Target Treatment Research Articles

Abstract 4078: Optimized chimeric antigen receptors (CARs) for CAR-NK cell therapies

Abstract Introduction: CAR-T-cell therapy has shown great success in treating hematopoietic malignancies. Allogenic NK cell-based therapies have also been shown to mount potent responses against hematopoietic malignancies. Unlike T-cell therapies, allogeneic NK cells do not cause toxicities such as serious cytokine release syndrome, neurotoxicity, or graft-vs-host-disease. Several groups have demonstrated the clinical efficacy of allogeneic CAR-expressing NK cells that utilize CARs developed for T-cells. However, activating receptor signaling in NK cells is different from T cells. NK cell-mediated cytotoxicity is regulated by a repertoire of activating and inhibitory receptors. Activating receptors include natural cytotoxic receptors (NCRs) such as NKG2D, CD16, LFA-1, CD244 (2B4), and CD137 (4-1BB) and so on. These activating cell surface receptors have the capacity to trigger cytolytic programs as well as cytokine and chemokine secretion via intra-cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs) such as in 2B4 and 4-1BB and/or via other transmembrane signaling adaptors. Recent studies using NK cell-based activating receptor signaling modules such as NKG2D and 2B4 as CAR co-stimulatory domains proved increased anti-tumor activity compared to T-cell CARs. Methods: The goal of this study is to develop next-generation NK cell-optimized CARs to improve targeting and potency of NK cell treatment. To achieve this, we constructed a library of CARs containing signaling modules from diverse T cell signaling receptors and NK cell specific signaling receptors, and then screened for CAR activity using short-term and long-term NK cell cytotoxicity assays. In comparison with T cell signaling receptors, CAR-NK cells with NK cell signaling receptors showed more potent cytotoxicity. Using a repeated rounds of cancer cell clearance assay, serial re-stimulation by fresh cancer target cells was tested. CAR-NK cells with NK cell signaling receptors showed remarkable persistence and antigen-mediated expansion of CAR-NK cells compared with T cell signaling receptors. Results: We identified a NK cell-CAR containing two NK cell co-stimulatory domain and CD3z signaling domain,showing better persistence than T-cell CAR (CD28-CD28-zeta) and 2 previously described NK cell-CARs (NKG2D-2B4-zeta and 2B4). Conclusions: We have successfully identified an optimized CAR suitable for NK cells that enable increased potency of NK cells compared to other CAR designs. The most potent CARs identified in our screen are being engineered into a highly effective dual targeting BCMA-GPRC5D CAR-NK cell product as a next-generation “off-shelf” cell therapy. Citation Format: Cuiqing Yang, Yifang Wang, Tingting Liu, Fuwei Jiang, Qingyang Wang, Qin Wang, Gang Ye, Renhong Tang, Zhouxiao Cao. Optimized chimeric antigen receptors (CARs) for CAR-NK cell therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4078.

Abstract 6234: Targeting integrin alpha V beta 5 heterodimer stability using a novel small molecular inhibitor for tumor suppression

