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Limitations |
Several limitations of the present study should be mentioned. First, due to the SARS-CoV2 pandemic and the rigorous restrictions for the Austrian population, the period between the last training session and the qualitative interviews varied between 5.0 and 80.4 (MD = 52.9, IQR = 35.4) weeks. Therefore, it might have been difficult for some of the participants to remember the treatment well and give constructive feedback. Second, also due to COVID-19 restrictions, we were forced to conduct some of the interviews by telephone or video call because in-person meetings were prohibited. This, as well as working with translators, might have caused a certain bias in the interviews. Nevertheless, previous research demonstrated that both in-person and telephone interviews are accurate [ | PMC10625214 | ||
Conclusion | fits, PMLD |
The results of this study suggest that aPM+, a transdiagnostic psychological intervention, is a feasible and well-accepted intervention for Afghan refugees living in Austria. The study highlights the importance of considering subjectively perceived symptom burden to support treatment compliance and effectiveness. aPM + provides a culture-sensitive and person-oriented approach, is effective, and fits the specific needs of migrants and refugees. In the presented qualitative reports, it became clear that easily accessible interventions as well as repetitions support ongoing practice of certain strategies and the perceived effectiveness of the treatment. The interventions seem to address the problems associated with PMLD and to increase self-regulation. Thus, aPM + appears to be an appropriate intervention to reduce subjective symptom burden and facilitate daily functioning. In future research and treatment targeting refugees, such small but effective interventions should be considered and implemented into treatment routines. Regular practice and instructions from the therapist are necessary to improve treatment outcomes. Furthermore, it would be advisable to investigate the effectiveness of a planned booster session some weeks/months after completion of the training [ | PMC10625214 | |
Acknowledgements |
We would like to express our gratitude to all participants of our study for trusting us and sharing their experiences with us. Further, we want to thank the supporting outpatient treatment centres, NGOs, and the Outpatient Unit for Research, Teaching and Practice at the Faculty of Psychology, University of Vienna. We would especially like to thank Maria Böttche for the helpful clinical supervision, as well as Alexandra Liedl, Naser Morina and Mahmoud Hemmo acting as external advisory consultants and clinical supervisors. | PMC10625214 | ||
Author’s contributions |
VK and DW wrote the main manuscript text and prepared tables to equal parts. Further, they analised all qualitative data. JSJ and MK analised parts of the data (interrater reliability) and reviewed the final code scheme of the first qualitative part (PSYCHLOPS). MK and BLS were regularly consulted during the data analisis of the second qualitative part of the manuscript (aPM+). MK assessed the quantitative analysis and LV and BLS reviewed the whole manuscript. All authors read and approved the final manuscript. | PMC10625214 | ||
Funding |
This study was funded by the Austrian Science Fund (FWF) (grant number: KLI 755-B).Open access funding provided by Austrian Science Fund (FWF). | PMC10625214 | ||
Data Availability |
The datasets used during the current study are available from the corresponding author on reasonable request. | PMC10625214 | ||
Declarations | PMC10625214 | |||
Ethical approval and consent to participate |
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2013.
The study was registered at the Internet Portal of the German Clinical Trials Register (DRKS; registration number: DRKS00016538). Ethical approval was granted by the IRB of the University of Vienna (reference numbers 00356 and 00445). Furthermore, we obtained a Universal Trial Number (UTN) to facilitate the unambiguous identification of our trial (UTN: U1111-1226-3285).
Clinical psychologists explained the study to participants prior to their participation at the baseline assessment using an information sheet (German and Dari versions) with the help of an interpreter. Participants who agreed to participate gave written informed consent. | PMC10625214 | ||
Consent for publication | Not applicable. | PMC10625214 | ||
Competing interests | The authors declare no competing interests. | PMC10625214 | ||
References | PMC10625214 | |||
Keywords | Eyebrows | HYPOTRICHOSIS | Eyebrows are an important feature of facial identity and communications in human beings as well as an important eye defense shield from dust and foreign bodies. To compare the efficacy and safety between 0.01%, 0.03% bimatoprost and minoxidil 2% in gel formulations for eyebrow enhancement. Sixty eligible subjects were female or male, aged 18 years or older with eyebrow hypotrichosis, defined as either a Grade 1 or 2 on the Global Eyebrow Assessment (GEBA) scale. Patients were randomized into 3 groups using block randomization. Group a (20 patients) applied topical 0.03% bimatoprost gel once daily onto both eyebrows, group b (20 patients) applied topical 0.01% bimatoprost gel once daily onto both eyebrows while group c (20 patients) applied topical minoxidil 2% gel once daily onto both eyebrows. A significant improvement in GEBA score was reported in all the three groups after treatment (Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10514173 |
