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Results | Thirty patients were randomized into two groups: Surgery Group (SG, | PMC10017559 | ||
Conclusion | gastro-cutaneous fistula, post-LSG gastric leak | Endoscopic intervention may offer a successful modality in managing post-LSG gastric leak and gastro-cutaneous fistula that do not respond to conservative measures in stable patients. | PMC10017559 | |
Keywords | MORBID OBESITY | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).Laparoscopic sleeve gastrectomy (LSG) is one of the most performed surgical procedures for treatment of morbid obesity [ | PMC10017559 | |
Patients and methods | PMC10017559 | |||
Patients | gastric leak, fistula | MAY, SECONDARY, RECURRENCE | We included all bariatric patients who developed gastric leak or fistula after LSG either performed at the Department of Surgery, Zagazig University Faculty of Medicine or referred to our department between December 2019 and March 2021. While all included patients were of the American Society of Anesthesiologists (ASA) Physical status I–II, patients with ASA status III–IV or those who demonstrated a satisfactory response to the conservative measures were excluded (Patients with physical status III and IV were managed according to their general, condition, clinical status and radiological and endoscopic findings either by conservative measures or surgery). This prospective randomized controlled clinical trial was approved by Zagazig University Faculty of Medicine Institutional Review Board (Approval Number: 11130/2.12.2019) and performed in accordance with the code of ethics of the World Medical Association (Declaration of Helsinki) for studies involving human subjects. This study was retrospectively submitted in clinicaltrials.gov in May 2021 (NCT04879667). Written informed consent was obtained from all participants after explaining to them all the study procedures with its benefits and hazards.Included patients were randomized at a 1:1 ratio to “Surgery Group, SG” or “Endoscopic Group” via the drawing of sealed envelopes containing computer-generated random numbers prepared by a third party before the start of the intervention. Sample size was calculated using open Epi program using the following data: confidence interval 95%, power of test 80%, ratio of unexposed/exposed 1, percent of patients with successful management of persistent gastric leak or fistula by surgical intervention 50% and those with successful management by endoscopy 99%, odds ratio 99%, and risk ratio 2.Primary and secondary outcomes were recurrence of the fistula and mortality in each group after the intervention during the 3 months follow-up period, respectively. | PMC10017559 |
Diagnosis | gastric leak, fistula, gastro-cutaneous fistula | FREE FLUID | After full history taking and complete physical examination, post-LSG gastric leak was clinically suspected and then confirmed by laboratory investigations (complete blood picture, liver and kidney functions, coagulation profile), radiological imaging (chest X-ray, computed tomography (CT) with oral and I.V contrast) and upper GI endoscopy to assess the site, size and cause of the leak. We adopted a protocol of initial radiological or laparoscopic drainage according to the amount of intraperitoneal free fluid detected by CT scan, then endoscopically inserting a stent. If the leak did not satisfactorily respond to the initial measures within 6 weeks (recommended period of 5–8 weeks by the stent’s manufacturer and asa routine in our hospital for complete healing and easy extraction of the stent), a persistent gastric leak or fistula was considered, and the patient was evaluated for eligibility to be included in this study. The included eligible patients underwent another upper GI endoscopy to reconfirm site and size of the fistula, and CT abdomen with oral and I.V contrast to determine whether the fistula had a track (gastro-cutaneous fistula) or not (gastric leak). | PMC10017559 |
Intervention | Over-The-Scope, OverStitch, fistula | Patients, randomized to the endoscopy group, underwent endoscopic stenting (fully covered self-expanded metallic stent, FCSEMS) in case of gastric leak, endoscopic Over-The-Scope Clipping (OTSC, Ovesco Endoscopy AG, Tubingen, Germany) in case of gastric-cutaneous fistula, endoscopic suturing (OverStitch [ | PMC10017559 | |
Follow up after endoscopy and discharge from the hospital | DILATION | All patients were clinically examined, and laboratory checked during the hospital stay. Any suspected gastric leak post repair mandated CT scan with oral and I.V contrast and upper GI endoscopy. After discharge, patients who had undergone balloon dilation as a part of their repair procedure, were endoscoped every 4 weeks to continue the dilation till relief of distal pouch narrowing. Patients were followed-up for 18 months post repair. | PMC10017559 | |
Statistical analysis | Analysis of data was performed using SPSS (Statistical Package of Social Services) version 22. Quantitative variables were described as mean (± SD, standard deviation) and median (range) according to Shapiro test of normality. Qualitative variables were described as number and percentage. Chi-square test was used to compare qualitative variables between the two groups. Fisher exact test was used when one expected cell or more are less than five. Unpaired t-test was used to compare quantitative variables, in parametric data (SD < 30% of the mean). Mann Whitney test was used instead of unpaired | PMC10017559 | ||
Results | post-LSG leak, fistula, post-LSG gastric leak | Of 67 (12 and 55 post-LSG leak or fistula patients with primary surgery performed in our department and other centers, respectively) patients who presented with post-LSG leak or fistula, 30 patients (12/30 and 18/30 with primary LSG performed in our department and other centers, respectively) met the inclusion criteria for this study. The eligible 30 patients were randomized into two groups: SG and EG (Fig. Consort flow chartMean age of patients with post-LSG gastric leak or fistula was 42.3 ± 8.7 and 42.6 ± 8.3 years-old in SG and EG, respectively. Females constituted 73.3% (11/15) and 80% (12/15) of patients in SG and EG, respectively (Table Characteristics of the patientsOperative intervention and postoperative recurrenceHighly significant The observed incidence of recurrent gastric leak during the first week post-repair was significantly higher in SG than EG (No patients died in EG, while two patients died in SG and this difference was not statistically significant ( | PMC10017559 | |
Discussion | fits, fistula, gastro-cutaneous fistula, leaks, adhesions | RECURRENCE, COMPLICATION, STRICTURE, ANASTOMOTIC LEAK, DILATION, ADHESIONS | In general, the most frightful complication after bariatric surgery is the anastomotic leak with an incidence of 0.8–6% [In our department, we perform about 500 LSG/year, and the incidence of post-LSG leaks or fistula is about 2.5%. Surgical management of gastro-cutaneous fistula after laparoscopic sleeve gastrectomy has increased incidence rates of morbidity and mortality. In this study, we experienced high failure rate of surgical intervention (93.3%) within the first week post-repair (recurrence of fistula within one week in surgical group patients was due to long remaining sleeve pouch with axial rotation or marked narrowing of the pouch so, primary repair and gastrojejunostomy are usually associated with high recurrence rates of fistula because the main cause is not corrected, with axial rotation or marked narrowing of remaining pouch, the intra-gastric pressure increases and site of fistula opens again. This can be solved by classic Roux- en- y gastric bypass but not all patients are candidates for it, and also if the fistula occurred at upper third of the remaining pouch (most common site of fistula), the recurrence rate becomes high and classic Roux- en- y gastric bypass becomes difficult in case of upper third fistula due to marked adhesions and unhealthy remaining tissue at site of fistula). Immediate surgical intervention, with abdominal washout, irrigation, wide drainage and attempts for suturing of the leak if the tissues permit, may be preferred in unstable patients with early type leak [On the other hand, endoscopic intervention has become the corner stone in managing the post-LSG gastric leak or gastro-cutaneous fistula with different modalities such as stenting, clipping, balloon dilatation and endo-suturing. In our study, OTSC, along with dilation, was used in two patients (2/15 of endoscopic group), and none demonstrated clip migration or development of post-OTSC stricture over 3 months follow-up period. We started deploying the clips perpendicular to the long axis of the defect. If needed, multiple clips were placed sequentially, starting at either edge of the defect towards the center. Standard clips were passed through-the-scope to achieve superficial tissue apposition engaging the mucosa and submucosa (with 1.2 mm-wide and 6 mm-long arms capable of an approximately 12 mm grasp) and were used in conjunction with thermal ablation or mechanical scraping of the tissue around the edges of the defect to achieve a more resilient seal. In a retrospective study, OTSC demonstrated a lower success rate (50%) in managing GI fistulas in 30 patients (25/30 patients were post-bariatric surgery: 22 post-sleeve gastrectomy