Abstract Integrins have long been sought as therapeutic targets in cancer, but there are no FDA approved drugs to target this gene family. Since integrins require the dimerization between an alpha and beta subunit to function, we developed a CRISPR library targeting all 26 alpha and beta subunits to identify which pair is the most important. We found a strong correlation between ITGAV and ITGB5 (Integrin Beta 5), which form a known heterodimer, in solid tumors. CRISPR targeting either ITGAV or ITGB5 led to attenuated cell proliferation with increased cell cycle stalling and apoptosis. As the more essential partner, we designed a CRISPR tiling scan targeting the entire coding region of ITGAV and determine the essential nature of each amino acid. We found a sub-domain within the beta propeller to be important for ITGAV function, the CRISPR identified pocket (CIP). Genetic targeting of this pocket disrupted the ability to detect the heterodimer signal of ITGAV-ITGB5 by a specific antibody. Furthermore, we confirmed that essential amino acids within the CIP responsible for the heterodimer stability by the NanoBRET energy transfer system. Knowing the role of the CIP in heterodimer stability we searched for a small molecule to bind in the CIP to phenocopy our genetic findings. A combined in-silico and in-vitro high throughput drug screen started tested compounds for cell killing and disruption of the ITGAV-ITGB5 heterodimer. “Compound 2” (cpd_2) showed both strong cell killing and dissociation of the heterodimer. Disruption was measured by detection by flow cytometry and through the NanoBRET system. Cpd_2’s binding was confirmed with thermal shift studies with purified ITGAV beta propeller, validating that this compound is behaving and binding as we expect at the CIP. Next, we sought to understand how the ITGAV-ITGB5 heterodimer controls cancer cell survival. From the Dependency Map Public database (DepMap) we found that Rac1 dependency is significantly correlated only with ITGAV and ITGB5. We hypothesized that this meant that ITGAV-ITGB5 regulated Rac1 activity. Loss of Rac1 phenocopies knock out of ITGAV or ITGB5 and loss of either Rac1 or ITGAV led to dysregulation of the actin cytoskeleton, a known downstream feature of Rac1. A constitutively Rac1 (CA_Rac1) rescues the effects of targeting of ITGAV or treatment with cpd_2. Altogether this data suggests that ITGAV-ITGB5 signals to Rac1 and that attenuation of their function can be reversed by an active Rac1 In summary, our study highlights a novel strategy of targeting the integrin heterodimer ITGAV-ITGB5 with a small molecule binding to a novel subdomain, CIP, of ITGAV. The CIP is responsible for the heterodimer stability of ITGAV and ITGB5. Disruption of this heterodimer led to the dysregulation of Rac1 and destabilization of the actin cytoskeleton. This mechanism highlights a novel strategy for targeting integrins as a therapeutic target in cancer. Citation Format: Nicole Mattson, Kazuya Miyashita, Anthony Chan, Lu Yang, Sheela Pangeni Pokharel, Wei Liu, Ming li, Qiao Liu, Xiaobao Xu, Priyanka Singh, Leisi Zhang, Mingye Feng, Chun-Wei Chen. Targeting integrin alpha V beta 5 heterodimer stability using a novel small molecular inhibitor for tumor suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6234.

Associations of polygenic risk scores with posttraumatic stress symptom trajectories following combat deployment.

Identification of genetic risk factors may inform the prevention and treatment of posttraumatic stress disorder (PTSD). This study evaluates the associations of polygenic risk scores (PRS) with patterns of posttraumatic stress symptoms following combat deployment. US Army soldiers of European ancestry (n = 4900) provided genomic data and ratings of posttraumatic stress symptoms before and after deployment to Afghanistan in 2012. Latent growth mixture modeling was used to model posttraumatic stress symptom trajectories among participants who provided post-deployment data (n = 4353). Multinomial logistic regression models tested independent associations between trajectory membership and PRS for PTSD, major depressive disorder (MDD), schizophrenia, neuroticism, alcohol use disorder, and suicide attempt, controlling for age, sex, ancestry, and exposure to potentially traumatic events, and weighted to account for uncertainty in trajectory classification and missing data. Participants were classified into low-severity (77.2%), increasing-severity (10.5%), decreasing-severity (8.0%), and high-severity (4.3%) posttraumatic stress symptom trajectories. Standardized PTSD-PRS and MDD-PRS were associated with greater odds of membership in the high-severity v. low-severity trajectory [adjusted odds ratios and 95% confidence intervals, 1.23 (1.06-1.43) and 1.18 (1.02-1.37), respectively] and the increasing-severity v. low-severity trajectory [1.12 (1.01-1.25) and 1.16 (1.04-1.28), respectively]. Additionally, MDD-PRS was associated with greater odds of membership in the decreasing-severity v. low-severity trajectory [1.16 (1.03-1.31)]. No other associations were statistically significant. Higher polygenic risk for PTSD or MDD is associated with more severe posttraumatic stress symptom trajectories following combat deployment. PRS may help stratify at-risk individuals, enabling more precise targeting of treatment and prevention programs.

Virtual Treatment Zone From Cone Beam CT Commonly Alters Treatment Plan and Identifies Tumor at Risk for Under-Treatment in US or US Fusion-Guided Microwave Ablation of Liver Tumors.

