Subhazard Ratio Research Articles

Retinoblastoma Outcomes in the Americas: A Prospective Analysis of 491 Children With Retinoblastoma From 23 American Countries

Globally, disparities exist in retinoblastoma treatment outcomes between high- and low-income countries, but independent analysis of American countries is lacking. We report outcomes of American retinoblastoma patients and explore factors associated with survival and globe salvage. Subanalysis of prospective cohort study data. Multicenter analysis at 57 American treatment centers in 23 countries of varying economic levels (low income [LIC], lower-middle income [LMIC], upper-middle income [UMIC], and high income [HIC]) of 491 treatment-naïve retinoblastoma patients diagnosed in 2017 and followed through 2020. Survival and globe salvage rates analyzed with Kaplan-Meier analysis and Cox proportional hazard models. Of patients, 8 (1.6%), 58 (11.8%), 235 (47.9%), and 190 (38.7%) were from LIC, LMIC, UMIC, and HIC groups, respectively. Three-year survival rates in LICs were 60.0% (95% confidence interval [CI] 12.6-88.2) compared with 99.2% (95% CI 94.6%-99.9%) in HICs. Death was less likely in patients >4 years of age (vs ≤4 years, HR = 0.45 [95% CI 0.27-0.78], P = .048). Patients with more advanced tumors (eg, cT3 vs cT1, HR = 4.65 × 109 [95% CI 1.25 × 109-1.72 × 1010], P < .001) and females (vs males, HR = 1.98 [95% CI 1.27-3.10], P = .04) were more likely to die. Three-year globe salvage rates were 13.3% (95% CI 5.1%-25.6%) in LMICs and 46.2% (95% CI 38.8%-53.3%) in HICs. At 3 years, 70.1% of cT1 eyes (95% CI 54.5%-81.2%) vs 8.9% of cT3 eyes (95% CI 5.5%-13.3%) were salvaged. Advanced tumor stage was associated with higher enucleation risk (eg, cT3 vs cT1, subhazard ratio = 4.98 [95% CI 2.36-10.5], P < .001). Disparities exist in survival and globe salvage in American countries based on economic level and tumor stage demonstrating a need for childhood cancer programs.

The determinant role of high-density lipoprotein cholesterol on the recovery of left ventricle ejection fraction after acute coronary syndromes

Abstract Background Higher levels of high-density lipoprotein cholesterol (HDLc) have been associated to lower atherosclerosis-associated cardiovascular disease. Patients admitted for acute coronary syndromes (ACS) usually have low levels of HDLc. Methods Between 2015 and 2020 a total of 1,794 patients were admitted from an ACS; 75 (4.23%) died within the hospitalization, 619 (36.0%) were discharged having a LVEF &amp;lt;0.50 from whom 562 (90.79%) had an echocardiogram available within the first 12 months after discharge. We evaluated the evolution of LVEF and assessed the percentage of patients with postdischarge LVEF &amp;gt;0.35 or &amp;gt;0.50. Multivariate analyses were performed by competing risk regression considering all-cause mortality as a competing event and adjusted by risk factors, age, medical treatment at discharge and revascularization; results are presented as sub-hazard ratio (sHR). Results Mean (standard deviation) age was 65.61 (12.16), 21.% were males, 28.6% had DM and 51% were discharged after an ST-elevation myocardial infarction (STEMI). During the ACS, LVEF was 43.19 (11.12) and 33.92% had LVEF ≤0.35. Mean HDLc was 40.73 (13.94) mg/dL and no differences were observed in patients with LVEF 0.35 or &amp;lt;0.20. Median time to postdischarge echocardiogram was 200 days (IQ range 90-295). Postdischarge LVEF was 48.61 (12.83), 54.8% had LVEF &amp;gt;0.50 and 14.41% had LVEF ≤0.35. Eleven patients died before having a postdischarge echocardiogram. Patients with postdischarge LVEF &amp;lt;0.50 had the same age and sex but had more frequently STEMI (56.13 vs. 47.71%; p=0.048), Killip class &amp;gt;I (47.43% vs. 25.82%; p&amp;lt;0.01), lower LVEF at the ACS (37.24 (0.58) vs. 48.17 (0.58); p&amp;lt;0.01) and specially LVEF&amp;lt;0.35 (45.68% vs. 20.19%; p&amp;lt;0.01). Patients who had postdischarge LVEF &amp;lt;0.50 had lower HDLc (38.19 (0.79) vs 41.11 (0.70) mg/dL; p&amp;lt;0.01) and lower LDLc (85.64 (37.64) vs. 97.45 (35.95) mg/dL; p&amp;lt;0.001) and glomerular filtration rate (73.47(24.57) vs. 78.54 (20.60) ml/min/1.72m2; p&amp;lt;0.001); no differences were observed in triglycerides, hemoglobin or C-reactive protein. The competing risk regression identified an independent predictive value of HDLc for LVEF improvement (figure). HDLc &amp;gt;40 mg/dL in the ACS was independently associated to higher probability of postdischarge LVEF &amp;gt;0.50 (sHR: 1.28 95% CI 1.07-1.53; p&amp;lt;0.001). Conclusions HDLc levels, measured during an ACS hospitalization, predict LVEF recovery in patients discharged with LVEF &amp;lt;0.50.

