Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer.

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.

Immediate and delayed risk of breast cancer associated with classic lobular carcinoma in situ and its variants.

OBJECTIVE: To determine the risk of breast cancer due to lobular carcinoma in situ (LCIS). METHODS: This retrospective IRB-approved study identified cases of LCIS after percutaneous breast biopsy from 7/2005 to 7/2022. Excluded were cases with less than 2 years of imaging surveillance or a concurrent ipsilateral breast cancer diagnosis within 6 months of the LCIS diagnosis. Final outcomes of cancer versus no cancer were determined by pathology at surgical excision or the absence of cancer on imaging surveillance. RESULTS: A total of 116 LCIS lesions were identified. The primary imaging findings targeted for percutaneous biopsy included calcifications (50.0%, 58/116), MR enhancing lesions (25.0%, 29/116), noncalcified mammographic architectural distortions (10.3%, 12/116), or masses (14.7%, 17/116). Surgical excision was performed in 49.1% (57/116) and imaging surveillance was performed in 50.9% (59/116) of LCIS cases. There were 22 cancers of which 11 cancers were discovered at immediate excision [19.3% (11/57) immediate upgrade] and 11 cancers developed later while on imaging surveillance [18.6% (11/59) delayed risk for cancer]. Among all 22 cancers, 63.6% (14/22) occurred at the site of LCIS (11 at immediate excision and 3 at surveillance) and 36.4% (8/22) occurred at a location away from the site of LCIS (6 in a different quadrant and 2 in the contralateral breast). CONCLUSION: LCIS has both an immediate risk (19.3%) and a delayed risk (18.6%) for cancer with 90.9% occurring in the ipsilateral breast (63.6% at and 27.3% away from the site of LCIS) and 9.1% occurring in the contralateral breast.

Measuring waning protection from seasonal influenza vaccination during nine influenza seasons, Ontario, Canada, 2010/11 to 2018/19.

BackgroundWaning immunity from seasonal influenza vaccination can cause suboptimal protection during peak influenza activity. However, vaccine effectiveness studies assessing waning immunity using vaccinated and unvaccinated individuals are subject to biases.AimWe examined the association between time since vaccination and laboratory-confirmed influenza to assess the change in influenza vaccine protection over time.MethodsUsing linked laboratory and health administrative databases in Ontario, Canada, we identified community-dwelling individuals aged ≥ 6 months who received an influenza vaccine before being tested for influenza by RT-PCR during the 2010/11 to 2018/19 influenza seasons. We estimated the adjusted odds ratio (aOR) for laboratory-confirmed influenza by time since vaccination (categorised into intervals) and for every 28 days.ResultsThere were 53,065 individuals who were vaccinated before testing for influenza, with 10,264 (19%) influenza-positive cases. The odds of influenza increased from 1.05 (95% CI: 0.91-1.22) at 42-69 days after vaccination and peaked at 1.27 (95% CI: 1.04-1.55) at 126-153 days when compared with the reference interval (14-41 days). This corresponded to 1.09-times increased odds of influenza every 28 days (aOR = 1.09; 95% CI: 1.04-1.15). Individuals aged 18-64 years showed the greatest decline in protection against influenza A(H1N1) (aORper 28 days = 1.26; 95% CI: 0.97-1.64), whereas for individuals aged ≥ 65 years, it was against influenza A(H3N2) (aORper 28 days = 1.20; 95% CI: 1.08-1.33). We did not observe evidence of waning vaccine protection for individuals aged < 18 years.ConclusionsInfluenza vaccine protection wanes during an influenza season. Understanding the optimal timing of vaccination could ensure robust protection during seasonal influenza activity.

Frem1 activity is regulated by Sonic hedgehog signaling in the cranial neural crest mesenchyme during midfacial morphogenesis.