Tumor ablation is included in several major cancer therapy guidelines. One technical challenge of percutaneous ablation is targeting and verification of complete treatment, which is prone to operator variabilities and human imperfections and are directly related to successful outcomes, risk for residual unablated tumor and local progression. The use of "Prediction Ablation Volume Software" may help the operating Interventional Radiologist to better plan, deliver, and verify before the ablation, via virtual treatment zones fused to target tumor. Fused and superimposed images provide 3-dimensional information from different timepoints, just when that information is most useful. The aim of this study is to evaluate the technical success and efficacy of an ablation treatment flowchart provided by a cone beam computed tomography (CBCT) "Prediction Ablation Volume Software." This is a single-center retrospective study. From April 2021 to January 2022, 29 nonconsecutive evaluable patients with 32 lesions underwent liver ablation with Prediction Ablation Volume Software. Each patient was discussed in a multidisciplinary tumor board and underwent an enhanced computed tomography or magnetic resonance imaging approximately 1 month before the procedure, as well as ∼1 month after. Technical success was defined as treatment of the tumor according to the protocol, covered completely by the Prediction Ablation Volume. Technical efficacy was defined as assessment of complete ablation of the target tumor at imaging follow up (∼1 month). Technical success, technical efficacy, and procedural factors were studied. Technical success was achieved in 30 of 32 liver lesions (94%), measuring 20 mm mean maximum diameter. The antenna was repositioned in 16 of 30 (53%) evaluable target lesions. Residual tumor was detected at 1 month imaging follow up in only 4 of 30 (13%) of the treated lesion. Technical efficacy was of 87% in this retrospective description of our process. The implementation of a CBCT Prediction Ablation Volume Software and flowchart for the treatment of liver malignancies altered the procedure, and demonstrated high technical success and efficacy. Such tools are potentially useful for procedural prediction and verification of ablation.

432: EFFICACY OF TARGETED VS. NONTARGETED BETA-LACTAM THERAPY FOR MSSA BACTEREMIA: A MATCHED COHORT STUDY

Introduction: Methicillin-susceptible Staphylococcus aureus (MSSA) is implicated in blood stream infections with high morbidity and mortality. Targeted treatment (TT) with nafcillin or cefazolin is considered first-line therapy, however patients may receive broad spectrum therapy for MSSA bacteremia for various reasons. We hypothesize non-targeted beta-lactams (NT) are less effective for blood culture clearance compared to TT for MSSA bacteremia. Methods: Critically ill patients >18 years old with an MSSA positive blood culture between 7/1/2014 and 12/31/2020 were included. Patients were identified retrospectively through the electronic medical record and must have received either a NT (ampicillin/sulbactam, ceftriaxone, cefepime, piperacillin/tazobactam, meropenem) or TT. The TT cohort included the receipt of or de-escalation to nafcillin or cefazolin within 72 hours of antibiotic initiation. Patients with lack of follow-up blood cultures, death, or discharge within 48 hours of positive culture were excluded. Patients were matched according to age, Charlson Comorbidity Index (CCI), presence of a central line, and source of bacteremia. The primary outcome was duration of bacteremia. Secondary outcomes included hospital and intensive care unit (ICU) length of stay (LOS) and inpatient mortality. Results: Of 423 patients, 178 were included based on matching criteria. The majority of patients were male (63%) and Caucasian (92%) with a median age of 56 (interquartile range [IQR], 47-65). Median CCI was 5 in both groups (IQR, 3-8). The most frequent NT were piperacillin/tazobactam (56%) and cefepime (34%). There was no significant difference in duration of bacteremia (3.4 vs 3.4 days, p=0.653), hospital LOS (18.9 vs 26.4 days, p=0.071), or ICU LOS (5.3 vs 5.9 days, p=0.966) in the TT vs NT cohorts, respectively. Patients in the TT cohort had significantly lower mortality compared to those in the NT cohort (12.4% vs 24.7%, p=0.034). Conclusions: ICU patients who received TT or NT had similar duration of bacteremia, hospital LOS, and ICU LOS. Exposure to NT was associated with increased mortality. Although these results should be validated prospectively, clinicians should be cognizant of this risk when evaluating those with MSSA bacteremia and consider de-escalation to TT as soon as clinically appropriate.

An integrated cytokine and kynurenine network as the basis of neuroimmune communication.

Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of 'tonic' kynurenine pathway affecting baseline activity and the superimposed 'phasic' cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.

Amoxicillin Plus Clavulanic Acid Versus Appendicectomy for Treatment of Acute Uncomplicated Appendicitis

