Key points
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It is often assumed that automatic movements such as walking require little conscious attention and it has therefore been argued that these movements require little cortical control.
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In humans, however, the gait function is often heavily impaired or completely lost following cortical lesions such as stroke.
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In this study we investigated synchrony between cortical signals recorded with electroencephalography (EEG) and electromyographic signals (EMG activity) recorded from the tibialis anterior muscle (TA) during walking.
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We found evidence of synchrony in the frequency domain (coherence) between the primary motor cortex and the TA muscle indicating a cortical involvement in human gait function.
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This finding underpins the importance of restoration of the activity and connectivity between the motor cortex and the spinal cord in the recovery of gait function in patients with damage of the central nervous system.
Indirect evidence that the motor cortex and the corticospinal tract contribute to the control of walking in human subjects has been provided in previous studies. In the present study we used coherence analysis of the coupling between EEG and EMG from active leg muscles during human walking to address if activity arising in the motor cortex contributes to the muscle activity during gait. Nine healthy human subjects walked on a treadmill at a speed of 3.5–4 km h−1. Seven of the subjects in addition walked at a speed of 1 km h−1. Significant coupling between EEG recordings over the leg motor area and EMG from the anterior tibial muscle was found in the frequency band 24–40 Hz prior to heel strike during the swing phase of walking. This signifies that rhythmic cortical activity in the 24–40 Hz frequency band is transmitted via the corticospinal tract to the active muscles during walking. These findings demonstrate that the motor cortex and corticospinal tract contribute directly to the muscle activity observed in steady‐state treadmill walking.
Pancreatitis is a known risk factor for pancreatic cancer; however, an unknown fraction of the disease is thought to be a consequence of tumor-related duct obstruction.
A pooled analysis of a history ...of pancreatitis and risk of pancreatic cancer was carried out considering the time interval between diagnoses and potential modification by covariates. Adjusted pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from 10 case–control studies (5048 cases of ductal pancreatic adenocarcinoma and 10 947 controls) taking part in the International Pancreatic Cancer Case-Control Consortium (PanC4).
The association between pancreatitis and pancreatic cancer was nearly three-fold at intervals of >2 years between diagnoses (OR: 2.71, 95% CI: 1.96–3.74) and much stronger at intervals of ≤2 years (OR: 13.56, 95% CI: 8.72–21.90) probably reflecting a combination of reverse causation and antecedent misdiagnosis of pancreas cancer as pancreatitis. The younger (<65 years) pancreatic cancer cases showed stronger associations with previous (>2 years) pancreatitis (OR: 3.91, 95% CI: 2.53–6.04) than the older (≥65 years) cases (OR: 1.68, 95% CI: 1.02–2.76; P value for interaction: 0.006).
Despite a moderately strong association between pancreatitis (diagnosed before >2 years) and pancreatic cancer, the population attributable fraction was estimated at 1.34% (95% CI: 0.612–2.07%), suggesting that a relatively small proportion of pancreatic cancer might be avoided if pancreatitis could be prevented.
Ovarian carcinomas presenting homologous recombination deficiency (HRD), which is observed in about 50% of cases, are more sensitive to platinum and PARP inhibitor therapies. Although platinum ...resistant disease has a low chance to be responsive to platinum-based chemotherapy, a set of patients is retreated with platinum and some of them are responsive. In this study, we evaluated copy number alterations, HR gene mutations and HR deficiency scores in ovarian cancer patients with prolonged platinum sensitivity.
In this retrospective study (2005 to 2014), we selected 31 patients with platinum resistant ovarian cancer retreated with platinum therapy. Copy number alterations and HR scores were evaluated using the OncoScan® FFPE platform in 15 cases. The mutational profile of 24 genes was investigated by targeted-NGS.
The median values of the four HRD scores were higher in responders (LOH = 15, LST = 28, tAI = 33, CS = 84) compared with non-responders (LOH = 7.5, LST = 17.5, tAI = 23, CS = 47). Patients with high LOH, LST, tAI and CS scores had better response rates, although these differences were not statistically significant. Response rate to platinum retreatment was 22% in patients with CCNE1 gains and 83.5% in patients with no CCNE1 gains (p = 0.041). Furthermore, response rate was 54.5% in patients with RB1 loss and 25% in patients without RB1 loss (p = 0.569). Patients with CCNE1 gains showed a worse progression free survival (PFS = 11.1 months vs 3.7 months; p = 0.008) and a shorter overall survival (OS = 39.3 months vs 7.1 months; p = 0.007) in comparison with patients with no CCNE1 gains. Patients with RB1 loss had better PFS (9.0 months vs 2.6 months; p = 0.093) and OS (27.4 months vs 3.6 months; p = 0.025) compared with cases with no RB1 loss. Four tumor samples were BRCA mutated and tumor mutations were not associated with response to treatment.
