Indeterminate Responses Research Articles

Trends in Sexual Orientation and Gender Identity Data Collection.

The aim of this study was to determine response patterns to sexual orientation and gender identity (SOGI) questions in the Behavioral Risk Factor Surveillance System (BRFSS) over time and to assess nonresponse and indeterminate responses by demographic characteristics. This is a secondary data analysis of the SOGI module of the BRFSS. We used data from 46 states and Guam that implemented SOGI questions between 2014 and 2022. We used weighted analyses that accounted for the sampling design, determined SOGI response patterns by year, and assessed nonresponse and indeterminate responses by demographic characteristics. Over time, increasing numbers self-reported as sexual and gender minority respondents, while heterosexual identity declined. Sexual orientation nonresponse and indeterminate responses increased with time, while respondents' reports of not knowing gender identity declined. Hispanic, older, respondents, those with lower education, and those who completed the questionnaire in Spanish had higher SOGI nonresponse and indeterminate responses. The low amount of SOGI nonresponse and indeterminate responses in the BRFSS can be instructive for the implementation of SOGI questions in medical settings. SOGI data collection in all settings requires improving procedures for the groups that have been shown to have elevated nonresponse and indeterminate response.

Unraveling emergent network indeterminacy in complex ecosystems: A random matrix approach

Indeterminacy of ecological networks-the unpredictability of ecosystem responses to persistent perturbations-is an emergent property of indirect effects a species has on another through interaction chains. Thus, numerous indirect pathways in large, complex ecological communities could make forecasting the long-term outcomes of environmental changes challenging. However, a comprehensive understanding of ecological structures causing indeterminacy has not yet been reached. Here, using random matrix theory (RMT), we provide mathematical criteria determining whether network indeterminacy emerges across various ecological communities. Our analytical and simulation results show that indeterminacy intricately depends on the characteristics of species interaction. Specifically, contrary to conventional wisdom, network indeterminacy is unlikely to emerge in large competitive and mutualistic communities, while it is a common feature in top-down regulated food webs. Furthermore, we found that predictable and unpredictable perturbations can coexist in the same community and that indeterminate responses to environmental changes arise more frequently in networks where predator-prey relationships predominate than competitive and mutualistic ones. These findings highlight the importance of elucidating direct species relationships and analyzing them with an RMT perspective on two fronts: It aids in 1) determining whether the network's responses to environmental changes are ultimately indeterminate and 2) identifying the types of perturbations causing less predictable outcomes in a complex ecosystem. In addition, our framework should apply to the inverse problem of network identification, i.e., determining whether observed responses to sustained perturbations can reconstruct their proximate causalities, potentially impacting other fields such as microbial and medical sciences.

Coexistence of Hashimoto's Thyroiditis in Differentiated Thyroid Cancer: Post-Operative Monitoring of Anti-Thyroglobulin Antibodies and Assessment of Treatment Response.

Differentiated thyroid carcinoma (DTC) is frequently found in conjunction with autoimmune thyroid disorders, particularly Hashimoto's thyroiditis (HT). This study investigates the impact of coexisting HT on the persistence of an indeterminate response to therapy due to positive anti-thyroglobulin antibodies (AbTg), measured via competitive immunoassay, in a consecutive patient series from Calabria, Southern Italy. This retrospective longitudinal study analyzed 259 consecutive DTC patients managed at the Endocrinology Unit of Renato Dulbecco Hospital (Catanzaro, Italy) up to 2023. Patients with medullary and undifferentiated thyroid carcinoma, partial thyroidectomy, less than six months of post-operative monitoring, or missing clinical data were excluded. Demographic information, histological findings, initial tumor stage, and ATA risk category were collected. The response to therapy was assessed based on ATA guidelines. Among the 259 patients, 29% had coexisting HT. Patients with HT exhibited distinct characteristics: a higher proportion of females (87.0% vs. 74.7%), a shorter post-operative monitoring duration (median 3 vs. 5 years), and a higher prevalence of papillary thyroid carcinoma (PTC) (97.4% vs. 86.3%). The tumor size, lymph node involvement, and distant metastasis were similar between the groups, with patients without HT having a higher incidence of extrathyroidal tumor extension. However, the initial TNM stage and ATA risk category did not differ significantly. At the six-month follow-up, HT patients showed a higher rate of indeterminate responses, primarily due to positive AbTg. After 12 months, the response categories aligned, with decreasing AbTg levels in the HT group. After 24 months, most patients with long-term follow-up demonstrated an excellent response to DTC therapy, irrespective of HT coexistence. While HT does not worsen DTC prognosis, it may result in indeterminate responses. AbTg measurements in the peri-operative period should be encouraged to facilitate post-operative monitoring, emphasizing the importance of using standardized assays. Further research in larger populations with extended follow-up is needed to comprehensively understand the HT-DTC relationship.

