It remains unclear which individuals with subthreshold depression benefit most from psychological intervention, and what long-term effects this has on symptom deterioration, response and remission.

To synthesise psychological intervention benefits in adults with subthreshold depression up to 2 years, and explore participant-level effect-modifiers.

Randomised trials comparing psychological intervention with inactive control were identified via systematic search. Authors were contacted to obtain individual participant data (IPD), analysed using Bayesian one-stage meta-analysis. Treatment–covariate interactions were added to examine moderators. Hierarchical-additive models were used to explore treatment benefits conditional on baseline Patient Health Questionnaire 9 (PHQ-9) values.

IPD of 10 671 individuals (50 studies) could be included. We found significant effects on depressive symptom severity up to 12 months (standardised mean-difference [s.m.d.] = −0.48 to −0.27). Effects could not be ascertained up to 24 months (s.m.d. = −0.18). Similar findings emerged for 50% symptom reduction (relative risk = 1.27–2.79), reliable improvement (relative risk = 1.38–3.17), deterioration (relative risk = 0.67–0.54) and close-to-symptom-free status (relative risk = 1.41–2.80). Among participant-level moderators, only initial depression and anxiety severity were highly credible (P > 0.99). Predicted treatment benefits decreased with lower symptom severity but remained minimally important even for very mild symptoms (s.m.d. = −0.33 for PHQ-9 = 5).

Psychological intervention reduces the symptom burden in individuals with subthreshold depression up to 1 year, and protects against symptom deterioration. Benefits up to 2 years are less certain. We find strong support for intervention in subthreshold depression, particularly with PHQ-9 scores ≥ 10. For very mild symptoms, scalable treatments could be an attractive option.

Wishes to hasten death (WTHDs) are common in patients with serious illness. The Schedule of Attitudes Toward Hastened Death (SAHD) is a validated 20-item instrument for measuring WTHD. Two short versions have also been developed based on statistical item selection. However, all existing versions show some limitations with potential for improvement. This study aims to develop and initially validate a theory-driven and statistically sound SAHD short version based on a large multinational sample to advance the WTHD assessment in different countries and with different legislations.

A 3-step procedure was carried out including (1) theory-driven item selection, (2) exploratory, and (3) confirmatory factor analysis. We used a data set collected between 1998 and 2020 across 3 different countries (Germany, Spain, USA). Participants were N = 1156 complete cases (n = 181 German, n = 101 Spanish and n = 874 US) of severely ill adult in- and outpatients. They had to be ≥18 years and give informed consent.

The exploratory factor analysis revealed that 10 of 11 items previously selected theory-driven loaded on either of 2 factors: (1) WTHD and (2) internal locus of control. These factors showed good to excellent reliability according to Cronbach’s α and McDonald’s Ω, as well as an excellent fit of our data as an overall model for the total sample.

The developed SAHD-10 represents a reliable and valid alternative to the SAHD and an efficient means to measure and further investigate a WTHD in cross-cultural clinical and research settings.

To understand healthcare workers’ (HCWs) beliefs and practices toward blood culture (BCx) use.

Cross-sectional electronic survey and semi-structured interviews.

Academic hospitals in the United States.

HCWs involved in BCx ordering and collection in adult intensive care units (ICU) and wards.

We administered an anonymous electronic survey to HCWs and conducted semi-structured interviews with unit staff and quality improvement (QI) leaders in these institutions to understand their perspectives regarding BCx stewardship between February and November 2023.

Of 314 HCWs who responded to the survey, most (67.4%) were physicians and were involved in BCx ordering (82.3%). Most survey respondents reported that clinicians had a low threshold to culture patients for fever (84.4%) and agreed they could safely reduce the number of BCx obtained in their units (65%). However, only half of them believed BCx was overused. Although most made BCx decisions as a team (74.1%), a minority reported these team discussions occurred daily (42.4%). A third of respondents reported not usually collecting the correct volume per BCx bottle, half were unaware of the improved sensitivity of 2 BCx sets, and most were unsure of the nationally recommended BCx contamination threshold (87.5%). Knowledge regarding the utility of BCx for common infections was limited.

HCWs’ understanding of best collection practices and yield of BCx was limited.

In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.

A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.

We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.

The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

In 2016, the US FDA issued an industry guidance document “Quality Attribute Considerations for Chewable Tablets” which describes the quality attributes to be considered when developing chewable tablets. It includes recommendations on selection of acceptance criteria for measuring palatability (having a taste acceptable to the patient or has adequate masking). These data are now recommended as part of ANDA submissions. Palatability is a known positive contributing factor to drug adherence and persistence. We summarize here palatability data for a new amphetamine extended-release tablet (Dyanavel XR® Extended Release Tablet; AMPH ER TAB).

