Variability of corticospinal and spinal reflex excitability for the ankle dorsiflexor tibialis anterior across repeated measurements in people with and without incomplete spinal cord injury.

To adequately evaluate the corticospinal and spinal plasticity in health and disease, it is essential to understand whether and to what extent the corticospinal and spinal responses fluctuate systematically across multiple measurements. Thus, in this study, we examined the session-to-session variability of corticospinal excitability for the ankle dorsiflexor tibialis anterior (TA) in people with and without incomplete spinal cord injury (SCI). In neurologically normal participants, the following measures were obtained across 4 days at the same time of day (N = 13) or 4 sessions over a 12-h period (N = 9, at 8:00, 12:00, 16:00, and 20:00): maximum voluntary contraction (MVC), maximum M-wave and H-reflex (Mmax and Hmax), motor evoked potential (MEP) amplitude, and silent period (SP) after MEP. In participants with chronic incomplete SCI (N = 17), the same measures were obtained across 4 days. We found no clear diurnal variation in the spinal and corticospinal excitability of the TA in individuals with no known neurological conditions, and no systematic changes in any experimental measures of spinal and corticospinal excitability across four measurement days in individuals with or without SCI. Overall, mean deviations across four sessions remained in a range of 5-13% for all measures in participants with or without SCI. The study shows the limited extent of non-systematic session-to-session variability in the TA corticospinal excitability in individuals with and without chronic incomplete SCI, supporting the utility of corticospinal and spinal excitability measures in mechanistic investigation of neuromodulation interventions. The information provided through this study may serve as the reference in evaluating corticospinal plasticity across multiple experimental sessions.

Enzymatic debridement in critically injured burn patients - Our experience in the intensive care setting and during burn resuscitation.

BACKGROUND: Much of the recent literature on bromelain based enzymatic debridement of burn injury has focused on its use in smaller burn injury and specialist areas such as the hands or genitals (Krieger et al., 2012; Schulz et al., 2017a,b,c,d). This is despite the original papers describing its use in larger burn injury (Rosenberg et al., 2004, 2014). The current EMA license for Nexobrid™ advises that it should not be used for burn injuries of more than 15% TBSA and should be used with caution in patients with pulmonary burn trauma and suspected pulmonary burn trauma. The original safety and efficacy trial of NexoBrid™ limited its use to 15% TBSA aliquots with concern regarding the effect of bromelain on coagulation. In a European consensus paper of experienced burns clinicians, now on its second iteration, 100% of respondents agreed that "up to 30% BSA can be treated by enzymatic debridement based on individual decision" (Hirche et al., 2017). Hofmaenner et al.'s recent study on the safety of enzymatic debridement in extensive burns larger than 15% provides some further evidence that "bromelain based enzymatic debridement can be carried out safely in large-area burns" (Hofmaenner et al., 2020) but the literature is scant in these larger debridement areas. In our centre we have been using enzymatic debridement for resuscitation level burn injury since 2016. We have gained significant learning in this time; this article aims to describe our current protocol for enzymatic debridement in this patient population and highlight specific learning points that might aid other centres in using enzymatic debridement for larger burn injury. METHOD: We performed a search of the IBID database to identify all adult patients who satisfied the inclusion criteria of resuscitation level burn injury (defined as total burn surface area (TBSA) ≥15% in patients aged >16 years), or level 3 admission following burn injury and who underwent Enzymatic Debridement. A case note review was completed, and details comprising patient demographics, TBSA, mechanism of burn, presence of inhalation injury, sequencing of debridement, length of ICU and hospital stay, blood product utilisation and the need for autografting were recorded. No ethical approval has been sought for this retrospective review. RESULTS: We identified 29 patients satisfying the inclusion criteria (Table 1). Between June 2016 and June 2020 the average total burn size of patients who had at least some of their burn treated by enzymatic debridement increased from 21.4% in 2016/17 to 34.7% in 2019/20. In these patients the actual area treated by enzymatic debridement also increased from 11.9% TBSA to 20.3% TBSA. 19 patients (66%) had enzymatic debridement performed within 24 h of injury, a further 2 patients (7%) within 48 h after injury. Patients were more likely to have enzymatic debridement commenced in the first 24 h after injury if they had circumferential limb injury (39% vs 9%) or were planned for enzyme only debridement (78% vs 28%). Those who were planned for combination enzyme and surgical debridement were more likely to have enzymatic debridement commenced after the first 48 h (75%). We have performed enzymatic debridement overnight on one occasion, for a patient who presented with circumferential limb injury and was determined to undergo urgent debridement. CONCLUSION: Much of the literature has described the use of enzymatic debridement in smaller burns, and specialist areas. However, it is our opinion that the advantages of enzymatic debridement appear to be greater in larger burns with a facility for whole burn excision on the day of admission in the ICU cubicle. We have demonstrated significantly reduced blood loss, improved dermal preservation, reduced need for autografting, and a reduction in the number of trips to theatre. We would advocate that both the team and the patient need to be as prepared as they would be for a traditional surgical excision. The early part of our learning curve for enzymatic debridement in resuscitation level injuries was steep, and we were able to build on experience from managing smaller injuries. We recommend any team wishing to using enzymatic debridement gain experience in the same way and develop robust local pathways prior to attempting use in larger burn injuries.

