Update Protocol Research Articles

Pediatric intracranial empyema complicating otogenic and sinogenic infection

ObjectiveTo describe and compare clinical and microbiological features, surgical and medical management, and outcomes of children with otogenic and sinogenic intracranial empyema (IE) in an institution with an established multidisciplinary protocol. To use the study findings to inform and update the institutional algorithm. MethodsRetrospective analysis was carried out on the electronic healthcare records of all children with oto-sinogenic IE admitted in a 5-year period. ResultsA total of 76 patients were identified and treated according to an institutional protocol. Two distinct groups were identified: intracranial empyema related to otogenic infection (OI-IE, n = 36) or sinogenic infection (SI-IE, n = 40). SI-IE was seen in older children and had a significantly higher morbidity. Sub-dural IE was seen in a minority (n = 16) and only in SI-IE and required urgent collaborative ENT-neurosurgery. Extra-dural IE occurred more frequently and was seen in both SI-IE and OI-IE. No death and overall low morbidity were observed. Particularities found in SI-IE and OI-IE groups (as thrombosis, microbiology, antibiotic treatment, duration and outcome) permitted the delineation of these groups in our updated algorithm. ConclusionThe presence of a collaborative multidisciplinary protocol permits the step-wise co-ordination of care for these complex patients in our institution. All patients received prompt imaging, urgent surgical intervention, and antibiotic treatment. Microbiological identification was possible for each patient and antibiotic rationalization was permitted through use of Polymerase chain reaction (PCR) testing in cases of sterile cultures. Of note, intracranial empyema related to sinogenic infection is shown to have significantly more severe clinical presentation, a higher morbidity, and a longer duration of antibiotic therapy than that related to otogenic infection. Study findings allowed for the update and clarification of the institutional protocol, which now clearly demarcates the clinical presentation, biological evidence, radiology, surgical and medical treatments in children with oto-sinogenic IE.

Protocol Update and Issues in EASTYLE Trial

Protocol Update and Issues in EASTYLE Trial

ANALYSIS OF THE DYNAMICS OF UROPATHOGENS ANTIMICROBIAL RESISTANCE IN PATIENTS OF MULTI-SPECIALTY HOSPITAL

Urinary tract infections are among the most common bacterial infections. Currently, one of the main problems of therapy, as for the infections of other localizations, is the high level of antibiotic resistance. Timely prescribed and adequately selected antimicrobial therapy is the main factor determining the treatment outcome. The aim of the study. To carry out dynamic analysis of the etiological structure of urinary tract microflora and to assess antibiotic resistance of the most significant uropathogens in patients of the Clinics of the Irkutsk State Medical University (Clinics of ISMU) in order to optimize the use of antimicrobial drugs in a multidisciplinary hospital. Materials and methods. We analyzed bacterial strains (n = 2414) collected from urine of patients treated at the Clin-ics of ISMU from 2018 to 2022. Microbiological examination of urine was conducted in bacteriological laboratory of the Clinics of ISMU. Results. During the study period, E. coli remained the main uropathogen. There has been an increase in antibiotic resistance of E. coli to the main antimicrobial agents which are traditionally used to treat urinary tract infections, including fluoroquinolones and third-generation cephalosporins. There is an increase in the frequency of detection of E. coli strains producing extended-spectrum b-lactamases from 5.4 % to 12.4 %. Meropenem and nitrofurantoin retain the greatest activity against E. coli. Conclusion. The results of this study indicate the need to strengthen control over the use of antimicrobial agents in medical organizations, the importance of constant microbiological monitoring in order to identify the characteristics of local antibiotic resistance and update protocols for empirical treatment of urinary tract infections.

Impact of a Hyperkalemia Protocol Tailored to Glucose Concentration and Renal Function on Insulin-Induced Hypoglycemia in Patients with Low Pretreatment Glucose

