Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC)

INTRODUCTION: Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS: One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at \u3c40 or breast cancer \u3c50 years of age). RESULTS: Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION: Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies

Social and economic characteristics of street youth by gender and level of street involvement in Eldoret, Kenya.

Street-connected youth are a neglected and vulnerable population, particularly in resource-constrained settings. The development of interventions and supports for this population requires insight into how they live. This study describes the social and economic characteristics of a convenience sample of street youth (SY) in Eldoret, Kenya.Participants were eligible if they were aged 12-21, living in Eldoret, spending days only (part-time), or nights and days on the street (full-time) and able and willing to consent or assent. Data were collected using a standardized interview conducted in English or Kiswahili. Binary dependent variables were having been arrested and/or jailed, and first priority for spending money (food vs. other). Nominal categorical dependent variables included major source of support, and major reason for being street-involved. Multivariable analysis used logistic regression models to examine the association of gender and level of street-involvement with social and economic factors of interest adjusting for age and length of time on the street. Data were analyzed using SAS 9.3.Of the 200 SY enrolled, 41% were female, mean age of 16.3 years; 71% were on the street full-time, and 29% part-time. Compared with part-time SY, full-time SY were more likely to have been arrested (Adjusted Odds Ratio [AOR]: 2.33, 95% Confidence Interval [95%CI]:1.01-5.35), name food as their first spending priority (AOR: 2.57, 95%CI:1.03-6.45), have left home due to violence (AOR: 5.54, 95%CI: 1.67-18.34), and more likely to report friends on the street as a major source of support (AOR: 3.59, 95% CI: 1.01-12.82). Compared with females, males were more likely to have ever been arrested (AOR: 2.66, 95%CI:1.14-6.18), and to have ever been jailed (AOR: 3.22, 95%CI:1.47-7.02).These results suggest a high degree of heterogeneity and vulnerability among SY in this setting. There is an urgent need for interventions taking into consideration these characteristics

Aortic Neck IFU Violations During EVAR for Ruptured Infrarenal Aortic Aneurysms are Associated with Increased In-Hospital Mortality

ObjectiveVascular surgeons treating patients with ruptured abdominal aortic aneurysm must make rapid treatment decisions and sometimes lack immediate access to endovascular devices meeting the anatomic specifications of the patient at hand. We hypothesized that endovascular treatment of ruptured abdominal aortic aneurysm (rEVAR) outside manufacturer instructions-for-use (IFU) guidelines would have similar in-hospital mortality compared to patients treated on-IFU or with an infrarenal clamp during open repair (ruptured open aortic aneurysm repair [rOAR]).MethodsVascular Quality Initiative datasets for endovascular and open aortic repair were queried for patients presenting with ruptured infrarenal AAA between 2013-2018. Graft-specific IFU criteria were correlated with case-specific proximal neck dimension data to classify rEVAR cases as on- or off-IFU. Univariate comparisons between the on- and off-IFU groups were performed for demographic, operative and in-hospital outcome variables. To investigate mortality differences between rEVAR and rOAR approaches, coarsened exact matching was used to match patients receiving off-IFU rEVAR with those receiving complex rEVAR (requiring at least one visceral stent or scallop) or rOAR with infrarenal, suprarenal or supraceliac clamps. A multivariable logistic regression was used to identify factors independently associated with in-hospital mortality.Results621 patients were treated with rEVAR, with 65% classified as on-IFU and 35% off-IFU. The off-IFU group was more frequently female (25% vs. 18%, P = 0.05) and had larger aneurysms (76 vs. 72 mm, P= 0.01) but otherwise was not statistically different from the on-IFU cohort. In-hospital mortality was significantly higher in patients treated off-IFU vs. on-IFU (22% vs. 14%, P= 0.02). Off-IFU rEVAR was associated with longer operative times (135 min vs. 120 min, P= 0.004) and increased intraoperative blood product utilization (2 units vs. 1 unit, P= 0.002). When off-IFU patients were matched to complex rEVAR and rOAR patients, no baseline differences were found between the groups. Overall in-hospital complications associated with off-IFU were reduced compared to more complex strategies (43% vs. 60-81%, P< 0.001) and in-hospital mortality was significantly lower for off-IFU rEVAR patients compared to the supraceliac clamp group (18% vs. 38%, P= 0.006). However, there was no significantly increased mortality associated with complex rEVAR, infrarenal rOAR or suprarenal rOAR compared to off-IFU rEVAR (all P> 0.05). This finding persisted in a multivariate logistic regression.ConclusionsOff-IFU rEVAR yields inferior in-hospital survival compared to on-IFU rEVAR but remains associated with reduced in-hospital complications when compared with more complex repair strategies. When compared with matched patients undergoing rOAR with an infrarenal or suprarenal clamp, survival was no different from off-IFU rEVAR. Taken together with the growing available evidence suggesting reduced long-term durability of off-IFU EVAR, these data suggest that a patient's comorbidity burden should be key in making the decision to pursue off-IFU rEVAR over a more complex repair when proximal neck violations are anticipated preoperatively

