Cohort Of Adult Patients Research Articles

Abstract 17470: Comparison of Outcomes for Adult Patients With Subaortic Stenosis by Surgical or Medical Management: Single-Center Cohort Study

Introduction: Surgery is recommended subaortic stenosis (SAS) patients with severe left ventricular outflow tract obstruction and symptoms, left ventricular dysfunction and sometimes aortic regurgitation, although how surgery modifies patient prognosis is not well understood. We compared the outcomes of SAS based on past and follow-up treatment disposition. Methods: This is a retrospective observation study of adult patients (≥ 18 years) evaluated for SAS on transthoracic echocardiography at our institution during 1/1/2001 to 6/30/2022. Patients were divided into three groups: 1. Patients with prior SAS surgery at index visit; 2. Patients who underwent surgery during follow-up without prior SAS surgery; and 3. Patients managed medically. Primary follow-up endpoint all-cause mortality and secondary endpoint heart failure (HF) hospitalization were compared between groups. Results: There were a total of 115, 106, and 263 patients in group 1, 2, and 3 respectively. The mean age was 45.7±20 years and 67.1% were females. Over median follow-up of 5.5 years, there were 8, 6 and 42 deaths, 3, 9 and 21 heart failure hospitalization, and 20, 15, and 25 SAS recurrences in groups 1, 2, and 3, respectively. Multivariate analysis showed that patients with shortness of breath (odds ratio 3.64, 95% confidence interval 1.20-11.05, P=0.02) and those who are treated medically (1.77 (1.03-3.05), P=0.03) are associated with higher rates of composite death and HF hospitalization. The figure illustrates the Kaplan-Meier survival curves for the primary and secondary endpoint. Group 3 had significantly worse all-cause mortality (P=0.04) and heart failure hospitalization (P=0.03) rates during follow-up. Conclusions: The cohort of adult SAS patients that were managed medically were associated with worse prognosis.

Abstract 15405: Changes in Cardiometabolic Risk Factors Following SARS-CoV-2 Infection

Introduction: Post-acute sequelae of SARS-CoV-2 infection consist of pulmonary and extrapulmonary conditions, including a higher incidence of type 2 diabetes, but it remains unknown whether other cardiometabolic pathways are impacted by infection. Research Question: Does SARS-CoV-2 infection predict worsening cardiometabolic risk factors? Methods: Using data from OneFlorida+ (a PCORnet CRN), we compared changes over time in body mass index (BMI), systolic blood pressure (SBP) and low-density lipoprotein (LDL). We compared an Exposed cohort with a positive SARS-CoV-2 test or COVID-19 diagnosis code between March 2020 - January 2022 (n = 75,217; age: 48.5 y, 64% female), relative to a contemporary Unexposed cohort of adult patients with negative SARS-CoV-2 tests (n = 240,575; age: 52.7 y, 61% female), and an age/sex-matched Historical control cohort (March 2018 - January 2020; n = 75,217; age: 48.5 y, 64% female). We used multiple imputation for missingness in demographic and clinical factors and inverse probability weighting for confounding and loss to follow-up. We used doubly robust marginal structural models to estimate baseline and longitudinal differences in cardiometabolic indicators by cohort. Results: At the start of the follow-up period, adjusted for covariates and relative to the Exposed, the Unexposed (BMI: -0.5 [-0.6,-0.4] kg/m 2 , SBP: -0.5 [-0.8,-0.2] mmHg, LDL: -7.7 [-14.5, -1.0] mg/dL) and Historical control (BMI: -0.4 [-0.5,-0.3] kg/m 2 , SBP: -1.0 [-1.5,-0.6] mmHg, LDL: 12.5 [-58.3, 83.3] mg/dL) cohorts had better cardiometabolic profiles ( Figure ). Relative to changes in the Exposed, control cohorts displayed faster decreases in BMI (Unexposed only), slower increases in SBP, and no changes in LDL during the follow-up period. Conclusions: SARS-CoV-2 infection was associated with weight retention and a rise in blood pressure. Longer follow-up can help identify stability and impacts of these cardio-metabolic indices on events and mortality.

Impact of MTHFR Polymorphisms C677T and A1298C in Acute Lymphoblastic Leukemia and Burkitt Lymphoma Patients Exposed to Methotrexate and Asparaginase

