Incidence of childhood cancer in Canada during the COVID-19 pandemic

Background:The COVID-19 pandemic has had a major impact on access to health care resources. Our objective was to estimate the impact of the COVID-19 pandemic on the incidence of childhood cancer in Canada. We also aimed to compare the proportion of patients who enrolled in clinical trials at diagnosis, presented with metastatic disease or had an early death during the first 9 months of the COVID-19 pandemic compared with previous years.Methods:We conducted an observational study that included children younger than 15 years with a new diagnosis of cancer between March 2016 and November 2020 at 1 of 17 Canadian pediatric oncology centres. Our primary outcome was the monthly age-standardized incidence rates (ASIRs) of cancers. We evaluated level and trend changes using interventional autoregressive integrated moving average models. Secondary outcomes were the proportion of patients who were enrolled in a clinical trial, who had metastatic or advanced disease and who died within 30 days. We compared the baseline and pandemic periods using rate ratios (RRs) and 95% confidence intervals (CIs).Results:Age-standardized incidence rates during COVID-19 quarters were 157.7, 164.6, and 148.0 per million, respectively, whereas quarterly baseline ASIRs ranged between 150.3 and 175.1 per million (incidence RR 0.93 [95% CI 0.78 to 1.12] to incidence RR 1.04 [95% CI 0.87 to 1.24]). We found no statistically significant level or slope changes between the projected and observed ASIRs for all new cancers (parameter estimate [β], level 4.98, 95% CI −15.1 to 25.04, p = 0.25), or when stratified by cancer type or by geographic area. Clinical trial enrolment rate was stable or increased during the pandemic compared with baseline (RR 1.22 [95% CI 0.70 to 2.13] to RR 1.71 [95% CI 1.01 to 2.89]). There was no difference in the proportion of patients with metastatic disease (RR 0.84 [95% CI 0.55 to 1.29] to RR 1.22 [0.84 to 1.79]), or who died within 30 days (RR 0.16 [95% CI 0.01 to 3.04] to RR 1.73 [95% CI 0.38 to 15.2]).Interpretation:We did not observe a statistically significant change in the incidence of childhood cancer, or in the proportion of children enrolling in a clinical trial, presenting with metastatic disease or who died early during the first 9 months of the COVID-19 pandemic, which suggests that access to health care in pediatric oncology was not reduced substantially in Canada.

Concerns have been raised that the COVID-19 pandemic disrupted health care–seeking behaviours and access to health care, affecting the diagnosis and management of other conditions such as cancer. Studies conducted in the Netherlands and United Kingdom using administrative data have shown as much as a 50% reduction in cancer incidence in adults after March 2020.^1,2 Other studies in adult populations thus far have shown a decrease in the number of new cancer diagnoses, and cancer-related medical visits, therapies and surgeries, ^1,3–5 raising concerns about potential excess cancer mortality in the upcoming years.⁶ This may be explained partly by the suspension or reduction of cancer-screening procedures, such as mammography, colonoscopy and cervical cytology by up to 90%,^3,5,7 because these screening initiatives play a critical role in the detection of cancers in adults. A 2020 retrospective single-centre cohort study in Japan that involved 123 patients with colorectal cancer reported that significantly more of these patients presented with complete intestinal obstruction, which suggests that detection delays might have contributed to diagnosis at later stages of the disease.⁸ It is unclear whether these findings apply to childhood cancer because cancer screening is not part of routine pediatric care, and early detection may not be as important in childhood cancer than in its adult counterpart.⁹In children, case series and single-centre retrospective cohort studies, notably from Italy and the United States, suggested a marked reduction in incident cancers, along with high acuity of care at presentation.^10–13 Similar concerns of delayed clinical presentation were raised in other pediatric patient populations, with reports of children presenting at late stages of sepsis or diabetic ketoacidosis, which suggests a delay in seeking care.^14,15It is possible that fear of COVID-19 dissuaded families with children from seeking care for nonspecific symptoms such as pain, headache or fatigue, which are typical triggers leading to a pediatric cancer diagnosis. Understanding the indirect effects of health policies during the COVID-19 pandemic is important to guide policy-making and mitigate barriers to essential health care in future public health crises.Our objective was to measure the impact of the COVID-19 pandemic and associated restrictions on the incidence of childhood cancer in Canada. We also aimed to compare the proportion of patients who enrolled in clinical trials at diagnosis, presented with metastatic disease or died during the first 9 months of the COVID-19 pandemic compared with previous years.     