Acute appendicitis is the most common indication for surgery in patients admitted to hospital for acute abdominal pain. In about 20% of cases, acute appendicitis is complicated, leading to local or diffuse peritonitis mostly. Although urgent appendicectomy is still the recommended treatment for acute uncomplicated appendicitis and also antibiotic treatment can cure acute appendicitis or can be the first line of treatment. In the Current study we assessed the efficacy of amoxicillin plus clavulanic acid by comparison with emergency appendicectomy for treatment of patients with uncomplicated acute appendicitis. In this Study open-label, non-inferiority, randomized trial, adult patients (aged 18–68 years) with uncomplicated acute appendicitis, as assessed by CT scan, were enrolled at Pakistan Instiute of Medical Sciences (PIMS) Hospital Islamabad Pakistan. A computer-generated randomization sequence was used to allocate patients randomly in a 1:1 ratio to receive amoxicillin plus clavulanic acid (3 g per day) for 8–15 days or emergency appendicectomy. The primary endpoint was occurrence of post intervention peritonitis within 30 days of treatment initiation. Non-inferiority was shown if the upper limit of the two-sided 95% CI for the difference in rates was lower than 10 percentage points. Both intention-to-treat and per-protocol analyses were done. The Current research Result show that Of 243 patients randomised, 123 were allocated to the antibiotic group and 120 to the appendicectomy group. Four were excluded from analysis because of early dropout before receiving the intervention, leaving 239 (antibiotic group, 120; appendicectomy group, 119) patients for intention-to-treat analysis. 30-day post intervention peritonitis was significantly more frequent in the antibiotic group (8%, n=9) than in the appendicectomy group (2%, n=2; treatment difference 5•8; 95% CI 0•3–12•1). In the appendicectomy group, despite CT-scan assessment, 21 (18%) of 119 patients were unexpectedly identified at surgery to have complicated appendicitis with peritonitis. In the antibiotic group, 14 (12% [7•1–18•6]) of 120 underwent an appendicectomy during the first 30 days and 30 (29% [21•4–38•9]) of 102 underwent appendicectomy between 1 month and 1 year, 26 of whom had acute appendicitis (recurrence rate 26%; 18•0–34•7).The Current result conclude that Amoxicillin plus clavulanic acid was not non-inferior to emergency appendicectomy for treatment of acute appendicitis. Identification of predictive markers on CT scans might enable improved targeting of antibiotic treatment. Keywords: Amoxicillin, clavulanic acid versus appendicectomy

The discrepancies between clinical and histopathological diagnoses of cardiomyopathies in patients with stage D heart failure undergoing heart transplantation.

BackgroundThis study aimed to determine the etiology of stage-D heart failure (HF) and the prevalence and prognosis of misdiagnosed cardiomyopathy in patients undergoing heart transplantation.Methods and resultsWe retrospectively reviewed 127 consecutive patients (mean age, 42 years; 90 [71%], male) from February 1994 to September 2021 admitted for heart transplant in our tertiary center. Pre-transplant clinical diagnosis was compared with post-transplant pathological diagnosis. The most common misdiagnosed cardiomyopathy was nonischemic cardiomyopathy accounting for 6% (n = 8) of all patients. Histopathological examination of explanted hearts in misdiagnosed patients revealed 2 arrhythmogenic cardiomyopathy, 2 sarcoidosis, 1 hypertrophic cardiomyopathy, 1 hypersensitivity myocarditis, 1 noncompacted cardiomyopathy, and 1 ischemic cardiomyopathy. Pre-transplant cardiac MRI and endomyocardial biopsy (EMB) were performed in 33 (26%) and 6 (5%) patients, respectively, with both performed in 3 (3% of patients). None of the patients undergoing both cardiac tests were misdiagnosed. During the 5-years follow-up period, 2 (25%) and 44 (37%) patients with and without pretransplant misdiagnosed cardiomyopathy died. There was no difference in survival rate between the groups (hazard ratio: 0.52; 95% CI:0.11–2.93; P = 0.314).ConclusionsThe prevalence of misdiagnosed cardiomyopathy was 6% of patients with stage-D HF undergoing heart transplantation, the misdiagnosis mostly occurred in nonischemic/dilated cardiomyopathy. An accurate diagnosis of newly detected cardiomyopathy gives an opportunity for potentially reversing cardiomyopathy, including sarcoidosis or myocarditis. This strategy may minimize the need for advanced HF therapy or heart transplantation. With advances in cardiac imaging, improvements in diagnostic accuracy of the etiology of HF can improve targeting of treatment.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Early endoscopic injection may prevent new scarring in idiopathic detrusor overactivity disorder with vesicoureteral reflux in children.

To present baseline characteristics and the long-term treatment results of three groups of patients with idiopathic detrusor overactivity (IDOD) and vesicoureteral reflux (VUR) according to different treatment regimens, which underwent endoscopic subureteric injection (STING) in the early phase of targeted treatment (TT) (ES group), underwent STING in the late phase of TT (LS group) and with TT only (TT group). A total of 49 IDOD cases with VUR which were divided into three groups according to treatment regimens were evaluated in terms of age, symptoms, bladder capacities, involuntary contraction pressures (ICP), presence and degree of renal scar, differential renal functions (DF), new scar formation and STING success. There was no significant difference between the groups in terms of age, side, symptoms, presence of urinary tract infection (UTI), DF, ICP and bladder capacity at diagnosis. A high grade of reflux was found to be significantly lower in the TT group (p = 0.037). There was no significant difference in terms of ICP, DF, bladder capacity and reflux grade between ES and LS Group. But new scar formation was more in LS Group (p = 0.003). The STING success is satisfactory in IDOD cases with VUR, waiting a long period of time for diminishing symptoms may cost new scar formation.