ChatGPT takes on the european exam in core cardiology: an AI success story

Abstract Background ChatGPT, the trending novel artificial intelligence has triggered ongoing debate regarding its capabilities.Recently, preliminary reports showed that answered correctly in the majority of questions of the United States Medical License Examinations (USMLE). However, its ability to succeed a more precise, challenging and high-stakes post-graduate test, such as the final exam for the completion of medical residency , like the European Exam in Core Cardiology (EECC), is not known yet. Purpose We sought to evaluate the performance of ChatGPT on EECC, to test its capability on a more demanding, high-stakes post-graduate exam in Cardiology training. Methods A total of 488 publicly-available single-answer multiple choice questions (MCQs) were randomly obtained from three different MCQs sources that are traditionally used for the preparation for the EECC: 88 from the sample exam questions released since 2018 from the official ESC website, 200 from the 2022 edition of StudyPRN and 200 from the Braunwald's Heart Disease Review and Assessment (BHDRA). Questions containing audio or visual assets were excluded. After filtering, 362 MCQ items (ESC sample: 68, BHDRA:150, StudyPRN: 144) were included and considered as input source. False responses and indeterminate responses were considered as not correct. Results ChatGPT answered to 340 questions out of 362, with 22 indeterminate answers in total. The overall accuracy was 58.8% across all the question sources. More specifically, it demonstrated an accuracy for the ESC sample, BHDRA and StudyPRN of 61.7%, 52.6%, 63.8% respectively. It answered correctly 42/68 (4 indeterminate) of ESC sample questions, 79/150 (11 indeterminate) of the BHDRA and 92/144 (7 indeterminate) of the StudyPRN. Conclusion ChatGPT manages to correctly answer the majority of EECC’s questions and perform within the passing threshold range. Although it cannot yet process visual content, it can provide rational and correct answers to text-based inputs in most scenarios. The model may be able to efficiently handle a massive amount of acquired medical knowlededge, but the current approach may not substitue for critical thinkg, innovation and creativity; some of the key attibutes that doctors are expected to showcase.Performance of ChatGPT on EECCExample of MCQ input at ChatGPT

Integrating SARS-CoV-2-specific interferon-γ release assay testing in the evaluation of patients hospitalized with COVID-19.

T cell-mediated immunity is crucial for protection against severe COVID-19. The performance of SARS-CoV-2-specific IFN-γ release assays (IGRAs) to measure T cell responses during severe acute infection is unknown. We conducted a prospective, longitudinal analysis of patients hospitalized for confirmed COVID-19. A standardized SARS-CoV-2-specific quantitative IGRA was measured on admission. Follow-up lasted 90 days. Two hundred forty-eight patients were included; 181 (73%) were vaccinated, 142 (57.3%) were infected with the Omicron variant, and 106 (42.7%) were infected with the Delta variant. The SARS-CoV-2-IGRA result was positive (>200 mIU/mL) in 125 (50.5%) patients, with 44 (35.2%) showing concomitant mitogen-induced IFN-γ response. Compared with patients with negative and borderline results, those with positive SARS-CoV-2 IGRA were younger and showed lower frequency of co-existing comorbidities, lower median Charlson comorbidity index, lower frequency of World Health Organization (WHO) severity score > 4, higher peripheral arterial oxygen saturation to inspired fraction of oxygen (SpO2/FiO2) ratio on admission, higher S-IgG and N-IgG antibody responses, and lower mortality at 28/60/90 days. These findings were consistent for both the Omicron and Delta variants. Similar patterns to those described above were observed in the subset of patients with positive SARS-CoV-2-IGRA and indeterminate mitogen-induced responses, as well as in those exhibiting both positive SARS-CoV-2-specific and mitogen responses. Twenty-eight (11.3%) patients had borderline (100-200 mIU/mL) SARS-CoV-2-IGRA results and shared several similarities with patients with negative SARS-CoV-2 IGRA. In an adjusted Cox model, a negative SARS-CoV-2-IGRA result was found to be an independent predictor of mortality. Using a receiver operating characteristics curve analysis, we found that an IFN-γ value of 150 mIU/mL was identified as the optimal cut-off point for predicting mortality, with 79% [95% confidence interval (CI) 61-93] sensitivity, 61% (95% CI 55-68) specificity, 18% (95% CI 15-22) positive predictive value, 96% (95% CI 93-98) negative predictive value, and an area under the curve (AUC) of 70%. The assay's performance remained consistent regardless of mitogen results or the presence of the Delta or Omicron variants. IMPORTANCE The cellular immune response is essential in the protection against severe disease in patients with established SARS-CoV-2 infection. The novelty of this study lies in the evaluation of the overall performance of a standardized assay to measure cellular immune response, the SARS-CoV-2-specific interferon-γ release assay (IGRA), in hospitalized patients with severe COVID-19. The SARS-CoV-2 IGRA was shown to accurately classify patients based on disease severity and prognosis, and the study revealed that test performance was not affected by the SARS-CoV-2 variant or control tube results. We identified an assay cut-off point with a high negative predictive value against mortality. The SARS-CoV-2 IGRA in patients hospitalized for COVID-19 may be a useful tool to assess cellular immunity and adopt targeted therapeutic and preventive measures.