Abdominal computed tomography measurements of body composition and waitlist mortality in kidney transplant candidates

Body mass index is often used to determine kidney transplant (KT) candidacy. However, this measure of body composition (BC) has several limitations, including the inability to accurately capture dry weight. Objective computed tomography (CT)-based measures may improve pre-KT risk stratification and capture physiological aging more accurately. We quantified the association between CT-based BC measurements and waitlist mortality in a retrospective study of 828 KT candidates (2010-2022) with clinically obtained CT scans using adjusted competing risk regression. In total, 42.5% of candidates had myopenia, 11.4% had myopenic obesity (MO), 68.8% had myosteatosis, 24.8% had sarcopenia (probable = 11.2%, confirmed = 10.5%, and severe = 3.1%), and 8.6% had sarcopenic obesity. Myopenia, MO, and sarcopenic obesity were not associated with mortality. Patients with myosteatosis (adjusted subhazard ratio [aSHR] = 1.62, 95% confidence interval [CI]: 1.07-2.45; after confounder adjustment) or sarcopenia (probable: aSHR = 1.78, 95% CI: 1.10-2.88; confirmed: aSHR = 1.68, 95% CI: 1.01-2.82; and severe: aSHR = 2.51, 95% CI: 1.12-5.66; after full adjustment) were at increased risk of mortality. When stratified by age, MO (aSHR = 2.21, 95% CI: 1.28-3.83; P interaction = .005) and myosteatosis (aSHR = 1.95, 95% CI: 1.18-3.21; P interaction = .038) were associated with elevated risk only among candidates <65 years. MO was only associated with waitlist mortality among frail candidates (adjusted hazard ratio = 2.54, 95% CI: 1.28-5.05; P interaction = .021). Transplant centers should consider using BC metrics in addition to body mass index when a CT scan is available to improve pre-KT risk stratification at KT evaluation.

Abstract 17240: Preoperative Pectoralis Muscle Area Index is Associated With Increased Post-LVAD Length of Stay and 90-day Readmission

Background: In LVAD pts, preoperative sarcopenia, as measured by pectoralis muscle area index (PMI), has been associated with mortality and GI bleed; however, the association with length of stay (LOS) and readmission is unknown. Methods: This was a single-center retrospective cohort study of pts who underwent LVAD 01/2015-10/2018. Preoperative pectoralis muscle area was measured on CT chest prior to implant using Tera Recon, adjusted for height squared to give the PMI. Multivariable negative binomial regressions were used to assess the association between PMI and LOS. Subhazard ratios (SHR) and cause-specific hazard ratios (CSHR) were used to assess the association between PMI and freedom from 90-day readmission. Results: Of 254 LVAD pts, 95 had a preop CT chest and were included (median days CT to LVAD: 7 [IQR 3-13]). Pts with PMI in the lowest quartile (PMI &lt; 4.86 cm 2 /m 2 ) constituted the low PMI cohort; all others served as the reference cohort. Baseline characteristics are shown in the Table. During index hospitalization, 2 low PMI pts died vs 7 reference; 0 low PMI pts were transplanted vs 2 reference. Low PMI was associated with longer post-LVAD LOS (adjusted incidence rate ratio 1.31 [95% CI 1.03-1.66], p =0.03) and increased risk of 90-day readmission (aSHR, accounting for risk of death and transplantation, 3.77 [1.17-12.1], p =0.03; aCSHR 3.67 [1.35-9.96], p =0.01) (Fig). The most common reason for readmission in low PMI pts was infection (n=3). Conclusions: Low PMI is associated with longer LOS and higher likelihood of 90-day readmission after LVAD. PMI could be used to identify sicker patients at risk for more intensive medical intervention and potentially higher health care cost.

Does Sustained Reduction of Functional Mitral Regurgitation Impact Survival?

Functional mitral regurgitation (FMR) is associated with increased mortality and has been considered a marker for advanced heart disease, yet the value of mitral valve repair (MVr) in this population remains unclear. This study aims to evaluate the impact of reducing FMR burden through surgical MVr on survival. Patients with severe FMR who underwent MVr with an undersized, complete, rigid, annuloplasty between 2004 and 2017 were assessed (n = 201). Patients were categorized based on grade of recurrent FMR (0-4). Time-to-event Kaplan-Meier estimations of freedom from death or reoperation were performed using the log-rank test. Cox proportional hazards models evaluated all-cause mortality and reported in hazards ratios (HR) and 95% confidence intervals (CI). Patients were categorized by postoperative recurrent FMR: 45% (91/201) of patients had grade 0, 29% (58/201) grade 1, 20% (40/201) grade 2, 2% (4/201) grade 3%, and 4% (8/201) grade 4. The cumulative incidence of reoperation with death as a competing risk was higher in patients with grades ≥3 recurrent FMR compared to grades ≤2 (44.6% vs 14.6%, subhazard ratio 3.69 [95% CI, 1.17-11.6]; P = 0.026). Overall freedom from death or reoperation was superior for recurrent FMR grades ≤2 compared to grades ≥3 (log-rank P < 0.001). Increasing recurrent FMR grade was independently associated with mortality (HR 1.30 [95% CI, 1.07-1.59] P = 0.009). Reduced postoperative FMR grade resulted in an incrementally lower risk of death or reoperation after MVr. These results suggest that achieving a durable reduction in FMR burden improves long-term survival.

