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Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of King’s College London (HR-17/18-5341; approval granted January 2018). | PMC9919979 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9919979 | ||
Data Availability Statement | Data available on request. The data presented in this study are available on request from the corresponding author. The data are not publicly available due to nature of consent obtained from participants. | PMC9919979 | ||
Conflicts of Interest | IBS, TG | AC was funded by a PhD studentship funded by Almond Board of California. ED has received an education grant from Alpro, research funding from the British Dietetic Association, the Almond Board of California, the International Nut and Dried Fruit Council and Nestec Ltd. and has served as a consultant for Puratos. TG supervises PhD students partially funded by Mondelez and McCain Foods Ltd., and has previously received research funding from The Almond Board of California. SEB has received grant funding from Almond Board of California, Malaysian Palm Oil Board and ZOE Ltd., and receives consultancy and options from ZOE Ltd. KW has received research funding from Almond Board of California, Danone, International Dried Fruit and Nut Council, and is the co-inventor of volatile organic compounds in the diagnosis and dietary management of IBS. EH declares no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC9919979 | |
References | Consort diagram.Particle size distributions of masticated whole and ground almonds (Demographic characteristics of participants.Participant dentition.Data are number, Particle size distributions of masticated whole and ground almonds assessed by the mechanical sieving technique.Values are mean (SD) or mean difference (95% confidence interval); Particle size distributions of masticated whole and ground almonds assessed by laser diffraction.Values are mean (SD) or mean difference (95% confidence interval); | PMC9919979 | ||
Summary | PMC9860215 | |||
Background | POLIOMYELITIS | Type 2 circulating vaccine-derived polioviruses (cVDPV2) from Sabin oral poliovirus vaccines (OPVs) are the leading cause of poliomyelitis. A novel type 2 OPV (nOPV2) has been developed to be more genetically stable with similar tolerability and immunogenicity to that of Sabin type 2 vaccines to mitigate the risk of cVDPV2. We aimed to assess these aspects of nOPV2 in poliovirus vaccine-naive newborn infants. | PMC9860215 | |
Methods | diarrhoea, infection, vomiting, immunodeficiency disorder | ADVERSE EVENTS, INFECTION, IMMUNODEFICIENCY DISORDER | In this randomised, double-blind, controlled, phase 2 trial we enrolled newborn infants at the Matlab Health Research Centre, Chandpur, Bangladesh. We included infants who were healthy and were a single birth after at least 37 weeks' gestation. Infants were randomly assigned (2:1) to receive either two doses of nOPV2 or placebo, administered at age 0–3 days and at 4 weeks. Exclusion criteria included receipt of rotavirus or any other poliovirus vaccine, any infection or illness at the time of enrolment (vomiting, diarrhoea, or intolerance to liquids), diagnosis or suspicion of any immunodeficiency disorder in the infant or a close family member, or any contraindication for venipuncture. The primary safety outcome was safety and tolerability after one and two doses of nOPV2, given 4 weeks apart in poliovirus vaccine-naive newborn infants and the primary immunogenicity outcome was the seroconversion rate for neutralising antibodies against type 2 poliovirus, measured 28 days after the first and second vaccinations with nOPV2. Study staff recorded solicited and unsolicited adverse events after each dose during daily home visits for 7 days. Poliovirus neutralising antibody responses were measured in sera drawn at birth and at age 4 weeks and 8 weeks. This study is registered on | PMC9860215 |
Findings | ADVERSE EVENTS | Between Sept 21, 2020, and Aug 16, 2021, we screened 334 newborn infants, of whom three (<1%) were found to be ineligible and one (<1%) was withdrawn by the parents; the remaining 330 (99%) infants were assigned to receive nOPV2 (n=220 [67%]) or placebo (n=110 [33%]). nOPV2 was well tolerated; 154 (70%) of 220 newborn infants in the nOPV2 group and 78 (71%) of 110 in the placebo group had solicited adverse events, which were all mild or moderate in severity. Severe unsolicited adverse events in 11 (5%) vaccine recipients and five (5%) placebo recipients were considered unrelated to vaccination. 306 (93%) of 330 infants had seroprotective maternal antibodies against type 2 poliovirus at birth, decreasing to 58 (56%) of 104 in the placebo group at 8 weeks. In the nOPV2 group 196 (90%) of 217 infants seroconverted by week 8 after two doses, when 214 (99%) had seroprotective antibodies. | PMC9860215 | |
Interpretation | nOPV2 was well tolerated and immunogenic in newborn infants, with two doses, at birth and 4 weeks, resulting in almost 99% of infants having protective neutralising antibodies. | PMC9860215 | ||
Funding | Bill & Melinda Gates Foundation. | PMC9860215 | ||
Introduction | acute flaccid paralysis, poliomyelitis, vaccine-associated paralytic | POLIOMYELITIS, POLIO | Although live oral poliovirus vaccines (OPVs) are safe and effective and have led to the elimination of poliomyelitis from most of the world, in rare circumstances the attenuated viruses in OPVs can mutate and reacquire neurovirulence. This mutation can result in vaccine-associated paralytic polio in vaccine recipients and susceptible close contacts and, in settings of persistently poor immunisation coverage, can lead to the emergence of circulating vaccine-derived polioviruses (cVDPVs).However, despite the switch and cessation of routine use of live type 2 OPVs (OPV2), type 2 cVDPV (cVDPV2) outbreaks have occurred in many countries, resulting in cases of acute flaccid paralysis, which represent the majority of such polio cases worldwide.