Introduction | glaucoma, hypotrichosis, Eyebrows | HAIR LOSS, HYPOTRICHOSIS, GLAUCOMA | Eyebrows are an important feature of facial identity and communications in human beings as well as an important eye defense shield from dust and foreign bodies [The eyebrow hair cycle is comprised no differently from other hairs of three phases (anagen, catagen and telogen) however with specific characteristics. Almost 10–15% of eyebrow follicles are in anagen phases which last from 15 to 30 days in average while the majority of follicles (85–90%) are in telogen phase which last for 60–90 days [Minoxidil has been approved for treating male and female pattern hair loss and was found to stimulate hair growth by limiting and regressing the telogen phase of hair follicles as well as by prolongation of the anagen phase resulting in increased hair follicle size. A few number of reports and studies proved an eyebrow enhancement and favorable safety effect of topical minoxidil use in eyebrow hyptrichosis [Bimatoprost is a prostamide, a sytnthetic prostaglandin used to treat glaucoma. The mechanism of bimatoprost and prostamides for enhancing hair growth is still unclear. It is well-known that prostaglandin receptors exist in dermal hair papillae and outer root sheath of the hair follicles. It is predicted that bimatoprost may stimulate the transition of hair follicles from the telogen to the anagen phase and prolong the duration of the anagen phase as well as stimulate melanogensis increasing hair length and darkness [Bimatoprost in its 0.03 and 0.01 formulations was studied in a number of recent studies and compared to one another which revealed its safety and efficacy as a therapeutic potential for eyebrow hypotrichosis [To our knowledge, there has been no previous report of randomized trials comparing, the efficacy and safety between 0.01%, 0.03% bimatoprost and minoxidil 2% in gel formulations for eyebrow enhancement has been published to date which is the main aim of the presented study. | PMC10514173 |
Patients and methods | atopic dermatitis, trichotillomania, fullness, hypotrichosis, dermatitis | SYSTEMIC DISEASE, EYEBROW LOSS, ALOPECIA AREATA, THYROID DISEASES, HYPOTRICHOSIS | This was a randomized, triple armed single blinded randomized study to compare the efficacy and safety of topical 0.01% and 0.03% bimatoprost versus topical 2% minoxidil. The sample size was calculated based on data from a previous comparative study in a Thai population, with a 5% significance level and 90% power. The calculated minimum number of subjects was 50. Considering dropout, we recruited a total of 60 subjects. This study was approved by the ethical committee for research in AL-Azhar University, Damietta faculty of medicine and all patients provided written informed consent prior to starting the study.
Sixty eligible subjects were female or male, aged 18 years or older with eyebrow hypotrichosis, defined as either a Grade 1 or 2 on the Global Eyebrow Assessment (GEBA) scale. The GEBA instrument is a validated 4-point scale used to grade fullness of the eyebrows (1 = very sparse, 2 = sparse, 3 = full, and 4 = very full). Subjects with recent eye operations, those suffering from systemic diseases that can possibly affect eyebrow loss; alopecia areata, trichotillomania, thyroid diseases, atopic dermatitis, seborrheic dermatitis; and those receiving treatment of hypotrichosis within 6 months of enrollment were excluded. Females who had microblading, eyebrow tattoos at screening and female subjects who were pregnant, nursing, or planning for a pregnancy during the study were excluded.Patients were randomized into 3 groups using block randomization. Group a (20 patients) applied topical 0.03% bimatoprost gel once daily onto both eyebrows, group b (20 patients) applied topical 0.01% bimatoprost gel once daily onto both eyebrows while group c (20 patients) applied topical minoxidil 2% gel once daily onto both eyebrows. Containers were identical and were different in color for each. Each bottle was labeled with a container number, dosing instruction, and storage condition. Containers were provided to subjects and refilled at every scheduled follow up monthly visit.The study was scheduled for 16 weeks and at every visit standard photographs were taken using digital camera and trichoscopic eyebrow assessment was carried out using DL-4.Hair count and diameter were assessed using a folliscope and measurements were performed up a vertical line drawn from mid papillary line. Eyebrow number and diameter were analyzed using image analysis software and by manual count.For outcomes, the GEBA scale was evaluated from standard photographs by two blinded dermatologists as subjective parameter in every visit. Another outcome measurement in our study was the 7-point rating scale, defined as follows: marked deterioration (− 3), moderate deterioration (− 2), slight deterioration (− 1), no change (0), slight improvement (+ 1), moderate improvement (+ 2), and marked improvement (+ 3). | PMC10514173 |
Preparation of minoxidil 2% gel (20 mg/g) | The first step was to dissolve 1% carbopol in distilled water (2 g is dissolved in 100 ml of distilled water under stirring conditions), the second step was to activate carbopol gel formation by using seven drops of triethanolamine for every 100 ml of gel, and the third step was to incorporate the gel preparation into the base with 5 min of continuous stirring and stirring to obtain a homogeneous clear drug–gel solution.