The outcomes of patients with kidney failure due to focal segmental glomerulosclerosis (FSGS) in Australia and New Zealand: A cohort study using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA).

The outcomes of patients with focal segmental glomerulosclerosis (FSGS) on kidney replacement therapy (KRT) have not been well described. This study evaluated the outcomes of patients with kidney failure due to FSGS on KRT including dialysis and kidney transplantation. All adult patients with kidney failure who commenced KRT in Australia and New Zealand from 15th of May 1963 to 31st of December 2018 were retrospectively extracted from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Outcomes of patients with FSGS were compared to those with other causes of kidney failure (non-FSGS). 85,052 patients commenced KRT during the study period, of whom 2991 (3.5%) were patients with FSGS. Compared to patients with non-FSGS, patients with FSGS experienced similar mortality on dialysis (adjusted hazard ratio [aHR] 0.98, 95% CI 0.90-1.06, p = 0.55) and following kidney transplantation (aHR 0.92, 95% CI 0.73-1.15, p = 0.47). The risk of first kidney allograft loss was higher in patients with FSGS (aHR 1.20, 95% CI 1.04-1.37, p = 0.01). However, when death was analysed as a competing risk, the survival in both groups was similar (sub-hazard ratio [SHR] 1.09, 95% CI 0.94-1.28, p = 0.26). Patients with FSGS had a longer waiting time for kidney transplantation (aHR 0.92, 95% CI 0.86-0.98, p = 0.02) and experienced an increased risk of disease recurrence in the allograft (aHR 1.73, 95% CI 1.35-2.21, p<0.001). Compared to patients with other forms of glomerular disease, patients with FSGS experienced similar dialysis and transplant patient survival and death-censored rate of kidney transplantation and allograft loss but higher rates of primary kidney disease recurrence. FSGS was associated with similar dialysis and transplant patient survival and death-censored first allograft loss compared to non-FSGS and other forms of glomerular disease.

Patients with trochanteric hip fractures and pre-existing osteoarthritis can be treated with nailing osteosynthesis without significant decrease in functional status

PurposeFunctional outcome in patients after trochanteric fracture fixation with pre-existing radiographic osteoarthritis (OA) is unclear. Analyzing their function and independence, before and after fracture, could optimize their treatment and decrease the socioeconomic burden in this particular group. MethodsThe influence of pre-existing radiographic hip OA on functional outcome was retrospectively analyzed with a cohort of patients undergoing proximal femoral nailing for trochanteric fracture. OA was graded according to the Tonnis classification. Functional outcome was assessed preoperatively and 12 months after surgery by the Parker Mobility Score (PMS). We consider a meaningful reduction a difference between preoperatively PMS and 12 months after surgery ≥ 2. In order to evaluate if OA is related to PMS reduction ≥ 2, we calculate the SubHazard ratio (SHR) performing a competing risk regression model considering death as a competing risk event, adjusting by confounders. Death, reoperations, readmissions, surgical time, and fracture reduction quality in patients with and without osteoarthritis were recorded. Results375 trochanteric hip fractures treated with cephalomedullary nails were included, from which 80 (21% CI95% 17%-21%) were classified as Tonnis 2 or 3. This group of patients with pre-existing OA was significantly older (mean age of 88.6 [SD 5.65] vs 85.5 years [SD 6.95]) than the group without OA. The preoperatively PMS score was 6.28 (2.71) in non-OA patients and 5.69 (2.67) in OA patients. The mean PMS reduction 12 months after surgery was 1.3 (SD 2.05) in OA patients and 1.07 (SD 2.2) in non-OA patients (p = 0.43). Competing risks analysis, adjusted by confounders had an SHR of 1.15 (IC95% 0.77 - 1.69). Death, readmission, reoperations, surgical time, and fracture reduction quality did not differ in both groups. ConclusionsPatients with pre-existing radiographic OA treated with femoral nailing have a similar reduction in functional outcomes compared to the non-OA group at one-year follow-up. Further studies will be needed to compare the results of the functional outcome in arthroplasty with those of femoral nailing for the treatment of trochanteric femur fractures in patients with OA.

The Association Between Homelessness and Key Liver-Related Outcomes in Veterans With Cirrhosis.

