Common Events Research Articles

Gravitational wave spectral synthesis

ABSTRACT We study the Laser Interferometer Space Antenna (LISA) sources that arise from isolated binary evolution, and how these depend on age and metallicity, using model stellar populations from bpass. We model these as single-aged populations which are analogous to star clusters. We calculate the combined gravitational wave (GW) spectrum of all the binaries within these model clusters, including all types of compact binaries as well as those with living stars. These results allow us to evaluate the detectability of star clusters with LISA. We find at late times the dominant sources are WD–WD binaries by factors of 50–200, but at times between 108 and 109 yr we find a significant population of NS–WD and BH–WD binaries (2–40 per 106 M⊙), which is related to the treatment of mass transfer and common-envelope events in bpass, wherein mass transfer is relatively likely to be stable. Metallicity also has an effect on the GW spectrum and on the relative dominance of different types of binaries. Using the information about known star clusters will aid the identification of sky locations where one could expect LISA to find GW sources.

Generative and non-parametric model for real-time event detection in social networks based on textual analysis

One of the things that is followed in monitoring systems is the detection of rare events in real time among the multitude of common events in social networks. Considering the lack of recognition and unavailability of rare events, their detection is considered a challenge. In this research, a new architecture and approach based on generative adversarial network infrastructure was presented to detect common and rare events in real time. In this research, the attempt is to provide a new approach to the performance of architectures based on deep generative adversarial networks, a way to solve various problems without supervision with a semi-supervisory approach and adversarial generative infrastructure. This architecture is based on the automatic extraction and use of video input data features. The results of the equal error rate in the UCSDped1 and UCSDped2 datasets were 2.0 and 17.0, respectively, in the performance characteristic curve.

Genomic Evidence of mcr-1.26 IncX4 Plasmid Transmission between Poultry and Humans.

Colistin is still commonly used and misused in animal husbandry driving the evolution and dissemination of transmissible plasmid-mediated colistin resistance (mcr). mcr-1.26 is a rare variant and, so far, has only been detected in Escherichia coli obtained from a hospitalized patient in Germany in 2018. Recently, it was also notified in fecal samples from a pigeon in Lebanon. We report on the presence of 16 colistin-resistant, mcr-1.26-carrying extended-spectrum beta-lactamase (ESBL)-producing and commensal E. coli isolated from poultry samples in Germany, of which retail meat was the most common source. Short- and long-read genome sequencing and bioinformatic analyses revealed the location of mcr-1.26 exclusively on IncX4 plasmids. mcr-1.26 was identified on two different IncX4 plasmid types of 33 and 38 kb and was associated with an IS6-like element. Based on the genetic diversity of E. coli isolates, transmission of the mcr-1.26 resistance determinant is mediated by horizontal transfer of IncX4 plasmids, as confirmed by conjugation experiments. Notably, the 33-kb plasmid is highly similar to the plasmid reported for the human sample. Furthermore, we identified the acquisition of an additional beta-lactam resistance linked to a Tn2 transposon on the mcr-1.26 IncX4 plasmids of three isolates, indicating progressive plasmid evolution. Overall, all described mcr-1.26-carrying plasmids contain a highly conserved core genome necessary for colistin resistance development, transmission, replication, and maintenance. Variations in the plasmid sequences are mainly caused by the acquisition of insertion sequences and alteration in intergenic sequences or genes of unknown function. IMPORTANCE Evolutionary events causing the emergence of new resistances/variants are usually rare and challenging to predict. Conversely, common transmission events of widespread resistance determinants are quantifiable and predictable. One such example is the transmissible plasmid-mediated colistin resistance. The main determinant, mcr-1, has been notified in 2016 but has successfully established itself in multiple plasmid backbones in diverse bacterial species across all One Health sectors. So far, 34 variants of mcr-1 are described, of which some can be used for epidemiological tracing-back analysis to identify the origin and transmission dynamics of these genes. Here, we report the presence of the rare mcr-1.26 gene in E. coli isolated from poultry since 2014. Based on the temporal occurrence and high similarity of the plasmids between poultry and human isolates, our study provides first indications for poultry husbandry as the primary source of mcr-1.26 and its transmission between different niches.

Differential Protein and Glycan Packaging into Extracellular Vesicles in Response to 3D Gastric Cancer Cellular Organization.

