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Secondary
infection, febrile illness
INFECTION, FEBRILE ILLNESS
To estimate the relative and absolute rate reduction (derived from the same model) of symptomatic culture-confirmed S. Typhi infection among participants in vaccine clusters compared to participants in non-vaccine clusters (overall effect)To estimate the relative and absolute rate reduction of symptomatic culture-conf...
PMC10399005
Exploratory
infection
INFECTION
To estimate the relative and absolute rate reduction of symptomatic culture-confirmed S. Typhi infection in TyphiBEV® unvaccinated participants in vaccine clusters compared to unvaccinated participants in non-vaccine clusters (indirect effect)To estimate the relative and absolute rate reduction of the incidence of hos...
PMC10399005
Design
Our study is an observer-blinded, cluster-randomised trial set up among the population of 30 wards in Vellore that are part of the Vellore Health and Demographic Surveillance System (VDSS). Data from the VDSS will be updated with a door-to-door survey and individual residents between the ages of 1 and 30 years will be ...
PMC10399005
Comparator
Hepatitis A
HEPATITIS A, JAPANESE B ENCEPHALITIS
No control vaccine will be used. All those in the no-intervention arm will receive the vaccine after the study ends. Potential comparator vaccines, i.e. Hepatitis A and Japanese B Encephalitis, were considered to have non-compelling risk-to-benefit ratios by the Christian Medical College (CMC) Vellore’s Institutional R...
PMC10399005
Methods and analysis
PMC10399005
Healthcare provider network
fever illness, fever, febrile
We invited the most utilised healthcare providers in the study area (determined by previous surveys) to participate in the fever surveillance based on their ability to follow a standard fever illness management protocol, i.e. to conduct a blood culture prior to the start of antimicrobial treatment in febrile patients. ...
PMC10399005
Eligibility and recruitment
typhoid
RECRUITMENT, TYPHOID
Field Research Assistants (FRAs) will survey all households in the study area to identify individuals listed in the VDSS and those that may have migrated in or out. They will then approach individuals between the ages of 1 and 30 years for informed consent, and those who consent and do not plan to leave the study area ...
PMC10399005
Fever surveillance
febrile, illness, fever
EVENTS, ENTERIC FEVER
To capture febrile events, all participants will be asked to call a 24/7 helpline number before they visit a healthcare facility for an illness. In case the illness is febrile, our helpline operators will raise a unique digital token that the fever surveillance team will use (via an online dashboard) to track the patie...
PMC10399005
Laboratory methods
acute febrile illness
ENTERIC FEVER
All healthcare facilities partnered with the study will be encouraged to conduct a blood culture in case a patient has an acute febrile illness that lasts more than 2 days, has a temperature of ≥ 38 °C documented at the facility, or if the physician intends to begin antimicrobial therapy. The physician may defer the bl...
PMC10399005
Vaccination
allergic, ®, fever, febrile illness, typhoid
ADVERSE EVENTS, RECRUITMENT, FEBRILE ILLNESS, TYPHOID
Once the fever surveillance is operational, eligible participants from selected vaccine clusters will be invited to designated vaccination clinics over a period of 2 months and have a unique vaccination code sent to their phones. This process will be repeated after the mop-up recruitment drive. In case of vaccination w...
PMC10399005
Blinding
fever
The study participants will not be blinded to their vaccination statuses as there is no control vaccine. Only the teams conducting fever surveillance and monthly contacts will be blinded to this and be trained to not seek out vaccination details. The coding for the primary analysis will be first conducted in a dataset ...
PMC10399005
Sample size calculation
infectious disease, typhoid fever, typhoid
INFECTIOUS DISEASE, CNS INFECTIONS, TYPHOID FEVER, TYPHOID
The sample size was calculated using a simulation approach as outcome is an infectious disease that affects the probability of further infections in that cluster. The required number of participants was sampled from the VDSS 2021 dataset so that the simulation used the empirical distributions of age and household size ...
