Development of a core outcome set for breast cancer-related lymphedema: a Delphi study.

PURPOSE: For breast cancer survivors (BCS) living with breast cancer-related lymphedema (BCRL), what outcome domains (OD) should be measured to assess the burden of the disease and efficacy of interventions? A Core Outcome Set (COS) that promotes standardized measurement of outcomes within the constraints of time influenced by work environments is essential for patients and the multidisciplinary professionals that manage and research BCRL. METHODS: Using Delphi methodology, a multidisciplinary group of BCRL experts (physical and occupational therapists, physicians, researchers, physical therapist assistants, nurses, and massage therapist) completed two waves of online surveys. BCRL expert respondents that completed the first survey (n = 78) had an average of 26.5 years in practice, whereas, respondents who completed the second survey (n = 33) had an average of 24.9 years. ODs were included in the COS when consensus thresholds, ranging from 70% to 80%, were met. RESULTS: A total of 12 ODs made up the COS. Reaching a minimum consensus of 70%; volume, tissue consistency, pain, patient-reported upper quadrant function, patient-reported health-related quality of life, and upper extremity activity and motor control were recommended at different phases of the BCRL continuum in a time-constrained environment. Joint function, flexibility, strength, sensation, mobility and balance, and fatigue met an 80% consensus to be added when time and resources were not constrained. CONCLUSION: The COS developed in this study thoroughly captures the burden of BCRL. Using this COS may reduce selective reporting, inconsistency in clinical use, and variability of reporting across interdisciplinary healthcare fields, which manage or research BCRL.

Development of a core set of outcome measures to be applied toward breast cancer-related lymphedema core outcome domains.

PURPOSE: For breast cancer survivors (BCS) living with breast cancer-related lymphedema (BCRL), what outcome measures (OMs) are recommended to be used to measure standardized outcome domains to fully assess the burden of the disease and efficacy of interventions? An integral component of a standardized core outcome set (COS) are the OMs used to measure the COS. METHODS: A supplemental online survey was linked to a Delphi study investigating a COS for BCRL. OMs were limited to a maximum of 10 options for each outcome domain (OD). There were 14 ODs corresponding to the International Classification of Functioning, Disability, and Health (ICF) framework and respondents rated the OMs with a Likert level of recommendation. The feasibility of the listed OMs was also investigated for most outpatient, inpatient, and research settings. RESULTS: This study identified 27 standardized OMs with a few ODs having 2-3 highly recommended OMs for proper measurement. A few of the recommended OMs have limitations with reliability due to being semi-quantitative measures requiring the interpretation of the rater. CONCLUSION: Narrowing the choices of OMs to 27 highly recommended by BCRL experts may reduce selective reporting, inconsistency in clinical use, and variability of reporting across interdisciplinary healthcare fields which manage or research BCRL. There is a need for valid, reliable, and feasible OMs that measure tissue consistency. Measures of upper extremity activity and motor control need further research in the BCS with BCRL population.

Preclinical transmission of prions by blood transfusion is influenced by donor genotype and route of infection.

Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease resulting from zoonotic transmission of bovine spongiform encephalopathy (BSE). Documented cases of vCJD transmission by blood transfusion necessitate on-going risk reduction measures to protect blood supplies, such as leucodepletion (removal of white blood cells, WBCs). This study set out to determine the risks of prion transmission by transfusion of labile blood components (red blood cells, platelets, plasma) commonly used in human medicine, and the effectiveness of leucodepletion in preventing infection, using BSE-infected sheep as a model. All components were capable of transmitting prion disease when donors were in the preclinical phase of infection, with the highest rates of infection in recipients of whole blood and buffy coat, and the lowest in recipients of plasma. Leucodepletion of components (<106 WBCs/unit) resulted in significantly lower transmission rates, but did not completely prevent transmission by any component. Donor PRNP genotype at codon 141, which is associated with variation in incubation period, also had a significant effect on transfusion transmission rates. A sensitive protein misfolding cyclic amplification (PMCA) assay, applied to longitudinal series of blood samples, identified infected sheep from 4 months post infection. However, in donor sheep (orally infected), the onset of detection of PrPSc in blood was much more variable, and generally later, compared to recipients (intravenous infection). This shows that the route and method of infection may profoundly affect the period during which an individual is infectious, and the test sensitivity required for reliable preclinical diagnosis, both of which have important implications for disease control. Our results emphasize that blood transfusion can be a highly efficient route of transmission for prion diseases. Given current uncertainties over the prevalence of asymptomatic vCJD carriers, this argues for the maintenance and improvement of current measures to reduce the risk of transmission by blood products.