| PMC10514173 | ||
Preparation of bimatoprost gel | The first step was to dissolve 1% carbopol in distilled water (2 g is dissolved in 100 ml of distilled water under stirring conditions), the second step was to activate carbopol gel formation by using 0.01 gm or 0.03 gm of bimatoprost for every 100 ml of gel, and the third step was to incorporate the gel preparation into the base with 5 min of continuous stirring and stirring to obtain a homogeneous clear drug–gel solution. | PMC10514173 | ||
Acknowledgements | Authors would like to express their full gratitude to Dr. Emad Zahran; PhD; MSc for preparation of the bimatoprost formulations used in this study. | PMC10514173 | ||
Author contribution | MZ, OH, SM and ME, designed and performed the research. MZ, OH, SM and ME performed the work. MZ, OH, SM and ME analyzed and wrote the paper. All authors contributed equally in production of this work. | PMC10514173 | ||
Funding | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). No funding. | PMC10514173 | ||
Data availability | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC10514173 | ||
Declarations | PMC10514173 | |||
Conflict of interest | The author declares that they have no competing interest. | PMC10514173 | ||
Ethical approval | The study was approved by an ethics committee of Faculty of Medicine IRB (00012367-21-03-007), AL-Azhar University, Damietta; Egypt. | PMC10514173 | ||
References | PMC10514173 | |||
Study design | GROUP B | A single-blind prospective cohort study was performed. The high-fidelity simulation model was used in a formal NRP training course for trainees caring for neonatal patients. The trainees were divided into a group that conducted the scenario after the lecture (Group A) and a group that attended the lecture after the scenario (Group B) and they both took the test before, during, and after the training. | PMC9916567 | |
Results | GROUP B | The increase in score after theory training was statistically significant in both groups, but the final score did not differ between the two groups. However, when compared by career, in Group A, trainees under 24 months tended to be more effective, and in Group B, trainees over 24 months tended to be more effective. | PMC9916567 | |
Conclusion | The difference in short-term memory of trainees according to the order of education identified by the test score was not prominent, but it was found that the degree of difference in test scores for the order of education tended to be different according to the career. It is thought that the effectiveness of the training might be increased by changing the education order according to the degree of experience of each trainee. More effective educational methods should be introduced by continuously developing lectures for repeated education of various trainees in the future. | PMC9916567 | ||
Data Availability | All relevant data are within the manuscript and its | PMC9916567 | ||
Introduction | GROUP B | The Neonatal Resuscitation Program (NRP) is a field of cardiopulmonary resuscitation (CPR) designed and published based on improving the prognosis by providing appropriate early management to newborns [There are many reports that NRP training using high-fidelity simulation provides training effectively [The authors intend to find a teaching method that allows trainees to receive NRP training methods more accurately and effectively through simulation, considering the early providers who need to work immediately after receiving a licence to work in the medical field. This study was conducted to determine which method is more influential: simulation after lecture (Group A: reflects a student environment) and lecture after simulation (Group B: reflects a real working environment) to identify more memorable education methods for NRP training through simulation. | PMC9916567 | |
Materials and methods | PMC9916567 | |||
Study population | HEART | Thirty-three neonatal staff (19 neonatal intensive care unit (NICU) nurses, 4 nursery nurses, 6 delivery room (DR) nurses, 2 physician-assisted (PA) nurses, 2 paediatric residents) without experience in simulation training through scenarios were included. According to hospital regulations, trainees were randomly assigned to NRP regular training conducted once a year, and the NRP training was conducted through simulation by developing two scenarios. All trainees were informed in advance about the implementation of NRP education, including the simulation practice, and self-directed learning was recommended in advance. All of them signed a consent form prior to training. This study was reviewed by the Hallym University Dongtan Sacred Heart Hospital Institutional Review Board (IRB) (IRB No. 2021-01-018). | PMC9916567 | |
