Implementation and Evaluation of an IPAC SWAT Team Mobilized to Long-Term Care and Retirement Homes During the COVID-19 Pandemic: A Pragmatic Health System Innovation.

Long-term care facilities (LTCFs), retirement homes (RHs), and other congregate care settings in Canada and worldwide have experienced significant COVID-19 outbreaks. As a health system response, our acute care hospital in Toronto, Ontario, Canada, developed and mobilized an onsite Infection Prevention and Control (IPAC) SWAT team (IPAC-SWAT) to regional settings on outbreak and implemented a strategy of support through education, training, and engagement. Between April 28, 2020, and June 30, 2020, IPAC-SWAT assessed 7 LTCFs and 10 RHs for IPAC preparedness and actively managed 10 of 13 COVID-19 outbreaks (LTCF n=5; RH n=5). IPAC-SWAT strategies were multi-interventional and intended to mitigate further viral transmission or prevent outbreaks. Dedicated training of local "IPAC champions" was facilitated at 7 sites (LTCF = 5; RH = 2) using a "train-the-trainer" approach to promote local knowledge, autonomy, and site-led audits and feedback.

Second-hand smoke as a predictor of smoking cessation among lung cancer survivors.

PURPOSE: Second-hand smoke (SHS; ie, exposure to smoking of friends and spouses in the household) reduces the likelihood of smoking cessation in noncancer populations. We assessed whether SHS is associated with cessation rates in lung cancer survivors. PATIENTS AND METHODS: Patients with lung cancer were recruited from Princess Margaret Cancer Centre, Toronto, ON, Canada. Multivariable logistic regression and Cox proportional hazard models evaluated the association of sociodemographics, clinicopathologic variables, and SHS with either smoking cessation or time to quitting. RESULTS: In all, 721 patients completed baseline and follow-up questionnaires with a mean follow-up time of 54 months. Of the 242 current smokers at diagnosis, 136 (56%) had quit 1 year after diagnosis. Exposure to smoking at home (adjusted odds ratio [aOR], 6.18; 95% CI, 2.83 to 13.5; P < .001), spousal smoking (aOR, 6.01; 95% CI, 2.63 to 13.8; P < .001), and peer smoking (aOR, 2.49; 95% CI, 1.33 to 4.66; P = .0043) were each associated with decreased rates of cessation. Individuals exposed to smoking in all three settings had the lowest chances of quitting (aOR, 9.57; 95% CI, 2.50 to 36.64; P < .001). Results were similar in time-to-quitting analysis, in which 68% of patients who eventually quit did so within 6 months after cancer diagnosis. Subgroup analysis revealed similar associations across early- and late-stage patients and between sexes. CONCLUSION: SHS is an important factor associated with smoking cessation in lung cancer survivors of all stages and should be a key consideration when developing smoking cessation programs for patients with lung cancer.

Comorbidity and prognosis in head and neck cancers: Differences by subsite, stage, and human papillomavirus status.

BACKGROUND: The prognostic utility of comorbidity on head and neck cancer may differ by subsite, stage, and human papillomavirus (HPV) status. METHODS: We reviewed the medical records of 4953 patients with head and neck cancer for comorbidity (Charlson Comorbidity Index [CCI]), smoking, and alcohol history. Multivariate proportional hazards assessed the association of CCI with survival. HPV status was determined using p16 immunohistochemistry. RESULTS: After accounting for stage, higher CCI was associated with worse overall survival (OS) in nasopharyngeal (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.53-5.62), oropharyngeal (HR, 1.99; 95% CI, 1.63-2.43), and oral cavity cancers (HR, 1.54; 95% CI, 1.27-1.86). These associations were most prominent in the early stage oral cavity (HR, 2.11; 95% CI, 1.50-2.96) and laryngeal (HR, 1.87; 95% CI, 1.35-2.58) cancers, and in advanced stage oropharyngeal (HR, 2.23; 95% CI, 1.81-2.74) and nasopharyngeal (HR, 3.50; 95% CI, 1.76-6.97) cancers. CCI was independently prognostic even in the HPV-adjusted oropharyngeal cancers. CONCLUSION: Comorbidity was prognostic in subsets of nasopharyngeal, oropharyngeal, oral cavity, and laryngeal cancers. Comorbidity may be a partial surrogate for age and social habits.

The changing incidence of human papillomavirus-associated oropharyngeal cancer using multiple imputation from 2000 to 2010 at a Comprehensive Cancer Centre.