and three post-RYGB) with a median-time-to-OTSC delivery was 147 (range = 5–880) days [In this study, we used a fully covered stent (Mega stent, Taewoong Medical Industries, Gyeonggi-do, South Korea) ultra large and long (length: 24 cm, diameter: 36 mm) stent. We did not experience any complication with Mega stent, particularly migration, thanks to the design of Mega stent that fits well for the post-sleeve anatomy with reduction of migration. It completely covers the whole sleeve pouch and its lower end rests in the duodenum [OverStitching is theoretically an optimum method of leak closure because it is the only true full thickness leak closure and performed endoscopically despite being a complex procedure. In this study, OverStitching was used in 33.3% of patients who underwent endoscopic management. The procedure began with de-epithelialization of the edges of the leak using argon plasma coagulation before applying the OverStitching system. We did not experience post-OverStitch gastric leak. Granata et al. reported 77% success rate of endoscopic management of gastric leak using direct stitches only [This study has some limitations. The small sample size that may not give powerful statistical conclusions. Exclusion of patients with ASA status > II is another limitation. Regarding the de-epithelization of the edges of fistula either for OTSC or OverStitch, there was not a single method, and it was up to the endoscopist to use argon plasma laser or mechanical scrapping of the edges. Moreover, this study showed only 3 months follow-up period. The strength of the present study is being a randomized controlled trial and comparing different endoscopic interventions on one hand with the surgical intervention on the other hand. | PMC10017559 |
Author contributions | The manuscript has been read and approved by all the authors; the requirements for authorship have been met; each author believes that the manuscript represents honest work. SN, AF and AS were directly involved in the entire procedure and designed the clinical case. BM screened the literature MA and TA were responsible for data acquisition and creation of supplementary information files. SN, AF, BM and MA were involved in manuscript preparation. AA and EA were involved in critical revision, editing and reviewing of the paper. All authors read and approved the final manuscript. | PMC10017559 | ||
Funding | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). The authors Said Negm, Ahmed Farag, Ahmed Shafiq, Bassam Mousa, Taha Abdelkader, Mohamed Abozied, Adel Attia, Ehab Abdella no funding to declare. | PMC10017559 | ||
Data availability | MINOR | All data generated during this study are included in this published article and its supplementary information files. Further minor datasets are available from the corresponding author on reasonable request. | PMC10017559 | |
Declarations | PMC10017559 | |||
Disclosures | The authors Said Negm, Ahmed Farag, Ahmed Shafiq, Bassam Mousa, Taha Abdelkader, Mohamed Abozied, Adel Attia, Ehab Abdella declare that they have no competing interests. | PMC10017559 | ||
Ethical approval | MAY | The study was prospectively approved by Zagazig University Faculty of Medicine Institutional Review Board (Approval Number: 11130/2.12.2019), and was retrospectively submitted in clinicaltrials.gov in May 2021 (NCT04879667). The study was performed in accordance with the code of ethics of the World Medical Association (Declaration of Helsinki) for studies involving human subjects. | PMC10017559 | |
Informed consent | Written informed consent was obtained from all participants after explaining to them all the study procedures with its benefits and hazards. | PMC10017559 | ||
Consent for publication | Obtained. | PMC10017559 | ||
References | PMC10017559 | |||
Summary | Contributed equally and are co-first authorsContributed equally and are joint last authorsMembers are listed in the | PMC10682370 | ||
Background | VIRUS, INFLUENZA | The live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine (dNS1-RBD, Pneucolin; Beijing Wantai Biological Pharmacy Enterprise, Beijing, China) confers long-lasting and broad protection in animal models and is, to our knowledge, the first COVID-19 mucosal vaccine to enter into human trials, but its efficacy is still unknown. We aimed to assess the safety and efficacy (but not the immunogenicity) of dNS1-RBD against COVID-19. | PMC10682370 | |
Methods | ASYMPTOMATIC SARS-COV-2 INFECTION, DISEASE, CAVITY | We did a multicentre, randomised, double-blind, placebo-controlled, adaptive design, phase 3 trial at 33 centres (private or public hospitals, clinical research centres, or Centre for Disease Control and Prevention) in four countries (Colombia, Philippines, South Africa, and Viet Nam). Men and non-pregnant women (aged ≥18 years) were eligible if they had never been infected with SARS-CoV-2, and if they did not have a SARS-CoV-2 vaccination history at screening or if they had received at least one dose of other SARS-CoV-2 vaccines 6 months or longer before enrolment. Eligible adults were randomly assigned (1:1) to receive two intranasal doses of dNS1-RBD or placebo administered 14 days apart (0·2 mL per dose; 0·1 mL per nasal cavity), with block randomisation via an interactive web-response system, stratified by centre, age group (18–59 years or ≥60 years), and SARS-CoV-2 vaccination history. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary outcomes were safety of dNS1-RBD in the safety population (ie, those who had received at least one dose of dNS1-RBD or placebo) and efficacy against symptomatic SARS-CoV-2 infection confirmed by RT-PCR occurring 15 days or longer after the second dose in the per-protocol population (ie, those who received two doses, were followed up for 15 days or longer after the second dose, and had no major protocol deviations). The success criterion was predefined as vaccine efficacy of more than 30%. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100051391) and is completed. | PMC10682370 | |
Findings | deaths, rhinorrhoea, headache | ADVERSE REACTIONS, ASYMPTOMATIC SARS-COV-2 INFECTION, ADVERSE EVENTS, MAY, ADVERSE REACTION | Between Dec 16, 2021, and May 31, 2022, 41 620 participants were screened for eligibility and 31 038 participants were enrolled and randomly assigned (15 517 in the vaccine group and 15 521 in the placebo group). 30 990 participants who received at least one dose (15 496 vaccine and 15 494 placebo) were included in the safety analysis. The results showed a favourable safety profile, with the most common local adverse reaction being rhinorrhoea (578 [3·7%] of 15 500 vaccine recipients and 546 [3·5%] of 15 490 placebo recipients) and the most common systemic reaction being headache (829 [5·3%] vaccine recipients and 797 [5·1%] placebo recipients). We found no differences in the incidences of adverse reactions between participants in the vaccine and placebo groups. No vaccination-related serious adverse events or deaths were observed. Among 30 290 participants who received two doses, 25 742 were included in the per-protocol efficacy analysis (12 840 vaccine and 12 902 placebo). The incidence of confirmed symptomatic SARS-CoV-2 infection caused by omicron variants regardless of immunisation history was 1·6% in the vaccine group and 2·3% in the placebo group, resulting in an overall vaccine efficacy of 28·2% (95% CI 3·4–46·6), with a median follow-up duration of 161 days. | PMC10682370 |
Interpretation | Although this trial did not meet the predefined efficacy criteria for success, dNS1-RBD was well tolerated and protective against omicron variants, both as a primary immunisation and as a heterologous booster. | PMC10682370 | ||
Funding | Beijing Wantai Biological Pharmacy Enterprise, National Science and Technology Major Project, National Natural Science Foundation of China, Fujian Provincial Science and Technology Plan Project, Natural Science Foundation of Fujian Province, Xiamen Science and Technology Plan Special Project, Bill & Melinda Gates Foundation, the Ministry of Education of China, Xiamen University, and Fieldwork Funds of Xiamen University.
| PMC10682370 | ||
Research in context | respiratory infectious diseases | CORONAVIRUS, VIRUS, ADVERSE EVENT, INFLUENZA |
We searched PubMed for clinical trials published from database inception to June 27, 2023, with the following terms: “(intranasal OR nasal OR mucosal OR aerosolized OR inhaled) AND (coronavirus OR COVID-19 OR SARS-CoV-2) AND (vaccine) AND (clinical trial)”. No language restrictions were applied. In addition to dNS1-RBD reported in this Article, the results associated with two other mucosal vaccines have been reported in peer-reviewed clinical trials, but without information on their efficacy. In an open-label phase 1 trial (
To our knowledge, this study is the first to report efficacy data for an intranasal SARS-CoV-2 vaccine. We evaluated the safety and efficacy of dNS1-RBD with a two-dose regimen in this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The results indicated that dNS1-RBD was well tolerated, with no vaccine-related serious adverse event reported. This trial did not meet the predefined efficacy criteria for success, but based on efficacy data, it can be preliminarily inferred that dNS1-RBD provides sustained protection without a rapid decline (≥15 days with a median follow-up duration of 161 days).