Diffusion-weighted imaging complements T2-weighted MRI for tumour response assessment in squamous anal carcinoma

ObjectivesA published tumour regression grade (TRG) score for squamous anal carcinoma treated with definitive chemoradiotherapy based on T2-weighted MRI yields a high proportion of indeterminate responses (TRG-3). We investigate whether the addition of diffusion-weighted imaging (DWI) improves tumour response assessment in the early post treatment period.Materials and methodsThis retrospective observational study included squamous anal carcinoma patients undergoing MRI before and within 3 months of completing chemoradiotherapy from 2009 to 2020. Four independent radiologists (1–20 years’ experience) scored MRI studies using a 5-point TRG system (1 = complete response; 5 = no response) based on T2-weighted sequences alone, and then after a 12-week washout period, using a 5-point DWI-TRG system based on T2-weighted and DWI. Scoring confidence was recorded on a 5-point scale (1 = low; 5 = high) for each reading and compared using the Wilcoxon test. Indeterminate scores (TRG-3) from each reading session were compared using the McNemar test. Interobserver agreement was assessed using kappa statistics.ResultsEighty-five patients were included (mean age, 59 years ± 12 [SD]; 55 women). T2-weighted TRG-3 scores from all readers combined halved from 24% (82/340) to 12% (41/340) with DWI (p < 0.001). TRG-3 scores changed most frequently (41%, 34/82) to DWI-TRG-2 (excellent response). Complete tumour response was recorded clinically in 77/85 patients (91%). Scoring confidence increased using DWI (p < 0.001), with scores of 4 or 5 in 84% (287/340). Interobserver agreement remained fair to moderate (kappa range, 0.28–0.58).ConclusionDWI complements T2-weighted MRI by reducing the number of indeterminate tumour responses (TRG-3). DWI increases radiologist’s scoring confidence.Clinical relevance statementDiffusion-weighted imaging improves T2-weighted tumour response assessment in squamous anal cancer, halving the number of indeterminate responses in the early post treatment period, and increases radiologists’ confidence.Key PointsTumour response based on T2-weighted MRI is often indeterminate in squamous anal carcinoma.Diffusion-weighted imaging alongside T2-weighted MRI halved indeterminate tumour regression grade scores assigned by four radiologists from 24 to 12%.Scoring confidence of expert and non-expert radiologists increased with the inclusion of diffusion-weighted imaging.

New Artificial Intelligence ChatGPT Performs Poorly on the 2022 Self-assessment Study Program for Urology.