BACKGROUND: Frem1 has been linked to human face shape variation, dysmorphology, and malformation, but little is known about its regulation and biological role in facial development. RESULTS: During midfacial morphogenesis in mice, we observed Frem1 expression in the embryonic growth centers that form the median upper lip, nose, and palate. Expansive spatial gradients of Frem1 expression in the cranial neural crest cell (cNCC) mesenchyme of these tissues suggested transcriptional regulation by a secreted morphogen. Accordingly, Frem1 expression paralleled that of the conserved Sonic Hedgehog (Shh) target gene Gli1 in the cNCC mesenchyme. Suggesting direct transcriptional regulation by Shh signaling, we found that Frem1 expression is induced by SHH ligand stimulation or downstream pathway activation in cNCCs and observed GLI transcription factor binding at the Frem1 transcriptional start site during midfacial morphogenesis. Finally, we found that FREM1 is sufficient to induce cNCC proliferation in a concentration-dependent manner and that Shh pathway antagonism reduces Frem1 expression during pathogenesis of midfacial hypoplasia. CONCLUSIONS: By demonstrating that the Shh signaling pathway regulates Frem1 expression in cNCCs, these findings provide novel insight into the mechanisms underlying variation in midfacial morphogenesis.

Effectiveness of maternal influenza vaccination during pregnancy against laboratory-confirmed seasonal influenza among infants under 6 months of age in Ontario, Canada.

BACKGROUND: Randomized trials conducted in low- and middle-income settings demonstrated efficacy of influenza vaccination during pregnancy against influenza infection among infants <6 months of age. However, vaccine effectiveness (VE) estimates from settings with different population characteristics and influenza seasonality remain limited. METHODS: We conducted a test-negative study in Ontario, Canada. All influenza virus tests among infants <6 months from 2010-2019 were identified and linked with health databases to ascertain information on maternal-infant dyads. VE was estimated from the odds ratio for influenza vaccination during pregnancy among cases versus controls, computed using logistic regression with adjustment for potential confounders. RESULTS: Among 23,806 infants tested for influenza, 1,783 (7.5%) were positive and 1,708 (7.2%) were born to mothers vaccinated against influenza during pregnancy. VE against laboratory-confirmed infant influenza infection was 64% (95% confidence interval [CI]: 50%-74%). VE was similar by trimester of vaccination (1st/2nd: 66%, 40%-80%; 3rd: 63%, 46%-74%), infant age at testing (0-<2 months: 63%, 46%-75%; 2-<6 months: 64%, 36%-79%), and gestational age at birth (≥37 weeks: 64%, 50%-75%; < 37 weeks: 61%, 4%-86%). VE against influenza hospitalization was 67% (95%CI: 50%-78%). CONCLUSIONS: Influenza vaccination during pregnancy offers effective protection to infants <6 months, for whom vaccines are not currently available.

Evaluating the Impact of Statin Use on Influenza Vaccine Effectiveness and Influenza Infection in Older Adults.

BACKGROUND: Older adults are recommended to receive influenza vaccination annually, and many use statins. Statins have immunomodulatory properties that might modify influenza vaccine effectiveness (VE) and alter influenza infection risk. METHODS: Using the test-negative design and linked laboratory and health administrative databases in Ontario, Canada, we estimated VE against laboratory-confirmed influenza among community-dwelling statin users and nonusers aged ≥66 years during the 2010-2011 to 2018-2019 influenza seasons. We also estimated the odds ratio for influenza infection comparing statin users and nonusers by vaccination status. RESULTS: Among persons tested for influenza across the 9 seasons, 54 243 had continuous statin exposure before testing and 48 469 were deemed unexposed. The VE against laboratory-confirmed influenza was similar between statin users and nonusers (17% [95% confidence interval, 13%-20%] and 17% [13%-21%] respectively; test for interaction, P = .87). In both vaccinated and unvaccinated persons, statin users had higher odds of laboratory-confirmed influenza than nonusers (odds ratios for vaccinated and unvaccinated persons 1.15 [95% confidence interval, 1.10-1.21] and 1.15 [1.10-1.20], respectively). These findings were consistent by mean daily dose and statin type. VE did not differ between users and nonusers of other cardiovascular drugs, except for ß-blockers. We did not observe that vaccinated and unvaccinated users of these drugs had increased odds of influenza, except for unvaccinated ß-blocker users. CONCLUSIONS: Influenza VE did not differ between statin users and nonusers. Statin use was associated with increased odds of laboratory-confirmed influenza in vaccinated and unvaccinated persons, but these associations might be affected by residual confounding.