Alterations of the glycosylation machinery are common events in cancer, leading to the synthesis of aberrant glycan structures by tumor cells. Extracellular vesicles (EVs) play a modulatory role in cancer communication and progression, and interestingly, several tumor-associated glycans have already been identified in cancer EVs. Nevertheless, the impact of 3D tumor architecture in the selective packaging of cellular glycans into EVs has never been addressed. In this work, the capacity of gastric cancer cell lines with differential glycosylation is evaluated in producing and releasing EVs when cultured under conventional 2D monolayer or in 3D culture conditions. Furthermore, the proteomic content is identified and specific glycans are studied in the EVs produced by these cells, upon differential spatial organization. Here, it is observed that although the proteome of the analyzed EVs is mostly conserved, an EV differential packaging of specific proteins and glycans is found. In addition, protein-protein interaction and pathway analysis reveal individual signatures on the EVs released by 2D- and 3D-cultured cells, suggesting distinct biological functions. These protein signatures also show a correlation with clinical data. Overall, this data highlight the importance of tumor cellular architecture when assessing the cancer-EV cargo and its biological role.

#4720 SEPSIS, AKI AND MORTALITY. SEARCHING FOR NEW MARKERS: OUR EXPERIENCE WITH ENDOGENOUS OUABAIN

Abstract Background and Aims Sepsis and septic shock are quite common events in the hospital setting. The classification of these events has changed a lot over the years, to ensure better sensitivity in recognizing a situation that, if not managed properly and quickly, leads to the death of the patient. In our study we focused on the search for predictors of acute kidney injury and mortality during the evolution of this pathology, with particular attention to the role of the Endogenous Ouabain hormone. Method We enrolled 177 patients diagnosed with sepsis or septic shock, under an ordinary hospital stay. We standardized patients according to the latest classification criteria (Sepsis-III), we focused our attention specifically on SOFA score and the relationship with acute kidney injury and mortality, including its relationship with other laboratory parameters, especially lactates. In a subgroup of patients was also dosed the level of Endogenous Ouabain (EO - hormone produced by the adrenal glands but which has an important impact on renal hemodynamics), through a venous sampling in 3 different times (at the beginning of the septic state, 24 and 48 hours later). Subsequently the variation of EO and the correlation with laboratory parameters was investigated in this period, to assess its impact on the development of kidney damage and mortality. Results The 70.1% of septic patients in our study develop AKI and, of this percentage, 75% in a severe form (stage 2-3 KDIGO). Both the presence and severity of AKI are unable to predict mortality in our sample (p-value 0.13). The presence of an impaired hemodynamics status (expressed ad MAP < 70 mmHg) has a strong impact in the severe stages of AKI but not in the mild form (p-value 0.006; ExpB 1.81 vs p-value 0.105; ExpB 1.46). The other elements related to the development of AKI were found to be the high levels of white blood cells, respiratory distress and the SOFA value at the presentation, while we found no correlation with CRP and lactate levels. Lactate levels well correlate with SOFA (p-value <0.0001 and Pearson's index 0.407) and mortality, particularly when the initial values are > 2mg/dL (p < 0.0001; ExpB 5.31, IC95% [2.07-13.57]). In the subgroup of patients in which EO was dosed, there was a strong correlation of the basal levels of this hormone with mortality even after correction for lactate levels and SOFA (p-value 0.009) but not with the development of AKI. However, patients in AKI stage-3 show persistently higher levels of EO both at 24 and 48 h (p = 0.015). Conclusion The presence of high levels of lactates at the onset is the most important predictor of mortality, followed by EO levels at presentation and the SOFA value. Elevation of Endogenous Ouabain levels is indicative of an acute state of stress but is not a parameter influenced by the SOFA score, nor by the general condition of patient. It seems non directly related with the development of AKI, tissue hypoperfusion or activation of the inflammatory response but is associated with an inability to rapidly recover renal function. The EO could be very useful in predicting mortality in patients with sepsis and septic shock as it seems to be an earlier, more specific, and sensitive than the other laboratory parameters used so far.