| PMC9860215 |
Research in context | infection | INFECTION, PARALYTIC POLIOMYELITIS, POLIO |
Outbreaks of circulating vaccine-derived poliovirus type 2 (cVDPV2) are now the main cause of paralytic poliomyelitis worldwide. A novel, genetically more stable monovalent type 2 oral polio vaccine that was developed for use in outbreak control with less inherent chance of propagating more cVDPV2 has been studied in clinical trials involving infants, children, adolescents, and adults previously primed with at least one dose of type 2-containing poliovirus vaccine and shown to be safe, well tolerated, and immunogenic. On the basis of this clinical evidence, WHO authorised the use of a novel oral poliovirus vaccine type 2 (nOPV2) for outbreak control through the emergency use listing (EUL) procedure and more than 450 million doses have been distributed for use since March 2021. However, no clinical trial data are available for the use of nOPV2 in poliovirus vaccine-naive infants, who are at particular risk of infection during cVDPV2 outbreaks.
The EUL-enabling clinical data on nOPV2 included safety and immunogenicity data in infants who had already received a dose of inactivated poliovirus vaccine. Thus, generating vaccine performance data in poliovirus vaccine-naive infants or newborn babies was important to complete the clinical database on the new vaccine. Moreover, the highest-risk groups in cVDPV outbreaks are those with incomplete or no poliovirus vaccination such as newborn and very young infants. These groups will be priority targets in vaccination campaigns with nOPV2 for cVDPV2 outbreak control. Our data showing that nOPV2 is safe, well tolerated, and immunogenic in newborn infants are important for those health-care administrators and decision makers responsible for implementing such campaigns as well as being reassuring for the parents and carers of affected children. Equally important is our observation that nOPV2 use in newborn infants will not lead to excessive faecal excretion of live nOPV2, further minimising the risks of propagating a cVDPV2 outbreak.
Since WHO declared that cVDPV2 outbreaks are a public health emergency of international concern and following submission of earlier clinical data on nOPV2 in individuals aged at least 18 weeks to adults, WHO authorised the distribution and use of the vaccine in such outbreaks as the first vaccine to be used under the EUL process. To date, more than 450 million doses of nOPV2 have been distributed and have been used in all age groups targeted for outbreak response with no exclusion of use in newborn infants. The data from this study can inform policy makers, regulators, and health-care providers that the use of nOPV2 in poliovirus vaccine-naive newborn infants, the age group considered most vulnerable for poliovirus transmission, is safe and immunogenic.The clinical development of nOPV2 is ongoing, but the successful demonstration of its safety, immunogenicity, and genetic stability in phase 1 and phase 2 studies coupled with the public health emergency of international concern constituted by cVDPV2 outbreaks led to the authorisation by WHO of the vaccine's use under WHO's emergency use listing (EUL) procedure. To date, over 450 million doses have been distributed for outbreak control. | PMC9860215 |
Methods | PMC9860215 | |||
Study design and participants | diarrhoea, infection, vomiting, immunodeficiency disorder | INFECTION, DISEASE, IMMUNODEFICIENCY DISORDER | We did a randomised, double-blind, phase 2 clinical study at the Matlab Health Research Center in Chandpur, rural Bangladesh. The protocol was approved by the research review committee and the ethical review committee at the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b).Women in the third trimester of their pregnancy were identified by local community health workers and had study objectives and procedures explained to them before they were invited to enrol their infant. Enlisted pregnant women were requested to give birth at the Matlab hospital or subcentre, icddrb, and were asked to enrol their newborn infant for study vaccination within 0–3 days of birth. Eligibility criteria for the mother required willingness and ability to comply with the study procedures and provision of consent for their infant to participate for the entire duration of the study. Eligibility criteria for newborn infants at screening were that they were healthy and were a single birth after at least 37 weeks' gestation. Major exclusion criteria included receipt of rotavirus or any other poliovirus vaccine, any infection or illness at the time of enrolment (vomiting, diarrhoea, or intolerance to liquids), diagnosis or suspicion of any immunodeficiency disorder in the infant or a close family member, or any contraindication for venipuncture (This study was done in compliance with the relevant regulatory requirements and the International Council for Harmonisation Good Clinical Practice guidelines of the Declaration of Helsinki for biomedical research involving human subjects under the guidance of the icddr,b data and safety monitoring board. All parents and guardians who volunteered their children to participate provided written informed consent before enrolment. This study is registered on | PMC9860215 |