Self-harm among youth during the first 28 months of the COVID-19 pandemic in Ontario, Canada: a population-based study.

BACKGROUND: Youth have reported worsening mental health during the COVID-19 pandemic. We sought to evaluate rates of pediatric acute care visits for self-harm during the pandemic according to age, sex and mental health service use. METHODS: We conducted a population-based, repeated cross-sectional study using linked health administrative data sets to measure monthly rates of emergency department visits and hospital admissions for self-harm among youth aged 10-17 years between Jan. 1, 2017, and June 30, 2022, in Ontario, Canada. We modelled expected rates of acute care visits for self-harm after the pandemic onset based on prepandemic rates. We reported relative differences between observed and expected monthly rates overall and by age group (10-13 yr and 14-17 yr), sex and mental health service use (new and continuing). RESULTS: In this population of about 1.3 million children and adolescents, rates of acute care visits for self-harm during the pandemic were higher than expected for emergency department visits (0.27/1000 population v. 0.21/1000 population; adjusted rate ratio [RR] 1.29, 95% confidence interval [CI] 1.19-1.39) and hospital admissions (0.74/10 000 population v. 0.43/10 000 population, adjusted RR 1.72, 95% CI 1.46-2.03). This increase was primarily observed among females. Rates of emergency department visits and hospital admissions for self-harm were higher than expected for both those aged 10-13 years and those aged 14-17 years, as well as for both those new to the mental health system and those already engaged in care. INTERPRETATION: Rates of acute care visits for self-harm among children and adolescents were higher than expected during the first 2 and a half years of the COVID-19 pandemic, particularly among females. These findings support the need for accessible and intensive prevention efforts and mental health supports in this population.

Amenable deaths among adults with intellectual and developmental disabilities including Down syndrome: An Ontario population-based cohort study.

BACKGROUND: Rates of death and avoidable deaths are reportedly higher among people with intellectual and developmental disabilities. This study contributes to our understanding of how mortality and intellectual and development disabilities are associated. METHOD: General population and intellectual and developmental disabilities adult cohorts were defined using linked administrative data. All-cause and amenable deaths between 2010 and 2015 were reported for these cohorts and subcohorts with and without Down syndrome. Cox proportional hazards models evaluated the impact of potential contributors to amenable deaths. RESULTS: Adults with intellectual and developmental disabilities had higher all-cause (6.1 vs. 1.6%) and amenable death percentages (21.4 vs. 14.1%) than general population comparators. Within intellectual and developmental disabilities, those with Down syndrome had higher all-cause (12.0 vs. 6.0%) but lower amenable death percentages (19.2 vs. 21.8%) than those without. CONCLUSIONS: Results suggest that interventions to reduce amenable deaths target provider-care-recipient interactions and coordination across care and support sectors.

Increased medical student understanding of dementia through virtual embodiment.

Given the growing prevalence of Alzheimer's disease (AD), we assessed the impact of virtually embodying someone with progressive AD. This pilot explored students' understanding of individuals' needs with dementia, as well as, the efficacy of virtual reality (VR) as a curricular tool. Second-year medical students (n = 150) completed a pre-survey, Embodied Labs, Inc. Beatriz Lab VR module, and a post-survey. Most students knew someone with dementia (72%), were a family member of someone with dementia (52%) or had worked with a patient (61%) with dementia. Using paired survey questions, students reported significant increases in understanding how their lives would be affected by dementia (71% vs. 94%) and the needs of a person with dementia (64% vs. 95%) after VR. They reported increased understanding of being a caregiver of someone with dementia (24% vs. 81%) and the impact it can have on the entire family (64% vs. 97%). Overall students agreed this simulation made them think about their approach to clinical skills (94%) and should be utilized more in the curriculum (76%). This pilot study indicated that this VR experience can be used to advance understanding of a person's experiences with dementia and that integrating VR into the medical curricula should be considered.