P100 Research priorities to reduce the impact of musculoskeletal disorders

Abstract Background/Aims Involving research users in setting priorities for research is essential to ensure research outcomes are patient-centred and to maximise research value and impact. In 2019, Versus Arthritis convened a Musculoskeletal Disorders (MSKD) Research Advisory Group (RAG) which included 25 members: people with musculoskeletal conditions, researchers and healthcare professionals. The RAG identified a need for a research prioritisation exercise for adult non-inflammatory MSKD. Methods The Child Health and Nutrition Research Initiative (CHNRI) method was selected. The MSKD RAG identified, through consensus, four research Domains: Mechanisms of Disease; Diagnosis and Impact; Living Well with MSK disorders and Successful Translation. Following ethical approval, an initial electronic survey was distributed to stakeholders (people with musculoskeletal conditions, researchers, healthcare professionals, industry, research funders, healthcare providers, government and charities) asking for important research uncertainties in the four domains. Uncertainties were organised into themes and refined into research questions using a series of MSKD RAG workshops. Research questions underwent lay review to optimise readability. A second e-survey was distributed to stakeholders as above, where participants were asked to score each research question for two criteria, importance and impact, on a 1-10 numeric rating scale. Median criterion scores for impact and importance were calculated for each question and summed to create a total score. Research questions were ranked according to total score. Results The first survey had 209 respondents, who described 1290 research uncertainties, which were refined into 68 research questions. 285 people responded to the second survey, of which 189 fully completed. 74(39.2%) were public/lay responders, 48(25.4%) researchers, 43(22.8%) clinicians, 24(12.6%) other/unrecorded. The research questions, total scores and rankings are summarised in Table 1. Total scores ranged from 12 to 18 (maximum possible score 20). Conclusion For the first time, we have summarised priorities for research across MSKD, from discovery science to applied clinical and health research, including translation. Key priorities include developing and testing new treatments, better targeting of treatments, early diagnosis, prevention and better understanding and management of pain, with an emphasis on understanding the underpinning mechanisms. We present a call to action to researchers and funders to target these priorities. Disclosure Z. Paskins: Grants/research support; NIHR, Versus Arthritis, Royal Osteoporosis Society. C.E. Farmer: None. R.K. Jones: None. A. Clark: None. L. Troeberg: Grants/research support; Versus Arthritis. H. Pandit: Consultancies; Depuy J&J, Zimmer Biomet, Smith and Nephew, Medacta International, Meril Life, JRI Orthopaedics, Invibio and Kennedy’s Law. Grants/research support; NIHR, VA (Versus Arthritis) and UKIERI (UK India Education and Research Initiative). S.M. Richardson: None. J. Loughlin: None. C.A. Brown: Grants/research support; Versus Arthrtitis. E.J. Taylor: None. C.L. Le Maitre: None. R.K. Wilcox: Grants/research support; EPSRC, Versus Arthritis, NIHR, DePuy Synthes. F.L. Bishop: None. E. Salt: None. E.M. Clark: Grants/research support; Versus Arthritis, NIHR. Other; I am Associate Editor of Journal of Bone and Mineral Research Plus for which I receive a salary, I am part of the Lot 2 provider for analysis of the national Joint Registry of England and Wales, funded by HQIP. D.A. Andersson: None. M. McCarron: None. D.J. Mason: None. C.M. Wilkinson: None. T. Barlow: None. G.M. Peat: None. F.E. Watt: Consultancies; Pfizer.

Symptom profiles and accuracy of clinical case definitions for COVID-19 in a community cohort: results from the Virus Watch study.