There remains a need for clinical development of safe, broad-spectrum, and needle-free vaccines to protect against SARS-CoV-2 variants. As an intranasal SARS-CoV-2 vaccine developed using the ancestral SARS-CoV-2 strain, the available evidence suggests that the NS1-deleted and cold-adapted influenza virus vector-based SARS-CoV-2 vaccine is well tolerated and protects against COVID-19 caused by omicron variants. Our findings support the development of intranasal spray vaccines or other mucosal vaccines for respiratory infectious diseases and further investigation of the underlying protection mechanisms. | PMC10682370 |
Introduction | infections, respiratory mucosal SARS-CoV-2 vaccine | DISEASE, INFECTIONS | SARS-CoV-2 omicron sublineages have shown a strong ability to evade neutralising antibodies because of their continuous evolution.Although evidence indicates that a booster dose of existing SARS-CoV-2 vaccines provides sustained protection against severe disease or hospitalisation caused by omicron variants, the effectiveness against symptomatic infections rapidly wanes within 3–6 months of vaccination for the primary series and booster dose.The development of mucosal SARS-CoV-2 vaccines has been the subject of intense focus, owing to the advantage of inducing local immunity in the respiratory tract faster than effectors present in peripheral circulation.In December, 2022, dNS1-RBD obtained emergency use authorisation in China. We aimed to assess the safety and efficacy (but not the immunogenicity) of dNS1-RBD against COVID-19, representing a breakthrough in respiratory mucosal SARS-CoV-2 vaccine research. | PMC10682370 |
Methods | PMC10682370 | |||
Study design and participants | DISEASE | This multicentre, randomised, double-blind, placebo-controlled, case-driven, and adaptive design phase 3 trial was done at 33 sites (private or public hospitals, clinical research centres, or Center for Disease Control and Prevention) in Colombia, the Philippines, South Africa, and Viet Nam (Participants in South Africa and Viet Nam were limited to those who had previously received one or more doses of SARS-CoV-2 vaccines due to the requirements of national regulatory authorities. On March, 2022, an addendum was added to the protocol (version 2.0, dated Aug 10, 2021) to include individuals in Viet Nam who had received the last vaccine dose 3–6 months before signing the informed consent, because a nationwide mass booster SARS-CoV-2 vaccination campaign was being carried out.The trial protocol, the written informed consent form, and other materials related to the participants were approved by the ethics committees at all sites. The trial was done in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. The study protocol is available in the | PMC10682370 | |
Randomisation and masking | All enrolled participants were randomly assigned (1:1) to receive two doses of either the dNS1-RBD vaccine or placebo. Block randomisation was done at each study centre by trained blinded investigators using an interactive web-response system, stratified according to centre, age group (18–59 years or ≥60 years), and the presence or absence of any previous SARS-CoV-2 vaccination. The unblinded statistician from the contract research organisation (Hangzhou Tigermed Consulting, Hangzhou, China) who designed the randomisation plan and generated the block randomisation codes was not involved further in the trial.The vaccine and placebo were identical in appearance. To prevent cross-contamination between the vaccine and placebo groups during administration, which has been reported previously, | PMC10682370 | ||
Procedures | sore throat, nausea or vomiting, diarrhoea, myalgia, delirium, fatigue, fever, dysfunction of arousal and content); (2), dementia, cough, loss of taste or smell, rhinitis, infection, coma, headache, depression, shortness of breath | SORE THROAT, SARS-COV-2 INFECTION, LACK OF APPETITE, ADVERSE EVENTS, ASYMPTOMATIC SARS-COV-2 INFECTION, INFECTION, RHINITIS, ADVERSE EVENT, COMA, EVENTS | The vaccine dNS1-RBD was a liquid preparation, containing 1 × 10All participants were observed for at least 30 min after vaccination for any acute reactions and were trained to record any local and systemic events using a diary card. Monitoring for adverse events included spontaneous reporting from participants and telephone contacts by investigators (once a week for 30 days after each dose for any adverse event, and at least once every 4 weeks after that for serious adverse events, medically attended adverse events, and adverse events of special interest). Definitions of these adverse events are provided in the After the first dose, all participants were monitored for suspected symptoms of COVID-19 by the investigators once per week for the entire efficacy observation period, via telephone or a visit within 30 days, and via telephone after 30 days. Suspected SARS-CoV-2 infection was defined as the presence of one or more of the following: (1) at least two symptoms, persisting for 2 days or longer, which included fever (oral temperature ≥38·0°C or axillary temperature ≥37·8°C), sore throat, generalised weakness or fatigue, rhinitis, myalgia, headache, lack of appetite, nausea or vomiting, diarrhoea, and mental status changes; changes in mental status were described as delirium (acute change in arousal and content), depression (chronic change in arousal), dementia (chronic change in arousal and content), and coma (dysfunction of arousal and content); (2) at least one respiratory sign or symptom, including cough (persisting for ≥2 days), loss of taste or smell (persisting for ≥2 days), and shortness of breath; or (3) clinical or imaging evidence of COVID-19. Once a suspected case was identified by a clinician or clinically qualified investigator, two nasopharyngeal swab samples were simultaneously collected (preferably within 72 h), with one swab sent to the central laboratory (Cerba Research, Paris, France) and the other to a local laboratory near each site or centre if in Colombia, South Africa, and Viet Nam, or to a local professional agency if in the Philippines (Detoxicare, Manila, Philippines). Clinical follow-up was guided by immediate RT-PCR results from the local laboratory. When the initial test result of the sample was negative but symptoms persisted, a second sampling was taken within 3–5 days. When the test result was positive, subsequent sampling occurred every 7–10 days until a negative result was obtained and symptoms resolved. We defined participants with a confirmed symptomatic SARS-CoV-2 infection as those with a suspected infection (according to the aforementioned criteria) who had at least one RT-PCR-positive nasopharyngeal swab tested by the central laboratory. Further details of the monitoring procedures, definition, and classification criteria of symptomatic SARS-CoV-2 infection according to WHO and China's National Health Commission are provided in the | PMC10682370 |
Outcomes | deaths, clear chronic disease | ADVERSE EVENTS, ADVERSE EVENT, ASYMPTOMATIC SARS-COV-2 INFECTION, SECONDARY | The specific details regarding the safety and efficacy analyses were prespecified in the statistical analysis plan (version 2.0, dated Dec 6, 2022), which was finalised before data locking. The primary safety endpoints were solicited adverse events and reactions occurring within 7 days of either dose; adverse events and reactions occurring within 30 days of any dose; and serious adverse events, medically attended adverse events, and adverse events of special interest from the first dose (ie, day 0) to 12 months after the second dose.Adverse events were graded according to the China National Medical Products Administration (NMPA) guidelines (The primary efficacy endpoint was symptomatic SARS-CoV-2 infection confirmed by RT-PCR occurring 15 days or longer after the second dose. The secondary efficacy endpoints were virologically confirmed symptomatic SARS-CoV-2 infection of any severity in participants with or without a history of SARS-CoV-2 vaccination; in individuals of different age groups (18–59 years and ≥60 years); and in those with clear chronic disease; number of individuals with severe and critical COVID-19; and deaths from COVID-19. All secondary efficacy endpoints were assessed at 15 days or longer after the second vaccination.Due to the low number of individuals with COVID-19 we observed and ongoing virological-related studies, some of the prespecified exploratory endpoints ( | PMC10682370 |
Statistical analysis | ADVERSE EVENTS, DISEASE | In accordance with the 2020 WHO guidelines,The originally planned interim analysis was scheduled to be done when the number of individuals for the primary efficacy endpoint reached 75 (The safety data were collected for 12 months after the final dose (ie, safety observation period; completed on June 30, 2023), whereas the efficacy analysis was case driven and the observation period for efficacy endpoints (ie, the primary efficacy analysis was triggered once the number of cases for the primary endpoint reached 150; The safety analysis population comprised all participants who had received at least one dose of dNS1-RBD or placebo, and it was based on the actual administrations, correcting for vaccination errors. The primary efficacy analysis included the per-protocol population. Additional prespecified efficacy analyses were performed in the modified intention-to-treat population (ie, all randomly assigned patients who received two doses and were followed up for 15 days or longer after the second dose; listed in the protocol as mITT2).The rate difference, defined as the difference in incidence of adverse events or reactions between the vaccine group and the placebo group, was used in the safety analysis to compare the safety profile of the vaccine and placebo. For each rate difference, we estimated the 95% CIs using the Wilson score method. We also did prespecified subgroup analyses of the safety endpoints by age group (18–59 years We also did analyses to assess vaccine efficacy in the short term (15–90 days; prespecified) and estimate the incidence of hospitalisation among participants who received at least one dose (post hoc). To further differentiate the severity of COVID-19 in non-hospitalised individuals or those with mild disease, we quantified disease severity according to the number of suspected symptoms in a post-hoc analysis, which was defined as omicron symptom index (Independent statisticians from the contract research organisation (Hangzhou Tigermed Consulting) did all the analyses using SAS (version 9.4). An independent data monitoring committee was responsible for safeguarding trial participants, assessing safety during the trial period, and reviewing data after the final analysis. A blinded independent endpoint adjudication committee confirmed the endpoints and determined the severity of COVID-19 on the basis of clinical manifestation and related data. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2100051391). | PMC10682370 | |