Bioinformatic Expansion of Borosins Uncovers Trans-Acting Peptide Backbone N-Methyltransferases in Bacteria.

Backbone N-methylation is one of the prominent peptide modifications that can greatly enhance the pharmacological properties of a peptide. Naturally occurring backbone N-methylated peptides are produced via nonribosomal or ribosomal pathways, the latter of which was only recently identified in the borosin family of ribosomally synthesized and post-translationally modified peptides. Although previous bioinformatic analyses have revealed new putative genes for borosin biosynthesis, the natural scope of structural and biosynthetic diversity of the borosin family has not been thoroughly explored. Here, we report a comprehensive overview of the borosin family of peptide natural products. Using a genome mining approach, we identified more than 1400 new putative biosynthetic gene clusters for borosins and demonstrated that, unlike those previously reported, most of them are found in bacterial genomes and encode a precursor peptide unfused to its cognate methyltransferase enzyme. Biochemical analysis confirmed the backbone N-methylation of the precursor peptide in trans in eight enzyme-precursor pairs and revealed two novel types of enzyme-recognizing sequences in the precursor peptide. This work significantly expands the biosynthetic diversity of borosins and paves the way for the enzymatic production of diverse backbone N-methylated peptides.

Diagnosis of Chronic Hepatitis B Pericomplication: Risk factors and Trends Over Time.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) is a major cause of chronic liver disease, which can progress to cirrhosis, hepatocellular carcinoma, and death. A timely diagnosis allows for antiviral treatment, which can prevent liver-related complications. Conversely, a late diagnosis signals a missed opportunity for earlier care and treatment. Our objective was to measure the proportion of chronic HBV diagnoses that are made within 6 months of presentation with a liver disease-related complication and examine associated factors and trends over time. APPROACH AND RESULTS: We used provincial laboratory data to identify patients with chronic HBV diagnosed from 2003 to 2014. We measured the proportion who experienced a liver disease complication (decompensated cirrhosis, hepatocellular carcinoma, or liver transplant) within ±6 months of their HBV diagnosis date. A multivariable logistic regression model was used to identify factors associated with HBV diagnosis pericomplication. Of 18,434 patients with chronic HBV, 1,279 (6.9%) developed an HBV-related complication during the follow-up period. Among these, 570 (44.6%) had a first diagnosis pericomplication. HBV diagnosis pericomplication did not decrease over time and was independently associated with older age at HBV diagnosis, rural residence, alcohol use, and moderate to high levels of comorbidity. Female patients, immigrants, and those with more outpatient physician visits were less likely to have an HBV diagnosis pericomplication. CONCLUSIONS: A high proportion of patients with HBV-related complications are first diagnosed with HBV pericomplication. These signal missed opportunities for earlier detection and treatment. Our findings support expansion of HBV screening.

Axillary Nodal Metastases in Invasive Lobular Carcinoma Versus Invasive Ductal Carcinoma: Comparison of Node Detection and Morphology by Ultrasound.