Randomisation and masking | Participants were randomly assigned (2:1) to either nOPV2 or placebo, using a block randomisation of size 6 or 12 generated by a statistician who was not otherwise involved in the study. The statistician prepared randomisation lists for study nurses or investigators who were masked to the allocation of the vaccine or placebo. Parents, investigators, and laboratory personnel responsible for the various analyses remained masked to group allocation until the end of the study. | PMC9860215 | ||
Procedures | deaths, acute flaccid paralysis, vaccine-associated | VIRAL DISEASES, ADVERSE EVENTS, ENCEPHALITIS, POLIO, ASEPTIC MENINGITIS, ADVERSE EVENT, DISEASE, POLIO | Infants in the nOPV2 group received a vaccine (PT Bio Farma, Indonesia) composed of an attenuated serotype 2 poliovirus derived from a modified Sabin 2 infectious clone propagated in Vero cells.The first vaccine or placebo dose was given within a window of 0–3 days after birth and all participants received a second dose of their assigned vaccine or placebo 4 weeks after the first dose. Because this was the first planned use in newborn infants, study administrations were first given to 30 participants in a blinded manner (20 [67%] participants with nOPV2 and ten [33%] participants with placebo) and the safety data from these participants were reviewed by the data and safety monitoring board before approval to continue vaccination of the remaining infants.Following vaccine or placebo administration participants were observed for 30 min to record any immediate reaction or adverse event. After each vaccination study staff visited participants' homes daily for 7 days to record in electronic diaries solicited systemic adverse events. Mothers of participants were provided with a telephone number to communicate with the investigator or study staff to report any serious adverse events and weekly study visits were continued throughout the study duration to collect and record any reports of unsolicited adverse events, serious adverse events, or adverse events of special interest, notably anaphylactic reactions, aseptic meningitis or encephalitis, unexplained deaths, or acute flaccid paralysis due to cVDPV or vaccine-associated paralytic polio. The intensity of any recorded solicited or unsolicited adverse event was assessed by the investigator using a standard grading scheme (Before the vaccine administrations at birth and 4-week visits, 1-mL blood samples were drawn and kept refrigerated (2–8°C) during shipping to the icddr,b Matlab laboratory, where sera were prepared within 24 h. Serum aliquots were stored at –20°C and shipped to the Polio and Picornavirus Laboratory of the Division of Viral Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA for measurement of neutralising antibodies against the three polio types by microneutralisation assay. Antibody titres below 1:8 were considered non-detectable and the highest reported reciprocal titre was calculated as at least 1:1448 (10·5 logMothers were asked to collect samples of approximately 8 g of stool at birth and at 2, 4, 6, 8, 10, and 12 weeks during the study ( | PMC9860215 |
Outcomes | ADVERSE EVENTS, DECAY, SECONDARY, VIRAL SHEDDING | The coprimary objectives were to assess the safety and tolerability, and the immunogenicity (measured by seroconversion rate) after one and two doses of nOPV2 when given 4 weeks apart in poliovirus vaccine-naive newborn infants. The secondary outcome was an assessment of the rate, duration, and extent of faecal viral shedding measured by real-time RT-PCR.The safety and tolerability objective was assessed as the incidence rates of solicited adverse events in the 7 days after each vaccination, and unsolicited adverse events, serious adverse events, and adverse events of special interest over the entire study duration, with comparison between nOPV2 and placebo groups. The primary immunogenicity outcome was the seroconversion rate for neutralising antibodies against type 2 poliovirus measured 28 days after the first and second vaccinations with nOPV2. We defined the seroconversion rate cumulatively as the proportions for each group who either (1) became seropositive (≥1:8 titre) after being seronegative (<1:8) at baseline, or (2) had a four-fold or greater increase above the predicted titre in baseline seropositive participants. The predicted titre was calculated assuming an exponential decay from baseline with a half-life of 28 days. | PMC9860215 | |
Statistical analysis | We selected a sample size of 220 participants in the nOPV2 group, with a placebo control group with half that number of participants (n=110), to provide sufficient power to assess the immunogenicity of the candidate vaccines on the basis of previous studies. In a study done in India in 2008, before the cessation of OPV2 usage, Sutter and colleagues | PMC9860215 | ||
Role of the funding source | MH | Four authors, KZ, JDC, AGR, and MH, were employees of the study sponsor, and one, ASB, is employed by the study funder, who were involved in study design, data collection, and writing of the study report. | PMC9860215 | |
