 3D
DESIGNING AND ANALYSIS SOFTWARES:
STAAD PRO
SAP 2000
SOFTWARES FOR HIGHWAY DESIGNING AND PLANNING:
MX ROADS
HDM
AUTO PLOTTER
In this study we have discussed some of the latest advancements and developments in the construction industry and found out that, by studying and using current developments in practice, the construction industry throughout the world can achieve greater quality of work while attaining the cost-efficiency at the same time fulfilling the requirements of both present and the future. By using modern technologies, we can achieve milestones in the architectural beauty, structural strength, cost efficiency and many more.
REFRENCES
World Economic Forum. (2012). Strategic Infrastructure: Steps to Prioritize and Deliver
Infrastructure Effectively and Efficiently. Geneva: World Economic Forum.
World Economic Forum. (2013). Strategic Infrastructure: Steps to Prepare and Accelerate
Public Private Partnerships. Geneva: World Economic Forum.
World Economic Forum. (2014). Strategic Infrastructure: Steps to Operate and Maintain
Infrastructure Efficintly and Effectively. Geneva: World Economic Forum.
Causes of Global Warming and Different Solutions
An Introduction of Image Processing with MATLAB Tool


Gentle readers, are you getting pumped for an exciting weekend in Ypsilanti? Heritage Festival starts tonight and runs through Sunday in Riverside Park. It promises live music and an eclectic mix of history, entertainment and vendors. If you're looking for a reason to get out of Ann Arbor, look no further.
After you check out Heritage Fest, why not swing by DIYpsi, it's just up the hill at Corner Brewery. DIYpsi will also feature an eclectic group of vendors hawking their wares. It's always a fun event.
So gentle reader, will we see you in Ypsi this weekend?


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