PMC10399005
Randomisation
Randomisation will be stratified according to four broad areas in the city with different anticipated incidences of
PMC10399005
Outcomes
Febrile illness
ADVERSE EVENTS, INDURATION, SECONDARY, TYPHOID FEVER, FEBRILE ILLNESS
The primary outcome is blood culture-confirmed typhoid fever.The secondary effectiveness outcomes are:• Febrile illness episodes lasting at least 3 days where healthcare is sought• Hospitalised culture-confirmed The safety outcomes, defined only in vaccine recipients, are:o Local induration at site of vaccinationo Repo...
PMC10399005
Estimands
To provide full clarity for our first two objectives, the corresponding estimands are described in Table Structured statement of estimands
PMC10399005
Statistical analysis
febrile illness
EVENT, RECRUITMENT, FEBRILE ILLNESS, REGRESSION, EVENTS, TYPHOID FEVER
Our primary summary measure of the effect is a rate ratio (RR), from which vaccine effectiveness can be expressed as (1 − RR) × 100%. This will be estimated using an individual-level analysis using Poisson regression that will account for time at risk with censoring at the last known follow-up time. This is expected to...
PMC10399005
Data management, confidentiality, and quality assurance (QA)
CRF
RECRUITMENT, CRF
Operational management of the trial will be aided by an externally validated, custom-built database management software. It will link with the VDSS and be used for recruitment, scheduling, and tracking of participant contacts and outcomes. Primary clinical data will be recorded on validated instances of Redcap (Researc...
PMC10399005
Trial oversight
EVENTS, EVENT, RECRUITMENT
A Trial Steering Group (TSG), comprised of the lead investigators, the data manager, internal quality manager, and the trial statisticians, will meet at least once a month to discuss trial operations. Interim reports will be prepared for the independent Data Safety and Monitoring Board (DSMB), comprised of an epidemiol...
PMC10399005
Discussion
®, typhoid
TYPHOID
TCVs are highly efficacious interventions against typhoid that are cost-effective and can be used to protect children from the age of 6 months [Efficacy studies of TCVs in various settings, regions, and age groups are necessary to help with their effective programmatic use. Our trial’s results will also inform the Indi...
PMC10399005
Trial status
TYPHOID
This manuscript is based on protocol version 1.1, dated 26/04/2023 and titled ‘Vellore Typhoid Vaccine Impact Trial’. A timeline of the study can be found in Fig. Timeline of study procedures (SPIRIT figure)
PMC10399005
Acknowledgements
We would like to acknowledge the support provided by Peter Smith from the London School of Hygiene and Tropical Medicine, Nicholas Grassly from the Imperial College London, Jason Andrews from Stanford University, Andrew Pollard and Xinxue Liu from the University of Oxford, Supriya Kumar and Thea Norman from the Bill an...
PMC10399005
Publication policy
A manuscript detailing the results of this study will form the primary publication and be published in a peer-reviewed journal. Authorship will be determined as per ICMJE guidelines and all other contributors will be acknowledged. The authors will also acknowledge that this trial was funded by the Bill and Melinda Gate...
PMC10399005
Authors’ contributions
JJ, DKA
The study was conceptualised by JJ and GK. JJ, AC, TM, VA, WR, VB, PS, VRM, JAS, PK, DKA, and NS formulated the study design. TM, PS, AC, and JJ developed the analysis plan. The protocol was drafted by NS and DKA, with subsequent edits by JJ, TM, and AC. All authors have approved the submitted protocol manuscript. All ...
PMC10399005
Funding
typhoid
TYPHOID
This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation (grant number INV-036437). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. Biol...
PMC10399005
Availability of data and materials
De-identified, participant-level data will be made available via a public archive within 3 months of the primary publication, along with the statistical analysis plan and analysis code. Genome sequences obtained will be uploaded to a sequence library. Supplementary analyses may be conducted on this data with attributio...