Results | pneumonia, hepatitis A/B, vomiting, watery diarrhoea, gastrointestinal disorders | PNEUMONIA, ADVERSE EVENTS, VIRAL SHEDDING, SECONDARY, GASTROINTESTINAL DISORDERS | Between Sept 21, 2020, and Aug 16, 2021, we screened 334 newborn infants, of whom three (<1%) were found to be ineligible and one (<1%) was withdrawn by the parents; the remaining 330 (99%) infants were assigned to the two study groups (220 [67%] assigned to nOPV2 and 110 [33%] to placebo; Trial profilenOPV2=novel oral poliovirus vaccine type 2.Demographics of study participants at enrolment (intention-to-treat population)Data are n (%), n/N (%), or mean (SD). nOPV2=novel oral poliovirus vaccine type 2.Other vaccines included one case of a prophylactic dose of hepatitis A/B at birth.We found that nOPV2 was as well tolerated as placebo; adverse events were reported in 183 (83%) of 220 nOPV2 recipients and in 90 (82%) of 110 placebo recipients (Rates of solicited adverse events within 7 days of the first and second doses in the nOPV2 and placebo groupsSeverity shown only for placebo group as all adverse events in the nOPV2 group were reported as mild. nOPV2=novel oral poliovirus vaccine type 2.Most of the severe unsolicited adverse events were also considered to be serious adverse events. In 16 participants we reported 19 serious adverse events, none of which were considered to be related to study treatment when assessed by the study investigators. With the exception of one infant in the nOPV2 group who was diagnosed with severe pneumonia 5 days after the second vaccination, all serious adverse events occurred more than 9 days after receiving a first or second dose of nOPV2 or placebo. We reported no adverse events of special interest, but when unsolicited adverse events were specifically analysed for gastrointestinal disorders that could potentially be related to an oral vaccine we found six adverse events in nOPV2 recipients: five mild cases (one of vomiting, two of abdominal distension, and two of watery diarrhoea) and one umbilical hernia described as moderate in severity. In placebo recipients we found one case of mild watery diarrhoea. Investigators did not consider that any of these gastrointestinal disorders were related to vaccination.Most newborn infants had neutralising antibodies against polioviruses at birth, presumed due to transfer of maternal antibodies. Seroprotective titres (≥1:8) were present in 204 (93%) of 220 infants in the nOPV2 group and 102 (93%) of 110 in the placebo group (Seroconversion and seroprotection rates for type 2 poliovirus neutralising antibodies (per protocol)Data are n/N (%; 95% CI). nOPV2=novel oral poliovirus vaccine type 2.Only measured in participants whose baseline titre was low enough to allow measurement of a four-times increase without exceeding the maximum titre of 1448. All participants qualified at week 8.Neutralising antibody responses to two doses of nOPV2 or placeboLarge panel shows GMTs against poliovirus type 2 and smaller panels show GMTs against poliovirus types 1 and 3 (Seroconversion resulted in 214 (99%) of 217 vaccine recipients having seroprotective titres (≥1:8) at 8 weeks, after this proportion had initially reduced to 198 (90%) of 219 vaccine recipients at week 4 (Titres of neutralising antibodies against poliovirus types 1 and 3 decreased from birth to week 8 in both nOPV2 and placebo groups, with no notable differences between groups (With respect to the secondary objective of viral shedding, as expected, we found no RT-PCR-detectable shedding of poliovirus types 1, 2, or 3 in baseline stool samples; however, 2 weeks after the first dose of nOPV2, type 2 viral shedding was detectable in 114 (52%) of 219 nOPV2 recipients (Rates of faecal viral shedding by type assessed by real-time RT-PCR over the course of the study (per protocol)CCID50=cell culture infectious dose of 50%. IPV=inactivated poliovirus vaccine. nOPV2=novel oral poliovirus vaccine type 2. OPV=oral poliovirus vaccine.n=110 at baseline and week 2, n=108 at weeks 4 and 6, n=105 at week 8, and n=107 at weeks 10 and 12.The peak positivity of 17% (38/219) in the CCIDWe found two instances each of shedding of poliovirus types 1 and 3 before the administration of bivalent OPV at week 8, with stool samples from two different placebo recipients being PCR positive for type 1 at weeks 6 and 8, and two nOPV2 vaccinees with samples PCR positive for type 3 at week 8. Following doses of bivalent OPV and fractional IPV administration at week 8, poliovirus types 1 and 3 were detected by PCR, but with a small difference in the type 1 shedding in nOPV2 and placebo recipients. 2 weeks after bivalent OPV administration, 77 (72%) of 107 infants in the placebo group were shedding PCR-detectable type 1 poliovirus, which decreased to 43 (40%) of 107 by 12 weeks. In the nOPV2 group, these rates were lower, at 57% (124/219) at week 10 and 27% (60/219) at week 12. Shedding of type 3 poliovirus was similar in both groups and appeared to last longer than that of type 1. Thus, type 3 poliovirus was detectable in 146 (67%) of 219 infants in the nOPV2 group and 71 (66%) of 107 in the placebo group at week 10 and was still detectable in 122 (56%) infants in the nOPV2 group and 60 (56%) in the placebo group at week 12. | PMC9860215 |