Materials and methods | COVID-19 infection | GROUP B, COVID-19 INFECTION | As a prospective cohort study, this study was conducted in 8 morning and afternoon sessions from March 22, 2021, to March 26, 2021. Each session consisted of 50 minutes of a short, key-summary lecture, 10 minutes of break, and 2 cycles of simulation, each cycle lasting approximately 40 minutes. Simulation scenarios and tests were developed under the supervision of a neonatal subspecialist with over 10 years of experience based on NRP and confirmed by peer review. The scenario was used in common for all participants. The trainees received training with the same content, and the same test questions were administered 3 times (before, during, and after the training). The simulation consisted of briefing-scenario-debriefing, and video monitoring was applied to the debriefing. The teaching method for each session was arbitrarily divided, and Group A conducted a simulation after the lecture and Group B attended the lecture after simulation education. All trainees were informed that this was a routine, once-a-year, neonatal CPR training and selected a date and time that suited their individual working conditions; therefore, they were blinded to the study situation and intent at that time. Prior to the start of the lecture, informed consent was obtained for the purpose of the experiment, the order of the practice, and participation. This study conducted a prospective cohort of interventions and follow-up measures for each group by conducting training for each group over a continuous period time.To increase the effectiveness of the simulation training, the number of participants per session was limited to 5 people. In accordance with the COVID-19 infection prevention rules, participants were quarantined 2 m apart in the classroom, and during the simulation scenario, they wore a mask and practised hand hygiene. In the course of the experiment, the security of the content was emphasized to the subjects each time. The trainee’s test was conducted three times (pre, interim, post) ( | PMC9916567 |
A Schematic diagram of the research. | Newborn PEDI | PMC9916567 | ||
Data analysis | Age, gender, years of career in the relevant department, and 1 | PMC9916567 | ||
Results | GROUP B | There was no epidemiologic difference between Group A and Group B. The prelecture test scores did not differ between the two groups (32.3±28.4 vs. 37.1±20.4), and interim tests conducted after the first turn showed significant differences between the two groups (65.7±24.0 vs. 47.4±18.2 p = 0.021). It was also confirmed that there was a significant difference between the groups in the difference between the first test score and the second test score (33.4±21.8 vs. 10.29±6.9 p = 0.001). There was also a significant difference between the two groups in the final test score after the second turn (0.63±4.5 vs. 25.29±13.8 p<0.001). Group B had a higher score than Group A, but the difference was not statistically significant (66.3±24.43 vs. 72.7±12.74 p = 0.360). The difference between the first and final test scores was not significantly different between the two groups (34.06±22.6 vs. 35.59±15.7 p = 0.824) ( | PMC9916567 | |
Demographic findings and total score differentiation. | GROUP B | Each group (Group A vs. Group B) was divided into 2 subgroups (the <24 months and the ≥24 months subgroups) according to their experience, and the preliminary test results before the lecture were significantly different in Group B, the ≥24 months experience group (Group A 25.6±25.0 vs. 47.0±32.6 | PMC9916567 | |
Subgroup analysis by the order of the training. | GROUP B | To confirm the learning effect according to their experience, a subgroup analysis was performed targeting those with <24 months and ≥24 months of experience. In the <24 months subgroup, after the first turn, not only were the test scores higher in Group A than in Group B (66.18±23.47 vs. 47.0±18.17 | PMC9916567 | |
Subgroup analysis by careers, 24 months from neonatal care parts. | PMC9916567 | |||
Discussion | GROUP B | The lack of NRP clinical experience in neonatal care continues to appear [For the purpose of ongoing efforts to develop more powerful methods for sustaining cognitive abilities and skills, training professionals through simulation is considered safe and effective [In this study, no matter which training method was selected, the final test scores after training were similar when compared for the training methods. In particular, Group B showed no significant increase in interim test results, but the final score showed a tendency to be higher than that of Group A. From the interim exam to the final exam, the score of Group A did not increase significantly, while the score of Group B steadily increased, indicating that the score on the final exams was higher. Hakansson et al. [Considering that the nurse group with 2–3 years of career occupies the largest proportion compared to others [When the training methods were compared by career, it was confirmed that the score difference occurred more in group A in the interim test scores in the <24 months career group. Conversely, in the ≥24 months career group, the difference in the interim and final exam scores of Group B increased significantly. Hilosaka et al. [The limitations of this study are that the study was conducted with a small number of volunteers and that only short-term memory was evaluated, with no follow-up of mid-/long-term memory. In this regard, further research is needed.This study was conducted to identify more effective NRP training methods using high-fidelity simulation. The educational effects of the participants were confirmed through the test scores, and as a result, it is thought that the effect might be increased by changing the education order according to the degree of experience of each trainee. Further research might be needed to verify these findings. | PMC9916567 | |
Supporting information | (XLSX)Click here for additional data file.We thank all participants for their generous contributions. | PMC9916567 | ||
References | PMC9916567 | |||