PMC10399005
Declarations
PMC10399005
Ethics approval and consent to participate
The study proposal was reviewed and approved by India’s Health Ministry Screening Committee (proposal ID 2022–16229, dated 16 March 2022). The protocol was approved by the IRB of CMC Vellore (IRB minutes number 14247, dated 29/09/2021). Any changes or amendments made to the protocol will be submitted to the IRB for app...
PMC10399005
Consent for publication
Not applicable—no identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results.
PMC10399005
Competing interests
The authors declare that they have no competing interests.
PMC10399005
References
PMC10399005
Objective:
To establish whether the use of a WaterPik
PMC10693741
Design:
A single-centre, two-arm, parallel-group, single-blind, randomised controlled clinical trial with a 1:1 allocation ratio.
PMC10693741
Setting:
Orthodontic department at York Hospital, York Teaching Hospitals NHS Foundation Trust, UK.
PMC10693741
Participants:
A total of 40 fit and well participants, aged 10–20 years, being treated with upper and lower fixed orthodontic appliances.
PMC10693741
Methods:
Participants were randomly allocated, using stratified block randomisation, to the control group (MTB) or intervention group ‘(Waterpik
PMC10693741
Results:
PLAQUE
An interim analysis of results was performed with 40 patients recruited and 85% of data collected. The overall mean differences between the groups were as follows: plaque index = 0.199 (
PMC10693741
Conclusions:
In terms of oral hygiene, our study did not find evidence to support the claim of benefit of using a Waterpik
PMC10693741
Introduction
orthodontic
PLAQUE, DECALCIFICATION, PLAQUE
It is widely accepted that it is more difficult to maintain good oral hygiene when wearing orthodontic appliances (As well as the effect on the periodontium, stagnating plaque around orthodontic appliances predisposes to decalcification. This can leave permanent, unsightly white or brown marks on the teeth that can pro...
PMC10693741
Specific objectives and null hypotheses
The aim of the present study was to establish whether the use of a WaterPikNull hypotheses: the use of a WaterPik
PMC10693741
Methods
PMC10693741
Trial design and any changes after trial commencement
bleeding, coin toss
BLEEDING, RECRUITMENT
This study was a single-centre, single-operator, two-arm, parallel-group, stratified, single-blind RCT trial with a 1:1 allocation ratio, conducted in the Department of Orthodontics at York Hospital, UK.Changes after the commencement of the trial were as follows:Due to the COVID-19 pandemic, there was a reduced pool of...
PMC10693741
Participants, eligibility criteria and setting
Potential participants for the trial were consecutive patients treated by a single Specialty Registrar in Orthodontics at York Hospital, UK. Patients treated were non–fee-paying patients who were treated under the UK National Health Service (NHS). The eligibility criteria are shown in Eligibility criteria for participa...
PMC10693741
Interventions
The interventions provided for each group are shown in The interventions provided to both groups.DN, dental nurse; OHE, oral health education.
PMC10693741
Outcomes
trauma
PLAQUE, PLAQUE
Participants were seen at baseline (T0), 8 weeks (T1), 32 weeks (T2) and 56 weeks (T3). At these time points, clinical indices to assess oral hygiene and gingival health were completed. The trial indices were performed by the same clinician.The primary outcome was plaque level, measured using the Orthodontic Modificati...
PMC10693741
Sample size calculation
To establish sample size, a power calculation was performed by the trial statistician (JK) based on the primary outcome OMPI. The significance level of the study was set at 5% (α = 0.05). The clinically significant effect size was set as 0.5 based on previous studies (The Power Analysis and Sample Size software (PASS,
PMC10693741
Randomisation: Sequence generation, allocation concealment and implementation
PMC10693741
Sequence generation
orthodontic
Participants were allocated using stratified block randomisation. The participants were stratified based on three prognostic characteristics: gender, age and IBI at baseline. It has been shown that female orthodontic patients report cleaning their teeth more often than male patients (Using three prognostic characterist...
PMC10693741
Concealment
For allocation of the participants, sealed envelopes containing either intervention or control were used.