#5727 THE BURDEN OF SYMPTOMS AND PROCEDURES IN PATIENTS WITH RECURRENT KIDNEY STONES – A REPORT FROM A STONE CLINIC

Abstract Background and Aims Kidney stones (KS) are increasing in prevalence and becoming a major public health problem. The extent of the disease has been described as the stone burden, a measurement based on the size and number of stones. However, the quality of life of these patients is not affected by these parameters per se, but rather by the frequency and intensity of symptoms and the need for surgical procedures. The current data on this subject is very limited. The aim of our study was to record the frequency of symptoms and procedures in patients with recurrent KS and to evaluate possible associations with basic clinical data and common comorbidities. Method We report a retrospective study on 181 consecutive patients with recurrent KS who were examined at the University Medical Centre Ljubljana stone clinic for the first time during the period of 2018 – 2022. We performed a standardized questionnaire to record common KS symptoms, procedures, basic clinical data, and comorbidities. Events were defined as number of severe lumbar pain (SLP) events per year (8-10/10 on the visual analog scale – VAS) and number of surgical procedures (SP) for stone removal per year. Moderate lumbar pain (MLP) events (VAS 4-7/10) and passing of stones were quantified on a scale from 0-4. Due to the wide variety of frequencies the associations were analyzed with Chi-Square test using terciles when possible or with presence and absence of symptoms. We considered p values < 0.05 as statistically significant. Results Mean age was 51.1 (SD 14,5) years, with 51.8% females. Arterial hypertension (AH) was present in 29.8% of patients, diabetes mellitus in 6.6%, and a family history of KS in 30%. The median frequency of SLP and SP was 0.33 (IQR 0.01-1) events/year and 0.08 (IQR 0-0.33) procedures/year, respectively; while 26.7% and 12.8% of patients had at least one SLP event or SP per year, respectively. When comparing terciles of frequency of SLP we found an association with more common SLP events in patients with a positive family history of KS compared to a negative history (17%, 63%, 20% vs. 37%, 27%, 36%; p < 0.001). There was also a significant difference in the age of onset of KS in patients with and without a family history of KS. Mean decade of onset was 3 (IQR 3-5) and 4 (IQR 3-6) in patients with and without a family history of KS, respectively (p = 0.033). When comparing terciles of frequency of procedures we only found a trend towards more common procedures in patients with AH (p = 0.062). The frequency of MLP was as follows – 42.6% had it less than once per year, 11.6% had it once or twice per year, 11% three to five times per year, 12.9% every month, and 21.9% on a weekly basis. We found no statistically significant association between MLP and basic clinical data or comorbidities only a trend towards more frequent episodes in patients with AH (p = 0.096). In regards to the passing of KS we found the following frequencies – 72.4% had episodes less than once per year, 14.9% once or twice per year, 5.5% three to five times per year, 3.9% every month, and 3.3% on a weekly basis. There was statistically significant difference between passing of KS and sex, with 34.5% of males and 21.3% of females passing KS at least once per year, respectively (p = 0.047). Additionally, there was a significant difference between passing of KS and family history of KS, with 40.7% with and 21.6% of patients without a history of KS passing KS at least once per year, respectively (p = 0.008). Conclusion Our study showed that symptoms and surgical procedures were common in patients with recurrent KS referred to our clinic. Half of the patients had severe lumbar pain at least every three years, and a quarter had severe lumbar pain and passed KS at least once per year. About a third of patients had moderate lumbar pain at least once per month. Patients with a family history KS developed stones earlier in life and had more common severe lumbar pain and passed KS more frequently. These issues should be analyzed in greater detail, with symptom scores that would define the burden of KS in a more objective manner and help in assessing the effectiveness of KS therapies.

Extremity Rhabdomyosarcoma-An Integrated Clinicopathologic and Genomic Study to Improve Risk Stratification.

Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and regional lymph node involvement. To better define prognostic markers in this clinical subset, we investigated our experience of 61 patients with extremity RMS treated at our tertiary cancer center for the past 2 decades. The patients had a median age of 8 years at diagnosis, equal gender distribution, and two-thirds occurred in the lower extremity. Most (85%) patients had FOXO1 fusion-positive alveolar RMS (ARMS), with 70% having a PAX3::FOXO1 transcript. Remaining were seven patients with fusion-negative embryonal RMS (ERMS) and two with MYOD1-mutant spindle cell/sclerosing RMS (SRMS). In 40% of the patients, material was available for DNA-based targeted sequencing using MSK-IMPACT cancer gene panel. One-third of patients presented with localized disease at diagnosis while the remaining had regional nodal (18%) or distant metastases (51%). Metastatic disease, high-risk group, and age 10 years or older significantly affected the overall survival (OS; hazard ratio [HR], 2.68 [P = .004], 2.78 [P = .010] and 2.26 [P = .034], respectively). Although the presence of metastatic disease had a dismal impact on 5-year EFS and OS (19% and 29%, respectively), nodal involvement had a comparatively lower impact on 5-year EFS and 5-year OS (43% and 66%, respectively). PAX3::FOXO1 ARMS had worse prognosis and afflicted older children compared with PAX7::FOXO1 (HR = 3.45, P = .016). The most common events in the ARMS group included MED12 alterations, CDK4 amplifications, and CDKN2A deletions (8%-17%). The latter two abnormalities were mutually exclusive, enriched for acral and high-risk lesions, and correlated with poor outcome on OS (P = .02). Our data provide rationale for considering the integration of molecular abnormalities to refine risk stratification in extremity RMS.

FS-1502 in HER2-positive advanced breast cancer: Results from an open-label, phase 1 study.

