Proteomic Profiles of Human Arterioles Isolated From Fresh Adipose Tissue or Following Overnight Storage.

Arterioles are key determinants of the total peripheral vascular resistance, which, in turn, is a key determinant of arterial blood pressure. However, the amount of protein available from one isolated human arteriole may be less than 5 µg, making proteomic analysis challenging. In addition, obtaining human arterioles requires manual dissection of unfrozen clinical specimens. This limits its feasibility, especially for powerful multicenter clinical studies in which clinical specimens need to be shipped overnight to a research laboratory for arteriole isolation. We performed a study to address low-input, test overnight tissue storage and develop a reference human arteriolar proteomic profile. In tandem mass tag proteomics, use of a booster channel consisting of human induced pluripotent stem cell-derived endothelial and vascular smooth muscle cells (1:5 ratio) increased the number of proteins detected in a human arteriole segment with a false discovery rate of <0.01 from 1051 to more than 3000. The correlation coefficient of proteomic profile was similar between replicate arterioles isolated freshly, following cold storage, or before and after the cold storage (1-way analysis of variance; P = .60). We built a human arteriolar proteomic profile consisting of 3832 proteins based on the analysis of 12 arteriole samples from 3 subjects. Of 1945 blood pressure-relevant proteins that we curated, 476 (12.5%) were detected in the arteriolar proteome, which was a significant overrepresentation (χ2 test; P < .05). These findings demonstrate that proteomic analysis is feasible with arterioles isolated from human adipose tissue following cold overnight storage and provide a reference human arteriolar proteome profile highly valuable for studies of arteriole-related traits.

Raoultella planticola Urinary Tract Infection Presenting as Hyperbilirubinemia in a 3-Day-Old Infant.

Raoultella planticola is a Gram-negative, aerobic, nonmotile bacterium that is ubiquitous in the environment usually implicated in opportunistic infections. There have been very few reported cases of Raoultella planticola infection in the pediatric population. Most of these reports have been in cases of neonatal septicemia. This case report describes a case of a 3-day-old Hispanic full-term male that presented with recalcitrant hyperbilirubinemia despite maximal phototherapy found to have urinary tract infection with Raoultella planticola on multiple cultures. The patient's hyperbilirubinemia appropriately responded to treatment of the UTI. This report highlights that, albeit rare, neonatal UTI can present as recalcitrant hyperbilirubinemia. Raoultella planticola is a rare organism that is normally found in the environment but may be a bona fide etiologic agent in neonatal UTI.

Right Ventricular Free Wall Strain and Effect of Defibrillator Implantation in Patients With Nonischemic Systolic Heart Failure.

BACKGROUND: Patients with nonischemic systolic heart failure have an increased risk of malignant ventricular arrhythmias and sudden cardiovascular death. Because the risk is less pronounced than for patients with ischemic cause of heart failure more discriminating tools are needed to identify patients most likely to benefit from implantable cardioverter-defibrillator (ICD) implantation. Right ventricular (RV) dysfunction is associated with a worse prognosis, but whether RV free wall strain (RV-FWS) measured with echocardiography can identify the patients most likely to benefit from ICD implantation is not known. METHODS AND RESULTS: In this extended follow-up analysis of the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial, RV-FWS was measured with echocardiography in 445 patients before randomization. RV dysfunction was defined as an RV-FWS of greater than -20%. The primary end point was all-cause mortality. The median RV-FWS was -18% (quartiles -23% to -14%), and RV dysfunction was measured in 255 patients (57%). During a median follow-up of 5.7 years, 170 patients (38%) died. There was a statistically significant interaction between RV dysfunction and the effect of ICD implantation (P = .003), also after adjusting for known cardiovascular risk factors (P = .01). ICD implantation significantly decreased all-cause mortality in patients with RV dysfunction (hazard ratio 0.54, 95% confidence interval 0.36-0.80, P = .002), but not in patients with normal RV function (hazard ratio 1.34, 95% confidence interval 0.84-2.12, P = .22). CONCLUSIONS: In patients with nonischemic systolic heart failure, RV dysfunction on echocardiography was associated with a greater effect of ICD implantation and could be used to select patients with benefit from ICD treatment.