BackgroundHyperkalemia is a common electrolyte abnormality that requires urgent treatment. Insulin is an effective treatment for hyperkalemia, but risk factors for developing insulin-induced hypoglycemia exist (e.g., low pretreatment glucose or renal impairment). ObjectiveThis study evaluated the impact of a hyperkalemia protocol tailored to glucose concentration and renal function on insulin-induced hypoglycemia. MethodsThis was a retrospective cohort study of emergency department patients with glucose ≤ 100 mg/dL treated with insulin for hyperkalemia. The primary outcome was incidence of hypoglycemia in patients treated prior to (July 1, 2018–June 30, 2019) vs. after (January 1, 2020–December 31, 2020) the protocol update, which individualized insulin and dextrose doses by glucose concentration and renal function. Secondary outcomes included change in potassium and protocol safety. We assessed factors associated with hypoglycemia using multiple logistic regression. ResultsWe included 202 total patients (preimplementation: 114, postimplementation: 88). Initial insulin dose was lower in the postimplementation group (p < 0.001). We found a nonsignificant reduction in hypoglycemia in the postimplementation group (42.1% vs. 30.7%, p = 0.10). Degree of potassium reduction was similar in patients who received insulin 5 units vs. 10 units (p = 0.72). Higher pretreatment glucose (log odds ratio [OR] −0.05, 95% confidence interval [CI] −0.08 to −0.02) and additional insulin administration (log OR −1.55, 95% CI −3.01 to −0.25) were associated with reduced risk of developing hypoglycemia. ConclusionA hyperkalemia protocol update was not associated with a significant reduction in hypoglycemia, and the incidence of hypoglycemia remained higher than anticipated. Future studies attempting to optimize treatment in this high-risk population are warranted.

OP167 An Analysis Of Medication Exclusion Reports In The Health Technology Assessment Process For The Brazilian Unified Health System

IntroductionThe National Committee for Health Technology Incorporation of the Brazilian Public Health System (Conitec), which was created in 2011 by federal law, defines the criteria for incorporating and excluding health technologies in the Brazilian health system. For technology evaluation proposals a recommendation report is carried out, which finds the best scientific evidence about the efficacy, accuracy, effectiveness, and safety of the technology being analyzed. The report also provides a comparative economic evaluation of the technologies already in the health system to promote and protect public health, achieve the best allocation of resources, and reduce regional inequalities.MethodsThis exploratory, descriptive, and retrospective study aimed to identify the criteria considered for the exclusion of medicines within the Brazilian health system from 2012 to November 2022. Data were extracted from Conitec’s website into a specific extraction form and analyzed using descriptive statistics.ResultsDuring the evaluation period, 763 technology recommendations by Conitec were identified, of which 75 (10%) related to the exclusion of medicines. Several criteria were identified among the exclusion recommendations, including protocol updates, expiry or lack of registration in the National Health Surveillance Agency, and drugs whose clinical indication was not included in the list of drugs registered for treatments in the health system.ConclusionsAlthough there is no standardization of criteria in Conitec for recommendations on the exclusion of health technologies, this study contributes to a better understanding of these technologies. Disinvestment of technologies positively impacted the population because it resulted in better allocation of resources in the health system, and some of the excluded technologies presented a greater risk of interactions and undesirable adverse reactions.

RUNX1 Mutation Does Not Significantly Impact the Outcome of Newly Diagnosedadult AML: A Retrospective Study of Chinese AML Patients