Redirecting meiotic DNA break hotspot determinant proteins alters localized spatial control of DNA break formation and repair

During meiosis, DNA double-strand breaks (DSBs) are formed at high frequency at special chromosomal sites, called DSB hotspots, to generate crossovers that aid proper chromosome segregation. Multiple chromosomal features affect hotspot formation. In the fission yeast S. pombe the linear element proteins Rec25, Rec27 and Mug20 are hotspot determinants – they bind hotspots with high specificity and are necessary for nearly all DSBs at hotspots. To assess whether they are also sufficient for hotspot determination, we localized each linear element protein to a novel chromosomal site (ade6 with lacO substitutions) by fusion to the Escherichia coli LacI repressor. The Mug20-LacI plus lacO combination, but not the two separate lac elements, produced a strong ade6 DSB hotspot, comparable to strong endogenous DSB hotspots. This hotspot had unexpectedly low ade6 recombinant frequency and negligible DSB hotspot competition, although like endogenous hotspots it manifested DSB interference. We infer that linear element proteins must be properly placed by endogenous functions to impose hotspot competition and proper partner choice for DSB repair. Our results support and expand our previously proposed DSB hotspot-clustering model for local control of meiotic recombination.     

Development of Chlorenchyma and Window Tissues in Leaves of Peperomia columella

Window leaves consist primarily of tissues specialized for waterstorage (window tissue) and photosynthesis (chlorenchyma). Theobjective of our research was to determine when these specializationsoccur during leaf development in Peperomia columella, a succulentwindow plant, native to deserts of South America. We measuredabsolute and relative volumes of leaf tissues. Young leavesconsist of approximately 75% chlorenchyma and 12% window tissue,suggesting that they are structurally specialized primarilyfor photosynthesis rather than water storage. In mature leavesthe percentages of chlorenchyma and window tissue are approximately20% and 58%, respectively, indicating that specialization forwater storage occurs during later stages of leaf development.The percent window tissue decreases in mature leaves, but increasesin young leaves with water stress.Copyright 1993, 1999 AcademicPress Chlorenchyma, Peperomia columella, succulent, window plant     

Errors in aerial survey count data: Identifying pitfalls and solutions

Accurate estimates of animal abundance are essential for guiding effective management, and poor survey data can produce misleading inferences. Aerial surveys are an efficient survey platform, capable of collecting wildlife data across large spatial extents in short timeframes. However, these surveys can yield unreliable data if not carefully executed. Despite a long history of aerial survey use in ecological research, problems common to aerial surveys have not yet been adequately resolved. Through an extensive review of the aerial survey literature over the last 50 years, we evaluated how common problems encountered in the data (including nondetection, counting error, and species misidentification) can manifest, the potential difficulties conferred, and the history of how these challenges have been addressed. Additionally, we used a double‐observer case study focused on waterbird data collected via aerial surveys and an online group (flock) counting quiz to explore the potential extent of each challenge and possible resolutions. We found that nearly three quarters of the aerial survey methodology literature focused on accounting for nondetection errors, while issues of counting error and misidentification were less commonly addressed. Through our case study, we demonstrated how these challenges can prove problematic by detailing the extent and magnitude of potential errors. Using our online quiz, we showed that aerial observers typically undercount group size and that the magnitude of counting errors increases with group size. Our results illustrate how each issue can act to bias inferences, highlighting the importance of considering individual methods for mitigating potential problems separately during survey design and analysis. We synthesized the information gained from our analyses to evaluate strategies for overcoming the challenges of using aerial survey data to estimate wildlife abundance, such as digital data collection methods, pooling species records by family, and ordinal modeling using binned data. Recognizing conditions that can lead to data collection errors and having reasonable solutions for addressing errors can allow researchers to allocate resources effectively to mitigate the most significant challenges for obtaining reliable aerial survey data.     