3044 Background: FS-1502 is an anti-HER2 antibody-drug conjugate that was well tolerated and showed good antitumor activity in patients (pts) with advanced HER2 -expressing solid tumors in the dose-escalation stage of the current Phase 1 study. The results were presented at SABCS 2022. The recommend Phase 2 dose (RP2D) was 2.3 mg/kg IV once every 3 weeks. Here, we report the efficacy and safety of HER2-positive breast cancer (BC) pts treated with FS-1502 at the RP2D. Methods: This open-label Phase 1 trial was conducted at 9 hospitals in China. Heavily pretreated HER2-positive (IHC 3+ or 2+/FISH+) BC pts who had failed prior anti-HER2 therapy were recruited in the dose-expansion stage. All HER2-positive BC pts treated at the RP2D were pooled for analysis. Efficacy endpoints included objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Safety endpoints included treatment-emergent adverse events (TEAEs) and the laboratory data. Results: As of cutoff date, December 24, 2022, the median study follow-up duration was 5.2 months. A total of 70 female HER2-positive BC pts, with a median age of 51.8 (range: 31-76) years, were enrolled and received at least one dose of FS-1502. The median prior therapy line was 3 (range: 1-16), and 91.4% (64/70) of pts had previously received at least 2 therapy lines. The most common metastasis organs were lung 55.7% (39/70), lymph node 54.3% (38/70) and bone 50% (35/70). 81.4% (57/70) of pts had at least 3 metastatic lesions. All pts had previously received anti-HER2 therapy, among which trastuzumab ± pertuzumab (n = 67, 96%) and pyrotinib (n = 52, 74%) were the most common. Among 68 efficacy-evaluable pts, the best ORR of 52.9% (36/68) (95% CI, 40.45-65.17) was achieved with 2 complete responses and 34 partial responses. DCR was 88.2% (60/68), median progression-free survival was 15.5 months (95% CI, 4.57,-), and median duration of response was 12.9 months (95% CI, 5.72,-). FS-1502 was well tolerated. No related interstitial lung disease occurred in any grade. Eye toxicity was mostly Grade 1 or 2 of dry eye and keratitis. Grade ≥ 3 study-related TEAEs were reported in 27 (38.6%) pts, in which the most common events (≥ 5%) were hypokalemia (18.6%), platelet count decreased (7.1%), and neutrophil count decreased (5.7%). One (1.4%) patient experienced adverse events leading to drug discontinuation (hemoptysis). Adverse events leading to death were reported in 2 (2.9%) pts (bacterial pneumonia and hemoptysis, respectively). Bacterial pneumonia was not related to FS-1502, while hemoptysis was possibly related to the drug. Conclusions: FS-1502 demonstrated very promising antitumor activity and was well tolerated in heavily pretreated HER2-positive BC, with mild eye toxicity and no related interstitial lung disease reported. A Phase 3 clinical trial is under planning to further confirm efficacy and safety of FS-1502 in pts with advanced HER2-positive BC. Clinical trial information: NCT03944499 .

Risk factors for venous thromboembolism (VTE) among patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) receiving amivantamab plus lazertinib versus either agent alone.

9137 Background: Amivantamab (ami), an EGFR and cMET bispecific antibody with immune cell-directing activity, and lazertinib (laz), a CNS-penetrant 3rd-generation EGFR tyrosine kinase inhibitor have shown clinical activity in biomarker-selected patients (pts) with advanced NSCLC. Antitumor activity has been suggested to be improved when the agents are given in combination (Leighl Ann Oncol 2021;32:suppl_5, 1192MO). We examined the incidence of VTE, a common adverse event (AE) among pts with lung cancer, for those receiving ami monotherapy, laz monotherapy, and ami+laz to investigate if there is elevated risk and understand potential predisposing risk factors. Methods: CHRYSALIS (NCT02609776; ami monotherapy and ami+laz), CHRYSALIS-2 (NCT04077463; ami+laz), and LASER201 (NCT04075396; laz monotherapy) are ongoing open-label studies of locally advanced/metastatic NSCLC. Two descriptive, univariate risk analyses were performed, with the primary analysis including all treatment-emergent VTE events (grouped term) and a secondary analysis that excluded VTE events occurring after progression of disease (PD) or within 30 days prior to PD. Results: This analysis included 560 pts who received ami monotherapy, 536 ami+laz, and 252 laz monotherapy, predominantly in the TKI-relapsed setting. The incidence of VTE events of any grade was numerically higher in pts who received ami+laz (21%) than those who received ami (11%) or laz (11%) monotherapy. The median time to onset of the first VTE event was 84.5 days for ami, 79 days for ami+laz, and 170 days for laz. The majority (64%) of ami+laz pts had VTE events in the first 4 months. The most common VTE events by preferred term were pulmonary embolism and deep vein thrombosis. The incidence of grade ≥3 VTE events was comparable among pts receiving ami (5%), ami+laz (6%), and laz (6%), and there were no grade 5 VTE events for ami+laz. The overall incidence of serious VTE AEs was low (ami, 3%; ami+laz, 5%; laz, 4%). There were 6 discontinuations due to VTE, 1 (0.2%) ami, 2 (0.4%) for ami+laz, and 3 (1.2%) laz. In the primary analysis, age ≥60 years was a significant risk factor ( P< 0.05). In the secondary analysis, age ≥60 years, ECOG performance status of 1 (vs 0), and response to therapy (partial response or better) were significant risk factors ( P< 0.05). Conclusions: Lung cancer diagnosis is a known risk factor for VTE. In a review across clinical trials, single-arm cohort data suggest there is a numerically higher incidence of VTE for ami+laz compared with each monotherapy. Age ≥60 years, ECOG performance status, and response to treatment are potential risk factors. The relationship between response and VTE is emerging and may reflect possible immune or inflammatory-mediated mechanisms. Further efforts to understand VTE-associated risk factors in randomized clinical trials are ongoing. Clinical trial information: NCT02609776 , NCT04077463 , NCT04075396 .

