Burden Threshold Research Articles

Time to consider health services dedicated for adults living with cerebral small vessel disease: Report of a ESO scientific seminar.

Cerebral small vessel disease (cSVD) is a highly prevalent disorder leading to physical, cognitive and functional decline. We report key barriers in the management of individuals with cSVD, the potential benefit of cSVD-dedicated health services, and evidence from existing models of care for adults with cSVD. We examined information from a scientific seminar developed between seven experts in cSVD during the eighth European Stroke Organisation Conference that discussed the optimal health care for adults with cSVD and what health services dedicated to cSVD should include. Barriers in cSVD care include unrecognised symptoms and modifiable risk factors, heterogeneity of clinical presentations, inefficient inter/intra-clinical services communication/organisation, and uncertainties regarding what assessments/treatments should be routinely done, when and by whom. However, existing health services and research studies suggest models of care in cSVD. Multi-step approaches can be used for identification and aetiological workup in individuals with cSVD, including basic and selected advanced evaluations, for example, monogenic cSVD testing. Although current guidelines for management of cSVD illlustrate limitations, there are recommendations on risk factors and lifestyle considerations, as well as pharmacological and non-pharmacological interventions for people with cSVD. Existing healthcare models do not provide optimal care for individuals with cSVD. Lack of awareness of heterogeneous clinical presentations and uncertainty in threshold of cSVD 'burden' for referral to specialist multidisciplinary services, are key challenges for health services to overcome. Creating cSVD-dedicated services may prevent underdiagnosing and achieve standardised holistic management to improve outcomes in people with cSVD. However, adequate prevention and early management should be offered at all levels of care.

Using Atrial Fibrillation Burden Trends and Machine Learning to Predict Near-Term Risk of Cardiovascular Hospitalization.

Atrial fibrillation is associated with an increased risk of cardiovascular hospitalization (CVH), which may be triggered by changes in daily burden. Machine learning of dynamic trends in atrial fibrillation burden, as measured by insertable cardiac monitors (ICMs), may be useful in predicting near-term CVH. Using Optum's deidentified Clinformatics Data Mart Database (2007-2019), linked with the Medtronic CareLink ICM database, we identified patients with >1 days of ICM-detected atrial fibrillation. ICM-detected diagnostic parameters were transformed into simple moving averages over different periods for daily follow-up. A diagnostic trend was defined as the comparison of 2 simple moving averages of different periods for each diagnostic parameter. CVH was defined as any hospital, emergency department, or ambulatory surgical center encounter with a cardiovascular diagnosis-related group or diagnosis code. Machine learning was used to determine which diagnostic trends could best predict patient risk 5 days before CVH. A total of 2616 patients with ICMs met the inclusion criteria (71±11 years; 55% male). Among them, 1998 (76%) had a planned or unplanned CVH over 605 363 days. Machine learning revealed distinct groups: (A) sinus rhythm (reference), (B) below-average burden, (C) above-average burden, and (D) above-average burden with decreasing patient activity. The relative risk was increased in all groups versus the reference (B, 4.49 [95% CI, 3.74-5.40]; C, 8.41 [95% CI, 7.00-10.11]; D, 11.15 [95% CI, 9.10-13.65]), including a 21% increase in CVH detection over prespecified burden thresholds of duration (≥1 hour) and quantity (≥5%). The area under the receiver operating characteristic curve increased from 0.55 when using hourly burden amounts to 0.66 when using burden trends and decreasing patient activity (P<0.001), a 20% increase in predictive power. Trends in atrial fibrillation were strongly associated with near-term CVH, especially above-average burden coupled with low patient activity. This approach could provide actionable information to guide treatment and reduce CVH.

Managing more than bones: the psychological impact of a recurrent fracture-related infection.