Homelessness adversely affects patient outcomes in broad cohort studies; however, its impact on key liver-related outcomes in patients with cirrhosis is understudied. We aimed to address this knowledge gap using data from the Veterans Health Administration, a cohort disproportionately affected by homelessness. This was a retrospective cohort study of the Veterans Health Administration patients with incident cirrhosis diagnosis between January 2008 and February 2022. Homeless status was classified at baseline and as time-updating variable during follow-up. Inverse probability treatment weighted Cox regression was performed to evaluate the association between homelessness and outcomes of all-cause mortality, cirrhosis decompensation, and hepatocellular carcinoma. A total of 117,698 patients were included in the cohort, of whom 14,243 (12.1%) were homeless at baseline. In inverse probability treatment weighted Cox regression, homelessness was associated with a 24% higher hazard of all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.22-1.26, P < 0.001). However, in competing risk regression models, homelessness was associated with a reduced subhazard of decompensation (subhazard ratio 0.86, 95% CI 0.84-0.88, P < 0.001) and hepatocellular carcinoma (subhazard ratio 0.86, 95% CI 0.83-0.89, P < 0.001). In cause-specific mortality analysis, homeless patients had significantly increased non-liver-related and liver-related mortality; however, the magnitude of effect size was greater for non-liver-related mortality (csHR 1.38, 95% CI 1.35-1.40, P < 0.001). Homelessness in veterans with cirrhosis is associated with increased all-cause mortality; however, this is likely mediated primarily through non-liver-related factors. Future studies are needed to explore drivers of mortality and improve mitigation strategies in these patients.

A randomized controlled trial of teprenone in terms of preventing worsening of COVID-19 infection.

Some COVID-19 patients develop life-threatening disease accompanied by severe pneumonitis. Teprenone induces expression of heat-shock proteins (HSPs) that protect against interstitial pneumonia in preclinical models. We explored whether teprenone prevented worsening of COVID-19 infections. This open-label, randomized, pilot phase 2 clinical trial was conducted at five institutions in Japan. We randomized patients hospitalized for COVID-19 with fever to teprenone or no-teprenone groups in a 1:1 ratio. We stratified patients by sex, age < and ≥ 70 years and the existence (or not) of complications (hypertension, diabetes, ischemic heart disease, chronic pulmonary disease and active cancer). No limitation was imposed on other COVID-19 treatments. The primary endpoint was the intubation rate. One hundred patients were included, 51 in the teprenone and 49 in the no- teprenone groups. The intubation rate did not differ significantly between the two groups: 9.8% (5/51) vs. 2.0% (1/49) (sub-hazard ratio [SHR] 4.99, 95% confidence interval [CI]: 0.59-42.1; p = 0.140). The rates of intra-hospital mortality and intensive care unit (ICU) admission did not differ significantly between the two groups: intra-hospital mortality 3.9% (2/51) vs. 4.1% (2/49) (hazard ratio [HR] 0.78, 95%CI: 0.11-5.62; p = 0.809); ICU admission 11.8% (6/51) vs. 6.1% (3/49) (SHR 1.99, 95%CI: 0.51-7.80; p = 0.325). Teprenone afforded no clinical benefit. Japan Registry of Clinical Trials jRCTs061200002 (registered on 20/May/2020).

Extensive Perineural Invasion vs Nerve Caliber to Assess Cutaneous Squamous Cell Carcinoma Prognosis

Perineural invasion (PNI) is an adverse risk feature in cutaneous squamous cell carcinoma (CSCC) that affects patient prognosis and disease management. However, research comparing different PNI patterns on patient outcomes is limited. To compare 4 assessments of PNI in CSCC, their associations with poor outcomes, and implications for their inclusion in the Brigham and Women's Hospital (BWH) staging system. This retrospective cohort study was performed at a single tertiary care institution and compared 4 PNI assessments: nerve caliber, number of involved nerves per section, PNI maximal depth, and PNI location with respect to tumor. Patients with primary, localized, invasive CSCC with PNI diagnosed between January 1, 2000, and December 31, 2017, were identified via an electronic in-house database. Available pathology slides were secondarily reviewed by study authors. Relevant patient and tumor characteristics and outcomes were abstracted from the medical record. Data analysis was performed between September 6 and October 20, 2022. Risks of recurrence, disease-specific death, and a composite end point (any poor outcome) were calculated via multivariable stepwise Fine and Gray competing-risks regression. Considered revisions to the BWH staging system were assessed via receiver operating characteristic curves and test characteristics. This study included 140 patients with CSCC, with a mean (SD) age of 75.1 (11.2) years. More than half of the patients were men (93 [66.4%]), and most identified as White (132 [94.3%]). Of the 4 PNI assessments studied, only involvement of multiple nerves was associated with poor outcomes. Perineural invasion of 5 or more distinct nerves (extensive PNI [ePNI]) was independently associated with local recurrence (subhazard ratio [SHR], 13.83 [95% CI, 3.50-54.62]; P < .001), disease-specific death (SHR, 6.20 [95% CI, 1.59-24.21]; P = .009), and any poor outcome (SHR, 10.21 [95% CI, 2.88-36.15]; P < .001). A revised BWH staging system with substitution of ePNI for large-caliber PNI resulted in improved area under the curve and test characteristics compared with current BWH staging criteria that use nerve caliber as the measure of PNI. The findings of this cohort study suggest that ePNI is the best prognostic measure of PNI. Because ePNI obviated the need for a micrometer and had superior prognostic capacity to nerve caliber in this cohort, ePNI should be considered for inclusion in CSCC tumor staging. Inclusion of ePNI as a high-risk factor in CSCC staging systems may optimize patient selection for primary treatment and adjuvant interventions.