PMC10693741
Implementation
Patients were enrolled into the trial at the start of their visit by DT. At the end of the appointment to place the fixed appliances, DT then allocated the participant into one of the eight blocks and informed the dental nurse of which block they were in. DT then left the clinic and the dental nurse took out the releva...
PMC10693741
Blinding
BLIND
This was a single blind trial. The operator carrying out the indices (DT) was blinded to the patient allocation. The participants could not be blinded to their allocation. The participants were told that they must not tell DT whether they had a WaterPik
PMC10693741
Statistical analysis
gingiva, trauma, bleed
SECONDARY, BLEED
Statistical analysis was performed using IBM SPSS version 27 software (IBM Corp., Armonk, NY, USA). Summary descriptive statistics were produced to report demographic features and for each oral health variable.A generalised linear mixed model was used to assess whether there was a difference between the intervention an...
PMC10693741
Ethical considerations
Ethical approval was sought for the trial through the Integrated Research Application System (IRAS). This was approved by the Health Research Authority and Health and Care Research Wales (HRA & HCRW) on 23 August 2019. The IRAS project ID was 266235. The trial was registered with York Teaching Hospital NHS Foundation T...
PMC10693741
Results
PMC10693741
Participant flow
RECRUITMENT
A flow chart of participants through the trial is shown in CONSORT participant flow chart.Adapted from A single patient in the intervention group withdrew from the study after the 32-week indices, as he wished to start using an electric toothbrush.Recruitment for the trial began on 15 November 2019. The first patient t...
PMC10693741
Baseline data
Baseline data are shown in Baseline data.The groups were similar at baseline in terms of age. There were more female patients in the control group. The PI and GI were very similar at baseline between the two groups. The mean IBI was slightly higher in the control group.
PMC10693741
Numbers analysed for each outcome
Bleeding, trauma
BLEEDING, PLAQUE
The analysis was performed on an intention-to-treat basis. This means that all patients who were randomised to receive an intervention were included in the analysis, regardless of whether they completed the trial (The results for PI, GI and IBI are shown in Difference of each outcome between control and treatment group...
PMC10693741
Adherence with oral hygiene regime
In terms of adherence with an oral hygiene regime, <25% of the oral hygiene diaries were returned, so it was not appropriate to analyse the data and draw any conclusions on adherence with prescribed oral hygiene regime. As a research group, it was thought that the data from those participants who did return the diaries...
PMC10693741
Satisfaction with oral hygiene regime
Questionnaire responses regarding satisfaction with an oral hygiene regime are shown in
PMC10693741
Harms
No harms were reported or detected for any participant.
PMC10693741
Discussion
PMC10693741
Interpretation
orthodontic
PLAQUE
Based on the results of this trial, there is no benefit, in terms of plaque control or gingival health, in using a WaterPikThere is only one other published trial assessing orthodontic patients with a WaterPikPatients were recruited for the trial by
PMC10693741
Limitations
orthodontic
PLAQUE
There was a higher proportion of female participants in the control group (65%) compared to the intervention group (50%). As previously stated, female patients have been shown to have lower levels of plaque and have a greater level of knowledge of oral health (In terms of outcome measures, although the descriptors for ...
PMC10693741
Generalisability
The trial was carried out in a single NHS district general hospital and treatment was carried out by a single clinician. Patients in this setting do not pay for their treatment because it is funded by the NHS. It has been demonstrated that patients who self-fund orthodontic treatment have higher levels of compliance th...
PMC10693741
Conclusions
In the population studied, there was no benefit in terms of oral hygiene in the use of a WaterPik
PMC10693741
Supplemental Material
PMC10693741
References
PMC10693741
Background
extensive-stage small-cell lung cancer
Anlotinib plus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC) achieves good efficacy, but there is still room for improvement. This clinical study examined the effectiveness of anlotinib plus etoposide for maintenance therapy in ES-SCLC.
PMC10663256
Methods
Cancer
DISEASE PROGRESSION, ADVERSE EVENTS, DISEASE, REMISSION, CANCER
The current single-arm, prospective phase II study was performed at Jiangsu Cancer Hospital (March 2019 to March 2022). After successful primary etoposide-based therapy, anlotinib was administered at 12 mg/day on days 1 to 14 of 21-day cycles until disease progression or consent withdrawal. All patients also received e...