Role of the funding source | The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. | PMC10682370 | ||
Results | infection, rhinorrhoea | ADVERSE REACTIONS, ADVERSE EVENTS, ADVERSE EVENT, DISEASE, ASYMPTOMATIC SARS-COV-2 INFECTION, MAY, INFECTION, BLIND | Between Dec 16, 2021, and May 31, 2022, 41 620 participants were screened for eligibility, of whom 31 038 were enrolled and randomly assigned (17 210 with a history of SARS-CoV-2 vaccination and 13 828 without; 15 517 in the vaccine group and 15 521 in the placebo group). 30 990 participants received at least one dose of the vaccine or placebo, including 17 176 participants with a history of SARS-CoV-2 vaccination and 13 814 participants without (Trial profile*The 384 Colombian participants without previous SARS-CoV-2 vaccinations who received at least one dose were excluded from the primary efficacy analysis during the blind data review meeting for this trial because the sample size from each site was too small. †An addendum was made to the protocol to permit the enrolment of individuals in Viet Nam who received their last vaccine dose 3–6 months before signing the informed consent because of the ongoing national SARS-CoV-2 vaccine booster campaign, but these participants were not included in the primary efficacy analysis. ‡Eight participants had vaccination errors. Five participants (four with previous SARS-CoV-2 vaccinations and one without) were assigned to the placebo group but received at least one dose of dNS1-RBD, and were included in the vaccine group for the safety analysis; one participant without previous SARS-CoV-2 vaccinations who was assigned to the vaccine group but received two doses of placebo was included in the placebo group for the safety analysis; and two participants with previous SARS-CoV-2 vaccinations who were assigned to the vaccine group but received one dose of placebo and one dose of vaccine were included in the vaccine group for the safety analysis.Extreme difficulty in recruiting participants without previous SARS-CoV-2 vaccination in Colombia resulted in a smaller sample size than initially planned. 389 participants without a SARS-CoV-2 vaccination history were enrolled from eight centres (sample size range 4–159) who received at least one dose in this trial. A small sample size in each centre in Colombia might have resulted in additional uncertainties and confounding factors between treatment groups when the incidence of target disease is extremely high and fluctuates rapidly, and the independent randomisation done at each centre might lead to an uneven distribution of participant characteristics across the groups. In addition to the small sample size, there was also an increased possibility of false negative SARS-CoV-2 antibodies results at baseline due to an omicron (BA.1 and BA.2) outbreak in the country before enrolment. Because of the small sample size and possibility of false negatives, 389 Colombian participants (including eight participants with confirmed COVID-19) were excluded from all efficacy analyses (five of them were excluded firstly because they did not receive the second dose; The median efficacy follow-up was 161 days (IQR 111–189), with an overall dropout rate of 2·2% (668/30 990) and no significant differences between the two groups (Demographic and baseline characteristics in participants who received at least one doseData are median (IQR) or n (%). Percentages might not total 100% because of rounding.Participants who received at least one dose of vaccine or placebo, based on randomised grouping information, not adjusted for actual administrations (ie, without correcting for vaccination errors).Undifferentiated sex means that sex cannot be determined on the basis of physiological characteristics.Underlying chronic conditions were those that were ongoing at baseline and could increase the risk of SARS-CoV-2 infection.30 participants had a positive test result for SARS-CoV-2 antibodies but were accidentally enrolled and categorised as participant without a SARS-CoV-2 vaccination history.30 990 participants were included in the safety analysis set. Overall, adverse reactions including local and systemic were largely absent or mild (ie, about 96% of adverse reactions were grade 1 or 2; Adverse events and reactions that occurred after any dose in the safety populationData are n (%), unless otherwise stated. Any refers to all participants with any grade of adverse events or reactions. NA=not applicable.Participants who received at least one dose of vaccine or placebo, based on actual administrations.Among all vaccine recipients, the most commonly reported local solicited adverse reactions were rhinorrhoea (578 [3·7%] of 15 500 participants in the vaccine group Solicited local and systemic adverse reactions that occurred within 7 days after any dose in the safety population*Incidence and severity of local and systemic adverse reactions in participants without a previous SARS-CoV-2 vaccination history (A) and in those with a SARS-CoV-2 vaccination history (B). All adverse reactions were graded according to the China National Medical Products Administration guidelines. *Participants who received at least one dose of vaccine or placebo.No difference was observed in the occurrence of adverse events and reactions between participants in the vaccine and placebo groups in all prespecified subgroups, including older recipients (aged ≥60 years) and participants with underlying chronic conditions at baseline (Among the 30 290 participants who received two doses, 25 742 were included in the per-protocol population for efficacy analysis (Regarding the primary efficacy endpoint, regardless of baseline immunisation history, the two-dose vaccine efficacy in the per-protocol population against confirmed symptomatic SARS-CoV-2 infections during the efficacy observation period was 28·2% (95% CI 3·4 to 46·6; Vaccine efficacy 15 days or more after the second dose in the per-protocol population* and in the modified intention-to-treat population†The vertical line at 30% shows the prespecified vaccine efficacy target. *Participants who received two doses of vaccine or placebo, were followed up for 15 days or longer after the second dose, and had no major protocol deviations. †Participants who received two doses of vaccine or placebo and were followed up for 15 days or longer after the second dose.During the efficacy observation period, five participants in the placebo group (none in the vaccine group) were hospitalised (WHO score ≥4) with onset at any time after the first dose (In a post-hoc analysis of individuals with more typical symptomatic SARS-CoV-2 infections who reported three or more suspected symptoms (omicron symptom index ≥3), 125 participants were included (47 in the vaccine group and 78 in the placebo group). Among participants in the per-protocol population, the vaccine efficacy against typical symptomatic SARS-CoV-2 infections during the efficacy observation period (≥15 days) was 39·6% (95% CI 13·3 to 57·9), whereas the efficacy within 3 months (15–90 days) of the second dose was 42·3% (15·7 to 60·5). During the efficacy observation period, vaccine efficacy against typical infection was 56·3% (–6·3 to 82·0) in participants without a SARS-CoV-2 vaccination history and 35·1% (3·4 to 56·4) in those with a SARS-CoV-2 vaccination history ( | PMC10682370 |
Discussion | infection, death, –27·7, pain | VIRUS, ASYMPTOMATIC SARS-COV-2 INFECTION, DISEASE, INFECTION, DISEASES, INFLUENZA | To our knowledge, this study is the first report on the efficacy of a mucosal SARS-CoV-2 vaccine in a large-scale phase 3 trial. The favourable safety profile observed in early phase clinical trialsCompared with parenteral injection, intranasal vaccination offers the advantages of being needle-free and non-invasive, thereby eliminating the pain and fear commonly associated with administration. Moreover, our study has shown the safety of the dNS1-RBD intranasal spray vaccine, including in older people (aged ≥60 years), in individuals with underlying medical conditions, and in those with respiratory or nose-related diseases. The widespread acceptance and ease of administration of intranasal vaccination hold promise for diminishing vaccine hesitancy and extending immunisation coverage during viral outbreaks, thereby alleviating disease burden, especially among vulnerable populations.Although currently licensed SARS-CoV-2 vaccines might be effective against severe disease or death caused by some SARS-CoV-2 variants,To date, efficacy data from randomised controlled clinical trials conducted during the omicron-dominant phase have rarely been reported, and those available mostly assessed vaccine efficacy in SARS-CoV-2 naive children (without infection or vaccination history). In the observer-blinded, placebo-controlled trial of mRNA-1273 (elasomeran, Spikevax; Moderna Biotech, Cambridge, MA, USA) published in 2022, the vaccine efficacy at around 70 days after the second dose against symptomatic SARS-CoV-2 infection caused by omicron (B.1.1.529) was 46·4% (95% CI 19·8 to 63·8) in children aged 2–5 years and 31·5% (–27·7 to 62·0) in children aged 6–23 months, which are lower than that against previously circulating variants of concern.The most crucial challenge faced in the ongoing control of COVID-19 is the need for annual re-vaccination with updated formulations of the vaccines that often do not keep up with the rapid pace of viral variation.Nonetheless, the development of mucosal SARS-CoV-2 vaccines encounters challenges. First, the complexity of local mucosal immune responses poses a challenge in comprehending the mechanisms by which dNS1-RBD elicits broad protection. Second, the lack of validated sampling and detection methods for assessing cellular immunological markers in respiratory tracts has impeded the identification of immunological markers strongly associated with protection. In early human clinical trials,Evidence suggests that the first infection and replication of SARS-CoV-2 occurs in the nasal epithelium,This trial has several limitations. First, it was not powered to assess efficacy against severe disease due to the small number of participants with severe COVID-19. We did not anticipate that the omicron sublineages would have stronger transmissibility and immune escape ability, but substantially attenuated pathogenicity.In conclusion, although this clinical trial did not meet the predefined efficacy criteria for success, we have shown the potential of this intranasal spray influenza virus vector-based SARS-CoV-2 vaccine as a safe and broad-spectrum next-generation vaccine. In-depth studies, such as real-world studies and mechanistic research, are ongoing. | PMC10682370 |