Background: Asparaginase (Asp) and high-dose methotrexate (HDMTX) are pivotal drugs in the treatment of aggressive hematological malignancies as acute lymphoblastic leukemia (ALL) and Burkitt lymphoma (BL). Asp and MTX present specific drug-related toxicities; for Asp, prothrombotic alteration of the coagulation profile, hepatobiliary and pancreatic toxicities, for MTX, renal, hepatobiliary, hematologic, gastro-intestinal and neuro- toxicity. The 5,10-methylenetetrahydrofolate reductase (MTHFR) is the enzyme involved in conversion of homocysteine into methionine. MTHFR most frequent single nucleotide polymorphisms C677T and A1298C are associated with reduced enzymatic activity up to 60%, that implies hyperhomocysteinemia and increased toxicity of MTX. Numerous studies have explored the relationship between C677T and A1298C polymorphisms of MTHFR and MTX toxicity and/or outcome in children ALL, but results are controversial. Nevertheless, it is common practice to reduce MTX dosage in adult patients in homozygosis. Aims: To explore the relationship between the MTHFR C677T and A1298C polymorphisms in homozygosis and development of MTX toxicity in a cohort of adult patients; furthermore, to evaluate the relationship with thrombotic risk in patients exposed to Asp. Materials and Methods: Data from consecutive adult onco-hematologic patients for whom MTHFR C677T and A1298C polymorphism analysis was available, treated with chemotherapeutic regimens containing HDMTX and/or Asp was retrospectively collected at a single center Italian institution. Adverse events (AEs) were graded according to CTCAE 5.0. Statistical analysis was performed with R language. The impact of MTHFR polymorphisms was evaluated by mean of a multivariate analysis adjusting Odds Ratio (OR) estimates for drug dosage and disease status. Results: Data from 78 patients, 57 affected by ALL, 3 by mixed phenotype leukemia (MPAL) and 18 by BL, was retrospectively collected. Overall, 13 (16.7%) of patients were 677TT and 8 (10.3%) were 1298CC. Patients with ALL/MPAL received mostly pediatric-inspired chemotherapy regimens (containing MTX 2.5 - 5 g/m 2 and Asp 1000-2000 UI/m 2), patients with BL received modified Rituxumab (R)-BFM protocol (MTX 1.5 g/m2); age/comorbidities-adjusted dose reduction was performed according to institutional guidelines. Median age for ALL and BL patients was 37.5 (IQR 27.0-54.2) and 33.5 (26.0-49.7) years, respectively; 54/78 (69.2%) of patients were male. Patients received a median of 3 (IQR 2-6) cycles containing HDMTX and/or Asp, for a total number of 299 cycles (94 containing Asp, 184 HDMTX and 24 both); 142 (48.0%) cycles were administered for active disease (AD), at diagnosis/relapse, and 154 (52.0%) in complete remission (CR). The impact of different dosages of Asp < 1000 UI/m 2 and ≥ 1000 UI/m² and of HDMTX <1.5 g/m 2 and ≥ 1.5 g/m 2 as well as the impact of disease status (AD vs CR) on AEs was explored. Concerning Asp therapy and thrombotic risk, 13 deep vein thrombosis (DVT) were observed, but no association between 677TT nor 1298CC was appreciated. AD status was strongly related to DVT (21.4% vs 1.8%, p 0.003). Coherently with the MTHFR-independent drug's mechanism of action, the polymorphisms had no impact on the development of Asp-related toxicities. Diversely, concerning HDMTX, in multivariate analysis, patients with 677TT were more likely to experience AST increase grade ≥3 (OR 10.55, 95%CI 1.34-83.09) while a protective role versus any grade GGT increase was observed (OR 0.09, 95%CI 0.01-0.71) (Figure 1A). Patients with 1298CC exhibited a superior incidence any grade AST/ALT increase, not confirmed for grade ≥3 (Figure 1B). No significant superior toxicity was observed in terms of renal, gastro-intestinal, hematologic AEs. The impact of a MTX dose reduction >25% of expected dose was then explored in a homogeneous population of 45 front-line pediatric-regimen treated ALL patients (35 received MTX dose ≥75% and 10 < 75%) and no impact in terms of OS and RFS was appreciated. Conclusions: The analysis ofMTHFR polymorphisms in adult patients is useful in identifying patients at higher risk for transaminitis, providing a biological parameter to integrate with hepatosteatosis, liver stiffness evaluation and BMI, for a comprehensive hepatic baseline evaluation. Patients at higher risk for hepatic complications may benefit from MTX dose reduction with no impact on disease outcome.

Metabolism-Related Features Identify the Combination Metformin Plus NAMPT Inhibitors As a Selective Treatment Strategy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous disease, which remains difficult to treat due to its heterogeneous nature. Recently, metabolic adaptation has been recognized as a trademark of leukemogenesis. Notably, altered function of mitochondria (mt) in leukemic stem cells (LSCs) has been linked to chemoresistance in some patients, causing relapse of disease. Thus, targeting the rewired energy metabolism of leukemic cells has gained a lot of attention in recent years. Here, using a large cohort of adult de novo AML samples (n=502 patients, all intensively treated with 3+7 scheme), we identified a subset of patients with increased mitochondrial DNA content (mtDNAcn, n=163) compared to age- and sex-matched healthy controls (n=308). mtDNAcn was significantly higher in patients harboring FLT3-ITD (31%) and IDH1 mutations (50%). Patients with high mtDNAcn were associated with worse clinical outcomes regardless of European Leukemia Net (ELN) risk stratification, sex, and age. In contrast, high mtDNAcn was not a predictive survival marker in a cohort of adult AML patients treated with venetoclax (VEN) + hypomethylating agents (HMA), indicating that these metabolic features are specifically linked to the resistance to intensive chemotherapy. Using label-free quantitative proteome analysis (11272 proteins) combined with metabolomic screening (173 metabolites) on sorted CD34 +/CD117 + AML blasts (n=26), we found that AMLs with high mtDNAcn were enriched for signatures like “GMP-like” and “mt complex I activity”, being metabolically enriched for long-chain fatty acids, suggesting that these cells rely more on oxidative phosphorylation (OXPHOS) metabolism. Functionally, AML blasts with high mtDNAcn displayed increased levels of BCL2, mt mass, and mt membrane potential, which was associated with increased oxygen consumption rate (OCR) measured by extracellular flux analysis. Considering the impact of mtDNAcn on AML survival in patients treated with intensive chemotherapy, which was not observed in the context of VEN+HMA, and considering the increased reliance of LSC on mtOXPHOS, we studied the impact of mtDNAcn on chemotherapy response. Ex vivo analysis of primary AML samples with high mtDNAcn indicated increased resistance to AraC-induced apoptosis, which was reverted upon knock-down of the DNA polymerase gamma gene (POLG) encoding the catalytic subunit of the mtDNA polymerase. Due to the link between mtDNAcn and mt complex I activity, we investigated if the treatment with metformin, known to inhibit complex I, would sensitize AML patients with high mtDNAcn to the standard of care AML drugs, such as Cytarabine (AraC), FLT3-inhibitors and VEN. Treatment with low dose of metformin (1 mM) effectively reduced the mtDNAcn in AML cells (n=40), resulting in decreased OCR, while glycolysis was increased, suggesting metabolic rewiring. Furthermore, the combination of metformin with AraC, VEN and FLT3-inhibitors synergistically increased drug-induced apoptosis in AML cells with high mtDNAcn and helped to overcome VEN resistance in AML cells. In vivo, combination of metformin with VEN prolonged the survival of mice transplanted with K562 cells (VEN resistant), resulting in decreased leukocyte counts and blood chimerism. Since treatment with metformin resulted in metabolic rewiring, with increased glycolysis and NAD + consumption, we wondered if the combination of metformin with glycolytic (2-DG/DAP) and NAMPT (KPT-9274) inhibitors would impede the metabolic rewiring, enhancing cytotoxicity. Among the different treatment combinations, we find that the combination of metformin and KPT-9274 gave the best therapeutic window by significantly increasing drug-induced apoptosis, with more pronounced effects in patients with high mtDNAcn, while sparing healthy CD34 + cells. Concomitantly, OXPHOS and glycolysis were diminished upon KPT-9274+metformin, suggesting that the combination was able to bypass the metabolic rewiring of the AML cells. In conclusion, we uncover a subgroup of patients with high mtDNAcn linked to increased mtOXPHOS that is resistant to chemotherapy-induced apoptosis and is characterized by poor clinical outcomes, which can be overcome by the inhibition of the mt complex I. Moreover, the quantification of mtDNAcn can be easily incorporated into clinical practice as a simple and cost-effective metabolic readout of AML patients to identify metabolic vulnerabilities.