Discussion | VIRUS, ADVERSE EVENTS, EVENT, ADVERSE EVENT, EVENTS | We found similar tolerability profiles in the nOPV2 and placebo groups, with only mild solicited adverse events and no related serious adverse events or adverse events of special interest reported. Solicited adverse event rates after nOPV2 and placebo were higher after second doses than after first doses, representing either an increase in the detection rate of such events in children aged 4–5 weeks compared with 0–10 days, or a true increase in the event rate. The immune response was shown against a background of waning maternal neutralising antibodies, evidenced in the placebo group, in which the seroprotection rate decreased from 93% at baseline to 56% at week 8. The 90% seroconversion rate elicited by two doses of nOPV2 resulted in 99% of nOPV2 recipients having seroprotective titres at week 8. Furthermore, in those infants who did not have protective maternal antibodies at birth, vaccination with nOPV2 resulted in 100% seroconversion after two doses, indicating that all infants had protective titres.Following the global withdrawal of OPV2 vaccines,Proportions of infants shedding type 2 virus 2 weeks after the first and second doses of nOPV2 were similar to the proportions shedding types 1 and 3 viruses 2 weeks after the first dose of bivalent OPV. These proportions declined progressively through weeks 4, 8, and 10, and only one infant was still shedding type 2 virus by week 12.Amounts of virus excreted were low, with only 17% at week 2 and 14% at week 6 shedding sufficient virus to be measurable by culture, 2 weeks after the nOPV2 doses, indicating no increased transmission risk for those receiving nOPV2 before any other poliovirus vaccination, relative to those previously receiving IPV.However, our data correspond well with previous observations of nOPV2 shedding in the phase 2 study in previously vaccinated infants in which infants who received nOPV2 displayed similar shedding characteristics to those who received monovalent OPV2 7 days after vaccination but then a significantly lower rate of shedding than monovalent OPV2 4 weeks after vaccination.We have no data on whether nOPV2 interferes with the viral replication or immune responses to Sabin types 1 and 3, as would occur with the later administration of bivalent OPV in routine vaccination schedules. This gap could be seen as a limitation of the present study, because we did not investigate the immune responses to bivalent OPV or the fractional dose IPV, but this question is being investigated in a parallel study (Concerns in industrialised nations where poliovirus is considered to be eliminated following the detection of cVDPV2 in sewage in London, UK,Data from this study support the use of nOPV2 in vulnerable vaccine-naive newborn infants, who might be at particular risk during cVDPV2 outbreaks. nOPV2 has already been widely implemented in outbreak responses, with over 450 million doses distributed under the WHO EUL procedure, with no restriction on the age of recipients. | PMC9860215 | |
Data sharing | Data for this study will be made available to others in the scientific community upon request. Standard criteria for making data available for valid research projects will be used, following application by suitably qualified researchers. For data access, please contact the Bill & Melinda Gates Foundationat | PMC9860215 | ||
Declaration of interests | ET is a full-time employee of the vaccine manufacturer, PT Bio Farma (Bandung, Indonesia). All other authors declare no competing interests. | PMC9860215 | ||
References | PMC9860215 | |||
Supplementary Material | PMC9860215 | |||
Supplementary appendix | PMC9860215 | |||
Acknowledgments | icddr,b acknowledges the commitment of the Bill & Melinda Gates Foundation to its research efforts. icddr,b is also grateful to the Governments of Bangladesh, Canada, Sweden, and the UK for providing core or unrestricted support. The authors are grateful to all the parents and guardians of the infants who were enrolled and participated in this study. We thank the staff at the CDC for performing the neutralising antibody assays and the detection and measurement of poliovirus in faecal samples. We thank Harish Verma, WHO, for his participation in the initial planning visit for the study. We also thank John F Modlin of Dartmouth College (NH, USA) for his input during the initial discussions to design the study. We thank Keith Veitch (keithveitch communications, Amsterdam, Netherlands) for editorial assistance with the manuscript. This activity was reviewed by the CDC and was conducted consistent with applicable federal law and CDC policy. | PMC9860215 | ||
Contributors | MH | KZ, MH, CG, MY, KMJ, JDC, AGR, BAM, ET, and ASB participated in the conception and design of the study and contributed to the writing of the protocol. RC and SACC provided scientific advice for the protocol and interpretation of the results. MH, MY, and KMJ were investigators treating participants. CG performed all statistical elements of study design and oversight of analysis of the results. BAM, JLK-A, WSH, and AV performed all viral analyses and assessments of the neutralising antibodies. ET supplied the nOPV2 vaccine. All authors contributed to the interpretation of the results. ASB led the writing of the initial drafts of the manuscript on which all authors commented, and all authors agreed with the decision to submit for publication. KZ, ASB, and CG accessed and verified the data and all authors had full access to the data. | PMC9860215 | |
Background | GENERALISED CONVULSIVE STATUS EPILEPTICUS | Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20–40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE.