Atypical fibroxanthoma and pleomorphic dermal sarcoma: Local recurrence and metastasis in a nationwide population-based cohort of 1118 patients.

BACKGROUND: The prognosis of patients with atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) remains uncertain and no standardized follow-up programs have been established. OBJECTIVE: To recommend a standardized follow-up program of patients with AFX and PDS based on nationwide long-term estimates of local recurrence and metastasis. METHODS: All patients with AFX and PDS in Denmark between 2002 and 2022 were included. Danish National Registries were used to estimate the risks of local recurrence and metastasis for AFX and PDS. RESULTS: The 5-year risk of local recurrence was 10% for AFX and 17% for PDS. The 5-year risk of metastasis was 0.8% for AFX and 16% for PDS. PDS metastasized within 3 years in >90% of the patients with the lungs as the primary metastasis site (50%). Invasion beyond the subcutis, perineural/intravascular infiltration, and increasing age significantly increased the risk of PDS relapse. LIMITATIONS: Risk of misclassification and lack of detailed surgical information. CONCLUSION: The follow-up of patients with AFX can be limited to clinical visits for 4 years. Patients with PDS should be followed with clinical visits and PET/CT twice a year for the first 3 years and once a year for a minimum of 1 year.

Endotoxin content in neonatal formulas, fortification, and lactoferrin products: association with outcomes and guidance on acceptable limits.

While endotoxin (lipopolysaccharide) can be harmful and contribute to morbidity and mortality with Gram-negative sepsis or necrotizing enterocolitis in preterm infants, non-toxic amounts are produced as part of the neonatal microbiome and may be present in enteral nutrition and medications administered. The United States Food and Drug Administration has given guidance for endotoxin concentration limits for intravenous medications and fluids of 5 endotoxin units/kg/hour (120 endotoxin units/kg/day), but no guidance for amounts of endotoxin in enteral products. To determine baseline exposure to infants in the neonatal intensive care unit, we examined endotoxin content of enteral formulas and fortification used for preterm infants, as well as bovine lactoferrin products. We also examined endotoxin exposure and outcomes in very low birth weight infants. Endotoxin content was measured using kinetic chromogenic limulus amebocyte lysate analysis. Daily endotoxin exposure from enteral formulas ranged between < 75 to 7110 endotoxin units/kg and from lactoferrin products from 7 to 3720 endotoxin units/kg. In examining neonatal outcomes from a bovine lactoferrin product studied at three different escalating doses (100, 200, and 300 mg/kg/day), we measured endotoxin in the lactoferrin product and daily exposure was 1089 (N = 10), 2178 (N = 10) and 3287 (N = 11) endotoxin units/kg, respectively. There were no cases of necrotizing enterocolitis or mortality and no lactoferrin-related adverse effects in these patients. Enteral endotoxin daily exposures from lactoferrin products are similar to amounts in preterm enteral nutrition and appear safe and not associated with patient harm. Testing enteral products and establishing safety limits may improve care of high risk patients.

Broad-acting therapeutic effects of miR-29b-chitosan on hypertension and diabetic complications.

MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. In addition, miR-29 is a master inhibitor of extracellular matrix gene expression, which may attenuate fibrosis but could also weaken tissue structure. The goal of this study was to test whether miR-29 could be developed as an effective, broad-acting, and safe therapeutic. Substantial accumulation of miR-29b and effective knockdown of Lypla1 in several mouse tissues were achieved using a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH-NP) injected systemically at 200 µg/kg body weight. miR-29b-CH-NP, injected once every 3 days, significantly attenuated angiotensin II-induced hypertension. In db/db mice, miR-29b-CH-NP treatment for 12 weeks decreased cardiac and renal fibrosis and urinary albuminuria. In uninephrectomized db/db mice, miR-29b-CH-NP treatment for 20 weeks significantly improved myocardial performance index and attenuated proteinuria. miR-29b-CH-NP did not worsen abdominal aortic aneurysm in ApoE knockout mice treated with angiotensin II. miR-29b-CH-NP caused aortic root fibrotic cap thinning in ApoE knockout mice fed a high-cholesterol and high-fat diet but did not worsen the necrotic zone or mortality. In conclusion, systemic delivery of low-dose miR-29b-CH-NP is an effective therapeutic for several forms of cardiovascular and renal disease in mice.