Caprine PRNP polymorphisms N146S and Q222K are associated with proteolytic cleavage of PrPC.

Expression of the cellular prion protein (PrPC) is crucial for the development of prion diseases. Amino acid changes in PrPC or a reduced amount of PrPC may modulate disease resistance. The relative abundance of C1, a natural α-cleavage fragment of PrPC, was previously found to be associated with a resistant PRNP genotype in sheep. Goats are another small ruminant where classical scrapie susceptibility is under strong genetic control. In this study, we assessed PrPC in goats for the existence of similar associations between PrPC fragments and genotype. Brain tissue homogenates from scrapie-free goats with wild type PRNP or polymorphisms (I142M, H143R, N146S, or Q222K) were deglycosylated prior to immunoblot for assessment of the relative abundance of the C1 fragment of PrPC. The presence of K222 or S146 alleles demonstrated significantly different relative levels of C1 compared to that observed in wild type goats, which suggests that the genotype association with C1 is neither unique to sheep nor exclusive to the ovine Q171R dimorphism.

Susceptibility of young sheep to oral infection with bovine spongiform encephalopathy decreases significantly after weaning.

Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) (or prion disease) that is readily transmissible to sheep by experimental infection and has the shortest incubation period in animals with the ARQ/ARQ PRNP genotype (at codons 136, 154, and 171). Because it is possible that sheep in the United Kingdom could have been infected with BSE by being fed contaminated meat and bone meal supplements at the same time as cattle, there is considerable interest in the responses of sheep to BSE inoculation. Epidemiological evidence suggests that very young individuals are more susceptible to TSE infection; however, this has never been properly tested in sheep. In the present study, low doses of BSE were fed to lambs of a range of ages (~24 h, 2 to 3 weeks, 3 months, and 6 months) and adult sheep. The incidence of clinical BSE disease after inoculation was high in unweaned lambs (~24 h and 2 to 3 weeks old) but much lower in older weaned animals The incubation period was also found to be influenced by the genotype at codon 141 of the PRNP gene, as lambs that were LF heterozygotes had a longer mean incubation period than those that were homozygotes of either type. The results suggest that sheep in the United Kingdom would have been at high risk of BSE infection only if neonatal animals had inadvertently ingested contaminated supplementary foodstuffs.

Factors influencing temporal variation of scrapie incidence within a closed Suffolk sheep flock.

Several studies have shown that transmission of natural scrapie can occur vertically and horizontally, and that variations in scrapie incidence between and within infected flocks are mostly due to differences in the proportion of sheep with susceptible and resistant PRNP genotypes. This report presents the results of a 12-year period of scrapie monitoring in a closed flock of Suffolk sheep, in which only animals of the ARQ/ARQ genotype developed disease. Among a total of 120 of these, scrapie attack rates varied between birth cohorts from 62.5 % (5/8) to 100 % (9/9), and the incidence of clinical disease among infected sheep from 88.9 % (8/9) to 100 % (in five birth cohorts). Susceptible sheep born to scrapie-infected ewes showed a slightly higher risk of becoming infected (97.2 %), produced earlier biopsy-positive results (mean 354 days) and developed disease at a younger age (median 736 days) than those born to non-infected dams (80.3 %, 451 and 782 days, respectively). Taken together, this was interpreted as evidence of maternal transmission. However, it was also observed that, for the birth cohorts with the highest incidence of scrapie (90-100 %), sheep born to infected and non-infected dams had a similar risk of developing scrapie (97.1 and 95.3 %, respectively). Compared with moderate-attack-rate cohorts (62.5-66.7 %), high-incidence cohorts had greater numbers of susceptible lambs born to infected ewes, suggesting that increased rates of horizontal transmission in these cohorts could have been due to high levels of environmental contamination caused by infected placentas.

Significant differences in incubation times in sheep infected with bovine spongiform encephalopathy result from variation at codon 141 in the PRNP gene.