This was a 2-arm preplanned secondary analysis from a comparative bioavailability study: single-dose AMPH ER TAB 20 mg chewed under fasting (Treatment A) and fed (Treatment B) conditions. Subjects rated the palatability of AMPH ER TAB (Treatments A+B) through a 5-question palatability questionnaire. The questions included in the palatability questionnaire were as follows:

1. 1. Oral sensation/mouth feel of the drug product

2. 2. Taste of the drug product

3. 3. How strong is the taste?

4. 4. Aftertaste of the product

5. 5. How strong is the aftertaste?

Subjects completed the questionnaire within 10 minutes from the time of drug administration, which was evaluated and scored according to the rubric below:

Q1, Q2, Q4: palatability- Very unpleasant (score of 1), Unpleasant (2), No sensation or mouthfeel (3), Pleasant (4), and Very pleasant (5)

Q3, Q5 (Taste/aftertaste strength): Very strong (score of 1), Strong (2), Moderate (3), Mild (4), No aftertaste (5).

Scores of 1-2 for both categories were Negative; score of 3 was Neutral, and 4-5 were Positive.

35 subjects comprised the palatability dataset (completed one question on the questionnaire). In the palatability analysis, for treatments A and B, most of the subjects rated the oral sensation/mouth feel of AMPH ER TAB (Question 1) and the taste of AMPH ER TAB (Question 2) as positive (pleasant to very pleasant) (70.1% and 83.6%, respectively).

When evaluating taste strength (Question 3): 43.3% rated the strength as positive (mild/no taste) and 43.3% of subjects rated the strength as neutral (moderate taste). Also, 82.1% rated the aftertaste of AMPH ER TAB (Question 4) as positive (pleasant/very pleasant) and 52.2% rated the strength of the aftertaste as positive (mild/no taste).

Most subjects rated the oral sensation and taste as pleasant or very pleasant, whether chewed under fasted conditions or after a meal. With respect to the taste strength, most subjects rated it as moderate (chewed under fasted conditions) or mild/no taste (chewed after a meal). Aftertaste was rated as pleasant or very pleasant in most subjects, with the strength as moderate (chewed under fasted conditions) or mild/no aftertaste (chewed after a meal). AMPH ER Tablets provided an overall pleasant taste and mouthfeel experience for patients.

Funding Acknowledgements: Tris Pharma, Inc.

Evaluate comparative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB, Tris Pharma, Inc., Monmouth Junction, NJ) 20 mg, swallowed whole or chewed and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; and evaluate whether a PK food effect exists on AMPH ER TAB (contains a 3.2:1 ratio of d- to l-amphetamine).

Healthy volunteers (18-55 yr) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted).

A crossover design was used. Samples were collected each period pre-dose and at time points to 60 h post-dose. D-and l-amphetamine were measured, and PK was calculated (90% CIs of the ratios of the geometric mean plasma levels) for Cmax, AUCt, and AUC0∞. Comparative bioavailability was determined when ratios were within 80 and 125%. Safety was also assessed.

32 subjects completed the study. Based on the calculated bioavailability ratios, for AMPH ER TAB swallowed vs. AMPH EROS fasted: d-amphetamine total and peak exposures were found to be similar: AUC0-t: 100.68-108.08%, AUC0-∞:101.47-109.52%, Cmax: 98.10-103.17%. For l-amphetamine, the total and peak exposures were similar: AUC0-t: 100.31-108.57%, AUC0-∞:101.27-111.09%, Cmax: 98.2-103.37%.

AMPH ER TAB chewed vs. AMPH EROS fasted: For d-amphetamine, the total and peak exposures were similar: AUC0-t: 99.23-106.62%, AUC0-∞: 99.58-107.59%, Cmax: 99.91-105.14%. For l-amphetamine, the total and peak exposure was similar: AUC0-t: 98.16-106.35%, AUC0-∞: 98.44-108.11%, Cmax: 99.53-104.75%.

Food effect: AMPH ER TAB, chewed, fasted vs. fed: For d-amphetamine, the total and peak exposure was similar: AUC0-t: 92.57-99.49%, AUC0-∞: 91.12-98.48%, Cmax: 94.22-99.17%.

For l-amphetamine, the total and peak exposure was similar: AUC0-t: 91.27-98.91%, AUC0-∞: 88.44-97.17%, Cmax: 94.52-99.50%).

No serious AEs were reported during the conduct of this study, and the AE profiles were observed to be similar in frequency of events and severity to other amphetamine formulations used in ADHD.