Subject terms | human immunodeficiency virus type 1 (HIV-1) cure. | 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 (In people with HIV-1 undergoing antiretroviral treatment interruption, lefitolimod combined with broadly neutralizing antibodies (bNAbs) did not delay viral rebound beyond that achieved with bNAbs alone, raising the question of how to optimize combination immunotherapy to control HIV-1. | PMC10579101 | |
Main | PWH | Human immunodeficiency virus type 1 (HIV-1) infection persists mainly in CD4Many HIV-1 curative strategies aim to enhance HIV-1-specific immunity as a means to achieve ART-free HIV-1 virologic control. Until recently, HIV-1 cure trials have typically involved people with HIV-1 (PWH) on long-term suppressive ART, which is continued during the therapeutic interventionsOne promising immunostimulatory agent is lefitolimod (MGN1703), a dumbbell-shaped DNA molecule that triggers Toll-like receptor (TLR) 9 signaling in human plasmacytoid dendritic cells (pDCs) and B cellsThe immunological effects of lefitolimod could potentially be boosted either by administering the drug in the presence of higher antigen load or by co-administration with broadly neutralizing anti-HIV-1 antibodies (bNAbs), such as 3BNC117 and 10-1074, which recognize non-overlapping epitopes on the HIV-1 envelope protein gp120 (refs. Collectively, these observations led us to hypothesize that lefitolimod alone or in combination with two doses of 3BNC117 and 10-1074 administered in the setting of ATI could potentially enhance elimination of infected cells and boost HIV-1-specific CD8 | PMC10579101 | |
TITAN trial design (a) and abbreviated CONSORT flow diagram (b). | Solid green arrows indicate lefitolimod injections. Solid red and blue triangles indicate 3BNC117 and 10-1074 infusions, respectively. Empty green arrows as well as red and blue triangles indicate placebo injections or infusions, respectively. Gray shaded areas indicate time on ART, and white shaded areas indicate still interrupting ART during the 25 weeks of ATI. The analysis section is presented in full in Extended Data Fig. | PMC10579101 | ||
Results | PMC10579101 | |||
Plasma HIV-1 RNA kinetics after ART interruption | To determine the impact of the interventions on ART-free virologic control, all participants underwent a closely monitored 25-week ATI. The study’s primary endpoint was time from stopping ART to the date of meeting the criteria for loss of virologic control (defined as 4 weeks with sustained plasma HIV-1 RNA ≥1,000 copies per milliliter or two consecutive measurements >100,000 copies per milliliter). All participants in the placebo/placebo group experienced loss of virologic control, which occurred at a median of 4.5 weeks (IQR: 3.0–11) after stopping ART (Fig. | PMC10579101 | ||
bNAb sensitivity and serum concentrations | The proviral reservoir’s sensitivity to neutralization by 3BNC117 and 10-1074 was assessed for each potential study participant as part of the inclusion criteria before randomization (see | PMC10579101 | ||
bNAb sensitivity at screening and viral rebound. | bNAb sensitivity was primarily analyzed using the PhenoSense Monoclonal Antibody Assay with predefined IC | PMC10579101 | ||
Quantification of intact HIV proviruses | We used a digital droplet PCR (ddPCR) assay (Intact Proviral DNA Assay (IPDA)) to estimate the proportion of intact proviruses in CD4 | PMC10579101 | ||
HIV-1-specific T cell immunity | The median frequency of HIV-1-specific CD8 | PMC10579101 | ||
Safety | ADVERSE EVENTS | Both lefitolimod and bNAbs were overall safe. A total of 253 adverse events (AEs) were registered, of which 94 were determined to be unrelated to any investigational drug, including placebo (Extended Data Tables | PMC10579101 | |
Discussion | PWH, viral suppression | In this randomized, placebo-controlled HIV-1 cure trial among PWH on long-term ART who screened sensitive to the study bNAbs, we found that two doses of 3BNC117 and 10-1074 in the setting of ATI led to a significant delay in viral rebound compared to placebo. We also observed that 36% of individuals in the placebo/bNAb group compared to none in the placebo group maintained partial or complete virologic control at the end of the 25-week ATI. There were no differences in time to viral rebound or change in reservoir size between the placebo/placebo and the lefitolimod/placebo group or between the placebo/bNAb and lefitolimod/bNAb group. Thus, although there was no added clinical or immunological benefit of combining lefitolimod with bNAbs, antibody treatment alone led to a significant delay in viral rebound, and some bNAb-treated individuals experienced long-term ART-free virologic control.Single-arm trials show that bNAb-sensitive PWH on long-term ART receiving 3–8 infusions of 3BNC117 and 10-1074 maintain prolonged viral suppression in the absence of ARTOf note, we administered 10-1074 at 20 mg kgIn our study, 18% of participants (2/11) in the placebo/bNAb group maintained complete virologic control (HIV RNA <20 copies per milliliter) throughout the 25-week ATI, and both elected to continue off ART after the ATI ended. In previous trials using the same bNAb combination, 0% (0/7)Although virologic or immunological features characteristic of post-bNAb controllers have yet to be identified, pre-ATI HIV-1 reservoir size was seven-fold lower in post-ART controllers compared to non-controllers in a