PMC10663256
Results
fatigue, proteinuria, hypertension, hemoptysis, all-grade, hand and foot syndrome
ORAL MUCOSITIS, DISEASE, GINGIVAL BLEEDING, LOSS OF APPETITE, HYPERTENSION
Twenty-eight patients were treated. Median PFS and OS were 8.02 (95%CI 5.36–10.67) and 11.04 (95%CI 10.37–11.68) months, respectively. Totally 9 and 18 participants showed a partial response and stable disease, respectively; ORR and DCR were 32.14% and 96.43%, respectively. The commonest all-grade AEs were fatigue (n =...
PMC10663256
Conclusion
Maintenance anlotinib plus etoposide achieves promising PFS and OS in clinical ES-SCLC.
PMC10663256
Registration number
ChiCTR1800019421.
PMC10663256
Supplementary Information
The online version contains supplementary material available at 10.1007/s10637-023-01398-9.
PMC10663256
Keywords
PMC10663256
Introduction
SCLC, Small-cell lung cancer
PEARLY DISEASE, METASTASES, SCLC
Small-cell lung cancer (SCLC) SCLC features fast doubling time, elevated growth fraction, and extensive metastases in early disease phases, generally showing widespread hematogenous metastases [The best SCLC management is based on surgery, chemotherapy, targeted therapy, and radiotherapy [The vascular endothelial growt...
PMC10663256
Materials and methods
PMC10663256
Study design
Cancer
ONCOLOGY, CANCER
The current single-arm, prospective phase II trial was performed at the Oncology Department of Jiangsu Cancer Hospital between March 2019 and March 2022. The study followed the Declaration of Helsinki (2000), and had approval from the Ethics Committee of Jiangsu Cancer Hospital. Each patient provided signed informed co...
PMC10663256
Participants
SCLC, tumor, pleural effusion, allergic, ascites, allergy, respiratory syndrome
PLEURAL EFFUSION, TUMOR, ASCITES, SCLC, ALLERGY, ONCOLOGY
Inclusion criteria were: (1) 18 to 75 years old; (2) proven with ES-SCLC by histopathological examination; (3) treatment with standard first-line Etoposide-platinum solely chemotherapy, without progression; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; (5) one or more computed tomography (CT)...
PMC10663256
Intervention
toxicity, PD, death, SD
DISEASE PROGRESSION, DISEASE, REMISSION, ADVERSE EFFECTS
All patients underwent baseline imaging assessment after enrollment. The participants started treatment within 3 weeks (21 calendar days) from screening. All participants were administered anlotinib plus etoposide. Specifically, all participants were treated with oral anlotinib 12 mg q.d. on days 1–14 of 21-day cycles....
PMC10663256
Endpoints
PD, death
DISEASE PROGRESSION, ADVERSE EVENT, ADVERSE EVENTS, DISEASE, DISEASE
The primary endpoint was PFS, which was the time elapsed from the start of therapy to first disease progression as judged by the investigators or per imaging findings or death. Secondary endpoints encompassed OS, ORR, disease control rate (DCR), and safety. OS represented the time elapsed from the start of therapy to d...
PMC10663256
Sample size
Previous data revealed a PFS of 2 months in ES-SCLC without maintenance therapy following standard first-line etoposide chemotherapy [
PMC10663256
Statistical analysis
The intent-to-treat (ITT) set encompassed all participants administered the treatment. The per-protocol analysis (PP) set included all participants with high compliance with the study protocol and strictly completed the trial processes per the study protocol. All participants in the PP set completed the drug therapy th...
PMC10663256
Results
PMC10663256
Characteristics of participants
SCLC
ONCOLOGY, SMALL CELL LUNG CANCER, SCLC
From March 2019 to March 2022, eligibility screening was conducted for 32 advanced SCLC cases with no progression through first-line therapy (Fig.  Study flowchart Baseline characteristics of the participantsITT: intent-to-treat; PP: per-protocol; ECOG PS: Eastern Cooperative Oncology Group Performance Status; ES-SCLC:...