Fracture-related infections (FRIs) are a devastating complication of fracture management. However, the impact of FRIs on mental health remains understudied. The aim of this study was a longitudinal evaluation of patients' psychological state, and expectations for recovery comparing patients with recurrent FRI to those with primary FRI. A prospective longitudinal study was conducted at a level 1 trauma centre from January 2020 to December 2022. In total, 56 patients treated for FRI were enrolled. The ICD-10 symptom rating (ISR) and an expectation questionnaire were assessed at five timepoints: preoperatively, one month postoperatively, and at three, six, and 12 months. Recurrent FRI cases consistently exceeded the symptom burden threshold (0.60) in ISR scores at all assessment points. The difference between preoperative-assessed total ISR scores and the 12-month follow-up was not significant in either group, with 0.04 for primary FRI (p = 0.807) and 0.01 for recurrent FRI (p = 0.768). While primary FRI patients showed decreased depression scores post surgery, recurrent FRI cases experienced an increase, reaching a peak at 12 months (1.92 vs 0.94; p < 0.001). Anxiety scores rose for both groups after surgery, notably higher in recurrent FRI cases (1.39 vs 1.02; p < 0.001). Moreover, patients with primary FRI reported lower expectations of returning to normal health at three (1.99 vs 1.11; p < 0.001) and 12 months (2.01 vs 1.33; p = 0.006). The findings demonstrate the significant psychological burden experienced by individuals undergoing treatment for FRI, which is more severe in recurrent FRI. Understanding the psychological dimensions of recurrent FRIs is crucial for comprehensive patient care, and underscores the importance of integrating psychological support into the treatment paradigm for such cases.

Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma.

The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known. Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti-PD-1 (n = 240) or dual anti-PD-1 and anti-CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score. TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; P < .001; HR, 0.61 [95% CI, 0.41 to 0.90]; P = .01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; P = .009; HR, 0.61 [95% CI, 0.42 to 0.88]; P = .007, respectively) patients. Dual ICI offered no significant advantage in BRAFwt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) BRAFmut patient subgroup for whom mono ICI may be preferable. TMB-H predicts superior outcomes on ICI while coassessment of BRAF status and TMB may inform first-line regimen choice.

Identification of novel resistance-associated mutations and discrimination within whole-genome sequences of fluoroquinolone-resistant Mycobacterium tuberculosis isolates.

This study aims to elucidate additional mutation loci associated with fluoroquinolone (FQ) resistance and evaluate the discriminatory capacity of mutation loci and allele mutation frequencies in identifying FQ-resistant Mycobacterium tuberculosis (MTB) isolates. A random selection of isolates was extracted from an ongoing collection. Drug resistance was determined using the resazurin microtiter assay (REMA) as the gold standard. Mutation loci and the burden of mutations in the quinolone resistance-determining region (QRDR) were elucidated through whole-genome sequencing (WGS). Novel amino acid mutations, namely, G520D and G520T, were identified in the gyrB and associated with FQ resistance. In the context of distinguishing FQ-resistant isolates, the AUC for the QRDR mutation frequency burden (0.969) surpassed that of the mutation locus (0.929), and this difference was statistically significant (P = 0.03). Furthermore, using the resistance mutation locus as a reference, setting the QRDR mutation frequency burden threshold at 1.31% resulted in a 3.60% increase in the accuracy of classifying FQ-resistant isolates (NRI = 3.60%, P < 0.001). The QRDR mutation frequency burden appears to offer superior diagnostic efficacy in discriminating FQ-resistant isolates compared to qualitative detection of mutant loci.IMPORTANCEFluoroquinolone (FQ) drugs are recommended as second-line drugs for the treatment of multidrug-resistant tuberculosis. With the massive use of FQ drugs in the clinical treatment of tuberculosis (TB), there is an increasing rate of drug resistance to FQ drugs. In this study, we identified and demonstrated novel amino acid mutations associated with FQ resistance in Mycobacterium tuberculosis (MTB), and we quantified the mutation sites and identified the quinolone resistance-determining region (QRDR) mutation frequency burden as a novel diagnostic method for FQ resistance. We hope that the results of this study will provide data support and a theoretical basis for the rapid diagnosis of FQ-resistant MTB.

Mathematical Model-Driven Deep Learning Enables Personalized Adaptive Therapy.

Generation of interpretable and personalized adaptive treatment schedules using a deep reinforcement framework that interacts with a virtual patient model overcomes the limitations of standardized strategies caused by heterogeneous treatment responses.

