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Limb girdle muscular dystrophy type 2A is linked to a skeletal muscle-speci¢c calpain isoform known as p94. Isolation of the intact 94-kDa enzyme has been di⁄cult to achieve due to its rapid autolysis, and uncertainty has arisen over its Ca 2+ -dependence for activity. We have expressed a C-terminally truncated form of the enzyme that comprises the protease core (domains I and II) along with its insertion sequence, IS1, and N-terminal leader sequence, NS. This 47-kDa p94I-II minicalpain was stable during puri¢cation. In the presence of Ca 2+ , p94I-II cleaved itself within the NS and IS1 sequences. Mapping of the autolysis sites showed that NS and IS1 have the potential to be removed without damage to the protease core. Ca 2+ -dependent autolysis must be an intramolecular event because the inactive p94I-II C129S mutant was not cleaved by incubation with wild-type p94I-II. In addition, the rate of autolysis of p94I-II was independent of the concentration of the enzyme.

Objective: To describe the immediate impact of the COVID-19 pandemic on cervical screening, colposcopy and treatment volumes in Ontario, Canada. Design: Population-based retrospective observational study Setting: Ontario, Canada Population: People with a cervix age 21 to 69 years who completed at least one cervical screening cytology test, colposcopy or treatment procedure for cervical dysplasia between January 2019 and August 2020. Methods: Administrative databases were used to compare cervical screening cytology, colposcopy and treatment procedure volumes before (historical comparator) and during the first six months of the COVID-19 pandemic (March to August 2020). Main Outcome Measures: Changes in cervical screening cytology, colposcopy, and treatment volumes; individuals with high-grade cytology awaiting colposcopy. Results: During the first six months of the COVID-19 pandemic, the monthly average number of cervical screening cytology tests, colposcopies and treatments decreased by 63.8% (range: -92.3% --41.0%), 39.7% (range: -75.1% --14.3%) and 31.1% (range: -43.5% --23.6%), respectively, when compared to the corresponding months in 2019. Between March and August 2020, on average 292 (-51.0%) fewer high-grade cytological abnormalities were detected through screening each month. As of August 2020, 1,159 (29.2%) individuals with high-grade screening cytology were awaiting follow-up colposcopy.Conclusions: The COVID-19 pandemic has had a substantial impact on key cervical screening and follow-up services in Ontario. As the pandemic continues, ongoing monitoring of service utilization to inform system response and recovery is required. Future efforts to understand the impact of COVID-19-related disruptions on cervical cancer outcomes will be needed.Funding: This study was conducted with the support of Ontario Health (Cancer Care Ontario) through in-kind contributions.

Key Points Question Did the delivery of services within a cancer system change during the first year of the COVID-19 pandemic? Findings This population-based cohort study conducted in Ontario, Canada, found a total of 4 476 693 cancer care services during the first year of the COVID-19 pandemic, compared with 5 644 105 services in the year prior, representing a reduction of 20.7% and suggesting a backlog of 1 167 412 cancer services during the first pandemic year. Limited change was observed in systemic treatments and emergency or urgent imaging examinations and surgical procedures, while major reductions were observed in cancer screening tests, biopsies, surgical treatments, and new consultations for systemic and radiation treatment. Meaning These findings provide evidence on the deficits in cancer care that occurred during the first year of the COVID-19 pandemic that are likely to inform continued delivery of care, recovery, and future pandemic planning.