Data sharing | The study protocol is available for review. The data in this Article will be available after publication and finalisation of the complete clinical study report for at least 6 months. Researchers who provide a scientifically sound proposal will be allowed to access the de-identified individual participant data. Proposals should be sent to the corresponding author TW ( | PMC10682370 | ||
Declaration of interests | JJ | JT, JJ, and XC were employees of Beijing Wantai Biological Pharmacy Enterprise during the conduct of the study. JH and XY are employees of and have stock options in Beijing Wantai Biological Pharmacy Enterprise. All other authors declare no competing interests. | PMC10682370 | |
References | PMC10682370 | |||
Supplementary Material | PMC10682370 | |||
Supplementary appendix | PMC10682370 | |||
Acknowledgments | This study was funded by Beijing Wantai Biological Pharmacy Enterprise, and was also funded by the National Science and Technology Major Project (2020YFC0842600), the National Natural Science Foundation of China (82041038), the Fujian Provincial Science and Technology Plan Project (2020YZ014001 and 2022L3081), the Natural Science Foundation of Fujian Province (2020J06007 and 2021J02006), the Xiamen Science and Technology Plan Special Project (2022CXY0103 and 2022CXY0106), the Bill & Melinda Gates Foundation (INV-005834), intramural special grants for SARS-CoV-2 research from Ministry of Education and Xiamen University, and the Fieldwork Funds for graduate students of Xiamen University (2022FG020). We thank the participants who volunteered to be part of this study; the investigators at each site; and the members of the endpoint adjudication committee (Wenhong Zhang, Yuanlin Song, and Xiangyang Yao) and the independent data monitoring committee (Jielai Xia, Aiqiang Xu, and Jiming Zhang). | PMC10682370 | ||
Contributors | JJ | TW, JZ, and NX made the development plan of the vaccine, designed the study protocol, and monitored the trial. FZ was the global principal investigator of this trial. AMJ, THD, JGP, AGD, LST, GMAZ, REMV, GPG, LLGB, and SPIP were the principal investigator of each site and managed the participants. SH, XL, QC, CZ, JH, JT, KZ, JQ, HL, JJ, and XC supervised the trial. FZ, SH, XL, QC, CZ, YS, TW, JZ, and NX have accessed and verified all the data in the study. QC, CZ, YS, TW, and JZ did the statistical analysis. HZ, JH, JC, YC, CL, and XY provided consultation for the investigational product. CZ, YH, TZ, and TW drafted the manuscript; TW, JZ, and NX reviewed the manuscript. All authors read and approved the final version of the manuscript for submission. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. | PMC10682370 | |
Abstract | PMC10417173 | |||
Background | breast cancer | DISEASE, BREAST CANCER | Patients' lack of knowledge about their own disease may function as a barrier to shared decision‐making and well‐being. This study aimed to evaluate the impact of written educational materials on breast cancer patients. | PMC10417173 |
Methods | BREAST CANCER DIAGNOSIS | This multicenter, parallel, unblinded, randomized trial included Latin American women aged ≥18 years with a recent breast cancer diagnosis yet to start systemic therapy. Participants underwent randomization in a 1:1 ratio to receive a customizable or standard educational brochure. The primary objective was accurate identification of molecular subtype. Secondary objectives included identification of clinical stage, treatment options, participation in decision‐making, perceived quality of information received, and illness uncertainty. Follow‐up occurred at 7–21 and 30–51 days post‐randomization. ClinicalTrials.gov identifier: NCT05798312. | PMC10417173 | |
Results | breast cancer | DISEASE, BREAST CANCER | One hundred sixty‐five breast cancer patients with a median age of 53 years and 61 days from diagnosis were included (customizable: 82; standard: 83). At first available assessment, 52%, 48%, and 30% identified their molecular subtype, disease stage, and guideline‐endorsed systemic treatment strategy, respectively. Accurate molecular subtype and stage identification were similar between groups. Per multivariate analysis, customizable brochure recipients were more likely to identify their guideline‐recommended treatment modalities (OR: 4.20, | PMC10417173 |
Conclusions | breast cancer | DISEASE CHARACTERISTIC, BREAST CANCER | Over one third of recently diagnosed breast cancer patients are incognizant of their disease characteristics and treatment options. This study demonstrates a need to improve patient education and shows that customizable educational materials increase patients' understanding of recommended systemic therapies according to individual breast cancer characteristics.
Cynthia Villarreal‐Garza and Ana S. Ferrigno: co‐first authors. | PMC10417173 |
INTRODUCTION | tumor, breast cancer | DISEASE, TUMOR, BREAST CANCER | Optimal treatment strategies and prognosis of breast cancer are largely dictated by three variables: molecular subtype, disease stage, and patient preferences.Limited data have been published regarding the knowledge level of breast cancer patients about their diagnosis. It has been reported that 13%–65% of patients do not know whether their tumor is hormone sensitive, 34%–70% are unaware of their HER2 status, and 28%–49% do not know their disease stage.Previous studies have demonstrated the feasibility and utility of educational interventions to improve breast cancer patients' awareness of their disease. | PMC10417173 |
MATERIALS AND METHODS | PMC10417173 | |||
Patient selection | intellectual disability | DEL, BREAST CANCER DIAGNOSIS, RECRUITMENT | This study is a parallel‐arm, multicenter, international, unblinded, randomized clinical trial. Women aged ≥18 years with a recent breast cancer diagnosis (i.e., <6 months) who were yet to start systemic therapy (i.e., chemotherapy, hormone therapy, anti‐HER2 agents, and immunotherapy) were eligible to participate if they were scheduled for their first medical oncology appointment on which they would discuss their systemic therapy options. Exclusion criteria included known intellectual disability and inability to read or write.Participant recruitment was undertaken in eight centers: Hospital Zambrano Hellion, San Pedro Garza Garcia, Mexico (05/2021–03/2022); Hospital Regional del Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Leon, Mexico (05–12/2021); Hospital de Gineco‐Obstetricia No. 4 “Luis Castelazo Ayala,” Mexico City, Mexico (10–12/2021); Unidad Medica de Alta Especialidad del Instituto Mexicano del Seguro Social, Merida, Mexico (08/2021–02/2022), Centro Médico Nacional de Occidente, Guadalajara, Mexico (11/2021–03/2022), Centro de Educación Medica e Investigaciones Clínicas “Norberto Quirno,” Buenos Aires, Argentina (01–03/2022), Hospital General de Mexico, Mexico City, Mexico (09/2021–02/2022), and Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru (10–12/2021). All consecutive, eligible patients were invited to participate. Those who consented were randomized in a 1:1 ratio in blocks of two, four, or six patients using the Sealed Envelope websiteSample size was calculated hypothesizing the proportion of patients that correctly identified their molecular subtype would be 20% greater in the customizable brochure group compared to the standard brochure group. A total of 194 participants were deemed necessary to detect a 20% difference with a power of 80% and an alpha of 0.05. Patient recruitment phase ended once the anticipated number of participants needed was achieved. | PMC10417173 |
Educational brochures | cancer, breast cancer | CANCER, BREAST CANCER | Educational brochures were developed by a multidisciplinary team comprised of a medical oncologist and a surgeon specialized in breast cancer, two clinical researchers, and a group of graphic designers with experience in educational materials for oncologic patients. Team members performed a pilot of the customizable brochure in a total of 27 patients from four healthcare centers to test for comprehension and perceived utility. Patients' opinions and feedback were incorporated into the design and content of the brochures. All members of the team and two psychologists specialized in caring for cancer patients approved the final versions. Both brochures contain the same educational content, explaining in lay terms what is breast cancer | PMC10417173 |
Follow‐up | DISEASE | Patients who consented to participate were asked to complete seven questionnaires either in‐person, by telephone, or email. Study coordinators were instructed not to suggest whether or how participants might use the brochure while answering study surveys. Three of the questionnaires were answered 7–21 days after having received the allocated brochure: (1) a multiple‐choice survey with two sections: sociodemographic and disease knowledge. The sociodemographic information included age, educational attainment, and employment status. The knowledge section asked patients to identify their clinical stage, molecular subtype, and appropriate systemic treatment options. All items in the knowledge section included “I don't know” as a possible answer; (2) a survey to evaluate participants' perception of the utility of their educational brochure on a four‐point Likert‐type scale; (3) the third survey was the European Health Literacy Survey Questionnaire—short version (HLS‐EU‐Q16) in Spanish to evaluate participants' understanding and communication of medical information.The four remaining questionnaires were answered 30–51 days after brochure receipt: (1) the knowledge section of the first survey was repeated to evaluate information retention; (2) the second survey was the 9‐item Shared Decision‐Making Questionnaire (SDM‐Q‐9) developed by Kriston et al., | PMC10417173 | |
Statistical analysis | DEL | All analyses were performed using R statistical (version 4.1.0, R Project for Statistical Computing) and RStudio (version 1.4.1717, R Foundation for Statistical Computing) software. Descriptive statistics were undertaken using frequency and proportions for categorical variables, and median and 95% confidence interval (95% CI) for quantitative variables. Fisher's exact and Mann–Whitney This trial was approved by the institutional review board of Escuela de Medicina del Instituto Tecnologico y de Estudios Superiores de Monterrey (protocol ID: P000329‐IMAP‐CM‐CEIC‐CR003) and was reviewed by appropriate authorities of each participating center. The protocol was conducted in accordance with The Code of Ethics of the World Medical Association and informed consent was obtained from each participant prior to inclusion. The complete study protocol is available from the corresponding author upon reasonable request. | PMC10417173 | |
RESULTS | PMC10417173 | |||
Participant characteristics | A total of 205 consecutive patients were eligible to participate (Figure Participant flow diagram.Table Sociodemographic and clinical characteristics of participants.