Application of Covalent Binding Body Burden in the HμREL Human Hepatocyte Coculture Model for Reactivity Risk Assessment of Metabolically Low Turnover Drugs.

The human hepatocyte suspension model has been a valuable tool to study covalent binding (CVB) for compounds that form reactive metabolites. However, accurately measuring CVB values with the suspension model becomes challenging for metabolically low turnover compounds. In this study, we evaluated the HμREL human hepatocyte coculture model relative to existing literature using human hepatocyte suspension for drugs of known drug-induced liver injury category. Our results indicate that this coculture model provides ample metabolic turnover to reproducibly measure CVB. It is sufficiently robust to apply a predefined 1 mg/day CVB body burden threshold for risk assessment to guide our discovery programs, allowing for expanded coverage to include metabolically low turnover compounds.

Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.

Three-Day Monitoring of Adhesive Single-Lead Electrocardiogram Patch for Premature Ventricular Complex: Prospective Study for Diagnosis Validation and Evaluation of Burden Fluctuation.

Wearable electrocardiogram (ECG) monitoring devices are used worldwide. However, data on the diagnostic yield of an adhesive single-lead ECG patch (SEP) to detect premature ventricular complex (PVC) and the optimal duration of wearing an SEP for PVC burden assessment are limited. We aimed to validate the diagnostic yield of an SEP (mobiCARE MC-100, Seers Technology) for PVC detection and evaluate the PVC burden variation recorded by the SEP over a 3-day monitoring period. This is a prospective study of patients with documented PVC on a 12-lead ECG. Patients underwent simultaneous ECG monitoring with the 24-hour Holter monitor and SEP on the first day. On the subsequent second and third days, ECG monitoring was continued using only SEP, and a 3-day extended monitoring was completed. The diagnostic yield of SEP for PVC detection was evaluated by comparison with the results obtained on the first day of Holter monitoring. The PVC burden monitored by SEP for 3 days was used to assess the daily and 6-hour PVC burden variations. The number of patients additionally identified to reach PVC thresholds of 10%, 15%, and 20% during the 3-day extended monitoring by SEP and the clinical factors associated with the higher PVC burden variations were explored. The recruited data of 134 monitored patients (mean age, 54.6 years; males, 45/134, 33.6%) were analyzed. The median daily PVC burden of these patients was 2.4% (IQR 0.2%-10.9%), as measured by the Holter monitor, and 3.3% (IQR 0.3%-11.7%), as measured in the 3-day monitoring by SEP. The daily PVC burden detected on the first day of SEP was in agreement with that of the Holter monitor: the mean difference was -0.07%, with 95% limits of agreement of -1.44% to 1.30%. A higher PVC burden on the first day was correlated with a higher daily (R2=0.34) and 6-hour burden variation (R2=0.48). Three-day monitoring by SEP identified 29% (12/42), 18% (10/56), and 7% (4/60) more patients reaching 10%, 15%, and 20% of daily PVC burden, respectively. Younger age was additionally associated with the identification of clinically significant PVC burden during the extended monitoring period (P=.02). We found that the mobiCARE MC-100 SEP accurately detects PVC with comparable diagnostic yield to the 24-hour Holter monitor. Performing 3-day PVC monitoring with SEP, especially among younger patients, may offer a pragmatic alternative for identifying more individuals exceeding the clinically significant PVC burden threshold.

Abstract PR001: Learning to adapt: Rational personalization of adaptive therapy using deep reinforcement learning