PMC10663256
Efficacy
DISEASE
Median PFS was 8.02 (95%CI 5.36–10.67) months (Table  Clinical outcomesITT: intent-to-treat; PP: per-protocol; mPFS: median progression-free survival; mOS: median overall survival; CR: complete response; PR: partial response; SD: stable disease; ORR: objective response rate; DCR: disease control rate ( (
PMC10663256
Safety
any-grade, TEAEs, TRAEs
Almost all participants (96.43%) experienced any-grade TEAEs. Any-grade TEAEs leading to anlotinib dose modification were observed in 35.71% of patients. TEAEs leading to anlotinib dose interruption were observed in 14.29% of cases. TEAEs leading to etoposide dose modification were observed in 7.14% of participants (Ta...
PMC10663256
Discussion
any-grade, SCLC, TEAEs
BRAIN METASTASIS, SCLC
This work examined the effectiveness of anlotinib combined with etoposide for maintenance treatment of ES-SCLC cases. The above findings suggest that maintenance treatment with anlotinib and etoposide after primary treatment with etoposide + platinum was effective and safe in clinical ES-SCLC.Patient survival in ES-SCL...
PMC10663256
Acknowledgements
We are grateful to all participants involved in the present trial as well as to the clinicians who supported this research.
PMC10663256
Authors’ contributions
Conceptualization: BS and YW. Data curation: YW, XFZ, WQZ, QW, ZXH, LFW, and WJZ. Formal analysis: YW, TZ, HZS, KHY, LS, BZP, and RHG. Funding acquisition: BS and YW. Investigation: YW, XFZ, and BS. Methodology: YW, XFZ, FJF, and BS. Project administration: GRZ, FJF, and BS. Resources: all authors. Software: BS. Superv...
PMC10663256
Funding
Cancer
CANCER
The current project was funded by the National Natural Science Foundation of China (Grant No. 82272863), the Beijing Medical and Health Foundation Project (Grant No. YWJKJJHKYJJ-F2030E), and the Huilan Public Interest Project (Grant No. HL-HS-2020102) (to Bo Shen) and the China International Medical Foundation Project ...
PMC10663256
Data Availability
The data generated or analyzed during this study are included in this published article.
PMC10663256
Declarations
PMC10663256
Competing interests
The authors declare no competing interests.
PMC10663256
Ethics approval
Cancer
CANCER
This trial complied with the Declaration of Helsinki (2000) of the World Medical Association. It had approval from the Ethics Committee of the Jiangsu Cancer Hospital. Signed informed consent was provided by each patient. The study was registered at the Chinese clinical trial registry (
PMC10663256
Consent to participate
Signed informed consent was provided by each patient.
PMC10663256
Consent to publish
N/A.
PMC10663256
Animal Studies
N/A.
PMC10663256
References
PMC10663256
Background
lung injury
Inhaling aerosolized nicotine and cannabis (colloquially called “vaping”) is prevalent among young adults. Instagram influencers often promote both nicotine and cannabis vaporizer products. However, Instagram posts discouraging the use of both products received national media attention during the 2019 outbreak of e-cig...
PMC10540020
Objective
This experiment tested the impact of viewing Instagram posts about EVALI, varying in image and text valence, on young adults’ perceived harmfulness of nicotine and cannabis products, perceived risk of nicotine and cannabis vaporizer use, and intentions to use nicotine and cannabis vaporizers in the future.
PMC10540020
Methods
REGRESSION, POSITIVE
Participants (N=1229) aged 18-25 (mean 21.40, SD 2.22) years were recruited through Qualtrics Research Services, oversampling for ever-use of nicotine or cannabis vaporizers (618/1229, 50.3%). Participants were randomly assigned to view Instagram posts from young people portraying their experiences of EVALI in a 2 (ima...
PMC10540020