Assessment of quality of care for hospitalized non-COVID-19 older adult patients with pneumonia before and after the COVID-19 pandemic

BackgroundThere is limited research into the clinical implications of the coronavirus disease 2019 (COVID-19) pandemic for non-COVID-19 pneumonia in older adults, as well as their quality of care or outcomes. This study aims to assess the process and outcome quality of care for hospitalized older adult patients with pneumonia before and after the pandemic. MethodsA retrospective cohort of older adult patients (age ≥ 65) hospitalized for non–COVID pneumonia were recruited from five Korean hospitals (January 20, 2019, to January 19, 2021). The quality of care before and after the COVID-19 pandemic was evaluated. ResultsA total of 7356 hospitalization episodes of older adult pneumonia were identified, and 978 cases (552 pre-pandemic and 426 during the pandemic) were analyzed. The pneumonia severity score was higher during the pandemic, and the waiting time from the emergency room to admission was also longer. Furthermore, the pneumonia mortality rate during the pandemic was higher than that in the pre-pandemic period (in-hospital mortality: 10.1% vs. 18.1%; 90-day mortality: 11.6% vs. 22.3%). A significantly higher mortality risk was observed during the pandemic than in the period prior (adjusted odds ratio: 1.74, 95% confidence interval: 1.14–2.63). ConclusionsWhile the quality of care for hospitalized pneumonia has been maintained during the pandemic, there has been an increase in mortality rates. Further investigations are needed to understand the underlying causes of this increase.

Results from an Intergroup Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Classic Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Research Group (E4412)

Background: Relapsed/refractory (R/R) Classic Hodgkin lymphoma (cHL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is an intergroup Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (N), and ipilimumab (I) in patients with R/R cHL. Here we present the efficacy and safety data on the full adult cohort of patients treated in Phase 2 randomized between BV/N and BV/N/I. Methods: Patients with confirmed R/R cHL were randomized between the doublet of BV/N with BV 1.8mg/kg and N 3mg/kg and BV/N/I with I 1mg/kg. BV and N were administered every 3 weeks, and I every 12 weeks for up to 1 year for BV and up to 2 years for N and I. Results: One hundred twenty-six patients were enrolled and treated; 8 patients (4 from each arm) were excluded from efficacy analysis based on ineligibility. Patients were not heavily pretreated, 65% had one prior line of therapy and an additional 27% had two prior lines, and 8% had more than 2 prior lines. The median age was 34; 51% of patients were male. Sixteen patients had prior BV: 10 (BV/N arm) and 6 (BV/N/I). Response: One hundred eighteen patients are evaluable for response: 61 treated with BV/N and 57 with BV/N/I. With BV/N 37 of 61 (60.7%) of patients had a complete response (CR) compared to 38 of 57 (66.7%) with BV/N/I for a difference of 6.7% (p-value 0.31). Additionally, 17 (28%) with BV/N and 12 (21%) of patients treated with BN/N/I had a partial response (PR) for an overall response rate (ORR) of 88% in both arms. In a planned analysis of patients with prior treatment with BV the CR rate was 25% in BV/N arm (2 of 8) and 60% in BV/N/I arm (3 of 5). The median follow-up for progression free survival (PFS), duration of response (DOR), and overall survival (OS) is 24.8 months and 33.7 months. The median PFS, duration of response and OS have not been reached for either arm with 24 months of follow-up ( Figure 1). In B/N 30 of 61 patients came off study to receive alternative treatments (primarily autologous stem cell transplant (SCT)) and in BV/N/I 23 of 57 patients did. Safety: Table 1 shows treatment-related Grade 3+ toxicity occurring in > 1 patient and adverse events (AE) of special interest. All 126 patients (118 eligible and 8 ineligible) are evaluable for safety. The rate of Grade 3+ treatment related toxicity is 43% (28/65) and 52% (32/61) for BV/N and BV/N/I, respectively. However, when rash is excluded the rate of treatment related toxicities is similar between the two arms 38.5% vs 39.3%. There was no grade 4 rash, and the rash was treatable in all cases with topical or oral steroids. There were no Grade 5 toxicities in either arm. Conclusion: In this randomized Phase 2 study comparing BV/N vs. BV/ N/I the difference in CR rate of 6.7% between the doublet and the triplet was not statistically significant. Additionally, the triplet had more grade 3 rash than the doublet, there was otherwise no significant difference in grade 3 or greater toxicity between the two arms. With a median follow-up of 24 months the PFS and DOR have not been reached for either arm, suggesting excellent disease control from both regimens. Differences in response for BV pre-treated patients between the two arms is intriguing especially as more patients are treated with BV in the frontline, but the sample size is too small to draw firm conclusions. Correlative studies are underway to elucidate a response vs. resistance signature, and biological understanding of differential benefit.