Abbreviations: HER2, human epidermal growth factor receptor 2; HLS‐EU‐Q16, European Health Literacy Survey Questionnaire, short version; HR, hormone receptor. | PMC10417173 | ||
Participant knowledge regarding breast cancer | REGRESSION, DISEASE, DISEASE CHARACTERISTIC | Participants' knowledge about their diagnosis and guideline‐recommended therapy was evaluated twice. A total of 141 patients completed the survey at the first prespecified timepoint after a median of 18 days (95% CI 15–19) since randomization and receipt of their corresponding brochure. One hundred forty‐nine participants completed the survey at the second‐prespecified timepoint after a median of 45 days (95% CI 42–48.7) from intervention allocation. At the first knowledge assessment available for each participant (median of 19 days [95% CI 18–20] post‐randomization), 75 of 157 respondents (48%) correctly identified their disease stage, 85 of 165 patients (52%) identified their molecular subtype, and 44 of 148 respondents (30%) accurately identified the systemic therapies they were eligible for according to their individual disease characteristics.A total of 125 (76%) participants answered the knowledge survey at both prespecified follow‐up periods. Overall, the proportion of patients that correctly identified their clinical stage improved upon second assessment (45% vs. 76%, Proportion of patients that correctly identified their clinical stage, molecular subtype, and systemic treatment options according to their disease characteristics on the first (left) and second (right) assessment. The colored lines between assessments represent the change in response between assessments, weighted according to the proportion of participants. Represented in green are participants that answered accurately, in yellow those that responded “I don't know,” and in red those that answered inaccurately in the second assessment.Table Participants' knowledge about their diagnosis and treatment options according to their disease characteristics at first and second assessment.
Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor.Bold values are statistically significant Univariate logistic regression analyses were performed to assess factors associated with identification of clinical stage, molecular subtype, and systemic therapy options per individual disease characteristics in the first knowledge survey available (Table Univariate logistic regression analyses.Abbreviation: OR, odds ratio.Bold values are statistically significant | PMC10417173 | |
Participant satisfaction with the educational brochure | In terms of satisfaction with the brochure received, the only statistically significant difference observed was in perception that the brochure helped patients participate in treatment decisions (patients who selected “strongly agree” in the customizable brochure group: 60% vs. standard: 42%, Participant satisfaction with the educational brochure received.
A total of 141 participants answered the QLQ‐INFO25 questionnaire. The global score was similar in patients that received a customizable brochure and those who received a standard brochure (median score 55.6 [95% CI 48.5–58.4] vs. 54.7 [95% CI 48.4–56.5], In terms of illness uncertainty, there was no difference according to the brochure received (median score 67 [95% CI 62–74] in the customizable group vs. 73 [95% CI 66.4–76.8] in the standard group, | PMC10417173 | ||
DISCUSSION | tumor, breast cancer | TUMOR, BREAST CANCER, AIDS, DISEASE, DISEASE CHARACTERISTIC | In this study, approximately half of recently diagnosed, Latin American breast cancer patients were able to correctly identify their disease stage or molecular subtype. Furthermore, only one third of participants identified which systemic treatments were recommended according to their individual tumor characteristics. These findings underscore the need to improve information provision and promote breast cancer patient education. In the research protocol, a customizable brochure was hypothesized to result in improved identification of molecular subtype by encouraging a dialog between patients and their treating physicians when identifying the options applicable to each case. However, no statistical differences were observed in patient knowledge about their molecular subtype or clinical stage at diagnosis according to the type of educational brochure received. Therefore, the hypothesis that the proportion of patients who would identify their molecular subtype with the customizable brochure would be 20% greater than the standard group was not met. Notably, patients allocated to the customizable brochure were significantly more likely to identify which systemic therapy they should receive according to their disease characteristics and perceived a stronger agreement that the brochure helped them participate in treatment decisions. This suggests that personalizing written materials was an effective tactic to enhance their educational value, possibly by stimulating shared‐decision making between patients and their treating physicians.Previous studies have demonstrated that patient education interventions can enhance breast cancer patients' knowledge and comprehension. Buscemi et al. developed a culturally tailored smartphone application for Hispanic patients and found that its use was associated with a significant improvement in general breast cancer knowledge in this population.Patient knowledge regarding individual characteristics of their breast cancer can improve their understanding on recommended treatment strategies (e.g., hormone therapy in cases of hormone‐sensitive disease or trastuzumab in cases with HER2 amplification), which can lead to guideline‐endorsed treatment decisions and greater therapeutic adherence.This study has limitations to consider when interpreting the results. First, the study is underpowered to detect subtle differences according to the type of brochure received. Second, no multiple comparison correction was undertaken. Third, the sample studied is not representative of all Latin America and the results cannot be generalized. Fourth, because of the nature of the intervention, blinding of participants and treating physicians was not possible. Fifth, clinicians at participating centers were aware that patient knowledge was being assessed and it is possible that they might have been more inclined to emphasize disease characteristics. Sixth, due to participant attrition and nonresponse throughout the protocol, nonresponder bias cannot be excluded. Seventh, improvement in knowledge about their disease directly after receiving each of the brochures was not assessed as no pre‐intervention questionnaires were applied. Eight, patients assigned to the customizable educational brochure were encouraged to personalize their material with the assistance of healthcare providers, but mandatory discussion of brochures with the treating physicians was not enforced. Hence, patients assigned to customizable brochures might not have filled out the material or might have done so incorrectly if they did not discuss the contents with a physician, potentially underestimating the true utility of this type of written educational material.Although patients were not involved in the development of the content of the educational material, they were interviewed to identify whether the vocabulary employed in the brochures was comprehensible and to evaluate the general perception of its utility. Their feedback and comments were incorporated into the final version of the brochure. Noteworthy, the purpose of this project was not to propose this brochure as a standard to be widely used, but to demonstrate that a customizable, educational material aids patients. The results are in line with this objective and affirm the usefulness of providing customizable, educational materials to patients. | PMC10417173 |
CONCLUSION | tumor, breast cancer | DISEASE, TUMOR, BREAST CANCER | In conclusion, a high proportion of recently diagnosed Latin American breast cancer patients remain oblivious to tumor characteristics such as molecular subtype and disease stage despite having received written educational materials. Both a customizable educational brochure and a standard, non‐customizable brochure were perceived as useful by participants in understanding their own disease. Nonetheless, most participants expressed a need for additional information and moderate‐to‐high levels of uncertainty, underscoring the need for improved information delivery strategies and the development of patient‐centered education materials that can address the unmet information needs of Latin American breast cancer patients. Notably, patients that received a customizable brochure were more likely to correctly identify which systemic treatment modalities they should receive according to their tumor characteristics. This finding indicates that customizable brochures improved patients' understanding of the recommended treatment modalities and could be an effective strategy to implement in clinical practice. | PMC10417173 |
AUTHOR CONTRIBUTIONS | PMC10417173 | |||
FUNDING INFORMATION | This work was supported by Roche Mexico. | PMC10417173 | ||
CONFLICT OF INTEREST STATEMENT | C.V.G | ONCOLOGY | C.V.G: Reports grants, personal fees, and non‐financial support from AstraZeneca; grants, personal fees, and non‐financial support from Roche; personal fees and non‐financial support from MSD Oncology; personal fees and non‐financial support from Pfizer; non‐financial support from Novartis; and personal fees from Eli Lilly outside the submitted work. A.S.F: Reports consulting with Roche Mexico. S.N.D: Reports consultancy role for AstraZeneca, Genentech, GlaxoSmithKline, Medscape, Merck‐Sharp, Novartis, Pfizer, Roche, Janssen; institutional financial support from Amgen, AstraZeneca, Bristol‐Myers Squibb, Daiichi, Novartis, Merck, Millenium, Pfizer, Roche, Pfizer; being Chair for ABC Global Alliance and ABC Consensus. M.S.G: Reports honoraria from Roche, ESAI, AMGEN. Y.R.B: Reports support for meetings or travel from Bristol‐Myers Squibb and Bayer. J.T.S: Reports grant support and honoraria from Roche Mexico. Other authors: No disclosures. | PMC10417173 |
Supporting information |
Figure S1.