Prevalence of white spot lesions and gingival index during orthodontic treatment in an academic setting.

INTRODUCTION: The objective of this study was to determine the prevalence of white spot lesions (WSL) in orthodontic patients in an academic setting. Specific aims include using a novel combination to measure plaque accumulation (PA) and detect the association between WSL and PA and the associations between multiple independent variables. METHODS: Cross-sectional data were collected on 111 patients. To enhance standardization, a combination of plaque-disclosing agents and standardized intraoral photographs was used to analyze plaque index (PI) and WSL for all teeth except molars. Factors including time in fixed appliances (FA), number of teeth, location of the lesions, and demographic information were reported. A multiple linear regression model was used to detect associations between the PI and WSL and the independent variables (P <0.05). RESULTS: Approximately 79.3% of participants had at least one WSL, with a mean of 4 affected teeth per patient. A significant association was found between time in FA and the more severe PI reporting (P <0.001). There was no significant association between WSL and PI or the other variables. WSL was greater in the maxilla than in the mandible. PI was greater on the left than on the right side. Interexaminer reliability was assessed for PI and WSL (κ = 0.93 and 0.92). CONCLUSIONS: The prevalence of WSL for orthodontic patients treated at this institution was greater than previously reported in the literature. In addition, the severity of PI was associated with increased time in FAs. Combining the proposed method of reporting PA facilitates standardization, calibration, and documentation in an academic environment.

Histologically resolved small RNA maps in primary focal segmental glomerulosclerosis indicate progressive changes within glomerular and tubulointerstitial regions.

Pathological heterogeneity is common in clinical tissue specimens and complicates the interpretation of molecular data obtained from the specimen. As a typical example, a kidney biopsy specimen often contains glomeruli and tubulointerstitial regions with different levels of histological injury, including some that are histologically normal. We reasoned that the molecular profiles of kidney tissue regions with specific histological injury scores could provide new insights into kidney injury progression. Therefore, we developed a strategy to perform small RNA deep sequencing analysis for individually scored glomerular and tubulointerstitial regions in formalin-fixed, paraffin-embedded kidney needle biopsies. This approach was applied to study focal segmental glomerulosclerosis (FSGS), the leading cause of nephrotic syndrome in adults. Large numbers of small RNAs, including microRNAs, 3'-tRFs, 5'-tRFs, and mitochondrial tRFs, were differentially expressed between histologically indistinguishable tissue regions from patients with FSGS and matched healthy controls. A majority of tRFs were upregulated in FSGS. Several small RNAs were differentially expressed between tissue regions with different histological scores in FSGS. Notably, with increasing levels of histological damage, miR-21-5p was upregulated progressively and miR-192-5p was downregulated progressively in glomerular and tubulointerstitial regions, respectively. This study marks the first genome scale molecular profiling conducted in histologically characterized glomerular and tubulointerstitial regions. Thus, substantial molecular changes in histologically normal kidney regions in FSGS might contribute to initiating tissue injury or represent compensatory mechanisms. In addition, several small RNAs might contribute to subsequent progression of glomerular and tubulointerstitial injury, and histologically mapping small RNA profiles may be applied to analyze tissue specimens in any disease.

Risk factors for local atypical fibroxanthoma recurrence and progression to pleomorphic dermal sarcoma: A meta-analysis of individualized participant data.

BACKGROUND: Risk factors for local atypical fibroxanthoma (AFX) recurrence and progression to pleomorphic dermal sarcoma (PDS) have not previously been identified. OBJECTIVE: To identify risk factors and provide follow-up suggestions for local AFX recurrence and progression to PDS. METHODS AND MATERIALS: A literature search was performed in the PubMed, EMBASE, and Cochrane databases. The PRISMA and MOOSE guidelines were followed. The risks of local AFX recurrence and progression to PDS were presented as Kaplan-Meier plots and risk factors were presented as hazard ratios (HRs) calculated with univariate and multivariate Cox regression. RESULTS: Five hundred and ninety-eight patients with AFX from 14 studies were included. Age >74 years and male sex significantly increased the risk of local recurrence (HR: 7.31 [95% confidence interval [CI]: 1.78-30.0], p < 0.01 and HR: 2.89 [95% CI: 1.04-8.01], p < 0.05, respectively). There was no difference when comparing wide local excision and Mohs' micrographic surgery (p = 0.89). The risks of local AFX recurrence and progression to PDS after 2 years were <1%. CONCLUSION: A more intensive follow-up regimen could be considered in patients >74 years old and males due to the higher risk of local AFX recurrence.