| PMC9830759 | |
Methods | seizure | ADVERSE EVENTS, SECONDARY | This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90. | PMC9830759 |
Results | A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) | PMC9830759 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13054-022-04292-7. | PMC9830759 | ||
Keywords | PMC9830759 | |||
Introduction | epileptic, seizures, convulsive seizure | EPILEPTIC, GENERALISED CONVULSIVE STATUS EPILEPTICUS | Generalised convulsive status epilepticus (GCSE) is a diagnostic and therapeutic emergency and is defined as a convulsive seizure lasting more than 5 min, or as consecutive seizures without recovery of consciousness between seizures [Experts therefore considered that interventions should be proposed as treatment adjuncts to the recommended first- and second-line ASMs, for better controlling the epileptic process (namely, anti-epileptic activity) and to improve recovery (i.e. neuroprotective activity) in GCSE patients admitted to the ICU, as these represent GCSE cases at high risk of poor outcomes [We conducted a multicentre, double-blind, randomised controlled, and pragmatic trial to assess whether the addition of intravenous VPA to the recommended stepwise anti-epileptic strategy in patients admitted to the ICU for GCSE, would increase the number of living patients discharged from hospital by day 15 after GCSE onset [ | PMC9830759 |
Methods | PMC9830759 | |||
Study design | STATUS EPILEPTICUS | VALSE (VALproic Acid in Status Epilepticus) is a multicentre, in parallel, randomised double-blind, controlled trial conducted in 16 French ICUs. It compared the addition of intravenous VPA with placebo in patients admitted to the ICU for GCSE, as well as to first- and second-line ASMs and standard ICU care. The overall study duration for each participant was 3 months. The trial protocol has been published previously and is available with the full text of this article. [Sixteen centres, including 8 general hospitals and 8 university hospitals, participated in this study. Training on study procedures was provided to all participating staff members. | PMC9830759 | |
Eligibility criteria | status epilepticus, seizures, convulsive seizure | STATUS EPILEPTICUS | Adult patients were eligible if admitted to the ICU for GCSE, defined by 5 min or more of continuous or recurrent generalised convulsive seizure without recovery of consciousness between seizures [Main exclusion criteria were non-convulsive status epilepticus clinically characterised by altered mental status but with no motor symptoms at any time during the course of status epilepticus [All patients admitted for GCSE in one of the participating ICUs were screened for eligibility by the ICU physicians and reasons for non-randomisation were collected. | PMC9830759 |
Randomisation and interventions | seizures | Eligible patients were randomly assigned in a 1:1 ratio to receive either VPA or placebo. Randomisation, with stratification according to site, age, and presence of acute brain injury, was performed with the use of a central concealed, Web-based, automated randomisation system. VPA treatment consisted of intravenous administration of a loading dose of 30 mg/kg over 15 min followed by a continuous intravenous dose of 1 mg/kg/h over the next 12 h [In both groups, the anti-epileptic treatment was standardised. If not initiated before ICU admission, the patients had to receive the first- and second-line ASMs before the administration of VPA. More specifically, in patients who had not received a second-line ASM before their admission to the ICU, the second-line ASM was to be administered when the GCSE evolving over 5 to 30 min had required several intravenous boluses of benzodiazepines, or when the seizures were controlled by a single administration of benzodiazepines but beyond 30 min after their onset, as recommended by the 2009 French Expert Guidelines [ | PMC9830759 | |
Outcomes and assessment | super-refractory, abnormal movements, seizure | ADVERSE EVENTS, RECURRENCE | The primary outcome was the proportion of living patients discharged from hospital to their home or to a long-term care facility on day 15. The primary endpoint (i.e. hospital status at day 15) was collected by a local investigator, blinded to group assignment (Additional file Secondary outcomes were recurrence of seizure during ICU stay, occurrence of refractory and super-refractory GCSE during ICU stay, occurrence of adverse events whilst in hospital, and cognitive status at day 90 assessed with the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Glasgow Outcome Scale-Extended (GOSE). Follow-up visits occurred at day 15, at ICU and hospital discharge, and at day 90.Patients were assessed neurologically every 4 h whilst in the ICU, notably for awakening, focal neurological signs, and abnormal movements. In both groups, serum samples were obtained prior to, and 15 min and 12 h after, administration of the study drug load in order to measure serum VPA concentrations. Samples were stored at − 20 °C in the participating centres before being sent to the Department of Pharmacology and Toxicology of the Raymond Poincaré Teaching Hospital (Garches, France) for centralised VPA measurements. In every patient, administration of a standard EEG was recommended within 24 h of ICU admission and again between day 2 and day 7. EEGs were interpreted by the referring neurophysiological team of the participating centre, which was blinded to study drug groups.Up to hospital discharge, we collected the time to awakening, length of ICU and hospital stays, in-ICU and in-hospital mortality, and changes in the maintenance ASMs. At day 90, the referring neurologist or intensivist assessed MMSE and FAB through a medical examination and the GOSE by phone. | PMC9830759 |