Cannabis use is associated with patient and clinical factors in a population-based sample of colorectal cancer survivors.

PURPOSE: This study aimed to characterize patient and clinical factors associated with cannabis (marijuana) use among patients diagnosed with colorectal cancer (CRC). METHODS: We identified CRC patients, diagnosed from 2016 to 2018, using the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. CRC patients were recruited via mail and telephone, and participants completed a questionnaire eliciting information on medical history, demographics, and lifestyle factors, including cannabis use. Cancer stage was obtained from SEER registry data. RESULTS: Of 1,433 survey respondents, 339 (24%) were current cannabis users. Current cannabis use was associated with younger age at diagnosis, lower BMI, and a higher prevalence of cigarette smoking and alcohol consumption (p-value < 0.05). Cannabis use was also associated with lower quality of life scores (FACT-C) and advanced-stage cancer (p-value < 0.05). CONCLUSION: Cannabis use among CRC patients was common. Patients with more advanced disease were more likely to report cannabis use. Use also varied by some personal factors, consistent with patterns in the general population. Given the high prevalence of cannabis use among CRC patients, research is needed to determine the benefits and harms of cannabis use for symptom management in cancer patients.

Importance of case age in the purported association between phylogenetics and hemolytic uremic syndrome in Escherichia coli O157:H7 infections.

Escherichia coli O157:H7 is the largest cause of hemolytic uremic syndrome (HUS). Previous studies proposed that HUS risk varies across the E. coli O157:H7 phylogenetic tree (hypervirulent clade 8), but the role of age in the association is unknown. We determined phylogenetic lineage of E. coli O157:H7 isolates from 1160 culture-confirmed E. coli O157:H7 cases reported in Washington State, 2004-2015. Using generalised estimating equations, we tested the association between phylogenetic lineage and HUS. Age was evaluated as an effect modifier. Among 1082 E. coli O157:H7 cases with both phylogenetic lineage and HUS status (HUS n = 76), stratified analysis suggested effect modification by age. Lineages IIa and IIb, relative to Ib, did not appear associated with HUS in children 0-9-years-old. For cases 10-59-years-old, lineages IIa and IIb appeared to confer increased risk of HUS, relative to lineage Ib. The association reversed in ⩾60-year-olds. Results were similar for clade 8. Phylogenetic lineage appears to be associated with HUS risk only among those ⩾10-years-old. Among children <10, the age group most frequently affected, lineage does not explain progression to HUS. However, lineage frequency varied across age groups, suggesting differences in exposure and/or early disease manifestation.

A survey of northern Victorian dairy farmers to investigate dairy calf management: colostrum feeding and management.

OBJECTIVES: To describe colostrum management practices carried out in northern Victorian dairy herds and to identify weaknesses in these areas that may affect calf health and welfare by comparing the results with the current industry recommendations METHODS: A questionnaire to obtain information about colostrum management and calf-rearing practices was sent to commercial dairy farming clients of Rochester Veterinary Practice between June and September 2013. The questionnaire consisted of a general herd overview and colostrum harvesting practices. RESULTS: The response rate was 39% (58/150). Many dairy producers were not meeting the current industry recommendations in the following areas: (1) time of removal calf from the dam, (2) relying on calf suckling colostrum from the dam to achieve adequate passive transfer, (3) failing to supplement calves with colostrum, (4) feeding inadequate volumes of colostrum, (5) delayed colostrum harvesting, (6) pooling of colostrum, (7) failing to objectively assess colostrum quality or relying on visual assessment and (8) storing colostrum for a prolonged periods of time at ambient temperatures. CONCLUSION: The results from this survey highlight the need for greater awareness of industry standards for colostrum management and feeding hygiene.

A survey of northern Victorian dairy farmers to investigate dairy calf management: calf-rearing practices.