In Situ Equilibrium Polyethylene Passive Sampling of Soil Gas VOC Concentrations: Modeling, Parameter Determinations, and Laboratory Testing.

The use of low-density polyethylene (PE) sheets as equilibrium passive soil gas samplers to quantify volatile organic compounds (VOCs) such as benzene, toluene, ethylbenzene, and xylenes, and chlorinated solvents (e.g., trichloroethene and tetrachloroethene) in unsaturated subsurface environments was evaluated via modeling and benchtop testing. Two methods were devised to quantify such VOCs in PE. Key chemical properties, including PE-water (KPEw) and PE-air (KPEa) partition coefficients and diffusivities in the PE (Dpe), were determined. These KPEw, KPEa, and Dpe values were consistent with extrapolations of data based on larger compounds. Using these parameter values, field equilibration times of less than 1 day were estimated for such VOCs when using 70-100 µm thick PE sheets. Further, benchtop batch tests carried out in jars filled with VOC-contaminated soils, after 1 or 2 days, showed concentrations in soil air deduced from PE that were consistent with concentrations deduced by analyzing either water or headspace gases recovered from the same tests. Thus, PE-based measurements may overcome inaccuracies from using total soil concentrations and equilibrium partitioning models that may overestimate vapor phase concentrations up to 2 orders of magnitude.

Simultaneous Evaluation of Diagnostic Assays for Pharyngeal and Rectal Neisseria gonorrhoeae and Chlamydia trachomatis Using a Master Protocol.

BACKGROUND: Pharyngeal and rectal Neisseria gonorrhoeae and Chlamydia trachomatis play important roles in infection and antibacterial resistance transmission, but no US Food and Drug Administration (FDA)-cleared assays for detection at these sites existed prior to this study. The objective was to estimate performance of assays to detect those infections in pharyngeal and rectal specimens to support regulatory submission. METHODS: We performed a cross-sectional, single-visit study of adults seeking sexually transmitted infection testing at 9 clinics in 7 states. We collected pharyngeal and rectal swabs from participants. The primary outcome was positive and negative percent agreement for detection of N. gonorrhoeae and C. trachomatis for 3 investigational assays compared to a composite reference. Secondary outcomes included positivity as well as positive and negative predictive values and likelihood ratios. Subgroup analyses included outcomes by symptom status and sex. RESULTS: A total of 2598 participants (79% male) underwent testing. We observed N. gonorrhoeae positivity of 8.1% in the pharynx and 7.9% in the rectum and C. trachomatis positivity of 2.0% in the pharynx and 8.7% in the rectum. Positive percent agreement ranged from 84.8% to 96.5% for different anatomic site infection combinations, whereas negative percent agreement was 98.8% to 99.6%. CONCLUSIONS: This study utilized a Master Protocol to generate diagnostic performance data for multiple assays from different manufacturers in a single study population, which ultimately supported first-in-class FDA clearance for extragenital assays. We observed very good positive percent agreement when compared to a composite reference method for the detection of both pharyngeal and rectal N. gonorrhoeae and C. trachomatis. CLINICAL TRIALS REGISTRATION: NCT02870101.

High-Throughput Sequencing-Based Investigation of Viruses in Human Cancers by Multienrichment Approach.