Bioavailability of single dose of AMPH ER TAB for both d- and l-amphetamine was comparable, swallowed whole or chewed, to an equivalent 20 mg dose of the reference product AMPH EROS, 2.5 mg/mL fasted, and showed equivalent peak and overall exposure.

No food effect was observed for AMPH ER TAB administered chewed. All AEs were mild in severity and AE profiles were similar to other amphetamine formulations used for treatment of ADHD.

Tris Pharma, Inc.

Evaluate the relative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB) 20 mg, swallowed whole or chewed, and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; evaluate food effect on AMPH ER TAB.

Healthy volunteers (18–55 years) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted). A crossover study design was used. Plasma samples were collected each period predose and at time points to 60 hours postdose. d- and l-amphetamine were measured and pharmacokinetic (PK) was calculated (90% confidence intervals of the ratios of the plasma levels) for AUC0-t, AUC0-∞, and Cmax. Comparative relative bioavailability between formulations was determined when ratios were within 80% and 125%. Safety was also assessed.

Thirty-two subjects completed the study. AMPH ER TAB swallowed versus AMPH EROS (fasted): for d- and l-amphetamine, the total and peak exposure was similar: d: AUC0-t: 100.68% to 108.08%, AUC0-∞: 101.47% to 109.52%, Cmax: 98.10% to 103.17%; l: AUC0-t: 100.31% to 108.57%, AUC0-∞: 101.27% to 111.09%, Cmax: 98.2% to 103.37%. For d- and l-amphetamine when the tablet is swallowed whole, Tmax was 5.00 hours (with a range of 2.00–9.00 hours). AMPH ER TAB chewed versus AMPH EROS (fasted): for d- and l-amphetamine, the total and peak exposure was similar: d: AUC0-t: 99.23% to 106.62%, AUC0-∞: 99.58% to 107.59%, Cmax: 99.91% to 105.14%; l: AUC0-t: 98.16% to 106.35%, AUC0-∞: 98.44% to 108.11%, Cmax: 99.53% to 104.75%. For d- and l-amphetamine when the tablet has been chewed, Tmax was 5.00 hours (with a range of 3.00-7.00 hours). PK results were similar for patients in the fasted and fed groups, indicative of no presence of food effect. No serious adverse events (AEs) were reported, overall AE profiles between the tablet and oral suspension were comparable without any unanticipated safety concerns.

Single doses of AMPH ER TAB for both d- and l-amphetamine demonstrated comparable bioavailability to a 20 mg dose of AMPH EROS, 2.5 mg/mL under fasted conditions when chewed and swallowed whole, and demonstrated equivalent peak and overall exposure without apparent food effect. AMPH ER TAB was well-tolerated and consistent with adverse events noted in other amphetamine formulations.

We are developing the novel αIIbβ3 antagonist, RUC-4, for subcutaneously (SC)-administered first-point-of-medical-contact treatment for ST segment elevation myocardial infarction (STEMI).

We studied the (1) pharmacokinetics (PK) of RUC-4 at 1.0, 1.93, and 3.86 mg/kg intravenous (IV), intramuscular (IM), and SC in non-human primates (NHPs); (2) impact of aspirin on RUC-4 IC50 in human platelet-rich plasma (PRP); (3) effect of different anticoagulants on the RUC-4 IC50 in human PRP; and (4) relationship between αIIbβ3 receptor blockade by RUC-4 and inhibition of ADP-induced platelet aggregation.

(1) All doses of RUC-4 were well tolerated, but animals demonstrated variable temporary bruising. IM and SC RUC-4 reached dose-dependent peak levels within 5–15 minutes, with T1/2 s between 0.28 and 0.56 hours. Platelet aggregation studies in NHPs receiving IM RUC-4 demonstrated >80% inhibition of the initial slope of ADP-induced aggregation with all three doses 30 minutes post-dosing, with subsequent dose-dependent loss of inhibition over 4–5 hours. (2) The RUC-4 IC50 for ADP-induced platelet aggregation was unaffected by aspirin treatment (40±9 nM vs 37±5 nM; p = 0.39). (3) The RUC-4 IC50 was significantly higher in PRP prepared from D-phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK)-anticoagulated blood compared to citrate-anticoagulated blood using either thrombin receptor activating peptide (TRAP) (122±17 vs 66±25 nM; p = 0.05; n = 4) or ADP (102±22 vs 54±13; p<0.001; n = 5). (4) There was a close correspondence between receptor blockade and inhibition of ADP-induced platelet aggregation, with aggregation inhibition beginning with ~40% receptor blockade and becoming nearly complete at >80% receptor blockade.

Based on these results and others, RUC-4 has now progressed to formal preclinical toxicology studies.