Background RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML) with a frequency of 6%~15%. Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML- RUNX1mut) was eliminated from the 2022 WHO classification system. With the update of AML diagnosis and treatment protocol, different outcomes of AML- RUNX1muthave been reported. However, an in-depth study about the prognostic value of RUNX1 mutations, epecifically the classification change related to AML- RUNX1mut in a large well-annotated cohort is lacking. Methods The clinical data of 1065 AML (excluding acute promyelocytic leukemia and RUNX1 germline mutations) patients according to WHO 2016 and treated from January 2017 to December 2021 at Jiangsu Institute of Hematology were retrospectively collected and analyzed after informed consent. All AML diagnosis samples were analyzed by targeted Next Generation Sequencing (NGS) panel covering 172 frequently mutated genes in hematological malignancies. Demographic and clinical data, disease characteristics at diagnosis, first-line treatment and clinical outcome data were available for all patients. The survival time of allogeneic hematopoietic stem cell transplantation patients was censored at the time of stem cell transfusion. Cytogenetic and molecular characteristics were used to classify patients into ELN2017 and ELN2022 risk groups (excluding the effect of RUNX1 mutation). Results RUNX1 mutations were detected in 112 (10.5%) patients, namely, 66 (58.9%) male and 46 (41.1%) female. A total of 132 RUNX1 alterations were detected with a medianvariant allelic frequency of 40% (3%~93%). RUNX1 mutations were associated with older age (48.5 vs. 46.0 years old, P=0.087) and antecedent myeloid disorders (6.3% vs. 1.0%, P&amp;lt;0.001). One or more comutations were detected in 106 (94.7%) AML- RUNX1mut patients. The most frequent co-gene abnormalities were FLT3-ITD and DNMT3A mutations which represented the 23.2% and 18.7%. Mutations of CEBPA bZIP, NPM1 and translocations of t(8;21), t(16;16)/inv(16) were uncommon in AML- RUNX1mut with a frequency of 6.3%, 1.8%, 2.7%, 0%, respectively (Table 1). Compared with AML with wild-type RUNX1 (AML- RUNX1wt), AML- RUNX1mut patients had a lower complete remission rate (19.6% vs. 29.7%, P=0.034), lower overall response rate (ORR) (73.5% vs. 84.3%, P=0.006) and higher no response rate (26.5% vs. 15.5%, P=0.021) in the first induction chemotherapy. When comparing groups based on the ELN2017 risk stratification criteria, no significant difference in ORR was observed between RUNX1mut and RUNX1wt patients in the favorable (91.2% vs. 94.0%, P=0.572), intermediate (75.0% vs. 78.4%, P=0.570) and adverse (63.3% vs. 71.4%, P=0.370 ) subgroups (Table 2). The median duration of follow-up of the entire cohort was 8.7 months ( RUNX1wt: 8.4 months; RUNX1mut: 10.0 months). Comparing the two groups, patients with RUNX1 mutations had a lower 5-year overall survival (OS) rate (35.4% vs. 42.3%; HR=1.563; 95% CI: 1.091~2.237, P=0.026), but no significant difference was observed in the 5-year event-free survival (EFS) rate (40.8% vs. 35.4%; HR=1.084; 95% CI: 0.750~1.570, P=0.098) (Table 2). However, when patients were stratified according to the ELN2017 guidelines (excluding the effect of RUNX1 mutation), outcomes did not differ between patients withor without RUNX1 mutation in the favorable (OS: P=0.629, EFS: P=0.137), intermediate (OS: P=0.629, EFS: P=0.114) and adverse (OS: P=0.544; EFS: P=0.714) subgroups. Similar results were obtained according to the ELN2022 guidelines. In multivariate analysis, RUNX1 was not an independent prognostic factor for OS (HR=1.353, 95% CI: 0.922~1.985, P=0.122) and EFS (HR=1.422, 95% CI: 0.975~2.075, P=0.068), while significantly worse OS and EFS were observed in patients with mutated FLT3-ITD, TP53, and DNMT3A ( P-values were all less than 0.05). Conclusion RUNX1 mutations were rarely isolated genetic abnormities that conferred inferior outcomes. However, on the basis of ELN prognosis risk stratification, RUNX1mutation had no impact on the clinical outcomes of AML patients in stratified subgroups. RUNX1 was not an independent prognostic factor for survival. Overall, our findings agree with the updated WHO classification system for AML that AML- RUNX1mut should not be recognized as a distinct AML entity.

2734. Evaluation of Empiric Antimicrobial Therapy for End-Stage Liver Disease Patients at an Academic Medical Center

Abstract Background Patients with end-stage liver disease (ESLD) are prone to decompensation secondary to infections, with an increasing prevalence of multidrug-resistant organisms (MDROs). These patients often receive broad-spectrum antimicrobials prior to transplant, pre-disposing them to resistant pathogens. Our study assessed institutional guideline adherence, antimicrobial prescribing, and the incidence of MDROs in this population. Methods This IRB-approved, retrospective chart review included pre-transplant inpatients with ESLD on the adult liver transplant service who received antimicrobials between 1/1/20 and 10/30/20. Patients were excluded if they started antimicrobials post-transplant or transferred from another institution on parenteral antimicrobials. Per institutional guidelines for empiric antimicrobials in suspected infection in ESLD, patients were categorized into three infectious risk categories: Floor/Non-High-Risk (F-NHR), Floor/High-Risk (F-HR), and ICU or MELD greater than 35 (ICU/M35). Antimicrobial prescribing in each group was evaluated for guideline adherence and microbiology data. Results were analyzed using descriptive statistics. Results We included 92 patients: 28 F-NHR, 50 F-HR, and 14 ICU/M35. Table 1 summarizes baseline characteristics. The frequency of guideline adherence for the F-NHR, F-HR, ICU/M35 groups, respectively, was 11 (39%), 4 (8%), and 4 (29%) patients. For the F-NHR group, ceftriaxone (CRO) was most prescribed (n=17, 61%). For the F-HR group, 18 (36%) received CRO; 16 (32%) received vancomycin and piperacillin-tazobactam. In the ICU/M35 group, 13 patients (93%) received meropenem plus linezolid, and 11 (79%) also received caspofungin. No methicillin-resistant Staphylococcus aureus or carbapenem-resistant Enterobacterales were isolated. Two patients (14%) in the ICU/M35 group experienced C. difficile infection within 30 days of antimicrobial initiation.Table 1.Baseline characteristics among guideline cohorts Conclusion Our study showcases opportunities to optimize internal ESLD antimicrobial protocols and curtail unnecessary antimicrobial exposure. Study limitations include a small cohort at a single center. Future directions include data dissemination and protocol updates. Disclosures David Quan, PharmD, Mallinckrodt Pharmaceuticals: Advisor/Consultant Sarah B. Doernberg, MD, MAS, Basilea: Clinical events committee/adjudication committee participation|F2G: Grant/Research Support|Genentech: Advisor/Consultant|Gilead: Grant/Research Support|Janssen/J+J: Advisor/Consultant|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Shinogi: Clinical events committee/adjudication committee participation