cohort studyAs expected, we found that HIV-1-specific CD8The combination of 3BNC117 and 10-1074 neutralizes a broad range of HIV-1 subtypes ex vivoLefitolimod alone or in combination with bNAbs did not significantly impact time to viral rebound or any of the immunological or virologic outcomes in this trial. Unexpectedly, co-administration of lefitolimod led to a faster decline in bNAb serum concentrationsThe combination of a TLR7 agonist and PGT121 was shown to induce long-term ART-free virologic control among 34–45% of NHPsDespite lefitolimod’s well-documented ability to enhance DC-mediated cross-presentation, upregulate IFN-stimulated genes and activate multiple innate and adaptive immune cell subsetsThe reported results have limitations and may not be generalizable to all PWH. Specifically, our ability to predict proviral bNAb sensitivity based on the PhenoSense assay or sequence analysis is limited. Undetected bNAb resistance leading to treatment failure may have clinical implications, particularly if bNAbs were to replace modern ART regimens as suppressive antiviral treatment or if used in combination with the new long-acting small-molecule-based injectable antivirals. Most enrolled participants were male. In contrast to some bNAb trialsAlthough lefitolimod and bNAbs were overall safe, the CD4In conclusion, although there was no added benefit of combining a TLR9 agonist with bNAbs compared to bNAbs alone, this was, to our knowledge, the first placebo-controlled, double-blinded trial to show prolonged ART-free virologic control during ATI in individuals receiving just two doses of bNAbs. This finding provides further support for investigating bNAbs as a component in long-acting treatment and HIV-1 curative strategies. However, additional interventions, optimization of bNAbs and bNAb drug combinations | PMC10579101 | |
Methods | PMC10579101 | |||
Study design | This was a phase 2a, investigator-initiated, randomized, placebo-controlled, double-blinded international multicenter trial enrolling at six sites in Denmark (Aalborg, Aarhus, Gødstrup, Hvidovre, Odense and Rigshospitalet); one site in Oslo, Norway; and one site in Melbourne, Australia (EudraCT: | PMC10579101 | ||
Participants | PWH | PWH were aged 18–65 years and on ART for at least 18 months, with plasma HIV-1 RNA <50 copies per milliliter for at least 15 months and a CD4 T cell count >500 cells per mmThe sample size calculation was based on the primary endpoint: time to viral rebound during ATI. Time from stopping ART to loss of virological control was compared in the four randomization groups. If loss of virological control occurred, the date of the last measurement of plasma HIV-1 RNA ≥1,000 copies per milliliter or confirmed >100,000 copies per milliliter was defined as ‘date of viral rebound’. Using a two-sample comparison of means with an s.d. of 11 d | PMC10579101 | |
Randomization | The Clinical Trial Unit at Aarhus University generated the randomization sequence using permuted blocks of four or eight by computer-generated random numbers without stratification to sex and age. Randomization assignment was provided to each site using REDCap. | PMC10579101 | ||
Blinding | STERILE | Participants, study physicians and nurses handling administrations of the study drugs, as well as those individuals doing the analyses, were blinded to interventions. Only the pharmacy and study personnel preparing the study drugs were unblinded to interventions.The placebo for lefitolimod, 3BNC117 and 10-1074 was sterile physiological saline. Lefitolimod or placebo for lefitolimod was provided to the study physicians and nurses handling the injections as 4× 2-ml syringes. Placebo for 3BNC117 and 10-1074 or the bNAbs was administered by the study physicians and nurses handling the infusions as 250-ml piggy bags. Labeling contained only information of the study visit and an expiration date and time irrespective of either placebo or study drug. | PMC10579101 | |
Procedures | Lefitolimod or placebo was administered s.c. at a dose of 120 mg once weekly for the first 8 weeks from week −2 to week 5. Lefitolimod dosing was based on previously observed effects in clinical trials | PMC10579101 | ||
25-week analytical treatment interruption | At week 0, participants were instructed to discontinue ART the following day and continue off ART for 25 weeks unless one of four criteria was met. Details can be found in the study protocol. | PMC10579101 | ||
Plasma HIV-1 RNA measurements | Plasma HIV-1 RNA levels were measured with standardized clinical assays at every visit. After resumption of ART, we monitored plasma HIV-1 RNA every fourth week until levels were undetectable (<50 copies per milliliter). | PMC10579101 | ||
Doubling time of plasma HIV-1 RNA | REGRESSION | The initial increase in plasma HIV-1 RNA was calculated based on the first two consecutive plasma HIV-1 RNA measurements that increased, and the second measurement had to increase by 1,000 copies per milliliter compared to the previous measurement. The slope of this increase was calculated using a linear regression model. | PMC10579101 | |
bNAb sensitivity | bNAb sensitivity prediction was performed at screening for all participants primarily using the LabCorp–Monogram Biosciences PhenoSense HIV Monoclonal Antibody Assay on proviral HIV-1 DNA. bNAb sensitivity was a pre-specified inclusion criterion. For the PhenoSense assay, sensitivity was determined based on the concentration of bNAb required to inhibit viral replication by 90% (IC | PMC10579101 | ||