Statistical analysis | REGRESSION, SECONDARY | The study was powered to detect an absolute increase of 20% in the rate of patients discharged alive at day 15 with a power of 90% and a two-sided 0.05 significance level, assuming a 50% rate in the control group. Accordingly, the sample size was 124 patients per group. To account for potential errors in the administration of the allocated treatment, this number was increased to 150 per group.The analysis followed the intention to treat (ITT) principle, and all randomised participants were analysed in the group allocated by randomisation, regardless of the actual treatment received or other protocol deviations. Only participants withdrawing their consent during the study and opposing analysis of their data were excluded from the analysis. The Statistical Analysis Plan was developed blinded to treatment assignment (i.e. without knowledge of group allocation), except for the last amendment concerning fallback solutions when some models did not converge. When drafting the first version of the Statistical Analysis Plan, some changes were made compared to the original protocol: (1) the last observation carried forward approach to handle supplemented by multiple imputation for missing data, given that the primary outcome was missing for two participants only; (2) the analytic model for binary outcomes changed from logistic regression with random centre effects to a log-binomial model with robust standard errors in order to directly estimate relative risks (RRs) instead of odds ratios and limit issues with convergence of binomial generalised linear mixed models [Missing primary outcome data were treated as failures, and sensitivity analyses with the worst-case scenario imputation (imputing a failure in the experimental group but a success in the control group) or available data analysis were carried out. No imputation was performed for secondary efficacy and safety outcomes.Binary outcomes were analysed with a log-binomial model adjusted for the randomisation strata, with robust standard errors to account for centre [No correction for multiplicity and no hierarchical testing procedures were used in analysing secondary outcomes, which should be regarded as exploratory. Analyses were performed using R 4.0.5 software (The R Foundation for Statistical Computing, Vienna, Austria). | PMC9830759 | |
Anti-epileptic administration | Eighty-three of the 103 (42%) patients who had not received a second-line ASM before being admitted to the ICU received it within the first 24 h after admission, mainly within the first 6 h (Fig. Timing of second-line anti-seizure medicine (ASM) (panel | PMC9830759 | ||
Secondary outcomes | SUPER-REFRACTORY STATUS EPILEPTICUS | The ICU, hospital, and day 90 mortality rates were similar between the two groups as well as the proportion of patients developing refractory and super-refractory status epilepticus (Table | PMC9830759 | |
Adverse events | ADVERSE EVENTS | One or more adverse events of any grade of severity were declared by the investigators during hospital stay in 52 (44%) and 45 (36%) patients from the VPA and placebo groups, respectively ( | PMC9830759 | |
Discussion | epileptic, super-refractory | ADVERSE EVENTS, EPILEPTIC | In this multicentre, double-blind, randomised, controlled, and pragmatic trial, we found that the intravenous administration of VPA, in addition to first- and second-line ASMs, did not increase the proportion of patients discharged alive from hospital within the first 15 days. We also found that VPA did not increase the occurrence of adverse events and did not decrease incidence of refractory and super-refractory status epilepticus or 90-day mortality.The absence of impact of VPA on the patient status at day 15 could be a result of various factors. First, the observed median length of hospital stay (12 days) was close to what we had anticipated (15 days), whereas it was 21 days in the ICU-admitted GCSE population of the HYBERNATUS trial and 10 days in the pre-hospital GCSE population of the SAMUKeppra trial [Second, the low rate of mortality and refractoriness might suggest that our cohort is not representative of ICU-admitted GCSE patients. This is unlikely given that 16 general ICUs participated in our trial. Moreover, patients from this trial were appropriately referred to the ICU, as indicated not least by the fact that there was an 85% rate of invasive mechanical ventilation within the first 24 h. It is noteworthy that only a third and one half, respectively, of GCSE patients admitted to the ICU were intubated in the ESETT and RAMPART trials [The main explanation for the low rate of refractory and super-refractory GCSE is that the step-by-step anti-epileptic treatment had been closely followed and was effective. Of note is the rate of refractory GCSE at ICU admission, which was 9% in our trial but 25% in the HYBERNATUS study [We are not able to rule out that greater circulating levels of VPA would have allowed a better epileptic control and a greater neuroprotective effect, as evidenced in experiment models [Another limitation is related to the early termination of the trial. Although 99% (245/248) of the calculated sample size had been enrolled, which would have led to negligible loss of power, some participants did not receive the allocated treatment and a few outcomes were missing, so that the power of the trial may be slightly decreased. However, the confidence interval of the treatment difference on the primary outcome clearly ruled out the anticipated 20% risk reduction.