BACKGROUND. Invasive lobular carcinoma is more subtle on imaging compared with invasive ductal carcinoma; nodal metastases may also differ on imaging between these two. OBJECTIVE. The purpose of this study was to determine whether invasive lobular carcinoma and invasive ductal carcinoma differ in the detection rate by ultrasound (US) of metastatic axillary nodes and in the metastatic nodes' US characteristics. METHODS. This retrospective study included 695 women (median age, 53 years) who had breast cancer in a total of 723 breasts (76 lobular, 586 ductal, 61 mixed ductal and lobular histology) with biopsy-proven axillary nodal metastases and who underwent pretreatment US. A single breast radiologist reviewed US images in patients with suspicious nodes on US and classified number of nodes, size, and morphology. Morphologic assessment used a previously described classification according to the relationship between node cortex and hilum. Nodal findings were compared between lobular and ductal carcinoma. A second radiologist independently classified node morphology in 241 cancers to assess interreader agreement. RESULTS. A total of 99 metastatic axillary nodes (15 lobular, 66 ductal, 18 mixed histology) were not visualized on US and were diagnosed by surgical biopsy. The remaining 624 metastatic nodes (61 lobular, 520 ductal, 43 mixed ductal and lobular histology) were visualized on US and diagnosed by US-guided fine-needle aspiration. US detected the metastatic nodes in 80.3% for lobular carcinoma versus 88.7% for ductal carcinoma (p = .04). Among metastatic nodes detected by US, retrospective review identified three or more abnormal nodes in 50.8% of lobular carcinoma versus 69.2% of ductal carcinoma (p = .003); node size was 2.0 cm or smaller in 65.6% for lobular carcinoma versus 47.3% for ductal carcinoma (p = .03); morphology was type III or IV (diffuse cortical thickening without hilar mass effect) rather than type V or VI (marked cortical thickening with hilar mass effect) in 68.9% for lobular carcinoma versus 28.8% for ductal carcinoma (p < .001). Interreader agreement assessment for morphology exhibited a kappa coefficient of 0.63 (95% CI, 0.54-0.73). CONCLUSION. US detects a lower percentage of nodal metastases in lobular than in ductal carcinoma. Nodal metastases in lobular carcinoma more commonly show diffuse cortical thickening and with less hilar mass effect. CLINICAL IMPACT. A lower threshold may be warranted to recommend biopsy of suspicious axillary nodes detected on US in patients with lobular carcinoma.

Influenza Vaccine Effectiveness Against All-Cause Mortality Following Laboratory-Confirmed Influenza in Older Adults, 2010-2011 to 2015-2016 Seasons in Ontario, Canada.

BACKGROUND: Older adults are at increased risk of mortality from influenza infections. We estimated influenza vaccine effectiveness (VE) against mortality following laboratory-confirmed influenza. METHODS: Using a test-negative design study and linked laboratory and health administrative databases in Ontario, Canada, we estimated VE against all-cause mortality following laboratory-confirmed influenza for community-dwelling adults aged >65 years during the 2010-2011 to 2015-2016 influenza seasons. RESULTS: Among 54 116 older adults tested for influenza across the 6 seasons, 6837 died within 30 days of specimen collection. Thirteen percent (925 individuals) tested positive for influenza, and 50.6% were considered vaccinated for that season. Only 23.2% of influenza test-positive cases had influenza recorded as their underlying cause of death. Before and after multivariable adjustment, we estimated VE against all-cause mortality following laboratory-confirmed influenza to be 20% (95% confidence interval [CI], 8%-30%) and 20% (95% CI, 7%-30%), respectively. This estimate increased to 34% after correcting for influenza vaccination exposure misclassification. We observed significant VE against deaths following influenza confirmation during 2014-2015 (VE = 26% [95% CI, 5%-42%]). We also observed significant VE against deaths following confirmation of influenza A/H1N1 and A/H3N2, and against deaths with COPD as the underlying cause. CONCLUSIONS: These results support the importance of influenza vaccination in older adults, who account for most influenza-associated deaths annually.

The first BGICC consensus and recommendations for breast cancer awareness, early detection and risk reduction in low- and middle-income countries and the MENA region.