Association between hospital onset of infection and outcomes in sepsis patients – A propensity score matched cohort study based on health claims data in Germany

BackgroundHospital-acquired infections are a common source of sepsis. Hospital onset of sepsis was found to be associated with higher acute mortality and hospital costs, yet its impact on long-term patient-relevant outcomes and costs is unknown. ObjectiveWe aimed to assess the association between sepsis origin and acute and long-term outcomes based on a nationwide population-based cohort of sepsis patients in Germany. MethodsThis retrospective cohort study used nationwide health claims data from 23 million health insurance beneficiaries. Sepsis patients with hospital-acquired infections (HAI) were identified by ICD-10-codes in a cohort of adult patients with hospital-treated sepsis between 2013 and 2014. Cases without these ICD-10-codes were considered as sepsis cases with community-acquired infection (CAI) and were matched with HAI sepsis patients by propensity score matching. Outcomes included in-hospital/12-month mortality and costs, as well as readmissions and nursing care dependency until 12 months postsepsis. ResultsWe matched 33,110 HAI sepsis patients with 28,614 CAI sepsis patients and 22,234 HAI sepsis hospital survivors with 19,364 CAI sepsis hospital survivors. HAI sepsis patients had a higher hospital mortality than CAI sepsis patients (32.8% vs. 25.4%, RR 1.3, p < .001). Similarly, 12-months postacute mortality was higher (37.2% vs. 30.1%, RR=1.2, p < .001). Hospital and 12-month health care costs were 178% and 22% higher in HAI patients than in CAI patients, respectively. Twelve months postsepsis, HAI sepsis survivors were more often newly dependent on nursing care (33.4% vs. 24.0%, RR=1.4, p < .001) and experienced 5% more hospital readmissions (mean number of readmissions: 2.1 vs. 2.0, p < .001). ConclusionsHAI sepsis patients face an increased risk of adverse outcomes both during the acute sepsis episode and in the long-term. Measures to prevent HAI and its progression into sepsis may be an opportunity to mitigate the burden of long-term impairments and costs of sepsis, e.g., by early detection of HAI progressing into sepsis, particularly in normal wards; adequate sepsis management and adherence to sepsis bundles in hospital-acquired sepsis; and an improved infection prevention and control.

Glomerular hyperfiltration in patients with severe trauma

Background and objectiveAugmented renal clearance or glomerular hyperfiltration (GHF) can significantly affect the clinical outcomes of renally eliminated drugs by promoting subtherapeutic drug exposure. The aggression suffered in patients who suffer severe trauma is a predisposition to manifest GHF and the identification of these patients remains a clinical challenge. The main objective of this study was to describe the prevalence of GHF in a cohort of critically ill trauma patients. Materials and methodsProspective observational study of a cohort of adult patients admitted after suffering severe trauma or polytrauma in the Anesthesiology ICU of the University Hospital of Albacete (Spain). Creatinine clearance (ClCr) was calculated in a 4-h urine collection sample at 24, 72 and 168 h after admission applying the formula; CrCl: [Diuresis in ml (urine/4 h) × Creatinine in urine (mg/dl)] ÷ [240 (minutes) × Creatinine in plasma (mg/dl)]. A CrCl above 130 mL/min was considered GHF. The analyses were performed with the statistical software R version 4.0.4. Results85 patients were included. The median age of the patients was 51 years (IQR 26), 78.82% male. 68 patients were male (78.82%). 75.29% of the patients were polytraumatized. 61 patients (71.76%) presented GHF at some point in the CrCl determination. At 24 h of admission, 56.34% of the patients presented GHF with a mean CrCl of 195.8 ml/min, 61.11% of the patients presented it at 72 h with a mean CrCl of /min and 56.52% presented GHF at 168 h of admission with a mean CrCl of 207 ml/min. A significant positive relationship (p = 0.07) was found between GHF manifested at 72 h and at 168 h. We observed a statistically significant relationship between this phenomenon with younger ages, lower ISS scores and lower plasma creatinines. ConclusionsGHF are a common condition in critically ill patients admitted for severe trauma. We recommend the use of CrCl to assess renal function and make dosage adjustments. Studies are required to understand the clinical impact of these phenomena on drug elimination and to be able to establish the ideal dosage in those cases.

The Association Between Transverse Maxillary Deficiency and Septal Deviation in Adults with Obstructive Sleep Apnea.