Abstract Standard-of-care treatment regimens have long been designed for maximal cell kill, yet these strategies often fail when applied to metastatic cancers due to the emergence of drug resistance. Adaptive treatment strategies have been developed as an alternative approach, dynamically adjusting treatment to suppress the growth of treatment-resistant populations, delaying, or even preventing, tumor progression. Promising clinical results in prostate cancer indicate the potential to optimize adaptive treatment protocols. We propose the application of deep reinforcement learning (DRL) to guide adaptive drug scheduling, and demonstrate that these treatment schedules can outperform the current adaptive protocols in a mathematical model calibrated to prostate cancer dynamics, more than doubling the time to progression. We show that the DRL strategies are robust to patient variability, including both tumor dynamics and clinical monitoring schedules. We demonstrate that the DRL framework can produce interpretable, adaptive strategies based on a single tumor burden threshold, replicating and informing optimal treatment strategies. Given the DRL framework has no knowledge of the underlying mathematical tumor model, this demonstrates the capability of DRL to help develop treatment strategies in novel or complex settings. Finally, we propose a five-step pathway combining mechanistic modeling with the DRL framework to translate this approach to the clinic with limited information for a given patient. Integrating conventional tools to ensure the interpretability of traditionally `black-box' DRL models, we generate personalized treatment schedules that consistently outperform clinical standard-of-care protocols. Citation Format: Kit Gallagher, Maximilian Strobl, Robert Gatenby, Philip Maini, Alexander Anderson. Learning to adapt: Rational personalization of adaptive therapy using deep reinforcement learning [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR001.

Growth feedback confers cooperativity in resource-competing synthetic gene circuits

Modularity is a key concept in designing synthetic gene circuits, as it allows for constructing complex molecular systems using well-characterized building blocks. One of the major challenges in this field is that these modular components often do not function as expected when assembled into larger circuits. One of the major issues is caused by resource competition, where multiple genes in the circuit compete for the same limited cellular resources, such as transcription factors and ribosomes. In addition, the mutual inhibition between synthetic gene circuits and cell growth results in growth feedback that significantly impacts its host-circuit dynamics. However, the complexity of the gene circuit dynamics under intertwined resource competition and growth feedback is not fully understood. This study developed a theoretical framework to examine the dynamics of synthetic gene circuits by considering both growth feedback and resource competition. Our results suggest a cooperative behavior between resource-competing gene circuits under growth feedback. Cooperation or competition is non-monotonically determined by the metabolic burden threshold. These two diverse effects could lead to the activation or deactivation of one circuit by the other. Lastly, the cooperativity mediated by growth feedback can attenuate the winner-takes-all resource competition. These findings show that coupling growth feedback and resource competition plays a crucial role in the dynamics of the host-circuit system, and understanding its effects helps control unexpected gene expression behaviors.

Combination of device-detected heart failure status and sleep-disordered breathing for the prediction of atrial fibrillation occurrence

Abstract Funding Acknowledgements Type of funding sources: None. Aims Patients with atrial fibrillation (AF) frequently experience sleep disorder breathing, and both conditions are highly prevalent in presence of heart failure (HF). We explored the association between sleep apnea (SA) and the HF status and the incidence of AF in patients with implantable defibrillators (ICD). Methods Data were prospectively collected from 411 consecutive HF patients with ICD. The HF status was measured by the multisensor HeartLogic Index, and the ICD-measured Respiratory Disturbance Index (RDI) was computed to identify severe SA. The endpoints were: daily AF burden of ≥5minutes, ≥6hours and ≥23hours. Results During a median follow-up of 26 months, the time IN-alert HF state was 13% of the total observation period, according to the HeartLogic algorithm (Index &amp;gt;16). The RDI value was ≥30 episodes/h (severe SA) during 58% of the observation period. An AF burden of ≥5 minutes/day was documented in 139 (34%) patients, ≥6 hours/day in 89 (22%) patients, and ≥23 hours/day in 68 (17%) patients. The IN-alert HF state was independently associated with AF regardless of the daily burden threshold: hazard ratios from 2.17 for ≥5 min/day to 3.43 for ≥23 h/day (p&amp;lt;0.01). The occurrence of severe SA was associated only with AF burden ≥5 min/day (hazard ratio 1.55 [95%CI:1.11-2.16], p=0.001). The combination of HF alert and severe SA accounted for only 6% of the follow-up period and was associated with high rates of AF occurrence (from 28 events/100 patient-years for AF burden≥5 min/day to 22 events/100 patient-years for AF burden≥23 h/day). Conclusions In patients with heart failure (HF) and implantable defibrillators (ICD), the occurrence of atrial fibrillation (AF) was independently associated with the worsened HF status measured by a multisensor ICD algorithm and with ICD-diagnosed severe sleep apnea (SA). The HF status was independently associated with AF regardless of the daily burden, while severe SA was mainly associated with shorter AF episodes. The coexistence of these two conditions occurs rarely but is associated with a very high rate of AF occurrence.

