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.

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.

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.

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.

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.

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.

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.

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.

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.

The use of Biobrane by burn units in the United Kingdom: a national study.

Biobrane is a biosynthetic wound dressing, first used by Woodruff in 1979, which has many of the ideal properties of a dressing as outlined by Pruitt and Levine [Pruitt Jr BA, Levine NS. Characteristics and uses of biologic dressings and skin substitutes. Arch Surg 1984;119(3):312-22]. It is becoming increasingly popular in the management of superficial and moderate depth partial thickness burns and a range of other conditions. When used appropriately, it has been shown to reduce pain levels, healing time, inpatient stay and nursing requirements when compared to traditional dressings. We present the results of a national study concerning the use of Biobrane in the United Kingdom, highlight variations in practice, discuss the pertinent issues, make suitable recommendations and highlight the versatility of Biobrane as a wound dressing.

Burns inflicted by self or by others--an 11 year snapshot.

INTRODUCTION: In the United Kingdom, the incidence of assault by burning and of self inflicted burns increased significantly over the last decade. This has major implications both for service providers and society as a whole. Our aim was to investigate the differences in patients' characteristics, management and outcome following a burn sustained by either an assault or self immolation. METHODS: Acute admissions to a tertiary Burn Centre were retrospectively reviewed over an 11 year period (1994-2005). Demographic data and information regarding the circumstances surrounding the incident, burn severity, treatment and outcomes of the patients were collected. RESULTS: Over an 11 year period, 1745 patients were admitted to the tertiary Burn Centre. Of this total, 41 patients (mean age 29 years+/-16) sustained burns following an assault, a further 86 patients (mean age of 37 years+/-12) had self inflicted burn injuries; males were preponderant in both groups. In this series, a history of alcohol or substance abuse was present in 25% of both cohorts, 63% of the patients with self inflicted injuries having a previously diagnosed psychiatric disorder. Petrol, accelerants and other flammable liquids were the main agents chosen to inflict injury in both the assault and self inflicted groups. The burn depth and surface area distribution was greater in the self inflicted group compared to those assaulted (29% versus 21%). A difference was also noted in the pattern of distribution of burns between the two groups, as well as between genders although this difference was not significant. Two-thirds (67.4%) of the self immolated patients and 56% of the assaulted group required surgery. The length of hospital stay was similar for both groups, averaging 20 days. The crude mortality for the self inflicted group was 29%, whereas in the assaulted patients, the overall mortality was 4.9%. CONCLUSION: Although the incidence of burns caused either by assault or attempted suicide is low, the affected patients require a multidisciplinary approach. Their management requires significant medical, psychological occupational and social support. Increased awareness and education of those vulnerable individuals maybe of benefit to help prevent self inflicted injuries by burning.

Resuscitation burn card--a useful tool for burn injury assessment.

It is well recognised that the initial assessment of body surface area affected by a burn is often over estimated in Accident and Emergency Departments. A useful aide-memoir in the acute setting is Wallace's "rule of nines" or using the patients' palmar surface of the hand, which approximates 1% of the total body surface area, as a method of assessment. Unfortunately, as with every system, limitations apply. Factors such as patient size and the interpretation of what is exactly the 'palmar surface' may significantly influence burn size estimations and subsequently fluid resuscitation. Our aim is to develop a simple, quick and easy reproducible method of calculating burn injuries for medical professionals in the acute setting. Worldwide, the dimensions of a credit card are standardized (8.5 cm x 5.3 cm), thus producing a surface area of 45 cm2. We created a resuscitation burn card (RBC) using these exact same proportions, upon which a modified body surface area (BSA) nomogram was printed. Knowing the patient height and weight, we calculated the surface area of the card as percentage of total body surface area (TBSA). On the opposite site of the RBC, a Lund and Browder chart was printed, as well as the Parkland formula and a formula to calculate paediatric burn fluid requirements. The plastic, flexible RBC conformed well to the body contour and was designed for single use. We used the resuscitation burn card in the initial assessment of simulated burns in a Regional Burn Centre and in an Accident and Emergency Department. The information present on the card was found to be clear and straightforward to use. The evaluation of burn extent was found to be more accurately measured than the estimation obtained without the RBC. The resuscitation burn card can be a valuable tool in the hands of less experienced medical professionals for the early assessment and fluid resuscitation of a burn.

Reliability of the ICRP'S dose coefficients for members of the public: IV. basis of the human alimentary tract model and uncertainties in model predictions.

The biokinetic and dosimetric model of the gastrointestinal (GI) tract applied in current documents of the International Commission on Radiological Protection (ICRP) was developed in the mid-1960s. The model was based on features of a reference adult male and was first used by the ICRP in Publication 30, Limits for Intakes of Radionuclides by Workers (Part 1, 1979). In the late 1990s an ICRP task group was appointed to develop a biokinetic and dosimetric model of the alimentary tract that reflects updated information and addresses current needs in radiation protection. The new age-specific and gender-specific model, called the Human Alimentary Tract Model (HATM), has been completed and will replace the GI model of Publication 30 in upcoming ICRP documents. This paper discusses the basis for the structure and parameter values of the HATM, summarises the uncertainties associated with selected features and types of predictions of the HATM and examines the sensitivity of dose estimates to these uncertainties for selected radionuclides. Emphasis is on generic biokinetic features of the HATM, particularly transit times through the lumen of the alimentary tract, but key dosimetric features of the model are outlined, and the sensitivity of tissue dose estimates to uncertainties in dosimetric as well as biokinetic features of the HATM are examined for selected radionuclides.

The internal dosimetry code PLEIADES.

The International Commission on Radiological Protection (ICRP) has published dose coefficients for the ingestion or inhalation of radionuclides in a series of reports covering intakes by workers and members of the public, including children and pregnant or lactating women. The calculation of these coefficients divides naturally into two distinct parts-the biokinetic and dosimetric. This paper describes in detail the methods used to solve the biokinetic problem in the generation of dose coefficients on behalf of the ICRP, as implemented in the Health Protection Agency's internal dosimetry code PLEIADES. A summary of the dosimetric treatment is included.

In utero and postnatal haemopoietic tissue doses resulting from maternal ingestion of strontium isotopes from the Techa River.

Reliable estimates of tissue doses to individuals exposed as a result of radioactive releases to the Techa River are essential prerequisites for epidemiological analyses. This paper describes progress made in collaborative studies, sponsored by the European Union, between the Urals Research Center for Radiation Medicine and the UK Health Protection Agency to provide dose estimates to Techa River populations following in utero exposures and infant exposures resulting from breast-feeding. Studies have concentrated on the assessment of internal doses from 90Sr as the main contributor to internal doses to the Techa River populations.