Association between childhood adversities and premature and potentially avoidable mortality in adulthood: a population-based study

BackgroundThe association of childhood adversities with mortality has rarely been explored, and even less studied is the question of whether any excess mortality may be potentially preventable. This study examined the association between specific childhood adversities and premature and potentially avoidable mortality (PPAM) in adulthood in a representative sample of the general population. Also, we examined whether the associations were potentially mediated by various adult socioeconomic, psychosocial, and behavioral factors.MethodsThe study used data from the National Population Health Survey (NPHS-1994) linked to the Canadian Vital Statistics Database (CVSD 1994–2014) available from Statistics Canada. The NPHS interview retrospectively assessed childhood exposure to prolonged hospitalization, parental divorce, prolonged parental unemployment, prolonged trauma, parental problematic substance use, physical abuse, and being sent away from home for doing something wrong. An existing definition of PPAM, consisting of causes of death considered preventable or treatable before age 75, was used. Competing cause survival models were used to examine the associations of specific childhood adversities with PPAM in adulthood among respondents aged 18 to 74 years (rounded n = 11,035).ResultsDuring the 20-year follow-up, 5.4% of the sample died prematurely of a cause that was considered potentially avoidable. Childhood adversities had a differential effect on mortality. Physical abuse (age-adjusted sub-hazard ratio; SHR 1.44; 95% CI 1.03, 2.00) and being sent away from home (age-adjusted SHR 2.26; 95% CI 1.43,3.57) were significantly associated with PPAM. The associations were attenuated when adjusted for adulthood factors, namely smoking, poor perceived health, depression, low perceived social support, and low income, consistent with possible mediating effects. Other adversities under study were not associated with PPAM.ConclusionThe findings imply that the psychological sequelae of childhood physical abuse and being sent away from home and subsequent uptake of adverse health behavior may lead to increased risk of potentially avoidable mortality. The potential mediators identified offer directions for future research to perform causal mediation analyses with suitable data and identify interventions aimed at preventing premature mortality due to potentially avoidable causes. Other forms of adversities, mostly related to household dysfunction, may not be determinants of the distal health outcome of mortality.

Effect of radiotherapy on local recurrence, distant metastasis and overall survival in 1200 extremity soft tissue sarcoma patients. Retrospective analysis using IPTW-adjusted models

Background and purposeNeoadjuvant (NRTX) and adjuvant radiotherapy (ARTX) reduce local recurrence (LR) risk in extremity soft tissue sarcoma (eSTS), yet their impact on distant metastasis (DM) and overall survival (OS) is less well defined. This study aimed at analysing the influence of NRTX/ARTX on all three endpoints using a retrospective, multicentre eSTS cohort. Materials and methods1200 patients (mean age: 60.7 ± 16.8 years; 44.4 % females) were retrospectively included, treated with limb sparing surgery and curative intent for localised, high grade (G2/3) eSTS. 194 (16.2 %), 790 (65.8 %), and 216 (18.0 %) patients had received NRTX, ARTX and no RTX, respectively. For the resulting three groups (no RTX vs. NRTX, no RTX vs. ARTX, NRTX vs. ARTX) Fine&Gray models for LR and DM, and Cox-regression models for OS were calculated, with IPTW-modelling adjusting for imbalances between groups. ResultsIn the IPTW-adjusted analysis, NRTX was associated with lower LR-risk in comparison to no RTX (SHR [subhazard ratio]: 0.236; p = 0.003), whilst no impact on DM-risk (p = 0.576) or OS (p = 1.000) was found. IPTW-weighted analysis for no RTX vs. ARTX revealed a significant positive association between ARTX and lower LR-risk (SHR: 0.479, p = 0.003), but again no impact on DM-risk (p = 0.363) or OS (p = 0.534). IPTW-weighted model for NRTX vs. ARTX showed significantly lower LR-risk for NRTX (SHR for ARTX: 3.433; p = 0.003) but no difference regarding DM-risk (p = 1.000) or OS (p = 0.639). ConclusionNRTX and ARTX are associated with lower LR-risk, but do not seem to affect DM-risk or OS. NRTX may be favoured over ARTX as our results indicate better local control rates.