Impacts of Aerosol Scattering Attenuation on Free-Space Optical Communication in Owerri, Nigeria

In spite of the several benefits of using free-space optical (FSO) communication systems as complementary platforms for next-generation networks, the existence of atmospheric disturbances such fog and scintillations are key sources of signal impairment that affect system performance. Thus, it is crucial to learn about the specific weather patterns of the areas where FSO lines will be installed. The purpose of this work is to estimate the availability performance of FSO lines broadcasting at both 850 nm and 1550 nm by performing a statistical analysis of meteorological visibility data gathered for Owerri in Nigeria over a 21-year period (2000-2021). The results shows that the visibility during the most common fog events in Owerri is 100 meters. The probabilities of encountering and exceeding the scattering attenuations associated with Owerri’s most common fog event are 0.0002 and 0.0229, respectively. This research could be expanded in the future by exploring the effects of varying localized climatic conditions on the many forms of optical signals, such as plane, spherical, and Gaussian beam waves.

Palbociclib in solid tumor patients with genomic alterations in the cyclin D-CDK4/6-INK4a-Rb pathway: Results from NCI-COG pediatric MATCH trial Arm I (APEC1621I).

10006 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients aged 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm I evaluated palbociclib, a reversible, selective oral small molecule inhibitor of CDK 4 and 6 in tumors harboring specified genomic alterations in the cyclinD-cdk4/6-INK4a-Rb pathway: amplification of CDK4, CDK6, CCND1, CCND2, or CCND3. Positive Rb expression by IHC was required. Methods: Palbociclib was administered on days 1-21 at 75 mg/m2 once daily in 28-day cycles for up to 2 years, until disease progression, or intolerable toxicity. Response assessment occurred every 2-3 cycles. The primary endpoint was objective response (OR) rate; secondary endpoints included safety/tolerability and progression-free survival (PFS). Results: Twenty-three patients (median age 15 yrs; range 9-21) were enrolled between August 2018 and May 2022. Twenty patients received protocol therapy and were evaluable for response. Of treated patients, osteosarcoma was the most common diagnosis (9/20, 45%), with amplification of CCND3 detected in 6/9 patients, CDK4 in 2, and CDK6 in 1. Rhabdomyosarcoma was next most frequent (6/20, 30%), with all tumors harboring CDK4 amplifications. Other diagnoses were high grade glioma (n = 2), soft tissue sarcoma (n = 2), and neuroblastoma (NB) (n = 1). Additional genomic alterations were detected in 9/20 tumors, most frequently TP53 mutations (n = 4, including 2 patients with Li-Fraumeni syndrome). Palbociclib was generally well tolerated with hematologic toxicities being the most common treatment related events and no related grade 5 events. Neutropenia was the most common grade 3-4 adverse event (n = 10, 50%) followed by thrombocytopenia (n = 8, 40%), leukopenia (n = 7, 35%), and anemia (n = 5, 25%). Four patients came off study for toxicity (3 for prolonged thrombocytopenia (cycle 1 (x2) and cycle 2) and 1 for prolonged grade 4 neutropenia (cycle 3)). Non-hematologic toxicities were mild (grade 1-2). No ORs were seen. Two patients with tumors harboring CDK4 amplifications had stable disease (SD): one with NB had SD for 5 cycles and one with sarcoma had SD for 3 cycles but came off therapy for toxicity. Six-month PFS was 10% (95% CI: 1.7%-27.2%) and six-month overall survival was 65% (95% CI: 40.3%, 81.5%). Conclusions: The CDK4/6 inhibitor palbociclib at 75mg/m2 PO daily was well tolerated in this heavily-pretreated cohort. No objective responses were observed in these biomarker-selected patients with treatment-refractory solid tumors. Further evaluation of this agent in combination with chemotherapy in the pediatric population is ongoing. Clinical trial information: NCT03526250 .