Large language models have demonstrated impressive capabilities, but application to medicine remains unclear. We seek to evaluate the use of ChatGPT on the American Urological Association Self-assessment Study Program as an educational adjunct for urology trainees and practicing physicians. One hundred fifty questions from the 2022 Self-assessment Study Program exam were screened, and those containing visual assets (n=15) were removed. The remaining items were encoded as open ended or multiple choice. ChatGPT's output was coded as correct, incorrect, or indeterminate; if indeterminate, responses were regenerated up to 2 times. Concordance, quality, and accuracy were ascertained by 3 independent researchers and reviewed by 2 physician adjudicators. A new session was started for each entry to avoid crossover learning. ChatGPT was correct on 36/135 (26.7%) open-ended and 38/135 (28.2%) multiple-choice questions. Indeterminate responses were generated in 40 (29.6%) and 4 (3.0%), respectively. Of the correct responses, 24/36 (66.7%) and 36/38 (94.7%) were on initial output, 8 (22.2%) and 1 (2.6%) on second output, and 4 (11.1%) and 1 (2.6%) on final output, respectively. Although regeneration decreased indeterminate responses, proportion of correct responses did not increase. For open-ended and multiple-choice questions, ChatGPT provided consistent justifications for incorrect answers and remained concordant between correct and incorrect answers. ChatGPT previously demonstrated promise on medical licensing exams; however, application to the 2022 Self-assessment Study Program was not demonstrated. Performance improved with multiple-choice over open-ended questions. More importantly were the persistent justifications for incorrect responses-left unchecked, utilization of ChatGPT in medicine may facilitate medical misinformation.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: T cells normally recognize bacterial proteins originating from the gut microbiome, including some that cross-react with normal host B cell-specific proteins. A peptide-based strategy designed to activate and expand such pre-existing memory CD8+ T cells recognizing and driving anti-tumor activity against B cell malignancies was developed. EO2463 includes 4 synthetically produced peptides corresponding to cytotoxic CD8 HLA-A2 restricted epitopes which exhibit molecular mimicry with the B cell antigens CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a helper CD4 peptide, UCP2, derived from hTERT. Memory CD8+ T cell clones can be detected in the peripheral blood of healthy donors recognizing the EO2463 mimic peptides; in vitro, such cells can kill target T2 cells loaded with mimic or human counterpart peptides. Methods: This first-in-human trial include HLA-A2+ patients (pts) with follicular lymphoma (FL) and marginal zone lymphoma (MZL). In the safety lead-in dose-finding part, EO2463 is administered subcutaneously every other week (w) × 4, followed by monthly administrations for a max of 12 months. After 6 w of EO2463 monotherapy, oral lenalidomide (20 mg/day for 21/28 days up to 12 cycles) is added, and if no complete remission (CR) at w 19, rituximab (375 mg/m2 IV, weekly × 4, followed by q4 w infusions × 4) is also added. The peptide-dose is evaluated in a 3-by-3 safety design, starting at 150 μg/peptide, max escalation to 300 μg. Results: Pts in the 1st (150 μg dose; 3 pts) and 2nd (300 μg dose; 3 pts) cohorts received EO2463 monotherapy without related grade ≥3 adverse events. Three more pts are being enrolled at the 300 μg dose, prior to starting expansion cohorts. Among the initial 6 pts, 5 had FL and 1 MZL; median number of prior therapies was 1 (range 1–4). Objective response rate 67%, including 50% CR (at w18, w18, w42), and 17% partial remission (at w18; ongoing treatment). On EO2463 monotherapy (at w6), 3 stable disease (including one metabolic response in 5 of 6 target lesions), 2 indeterminate responses (increased FDG uptake, no size change), 1 progressive disease. Combination therapy toxicity; grade 3 thrombocytopenia, rash, anemia, atrial fibrillation, bronchitis and sepsis (all n = 1); in addition, grade 4 neutropenia (n = 2). Expansion of specific CD8+ T cells against the mimic peptides and targeted B cell proteins was detected in 4/6 pts, including in 2 pts with no measurable B cells at baseline (prior anti-CD20). Immune response was maintained even following addition of rituximab. In vitro expanded EO2463 specific CD8+ T cells from pts with immune response can kill malignant HLA-A2 B cell lines. Conclusions: EO2463 is well tolerated as monotherapy, and without additional safety signals when combined with lenalidomide and rituximab. We find evidence of on-target immune activation, and preliminary complete response rate is encouraging. Expanded data to be presented. NCT04669171. Keywords: Combination Therapies, Immunotherapy, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. A. A. Pinto Consultant or advisory role: Scientific Advisory Boards (F. Hoffmann-La Roche AG, Merck Sharp and Dohme, Incyte-Italy) Honoraria: Speaking engagements – Educational Lectures (F. Hoffmann-La Roche AG, Incyte –Italy, Merck Sharp and Dohme, Servier Affaires Medicales, BMS-CELGENE) Other remuneration: Speaker's Bureau: Incyte-Italy, F. Hoffmann-La Roche AG S. D. Smith Consultant or advisory role: ADC Therapeutics, Astrazeneca, Beigene, Epizyme, Karyopharm, KITE pharma, Incyte, Numab Therapeutics, AG Abbvie, Coherus Biosciences, advisory board (spouse): Genentech Research funding: ADC Therapeutics, Astrazeneca, Ayala (spouse), Bayer, Beigene, Bristol Myers Squibb (spouse), De Novo Biopharma, Enterome, Genentech, Ignyta (spouse), Incyte Corporation, Kymera Therapeutics, Merck Sharp and Dohme Corp., MorphoSys, Nanjing Pharmaceuticals Co., Ltd., Portola Pharmaceuticals, Viracta Therapeutics L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics Research funding: Gilead Sciences Other remuneration: Speakers’ Bureau: EUSA Pharma, Novartis R. Merryman Consultant or advisory role: Genmab, Adaptive Biotechnologies, Bristol Myers Squibb, Abbvie, Inteillia, Epizyme, Alphasights Research funding: Merck, Bristol Myers Squibb, Genmab, Genentech/Roche S. Ansel Research funding: Bristol Myers Squibb, SeaGen, Takeda, Regeneron, AstraZeneca, Pfizer, Affimed and ADC Therapeutics. P. Armand Consultant or advisory role: Merck, BMS, ADC Therapeutics, Tessa, GenMab, Enterome, Regeneron, Epizyme, Astra Zeneca, Genentech, Xencor, ATB Therapeutics Honoraria: Merck Research funding: Kite, Merck, BMS, Adaptive, Genentech, IGM P. L. Zinzani Consultant or advisory role: Secura Bio, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, MSD, AstraZeneca, Takeda, Roche, Eusa Pharma, Kyowa Kirin, Novartis, ADC Therap., Incyte, Beigene Other remuneration: Speaker's Bureau: Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, AstraZeneca, Takeda, Roche, Eusa Pharma, Kyowa Kirin, Novartis, Incyte, Beigene

Utilizing Dynamic Risk Stratification in Patients With Tall Cell Variant Papillary Thyroid Cancer.

Tall cell variant (TCV) papillary thyroid cancer (PTC) is a subtype of PTC associated with aggressive tumor behavior, advanced stage, and higher rates of recurrence and mortality. The present study aimed to test an established dynamic risk stratification tool in the TCV population, with the goal of better predicting the postoperative course of these patients. Retrospective chart review. A total of 94 patients with TCV who underwent total thyroidectomy with radioactive iodine ablation were retrospectively reviewed from 1998 through 2020. Biochemical, structural, and overall response to treatment was determined for each patient, based on postoperative thyroglobulin levels and imaging findings. Primary outcomes were locoregional and distant recurrence, presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. Patients with TCV who were stratified as having an excellent overall response to treatment had lower rates of locoregional recurrence than indeterminate, biochemical incomplete, and structural incomplete responses (2.0%, 33.3%, 55.0%, and 85.7% at 5 years respectively, p < 0.001). The same was true for distant recurrence as well (2.0%, 9.0%, 35.1%, and 42.9%, p < 0.001). An excellent response was also associated with lower rates of presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. Although TCV is an aggressive subtype associated with worse clinical outcomes than classical PTC, patients with an excellent overall response to treatment have significantly improved outcomes when compared to indeterminate, biochemical incomplete, and structural incomplete responses. 3 Laryngoscope, 133:2430-2438, 2023.