OBJECTIVES: To describe the calf-rearing practices carried out in northern Victorian dairy herds and to identify weaknesses that may affect calf health and welfare by comparing the results with current industry recommendations. METHODS: Survey of dairy farms from Rochester and the surrounding farming area. RESULTS: The response rate was 39% (58/150). Many dairy producers were not meeting the current industry recommendations in the following areas: (1) delayed access to pellets and roughage, (2) failing to provide access to water from birth, (3) delayed disbudding of calves, (4) delayed timing of booster vaccinations, (5) weaning based on age alone, (6) failing to isolate sick calves and (7) early sale age of excess calves. CONCLUSION: The results from this survey highlight the need for greater awareness of industry standards for calf husbandry and weaning.

Factors associated with colostrum immunoglobulin G concentration in northern-Victorian dairy cows.

OBJECTIVES: To determine the proportion of first-milking colostrum samples produced on four northern-Victorian dairy farms that meet industry standards in terms of immunoglobulin G (IgG) concentration and to identify risk factors that affect colostrum quality. METHODS: Colostrum IgG concentrations from 442 dairy cows on four farms were estimated using a Brix refractometer and risk factors for colostrum IgG concentration were determined using multivariable logistic regression. RESULTS: Only 39% of samples met the definition of high quality. The strongest predictor for colostrum quality was the interval from calving to colostrum harvesting. Colostrum harvested from cows within 12 h of calving was 6-fold more likely to be high quality compared with colostrum harvested later. Colostrum from cows in ≥ 4th lactation was nearly twice as likely to be high quality compared with cows entering their 1st lactation. If the calf was not allowed to suckle from the dam prior to colostrum harvesting, the odds of producing high-quality colostrum were nearly 4-fold greater. If the cow had not leaked colostrum prior to harvesting, it was more than 3-fold more likely to produce high-quality colostrum. CONCLUSIONS: The majority of samples assessed were below industry standard. Herd, lactation number, calf suckling or cow leaking colostrum prior to harvesting and time between calving and colostrum harvesting were factors that influenced colostrum IgG concentration. The results support current industry recommendations of harvesting colostrum shortly after parturition (ideally within 12 h of calving) and testing the quality of all colostrum prior to feeding to dairy calves.

Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study.

Background: TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation. Patients and methods: After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)-N0147 (NCT00079274) and PETACC3 (NCT00026273)-was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782). Results: TNM staging, MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61-0.68 in the TNM alone model to 0.63-0.71 in models with added molecular markers, 0.65-0.73 with clinicopathological features and 0.66-0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively. Conclusions: Incorporation of MSI, BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients.

Modeling Longitudinal Preclinical Tumor Size Data to Identify Transient Dynamics in Tumor Response to Antiangiogenic Drugs.

Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time-course data in a breast cancer xenograft model. We used a mixed-effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization. We estimated the characteristics of the window for mice treated with an anti-VEGF antibody (bevacizumab) or with a bispecific anti-VEGF/anti-angiopoietin-2 antibody (vanucizumab). We show how the mathematical model could theoretically be used to predict how to coordinate antiangiogenic therapy with radiotherapy or chemotherapy to maximize therapeutic effect, reducing the need for preclinical experiments that directly measure vessel normalization parameters.

Survey of bovine colostrum quality and hygiene on northern Victorian dairy farms.

One of the major challenges for dairy producers is to produce, harvest, and store high-quality colostrum and feed it to their replacement heifer calves. Limited published data are available in Australia regarding the relationship between colostrum management, hygiene, and quality. The objectives of this study were to investigate (1) the colostrum storage and handling practices carried out on farm; (2) the immunoglobulin concentration and bacterial composition of colostrum being fed to replacement dairy heifer calves; (3) the percentage of colostrum being fed to replacement dairy heifer calves that meet industry recommendations; and (4) risk factors for bacterial contamination of colostrum. The study was carried out on 24 dairy farms located near Rochester, Victoria, Australia. Two hundred forty colostrum samples were collected (10 samples per farm). Each farm harvested and stored first-milking colostrum under normal farm conditions. A 10-mL sample of the colostrum was collected in a sterile container immediately before feeding, and a Brix refractometer reading was taken. The samples were then frozen at -4°C and submitted for bacterial concentration analysis. Fifty-eight percent of colostrum samples met the recommended industry standard of a total plate count (TPC) of <100,000cfu/mL, and 94% of colostrum samples met the recommended industry standard of total coliform count (TCC) of 10,000cfu/mL. However, when all the current industry recommendations for TPC, TCC, and Brix refractometer percentage for colostrum quality were considered, only 23% of the samples met all standards. These findings demonstrate that a large number of calves were at risk of receiving colostrum of poor quality, with high bacterial loads that may have interfered with the acquisition of transfer of passive immunity and affected calf health. Further investigation is required to identify the farm-specific factors that may influence the level of bacterial contamination of colostrum. Recommendations as a result of this study include refrigeration of excess colostrum shortly (within 1h) after collection and thorough disinfection of the calf feeding apparatus before use.