Inkjet printing cellulose nanofibril/PVA hybrid dielectrics for large hysteresis and high-performance a-IGZO synaptic transistors

Inkjet printing green nanomaterials for high-performance synaptic transistors is a hot research topic in academic communities. However, it remains challenging to develop printable and sustainable dielectric inks for the devices with desirable properties of nonvolatile behavior and large hysteresis, which are the basis for emulating controllable weight update in neuron computing. To address this challenge, we present a solution by fabricating a biodegradable cellulose nanofibril (CNF) dielectric film through inkjet printing, which serves as the source of hysteresis in amorphous indium–gallium–zinc oxide (a-IGZO) synaptic transistors. By employing suitable additives and meticulously engineered microfluidic flows, we have successfully achieved the high-quality CNF/polyvinyl alcohol (PVA) composite electrolyte films by inkjet-printing. This accomplishment has enabled the emulation of excellent synaptic functionalities, including short-term to long-term potentiation/depression, as well as the implementation of a nearly symmetric and linear weight update protocol. This work holds significant promise in advancing the development of cost-effective and environmentally friendly synaptic electronics.

Protocol update and baseline characteristics for the TRIal to slow the Progression of Diabetes (TRIPOD) randomized controlled trial

BackgroundType 2 diabetes (T2D), a major risk factor for cardiovascular disease and other adverse health conditions, is on the rise in Singapore. TRIPOD is a randomized controlled trial aimed to determine whether complementing usual care with an evidence-based diabetes management package (DMP) —comprising access to an evidence-based app, health coaching, pedometer, glucometer and weighing scale, with or without a financial rewards scheme (M-POWER rewards), can improve mean HbA1c levels at months 6 and 12.MethodsThe protocol was published in Trials, accessible via https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3749-x1. This manuscript updates the protocol with changes to the study design due to challenges with recruitment and presents baseline characteristics. Key updates include changing the arm allocation ratio from 1:1:1 (Arm 1-Usual Care: Arm 2-DMP: Arm 3-DMP+M-POWER rewards) to 10:1:10, the sample size from 339 to 269, the intervention period from two to one year, and the primary hypothesis to focus solely on differences between Usual Care and DMP+M-POWER rewards. Recruitment for the study began on 19 October 2019 and ended on 4 June 2022.ResultsThe average age of participants was 55.0 (SD9.7) years old and 64.2% were male. The majority of participants (76.8%) were Chinese, 4.9% Malay and 18.3% Indian and of other ethnicities. 67.0% had a monthly household income of SGD$4000 or more. The mean baseline HbA1c was 8.10% (SD 0.95) and the mean body mass index was 26.8 kg/m2 (SD 5.3).DiscussionThe final participant completed month 12 follow-up data collection on 8 June 2023. All pre-planned analyses will be conducted and final results reported.Trial registrationClinicalTrials.govNCT03800680. Registered on 11 January 2019.