The susceptibility of sheep to prion infection is linked to variation in the PRNP gene, which encodes the prion protein. Common polymorphisms occur at codons 136, 154 and 171. Sheep which are homozygous for the A(136)R(154)Q(171) allele are the most susceptible to bovine spongiform encephalopathy (BSE). The effect of other polymorphisms on BSE susceptibility is unknown. We orally infected ARQ/ARQ Cheviot sheep with equal amounts of BSE brain homogenate and a range of incubation periods was observed. When we segregated sheep according to the amino acid (L or F) encoded at codon 141 of the PRNP gene, the shortest incubation period was observed in LL(141) sheep, whilst incubation periods in FF(141) and LF(141) sheep were significantly longer. No statistically significant differences existed in the expression of total prion protein or the disease-associated isoform in BSE-infected sheep within each genotype subgroup. This suggested that the amino acid encoded at codon 141 probably affects incubation times through direct effects on protein misfolding rates.

Susceptibility to scrapie and disease phenotype in sheep: cross-PRNP genotype experimental transmissions with natural sources.

It has long been established that the sheep Prnp genotype influences the susceptibility to scrapie, and some studies suggest that it can also determine several aspects of the disease phenotype. Other studies, however, indicate that the source of infection may also play a role in such phenotype. To address this question an experiment was set up in which either of two different natural scrapie sources, AAS from AA136 Suffolk and VVC from VV136 Cheviot sheep, were inoculated into AA136, VA136 and VV136 sheep recipients (n = 52). The immunohistochemical (IHC) profile of disease-associated PrP (PrPd) accumulation in the brain of recipient sheep was highly consistent upon codon 136 homologous and semi-homologous transmission, but could be either similar to or different from those of the inoculum donors. In contrast, the IHC profiles were highly variable upon heterologous transmission (VVC to AA136 and AAS to VV136). Furthermore, sheep of the same Prnp genotype could exhibit different survival times and PrPd profiles depending on the source of infection, and a correlation was observed between IHC and Western blot profiles. It was found that additional polymorphisms at codons 112 or 141 of AA136 recipients resulted in a delayed appearance of clinical disease or even in protection from infection. The results of this study strongly suggest that the scrapie phenotype in sheep results from a complex interaction between source, donor and recipient factors, and that the Prnp genotype of the recipient sheep does not explain the variability observed upon codon 136 heterologous transmissions, arguing for other genetic factors to be involved.

Secondary lymphedema from cancer therapy.

This manuscript is a summary of findings focusing on various aspects of secondary lymphedema specifically as a sequelae of treatment for cancer. The topic was addressed at a session held during the 8th International Congress on Cancer Metastasis that was unique a for the inclusion of patients with lymphedema and therapists joining physicians, healthcare professionals, and researchers in an effort to give an overview of secondary lymphedema following cancer therapy as well as highlighting the unknowns in the field. Lymphedema is defined and both diagnosis and incidence of cancer-related lymphedema are explored. Further, exploration of imaging options for lymphedema and information on the genetic research for patients with cancer-related secondary lymphedema are presented. Patient education and early detection methods are then explored followed by conservative treatment. Finally, an examination of surgical treatment methods available for patients with lymphedema is covered. Overall, this manuscript presents valuable information and updates for those not familiar with incidence, diagnosis, early detection, and rehabilitation of patients with cancer-related secondary lymphedema.

Experimental Bovine Spongiform Encephalopathy in Squirrel Monkeys: The Same Complex Proteinopathy Appearing after Very Different Incubation Times.

Incubation periods in humans infected with transmissible spongiform encephalopathy (TSE) agents can exceed 50 years. In humans infected with bovine spongiform encephalopathy (BSE) agents, the effects of a "species barrier," often observed when TSE infections are transmitted from one species to another, would be expected to increase incubation periods compared with transmissions of same infectious agents within the same species. As part of a long-term study investigating the susceptibility to BSE of cell cultures used to produce vaccines, we inoculated squirrel monkeys (Saimiri sp., here designated SQ) with serial dilutions of a bovine brain suspension containing the BSE agent and monitored them for as long as ten years. Previously, we showed that SQ infected with the original "classical" BSE agent (SQ-BSE) developed a neurological disease resembling that seen in humans with variant CJD (vCJD). Here, we report the final characterization of the SQ-BSE model. We observed an unexpectedly marked difference in incubation times between two animals inoculated with the same dilution and volume of the same C-BSE bovine brain extract on the same day. SQ-BSE developed, in addition to spongiform changes and astrogliosis typical of TSEs, a complex proteinopathy with severe accumulations of protease-resistant prion protein (PrPTSE), hyperphosphorylated tau (p-tau), ubiquitin, and α-synuclein, but without any amyloid plaques or ß-amyloid protein (Aß) typical of Alzheimer's disease. These results suggest that PrPTSE enhanced the accumulation of several key proteins characteristically seen in human neurodegenerative diseases. The marked variation in incubation periods in the same experimental TSE should be taken into account when modeling the epidemiology of human TSEs.