Background: Understanding symptomatology and accuracy of clinical case definitions for community COVID-19 cases is important for Test, Trace and Isolate (TTI) and future targeting of early antiviral treatment. Methods: Community cohort participants prospectively recorded daily symptoms and swab results (mainly undertaken through the UK TTI system). We compared symptom frequency, severity, timing, and duration in test positive and negative illnesses. We compared the test performance of the current UK TTI case definition (cough, high temperature, or loss of or altered sense of smell or taste) with a wider definition adding muscle aches, chills, headache, or loss of appetite. Results: Among 9706 swabbed illnesses, including 973 SARS-CoV-2 positives, symptoms were more common, severe and longer lasting in swab positive than negative illnesses. Cough, headache, fatigue, and muscle aches were the most common symptoms in positive illnesses but also common in negative illnesses. Conversely, high temperature, loss or altered sense of smell or taste and loss of appetite were less frequent in positive illnesses, but comparatively even less frequent in negative illnesses. The current UK definition had 81% sensitivity and 47% specificity versus 93% and 27% respectively for the broader definition. 1.7-fold more illnesses met the broader case definition than the current definition. Conclusions: Symptoms alone cannot reliably distinguish COVID-19 from other respiratory illnesses. Adding additional symptoms to case definitions could identify more infections, but with a large increase in the number needing testing and the number of unwell individuals and contacts self-isolating whilst awaiting results.

Implementation and Effectiveness of Novel Therapeutic Substances for Advanced Malignant Melanoma in Saxony, Germany, 2010-2020-Cohort Study Based on Administrative Data.

Simple SummaryNovel therapies have become available in the routine care of metastatic melanoma in recent years. We conducted a retrospective cohort study based on SHI data from Germany (2010–2020) to investigate overall mortality between patients that received different substance classes. We included 463 patients with distant metastases in the main analysis. Classical chemotherapeutics (CTx) as well as targeted therapeutics (TT) and immune checkpoint inhibitors (ICI) showed protective effects after treatment initiation, which decreased over time. Predicted survival of an average patient over five years since first metastasis was best by sequential treatment with ICI and TT. The worst survival was seen in patients treated with TT alone. However, it is conceivable that the observed high survival differences were overestimated due to bias, such as confounding by indication. It is likely that patients treated exclusively with TT were in an extremely serious condition and died before they could have received an ICI.(1) Background: Targeted (TT) and immune checkpoint inhibitor (ICI) therapies have become available in the routine care of metastatic melanoma in recent years. (2) Objective: We compared mortality in patients with metastatic melanoma and different systemic therapies. (3) Methods: A retrospective cohort study, based on pseudonymized health insurance data of about two million individuals from Saxony, Germany, was conducted for the years 2010 to 2020. Only patients with an advanced stage, i.e., distant metastases were considered for the main analysis. Relative survival since metastasis and predicted survivor curves derived from a Cox model were used to assess potential differences in mortality. (4) Results: Relative survival was highest in the subgroup with sequential use of ICI and TT. All treatments except interferon had significant hazard ratios (HR) in the Cox model with time-dependent effects indicating a protective effect after treatment initiation (HR 0.01–0.146) but decreasing over time (HR 1.351–2.310). The predicted survivor curves revealed best survival under ICI-TT treatment and worst survival under TT treatment alone. (5) Conclusions: We found real-world evidence for survival benefits of patients with metastatic melanoma who received sequential ICI and TT treatment. It is conceivable that the observed high survival differences were overestimated due to bias, such as confounding by indication.

Anthelmintic Resistance and Its Mechanism: A Review.

Helminths are a various types of parasites causing a major health problem for animals in different parts of the globe. Control of helminthiasis has largely relied on the use of pharmaceutical anthelmintics. Unfortunately, the exhaustive use of anthelmintic drugs has led to a serious and dramatic level of anthelmintic resistance. Anthelmintic resistance is a heritable loss of sensitivity of an anthelmintic in a parasite population that was in the past susceptible to the same anthelmintic. The development of anthelmintic resistance is evident to different helminths of almost every animal species and to different groups of anthelmintic in several continents. Frequent treatment, underdosing, genetics of the parasite, and targeting and timing of mass treatment are predisposing factors for anthelmintic resistance. Upregulation of cellular efflux mechanisms, an increase in drug metabolism, a change in drug receptor sites that reduces drug binding or the functional consequences of drug binding, and a decrease in drug receptor abundance through reduced expression within the parasite are the main mechanisms of anthelmintic resistance. In vivo method like fecal egg count reduction test and in vitro method such as egg hatch assays, larval motility test, larval development test and PCR can be used for the detection of anthelmintic resistance. Proper utilization of anthelmintic drugs, using combined anthelmintic and applying other alternatives are essential strategies to slow down the development of anthelmintic resistance. As anthelmintic resistance is a serious challenge throughout the world, proper utilization of the existing anthelmintics and reducing dependence on anthelmintics should be implemented to reduce its challenge.