BACKGROUND: Viruses and other infectious agents cause more than 15% of human cancer cases. High-throughput sequencing-based studies of virus-cancer associations have mainly focused on cancer transcriptome data. METHODS: In this study, we applied a diverse selection of presequencing enrichment methods targeting all major viral groups, to characterize the viruses present in 197 samples from 18 sample types of cancerous origin. Using high-throughput sequencing, we generated 710 datasets constituting 57 billion sequencing reads. RESULTS: Detailed in silico investigation of the viral content, including exclusion of viral artefacts, from de novo assembled contigs and individual sequencing reads yielded a map of the viruses detected. Our data reveal a virome dominated by papillomaviruses, anelloviruses, herpesviruses, and parvoviruses. More than half of the included samples contained 1 or more viruses; however, no link between specific viruses and cancer types were found. CONCLUSIONS: Our study sheds light on viral presence in cancers and provides highly relevant virome data for future reference.

Incidence and survival of hypopharyngeal cancer: a Danish Nation-Wide Study from 1980 to 2014.

Objectives: To evaluate changes in incidence and survival of patients diagnosed with hypopharyngeal cancer (HPC) in Denmark in the period 1980-2014.Methods: All patients registered with HPC in the Danish Cancer Registry (DCR) in the period 1980-2014 were included. Age-adjusted incidence rates (AAIRs), average annual percentage change in incidence, and overall survival were calculated.Results: Two thousand and nine patients were included (79.7% men). The overall AAIR increased significantly from 0.3 per 100,000 to 1.1 per 100,000 during the study period, corresponding to an increase of 4.1% per year. The most frequent histology was squamous cell carcinoma (SCC) comprising 90.3%. The overall five-year survival increased with 13.5 percentage points from 13.4% in the period 1980-1985 to 26.9% in the period 2010-2014. Women demonstrated better survival compared to men with a hazard ratio of 0.83, and patients with SCC had better survival compared to the remaining histology groups.Conclusions: This nation-wide study, covering nearly four decades, showed a significant increase in incidence and survival of HPC in Denmark.

Incidence and survival of laryngeal cancer in Denmark: a nation-wide study from 1980 to 2014.

Background: The purpose of this registry study was to evaluate trends in incidence and survival of laryngeal cancer in the Danish population from 1980 to 2014. Methods: This study includes all patients with laryngeal cancer registered in the Danish Cancer Registry (DCR) in the period 1980-2014. The age-adjusted incidence rate (AAIR) per 100,000 and average annual percent change (AAPC) were calculated. We evaluated the relative survival at five years in relation to gender, anatomical location, year at diagnosis, and histological type. Further, an age-period-cohort (APC) model of incidence was constructed. Results: A total of 8748 patients (82% males) were included. The median age at diagnosis was 60 years, range 18-101 years. The AAIR decreased from 3.6 per 100,000 in 1980 to 2.3 per 100,000 in 2014 with an AAPC of -0.8% (p < .008). Considering the anatomic location, we found that glottic cancer had a significantly better survival at five years compared to the other locations. We observed no significant difference in survival for supraglottic, subglottic and larynx unspecified cancer during the observation period. During the period 1980-2014, we found no improvement in five year relative survival. Conclusions: This nation-wide study reports a significant decrease in the incidence of laryngeal cancer. Glottic cancer had a significantly better survival at five years compared to other locations.

Development and external validation of nomograms in oropharyngeal cancer patients with known HPV-DNA status: a European Multicentre Study (OroGrams).

BACKGROUND: The proxy marker for human papillomavirus (HPV), p16, is included in the new AJCC 8th/UICC 8th staging system, but due to incongruence between p16 status and HPV infection, single biomarker evaluation could lead to misallocation of patients. We established nomograms for overall survival (OS) and progression-free survival (PFS) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and known HPV-DNA and p16 status, and validated the models in cohorts from high- and low-prevalent HPV countries. METHODS: Consecutive OPSCC patients treated in Denmark, 2000-2014 formed the development cohort. The validation cohorts were from Sweden, Germany, and the United Kingdom. We developed nomograms by applying a backward-selection procedure for selection of variables, and assessed model performance. RESULTS: In the development cohort, 1313 patients, and in the validation cohorts, 344 German, 503 Swedish and 463 British patients were included. For the OS nomogram, age, gender, combined HPV-DNA and p16 status, smoking, T-, N-, and M-status and UICC-8 staging were selected, and for the PFS nomogram the same variables except UICC-8 staging. The nomograms performed well in discrimination and calibration. CONCLUSIONS: Our nomograms are reliable prognostic methods in patients with OPSCC. Combining HPV DNA and p16 is essential for correct prognostication. The nomograms are available at www.orograms.org .

Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature.

BACKGROUND: The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs. METHODS: We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined. RESULTS: We identified a total of 3459 mutations with an average of 10 mutations per megabase and a median of 28 variants per sample. The most frequently mutated genes were KALRN (28%), SPTBN1 (32%), KMT2A (31%), ZNRF3 (9%), BNC2 (12%), NOTCH2 (25%), FGFR2 (12%), SMAD2 (6%), and AR (13%). Our findings were dominated by COSMIC signature 5 and 12, represented in other head and neck cancers and in hepatocellular carcinomas, respectively. CONCLUSIONS: We have identified multiple genetic aberrations in HPV+ OPSCCs, and the COSMIC signature 12 as most prevalent. The mutations harbour both therapeutic and prognostic potential.

Increasing incidence and survival of head and neck cancers in Denmark: a nation-wide study from 1980 to 2014.

BACKGROUND: The purpose of the study was to determine trends in age-adjusted incidence rates (AAIR) and survival probability in head and neck cancers (HNCs) in the Danish population from 1980 to 2014. MATERIAL AND METHODS: All patients registered with HNC in the nationwide Danish Cancer Registry from 1980 to 2014 were included. We evaluated the AAIR per 100,000 and the average annual percent change (AAPC). The relative survival probability at 5 years was calculated in relation to gender, anatomical location and histology, and we constructed age-period-cohort models of incidence. RESULTS: About 34,606 patients were included (64.7% men). The AAIR increased from 9.1 per 100,000 in 1980 to 17.4 per 100,000 in 2014 with an AAPC of 2.1%. The greatest incidence increase was observed in oropharyngeal cancer (AAPC: 5.4%) followed by hypopharyngeal cancer (AAPC: 4.2%). Adenocarcinomas had the highest AAPC (5.0%) followed by squamous cell carcinomas (AAPC: 2.0%). The AAPC was significantly higher in women (2.4%) compared with men (1.6%). For all HNC patients, the relative survival at 5 years rose significantly from 49.0% in 1980-1984 to 62.4% in 2010-2014. Women had a significantly higher survival than men with a relative survival of 61.7% compared to 50.0% in men. Laryngeal cancer had the best survival probability of cancers in the upper aerodigestive tract with hypopharyngeal cancer having the poorest survival. CONCLUSION: This nation-wide study showed a significant rise in incidence of HNC for men and women along with a significant increase in relative survival. Oropharyngeal cancer had the highest increase in incidence followed by hypopharyngeal cancer which showed the poorest survival of HNCs.

Incidence and survival of oropharyngeal cancer in Denmark: a nation-wide, population-based study from 1980 to 2014.

BACKGROUND: Oropharyngeal carcinomas (OPCs) constitute a significant and increasing proportion of head and neck carcinomas and are an important global cause of morbidity and mortality. The purpose of this study was to determine trends in incidence and survival in OPC in the Danish population from 1980 to 2014. METHODS: This study included all patients registered in the nationwide Danish Cancer Registry over the period 1980-2014. The age-adjusted incidence rates (AAIR) per 100,000, annual percentage change (APC) and average annual percent change (AAPC) were evaluated. Five-year relative survival (RS) was calculated with Cox regression analyses in relation to gender, anatomical location and histology. RESULTS: A total of 6555 patients (69% male) were included, with a median age at diagnosis of 60 years. The AAIR of patients with OPC increased from 0.815 per 100,000 in 1980 to 4.51 per 100,000 in 2014 with an AAPC of 5.3. The 5-year RS increased significantly from 33.1% over the period 1980-1984 to 58.5% (25.4% points) over the period 2010-2014. With no significant difference stratified for gender. Tumors located at the palatine tonsils (n = 3333) and salivary gland OPC (n = 90) had significantly better survival compared with other sub-locations and histology subtypes. In the APC model the birth cohort effect rate ratio increased until 1925 and then decreased until 1935 from which point it increased in the last cohorts. CONCLUSIONS: In this population-based study, we observed a significant increase in the incidence of OPCs and in the RS for OPC. We also identified a profound birth cohort effect on the incidence.