Self-reported Medicinal Cannabis Use as an Alternative to Prescription and Over-the-counter Medication Use Among US Military Veterans

BackgroundMental and other physical health concerns and substance use disorder are common and co-occurring events experienced by US veterans. Treatment with medicinal cannabis is a potential alternative to unwanted medication use for veterans, but more clinical and epidemiologic research is needed to understand the risks and benefits. MethodsData were collected from a cross-sectional, self-reported, anonymous survey asking US veterans about their health conditions, medical treatments, demographics, and medicinal cannabis use along with its self-reported effectiveness. In addition to descriptive statistics, logistic regression models were run to examine correlates of the use of cannabis as a substitution for prescription or over-the-counter medications. FindingsA total of 510 veterans of US military service participated in the survey, which was administered between March 3 and December 31, 2019. The participants reported experiencing a variety of mental and other physical health conditions. Primary health conditions reported included chronic pain (196; 38%), PTSD (131; 26%), anxiety (47; 9%), and depression (26; 5%). Most participants (343; 67%) reported using cannabis daily. Many reported using cannabis to reduce the use of over-the-counter medications (151; 30%) including antidepressants (130; 25%), anti-inflammatories (89; 17%), and other prescription medications. Additionally, 463 veterans (91% of respondents) reported that medical cannabis helped them to experience a greater quality of life and 105 (21%) reported using fewer opioids as a result of their medical cannabis use. Veterans who were Black, who were female, who served in active combat, and who were living with chronic pain were more likely to report a desire to reduce the number of prescription medications they were taking (odds ratios = 2.92, 2.29, 1.79, and 2.30, respectively). Women and individuals who used cannabis daily were more likely to report active use of cannabis to reduce prescription medication use (odds ratios = 3.05 and 2.26). ImplicationsMedicinal cannabis use was reported to improve quality of life and reduce unwanted medication use by many of the study participants. The present findings indicate that medicinal cannabis can potentially play a harm-reduction role, helping veterans to use fewer pharmaceutical medications and other substances. Clinicians should be mindful of the potential associations between race, sex, and combat experience and the intentions for and frequency of medicinal cannabis use.

Pressurized intra-peritoneal aerosol as a delivery system for macrophage reprogramming cellular therapy in conjunction with chemotherapy for the treatment of advanced peritoneal malignancies.

e14537 Background: Novel intraperitoneal delivery systems like Pressurized Intra Peritoneal Aerosol Chemotherapy (PIPAC) increase the therapeutic access with encouraging responses in patients with peritoneal carcinomatosis unresponsive to systemic therapy. However, survival rates remain at 11-16 months, and treatment options are limited, especially in patients with high tumor burden. Allocetra, an innovative immunomodulatory cellular therapy, has demonstrated antitumor activity in preclinical peritoneal tumor models, reprogramming macrophage function in the tumor microenvironment. The clinical study assesses the applicability and safety of Allocetra given by pressurized intra-peritoneal aerosol, in conjunction with PIPAC. Methods: Allocetra is manufactured from mononuclear cells collected from healthy non-matched donors, and induced to undergo early apoptosis. Safety of administration via pressurized aerosol was assessed by cell recovery and function. The clinical study is a dose-finding safety study with inter- and intra-patient dose escalation of Allocetra to determine safety of intraperitoneal Allocetra administration via pressurized aerosol system (Capnopen, Capnomed, Germany), with PIPAC. Patients have advanced peritoneal cancer, non-eligible for Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Two cohorts (n=3) are treated with escalating doses of Allocetra at 6-week intervals. Two subsequent cohorts (n=3) include patients treated at the maximal tolerated dose, to evaluate the sequencing of Allocetra and PIPAC. Results: Allocetra pressurized aerosol delivery demonstrated stable and acceptable cellular profiles, recovery and potency. In the first clinical cohort (n=3), patients received escalating doses of 1 x 109, 2.5 x 109 and 5 x 109 Allocetra cells, followed by PIPAC. Patients’ primary diseases were advanced colon and appendicular carcinomas with multiple prior treatment cycles (chemotherapy, biologics and immunotherapy). Patients were followed for a median 15 weeks (range 7-32) for adverse events. Adverse event profile following combined treatment with Allocetra included mostly mild common post surgical events: abdominal pain, pain around surgical wound, shoulder pain, abdominal wall hematoma, rash around surgical wound, urinary tract infection, inferior epigastric artery bleeding, and infected hematoma. None were considered related to Allocetra. All the patients are alive and continue to be followed. Conclusions: Initial results from the study indicate a favorable safety profile following pressurized intra-peritoneal aerosol administration of Allocetra cellular therapy. Additional patients will be treated with escalating doses of Allocetra to assess safety and initial response to treatment. Clinical trial information: NCT05431907 .