Recent evidence suggests that environmental factors impact craniofacial development. Specifically, the height and width of the maxilla may impact the degree of septal deviation. We sought to determine the relationship between transverse maxillary deficiency and severity of septal deviation. A prospective cohort of adult sleep surgery patients were evaluated by standardized CT imaging. Primary outcomes evaluated the relationship of a narrow, high-arched palate (the palatal height to width ratio) with the degree of septal deviation at the level of the 1st premolar and 1st molar. Secondary outcome evaluated the relationship of the palatal height-to-width ratio and nasal obstruction. Both adjusted and unadjusted linear regression were performed, including correction for multiple hypothesis testing. Ninety-three patients were included. On average, the cohort was middle aged (54.7 ± 12.7 years), obese (BMI 30.1 ± 4.5 kg/m2), predominantly male (74.2%), White (73.1%), and with severe obstructive sleep apnea (OSA) (AHI 30.0 ± 18.7 events/h). A moderate correlation was observed between both the relative and absolute inter-premolar palatal height and the degree of septal deviation at the inter-molar region. No significant correlation was observed between palatal dimensions and NOSE score. This study found that transverse maxillary deficiency is moderately associated with greater degree of septal deviation among a sample of OSA patients. This contributes to the concept that craniofacial development impacts the nasal airway, promoting a comprehensive evaluation of both endonasal and extranasal structures. 4 Laryngoscope, 134:2464-2470, 2024.

Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study

Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n= 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

Surface anatomical landmarks for spine surgery: A CT-based study of the sternal notch and sternal angle in 1,035 patients

BackgroundUnderstanding the location of surface anatomical landmarks in relation to the cervical and thoracic spine is important for a wide array of clinical applications. The objective of this study was to investigate the influence of patient demographic and anthropometric characteristics on the locations of the sternal notch and sternal angle in relation to the spine using computed tomography (CT) of a large cohort of young adult patients without spinal pathology. MethodsVertebral levels corresponding to the sternal notch and sternal angle were analyzed using CT of 1,035 patients. Influences of patient height, weight, body mass index (BMI), sex, and ethnicity were assessed. Results567 male and 468 female patients were included in this study. Mean patient height, weight, BMI, and age were 1.68 ± 0.11 m, 81.94 ± 24.39 kg, 27.79 ± 7.9 kg/m2, and 25.9 ± 5.9 years. Of the 1,035 patients, 495 were Hispanic or Latino, 321 were Caucasian, 130 were African American, 68 were Asian, 5 were identified as “other,” and 16 did not have racial or ethnic data available. The location of the sternal notch in relation to the thoracic spine demonstrated a bimodal distribution pattern clustered at the T2 and T3 vertebral bodies. The location of the sternal angle in relation to the thoracic spine demonstrated a bimodal distribution pattern clustered at the T4 and T5 vertebral bodies. Moderate, negative correlations were observed between patient weight and location of the sternal notch (r = −0.447; p <.001) and sternal angle (r = −0.499; p <.001), respectively. Zero significant correlations were observed between patient height and location of the sternal notch (r = −0.045; p =.377) or sternal angle (r = −0.080; p =.229). A weak, negative correlation was observed between patient BMI and location of the sternal notch (r = −0.378; p <.001). A moderate, negative correlation was observed between patient BMI and location of the sternal angle (r = −0.445; p <.001). The locations of the sternal landmarks did not differ based on patient sex, race or ethnicity. ConclusionsThe location of the sternal notch most frequently corresponds to the T2 or T3 vertebral body, while the sternal angle is most frequently located at the T4 or T5 vertebral body. Increased patient weight is associated with relatively cephalad sternal landmarks. Patient height, sex, and ethnicity are not associated with either sternal landmark.

The Association Between Prepandemic ICU Performance and Mortality Variation in COVID-19: A Multicenter Cohort Study of 35,619 Critically Ill Patients

During the COVID-19 pandemic, ICUs remained under stress and observed elevated mortality rates and high variations of outcomes. A knowledge gap exists regarding whether an ICU performing best during nonpandemic times would still perform better when under high pressure compared with the least performing ICUs. Does prepandemic ICU performance explain the risk-adjusted mortality variability for critically ill patients with COVID-19? This study examined a cohort of adults with real-time polymerase chain reaction-confirmed COVID-19 admitted to 156 ICUs in 35 hospitals from February 16, 2020, through December 31, 2021, in Brazil. We evaluated crude and adjusted in-hospital mortality variability of patients with COVID-19 in the ICU during the pandemic. Association of baseline (prepandemic) ICU performance and in-hospital mortality was examined using a variable life-adjusted display (VLAD) during the pandemic and a multivariable mixed regression model adjusted by clinical characteristics, interaction of performance with the year of admission, and mechanical ventilation at admission. Thirty-five thousand six hundred nineteen patients with confirmed COVID-19 were evaluated. The median age was 52 years, median Simplified Acute Physiology Score 3 was 42, and 18%underwent invasive mechanical ventilation. In-hospital mortality was 13%and 54%for those receiving invasive mechanical ventilation. Adjusted in-hospital mortality ranged from 3.6%to 63.2%. VLAD in the most efficient ICUs was higher than the overall median in 18%of weeks, whereas VLAD was 62%and 84%in the underachieving and least efficient groups, respectively. The least efficient baseline ICU performance group was associated independently with increased mortality (OR, 2.30; 95%CI, 1.45-3.62) after adjusting for patient characteristics, disease severity, and pandemic surge. ICUs caring for patients with COVID-19 presented substantial variation in risk-adjusted mortality. ICUs with better baseline (prepandemic) performance showed reduced mortality and less variability. Our findings suggest that achieving ICU efficiency by targeting improvement in organizational aspects of ICUs may impact outcomes, and therefore should be a part of the preparedness for future pandemics.

Referral and Prescription Patterns for Female Patients With Urinary Incontinence.