Prognosis of naevoid melanomas

IntroductionThere appear to be several variants of naevoid melanoma suspected as having different outcomes, but follow-up studies have been few. We aimed to assess the prognosis of naevoid melanomas in a multi-centre study. Material and methodsFrom histopathology records we ascertained patients in the UK, Australia and Italy diagnosed with maturing naevoid melanoma (n = 65; 14; 7 respectively) and nodular/papillomatous naevoid melanoma (12; 6; 0), and patients with superficial spreading melanoma (SSM) from UK (73) and Australia (26). Melanoma deaths in UK patients were obtained from NHS Digital; in Australia, via the National Death Index and cancer registry; and in Italy, through clinical records. For maturing naevoid vs. SSM, we used Cox-proportional hazard regression models to compare survival adjusted for age, sex, tumour thickness, and ulceration, and additionally Fine-Gray regression analysis, to calculate sub-hazard ratios (SHR) in the UK cohort, accounting for competing causes of death. ResultsAmong UK patients, there was a non-significantly lower risk of melanoma death in maturing naevoid vs SSM, including after accounting for competing causes of death (SHR 0.40, 95% confidence interval (CI) 0.12–1.31), while among nodular/papillomatous naevoid melanoma patients, there were no melanoma deaths on follow-up. Two melanoma deaths occurred in Australian SSM patients, and none in maturing or nodular/papillomatous naevoid melanoma patients, after 5 years’ minimum follow-up. None of the 7 Italian patients with maturing naevoid melanoma died of melanoma after nearly 12 years’ average follow-up. ConclusionsThere was no significant difference in risk of death from melanomas with naevoid features, and SSM. Nodular/ papillomatous naevoid melanoma patients did not carry higher risk of death than SSM patients though the very few cases of the papillomatous naevoid variant limited our assessment.

THU411 Fracture And Osteoporosis In Hereditary Connective Tissue Disorders: A Systematic Review And Meta-analysis

Abstract Disclosure: N. Charoenngam: None. T. Rittiphairoj: None. A. Jaroenlapnopparat: None. B. Ponvilawan: None. P. Waitayangkoon: None. P. Supakitjanusant: None. V. Prasitsumrit: None. C. Pongchaiyakul: None. M.F. Holick: None. Introduction: Hereditary connective tissue disorders (HCTDs) refer to a constellation of conditions caused by defects in the structure and synthesis of extracellular matrix. It is well-known that bone fragility is the hallmark feature of osteogenesis imperfecta. Interestingly, other HCTDs, including Ehlers-Danlos syndrome (EDS), Marfan’s syndrome (MFS) and Loeys-Dietz syndrome (LDS) are shown to be associated with bone fragility. However, most of the existing studies were small in sample sizes, thereby limiting validity and generalizability. Therefore, we aimed to identify all available data, using systematic review and meta-analysis, to determine the risks of fracture and osteoporosis in patients with HCTDs, including EDS, MFS and LDS. Methods: From inception to June 2022, potentially eligible studies were identified in the Medline and EMBASE databases using search strategy that included terms for “HCTD”, “Fracture” and “Osteoporosis”. Eligible studies must consist of a group of patients with HCTD and report prevalence/incidence of fracture/osteoporosis in their participants, with or without comparison with healthy individuals. Point estimates with standard errors were obtained from each study and combined using the generic inverse variance method. Results: Among the 4,206 articles that were identified, 19 studies fulfilled the eligibility criteria. The pooled prevalence of fracture in patients with EDS, MFS and LDS were 44% (95%CI, 25 - 65%, I2 88%), 17% (95%CI, 11 - 26%, I2 68%), 69% (95%CI, 47 - 85%, I2 83%), respectively. The pooled prevalence of osteoporosis among patients with EDS was 17% (95%CI, 8 - 34%, I2 96%). EDS was associated with fracture [pooled odds ratio 4.90 (95%CI, 1.49 - 16.08, I2 86%)], but not osteoporosis [pooled odds ratio 1.34 (95%CI, 0.28 - 6.36, I2 87%). One study reported a 5% (95%CI, 3 - 8%) prevalence of osteoporosis in MFS, and MFS was associated with fracture [incidence rate ratio 1.35 (95%CI, 1.18 - 1.55)] and osteoporosis [subhazard ratio 3.97 (95%CI, 2.53 - 6.25)]. Conclusion: EDS was associated with fracture, which could be independent of osteoporosis status. MFS had a milder degree of increased risk of fracture and osteoporosis. Despite the lack of data from cohort studies, there was a significantly higher rate of fracture in LDS. Presentation: Thursday, June 15, 2023

Disparities in Kidney Transplant Waitlisting Among Young Patients Without Medical Comorbidities