Subclinical infection occurs frequently following low dose exposure to prions by blood transfusion.

Infectious prion diseases have very long incubation periods, and the role that subclinical infections play in transmission, persistence and re-emergence of these diseases is unclear. In this study, we used a well-established model of vCJD (sheep experimentally infected with bovine spongiform encephalopathy, BSE) to determine the prevalence of subclinical infection following exposure by blood transfusion from infected donors. Many recipient sheep survived for years post-transfusion with no clinical signs and no disease-associated PrP (PrPSc) found in post mortem tissue samples by conventional tests. Using a sensitive protein misfolding cyclic amplification assay (PMCA), we found that the majority of these sheep had detectable PrPSc in lymph node samples, at levels approximately 105-106 times lower than in equivalent samples from clinically positive sheep. Further testing revealed the presence of PrPSc in other tissues, including brain, but not in blood samples. The results demonstrate that subclinical infection is a frequent outcome of low dose prion infection by a clinically relevant route for humans (blood transfusion). The long term persistence of low levels of infection has important implications for prion disease control and the risks of re-emergent infections in both humans and animals.

Caprine prion gene polymorphisms are associated with decreased incidence of classical scrapie in goat herds in the United Kingdom.

The application of genetic breeding programmes to eradicate transmissible spongiform encephalopathies in goats is an important aim for reasons of animal welfare as well as human food safety and food security. Based on the positive impact of Prnp genetics on sheep scrapie in Europe in the past decade, we have established caprine Prnp gene variation in more than 1100 goats from the United Kingdom and studied the association of Prnp alleles with disease phenotypes in 150 scrapie-positive goats. This investigation confirms the association of the Met142 encoding Prnp allele with increased resistance to preclinical and clinical scrapie. It reveals a novel association of the Ser127 encoding allele with a reduced probability to develop clinical signs of scrapie in goats that are already positive for the accumulation of disease-specific prion protein in brain or periphery. A United Kingdom survey of Prnp genotypes in eight common breeds revealed eleven alleles in over thirty genotypes. The Met142 encoding allele had a high overall mean allele frequency of 22.6%, whereas the Ser127 encoding allele frequency was considerably lower with 6.4%. In contrast, a well known resistance associated allele encoding Lys222 was found to be rare (0.9%) in this survey. The analysis of Prnp genotypes in Mexican Criollas goats revealed nine alleles, including a novel Phe to Leu substitution in codon 201, confirming that high genetic variability of Prnp can be found in scrapie-free populations. Our study implies that it should be feasible to lower scrapie prevalence in goat herds in the United Kingdom by genetic selection.

Genetic analysis of the SPRN gene in ruminants reveals polymorphisms in the alanine-rich segment of shadoo protein.

Prion diseases in ruminants, especially sheep scrapie, cannot be fully explained by PRNP genetics, suggesting the influence of a second modulator gene. The SPRN gene is a good candidate for this role. The SPRN gene encodes the shadoo protein (Sho) which has homology to the PRNP gene encoding prion protein (PrP). Murine Sho has a similar neuroprotective activity to PrP and SPRN gene variants are associated with human prion disease susceptibility. SPRN gene sequences were obtained from 14 species in the orders Artiodactyla and Rodentia. We report here the sequences of more than 20 different Sho proteins that have arisen due to single amino acid substitutions and amino acid deletions or insertions. All Sho sequences contained an alanine-rich sequence homologous to a hydrophobic region with amyloidogenic characteristics in PrP. In contrast with PrP, the Sho sequence showed variability in the number of alanine residues.