HR deficiency was found in 60% of our cases and HRD medium values were higher in responders than in non-responders. Despite the small number of patients tested, CCNE1 gain and RB1 loss discriminate patients with tumors extremely sensitive to platinum retreatment.
The clumped isotopic composition of carbonate‐derived CO2 (denoted Δ47) is a function of carbonate formation temperature and in natural samples can act as a recorder of paleoclimate, burial, or ...diagenetic conditions. The absolute abundance of heavy isotopes in the universal standards VPDB and VSMOW (defined by four parameters: R13VPDB, R17VSMOW, R18VSMOW, and λ) impact calculated Δ47 values. Here, we investigate whether use of updated and more accurate values for these parameters can remove observed interlaboratory differences in the measured T‐Δ47 relationship. Using the updated parameters, we reprocess 14 published calibration data sets measured in 11 different laboratories, representing many mineralogies, bulk compositions, sample types, reaction temperatures, and sample preparation and analysis methods. Exploiting this large composite data set (n = 1,253 sample replicates), we investigate the possibility for a “universal” clumped isotope calibration. We find that applying updated parameters improves the T‐Δ47 relationship (reduces residuals) within most labs and improves overall agreement but does not eliminate all interlaboratory differences. We reaffirm earlier findings that different mineralogies do not require different calibration equations and that cleaning procedures, method of pressure baseline correction, and mass spectrometer type do not affect interlaboratory agreement. We also present new estimates of the temperature dependence of the acid digestion fractionation for Δ47 (Δ*25‐X), based on combining reprocessed data from four studies, and new theoretical equilibrium values to be used in calculation of the empirical transfer function. Overall, we have ruled out a number of possible causes of interlaboratory disagreement in the T‐Δ47 relationship, but many more remain to be investigated.
Plain Language Summary
Measured stable and clumped isotope values are fundamentally tied to established compositions of international standard materials. When these standard compositions are updated, it impacts previously published isotope measurements such as those used to define the clumped isotope calibration relationship (the foundation for use of this isotopic proxy as a paleothermometer, recorder of burial history or past diagenetic conditions). Here we reprocess 14 published clumped isotope calibration studies using updated international standard compositions and identical data processing procedures to see if these changes would eliminate previously observed interlaboratory discrepancies in clumped isotope calibration relationships. We find that this update tightens the clumped isotope calibration relationship within most laboratories and improves overall agreement between laboratories but does not eliminate all interlaboratory differences. We also propose “best practices” for data processing and dissemination going forward. This study makes progress toward resolving discrepancies in clumped isotope calibration relationships between laboratories by eliminating a number of possible causes and moves the clumped isotope community closer toward our ultimate goal of applying this powerful new proxy routinely to exciting science questions.
Key Points
Updates to 17O correction parameters and international standard compositions affect clumped isotopic compositions
Reprocessing published calibration data using new parameters and consistent methodology slightly improves interlaboratory agreement
There is no evidence (within error) for mineral‐specific offsets in calibration equation or temperature dependence of acid digestion fractionation
The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, ...or heat (>43°C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/-mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.
In addition to a range of functional impairments seen in individuals with a lower-limb amputation, this population is at a substantially elevated risk of falls. Studies postulate that the lack of ...sensory feedback from the prosthetic limb contributes heavily to these impairments, but the extent to which sensation affects functional measures remains unclear.
The purpose of this study is to determine how sensory impairments in the lower extremities relate to performance with common clinical functional measures of balance and gait in individuals with a lower-limb amputation. Here we evaluate the effects of somatosensory integrity to clinical and lab measures of static, reactive and dynamic balance, and gait stability.
In 20 individuals with lower-limb amputation (AMP) and 20 age and gender-matched able-bodied controls (CON), we evaluated the effects of sensory integrity (pressure, proprioception, and vibration) on measures of balance and gait. Static, reactive, and dynamic balance were assessed using the Sensory Organization Test (SOT), Motor Control Test (MCT), and Functional Gait Assessment (FGA), respectively. Gait stability was assessed through measures of step length asymmetry and step width variability. Sensation was categorized into intact or impaired sensation by pressure thresholds and differences across groups were analyzed.
There were significant differences between AMP and CON groups for reliance on vision for static balance in the SOT, MCT, and FGA (p < 0.01). Despite differences across groups, there were no significant differences within the AMP group based on intact or impaired sensation across all functional measures.
Despite being able to detect differences between able-bodied individuals and individuals with an amputation, these functional measures cannot distinguish between levels of impairment within participants with an amputation. These findings suggest that more challenging and robust metrics are needed to evaluate the effects of sensation and function in individuals with an amputation.