Quantifying the risk-adjusted hospital costs of postoperative complications after lower extremity bypass in patients with claudication

ObjectiveIncreasing evidence has shown that the risks associated with surgical revascularization for intermittent claudication outweigh the benefits. The aim of our study was to quantify the cost of care associated with perioperative complications after elective lower extremity bypass (LEB) in patients presenting with intermittent claudication.MethodsAll patients undergoing first-time LEB for claudication in the Healthcare Database (2009-2015) were included. The primary outcome was in-hospital postoperative complications, including major adverse limb events (MALE), major adverse cardiac events (MACE), acute kidney injury, and wound complications. The overall crude hospital costs are reported, and a generalized linear model with log link and inverse Gaussian distribution was used to calculate the predicted hospital costs for specific complications.ResultsOverall, 7154 patients had undergone elective LEB for claudication during the study period. The median age was 66 years (interquartile range, 59-73 years), 67.5% were male, and 75.3% were white. Two thirds of patients (61.2%) had Medicare insurance, followed by private insurance (26.9%), Medicaid (7.7%), and other insurance (4.2%). In-hospital complications occurred in 8.5% of patients, including acute kidney injury in 3.0%, MALE in 2.8%, wound complications in 2.3%, and MACE in 1.0%. The overall median crude hospital cost was $11,783 (interquartile range,$8911-$15,767) per patient. The incremental increase in cost associated with a postoperative complication was significant, ranging from$6183 (95% confidence interval, $4604-$7762) for MALE to $10,485 (95$6529-$14,441) for MACE after risk adjustment.ConclusionsPostoperative complications after elective LEB for claudication are not uncommon and increase the in-hospital costs by 46% to 78% depending on the complication. Surgical revascularization for claudication should be used sparingly in carefully selected patients

Practice patterns surrounding the use of tibial interventions for claudication in the Medicare population.

OBJECTIVE: At present, no data are available to support the use of tibial interventions in the treatment of claudication. We characterized the practice patterns surrounding tibial peripheral vascular interventions (PVIs) for patients with claudication in the United States. METHODS: Using 100% Medicare fee-for-service claims from 2017 to 2019, we conducted a retrospective analysis of all patients who underwent an index PVI for claudication. Patients with any previous PVI, acute limb ischemia, or chronic limb-threatening ischemia in the preceding 12 months were excluded. The primary outcome was the receipt or delivery of tibial revascularization during an index PVI for claudication, defined as tibial PVI with or without concomitant femoropopliteal PVI. Univariable comparisons and multivariable hierarchical logistic regression were used to assess the patient and physician characteristics associated with the use of tibial PVI for claudication. RESULTS: Of 59,930 Medicare patients who underwent an index PVI for claudication between 2017 and 2019, 16,594 (27.7%) underwent a tibial PVI (isolated tibial PVI, 38.5%; tibial PVI with concomitant femoropopliteal PVI, 61.5%). Of the 1542 physicians included in our analysis, the median physician-level tibial PVI rate was 20.0% (interquartile range, 9.1%-37.5%). Hierarchical logistic regression suggested that patient-level characteristics associated with tibial PVI for claudication included male sex (adjusted odds ratio [aOR], 1.23), increasing age (aOR, 1.30-1.96), Black race (aOR, 1.47), Hispanic ethnicity (aOR, 1.86), diabetes (aOR, 1.36), no history of hypertension (aOR, 1.12), and never-smoking status (aOR, 1.64; P < .05 for all). Physician-level characteristics associated with tibial PVI for claudication included early-career status (aOR, 2.97), practice location in the West (aOR, 1.75), high-volume PVI practice (aOR, 1.87), majority of practice in an ambulatory surgery center or office-based laboratory setting (aOR, 2.37), and physician specialty. The odds of vascular surgeons performing tibial PVI were significantly lower compared with radiologists (aOR, 2.98) and cardiologists (aOR, 1.67; P < .05 for all). The average Medicare reimbursement per patient was dramatically higher for physicians performing high rates of tibial PVI (quartile 4 vs quartile 1-3, $12,023.96 vs$692.31 per patient; P < .001). CONCLUSIONS: Tibial PVI for claudication was performed more often by nonvascular surgeons in high-volume practices and high-reimbursement settings. Thus, a critical need exists to reevaluate the indications, education, and reimbursement policies surrounding these procedures

Unadjusted (UOR) and Adjusted Odds Ratios (AOR) and 95% Confidence Intervals (CI) for associations of gender and level of street involvement with key social and economic indicators among street-connected youth aged 12–21 (N = 200).

<p><b>(</b>Binary multivariable logistic regression analysis for the association of gender and level of street involvement with binary indicators adjusted for age and length of time on the street).</p><p>*reference category.</p

Economic characteristics of the study population by gender and level of street involvement (N = 200).

<p>Economic characteristics of the study population by gender and level of street involvement (N = 200).</p