Proviral HIV-1 | For screening of participants who failed the PhenoSense assay and post hoc for all participants receiving the bNAb combination, SGA, sequencing and genotypic analysis were performed on proviral HIV-1 For participants in whom these primers did not amplify All primer sequences, an overview of which primer set was used for each of the included participants and thermal cycler conditions can be found in Supplementary Table The | PMC10579101 | ||
Rebound plasma HIV-1 | VIRUS | Plasma rebound virus was sequenced for participants who received bNAbs and rebounded within the study period or were viremic at the end of the 25-week ATI. Extraction of RNA, cDNA synthesis and SGA of plasma HIV | PMC10579101 | |
HIV-1 sequence assembly and annotation | Assembly and annotation of HIV-1 sequences was performed by The Rockefeller University pipeline (Defective and Intact HIV Genome Assembler) | PMC10579101 | ||
Sequence-based assessment of bNAb sensitivity | The HIV-1 | PMC10579101 | ||
Plasma antiretroviral drug concentrations | Antiretroviral drug concentrations in plasma were determined at BioXpedia using liquid chromatography with tandem mass spectrometry (LC–MS/MS) assay for individuals not fulfilling the criteria for viral rebound at week 13. Two timepoints were analyzed: (1) week 0 and (2) end of study, defined as the timepoint for reaching criteria for viral rebound or week 25, whichever came first. | PMC10579101 | ||
Serum bNAb concentrations | Each bNAb concentration in human serum was quantitatively measured using a sandwich immunoassay on Meso Scale Discovery Electrochemiluminescence (MSD-ECL) platform at PPD Bioanalytical Lab. In this assay, the bNAb was captured by biotinylated anti-idiotypic anti-bNAb antibody coated onto an MSD streptavidin plate, which was then detected by SULFO-TAG-conjugated anti-idiotypic anti-bNAb antibody. The plate was read on an MSD plate reader, resulting in assay signal proportional to the concentration of each bNAb. The method was validated following current regulatory guidance, and a sensitivity of 100 ng mWe used multiple imputation to impute missing values in serum bNAb concentrations. A detailed description can be found in Supplementary Table | PMC10579101 | ||
Intact HIV-1 proviruses | IPDA | The IPDA is used to measure intact and defective HIV-1 proviruses by targeting the Ψ and RRE, which are frequently deleted or mutated in defective provirusesRegardless of the downstream assay applied—IPDA, IPDA with alternative RRE primer/probe or IPDA-like 3dPCR—CD4 | PMC10579101 | |
HIV-1-specific T cell immunity | HIV-1-specific T cell immunity was assessed using the AIM assay by flow cytometry at weeks 0, 6, 13 and 25 after ATI. Aliquots of cryopreserved PBMCs were thawed, washed and rested at 37 °C for 3 h. Cells were then plated into wells of a 96-well plate at a total of 1 × 10 | PMC10579101 | ||
Cytokine detection | Cytokine detection of IFN-γ and GzmB were measured in supernatants from Gag and non-stimulated AIM assay using MSD U-PLEX Custom Immuno-Oncology (K151AEM-2) according to the manufacturer’s instructions. The concentration of IFN-γ (pg ml | PMC10579101 | ||
HLA class I typing | HLA class I (HLA-A, HLA-B and HLA-C) alleles were genotyped at the American Safety and Health Institute-accredited laboratory HistoGenetics using sequence-based typing. | PMC10579101 | ||
Outcomes | The primary endpoint was time to loss of virological control during ATI (sustained plasma HIV-1 RNA ≥1,000 copies per milliliter for 4 weeks or confirmed plasma HIV-1 RNA >100,000 copies per milliliter). Secondary endpoints were (1) safety, including CD4 | PMC10579101 | ||
Statistical methods | SECONDARY | The analyses performed on primary, secondary and exploratory endpoints were pre-specified in the protocol. Paired two-tailed Wilcoxon tests and two-tailed Mann–Whitney tests were used to analyze non-parametric outcomes within and between groups, respectively. When more than two groups were compared, the Kruskal–Wallis test was used. Data are presented as median (IQR), median (range) or mean ± s.d. as indicated in each respective figure legend. The Kaplan–Meier estimator was used to assess the magnitude of the difference between the survival curves, and the log-rank test was used to compare time to loss of virologic control during ATI between groups. For correlations, Spearman’s correlation coefficient was used. We used the full analysis set, comprising all individuals receiving at least one dose of active treatment with assessable data, for the efficacy analyses and all enrolled individuals for the safety analyses. We used Stata version 17.0 and Prism version 7.0 software for statistical analyses. | PMC10579101 | |
Reporting summary | Further information on research design is available in the | PMC10579101 | ||
Online content | Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02547-6. | PMC10579101 | ||
Supplementary information |
Supplementary Tables 1–7, Supplementary Fig. 1 and CONSORT 2010 checklist and study protocol: TITAN-001, version 3.0, 2 July 2021.Reporting Summary | PMC10579101 | ||
Extended data | PMC10579101 | |||
A comprehensive CONSORT Flow Diagram. | ADVERSE EVENT | ART, antiretroviral therapy; ATI, ART interruption; bNAb, broadly neutralizing antibody, SAE, severe adverse event.