Safety and Efficacy of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem From a Phase 2, Randomized Clinical Trial in Pediatric Participants With Complicated Intra-abdominal Infection.

Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed. This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points. The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol. Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious.

First National Consensus on the Safe Practice of Medical Tourism for Bariatric Surgery in Mexico.

Medical tourism is increasing every year, especially in fields such as bariatric surgery. Global concerns rely on the fact of its safety, mainly because of a lack of standardization, unknown number of cases, and the type of specialists performing such procedures. Mexico continues to be among the top countries receiving patients from abroad, but there is no national consensus, guidelines, or recommendations about the practice in such fields. A group of 32 bariatric surgeons with an accumulated experience of 25,196 procedures in the medical tourism modality were gathered to perform a national consensus in bariatric surgery tourism. The Delphi methodology was used for this project, with a total of 52 items applied. A consensus was reached when the experts' position was ≥ 70% for each statement. The items included pre- and postoperative phases, patient selection, follow-up, and ethical and legal considerations. Of the 52 statements, 40 (76.9%) reached a consensus of ≥ 70%; 36 in favor, 5 against, and 11 with indeterminate responses. Although more than two-thirds of the statements related to high standard practice reached a consensus, weak points in the medical tourism modality were identified. This first consensus serves to establish the basis of safe practices, eventually reach national guidelines, and define the top standards of care when performing bariatric surgery tourism.

Thyroglobulin antibodies: Trend over time and clinical impact in differentiated thyroid carcinoma with and without radioiodine ablation

IntroductionThyroglobulin antibodies (TgAb) trend may be considered a surrogate marker for thyroglobulin in differentiated thyroid carcinoma. The aim of this study is to analyse, in cases with positive TgAb, trend over time and its relationship with response to treatment. Material and methodsRetrospective and descriptive study of 100 patients with differentiated thyroid carcinoma and positive TgAb (measured by electrochemoluminiscense) after thyroidectomy. Assessment of response to initial treatment was performed 6–24 months after surgery. Status at last follow-up was evaluated. ResultsAfter the first year nearly half of the patients showed a reduction in TgAb levels ≥50%, in 91% of these patients, status at last follow up was excellent response (65%) or indeterminate response due to decreasing TgAb levels (26%). At first assessment, indeterminate responses were found in 49% of cases, without significant differences among initial risk of recurrence category or whether radioiodine ablation was performed. At last evaluation (median 53.5 months), 15% of ablated low-risk patients had an indeterminate response (due to declining TgAb), vs 62% in the non-ablated low-risk group (p 0.03). Median time to negativization for post-surgical TgAb levels<100UI/ml was 11 months [3–94] vs 31 months [8–119] for patients with TgAb≥100UI/ml (p 0.0003). ConclusionA reduction of ≥50% in TgAb levels during the first year correlated with favourable outcomes. Non-ablated patients and patients with higher levels of post-surgical TgAb may need a longer time to achieve negative conversion.

Applicability of Adults 2015 American Thyroid Association Differentiated Thyroid Cancer Guidelines for Postoperative Risk Stratification and Postradioiodine Treatment Dynamic Risk Stratification in Pediatric Population.

Purpose This retrospective study aimed to study the applicability of 2015 adult American Thyroid Association (ATA) differentiated thyroid cancer (DTC) postoperative risk stratification and guidelines in the pediatric population for evaluating the number of metastatic lymph nodes in the postoperative risk stratification and postradioactive iodine (RAI) treatment dynamic risk stratification (DRS) using response to treatment (RTT) reclassification. In addition, the effect of pubertal status and gender was assessed on disease presentation and prognosis. Methods Data of 63 DTC patients aged 20 years or less, stratified into prepubertal, pubertal, and postpubertal age groups, was divided into low, intermediate, and high-risk groups using pediatric ATA recurrence risk stratification. Forty-seven patients were classified as responders (excellent and indeterminate responses) and incomplete responders (biochemical and structurally incomplete responses) by assessing the RTT at 1.5 years follow-up similar to recommendation of 2015 adult DTC ATA guidelines. Results Female-to-male ratio showed a trend of gradual increase with increasing age. Significantly more responders were observed in low- and intermediate-risk groups than in high-risk group ( p = 0.0013; p = 0.017, respectively), while prepubertal group had more extensive (N1b) disease. Using DRS at follow-up of 1.5 year, pubertal and postpubertal groups showed significantly better response to RAI. More female than male patients showed response and took significantly less time to respond to RAI ( p = 0.003). Conclusion RAI response in pediatric DTC depends on pubertal status, gender, and number of malignant nodes. DRS using RTT classification may be applicable early at 1.5 years after initial therapy in different pubertal age and risk groups.