Disparities in kidney transplant referral and waitlisting contribute to disparities in kidney disease outcomes. Whether these differences are rooted in population differences in comorbidity burden is unclear. To examine whether disparities in kidney transplant waitlisting were present among a young, relatively healthy cohort of patients unlikely to have medical contraindications to kidney transplant. This retrospective cohort study used the US Renal Data System Registry to identify patients with end-stage kidney disease who initiated dialysis between January 1, 2005, and December 31, 2019. Patients who were older than 40 years, received a preemptive transplant, were preemptively waitlisted, or had documented medical comorbidities other than hypertension or smoking were excluded, yielding an analytic cohort of 52 902 patients. Data were analyzed between March 1, 2022, and February 1, 2023. Kidney transplant waitlisting after dialysis initiation. Of 52 902 patients (mean [SD] age, 31 [5] years; 31 132 [59%] male; 3547 [7%] Asian/Pacific Islander, 20 782 [39%] Black/African American, and 28 006 [53%] White) included in the analysis, 15 840 (30%) were waitlisted for a kidney transplant within 1 year of dialysis initiation, 11 122 (21%) were waitlisted between 1 and 5 years after dialysis initiation, and 25 940 (49%) were not waitlisted by 5 years. Patients waitlisted within 1 year of dialysis initiation were more likely to be male, to be White, to be employed full time, and to have had predialysis nephrology care. There were large state-level differences in the proportion of patients waitlisted within 1 year (median, 33%; range, 15%-58%). In competing risk regression, female sex (adjusted subhazard ratio [SHR], 0.92; 95% CI, 0.90-0.94), Hispanic ethnicity (SHR, 0.77; 95% CI, 0.75-0.80), and Black race (SHR, 0.66; 95% CI, 0.64-0.68) were all associated with lower waitlisting after dialysis initiation. Unemployment (SHR, 0.47; 95% CI, 0.45-0.48) and part-time employment (SHR, 0.74; 95% CI, 0.70-0.77) were associated with lower waitlisting compared with full-time employment, and more than 1 year of predialysis nephrology care, compared with none, was associated with greater waitlisting (SHR, 1.51; 95% CI, 1.46-1.56). This retrospective cohort study found that fewer than one-third of patients without major medical comorbidities were waitlisted for a kidney transplant within 1 year of dialysis initiation, with sociodemographic disparities in waitlisting even in this cohort of young, relatively healthy patients unlikely to have a medical contraindication to transplantation. Transplant policy changes are needed to increase transparency and address structural barriers to waitlist access.

Rurality of patient residence and access to transplantation among children with kidney failure in the United States.

Residence in rural areas is often a barrier to health care access. To date, differences in access to kidney transplantation among children who reside in rural and micropolitan areas of the US have not been explored. A retrospective cohort study of children < 18years who developed kidney failure between 2000 and 2019 according to the United States Renal Data System (USRDS). We examined the association between rurality of patient residence and time to living and/or deceased donor kidney transplantation (primary outcomes) and waitlist registration (secondary outcome) using Fine-Gray models. We included 18,530 children, of whom 14,175 (76.5%) received a kidney transplant (39.8% from a living and 60.2% from a deceased donor). Residence in micropolitan (subhazard ratio (SHR) 1.16; 95% CI 1.06-1.27) and rural (SHR 1.18; 95% CI 1.06-1.3) areas was associated with better access to living donor transplantation compared with residence in metropolitan areas. There was no statistically significant association between residence in micropolitan (SHR, 0.95; 95%CI 0.88-1.03) and rural (SHR, 0.94; 95%CI 0.86-1.03) areas compared with metropolitan areas in the access of children to deceased donor transplantation. There was also no difference in the time to waitlist registration comparing micropolitan (SHR 1.04; 95%CI 0.98-1.10) and rural (SHR 1.05; 95% CI 0.98-1.13) versus metropolitan areas. In children with kidney failure, residence in rural and micropolitan areas was associated with better access to living donor transplantation and similar access to deceased donor transplantation compared with residence in metropolitan areas.

COVID-19–associated venous thromboembolism: risk of recurrence and major bleeding

BackgroundComplications under anticoagulant treatment in patients with COVID-19-associated venous thromboembolism (VTE) have not been consistently reported. ObjectivesThis study aimed to compare the 90-day rates of VTE recurrences and major bleeding in patients with COVID-19-associated VTE versus those with VTE without COVID-19. MethodsWe used the RIETE registry to compare the 3-month outcomes in patients with COVID-19-associated VTE versus those with VTE without COVID-19. ResultsThe study included 1,747 patients with COVID-19-associated VTE and 8,711 with VTE without COVID-19. Patients with COVID-19-associated VTE were more likely to be hospitalized at baseline and to present with pulmonary embolism. During the first 90 days, 123 patients (1.17%) developed VTE recurrences, and 266 (2.54%) experienced major bleeding. Patients with COVID-19-associated VTE had a similar rate of VTE recurrences (0.9% vs 1.2%) but a higher rate of major bleeding (4.6% vs 2.1%; P < .001) than those without COVID-19. Multivariable analysis adjusted for competing risks showed that patients with COVID-19-associated VTE had an increased risk of major bleeding (subhazard ratio, 1.395; 95% confidence interval, 1.037-1.877). The 30-day mortality after major bleeding was 26.3% in patients with COVID-19-associated VTE and 17.7% in those without COVID-19. ConclusionPatients with COVID-19-associated VTE had a 5-fold higher rate of major bleeding than VTE recurrences during the first 90 days of anticoagulation. In VTE patients without COVID-19, both rates were similar. These findings highlight the importance of carefully monitoring and optimizing anticoagulation in these patients.