In low-middle income countries (LMICs) and the Middle East and North Africa (MENA) region, there is an unmet need to establish and improve breast cancer (BC) awareness, early diagnosis and risk reduction programs. During the 12th Breast, Gynecological & Immuno-oncology International Cancer Conference - Egypt 2020, 26 experts from 7 countries worldwide voted to establish the first consensus for BC awareness, early detection and risk reduction in LMICs/MENA region. The panel advised that there is an extreme necessity for a well-developed BC data registries and prospective clinical studies that address alternative modalities/modified BC screening programs in areas of limited resources. The most important recommendations of the panel were: (a) BC awareness campaigns should be promoted to public and all adult age groups; (b) early detection programs should combine geographically distributed mammographic facilities with clinical breast examination (CBE); (c) breast awareness should be encouraged; and (d) intensive surveillance and chemoprevention strategies should be fostered for high-risk women. The panel defined some areas for future clinical research, which included the role of CBE and breast self-examination as an alternative to radiological screening in areas of limited resources, the interval and methodology of BC surveillance in women with increased risk of BC and the use of low dose tamoxifen in BC risk reduction. In LMICs/MENA region, BC awareness and early detection campaigns should take into consideration the specific disease criteria and the socioeconomic status of the target population. The statements with no consensus reached should serve as potential catalyst for future clinical research.

Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection.

BACKGROUND: Acute myocardial infarction can be triggered by acute respiratory infections. Previous studies have suggested an association between influenza and acute myocardial infarction, but those studies used nonspecific measures of influenza infection or study designs that were susceptible to bias. We evaluated the association between laboratory-confirmed influenza infection and acute myocardial infarction. METHODS: We used the self-controlled case-series design to evaluate the association between laboratory-confirmed influenza infection and hospitalization for acute myocardial infarction. We used various high-specificity laboratory methods to confirm influenza infection in respiratory specimens, and we ascertained hospitalization for acute myocardial infarction from administrative data. We defined the "risk interval" as the first 7 days after respiratory specimen collection and the "control interval" as 1 year before and 1 year after the risk interval. RESULTS: We identified 364 hospitalizations for acute myocardial infarction that occurred within 1 year before and 1 year after a positive test result for influenza. Of these, 20 (20.0 admissions per week) occurred during the risk interval and 344 (3.3 admissions per week) occurred during the control interval. The incidence ratio of an admission for acute myocardial infarction during the risk interval as compared with the control interval was 6.05 (95% confidence interval [CI], 3.86 to 9.50). No increased incidence was observed after day 7. Incidence ratios for acute myocardial infarction within 7 days after detection of influenza B, influenza A, respiratory syncytial virus, and other viruses were 10.11 (95% CI, 4.37 to 23.38), 5.17 (95% CI, 3.02 to 8.84), 3.51 (95% CI, 1.11 to 11.12), and 2.77 (95% CI, 1.23 to 6.24), respectively. CONCLUSIONS: We found a significant association between respiratory infections, especially influenza, and acute myocardial infarction. (Funded by the Canadian Institutes of Health Research and others.).

Looking across health and healthcare outcomes for people with intellectual and developmental disabilities and psychiatric disorders: population-based longitudinal study.

BACKGROUND: Intellectual and developmental disabilities (IDDs) and psychiatric disorders frequently co-occur. Although each has been associated with negative outcomes, their combined effect has rarely been studied. AIMS: To examine the likelihood of five negative health and healthcare outcomes for adults with IDD and mental health/addiction disorders (MHAs), both separately and together. For each outcome, demographic, clinical and system-level factors were also examined. METHOD: Linked administrative data-sets were used to identify adults in Ontario, Canada, with IDD and MHA (n = 29 476), IDD-only (n = 35 223) and MHA-only (n = 727 591). Five outcomes (30-day readmission, 30-day repeat ED visit, delayed discharge, long-term care admission and premature mortality) were examined by logistic regression models with generalised estimating equation or survival analyses. For each outcome, crude (disorder groups only) and complete (adding biosocial covariates) models were run using a general population reference group. RESULTS: The IDD and MHA group had the highest proportions across outcomes for both crude and complete models. They had the highest adjusted ratios for readmissions (aOR 1.93, 95%CI 1.88-1.99), repeat ED visit (aOR 2.00, 95%CI 1.98-2.02) and long-term care admission (aHR 12.19, 95%CI 10.84-13.71). For delayed discharge, the IDD and MHA and IDD-only groups had similar results (aOR 2.00 (95%CI 1.90-2.11) and 2.21 (95%CI 2.07-2.36). For premature mortality, the adjusted ratios were similar for all groups. CONCLUSIONS: Poorer outcomes for adults with IDD, particularly those with MHA, suggest a need for a comprehensive, system-wide approach spanning health, disability and social support.