MdBAK1 overexpression in apple enhanced resistance to replant disease as well as to the causative pathogen Fusarium oxysporum

Apple replant disease (ARD) is a complex syndrome caused by various biotic and abiotic stresses contained in replanted soil, leading to reduced plant growth and fruit yields and causing serious economic loss. Breeding disease-resistant varieties is an effective and practical method to control ARD. Effective plant defense depends in part on the plant immune responses induced by the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). BAK1 participates in the regulation of plant immunity as an important PRR-binding protein. In this study, MdBAK1 overexpression activated indeterminate immune responses in tissue-cultured apple plants. MdBAK1-overexpressing rooted apple plants exhibited enhanced resistance to ARD, as the inhibition of plant growth was significantly alleviated during the replanted soil treatment. In addition, MdBAK1-overexpressing apple plants showed abolished growth inhibition, wilting and root rot induced by Fusarium oxysporum, which is the main pathogen that causes ARD in China. MdBAK1 overexpression changed the microbial community structure in the rhizosphere soil, as reflected by the increase in bacterial content and the decrease in fungal content, and the root exudates of MdBAK1-overexpressing plants inhibited F. oxysporum spore germination compared with that of wild-type plants. Furthermore, the constitutive immunity and cell necrosis induced by the upregulation of MdBAK1 expression were involved in the inhibition of colonization and expansion of F. oxysporum in host plants. In short, MdBAK1 plays an important role in the regulation of apple resistance to ARD, suggesting that MdBAK1 may be a valuable gene for molecular breeding of ARD resistance.

Thyroglobulin antibodies: Trend over time and clinical impact in differentiated thyroid carcinoma with and without radioiodine ablation

IntroductionThyroglobulin antibodies (TgAb) trend may be considered a surrogate marker for thyroglobulin in differentiated thyroid carcinoma. The aim of this study is to analyse, in cases with positive TgAb, trend over time and its relationship with response to treatment. Material and methodsRetrospective and descriptive study of 100 patients with differentiated thyroid carcinoma and positive TgAb (measured by electrochemoluminiscense) after thyroidectomy. Assessment of response to initial treatment was performed 6–24 months after surgery. Status at last follow-up was evaluated. ResultsAfter the first year nearly half of the patients showed a reduction in TgAb levels ≥50%, in 91% of these patients, status at last follow up was excellent response (65%) or indeterminate response due to decreasing TgAb levels (26%). At first assessment, indeterminate responses were found in 49% of cases, without significant differences among initial risk of recurrence category or whether radioiodine ablation was performed. At last evaluation (median 53.5 months), 15% of ablated low-risk patients had an indeterminate response (due to declining TgAb), vs 62% in the non-ablated low-risk group (p 0.03). Median time to negativization for post-surgical TgAb levels<100UI/ml was 11 months [3–94] vs 31 months [8–119] for patients with TgAb≥100UI/ml (p 0.0003). ConclusionA reduction of ≥50% in TgAb levels during the first year correlated with favourable outcomes. Non-ablated patients and patients with higher levels of post-surgical TgAb may need a longer time to achieve negative conversion.

Outcomes with Cefiderocol Treatment in Patients with Bacteraemia Enrolled into Prospective Phase 2 and Phase 3 Randomised Clinical Studies.

IntroductionA post hoc, descriptive analysis of three prospective, randomised, controlled clinical studies investigating cefiderocol in gram-negative bacterial infections was conducted to assess its efficacy in patients with baseline bacteraemia.MethodsData from APEKS-cUTI (NCT02321800), APEKS-NP (NCT03032380) and CREDIBLE-CR (NCT02714595) studies were assessed individually. Patients received cefiderocol 2g, q8h, for 7–14 days or comparators (imipenem/cilastatin [APEKS-cUTI], meropenem [APEKS-NP] or best available therapy [BAT; CREDIBLE-CR]). Bacteraemia and clinical outcomes were assessed at early assessment (EA), end of treatment (EOT) and test of cure (TOC) for patients in the intention-to-treat populations with baseline blood samples positive for aerobic gram-negative species. Eradication, persistence or recurrence of baseline blood pathogen was confirmed from follow-up blood cultures; in the absence of follow-up blood cultures, clinical response, administration of additional antibiotics and vital status were used to assess bacteraemia outcome.ResultsOf 885 patients randomised, 84 had bacteraemia and 89 (cefiderocol: 55, comparators: 34) gram-negative pathogens were isolated, namely Enterobacterales (n = 62) and non-fermenters (n = 27). At EA, on-therapy bacteraemia eradication rates in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 100% (19/19), 50.0% (4/8) and 72.0% (18/25) with cefiderocol. Corresponding rates for comparators were 77.8% (7/9), 100% (10/10) and 69.2% (9/13), respectively. Persistence in blood at EA was seen in six patients overall (cefiderocol: 3, comparators: 3); indeterminate responses were common (cefiderocol: 8, comparators: 3), usually due to lack of blood cultures. Clinical cure/improvement rates at EA in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 100% (19/19), 62.5% (5/8) and 64.0% (16/25) with cefiderocol. Corresponding rates for comparators were 77.8% (7/9), 90.0% (9/10) and 30.8% (4/13), respectively. Bacteraemia eradication rates with cefiderocol in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 89.5%, 37.5% and 60.0% at EOT and 78.9%, 12.5% and 44.0% at TOC.ConclusionThis descriptive analysis suggests that cefiderocol may be a useful treatment option for gram-negative bacteraemia, including pathogens resistant to other antibiotics.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00598-9.