PO-03-146 PREMATURE VENTRICULAR CONTRACTIONS IN CHILDREN AND YOUNG ADULTS: RISK FACTORS FOR LEFT VENTRICULAR DYSFUNCTION

Premature ventricular contractions (PVCs) are common in children and are often perceived as benign. However, frequent PVCs can lead to left ventricular (LV) dysfunction. Risk factors for PVC-mediated LV dysfunction are not well defined in children. Characterize the frequency of and risk factors for LV dysfunction in children with frequent PVCs. Retrospective cohort study from 2003-18 including patients aged 1-21 years with frequent PVCs (>0.5% on Holter monitoring), a 12-lead ECG with 1+ PVC, and an echocardiogram. Risk factors for LV dysfunction (LVEF <50%) at time of presentation and during follow up in the subset of patients with echocardiographic follow up were evaluated using logistic regression and Cox proportional hazards analysis, respectively. Exclusion criteria included significant congenital heart disease and known personal or family history of primary arrhythmic or cardiomyopathic disease. We identified 202 patients and four were excluded due to diagnoses made after presentation with PVCs: Andersen-Tawil syndrome (2 siblings), and cardiomyopathy (2), leaving 198 for analysis with a median age 12.3 years. LV dysfunction was present at time of presentation in 4%, developed in an additional 6% during follow up, and was mild in most (LVEF <40% in only 1). Risk factors for LV dysfunction included older age; higher PVC burden; longer PVC duration; couplets, triplets, NSVT, and polymorphic ventricular ectopy (table 1). A PVC burden threshold of ≥15% was 100% sensitive and 76% specific for LV dysfunction at time of presentation (fig. 1) while a PVC duration threshold of ≥151ms was 100% sensitive and 74% specific. No risk factors were identified for developing LV dysfunction during follow up. In children who never received PVC-directed therapy or had serial Holter monitors before therapy was started, PVC burden decreased from a median of 10.2 to 1.8% (p < 0.001) over a median follow up period of 3.2 years. PVC-mediated LV dysfunction is rare in children and is mild in nearly all cases. Younger patients with <15% PVCs, PVC duration <151ms, and without complex ventricular ectopy are at extremely low risk for LV dysfunction. The natural history shows a reduction in PVC burden over time in most, but not all, patients. A minority of children who come to attention due to frequent PVCs have a serious underlying cardiovascular diagnosis.Tabled 1Table 1No LV Dysfunction (n = 191)LV Dysfunction (n = 7)OR [95% CI]p-valueDemographicsMale sex108 (57)6 (86)4.6 [0.5-39.0]0.161Age (years)12.1 (7.8-15.6)17.6 (16.2-17.6)4.5 [1.3-16.1] per 5 year increase0.021CHD8 (4)1 (14)3.8 [0.4-35.5]0.240PresentationPVCs incidentally noted140 (73)6 (86)2.2 [0.3-18.6]0.474Initial Holter Results%PVCs8.6 [3.9-14.9]33.6 [18.5-36.8]1.6 [1.3-2.2] per 5% increase<0.001Sustained VT3 (2)1 (14)10.4 [0.9-115.7]0.056NSVT11 (6)4 (57)21.8 [4.3-109.8]<0.001*Couplets73 (38)7 (100)*0.001Triplets26 (14)4 (57)8.5 [1.8-40.0]0.007Polymorphic ectopy9 (5)2 (29)8.1 [1.4-47.5]0.021ECG PVC CharacteristicsInferior QRS axis156 (82)6 (86)1.3 [0.2-11.5]0.786LBBB morphology141 (74)5 (71)0.9 [0.2-4.7]0.888Outflow tract morphology118 (62)5 (71)1.5 [0.3-8.2]0.608PVC coupling interval (ms)477 (420-531)467 (399-497)0.9 [0.7-1.1] per 25 ms increase0.420PVC duration (ms)135 (119-151)160 (157-168)4.0 [1.5-10.9] per 25 ms increase0.007ETT results (n = 99)PVC suppression during test78 (85)4 (57)0.2 [0.1-1.2]0.080VT during test3 (3)1 (14)4.9 [0.4-55.0]0.194∗Odds ratio cannot be estimated as all patients with dsyfunction are in one group; p-value estimated from Fisher's exact test. CHD = congenital heart disease, VT = ventricular tachycardia, NSVT = non-sustained ventricular tachycardia, LBBB = left bundle branch block, ETT = exercise tolerance test Open table in a new tab

Combination of an implantable defibrillator multi-sensor heart failure index and an apnea index for the prediction of atrial high-rate events.