•Clinical tasks cannot detect differences in sensation in individuals with amputation.•Neither sensation in the residual limb or in the intact limb correlated with these measures.•More challenging tasks are needed to evaluate sensory differences in this population.
Background
As a strong inducer of IgE antibodies to substituted ammonium ion epitopes (QAI), pholcodine (PHO) is a postulated cause of allergic anaphylaxis to neuromuscular blocking agents (NMBAs). ...Three years after withdrawal of PHO in Norway, a significant reduction in IgE sensitization and anaphylaxis reporting was seen.
Objective
Six‐year follow‐up study on the effects of PHO withdrawal on IgE sensitization and anaphylaxis reporting.
Methods
From 650 acute consecutive reports (2005–2013) to the Norwegian Network for Anaphylaxis under Anaesthesia (NARA), total number of reports on suspected anaphylactic reactions, number of reactions where NMBAs were administered, number of reactions where serum IgE antibodies (≥0.35 kUA/l) to suxamethonium (SUX) and PHO were present at time of reaction and anaphylaxis severity grades were retrieved. In addition, NMBA sales and prevalence of IgE sensitization to PHO and SUX among ‘allergics’ were monitored.
Results
From baseline period P0 (PHO on the market) through the first (P1) and second (P2), three‐year periods after withdrawal, significant falls in total reports (P < 0.001) and reports with IgE antibodies to PHO (P = 0.008) and SUX (P = 0.001) at time of reaction were found. Total NMBA sales in P2 were 83% of P0, and SUX and rocuronium (ROC) together made up 86% of sales throughout the study. Five NMBA‐related anaphylactic deaths occurred during P0 and P1 and, however, none during P2. Prevalence of IgE sensitization to SUX in ‘allergics’ fell to 0% at 4 and 5 years after withdrawal.
Conclusions
Six years after PHO withdrawal, the Norwegian population has become significantly less IgE‐sensitized and clinically more tolerant to NMBAs.
Promoting Transparency in Social Science Research Miguel, E.; Camerer, C.; Casey, K. ...
Science (American Association for the Advancement of Science),
01/2014, Letnik:
343, Številka:
6166
Journal Article
Recenzirano
Odprti dostop
Social scientists should adopt higher transparency standards to improve the quality and credibility of research.
There is growing appreciation for the advantages of experimentation in the social ...sciences. Policy-relevant claims that in the past were backed by theoretical arguments and inconclusive correlations are now being investigated using more credible methods. Changes have been particularly pronounced in development economics, where hundreds of randomized trials have been carried out over the last decade. When experimentation is difficult or impossible, researchers are using quasi-experimental designs. Governments and advocacy groups display a growing appetite for evidence-based policy-making. In 2005, Mexico established an independent government agency to rigorously evaluate social programs, and in 2012, the U.S. Office of Management and Budget advised federal agencies to present evidence from randomized program evaluations in budget requests (
1
,
2
).
Background: In patients with hymenoptera venom allergy diagnostic tests are often positive with honey bee and Vespula venom causing problems in selection of venoms for immunotherapy.
Methods: 100 ...patients each with allergic reactions to Vespula or honey bee stings and positive i.e. skin tests to the respective venom, were analysed for serum IgE to bee venom, Vespula venom and crossreacting carbohydrate determinants (CCDs) by UNICAP (CAP) and ADVIA Centaur (ADVIA). IgE‐antibodies to species specific recombinant major allergens (SSMA) Api m1 for bee venom and Ves v5 for Vespula venom, were determined by ADVIA. 30 history and skin test negative patients served as controls.
Results: By CAP sensitivity was 1.0 for bee and 0.91 for Vespula venom, by ADVIA 0.99 for bee and 0.91 for Vespula venom. None of the controls were positive with either test. Double positivity was observed in 59% of allergic patients by CAP, in 32% by ADVIA. slgE to Api m1 was detected in 97% of bee and 17% of Vespula venom allergic patients, slgE to Ves v5 in 87% of Vespula and 17% of bee venom allergic patients. slgE to CCDs were present in 37% of all allergic patients and in 56% of those with double positivity and were more frequent in bee than in Vespula venom allergic patients.
Conclusions: Double positivity of IgE to bee and Vespula venom is often caused by crossreactions, especially to CCDs. IgE to both Api m1 and Ves v5 indicates true double sensitization and immunotherapy with both venoms.
Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time–risk relationship are unclear, and there is limited information on ...the role of antidiabetic medications.
We analyzed individual-level data from 15 case–control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates.
Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72–2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03–1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14–0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75–8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53–1.70, for ≥15 years).
This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration–risk relationship.
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