1154. Safety and Efficacy of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Pediatric Participants With Complicated Intra-abdominal Infection: A Phase 2, Randomized Clinical Trial

BackgroundCeftolozane/tazobactam (C/T), a cephalosporin–β-lactamase inhibitor combination, is approved for treatment of complicated urinary tract infections, complicated intra-abdominal infections (cIAI), and nosocomial pneumonia in adults. Safety and efficacy of C/T in pediatric participants with cIAI was assessed.MethodsThis phase 2 study (NCT03217136) compared C/T + metronidazole (MTZ) with meropenem (MEM) for treatment of cIAI. Age- and weight-adjusted dosing is summarized in Table 1. The primary objective was to evaluate the safety and tolerability of C/T + MTZ compared with MEM. A key secondary endpoint was clinical cure at end of treatment (EOT) and test of cure (TOC).Table 1. Summary of Dosing and Pharmacokinetic Sampling Schedule by Age Cohort ResultsA total of 94 participants were randomized 3:1; 91 were treated with C/T + MTZ (n=70) or MEM (n=21) comprising the modified intent-to-treat (MITT) population. The clinically evaluable population included 78 participants at EOT (C/T + MTZ, n=59; MEM, n=19) and 77 participants at TOC (C/T + MTZ, n=58; MEM, n=19). The most common diagnosis and pathogen in the MITT population were complicated appendicitis (C/T + MTZ, 91.4%; MEM, 100%) and Escherichia coli (C/T + MTZ, 67.1%; MEM, 61.9%). The mean (SD) intravenous therapy/overall treatment duration was 6.4 (2.8)/9.3 (3.6) days and 5.8 (1.8)/9.0 (3.2) days for C/T + MTZ and MEM, respectively. In total, ≥1 adverse events (AE) occurred in 80.0% and 61.9% of participants receiving C/T + MTZ and MEM, respectively (Table 2), of which 18.6% and 14.3% were considered drug related. Serious AE occurred in 11.4% (8/70) and 0% (0/21) of participants receiving C/T + MTZ and MEM, respectively; none were considered drug related. No drug-related study drug discontinuations occurred. In the MITT population, rates of clinical cure for C/T + MTZ and MEM at EOT were 80.0% and 95.2%, and at TOC were 80.0% and 100%, respectively (Figure 1); 6 of the 14 failures for C/T + MTZ were indeterminate responses scored as endpoint failures per protocol. In the clinically evaluable (CE) population, rates of clinical cure for C/T + MTZ and MEM were 89.8% and 100% at EOT, and 89.7% and 100% at TOC, respectively (Figure 1). ConclusionC/T + MTZ was well tolerated in pediatric participants with cIAI, and rates of clinical success were high with C/T treatment. C/T is a promising new treatment option for children with cIAI.Disclosures Carl-Christian A. Jackson, MD, Merck & Co. Inc. (Shareholder) Julia Lonchar, MSc, Merck Sharp & Dohme Corp. (Employee, Shareholder) Feng-Hsiu Su, MPH, MBA, Merck Sharp & Dohme Corp. (Employee, Shareholder) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Myra W. Popejoy, PharmD, Merck Sharp & Dohme Corp. (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Carisa S. De Anda, PharmD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Elizabeth G. Rhee, MD, Merck Sharp & Dohme Corp (Employee, Shareholder) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

1285. Outcomes in Patients with Gram-Negative Bacteremia from Phase 2 and Phase 3 Clinical Trials of Cefiderocol, a Novel Siderophore Cephalosporin

