Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence:the randomized phase 2a TITAN trial

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .</p

Electrocardiographic Changes in a Horse with Induced Myocardial Infarction

During acute myocardial infarction (AMI), the ischemia and necrosis of the infarcted tissue result in local electrophysiological changes, which bring about deviations of the ST segment and T wave. In this case report, the aim was to investigate whether these changes could be detected with a 12-lead electrocardiogram (ECG) during acute occlusion of the coronary artery in a 15-year-old Standardbred mare (scheduled for euthanasia due to non-cardiac health problems). The left anterior descending (LAD) coronary artery was occluded using an angioplasty balloon catheter guided through the carotid artery. Two coronary occlusions of 30 min were induced, separated by a 10-min reperfusion phase. AMI led to ST deviations and T-wave amplitude changes (maximum ST deviation was 1.98 mV; T-wave amplitude increased from 6.58 to 9.25 mV). The ST segment almost returned to the baseline during the reperfusion phase. The ECG changes seen after the infarction were comparable to those reported in other species with AMI, suggesting that the 12-lead-ECG can potentially be used to detect signs of myocardial infarction in horses

Clinical application of ‘Sophia Observation withdrawal Symptoms-Paediatric Delirium’ screening tool in Danish version: A feasibility study

Aims and objectives: The aims of the present study were investigating the feasibility of: (1) using the Danish version of Sophia Observation withdrawal Symptoms-Paediatric Delirium (SOS-PD) screening tool in clinical practice and (2) comparing SOS-PD performance to a child psychiatrist's assessment using the diagnostic criteria as a reference standard. Background: Critically ill children risk developing delirium potentially causing discomfort and suffering. Intensive care delirium has a fluctuating course complicating detection. Systematic screening during and after intensive care is central to manage paediatric delirium. Design and methods: We used a descriptive and comparative design. First aim: Bedside nurses were asked to evaluate their experience of using the SOS-PD. Second aim: We compared the SOS-PD performance with the child psychiatrist assessment in 50 children aged 4 weeks to 18 years. Results: Nurses found the Danish version of the SOS-PD applicable and easy to use. Of the 50 children included, 13 were diagnosed with delirium by the child psychiatrist. Consistency was found between the SOS-PD score and the child psychiatrist's assessment (88%). We found three false-negative and three false-positive SOS-PD cases. The false-negative cases could be explained by the differences in time periods for the assessments. SOS-PD assessments covered the past 4 h, whereas the psychiatric assessments covered the past 24 h. We assume the false-positive cases represent an acceptable inconsistency between the two assessment methods. Conclusions: The Danish version of the SOS-PD appeared suitable for identifying paediatric delirium. Our results emphasised the importance of assessment at least once during each nursing shift to ensure delirium detection around the clock due to the fluctuating course of delirium. Relevance to clinical practice: Implementing the Danish SOS-PD may increase awareness of this critical disorder by improving systematic identification of paediatric delirium in clinical practice paving the way for improved delirium prevention and management

Development of a non-pharmacologic delirium management bundle in paediatric intensive care units

Background: Non-pharmacologic interventions might be effective to reduce the incidence of delirium in pediatric intensive care units (PICU). Aim: To explore expert opinions and generate informed consensus decisions regarding the content of a non-pharmacologic delirium bundle to manage delirium in PICU patients. Study design: A two-round online Delphi study was conducted from February to April 2021. PICU experts (nurses, physicians, researchers, physical therapists, play specialists, and occupational therapists) located in Europe, North America, South America, Asia, and Australia participated. Results: We developed a questionnaire based on the outcomes of a comprehensive literature search in the domains: 1) cognition support; 2) sleep support; and 3) physical activity support. Under these domains, we listed 11 strategies to promote support with 61 interventions. Participants rated the feasibility of each intervention on a 9-point Likert scale (ranging from 1 strongly disagree to 9 strongly agree). A disagreement index and panel median were calculated to determine the level of agreement among experts. In the second round, participants reassessed the revised statements and ranked the interventions in each domain in order of importance for age groups: 0–2, 3–5, and 6–18 years of age. During the first Delphi round, 53 of 74 (72%) questionnaires were completed, and in the second round 45 of 74 (61%) were completed. Five of the highest ranked interventions across the age groups were: 1) developing a daily routine, 2) adjusting light exposure according to the time of day, 3) scheduling time for sleep, 4) providing eyeglasses and hearing aids if appropriate, 5) encouraging parental presence. Conclusions: Based on expert consensus, we developed an age-specific non-pharmacologic delirium bundle of interventions to manage delirium in PICU patients. Relevance to Clinical Practice: An age-specific Non-Pharmacological Delirium bundle is now ready to be tested in the PICU and will hopefully reduce pediatric delirium

Electrocardiographic characteristics of trained and untrained standardbred racehorses

BACKGROUND: Long-term exercise induces cardiac remodeling that potentially influences the electrical properties of the heart. HYPOTHESIS/OBJECTIVES: We assessed whether training alters cardiac conduction in Standardbred racehorses. ANIMALS: Two hundred one trained and 52 untrained Standardbred horses. METHODS: Cross-sectional study. Resting ECG recordings were analyzed to assess heart rate (HR) along with standard ECG parameters and for identification of atrial and ventricular arrhythmias. An electrophysiological study was performed in 13 horses assessing the effect of training on sinoatrial (SA) and atrioventricular (AV) nodal function by sinus node recovery time (SNRT) and His signal recordings. Age and sex adjustments were implemented in multiple and logistic regression models for comparison. RESULTS: Resting HR in beats per minute (bpm) was lower in trained vs untrained horses (mean, 30.8 ± 2.6 bpm vs 32.9 ± 4.2 bpm; P = .001). Trained horses more often displayed second-degree atrioventricular block (2AVB; odds ratio, 2.59; P = .04). No difference in SNRT was found between groups (n = 13). Mean P-A, A-H, and H-V intervals were 71 ± 20, 209 ± 41, and 134 ± 41 ms, respectively (n = 7). We did not detect a training effect on AV-nodal conduction intervals. His signals were present in 1 horse during 2AVB with varying H-V interval preceding a blocked beat. CONCLUSIONS AND CLINICAL IMPORTANCE: We identified decreased HR and increased frequency of 2AVB in trained horses. In 5 of 7 horses, His signal recordings had variable H-V intervals within each individual horse, providing novel insight into AV conduction in horses