Patients with atrial fibrillation frequently experience sleep disorder breathing, and both conditions are highly prevalent in presence of heart failure (HF). We explored the association between the combination of an HF and a sleep apnoea (SA) index and the incidence of atrial high-rate events (AHRE) in patients with implantable defibrillators (ICDs). Data were prospectively collected from 411 consecutive HF patients with ICD. The IN-alert HF state was measured by the multi-sensor HeartLogic Index (>16), and the ICD-measured Respiratory Disturbance Index (RDI) was computed to identify severe SA. The endpoints were as follows: daily AHRE burden of ≥5 min, ≥6 h, and ≥23 h. During a median follow-up of 26 months, the time IN-alert HF state was 13% of the total observation period. The RDI value was ≥30 episodes/h (severe SA) during 58% of the observation period. An AHRE burden of ≥5 min/day was documented in 139 (34%) patients, ≥6 h/day in 89 (22%) patients, and ≥23 h/day in 68 (17%) patients. The IN-alert HF state was independently associated with AHRE regardless of the daily burden threshold: hazard ratios from 2.17 for ≥5 min/day to 3.43 for ≥23 h/day (P < 0.01). An RDI ≥ 30 episodes/h was associated only with AHRE burden ≥5 min/day [hazard ratio 1.55 (95% confidence interval: 1.11-2.16), P = 0.001]. The combination of IN-alert HF state and RDI ≥ 30 episodes/h accounted for only 6% of the follow-up period and was associated with high rates of AHRE occurrence (from 28 events/100 patient-years for AHRE burden ≥5 min/day to 22 events/100 patient-years for AHRE burden ≥23 h/day). In HF patients, the occurrence of AHRE is independently associated with the ICD-measured IN-alert HF state and RDI ≥ 30 episodes/h. The coexistence of these two conditions occurs rarely but is associated with a very high rate of AHRE occurrence. URL: http://clinicaltrials.gov/Identifier: NCT02275637.

TMBcat: A multi-endpoint p-value criterion on different discrepancy metrics for superiorly inferring tumor mutation burden thresholds.

Tumor mutation burden (TMB) is a widely recognized stratification biomarker for predicting the efficacy of immunotherapy; however, the number and universal definition of the categorizing thresholds remain debatable due to the multifaceted nature of efficacy and the imprecision of TMB measurements. We proposed a minimal joint p-value criterion from the perspective of differentiating the comprehensive therapeutic advantages, termed TMBcat, optimized TMB categorization across distinct cancer cohorts and surpassed known benchmarks. The statistical framework applies to multidimensional endpoints and is fault-tolerant to TMB measurement errors. To explore the association between TMB and various immunotherapy outcomes, we performed a retrospective analysis on 78 patients with non-small cell lung cancer and 64 patients with nasopharyngeal carcinomas who underwent anti-PD-(L)1 therapy. The stratification results of TMBcat confirmed that the relationship between TMB and immunotherapy is non-linear, i.e., treatment gains do not inherently increase with higher TMB, and the pattern varies across carcinomas. Thus, multiple TMB classification thresholds could distinguish patient prognosis flexibly. These findings were further validated in an assembled cohort of 943 patients obtained from 11 published studies. In conclusion, our work presents a general criterion and an accessible software package; together, they enable optimal TMB subgrouping. Our study has the potential to yield innovative insights into therapeutic selection and treatment strategies for patients.