Lymphedema following cancer therapy: overview and options.

This summit focusing on lymphedema following cancer therapy was held during the 7th International Symposium on Cancer Metastasis through the Lymphovascular System. It was unique for the inclusion of patients with lymphedema joining physicians, therapists, healthcare professionals, and researchers to highlight what is known and more importantly what is unknown about the current state of research and treatment in the United States. The session opened with an introduction to lymphedema and then explored the incidence of multiple cancer-related lymphedemas, imaging tools and techniques useful for the diagnosis of lymphatic system abnormalities, and the new findings concerning the genetics of cancer-related lymphedema. It closed with a review of advocacy for patients and healthcare professionals and both conservative and surgical treatment options, followed by a panel discussion and questions. The session provided important information and updates which will be of value for improving the rehabilitation and overall support of patients with cancer-related lymphedema.

Recommendations for action: a community meeting in preparation for a mass-casualty opioid overdose event in Southeastern Ontario.

Given the steady rise of overdose morbidity and mortality in North America, and increasing frequency of sudden clusters of non-fatal and fatal overdoses in other jurisdictions, regional preparedness plans to respond effectively to clusters of overdoses may reduce the impact of such events on the population. On the 27th of February 2017 in Kingston, Ontario, KFL&A Public Health, in collaboration with public health partners, hosted a full-day workshop involving table-top exercises and discussions for service partners on how to prepare for, respond to, and manage a mass-casualty event secondary to opioid overdose in Southeastern Ontario. The workshop assisted in identifying the various challenges faced by service partners, provided an understanding of the roles and responsibilities of partner agencies, and helped to determine next steps in preparation to address a mass opioid overdose situation at the local level. This report suggests key roles and responsibilities of partners involved in responding to a mass-casualty event secondary to opioid overdose, recommendations to address the feedback and challenges raised throughout the workshop, and a protocol to help determine when to activate an Incident Management System (IMS).

In a retrospective study of chronic obstructive pulmonary disease inpatients, respiratory comorbidities were significantly associated with prognosis.

BACKGROUND AND OBJECTIVE: Comorbidities may be related to the prognosis for chronic obstructive pulmonary disease (COPD). We examined respiratory comorbidities associated with length of stay and in-hospital mortality among COPD patients. METHODS: We used the Hospital Person Oriented Information (HPOI) database of Statistics Canada for a 5-year period. Over 4 years (fiscal years 1994-1995 to 1998-1999), 143,135 records listed COPD as the most responsible diagnosis for men and 122,065 records for women aged 40 years or more, and 75,780 men and 69,539 women were admitted to hospital at least once. Logistic regression modeling was used to examine the relationships between respiratory comorbidities and hospital outcomes adjusting for covariates. RESULTS: Of the COPD patients, 10% had pneumonia-influenza and 3% had asthma as comorbid conditions. Women had a higher prevalence of asthma than men. The median length of stay at hospital was approximately 7 days, and 95% of patients were discharged alive. The odds ratio (95% confidence interval) for pneumonia-influenza in relation to in-hospital death was 3.56 (3.31, 3.83) for men and 3.29 (3.00, 3.61) for women. For comorbid asthma the corresponding odds ratios were 0.56 (0.36, 0.61) and 0.54 (0.35, 0.57), respectively. CONCLUSIONS: COPD inpatients with pneumonia-influenza had a worse prognosis and those with asthma had a better prognosis.

An evaluation of the Ontario Rapid Risk Factor Surveillance System.

BACKGROUND: The Rapid Risk Factor Surveillance System (RRFSS) is an ongoing population health survey conducted by a collaborating group of Ontario public health units. This formative evaluation examined the process effectiveness, collaboration, utility and cost-effectiveness of RRFSS during its first year of operation. METHODS: An Evaluation Framework was developed with reference to guidelines for evaluation of surveillance systems developed by the World Health Organization and the U.S. Centers for Disease Control and Prevention. The study focussed on evaluable performance areas in a young surveillance system and on information needed to inform stakeholder decisions about future participation and improvement. Data were collected through surveys and interviews of key informants in participating health units, non-participating health units, the survey research house, and the provincial health ministry. RESULTS: Findings documented early use and dissemination of RRFSS data in health units after less than a year of surveillance system operation, stakeholder perceptions overall of data impact and value, and satisfaction with system functioning. Challenges to effectiveness were documented concerning data analysis, barriers to data use, and sustainability. Performance improvement strategies were identified for survey implementation and supports, data use, system participation, and reduced costs. CONCLUSION: In its first year, RRFSS was an effective collaborative method to collect population data for public health program planning and evaluation. The evaluation provided valuable information on use, functioning, effectiveness, strategic issues and areas for improvement in a young surveillance system, created opportunities for stakeholder input into evaluation and planning, and provided a baseline for future evaluations.