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Figure S2.
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Figure S3.
Click here for additional data file. | PMC10417173 | ||
ACKNOWLEDGMENTS | ALBERT | The authors thank Fundacion Mexicana Para la Salud (FUNSALUD), A.C. for their administrative role and Natalia Villarreal Cadena for her role in the design of the educational materials. The authors thank Ofelia Fernanda Aguiñaga‐Orozco, Calixto Camacho‐Rodriguez, Ana Maria Casillas‐Villarreal, Daniel Motola‐Kuba, Celeste Elizabeth‐Alanis, Fernando Mota, Clarisa Pelayo‐Aguirre, Emmeline Rochelle, and Albert Giancarlo Torres‐Tenorio for their assistance in participant follow‐up and data collection. | PMC10417173 | |
DATA AVAILABILITY STATEMENT | N/A. | PMC10417173 | ||
REFERENCES | PMC10417173 | |||
Abstract | PMC10603557 | |||
Introduction | HIV controllers have low viral loads (VL) without antiretroviral treatment (ART). We evaluated viraemic control in a community‐randomized trial conducted in Zambia and South Africa that evaluated the impact of a combination prevention intervention on HIV incidence (HPTN 071 [PopART]; 2013–2018). | PMC10603557 | ||
Methods | VL and antiretroviral (ARV) drug testing were performed using plasma samples collected 2 years after enrolment for 4072 participants who were HIV positive at the start of the study intervention. ARV drug use was assessed using a qualitative laboratory assay that detects 22 ARV drugs in five drug classes. Participants were classified as non‐controllers if they had a VL ≥2000 copies/ml with no ARV drugs detected at this visit. Additional VL and ARV drug testing was performed at a second annual study visit to confirm controller status. Participants were classified as controllers if they had VLs <2000 with no ARV drugs detected at both visits. Non‐controllers who had ARV drugs detected at either visit were excluded from the analysis to minimize potential confounders associated with ARV drug access and uptake. | PMC10603557 | ||
Results | The final cohort included 126 viraemic controllers and 766 non‐controllers who had no ARV drugs detected. The prevalence of controllers among the 4072 persons assessed was 3.1% (95% confidence interval [CI]: 2.6%, 3.6%). This should be considered a minimum estimate, since high rates of ARV drug use in the parent study limited the ability to identify controllers. Among the 892 participants in the final cohort, controller status was associated with biological sex (female > male, | PMC10603557 | ||
Conclusions | To our knowledge, this report presents the first large‐scale, population‐level study evaluating the prevalence of viraemic control and associated factors in Africa. A key advantage of this study was that a biomedical assessment was used to assess ARV drug use (vs. self‐reported data). This study identified a large cohort of HIV controllers and non‐controllers not taking ARV drugs, providing a unique repository of longitudinal samples for additional research. This cohort may be useful for further studies investigating the mechanisms of virologic control. | PMC10603557 | ||
INTRODUCTION | HIV infection | HIV INFECTION | HIV controllers naturally suppress their HIV viral load (VL) to low levels without antiretroviral treatment (ART) [Previous population‐level studies have reported the prevalence of elite and viraemic controllers as <1% [In this report, we evaluated factors associated with viraemic control in a community‐randomized trial conducted in Zambia and South Africa: HIV Prevention Trials Network (HPTN) 071 (PopART). This trial evaluated the impact of a combination prevention strategy, including universal testing and treatment, on HIV incidence [We identified viraemic controllers and non‐controllers in the HPTN 071 cohort and examined demographic factors associated with HIV control. All participants assessed in this report had prevalent HIV infection (duration >2 years). By definition, viraemic controllers were virally suppressed in the absence of ART. To minimize confounding by factors associated with ART in the HPTN 071 trial, this report only included non‐controllers who had no ARV drugs detected. | PMC10603557 |
METHODS | PMC10603557 | |||
Study cohort | This research was conducted using samples and data collected in the HPTN 071 (PopART) trial (NCT019000977; 2013–2018) [ | PMC10603557 | ||
Laboratory methods | Herpes simplex | VIRUS, HERPES SIMPLEX | Herpes simplex virus type 2 (HSV‐2) testing was performed at study sites using the Kalon HSV2 immunoglobulin G enzyme‐linked immunosorbent assay (ELISA; Kalon Biological), as described [ | PMC10603557 |
Statistical methods | Participants classified as viraemic controllers had VLs <2000 copies/ml with no ARV drugs detected at two annual study visits. This classification approach is consistent with methods described in previous reports [ | PMC10603557 | ||
Informed consent | Study participants provided written informed consent prior to enrolment in HPTN 071, which was approved by the institutional review board and ethics committees at the London School of Hygiene and Tropical Medicine, the University of Zambia and Stellenbosch University. | PMC10603557 | ||
RESULTS | herpes simplex | VIRUS, HERPES SIMPLEX | HPTN 071 included 4101 participants who were HIV positive at the start of the study intervention (PC0) and had a sample stored 2 years later (PC24; Figure Identification of viraemic controllers and non‐controllers in HPTN 071 (PopART). The figure shows the approach used to identify viraemic controllers and non‐controllers. The cohort included HPTN 071 (PopART) participants who were HIV positive at study enrolment (PC0) and had a sample available from a study visit 2 years later (PC24). Viral load and antiretroviral (ARV) drug data obtained at the PC24 visit were used to identify potential controllers and non‐controllers. Participants who had viral loads ≥2000 copies/ml with no ARV drugs detected at PC24 were classified as non‐controllers. Participants who had viral loads <2000 copies/ml with no ARV drugs detected at PC24 were classified as potential controllers. Testing was performed at a second study visit (PC0, PC12 or PC36) to identify the subset of potential controllers who met the criteria for viraemic control (viral load <2000 copies/ml with no ARV drugs detected at two visits at least 1 year apart). Shaded boxes indicate participants who had undetermined controller status or were excluded from the analysis due to ARV drug use. To determine which of the 218 potential controllers met the criteria for viraemic control, VL and ARV drug testing were performed using samples collected from a second visit (1–2 years earlier or 1 year later); results were obtained for 210 (96.3%) of the 218 potential controllers. Based on those results, 126 potential controllers were classified as viraemic controllers (VL <2000 copies/ml with no ARV drugs detected at two visits at least a year apart). The remaining 92 participants were excluded from further analysis, since controller status could not be determined based on available data. This group included eight participants who had no additional samples or were missing VL and/or ARV drug data from an additional visit, 49 participants who had VLs ≥2000 copies/ml at the second visit tested; and 35 participants who had VLs <2000 copies/ml with ARV drugs detected at the second visit tested. The final cohort included 126 controllers and 766 non‐controllers. The prevalence of viraemic control among the 4072 participants with PC24 data was 3.1% (95% confidence interval [CI]: 2.6%, 3.6%).We compared demographic and other characteristics for the 126 controllers and 766 non‐controllers (Table Factors associated with viraemic control in HPTN 071 (PopART)
Abbreviations: ARV, antiretroviral; HSV‐2, herpes simplex virus type 2; IQR, interquartile range; N/D, not determined; SD, standard deviation; yrs, years.Participants were classified as controllers if they had viral loads <2000 copies/ml with no ARV drugs detected at two annual study visits.Participants were classified as non‐controllers if they had a viral load ≥2000 copies/ml with no ARV drugs detected at the PC24 visit.Data from viral load testing are shown for the PC24 visit.