Quality of life after fracture-related infection of the foot

BackgroundFracture related infection (FRI) of the foot is a serious hazard. Despite successful therapy, the physiological and psychological involvement seems to be high. Therefore, we aim to analyze the impact of an FRI of the foot on the quality of life after successful surgical therapy and infect eradication. MethodsIn total, 25 patients from two German hospitals treated for FRI of the foot between March 2011 to January 2020 were retrospectively included. Quality of life was assessed by the German Short Form 36 (SF-36) and the EuroQol five-dimension three-level questionnaire (EQ-5D) as well as the ICD-10 based psychological symptom rating (ISR), and compared to a norm obtained from the general population of Germany. Results3.0 years (range 0.7–7.9 years) following final surgery after fracture-related infection of the foot, the mean physical health component score (PCS) of the SF-36 was 35.6 ± 12.3, and the mean mental health component score (MCS) of the SF-36 reached a value of 41.3 ± 12.9. Both values were significantly lower than in the general population of Germany (p< .019). The mean scores of the ISR of the cohort crossed the threshold of mild symptom burden in total, as well as for the subscales depression and somatization. The mean EQ-5D VAS rating (62.1 ± 18.6) and the EQ-5D index value (0.66 ± 0.27) were significantly lower in comparison to a score of 72.9 ± 1.0 and 0.88 obtained from an age-matched reference population (p < .01). ConclusionFRI of the foot represents a major burden for the patient. Physical and mental well-being of affected patients is restricted albeit successful treatment in terms of infect eradication and bone union has been achieved after a mean follow-up of 3.0 years. A patient-centered treatment approach focusing on improvement of quality of life during and after treatment is therefore warranted.

A Joint Model Considering Measurement Errors for Optimally Identifying Tumor Mutation Burden Threshold.

Tumor mutation burden (TMB) is a recognized stratification biomarker for immunotherapy. Nevertheless, the general TMB-high threshold is unstandardized due to severe clinical controversies, with the underlying cause being inconsistency between multiple assessment criteria and imprecision of the TMB value. The existing methods for determining TMB thresholds all consider only a single dimension of clinical benefit and ignore the interference of the TMB error. Our research aims to determine the TMB threshold optimally based on multifaceted clinical efficacies accounting for measurement errors. We report a multi-endpoint joint model as a generalized method for inferring the TMB thresholds, facilitating consistent statistical inference using an iterative numerical estimation procedure considering mis-specified covariates. The model optimizes the division by combining objective response rate and time-to-event outcomes, which may be interrelated due to some shared traits. We augment previous works by enabling subject-specific random effects to govern the communication among distinct endpoints. Our simulations show that the proposed model has advantages over the standard model in terms of precision and stability in parameter estimation and threshold determination. To validate the feasibility of the proposed thresholds, we pool a cohort of 73 patients with non-small-cell lung cancer and 64 patients with nasopharyngeal carcinoma who underwent anti-PD-(L)1 treatment, as well as validation cohorts of 943 patients. Analyses revealed that our approach could grant clinicians a holistic efficacy assessment, culminating in a robust determination of the TMB screening threshold for superior patients. Our methodology has the potential to yield innovative insights into therapeutic selection and support precision immuno-oncology.

Threshold of tumor mutational burden and association with survival in ovarian cancer (172)