Quantised data-driven iterative learning bipartite consensus control for unknown heterogeneous linear MASs with varying trial lengths

This paper aims to realise the robust output bipartite consensus for unknown heterogeneous linear time-varying multiagent systems (MASs) subject to varying trial lengths, unknown measurement disturbances and data quantisation. To this end, inspired by the idea of quantised control, a quantised data-driven adaptive iterative learning bipartite consensus (AILBC) method is proposed. Specifically, to address the problem of varying trial lengths, a distributed auxiliary output prediction system is constructed based on the agents' input-output (I/O) dynamic relationship. An adaptive update protocol is developed to estimate the measurement disturbances and unknown parameters of I/O dynamic relationship. Subsequently, a quantised distributed data-driven iterative learning control (ILC) approach based on the quantised output information is proposed for MASs to achieve robust bipartite consensus tracking, with an attempt to relax the need of explicit model information. The bipartite consensus tracking errors are ultimately bounded through rigorous analysis, and this result is further extended to switching topologies. Finally, numerical simulations are conducted to verify the validity of the AILBC method.

Recent AADSM Protocol Update: A Step Forward, or Backward?

Recent AADSM Protocol Update: A Step Forward, or Backward?

Response to “Recent AADSM Protocol Update: A Step Forward, or Backward?”

Response to “Recent AADSM Protocol Update: A Step Forward, or Backward?”

Illnesses and Injuries at a Remote American Residential Summer Camp Over 3 Seasons.

Residential and wilderness excursion summer camps are safe, but outdoor activities can lead to injuries. The frequency of various illnesses and injuries at summer camps has been incompletely described. The treatments provided and the need for escalation to higher levels of care are variable. A retrospective cohort analysis was conducted for all visits to a camp infirmary over 3 seasons at a residential summer camp in Minnesota. Seventeen descriptive categories of chief complaints and 13 categories of treatment disposition were created for all 695 eligible infirmary visits. The frequency and illness type for which escalation to a higher level of care beyond the camp infirmary was needed were reviewed. Four hundred one campers sought medical care 695 times over 3 seasons. The most common chief complaints were related to skin (35%), musculoskeletal injury (17%), and upper-respiratory symptoms (15%). The most common treatment and dispositions were over-the-counter medications (43%) and simple bandage or dressing (19%). Escalation of care to a clinic or emergency room was uncommon, with 35 (5%) infirmary visits requiring escalation. Musculoskeletal injuries were the most common reason for escalations of care. While overall less common than musculoskeletal injury, dental injury almost always resulted in escalation of care. An analysis of 3 y of visits to a summer camp infirmary was used by camp medical staff to update protocols and obtain new supplies for diagnosis and treatments. A more complete understanding of the prevalence of injuries and illnesses has the potential to allow better preparation for camp medical staff.

British Society of Echocardiography guideline for the transthoracic echocardiographic assessment of cardiac amyloidosis

These guidelines form an update of the BSE guideline protocol for the assessment of restrictive cardiomyopathy (Knight et al. in Echo Res Prac, 2013). Since the original recommendations were conceived in 2013, there has been an exponential rise in the diagnosis of cardiac amyloidosis fuelled by increased clinician awareness, improvements in cardiovascular imaging as well as the availability of new and effective disease modifying therapies. The initial diagnosis of cardiac amyloidosis can be challenging and is often not clear-cut on the basis of echocardiography, which for most patients presenting with heart failure symptoms remains the first-line imaging test. The role of a specialist echocardiographer will be to raise the suspicion of cardiac amyloidosis when appropriate, but the formal diagnosis of amyloid sub-type invariably requires further downstream testing. This document seeks to provide a focused review of the literature on echocardiography in cardiac amyloidosis highlighting its important role in the diagnosis, prognosis and screening of at risk individuals, before concluding with a suggested minimum data set, for use as an aide memoire when reporting.

Impact of Limiting Vancomycin Loading Doses in Patients With Methicillin-resistant Staphylococcus aureus Infections After Hospital Protocol Revision.