Peri-complication diagnosis of hepatitis C infection: Risk factors and trends over time.

BACKGROUND & AIMS: Hepatitis C virus (HCV) is a common and treatable cause of cirrhosis and its complications, yet many chronically infected individuals remain undiagnosed until a late stage. We sought to identify the frequency of and risk factors for HCV diagnosis peri-complication, that is within six months of an advanced liver disease complication. METHODS: This was a retrospective cohort study of Ontario residents diagnosed with chronic HCV infection between 2003 and 2014. HCV diagnosis peri-complication was defined as the occurrence of decompensated cirrhosis, hepatocellular carcinoma or liver transplant within ±6 months of HCV diagnosis. Multivariable logistic regression was used to identify risk factors for peri-complication diagnosis among all those diagnosed with HCV infection. RESULTS: Our cohort included 39,515 patients with chronic HCV infection, of whom 4.2% (n = 1645) were diagnosed peri-complication; these represented 31.6% of the 5,202 patients who developed complications in the follow-up period. Peri-complication diagnosis became more common over the study period and was associated with increasing age among baby boomers, alcohol use, diabetes mellitus, chronic HBV co-infection and moderate to high levels of morbidity. Female sex, immigrant status, having more previous outpatient physician visits, a previous emergency department visit, a history of drug use or mental health visits were associated with reduced risk of peri-complication diagnosis. CONCLUSIONS: Over a quarter of HCV-infected patients with complications were diagnosed peri-complication. This problem increased over time, suggesting a need to further expand HCV screening.

Breast Cancer Skip Metastases: Frequency, Associated Tumor Characteristics, and Role of Staging Nodal Ultrasound in Detection.

BACKGROUND. Staging nodal ultrasound (US) evaluates locations beyond those assessed during routine surgical dissection and has an increasing role in breast cancer management given the growing use of neoadjuvant systemic therapy before surgical staging. OBJECTIVE. The purpose of this study is to identify the patterns of nodal spread of breast cancer observed at staging nodal US and to determine the frequency of skip metastases and associated tumor characteristics. METHODS. This retrospective study included 1269 consecutive patients (31 with bilateral synchronous cancers) who had 1300 newly diagnosed, untreated, invasive breast cancers and underwent US examination of the ipsilateral regional nodal basins from January 2016 through March 2017. Cases with suspicious nodes on US underwent fine-needle aspiration (FNA) biopsy. Cases with benign results on FNA and no suspicious nodes on US underwent sentinel lymph node biopsy. Results of US with FNA were compared with final surgical pathology. Skip metastases were defined as spread across discontiguous nodal levels or distant metastases in the absence of ipsilateral nodal metastases. The incidence and patterns of spread of skip metastases were summarized; associations with tumor characteristics were tested using the Fisher exact test. RESULTS. A total of 591 metastatic cases (45.5%) were confirmed by needle biopsy or sentinel lymph node biopsy, comprising 463 nodal metastases (N+) confirmed by FNA, 121 nodal metastases (N+) confirmed by sentinel lymph node biopsy, and seven distant organ metastases without nodal metastases (N0M1) confirmed by CT-guided biopsy. US with FNA had sensitivity of 86.0%, specificity of 100.0%, PPV of 100.0%, NPV of 89.5%, and accuracy of 93.6%. There were 34 skip metastases, for an incidence of 2.6% (34/1300) (95% CI, 1.8-3.6%) among all invasive cancers and 7.2% (34/470) (95% CI, 5.1-9.9%) among metastatic cancers detected by US and FNA. Skip metastases occurred to axillary level III (n = 4), the supraclavicular nodal basin (n = 21), the contralateral axilla (n = 2), and distant organs (n = 7). Cancers with skip metastases, compared with those with nonskip metastases, had higher rates (p = .005) of lobular histology (23.5% vs 6.7%) and mixed ductal and lobular histology (11.8% vs 6.7%). Skip metastases were not associated with grade, T category, or molecular subtype (p > .05). CONCLUSION. Skip metastases to locations beyond standard surgical axillary dissection occur in 7.2% of metastatic breast cancers. CLINICAL IMPACT. Staging nodal US identifies skip metastases that otherwise would be undetected, helping to achieve more accurate staging and minimize undertreatment.