INTRODUCTION: Human papillomavirus (HPV) is a risk and prognostic factor for oropharyngeal cancer (OPC). Determining whether the incidence of HPV-associated OPC is rising informs health policy. METHODS: HPV status was ascribed using p16 immunohistochemistry in 683/1474 OPC patients identified from the Princess Margaret Hospital's Cancer Registry (from 2000 to 2010). Missing p16 data was estimated using multiple (n=100) imputation (MI) and validated using an independent OPC cohort (n=214). Non-OPC head and neck squamous cell carcinoma (HNSCC) (n=3262) were also used for time-trend comparison. Regression was used to compare HNSCC subsets and time-trends. The c-index was used to measure the predictive ability of MI. RESULTS: The incidence of OPC rose from 23.3% of all HNSCC in 2000 to 31.2% in 2010 (p=0.002). In the subset of OPC tested for p16, there was no change in p16 positivity over time (p=0.9). However, p16 testing became more frequent over time (p<0.0001), but was nonetheless biased, favouring never-smokers [OR 1.87 (95% CI 1.29-2.70)] and tumors of the tonsil [OR 2.30 (1.52-3.47)] or base-of-tongue [OR 1.72 (1.10-2.70)]. These same factors were also associated with p16-positivity [ORs 3.22 (1.27-8.16), 7.26 (3.50-15.1), 5.83 (2.70-12.7), respectively]. Following MI and normalization, the proportion of OPC that was p16-associated rose from 39.8% in 2000 to 65.0% in 2010, p=0.002, fully explaining the rise in OPC in our patient population. CONCLUSION: The rise in HNSCC referrals seen from 2000 to 2010 at our institution was driven primarily by p16-associated OPC. MI was necessary to derive reliable conclusions when cases with missing data are considerable.

Ubiquitin-specific protease 7 is a regulator of ubiquitin-conjugating enzyme UbE2E1.

Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme found in all eukaryotes that catalyzes the removal of ubiquitin from specific target proteins. Here, we report that UbE2E1, an E2 ubiquitin conjugation enzyme with a unique N-terminal extension, is a novel USP7-interacting protein. USP7 forms a complex with UbE2E1 in vitro and in vivo through the ASTS USP7 binding motif within its N-terminal extension in an identical manner with other known USP7 binding proteins. We show that USP7 attenuates UbE2E1-mediated ubiquitination, an effect that requires the N-terminal ASTS sequence of UbE2E1 as well as the catalytic activity of USP7. Additionally, USP7 is critical in maintaining the steady state levels of UbE2E1 in cells. This study reveals a new cellular mechanism that couples the opposing activities of the ubiquitination machinery and a deubiquitinating enzyme to maintain and modulate the dynamic balance of the ubiquitin-proteasome system.

Validation of a one-page patient-reported Charlson comorbidity index questionnaire for upper aerodigestive tract cancer patients.

OBJECTIVES: Cancer patients have a wide range of comorbidities that are important confounders for biomarker and clinical studies of prognosis and outcome. Comorbidities can be captured using the Charlson Comorbidity Index (CCI) through abstraction of medical records, but patient-reported outcome (PRO) questionnaires have also been used. The objective was to validate the PRO-CCI in a head and neck cancer (HNC) population, and to assess its level of agreement with the standard (std-CCI) method of chart review. METHODS: A one-page PRO-CCI was compared with the std-CCI obtained through independent abstraction in 882 HNC patients (2007-2010). Kappa statistics and associated measures (p(pos) and p(neg)) were used to assess agreement. Discrepancy for each comorbid illness was evaluated. Proportional hazard models compared the association of std-CCI and PRO-CCI with overall survival (OS). Adjustments were made and a modified PRO-CCI was re-evaluated in a new cohort of upper aerodigestive tract cancers patient. RESULTS: PRO-CCI was higher than the std-CCI (p < 0.0001). After adjustment, having at least two comorbidities according to either the std-CCI [HR 1.97 (1.38-2.80)] or the PRO-CCI [HR 1.62 (1.18-2.24)] was prognostic. Of the most prevalent comorbidities, agreement was high for most of the CCI elements (kappa 0.76-0.93), but poorest agreement for connective tissue disease (kappa = 0.29, p(pos) = 43%, p(neg) = 84%) and COPD (kappa = 0.48, p(pos) = 53%, p(neg) = 95%). When the connective tissue disease question was modified, agreement of this item improved (kappa = 0.47, p(pos) = 50%). CONCLUSION: PRO-CCI can be an easy and effective tool in prognostic and outcomes research in HNC patients.

Further insight into substrate recognition by USP7: structural and biochemical analysis of the HdmX and Hdm2 interactions with USP7.

Ubiquitin-specific protease 7 (USP7) catalyzes the deubiquitination of several substrate proteins including p53 and Hdm2. We have previously shown that USP7, and more specifically its amino-terminal domain (USP7-NTD), interacts with distinct regions on p53 and Hdm2 containing P/AxxS motifs. The ability of USP7 to also deubiquitinate and control the turnover of HdmX was recently demonstrated. We utilized a combination of biochemistry and structural biology to identify which domain of USP7 interacts with HdmX as well as to identify regions of HdmX that interact with USP7. We showed that USP7-NTD recognized two of six P/AxxS motifs of HdmX ((8)AQCS(11) and (398)AHSS(401)). The crystal structure of the USP7-NTD:HdmX(AHSS) complex was determined providing the molecular basis of complex formation between USP7-NTD and the HdmX(AHSS) peptide. The HdmX peptide interacted within the same residues of USP7-NTD as previously demonstrated with p53, Hdm2, and EBNA1 peptides. We also identified an additional site on Hdm2 ((397)PSTS(400)) that interacts with USP7-NTD and determined the crystal structure of this complex. Finally, analysis of USP7-interacting peptides on filter arrays confirmed the importance of the serine residue at the fourth position for the USP7-NTD interaction and showed that phosphorylation of serines within the binding sequence prevents this interaction. These results lead to a better understanding of the mechanism of substrate recognition by USP7-NTD.