Estimating and Comparing Health and Financial Risk Protection Outcomes in Economic Evaluations

ObjectivesImproving health and financial risk protection (FRP, the prevention of medical impoverishment) and their distributions is a major objective of national health systems. Explicitly describing FRP and disaggregated (eg, across socioeconomic groups) impact of health interventions in economic evaluations can provide decision makers with a broader set of health and financial outcomes to compare and prioritize interventions against each other. MethodsWe propose methods to synthesize such a broader set of outcomes by estimating and comparing the distributions in both health and FRP benefits procured by health interventions. We build on benefit-cost analysis frameworks and utility-based models, and we illustrate our methods with the case study of universal public finance (financing by government regardless of whom an intervention is targeting) of disease treatment in a low- and middle-income country setting. ResultsTwo key findings seem to emerge: FRP is critical when diseases are less lethal (eg, case fatality rates <1% or so), and quantitative valuation of inequality aversion across income groups matters greatly. We recommend the use of numerous sensitivity analyses and that all distributional health and financial outcomes be first presented in a disaggregated form (before potential subsequent aggregation). ConclusionsEstimation approaches such as the one we propose provide explicit disaggregated considerations of equity, FRP, and poverty impact for the development of health sector policies, with high relevance for population-based preventive measures.

Proof of concept study to develop a novel connectivity-based electric-field modelling approach for individualized targeting of transcranial magnetic stimulation treatment

Resting state functional connectivity (rsFC) offers promise for individualizing stimulation targets for transcranial magnetic stimulation (TMS) treatments. However, current targeting approaches do not account for non-focal TMS effects or large-scale connectivity patterns. To overcome these limitations, we propose a novel targeting optimization approach that combines whole-brain rsFC and electric-field (e-field) modelling to identify single-subject, symptom-specific TMS targets. In this proof of concept study, we recruited 91 anxious misery (AM) patients and 25 controls. We measured depression symptoms (MADRS/HAMD) and recorded rsFC. We used a PCA regression to predict symptoms from rsFC and estimate the parameter vector, for input into our e-field augmented model. We modeled 17 left dlPFC and 7 M1 sites using 24 equally spaced coil orientations. We computed single-subject predicted ΔMADRS/HAMD scores for each site/orientation using the e-field augmented model, which comprises a linear combination of the following elementwise products (1) the estimated connectivity/symptom coefficients, (2) a vectorized e-field model for site/orientation, (3) rsFC matrix, scaled by a proportionality constant. In AM patients, our connectivity-based model predicted a significant decrease depression for sites near BA9, but not M1 for coil orientations perpendicular to the cortical gyrus. In control subjects, no site/orientation combination showed a significant predicted change. These results corroborate previous work suggesting the efficacy of left dlPFC stimulation for depression treatment, and predict better outcomes with individualized targeting. They also suggest that our novel connectivity-based e-field modelling approach may effectively identify potential TMS treatment responders and individualize TMS targeting to maximize the therapeutic impact.

Non-invasive molecular imaging of kidney diseases.

In nephrology, differential diagnosis or assessment of disease activity largely relies on the analysis of glomerular filtration rate, urinary sediment, proteinuria and tissue obtained through invasive kidney biopsies. However, currently available non-invasive functional parameters, and most serum and urine biomarkers, cannot capture intrarenal molecular disease processes specifically. Moreover, although histopathological analyses of kidney biopsy samples enable the visualization of pathological morphological and molecular alterations, they only provide information about a small part of the kidney and do not allow longitudinal monitoring. These limitations not only hinder understanding of the dynamics of specific disease processes in the kidney, but also limit the targeting of treatments to active phases of disease and the development of novel targeted therapies. Molecular imaging enables non-invasive and quantitative assessment of physiological or pathological processes by combining imaging technologies with specific molecular probes. Here, we discuss current preclinical and clinical molecular imaging approaches in nephrology. Non-invasive visualization of the kidneys through molecular imaging can be used to detect and longitudinally monitor disease activity and can therefore provide companion diagnostics to guide clinical trials, as well as the safe and effective use of drugs.