Imaging Updates to Breast Cancer Lymph Node Management.

Metastatic lymph node involvement in breast cancer is a key determinant of the overall stage of disease and prognosis. Historically, lymph node status was determined by surgery first, with adjuvant treatments determined based on the results of the final surgical pathologic analysis. While this sequence is still applicable in many cases, neoadjuvant systemic treatment (NST) is increasingly being administered as the initial treatment. In cases that demonstrate good therapeutic response to drug therapies, NST may permit the option to perform less radical surgeries subsequently. Current breast cancer treatment has become multidisciplinary, with overlapping roles from the different disciplines. As surgery may be postponed, imaging and image-guided lymph node interventions have gained importance as the primary means of lymph node assessment. Imaging enables evaluation of all regional nodal basins, including locations where surgery is not usually performed. By differentiating limited versus extensive nodal involvement, imaging findings help determine whether initial treatment should be surgical or medical. If medical treatment with NST is indicated, imaging is performed to monitor the in vivo nodal response to drug therapy and ultimately to help determine the surgical technique to perform on the basis of the final imaging findings after NST. The authors discuss the imaging features of nodal metastases and the indications and techniques for the various image-guided procedures. The relative usefulness and shortcomings of the various imaging examinations are reviewed to discuss how they can be applied when biopsy results are not available. The role of imaging in the multidisciplinary team approach is emphasized based on past clinical trials of lymph node management and recent evolving knowledge of breast cancer staging. Online supplemental material is available for this article. ©RSNA, 2021.

Traumatic Brain Injury Incidence in Adults with Intellectual and Developmental Disabilities.

BACKGROUND: In Ontario, there are approximately 66,000 adults living with a diagnosis of intellectual and developmental disabilities (IDD). These individuals are nearly twice as likely to experience an injury compared to the general population. Falls are an important contributor to injuries in persons with IDD and in the general population, and are consistently found to be the leading cause of traumatic brain injury (TBI). There is currently no literature that quantitatively examines TBI among persons with IDD. The purpose of this study was to compare the risk of TBI for adults with and without IDD in Ontario over time and by demographic information. METHODS: Using administrative health databases, two main cohorts were identified: (1) adults with IDD, and (2) a random 10% sample of adults without IDD. Within each cohort, annual crude and adjusted incidence of TBI were calculated among unique individuals for each fiscal year from April 1, 2002 to March 31, 2017. RESULTS: Over the 15-year study period, the average annual adjusted incidence of TBI was approximately 2.8 new cases per 1000 among Ontario adults with IDD, compared to approximately 1.53 per 1000 among those without IDD. In both cohorts, a higher proportion of TBI cases were younger (19-29 years) and male. CONCLUSIONS: During the study period, persons with IDD experienced a significantly higher risk of TBI compared to the general population indicating the possibility, and need, for targeted TBI prevention.