Genomic characterization of vulvar squamous cell carcinoma to reveal differential gene expression based on clinical outcome.

e17633 Background: The greatest challenge in the management of vulvar squamous cell carcinoma (VSCC) is treatment of recurrent disease where options for surgery and radiation have been exhausted, or treatment of disease where distant metastasis is present. Identification of mutations differentially expressed between tumor from patients who died of aggressive disease and tumor from patients with an indolent course could reveal novel prognostic indicators and guide development of therapeutic drugs. Methods: From 202 consecutive patients with VSCC, patients who recurred and died of disease (group A) were identified and matched by age, tumor size, depth of invasion and nodal status with those whose disease did not recur (group B). Tumor and matched normal samples from 21 patients were assayed by a broad NGS panel covering 648 genes, including whole exome and transcriptome sequencing. Immunohistochemistry (IHC) for PD-L1 (22C3) and p16 was also performed. Results: Whole transcriptome data revealed 6 genes that were strongly differentially expressed between the aggressive and indolent groups: ACVR2A, TGM3, ROS1, NFEL2, CCND1 and BCL6. Biologically relevant DNA mutations were significantly greater in the aggressive cohort versus the indolent cohort: 7 vs 2.3 mutations per patient. The most common genomic alterations were mutations in TP53 and the promoter region of TERT. TP53 alterations occurred almost exclusively in group A. Other common genomic events include alterations of FAT1, CDKN2A, PIK3CA, CCND1, and LRP1B. All samples were MSI stable, and tumor mutational burden was similar in groups A and B. Most VSCC specimens (81%) were positive for PD-L1. Conclusions: We report that TGM3 and ACVR2A genes are significantly under-expressed in tumors with poor outcome. Further investigation into the silencing of these genes may advance knowledge of the pathogenesis of VSCC and potentially yield therapeutic targets. Clinical outcome of VSCC appears independent of MSI, TMB or PD-L1 status. [Table: see text]

Pathways to diagnosis: The lived experiences of obtaining a dementia diagnosis among care partners

AbstractBackgroundAchieving a timely diagnosis of Alzheimer’s disease and related dementias (ADRD) has been challenging, and racial/ethnic minority older adults often have delays in their ADRD diagnoses despite having a higher disease prevalence. This qualitative study engaged care‐partners of patients to identify key barriers that they have experienced during their ADRD diagnosis process, ascertain their recommendations for addressing these barriers, and assess racial differences in the diagnosis process.MethodWe purposively sampled 11 Black and 10 White care‐partners (n = 21) of persons who were diagnosed with ADRD within the past two years. We conducted semi‐structured interviews to gather details and to identify the barriers/facilitators that they experienced. To prompt discussion, we asked participants to complete a card sort activity identifying occurrence and order of common events in the diagnosis pathway. We applied content analysis guided by life course theory to identify themes and to explore differences in diagnosis pathways between Black and White participants.ResultOverall, about 70% of care‐partners were female, age 60 (on average), and 57% were adult children of persons with ADRD. Less than 30% of Black care‐partners reported having adequate knowledge about ADRD, whereas the proportion was 60% among their White counterparts. Most often, early signs of ADRD were first noticed by care‐partners. However, some considered these signs as part of the normal aging process. Care‐partners reported visiting multiple providers along the process, and some visits were related to other conditions. Some care‐partners noted that the involvement of other family members was a barrier to the ADRD diagnosis. Most care‐partners described the diagnosis process as difficult and devastating, and Black care‐partners discussed experiencing unmet needs along the process more frequently than White care partners. Some care‐partners suggested having a navigator that can walk them through the process would be helpful. They also shared that the navigator should be able to tailor services based on the needs, as each family’s situation is different.ConclusionThis study highlights the unmet needs experienced by care partners along the diagnosis process of ADRD. Black and White differences were also identified. More person‐centered care coordination programs are needed to promote early identification of ADRD.

Neurocognitive Outcomes

The brain is the most complex and sensitive organ in the body, so it is no wonder that major physiological disruptions can affect it in several ways. Functional disturbances in neurocognitive performance are the most common events impacting patients following cardiac surgery, yet are often not discussed with patients. Delirium occurs in up to 50% of older patients and can have long-term consequences including persistent cognitive decline. Other neurocognitive disorders such as delayed neurocognitive recovery (often described as poor short-term memory or “brain fog”) can be seen in around one-third of patients in the days to weeks following surgery. Even at 3 months, >10% of patients may suffer from a neurocognitive disorder. Impaired baseline cognitive function is a risk factor, amplified by the inflammatory and other responses to major surgery. It is possible that anaesthesia and intensive care unit management strategies can play a protective role to some extent, and there is increasing evidence that anaesthesia per se is not harmful in most circumstances. Perioperative care involves identifying at-risk individuals and implementing multidisciplinary care throughout the hospital stay. This presentation will discuss evidence for underlying mechanisms and what can be done now and in the future to mitigate this. It is also likely that better preparing patients for surgery, both physically and cognitively, may improve their outcomes.