Aortic Root Thrombosis in patients with HeartMate 3 left ventricular assist device support

BackgroundAortic root thrombus (ART) formation is a complication of continuous flow left ventricular assist device (LVAD) therapy. However, the incidence and related complications of ART in HeartMate 3 (HM3) patients remains unknown. MethodsPatients who underwent HM3 implantation from November 2014 through August 2020 at a quaternary academic medical center were included. Demographics and outcomes were abstracted from the medical record. Echocardiograms and contrast-enhanced CT studies were reviewed to identify patients who developed ART and/or moderate or greater aortic insufficiency (AI) on HM3 support. ResultsThe study cohort included 197 HM3 patients with a median post-implant follow-up of 17.5 months. Nineteen patients (9.6%) developed ART during HM3 support, and 15 patients (7.6%) developed moderate or greater AI. Baseline age, gender, race, implantation strategy, and INTERMACS classification were similar between the ART and no-ART groups. ART was associated with an increased risk of death, stroke, or AV intervention (subhazard ratio [SHR] 3.60 [95% CI 1.71-7.56]; p=0.001) and moderate or greater AI (SHR 11.1 [CI 3.60-34.1]; p<0.001) but was not associated with a statistically significantly increased risk of death or stroke on HM3 support (2.12 [0.86-5.22]; p=0.10). Of the 19 patients with ART, 6 (31.6%) developed moderate or greater AI, necessitating more frequent AV interventions (ART: 5 AV interventions [3 surgical repairs, 1 surgical replacement, 1 transcatheter replacement; 26.3%]; no-ART: 0). ConclusionNearly 10% of HM3 patients developed ART during device support. ART was associated with increased risk of a composite endpoint of death, stroke, or AV intervention as well as moderate or greater AI.

Thrombin Generation Is Associated with Venous Thromboembolism Recurrence, but Not with Major Bleeding and Death in the Elderly: A Prospective Multicenter Cohort Study.

It is currently unknown whether thrombin generation is associated with venous thromboembolism (VTE) recurrence, major bleeding, or mortality in the elderly. Therefore, our aim was to prospectively study the association between thrombin generation and VTE recurrence, major bleeding, and mortality in elderly patients with acute VTE. Consecutive patients aged ≥65 years with acute VTE were followed for 2 years, starting from 1 year after the index VTE. Primary outcomes were VTE recurrence, major bleeding, and mortality. Thrombin generation was assessed in 551 patients 1 year after the index VTE. At this time, 59% of the patients were still anticoagulated. Thrombin generation was discriminatory for VTE recurrence, but not for major bleeding and mortality in non-anticoagulated patients. Moreover, peak ratio (adjusted subhazard ratio 4.09, 95% CI, 1.12-14.92) and normalized peak ratio (adjusted subhazard ratio 2.18, 95% CI, 1.28-3.73) in the presence/absence of thrombomodulin were associated with VTE recurrence, but not with major bleeding and mortality after adjustment for potential confounding factors. In elderly patients, thrombin generation was associated with VTE recurrence, but not with major bleeding and/or mortality. Therefore, our study suggests the potential usefulness of thrombin generation measurement after anticoagulation completion for VTE to help identify among elderly patients those at higher risk of VTE recurrence.

Motoric cognitive risk syndrome and its association with falls: a secondary analysis of the Mexican Health and Aging Study

To reveal whether motoric cognitive risk syndrome (MCR) is associated with falls, recurrent falls, and complicated falls in older Mexican adults. This is a secondary analysis of the Mexican Health and Aging Study. MCR was assessed in 2012 and included fall-related outcomes (recurrent [≥2], complicated [need for medical treatment] and number) in the 2018 follow-up. Competing risks analysis was performed, and subhazard ratios (sHRs) were estimated, adjusting for different variables. Negative binomial regression was used to estimate the incidence rate ratio (IRR) of the number of falls. A total of 1 929 participants were included, with a median age of 62 years and 58.3% female. The prevalence of MCR was 17.4% and was associated with falls sHR 1.11 (95%CI: 1.11, 1.12), recurrent falls sHR 1.16 (95%CI: 1.15, 1.16) and complicated falls sHR 1.25 (95%CI: 1.24, 1.25). The number of falls was also independently associated with baseline MCR (IRR 1.19; 95% CI 1.01, 1.40; p=0.039). MCR is independently associated with falls. Increasing the evidence on how MCR anticipates burdensome problems in older adults could lead to actions to halt them; therefore, including it in screening assessments could be clinically useful.