| PMC10579101 | |
Time to plasma HIV-1 RNA above 50 and 1,000 copies/mL during 25 weeks of ATI. | (
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Plasma HIV-1 RNA kinetics for participants with partial and ongoing complete ART-free virologic control during the 25 weeks of ATI. | (
| PMC10579101 | ||
bNAb sensitivity at screening for the placebo/placebo and lefitolimod/placebo groups. | bNAb sensitivity was primarily analyzed using the PhenoSense Monoclonal Antibody Assay with predefined IC90 thresholds for 3BNC117 ( < 1.5 µg/mL) and 10-1074 ( < 2.0 µg/mL) and maximum percentage inhibition (MPI) ≥ 98%. In seven participants, the PhenoSense Assay failed, and we secondarily used proviral HIV-1 envelope (
| PMC10579101 | ||
Fraction and size of the defective HIV-1 proviruses. | Mean fraction of intact, 3′ and 5′ defective HIV-1 proviruses per 10
| PMC10579101 | ||
HIV-1-specific CD8+ and CD4+ immune responses during ATI. | (
| PMC10579101 | ||
Extended data | is available for this paper at 10.1038/s41591-023-02547-6. | PMC10579101 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02547-6. | PMC10579101 | ||
Acknowledgements | Neurological Disorders, Digestive, Stroke, Diabetes | INFECTIOUS DISEASES, LUNG, ALLERGY, STROKE, KIDNEY DISEASES, ABUSE, DIABETES, BLOOD, HEART, NEUROLOGICAL DISORDERS | We thank all study participants who devoted time to our research as well as every clinical research unit involved in the study. We acknowledge The Rockefeller University for providing 3BNC117 and 10-1074 and Mologen AG (now part of Gilead Sciences, Inc.) for providing lefitolimod. The funders were not involved in the study design/operations, data collection/analysis/interpretation or preparation of the manuscript. The study was funded through a Gilead HIV Cure grant to O.S.S. Study drugs were donated free of charge by The Rockefeller University (3BNC117 and 10–1074) and Mologen AG/Gilead Sciences, Inc. (lefitolimod) for use in this trial. J.D.G. is supported by the Lundbeck Foundation (R381–2021–1405). P.W.D. is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award P20 GM103427. Partial support for virologic analysis was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award R01AI47845 (RBJ), supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse and the National Heart, Lung, and Blood Institute. S.R.L. is supported by funding from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award UM1AI126611-01 and the National Health and Medical Research Council (NHMRC) of Australia (1135851 and 1149990). S.R.L. is an NHMRC Practitioner Fellow. O.S.S. is also supported by the Danish Council for Independent Research (grant 9060-00023B) and the Lundbeck Foundation (R313-2019-790). None of the specific sources of funding had any role in the conceptualization, design, data collection, analysis, decision to publish or preparation of the manuscript. | PMC10579101 |
Author contributions | H.N. | O.S.S. developed the trial design. J.F.H., M.H.P., P.W.D., M.T., M.C.N., M.C. and O.S.S. wrote the protocol. J.D.G., J.F.H., B.S., J.M., H.N., I.S.J., T.B., S.L., J.G., L.Ø., L.V., N.W., A.M.D.R., K.B.H.P., J.L., S.R.L., T.A.R., D.H.R. and O.S.S. did the clinical visits. J.D.G., M.H.P., M.R.U., M.H.S., R.O., D.C.C.J., N.L., T.T.H., V.R., R.B.J., M.T. and O.S.S. did the laboratory assays and validations. V.R. performed the bioinformatic analysis. J.D.G., M.H.P., M.R.U. and H.S. did the statistical analysis. J.D.G., M.H.P., M.R.U., P.W.D. and O.S.S. drafted the tables and figures. J.D.G. and O.S.S. drafted the article, which all authors critically revised for important intellectual content. J.D.G. and O.S.S. had full access to all the data in the study, verified the data and had final responsibility for the decision to submit for publication. | PMC10579101 | |
Peer review | PMC10579101 | |||
Data availability | Data are not available for download due to privacy/ethical restrictions under the European Union General Data Protection Regulation. Specific requests for access to the trial data may be sent to olesoega@rm.dk, and access may be provided to a named individual in agreement with the rules and regulations (All viral sequences have been deposited in GenBank with accession numbers | PMC10579101 | ||
Competing interests | M.C.N. is listed as an inventor on patents for the antibodies 3BNC117 and 10-1074. All other authors declare no competing interests. | PMC10579101 | ||
References | PMC10579101 | |||
Purpose | BREAST CANCER | To report the planning benchmark case results of the POTENTIAL trial—a multicenter, randomized, phase 3 trial—to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. | PMC10685528 | |
Methods | All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. | PMC10685528 | ||
Results | heart D | The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart D | PMC10685528 | |
Conclusion | The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials. | PMC10685528 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13014-023-02379-1. | PMC10685528 | ||
Keywords | PMC10685528 | |||
Background | breast cancer | BREAST CANCER | Regional nodal irradiation has been proven to benefit breast cancer patients with positive axillary nodes, and with negative axillary nodes and high-risk features [Pretrial quality assurance (QA) is very important in multicenter RT trials to guarantee uniform planning quality and enhance the reliability of outcomes [ | PMC10685528 |
Methods and materials | PMC10685528 |
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