An Analysis of Gothic Literature: Spatial Fears in Suat Derviş’s Novels

Suat Derviş is one of the important writers of Turkish Literature in the Republican Period. She has works in such different genres as a columnist, short story, translation and novel. She is often associated with social realism. However, gothic themes were found in her first novels. Sin, revenge, death, suicide, black spirits, bloody murder, and the seizure of the soul by the devil are the common themes and events of her novels. Places such as graves, hell, mysterious mansions, dark rooms and undergrounds were generally accompanied by night, lightning, wind, and autumn. Fantastic events and imaginary people created an atmosphere of fear and tension.
 The study aims to reveal the characteristics of gothic literature and how the place is handled in Suat Derviş’s novels Kara Kitap, Ne Bir Ses Ne Bir Nefes, Buhran Gecesi, Fatma’nın Günahı, Onu Bekliyorum, Onları Ben Öldürdüm. The study also intends to examine the effect of the space phenomena in creating the gothic atmosphere. In the novels, rural areas, graves, mysterious rooms and objects, hell, and scary and dark places have been identified and subjected to a categorical classification.

Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.

Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons.

The Boiling Liquid Expanding Vapour Explosion (BLEVE): A bibliometric review and futur trends

The phenomenon “Boiling Liquid Expanding Vapor Explosion” (BLEVE) is one of the most common accidental events in the chemical industry and in the transport of dangerous goods. A bibliographic search in the Web of Science Core Collection reported 375 publications related to BLEVEs from 1979 to the present (August 10, 2022). A bibliometric analysis was conducted using the VOSviewer tool to allow a better understanding of the scientific knowledge on this phenomenon. A comprehensive overview of BLEVE research is presented in terms of annual publication, top journals, countries/regions with the highest productivity, authors and their cooperation networks, key terms, and co-citation analysis. The 375 publications cover 691 authors, 83 journals, 44 countries or territories and 290 institutions. The key publication (highest number of citations and co-citations) for understanding the BLEVE phenomenon is. The results obtained constitute a snapshot of the current state of the art on BLEVEs and can be applied to improve the understanding of research on this topic and establish new trends of research.

(137) Surgical Outcomes at a Single Institution of Infrapubic insertion of Malleable Penile Prosthesis in Transmen after Phalloplasty

Abstract Introduction Penile reconstruction has allowed transmasculine individuals to attain the aesthetic appearance of male genitalia, however a penile prosthesis is needed to achieve the ridigity and bulk for penetration. High complication rates have been reported with penile prosthesis placement after phalloplasty, with the rate of reoperation exceeding 40% following both inflatable penile prosthesis (IPP) and malleable penile prosthesis (MPP). We describe the experience of a single surgeon with the infrapubic approach for MPP placement after phalloplasty. Objective To review the surgical outcomes of the infrapubic approach to the insertion of the MPP after phalloplasty in transgender men. Methods The infrapubic prosthesis insertion after phalloplasty technique involves a horizontal incision anterior to the pubic symphysis, which allows dissection of the neophallus channel and the anchor site on the pubic symphysis. Surgical outcomes using the Spectra (Boston Scientific, Marlborough, MA) and Genesis (Coloplast, Minneapolis, MN) MPP were analyzed between October 2017 and May 2022. Complications were reviewed and categorized into erosions, infections, device malposition and malfunction, and less common events like necrosis. Results The infrapubic MPP technique was performed on 40 patients by a single surgeon; 35 patients had a prior radial forearm free flap (RFFF) phalloplasty, and 5 had a prior anterolateral thigh flap (ALT) phalloplasty. Of the 30 patients who have continued to follow-up, mean follow-up was 34.9 months. Complications were not mutually exclusive, with 7 implant detachments from the anchor site, 3 malpositions, 2 with pain/activity limitation, and 1 infection. Surgical revision was required in 12 patients (40.0%). There were no neophallus erosions, flap loss, seromas, nor urethral injuries. More complications occurred with the Spectra MPP (9/17 or 52.9%) compared to the Genesis MPP (3/13 or 23.1%). Conclusions Infrapubic MPP insertion in transmen after phalloplasty is associated with high prosthetic surgical revision rates. Fewer complications were identified in the Genesis cohort. Longer term studies with patient reported outcome measures are required for further evaluation. Disclosure No