Age was analysed as a continuous variable (years) and by age category (18–24 years, 25–29 years, 30–34 years, 35–39 years and 40+ years).Data for HSV‐2 status are shown for the PC0 visit; data were not available for 13 participants (3 controllers and 10 non‐controllers). | PMC10603557 |
DISCUSSION | HIV infection, infections | HIV INFECTION, INFECTIONS | To our knowledge, this report presents the first large‐scale, multisite, population‐level study evaluating the prevalence of viraemic control and associated factors in Africa. The study was conducted in a generalized epidemic setting in two sub‐Saharan African countries and included men and women from urban and peri‐urban communities. Using the controller definition described in this report, we identified 126 viraemic controllers and 766 non‐controllers who were not on ART. An advantage of this study was that a biomedical assessment was used to assess ARV drug use. This assay detects 22 drugs in five classes, including those recommended for ART in the study countries at the time the trial was performed. Previous studies have demonstrated that self‐report of ART can be unreliable, as some participants in clinical trials and research studies may not accurately report their ART status [The prevalence of viraemic controllers identified in this report (3.1%) is similar to results from population‐level studies conducted in the United Kingdom (2.7%) [In the Department of Defense study noted above, viraemic control was not associated with biological sex [In the HPTN 071 cohort, viraemic control was more common in South Africa than in Zambia, although these findings were not statistically significant. Previous studies found above‐average rates of HIV control in South Africa, ranging from 5.6% in a cohort of young women [This study had several limitations. First, high rates of ARV drug use limited our ability to identify controllers. This study used VL and ARV drug data that were obtained in a prior study 2 years after the start of the study intervention. More participants may have met the criteria for viraemic control if testing had been performed at the study entry. For this reason, our estimated prevalence of 3.1% should be considered a minimum estimate. Second, HPTN 071 included a disproportionate number of women and was conducted in Zambia and South Africa, where almost all infections are caused by HIV subtype C. In a prior study, we performed HIV genotyping and subtyping for a subset of 758 participants in HPTN 071; 95.9% of those participants had subtype C HIV infection [ | PMC10603557 |
CONCLUSIONS | The prevalence of viraemic control in this population‐based study was 3.1%. Viraemic control was associated with biological sex (women > men). This study identified a large cohort of controllers and non‐controllers. Further characterization of this cohort may provide insights into the mechanisms of HIV control. | PMC10603557 | ||
COMPETING INTERESTS | None of the authors has competing interests or potential competing interests. | PMC10603557 | ||
AUTHORS’ CONTRIBUTIONS | WG‐M: designed the study, performed laboratory testing, analysed data and drafted the manuscript; EP‐M: HPTN 071 LC QA/QC Representative; WC: responsible for antiretroviral drug testing; AB: performed antiretroviral drug testing; KBZ: assisted with data management; AM: HPTN 071 Study Coordinator; HMA: HPTN 071 Zambia Site PI; BK: provided laboratory support for HPTN 071 in Zambia; KS: HPTN 071 (PopART) Zambia Site Investigator; PB: HPTN 071 South African Site Co‐PI; SAM: HPTN 071 Research Manager in South Africa; GM: provided laboratory support for HPTN 071 in South Africa; SF: HPTN 071 Protocol Co‐Chair; RH: HPTN 071 Protocol Chair; DD: HPTN 071 Statistician; SHE: HPTN 071 Virologist, designed the study, analysed data and drafted the manuscript. All authors contributed to the manuscript and approved the submitted version. | PMC10603557 | ||
FUNDING | AIDS | INFECTIOUS DISEASES, ALLERGY, AIDS, ABUSE, EMERGENCY | This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) through R01‐AI095068, the National Institute of General Medical Sciences (NIGMS) through R01‐GM136724 and by the HIV Prevention Trials Network (HPTN), which is sponsored by the NIAID under Cooperative Agreements UM1‐AI068619, UM1‐AI068617 and UM1‐AI068613, with funding from the U.S. President's Emergency Plan for AIDS Relief (PEPFAR). Additional support was provided by the Division of Intramural Research, NIAID. Additional funding for the HPTN 071 (PopART) trial was provided by the International Initiative for Impact Evaluation (3ie) with support from the Bill & Melinda Gates Foundation, as well as by NIAID, the National Institute on Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH), all part of NIH. RH also received support from the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, which is also part of the EDCTP2 programme supported by the European Union (MR/R010161/1). | PMC10603557 |
DISCLAIMER | The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID, NIMH, NIDA, PEPFAR, 3ie or the Bill & Melinda Gates Foundation. | PMC10603557 | ||
ACKNOWLEDGEMENTS | The authors thank Joel Blankson for his critical review of the manuscript, the HPTN 071 (PopART) study participants for their participation, and the laboratory staff at the study sites and the HPTN Laboratory Center for their assistance with sample processing and testing. | PMC10603557 | ||
DATA AVAILABILITY STATEMENT | The data sets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10603557 | ||
REFERENCES | PMC10603557 | |||
Background: | OBESE | Difficult peripheral venous access, especially in obese people, is challenging for novices. We conducted a randomized cross-over study to examine whether near-infrared venous imaging or ultrasound guidance is more useful for novice operators to obtain difficult peripheral venous access. | PMC10036034 | |
Methods: | SECONDARY, OBESE | Medical students were recruited as participants. After receiving basic training using commercial simulators, participants were randomly assigned to obtain simulated venous access using a difficult venous access simulator with near-infrared venous imaging or ultrasound guidance in a randomized cross-over design. A difficult venous access simulator was newly developed with deep and narrow vessels to simulate an obese patient. The primary outcome measure of the study was the first-time success rate (%), and the secondary outcome measures included procedure time (seconds) and the number of 3 consecutive successful attempts, to represent proficiency with the procedure. Pearson chi-square test, the Wilcoxon signed-rank test, and generalized estimating equations were used for statistical analysis. | PMC10036034 | |
Results: | Forty-one medical students with no experience performing peripheral venous access were enrolled in this study. The rate of successful first attempts did not differ between the 2 groups (70% for near-infrared; 65% for ultrasound guidance; | PMC10036034 | ||
Conclusion: | obese | OBESE | There was no difference in success rate of first-time attempts or acquiring proficiency for the 2 methods. However, duration of the first attempt was significantly shorter with near-infrared imaging than with ultrasound guidance. Near-infrared imaging may require less training than ultrasound guidance. Near-infrared venous imaging may be useful for novices to obtain difficult peripheral venous access in obese patients. | PMC10036034 |
1. Introduction | Obesity | OBESITY | Peripheral venous catheters are the most commonly used devices for vascular access in routine clinical practice. Obesity is associated with difficult peripheral venous access. | PMC10036034 |
2. Materials and methods | RECRUITMENT | The present study was approved by the Faculty of Medicine Research Ethics Committee, Kyorin University (approval number 1804) and registered in the University Hospital Medical Information Network Center Clinical Registration System (UMIN000045269). The study was conducted in accordance with Consolidated Standards of Reporting Trials guidelines.The study was designed as a randomized, prospective crossover study. Participants were recruited from among fourth and fifth-year medical students as volunteers. Exclusion criteria included experience of obtaining peripheral venous access in a patient, and refusal to participate. Written informed consent was obtained from all participants. Participant recruitment and data collection were performed from September 2021 to November 2022. | PMC10036034 | |
2.1. Simulation training | Before starting the study, simulation training was conducted. The Intravenous ARM III (Kyoto Kagaku Co., Japan) simulator was used to train the direct visual and palpation techniques for peripheral venous access for 30 minutes. The peripheral venous catheter was BD Insight 22G, 25 mm (Nippon Becton Dickinson Co., Japan). A brief explanation of the principles of near-infrared venous imaging was given, and each participant searched for a vein in his or her own arm using near-infrared vein imaging. The near-infrared visualization system was Vein Viewer Flex (Terumo Co., Japan).Next, the principles of ultrasound guidance were briefly explained, followed by a demonstration of ultrasound imaging of veins in the upper extremities. Ultrasound imaging was performed with a Sonotore Linear (linear probe 7.5 MHz, ALFABIO Co., Japan). Out-of-plane (dynamic needle tip positioning | PMC10036034 | ||
2.2. Difficult venous access simulator | SECONDARY | A simulator was developed especially for this study (Kyoto Kagaku Co., Japan) (Fig. Difficult venous access simulator. (a) Simulated vessels cannot be seen in the simulator with the eye. (b) Near-infrared imaging with the simulator, allowing 1 to see simulated vessels. (c) Ultrasound imaging with the simulator providing a view of simulated vessels.Punctures continued until 3 consecutive successful attempts were made. Even if 3 consecutive successful attempts were not achieved, the trial was terminated after 20 attempts. Three consecutive attempts were hypothesized to represent proficiency with the technique. Success was defined when water in the lumen of the simulated vessel was aspirated from the catheter after placement. Failure was defined as failure to place the catheter into the simulated vessel within 3 minutes, or not to achieve 3 consecutive successes within 20 attempts. The procedure time was defined as the time from the start of puncture to confirmation of water backflow from the simulated vessel. Participants performed the puncture using the assigned method (near-infrared or ultrasound), then performed using the other method (crossover study).The primary outcome measure of the study was the rate of successful first attempts, and the secondary outcome measures included procedure time and the number of 3 consecutive successful attempts. Data were electronically stored in an anonymized manner. | PMC10036034 | |
2.3. Statistical analysis | Success rates were expressed as percentages (%). Procedure times (seconds) and number of 3 consecutive successes were shown as median (first quartile, third quartile). The presence or absence of carryover effects was evaluated with the Mann–Whitney | PMC10036034 | ||
2.4. Power analysis | At the time the present study began, there were no comparative studies comparing near-infrared vein imaging and ultrasound guidance in adult patients. The clinical difference between the 2 techniques could not be determined. Therefore, assuming a clinically significant difference, the sample size required for 80% power at | PMC10036034 | ||
3. Results | fatigue | Forty-one medical students participated in the present study. One participant data was excluded due to missing data (refusal to continue participation due to fatigue, Fig. CONSORT diagram. CONSORT = consolidated standards of reporting trials. | PMC10036034 |
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