The micro-elimination approach - a new way of tackling hepatitis C in paediatric population

Recent advances in antiviral drug development towards the hepatitis C virus(HCV) have revolutionized the therapy and paved the way towards the elimi­nation of chronic hepatitis C (CHC). Difficulties in achieving time-bound elimination targets of the World Health Organization’s Global Strategy on viral hepatitis might be overcome through a novel micro-elimination approach. A new, emerging strategy focuses elimination efforts on high-risk and ignored populations, and therefore allows for quick, efficient targeting of treatment and prevention services. So far, gaps in antenatal and/or paedia­tric care, and a lack of reimbursement and approval of direct-acting antivirals (DAA) in the paediatric population have been a barrier to accessing treatment, leading to marginalization of children and adolescents. Recently approved DAAs for use in children aged ≥ 3 years seem to be the cornerstone of HCV elimination by reducing the risk of future horizontal and vertical transmission, firstly on a national, and ultimately on a global level.

DOP60 Simplified rules to identify bio-naïve patients with Crohn’s Disease with higher likelihood of clinical remission when initiating vedolizumab versus anti-TNFα therapies: Analysis of EVOLVE study data

Abstract Background Previously, we identified subsets of biologic-naïve patients (pts) with Crohn’s disease (CD) from the EVOLVE study who had higher rates of clinical remission (CR) [Fig 1] when initiating vedolizumab (VDZ) vs anti-TNFα treatment, using prediction models based on multiple baseline characteristics.1,2 To aid use in practice, we investigated whether these subsets could be identified using simpler rules based on fewer baseline characteristics. Methods Using data from EVOLVE, we used recursive partitioning and regression tree (RPART) classification to predict membership in the previously identified higher CR subsets for VDZ. The RPART algorithm repeatedly splits data, based on baseline predictors (demographics, prior treatments, clinical characteristics at treatment initiation, Charlson comorbidity index, prior extraintestinal manifestations [EIMs], and prior healthcare resource use). At each split, the predictor and its value as chosen by the algorithm to split the data were those that maximized the number of pts classified correctly. Simplified rules were developed from the resulting RPART decision trees. Analyses of the treatment effect of VDZ vs anti-TNFα were conducted in the subsets of pts identified by each rule. Results Pts with data on CR and candidate predictors were included (VDZ [n=195]; anti-TNFα [n=245]). Three simplified rules (A, B, &amp; C) were identified (Table 1). Pt characteristics included in the rules (exacerbation ongoing at treatment initiation, no emergency department/emergency room (ED/ER) visits prior to treatment initiation, no fistulae at most recent assessment prior to treatment initiation, pre-initiation disease behaviour) were among the main predictors of CR in VDZ pts identified previously. Pts identified by Rule A comprised 32% of the EVOLVE population, and were those who 1) had an exacerbation ongoing at index, 2) did not have ED/ER visits prior to initiation and 3) had pre-initiation disease behaviour classified as other than stricturing with/without perianal disease. Among these pts, median time to CR for VDZ and anti-TNFα pts were 6.7 and 18.1 months, respectively (unadjusted log-rank p&amp;lt;0.001), and the adjusted hazard ratio (HR) of CR for VDZ vs anti-TNFα was 2.9 (95% CI: 1.7, 5.0). Rules B &amp; C identified larger subsets in which VDZ vs anti-TNFα treatment differences were smaller but still statistically significant. Conclusion Simple rules were developed to identify biologic-naïve, CD pts in whom VDZ initiation appeared to have a larger effect on CR relative to anti-TNFα initiation. Validation of these rules in other data sources is important to confirm these findings; if validated, these simplified rules can inform targeting of treatment and optimization of outcomes for pts with CD treated with VDZ.

Survey on Endoparasites of Dairy Goats in North-Eastern Italy Using a Farm-Tailored Monitoring Approach.

With the spread of anthelmintic resistance (AR), endoparasite monitoring consolidates its role for a more sustainable targeting of treatments. A survey on endoparasites in dairy goat farms of north-eastern Italy was conducted to test a monitoring approach based on a farm-tailored sample size. Farm management and parasites control practices were investigated in 20 farms through a questionnaire survey. Further, fecal samples were collected (November 2018–September 2019) from 264 animals from 13 farms and were analyzed individually with a modified McMaster method and subsequently pooled to perform a coproculture. Coccidia (78.4%), gastrointestinal strongyles (37.9%), Strongyloides (28.4%), Skrjabinema (18.9%), Trichuris (8.0%) and Nematodirus/Marshallagia (0.4%) were identified. Abundances were higher for coccidia and gastrointestinal strongyles. Haemonchus (71%) was the dominant gastrointestinal nematode. Pasture and age class resulted in the main risk factors at the multivariable analysis through a negative binomial regression model. Results from farm monitoring indicate that our approach can be a cost-effective decision tool to target treatments more effectively, but farmers need to be educated about the importance of parasitological testing, which is currently scarcely implemented, against the risk of AR.