<b>Objectives:</b> Targeted therapies based on molecular profiling have been integrated into treatment guidelines for patients with ovarian cancer. Recently, the FDA approved pembrolizumab for patients with tumor mutational burden-high (TMB-H) (≥10 mutations/megabase [mut/Mb]) solid tumors. However, trials evaluating checkpoint inhibitors in patients with ovarian cancer have had limited efficacy. We characterized patients with ovarian cancer who had undergone next-generation sequencing to characterize the landscape tumor mutational burden by histologic subtype and clinical outcome. <b>Methods:</b> A retrospective cohort study was performed on patients diagnosed with ovarian cancer who underwent Foundation One testing between 2015 and 2021 at a single academic institution. Demographic and clinical characteristics were abstracted, including age, race/ethnicity, stage, histology, and follow-up time in months. Kaplan-Meier curves and Cox regression analyses were used to estimate overall survival (OS) and progression-free survival (PFS). <b>Results:</b> We identified 128 patients diagnosed with ovarian cancer and underwent Foundation One testing. Most patients (51, 39.8%) had high-grade serous histology. Other histologies included 24 (18.8%) low-grade serous, 20 (15.6%) clear cell, five (3.9%) mucinous, five (3.9%) endometrioid, one germ cell (0.8%), six sex cord-stromal (4.7%), 11 carcinosarcoma (8.6%), three adenocarcinomas not otherwise classified (2.3%), and two (1.6%) borderline tumors. The median age at diagnosis was 62 years (range: 18-78 years). TMB was available for 93/128 patients. Most patients (83, 89.2%) had low TMB defined as 0-5 mut/Mb. Ten patients (10.8%) had intermediate TMB defined as 6-19 mut/Mb. Tumors from patients with TMB ≤5 mut/Mb had significantly longer PFS (p=0.005) but not OS (p=0.55) than those with TMB > 5 mut/Mb. Eighty (62.5%) patients developed recurrent ovarian cancer. Of those who developed recurrent disease, there was a significant difference in PFS (p=0.02) but not OS (p=0.58) when comparing TMB ≤5 versus > 5. <b>Conclusions:</b> In an era of biomarker-driven care, TMB may be a useful adjunctive prognostic tool for patients with ovarian cancer. Future work should evaluate how TMB predicts response and benefit to immunotherapy.

Resource-aware whole-cell model of division of labour in a microbial consortium for complex-substrate degradation

BackgroundLow-cost sustainable feedstocks are essential for commercially viable biotechnologies. These feedstocks, often derived from plant or food waste, contain a multitude of different complex biomolecules which require multiple enzymes to hydrolyse and metabolise. Current standard biotechnology uses monocultures in which a single host expresses all the proteins required for the consolidated bioprocess. However, these hosts have limited capacity for expressing proteins before growth is impacted. This limitation may be overcome by utilising division of labour (DOL) in a consortium, where each member expresses a single protein of a longer degradation pathway.ResultsHere, we model a two-strain consortium, with one strain expressing an endohydrolase and a second strain expressing an exohydrolase, for cooperative degradation of a complex substrate. Our results suggest that there is a balance between increasing expression to enhance degradation versus the burden that higher expression causes. Once a threshold of burden is reached, the consortium will consistently perform better than an equivalent single-cell monoculture.ConclusionsWe demonstrate that resource-aware whole-cell models can be used to predict the benefits and limitations of using consortia systems to overcome burden. Our model predicts the region of expression where DOL would be beneficial for growth on starch, which will assist in making informed design choices for this, and other, complex-substrate degradation pathways.

Molting enhances internal concentrations of fipronil and thereby decreases survival of two estuarine resident marine crustaceans.

In aquatic arthropods, molting is a pivotal physiological process for normal development, but it may also expose them to higher risks from xenobiotics, because the organism may take up additional water during that time. This study aimed to assess the effects of molting on bioconcentration and survival after 96-h exposure to insecticide fipronil with or without oxygenase (CYP450s) inhibitor piperonyl butoxide (PBO) of two estuarine resident marine crustacean species: the sand shrimp Crangon uritai and the kuruma prawn Penaeus japonicus, with 96-h LC50 value of fipronil=2.0µg/L and 0.2µg/L, respectively. Two graded concentrations included group high (H) (equivalent to the 96-h LC50 values) and low (L) (one-tenth of the H group concentration). Molting and survival were individually checked, and internal concentrations of fipronil and its metabolites (fipronil desulfinyl, fipronil sulfide, fipronil sulfone) were measured. The results showed that, only fipronil and fipronil sulfone were detected from organism, and that internal concentrations of these insecticides in molted specimens were higher than those of unmolted ones but comparable with those of dead ones. Accordingly, mortality was more frequent in molted specimens than those that were unmolted. Furthermore, involvement of oxygenase and higher lethal body burden threshold may confer higher tolerance to fipronil in sand shrimp than in the kuruma prawn. This study is the first to demonstrate that the body-residue-based approach is useful for deciphering the causal factors underlying fipronil toxicity, but highlights the need to consider physiological factors in arthropods, which influence and lie beyond body burden, molting and drug metabolism.