Spectroscopic Characterization of Two Soluble Transducers from the Archaeon Halobacterium salinarum

In the present study, structural aspects of the two soluble transducers, HtrX and HtrXI, from the archaeon H. salinarum have been examined using UV circular dichroism and steady-state fluorescence spectroscopies. Circular dichroism (CD) data indicate that both HtrX and HtrXI exhibit salt-dependent protein folding. Under low-ionic-strength conditions (0.2 M NaCl or KCl) the CD spectra of HtrXI is similar to that of the Gdn-HCl- or urea-denatured forms and is indicative of random coil structure. In contrast, the CD spectrum of HtrX under low-ionic-strength conditions contains roughly 85% α-helical character, indicating a significant degree of folding. Addition of NaCl or KCl to solutions of HtrX or HtrXI results in CD features consistent with predominately α-helical character (>95%) for both proteins. In addition, the transition points (i.e., ionic strengths at which the protein converts from random coil to α-helical character) are quite distinct and dependent upon the type of salt present (i.e., either NaCl or KCl). Accessibility of tryptophan residues to the solvent was also examined for both HtrX and HtrXI in both folded and unfolded states using Kl quenching. The Stern–Volmer constants obtained suggest that the tryptophans (Trp35 in HtrX and both Trp47 and Trp74 in HtrXI) are partially exposed to the solvent, indicating that they are located near the surface of the protein in all three cases. Furthermore, fluorescence quenching with the single Trp mutants Trp74AIa and Trp47AIa of HtrXI indicates different environments for these two residues.     

The importance of peptide detectability for protein identification, quantification, and experiment design in MS/MS proteomics

Peptide detectability is defined as the probability that a peptide is identified in an LC-MS/MS experiment and has been useful in providing solutions to protein inference and label-free quantification. Previously, predictors for peptide detectability trained on standard or complex samples were proposed. Although the models trained on complex samples may benefit from the large training data sets, it is unclear to what extent they are affected by the unequal abundances of identified proteins. To address this challenge and improve detectability prediction, we present a new algorithm for the iterative learning of peptide detectability from complex mixtures. We provide evidence that the new method approximates detectability with useful accuracy and, based on its design, can be used to interpret the outcome of other learning strategies. We studied the properties of peptides from the bacterium Deinococcus radiodurans and found that at standard quantities, its tryptic peptides can be roughly classified as either detectable or undetectable, with a relatively small fraction having medium detectability. We extend the concept of detectability from peptides to proteins and apply the model to predict the behavior of a replicate LC-MS/MS experiment from a single analysis. Finally, our study summarizes a theoretical framework for peptide/protein identification and label-free quantification.     

Sialidase specificity determined by chemoselective modification of complex sialylated glycans

Sialidases hydrolytically remove sialic acids from sialylated glycoproteins and glycolipids. Sialidases are widely distributed in nature and sialidase-mediated desialylation is implicated in normal and pathological processes. However, mechanisms by which sialidases exert their biological effects remain obscure, in part because sialidase substrate preferences are poorly defined. Here we report the design and implementation of a sialidase substrate specificity assay based on chemoselective labeling of sialosides. We show that this assay identifies components of glycosylated substrates that contribute to sialidase specificity. We demonstrate that specificity of sialidases can depend on structure of the underlying glycan, a characteristic difficult to discern using typical sialidase assays. Moreover, we discovered that Streptococcus pneumoniae sialidase NanC strongly prefers sialosides containing the Neu5Ac form of sialic acid versus those that contain Neu5Gc. We propose using this approach to evaluate sialidase preferences for diverse potential substrates.