Background: Vancomycin loading doses are commonly used to quickly attain target serum concentrations; however, data supporting their effect on clinical patient outcomes is limited. In April 2020, our institution revised our pharmacist-driven vancomycin dosing protocol to reserve loading doses for hemodynamically unstable patients with suspected serious methicillin-resistant Staphylococcus aureus (MRSA) infections. Prior to the protocol update, all patients treated with vancomycin at our institution received a weight-based loading dose. The purpose of this study is to assess clinical efficacy and safety outcomes related to the use of vancomycin loading doses. Methods: A retrospective, quasi-experimental study was performed to compare clinical outcomes in adult patients treated with vancomycin for laboratory-confirmed MRSA infections. Patients who received vancomycin therapy prior to our institution's vancomycin dosing protocol revisions (pre-intervention) were compared to patients who received vancomycin after the revisions (post-intervention). The primary outcome was all-cause, inpatient mortality. Secondary outcomes included persistent signs and symptoms of infection ≥5 days after vancomycin initiation, switch to alternative anti-MRSA therapy, and nephrotoxicity. Results: A total of 122 patients (63 pre-intervention patients and 59 post-intervention patients) were included. Receipt of a vancomycin loading dose did not impact the rate of inpatient mortality (4.76%vs 6.78%; OR 1.46, 95% CI [0.31, 6.79]). All secondary outcomes were similar between the two groups, including persistent signs and symptoms of infection, switch to alternative anti-MRSA therapy, and nephrotoxicity. Conclusions: Routine use of vancomycin loading doses is not associated with improved outcomes in hemodynamically stable patients with MRSA infections.

Statistical analysis plan and protocol updates for Gestational diabetes in Uganda and India: Design and Evaluation of Educational Films for Improving Screening and Self-management (GUIDES) trial

BackgroundTimely detection and management of gestational diabetes mellitus (GDM) have been identified as a high priority for policymakers in low- and middle-income countries (LMICs). The GUIDES trial will evaluate a package of three interconnected film-based interventions aimed at improving the timely detection and management of GDM. The protocol for this trial has previously been published; this publication outlines the statistical analysis plan for the trial.Methods and designThe GUIDES study is a multi-country cluster-randomised controlled trial consisting of one trial conducted in Uganda and one in India (30 clusters in each country). Mixed effects models will be used to compare the primary study outcomes of the proportion of women who are tested for GDM between 24 and 32 weeks of pregnancy and the mean fasting blood sugar of women with GDM at 34-week follow-up while accounting for clustering. Secondary analyses will compare the proportion of women with self-reported GDM diagnosis at 32 weeks of pregnancy and the proportion of women with adverse perinatal outcomes related to GDM up to 4 weeks after birth in each trial arm.Trial status and discussionFollow-up is expected to end in March 2023 in Uganda and in May 2023 in India. Analyses will be carried out following this statistical analysis plan in the month following trial completion.Trial registrationClinicalTrials.gov NCT03937050. Registered on 3 May 2019. Clinical Trials Registry India CTRI/2020/02/023605. Registered on 26 February 2020.

Capacity Building, Knowledge Enhancement, and Consultative Processes for Development of a Digital Tool (Ni-kshay SETU) to Support the Management of Patients with Tuberculosis: Exploratory Qualitative Study.

Achieving the target for eliminating tuberculosis (TB) in India by 2025, 5 years ahead of the global target, critically depends on strengthening the capacity of human resources as one of the key components of the health system. Due to the rapid updates of standards and protocols, the human resources for TB health care suffer from a lack of understanding of recent updates and acquiring necessary knowledge. Despite an increasing focus on the digital revolution in health care, there is no such platform available to deliver the key updates in national TB control programs with easy access. Thus, the aim of this study was to explore the development and evolution of a mobile health tool for capacity building of the Indian health system's workforce to better manage patients with TB. This study involved two phases. The first phase was based on a qualitative investigation, including personal interviews to understand the basic requirements of staff working in the management of patients with TB, followed by participatory consultative meetings with stakeholders to validate and develop the content for the mobile health app. Qualitative information was collected from the Purbi Singhbhum and Ranchi districts of Jharkhand and Gandhinagar, and from the Surat districts of Gujarat State. In the second phase, a participatory design process was undertaken as part of the content creation and validation exercises. The first phase collected information from 126 health care staff, with a mean age of 38.4 (SD 8.9) years and average work experience of 8.9 years. The assessment revealed that more than two-thirds of participants needed further training and lacked knowledge of the most current updates to TB program guidelines. The consultative process determined the need for a digital solution in easily accessible formats and ready reckoner content to deliver practical solutions to address operational issues for implementation of the program. Ultimately, the digital platform named Ni-kshay SETU (Support to End Tuberculosis) was developed to support the knowledge enhancement of health care workers. The development of staff capacity is vital to the success or failure of any program or intervention. Having up-to-date information provides confidence to health care staff when interacting with patients in the community and aids in making quick judgments when handling case scenarios. Ni-kshay SETU represents a novel digital capacity-building platform for enhancing human resource skills in achieving the goal of TB elimination.