BackgroundCefiderocol (CFDC) is the first siderophore cephalosporin approved (US and EU) for a broad range of infections caused by Gram-negative (GN) bacteria, including carbapenem-resistant Enterobacterales (ENT) and non-fermenters (NFs). Bacteremia is a serious manifestation of GN infection and understanding how well an antibiotic works to clear the bacteremia is an important part of drug evaluation.MethodsAll completed clinical studies for CFDC development were used to identify patients with GN bacteremia. Information collected included the primary infection site, species identification and antibiotic susceptibility, post randomization blood cultures and clinical and bacteremia outcome. In patients with missing data (blood cultures) clinical response of cure was used to impute microbiological eradication. Indeterminate responses resulted from a combination of missing data and clinical failure, including death prior to test of cure (TOC).ResultsThree clinical studies randomized 900 patients (CFDC 552; comparators 348) of whom 84 (CFDC 52; comparators 32) had GN bacteremia at baseline (Table). Bacteremia rate by study was CREDIBLE-CR 25.3%, APEKS-cUTI 6.2%, APEKS-NP 6.0%. Escherichia coli (29), Klebsiella pneumoniae (23) and Acinetobacter spp (21) were most frequent species. Sources included urinary tract (31), lung (22), unknown (10), IV line (8), intraabdominal (6), or other (7). Persistence of bacteremia at TOC was seen in 2/52 (3.8%) CFDC and 2/32 (6.2%) control patients (Table), usually due to lack of source control. Clinical outcomes varied by study and infection source and were often confounded (indeterminate response). Eradication in patients with ENT at TOC was determined for 27/39 (69%) for CFDC and 16/23 (70%) for controls, and for 9/16 (56%) for CFDC and 10/11 (91%) for controls in patients with NFs, respectively.Table. Clinical and bacteremia microbiological outcomes per patient at TOC. ConclusionPost-treatment negative blood cultures were inconsistently collected, especially in APEKS-NP and -cUTI, however, negative blood cultures on therapy without recurrence was seen in 96% of CFDC patients with sufficient information. A dedicated clinical trial in GN bacteremia (GAME CHANGER; NCT03869437) is ongoing and will better delineate microbiological outcomes.Disclosures David Paterson, Accelerate (Speaker’s Bureau)BioMerieux (Speaker’s Bureau)BioMerieux (Advisor or Review Panel member)Entasis (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Merck (Grant/Research Support)Merck (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Shionogi & Co., Ltd. (Grant/Research Support)VenatoRx (Advisor or Review Panel member) Masahiro Kinoshita, MPharm, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)

Evaluation of the response levels of non-metastatic thyroid cancer patients in the postoperative twelfth month

Objective: Radioactive iodine (RAI) is used to ablate residual thyroid tissue after total thyroidectomy. The aim of this study was to evaluate the response according to the12th-month results of thyroid cancer patients and to investigate the changes in response level during follow-up.&#x0D; Materials and Methods: The study included 97 patients, comprising 88 (90.7%) females and 9 (9.3%) males, with a mean age of 41.68±13.25 years. None of the patients had lymph node or distant metastasis and all received RAI therapy. Thyroid-stimulating hormone (TSH), thyroglobulin (TG), and anti-TG levels and neck USG were examined in the 12th-month. Response to therapy was evaluated as an excellent response, biochemical incomplete response, structural incomplete response, or indeterminate response.&#x0D; Results: In the 12th month, 80 patients (82.47%) had excellent response, 13 patients (13.40%) had an indeterminate response, 3 patients (3.09%) had structural incomplete response and 1 patient (1.03 %) had biochemical incomplete response. Of the 80 patients with excellent response, 15 had no follow-up after the 12th month. The remaining 65 patients were followed up for 31.11±9.58 months. The response changed to indeterminate in the 18th month in 1 (1.54%) patient and to structural incomplete response in the 35th month in 1 (1.54%) patient. The 13 patients with indeterminate responses were followed up for 20.61±6.28 months.&#x0D; Conclusion: The TG level at 12th months provides accurate data about the course of the disease especially in patients with excellent responses. Patients with excellent response in the 12th month may be followed up less often and those with the indeterminate or incomplete responses should be followed up more often.

302 Increasing Appropriate Referrals to Genetic Counseling at the Time of Endoscopy

INTRODUCTION: The ACG recommends an initial assessment of family history of cancer and premalignant conditions be performed for all patients evaluated in gastroenterology practices to develop a preliminary determination of risk of familial cancer predisposition. Due to the fast-paced nature of practice and a knowledge gap, providers often miss referring high-risk patients for genetic counseling. For example, less than 2% of the projected 830,000 Lynch syndrome patients in the US are aware of their mutation status. In this quality improvement project, we implemented a one-page, patient-administered survey to identify those at high risk of common hereditary cancer syndromes and facilitate appropriate referral to genetic counseling. METHODS: We created a four-question survey based on National Comprehensive Cancer Network (NCCN) guidelines for genetic testing for several hereditary cancer syndromes, including Lynch syndrome and Hereditary Breast and Ovarian Cancer syndrome. It was provided to all English-speaking patients presenting for outpatient endoscopy, who voluntarily completed the survey in the waiting area. Completed surveys were assessed for meeting criteria for referral for genetic testing. The survey was implemented on April 1, 2019, and we assessed its initial impact by comparing the number of positive surveys (i.e. meeting NCCN guidelines for referral to genetic counseling) over two months post-implementation (Apr-May 2019) with the number of genetic counseling referrals by gastroenterology providers at our institution over two months pre-implementation (Feb-Mar 2019). RESULTS: In February-March 2019, 13 genetic counseling referrals were made by gastroenterology providers at our institution. In April-May 2019, 874 surveys were completed. 330 surveys (37.8%) had responses meeting NCCN guidelines for referral for genetic counseling and a high risk of familial cancer predisposition. 481 (55%) did not meet criteria for high-risk family history, and 63 (7.2%) had indeterminate responses, requiring additional evaluation to determine risk. CONCLUSION: We created a simple, self-administered survey that identified a far larger number of endoscopy patients meeting NCCN criteria for genetic counseling referral than the number of referrals placed over a comparable timeframe prior to implementation. To address the large gap in appropriate genetic counseling referrals, we aim to create a sustainable workflow for referral from endoscopy, and plan to assess patient follow-through on these referrals.