Susceptibility of European red deer (Cervus elaphus elaphus) to alimentary challenge with bovine spongiform encephalopathy.

European red deer (Cervus elaphus elaphus) are susceptible to the agent of bovine spongiform encephalopathy, one of the transmissible spongiform encephalopathies, when challenged intracerebrally but their susceptibility to alimentary challenge, the presumed natural route of transmission, is unknown. To determine this, eighteen deer were challenged via stomach tube with a large dose of the bovine spongiform encephalopathy agent and clinical signs, gross and histological lesions, presence and distribution of abnormal prion protein and the attack rate recorded. Only a single animal developed clinical disease, and this was acute with both neurological and respiratory signs, at 1726 days post challenge although there was significant (27.6%) weight loss in the preceding 141 days. The clinically affected animal had histological lesions of vacuolation in the neuronal perikaryon and neuropil, typical of transmissible spongiform encephalopathies. Abnormal prion protein, the diagnostic marker of transmissible encephalopathies, was primarily restricted to the central and peripheral nervous systems although a very small amount was present in tingible body macrophages in the lymphoid patches of the caecum and colon. Serial protein misfolding cyclical amplification, an in vitro ultra-sensitive diagnostic technique, was positive for neurological tissue from the single clinically diseased deer. All other alimentary challenged deer failed to develop clinical disease and were negative for all other investigations. These findings show that transmission of bovine spongiform encephalopathy to European red deer via the alimentary route is possible but the transmission rate is low. Additionally, when deer carcases are subjected to the same regulations that ruminants in Europe with respect to the removal of specified offal from the human food chain, the zoonotic risk of bovine spongiform encephalopathy, the cause of variant Creutzfeldt-Jakob disease, from consumption of venison is probably very low.

Sex difference in hospitalization due to asthma in relation to age.

To describe the sex and age differences in asthma hospitalization among the Canadian population, we conducted an analysis based on a total of 9,486,173 hospital records in Canada for a 3-year period (1994/1995, 1995/1996, and 1996/1997), including 204,304 asthma patients and 288,977 asthma-related records. Asthma as one of the first five diagnoses, accounted for 3.0% of total hospitalizations, which was almost constant across the 3-year study period. The 3-year cumulative incidence of asthma hospitalization was substantially higher for young boys than girls, and it was reversed for adults. The incidence ratio for females vs. males for asthma hospitalization reached 2.8 for individuals 25 to 34 years of age, decreased gradually with increasing age, and then approached unity for those aged 80 years or more. The data suggest that sex is an important determinant for asthma, and the sex effect varies considerably over a life span.

Hospital readmissions for asthma in children and young adults in Canada.

To examine the incidence rate of hospital readmission for asthma in relation to sex and age among Canadian children and young adults, we used data from 86,863 subjects under age 20 years when they had a first admission for asthma as 1 of first 5 diagnoses in Canada between April 1, 1994 and March 31, 1997. We calculated age- and sex-specific incidence rates, and used the Cox proportional hazards model for multivariate analysis. Of these subjects, 20,277 (23.3%) were readmitted to hospital for asthma during the study period. After adjusting for length of stay for first admission and province, the rate ratio for females vs. males was 0.86 for those under age 1 year, and close to unity for the 1-4-year and 5-9-year age groups, whereas it was 1.47 and 1.35 for the 10-14-year and 15-19-year age groups, respectively. The data showed similar trends for rehospitalization asthma as a primary diagnosis. The incidence rate of rehospitalization showed little sex difference between ages 1-9 years, but was markedly higher in females than in males 10-19 years of age. Airway size, female hormonal changes, increased use of cosmetic products, and cigarette smoking among adolescent girls may contribute to the age- and sex-differences in adolescence.