Although behavioral modifications, medications, and other interventions can improve urinary incontinence (UI), many women never receive them. To better characterize UI treatment patterns in primary care, we examined prescriptions and referrals to pelvic floor physical therapy (PFPT) and specialist physicians within a large Midwestern academic health system. Electronic health records were queried to identify a cohort of adult female patients receiving a new UI diagnosis during outpatient primary care visits from 2016 to 2020. Urinary incontinence referrals and referral completion were examined for the overall cohort, and medication prescriptions were examined for women with urgency or mixed UI. Logistic regression was used to assess the association of prescriptions and/or referrals with patient demographics, comorbidities, and UI diagnosis dates. In the year after primary care UI diagnosis, 37.2% of patients in the overall cohort (n = 4,382) received guideline-concordant care. This included 20.6% of women who were referred for further management: 17.7% to urology/urogynecology and 3.2% to PFPT. Most women who were referred attended an initial appointment. Among those with urgency (n = 2,398) or mixed UI (n = 552), 17.1% were prescribed medication. Women with stress (odds ratio [OR], 3.10; 95% CI, 2.53-3.79) and mixed UI (OR, 6.17; 95% CI, 4.03-9.66) were more likely to be referred for further management, and women diagnosed during the COVID-19 pandemic were less likely to be referred for further care (OR, 0.39; 95% CI, 0.29, 0.48). Only slightly above 1 in 3 women with a new diagnosis of UI in primary care received guideline-based medications or referrals within 1 year, suggesting missed opportunities for timely care.

THU338 Risks Of Stroke, Its Subtypes And Atrial Fibrillation Associated With Glucagon-like Peptide 1 Receptor Agonists Versus Sodium-glucose Cotransporter 2 Inhibitors: A Real-world Population-based Study In Hong Kong

Abstract Disclosure: D. Lui: None. E. Tang: None. T. Wu: None. I. Au: None. C. Lee: None. Y. Woo: None. K.C. Tan: None. C. Wong: None. Objectives: There are limited data on head-to-head comparative risk of stroke between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). Such a comparison may provide further insights in the selection of appropriate anti-diabetic agents. We compared risk of stroke with its subtypes and incident atrial fibrillation (AF) between them in a population-based cohort. Methods: A population-based cohort of adult patients (aged 18 years or above) with type 2 diabetes between 2008 and 2020 were identified from the electronic health records of Hong Kong Hospital Authority. Patients who received SGLT2i or GLP-1RA were matched pairwise by propensity score. The index date of each patient was set at the date of SGLT2i or GLP-1RA initiation. Patients with end-stage kidney disease or co-initiation of SGLT2i and GLP-1RA at the index date were excluded. The primary outcome was all events of stroke, consisting of hemorrhagic and ischemic stroke. Secondary outcomes included hemorrhagic stroke, ischemic stroke, incident AF, and cardioembolic stroke. Each patient was observed from the index date until the occurrence of events, death, treatment cross-over, or end-of-study (31 December 2020), whichever was earlier. Risks of stroke and AF were evaluated by hazard ratios (HRs) from the Cox proportional hazard regression models. Results: A total of 5,840 patients (2,920 SGLT2i users; 2,920 GLP-1RA users) were included (mean age 55.5 years, 56.1% men, mean HbA1c 8.9% and duration of diabetes 13.7 years). Upon median follow-up of 17 months (IQR: 8-34), there were 111 events of stroke. SGLT2i users had comparable risk of all stroke as GLP-1RA users (HR=1.46, 95%CI 0.99-2.17, p=0.058). SGLT2i users had higher risk of ischemic stroke (HR=1.53, 95%CI 1.01-2.33, p=0.044) but similar risk of hemorrhagic stroke (HR=1.29, 95%CI: 0.53-3.14, p=0.582) compared to GLP-1RA users. Although SGLT2i was associated with lower risk of incident AF (HR=0.43, 95%CI 0.23-0.79, p=0.006), risk of cardioembolic stroke was similar (HR=1.40, 95%CI: 0.62-3.17, p=0.414). Subgroup analyses showed no significant interaction between subgroups by age, sex, glycemic control and history of AF. However, patients with history of stroke appeared to benefit more from GLP-1RA use (p for interaction=0.043) than those without history of stroke. Patients with shorter duration of diabetes (&amp;lt;10 years) also appeared to benefit more from GLP-1RA use than those with longer duration of diabetes (p for interaction=0.017). Conclusions: Our real-world study demonstrated that GLP-1RA use was associated with lower risk of ischemic stroke, despite the association between SGLT2i use and lower risk of incident AF. There was no significant difference in hemorrhagic stroke risk. GLP-1RA may be the preferred agent for patients with type 2 diabetes at risk of ischemic stroke. Presentation: Thursday, June 15, 2023

Female sex and burden of depressive symptoms predict insufficient response to telemedical treatment in adult attention-deficit/hyperactivity disorder: results from a naturalistic patient cohort during the COVID-19 pandemic.