Alterations in neurofilaments and the transformation of the cytoskeleton in axons may provide insight into the aberrant neuronal changes of Alzheimer's disease.

Neurofilaments are major protein constituents of the brain, but are particularly abundant in specific subpopulations of neurons and likely have a key role in the regulation of axonal calibre. Neurofilament proteins may also be involved in the transformation of the neuronal cytoskeleton leading to substantial tau pathology in axons damaged by Aß, subsequently leading to neurofibrillary pathology in their cell bodies of origin. An understanding of neurofilamentous changes in axons and subsequent tau pathology may provide insight into how Aß pathology may stimulate an aberrant plasticity-related response of damaged neurons, leading to the progressive and degenerative changes in the neuronal cytoskeleton that result in synapse loss and neuronal degeneration.

Vascular phenotype identification and anti-angiogenic treatment recommendation: A pseudo-multiscale mathematical model of angiogenesis.

The development of anti-angiogenic drugs for cancer therapy has yielded some promising candidates, but novel approaches for interventions to angiogenesis have led to disappointing results. In addition, there is a shortage of biomarkers that are predictive of response to anti-angiogenic treatments. Consequently, the complex biochemical and physiological basis for tumour angiogenesis remains incompletely understood. We have adopted a mathematical approach to address these issues, formulating a spatially averaged multiscale model that couples the dynamics of VEGF, Ang1, Ang2 and PDGF, with those of mature and immature endothelial cells and pericyte cells. The model reproduces qualitative experimental results regarding pericyte coverage of vessels after treatment by anti-Ang2, anti-VEGF and combination anti-VEGF/anti-Ang2 antibodies. We used the steady state behaviours of the model to characterise angiogenic and non-angiogenic vascular phenotypes, and used mechanistic perturbations representing hypothetical anti-angiogenic treatments to generate testable hypotheses regarding transitions to non-angiogenic phenotypes that depend on the pre-treatment vascular phenotype. Additionally, we predicted a synergistic effect between anti-VEGF and anti-Ang2 treatments when applied to an immature pre-treatment vascular phenotype, but not when applied to a normalised angiogenic pre-treatment phenotype. Based on these findings, we conclude that changes in vascular phenotype are predicted to be useful as an experimental biomarker of response to treatment. Further, our analysis illustrates the potential value of non-spatial mathematical models for generating tractable predictions regarding the action of anti-angiogenic therapies.

Challenges and Opportunities for Quantitative Clinical Pharmacology in Cancer Immunotherapy: Something Old, Something New, Something Borrowed, and Something Blue.

Cancer immunotherapy (CIT) initiates or enhances the host immune response against cancer. Following decades of development, patients with previously few therapeutic options may now benefit from CIT. Although the quantitative clinical pharmacology (qCP) of previous classes of anticancer drugs has matured during this time, application to CIT may not be straightforward since CIT acts via the immune system. Here we discuss where qCP approaches might best borrow or start anew for CIT.

KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers.

BACKGROUND: Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics. METHODS: The population-based study included individuals diagnosed with CRC between 1998-2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status. RESULTS: Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13-1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival. CONCLUSION: Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC.

Results from a low-energy analysis of the CDMS II germanium data.

We report results from a reanalysis of data from the Cryogenic Dark Matter Search (CDMS II) experiment at the Soudan Underground Laboratory. Data taken between October 2006 and September 2008 using eight germanium detectors are reanalyzed with a lowered, 2 keV recoil-energy threshold, to give increased sensitivity to interactions from weakly interacting massive particles (WIMPs) with masses below ∼10 GeV/c(2). This analysis provides stronger constraints than previous CDMS II results for WIMP masses below 9 GeV/c(2) and excludes parameter space associated with possible low-mass WIMP signals from the DAMA/LIBRA and CoGeNT experiments.

Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations.

BACKGROUND: Little is known regarding cancer risks for relatives of women with very early-onset breast cancer. METHODS: We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth. RESULTS: For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers. CONCLUSION: First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

Dark matter search results from the CDMS II experiment.

Astrophysical observations indicate that dark matter constitutes most of the mass in our universe, but its nature remains unknown. Over the past decade, the Cryogenic Dark Matter Search (CDMS II) experiment has provided world-leading sensitivity for the direct detection of weakly interacting massive particle (WIMP) dark matter. The final exposure of our low-temperature germanium particle detectors at the Soudan Underground Laboratory yielded two candidate events, with an expected background of 0.9 +/- 0.2 events. This is not statistically significant evidence for a WIMP signal. The combined CDMS II data place the strongest constraints on the WIMP-nucleon spin-independent scattering cross section for a wide range of WIMP masses and exclude new parameter space in inelastic dark matter models.