Group Consensus of Second-Order Sample MASs via Distributed Event-Triggered Mechanism

The group consensus of second-order sample multi-agent systems is investigated by using the distributed event-triggered mechanism. Firstly, a consensus protocol is proposed with distributed event-triggered mechanism. Consensus protocol is updated only when the event-triggered condition is met, and the update of consensus protocol only depends on the data collected by the sample holder at the moment of triggering. Secondly, the sufficient condition to realize group consensus is obtained. Thirdly, the differential equation is constructed by comparison theorem to obtain a minimum positive and lower bound for any two trigger time intervals. The Zeno phenomenon is also avoided. Finally, the effectiveness is verified by a simulation example.

5610823 TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 1B CROSSWALK-A TRIAL EVALUATING THE SAFETY OF CROVALIMAB FOR THE MANAGEMENT OF ACUTE UNCOMPLICATED VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S (HbS). HbS polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute, painful episodes called VOEs. Although most VOEs are managed at home, >70% of emergency department visits and >90% of hospitalizations for SCD are VOE-related.1,2 Additionally, acute chest syndrome is one of the most severe complications of VOEs and is a leading cause of mortality.3,4 As there are no targeted therapies for the management of VOEs, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, which represents a significant unmet medical need. Overall, accumulating nonclinical data suggest a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.5 Complement pathway activation has been described in pts with SCD at baseline, in acute pain crises, and in pts with delayed hemolytic transfusion reaction. The complement pathway can be targeted with crovalimab, which is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase 1/2 study in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.6 Aims: CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase 1b study evaluating the safety of crovalimab in managing acute uncomplicated VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0) will be enrolled (Figure). Pts must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be current. Eligible pts will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. All pts will continue with pain management and other supportive care for their VOE, and may continue concurrent SCD-directed therapies. Pts will be followed during hospitalization until discharge and will also be followed post-discharge during an observational period. The study duration for an individual pt, including the hospitalization and observational periods, will be 12 weeks. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetic, pharmacodynamic, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Protocol updates are in progress. Results: CROSSWALK-a is scheduled to be completed in September 2023. Summary: CROSSWALK-a is enrolling pts with SCD in five countries.

5612539 TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2A CROSSWALK-C TRIAL EVALUATING THE EFFICACY OF CROVALIMAB AS ADJUNCT TREATMENT IN THE PREVENTION OF VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, with either homozygous inheritance or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. Hemoglobin S, produced as a result of this point mutation, polymerizes within RBCs under certain conditions, distorting them and generating dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute painful episodes called VOEs. Pts with SCD may also have severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. Current therapies for SCD include hydroxyurea, as well as newer treatments such as L-glutamine, crizanlizumab, and voxelotor. Despite these treatments, considerable morbidity and mortality among pts with SCD represents a significant unmet medical need. Complement pathway activation has been reported in pts with SCD at baseline, in acute pain crises, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.1 The complement pathway can be targeted with crovalimab, a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. In a Phase 1/2 paroxysmal nocturnal hemoglobinuria (a complement-mediated disorder) study, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.2 Aim: CROSSWALK-c (NCT05075824) is a randomized, double-blind, placebo-controlled, Phase 2a study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0), and presenting with 2 to 10 VOEs are eligible, including pts on concurrent SCD-directed therapies. Vaccinations against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumoniae are required. Pts with a history of hematopoietic stem cell transplant will be excluded. Eligible pts will be randomized 1:1 to the crovalimab or placebo arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be given on Week 1, Day 1, followed by SC dose on Week 1, Day 2, and then weekly SC doses on Weeks 2–4. Starting Week 5, a maintenance dose will be given every 4 weeks for 48 weeks. All study treatment will be given according to a weight-based tiered dosing schedule (pts weighing ≥ 40 kg to < 100 kg and pts ≥ 100 kg). The primary objective is to evaluate the efficacy of crovalimab vs placebo based on the annualized rate of medical facility VOEs. Key secondary efficacy objectives are the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin–creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetic, immunogenicity, and exploratory biomarker objectives will also be evaluated. Protocol updates are in progress. Results: Primary results are expected in July 2024. Summary: CROSSWALK-c is enrolling pts with SCD and chronic VOEs in six countries.