Attention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder, that typically manifests itself during childhood and persists in a majority of the affected individuals into adulthood, negatively affecting physical and mental health. Previous studies have shown detrimental effects of the COVID-19 pandemic on mental health in individuals with ADHD. Thus, telemedicine could be a useful tool for optimizing treatment-outcomes in adult ADHD by improving treatment adherence and persistence. However, data on telemedical treatment outcomes in adult patients with ADHD is scarce. We report here the sub-cohort analysis of a naturalistic cohort of adult patients (N = 254) recruited between April 2020-April 2021, comparing the effects of telemedical treatment on participants either clinically diagnosed with depression (N = 54) or ADHD (N = 67). Participants were asked to fill out the WHO-5 repetitively during >12 weeks of telemedical treatment. Furthermore scores of WHO-5, SCL-90R and BDI-II, psychopathology, psychosocial functioning, sociodemographic data, medical records and a feedback survey were analyzed for both groups and compared. Participants with ADHD were further stratified according to the development of well-being during the study period in order to identify factors associated with a satisfactory treatment outcome. Participants with depression reported a significant improvement of well-being during the course of the study, while no such effect could be seen in participants with ADHD on a group level. Despite the good outcome, participants with depression were more severely affected at baseline, with significantly worse psychopathology and a more precarious labor and financial situation. A detailed analysis of ADHD participants without clinical improvement revealed significantly higher BDI-II scores than for ADHD participants with a satisfactory outcome (p = 0.03, Mann-Whitney-U-Test), suggesting successful treatment was hampered by the combination of ADHD and depressive symptoms. Furthermore, female sex among ADHD patients was correlated with an unfavorable treatment outcome during the course of the study (p = 0.001, Spearman correlation) as well as living with children (p = 0.02, Spearman correlation). Besides screening for depressive symptoms before telemedical treatment, future research should address the specific needs of female ADHD patients as these patients may be at a particularly high risk of being overburdened with family work.

Characterization of Serum Cytokine Profiles of Patients with Active Lupus Nephritis.

Cytokines contribute to the pathogenesis of lupus nephritis (LN), yet their value as prognostic biomarkers is still debated. We aimed to describe the serum cytokines' profiles and prospectively assess correlations with disease features and renal response in a multicentric cohort of consecutive adult patients with biopsy-proven active LN. Cytokine associations with clinical and serological data were performed at LN diagnosis (T0), and at 3 (T3) and 6 months (T6) of follow up. Renal response according to EULAR definition was assessed at T3, T6 and T12. BAFF and interleukin (IL)-37 were measured by ELISA; IL-2, IL-10, IL-17A and IL-18 by a bead-based multiplex cytokine assay (Luminex). Thirty-nine patients with active LN (age 40.5 ± 15.6 years; F 71.8%; 84.6% proliferative LN) were enrolled, of whom twenty-nine displayed complete longitudinal records. At T0, we observed higher levels of IL-37 and IL-17 in proliferative vs. non-proliferative LN (IL-37: 0.0510 (0.0110-0.2300) vs. 0.0000 (0.0000-0.0397) ng/mL, p = 0.0441; IL-17: 2.0920 (0.5125-17.9400) vs. 0.0000 (0.0000-0.6025) pg/mL, p = 0.0026, respectively), and positive correlations between IL-10 and 24 h proteinuria (r = 0.416, p = 0.0249) and anti-dsDNA levels (r = 0.639, p = 0.0003). BAFF was higher in patients with low complement (p < 0.0001). We observed a sustained correlation between BAFF and IL-10 throughout T6 (r = 0.654, p = 0.0210). Higher baseline IL-37 and BAFF levels were associated with renal response at T3 and T6, respectively, while baseline IL-18 levels were higher in patients achieving response at T12. Our study highlights the complexity of the cytokine network and its potential value as a marker of active LN and renal response.

MyPathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment of a Tissue-Agnostic Cohort of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The MyPathway multiple-basket study (ClinicalTrials.gov identifier: NCT02091141) is evaluating targeted therapies in nonindicated tumors with relevant molecular alterations. We assessed pertuzumab + trastuzumab in a tissue-agnostic cohort of adult patients with human epidermal growth factor receptor 2 (HER2)-amplified and/or -overexpressed and/or -mutated solid tumors. The primary end point was objective response rate (ORR); secondary end points included survival and safety. At data cutoff (March 2022), 346 patients with HER2 amplification and/or overexpression with/without HER2 mutations (n = 263), or HER2 mutations alone (n = 83) had been treated. Patients with HER2 amplification and/or overexpression had an ORR of 25.9% (68/263, 95% CI, 20.7 to 31.6), including five complete responses (urothelial [n = 2], salivary gland [n = 2], and colon [n = 1] cancers). Activity was higher in those with wild-type (ORR, 28.1%) versus mutated KRAS (ORR, 7.1%). Among patients with HER2 amplification, ORR was numerically higher in patients with immunohistochemistry (IHC) 3+ (41.0%; 32/78) or 2+ (21.9%; 7/32), versus 1+ (8.3%; 1/12) or no expression (0%; 0/20). In patients with HER2 mutations alone, ORR was 6.0% (5/83, 95% CI, 2.0 to 13.5). Pertuzumab + trastuzumab showed activity in various HER2-amplified and/or -overexpressed tumors with wild-type KRAS, with the range of activity dependent on tumor type, but had limited activity in the context of KRAS mutations, HER2 mutations alone, or 0-1+ HER2 expression.

Follow-up of pre-motor symptoms of Parkinson’s disease in adult patients with Gaucher disease type 1 and analysis of their lysosomal enzyme profiles in the CSF

BackgroundParkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Its classic motor symptoms may be preceded by non-motor symptoms (NMS). Population studies have identified GBA variants as risk factors for idiopathic PD. The increased risk of PD has also been suggested in other Lysosomal Storage Disorders (LSDs). Objective: To assess the evolution of the prevalence of NMS compatible with PD in a cohort of South Brazilian adult patients with Gaucher Disease (GD) type 1, already evaluated 3 years ago (2018). Cerebrospinal Fluid (CSF) was collected to assess the levels of LSD enzymes (beta-hexosaminidases, beta-glucuronidase) and biomarker of macrophage activation (chitotriosidase, ChT), compared to controls (metachromatic leukodystrophy, MLD). Cognition was evaluated by the Montreal Cognitive Assessment (MoCA) questionnaire, daytime sleepiness by the Epworth Sleepiness Scale (ESS), depression by Beck´s Inventory, constipation by the Unified Multiple System Atrophy Rating Scale (UMSARS) scale, and REM sleep behavior disorder by the single-question screen. Hyposmia was assessed with Sniffin’ Sticks (SST).ResultsNineteen patients completed the follow-up (mean age of the sample was 44 years; range, 26–71). The patient with the highest number of NMS at the baseline (4 including the lowest SST score) was diagnosed with PD four years later. Apart from an improvement in the ESS score, no other statistical significance was found between the number of NMS between the first and second evaluation, nor between patients with one L444P variant (n = 5) and the rest of the cohort. CSF was collected in five patients (mean age of the sample was 40 years, range 30–53. A significant difference was found in the mean CSF activity levels of beta-hexosaminidases and beta-glucuronidase between GD1 and MLD patients. Mean ChT (CSF) was 62 nmol/h/mL in GD patients and 142 in MLD (n = 6) patients.ConclusionsThe patient with the highest number of NMS in our 2018 cohort was the one that developed PD, corroborating with the importance of this longitudinal follow-up. CSF and plasma analysis might allow a better understanding of the neurodegenerative processes connecting PD and the lysosomal environment. Further analysis is needed to understand this relationship.

High-purified cannabidiol efficacy and safety in a cohort of adult patients with various types of drug-resistant epilepsies

About 30% of patients with epilepsy are drug resistant. Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and tuberous sclerosis complex (TSC) are diseases for which high-purified-cannabidiol (CBD) known as Epidiolex® (GW pharma) can be prescribed in add-on of other medications in case of drug-resistance. Currently, there are only a few recent data in the literature about the efficacy and safety of CBD in other forms of refractory epilepsies especially focal epilepsies in adults. We report retrospectively the experience of high-purified-CBD use in two French reference medical centers for epilepsy in various forms of drug-resistant epilepsy. We distinguished two groups of patients: group A with epileptic encephalopathies and group B with focal or multifocal epilepsy. Safety and efficacy (% of responder patients) were evaluated. Finally, 73 patients (51 in group A and 22 in group B) used high-purified CBD as an add-on treatment for their drug-resistant epilepsy. Patients in group A were significantly younger (P=0.0155), with a longer exposition of treatment (P=0.0497) than group B and with higher doses (P=0.0300). Respectively, 15 patients (29.4%) and five patients (22.7%) were responders during the follow-up period (P=0.552). The association with clobazam was more frequent in responders than in non-responder patients (16 patients [80%] versus four [20%]). The most frequent side effect was somnolence. At the end of follow-up, 15 patients in group A (29.4%) and nine patients in group B (40.1%) had stopped the high-purified-CBD treatment due to aggravation of seizure, absence of positive effects, or adverse events. This study showed no significant difference regarding the type of drug-resistant epilepsy and suggests that this treatment may be of interest for all types of drug-resistant epilepsy.

An Analysis of Pre- and Post-Operative Patient Reported Outcome Measurements Following Elective Foot and Ankle Surgery

Category: Ankle; Bunion Introduction/Purpose: Using patient-reported outcomes (PRO) to predict which patients may or may not improve from orthopaedic surgery could be valuable for clinical decision making. The Patient Reported Outcome Instrumentation System (PROMIS) utilizes computerized adaptive testing based on item response theory to decrease administration time while maintaining accuracy. However, the data on the relationship between pre- and post-operative PROMIS scores for elective foot and ankle surgical patients and their ultimate PROs is limited, and the literature is conflicting. The purpose of this study is to assess preoperative PROMIS mobility, physical function (PF), and pain interference (PI) scores to determine their accuracy in predicting patient reported surgery success or failure, and to estimate preoperative score domains associated with patient reported surgery success. Methods: A retrospective chart review was used to identify a cohort of adult patients who underwent operative treatment for at least one foot or ankle surgery between 05/01/2020 – 06/01/2022. Descriptive statistics were calculated to describe the study population, clinical factors, PROMIS scores, and outcomes. Bivariate analyses were performed to assess potential associations between PROMIS score differences with other factors, and PROMIS score differences within levels of other factors. Logistic regression analysis was used to assess potential associations with patient-rated surgery success or failure with patient, clinical, and outcomes data. Significance was determined by associated p-values (p &lt; 0.05). Results: We found that preoperative PROMIS scores for mobility, PF, and PI were not significantly associated with patient-rated surgery success (p=0.092, 0.666, 0.869, respectively). Similarly, in a regression to identify individual factors that influenced patient reported surgical failure, preoperative mobility, PF, and PI scores were all not significant (p=0.095, 0.663, 0.626, respectively). However, preoperative cut-points based on 95% confidence intervals for means were estimated locally to determine the probability of optimal patient reported surgery success, and threshold scores for mobility, PF, and PI were chosen as ≥39, ≥47, and ≤55, respectively. We also found that the only preoperative patient factors that showed higher odds of patient reported surgical failure in a multivariate logistic regression model were age of 50-64 (p=0.004) and diabetes (p=0.006). Conclusion: Our study found no significant associations between preoperative PROMIS scores and patient reported success or failure for foot and ankle surgery. This may be encouraging to surgeons when considering that even patients with seemingly unfavorable preoperative scores have a similar chance as other patients for surgical success and improvement from the patient’s perspective. Additionally, identifying optimal patient PROMIS scores for surgery success can provide an ideal baseline score cutoff for surgeons for comparison when assessing an individual’s chances of surgical success for foot and ankle surgery. However, further study is needed to investigate the clinical utility of these estimates.