In conclusion, administration of VPA, when added to the recommended stepwise anti-epileptic regimen, is well tolerated but not associated with a significant impact on hospital discharge or evolution towards refractory or super-refractory status epilepticus in patients admitted to an ICU for GCSE. Altogether, our results indicate that most ICU-admitted GCSE patients were treated according to available guidelines and had good short-term outcomes.
| PMC9830759 |
Acknowledgements | Nawal Derridj-Ait-Younes, Yasmine Domingo-Saidji, Pierre Asfar, Raphaël Clere-Jehl | MARION, FRANCIS, HARLEY | We thank the members of the data and safety monitoring board (Nawal Derridj-Ait-Younes, Nabila Yasmine Domingo-Saidji, Abderraouf Hermez, Chanez Lazizi, Naima Imam-Sghiouar), Pr Philippe Aegerter for his support and advice in the early stages of the trial, and the trial participants who were willing to be randomly assigned to either a placebo or a valproic acid group and to adhere to a trial protocol that lasted 3 months. Laurent Argaud (Service de Médecine intensive—Réanimation, Hôpital Edouard Herriot, Lyon), Pierre Asfar (Réanimation Médicale, Centre hospitalo-universitaire, Angers, France), Eric Azabou (Service d’Explorations Fonctionnelles, Hôpital Raymond Poincaré, Garches, France), François Beloncle (Réanimation Médicale, Centre hospitalo-universitaire, Angers, France), Omar Ben Hadj (Réanimation Médico-Chirurgicale, Centre Hospitalier Intercommunal Poissy Saint-Germaine-en-Laye, Poissy, France), Pascal Blanc (Réanimation Médico-Chirurgicale, Centre Hospitalier René-Dubos, Pontoise, France), Pierre-Edouard Bollaert (Réanimation Médicale, Hôpital Central, Nancy, France), Francis Bolgert (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, Paris, France), Lila Bouadma (Réanimation Médicale, Hôpital Bichat, Paris, France), Patrick Chillet (Réanimation Polyvalente, Châlons-en-Champagne, France), Bernard Clair (Réanimation Médico-Chirurgicale, Hôpital Raymond Poincaré, Garches, France), Philippe Corne (Réanimation, Hôpital Lapeyronnie, Montpellier, France), Raphaël Clere-Jehl (Réanimation Médicale, Strasbourg, France), Martin Cour (Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Médecine Intensive-Réanimation, Lyon, France), Arielle Crespel (Neurologie, CHU, Montpellier, France), Véronique Déiler (Réanimation Médicale, Hôpital Bichat, Paris, France), Jean Dellamonica (Réanimation Médicale, Centre Hospitalo-Universitaire de Nice, Nice, France), Sophie Demeret (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, Paris, France), Marie-Line Harley (Réanimation Médicale, Strasbourg, France), Matthieu Henry-Lagarrigue (Médecine Intensive Réanimation Centre Hospitalier Départemental de Vendée, France), Julien Jabot (Réanimation Polyvalente, Hôpital Félix Guyon Saint Denis, France), Nicholas Heming (Réanimation Médico-Chirurgicale, Hôpital Raymond Poincaré, Garches, France), Romain Hernu (Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Médecine Intensive-Réanimation, Lyon, France), Achille Kouatchet (Réanimation Médicale, Centre hospitalo-universitaire, Angers, France), Christine Lebert (Réanimation Polyvalente, Centre Hospitalier Départemental de Vendée, France), Nicolas Lerolle (Réanimation Médicale, Centre hospitalo-universitaire, Angers, France), Eric Maury (Réanimation Médicale, Hôpital Saint-Antoine, Paris, France), Sophie Letrou (Réanimation Médicale, Hôpital Bichat, Paris, France), Aurélien Mazeraud (Neuroréanimation, GHU-Paris, Site Sainte-Anne, Paris, France), Alain Mercat (Réanimation Médicale, Centre hospitalo-universitaire, Angers, France), Satar Mortaza (Réanimation Médicale, Centre hospitalo-universitaire, Angers, France), Bruno Mourvillier (Réanimation Médicale, Hôpital Bichat, Paris, France), Hervé Outin (Réanimation Médico-Chirurgicale, Centre Hospitalier Intercommunal Poissy Saint-Germaine-en-Laye, Poissy, France), Catherine Paugham-Burtz, Hôpital Beaujon, Clichy, France), Marc Pierrot (Réanimation Médicale, Centre hospitalo-universitaire, Angers, France), Marion Provent (Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Médecine Intensive-Réanimation, Lyon, France), Benjamin Rohaut (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, Paris, France), Sylvie De La Salle (Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Médecine Intensive-Réanimation, Lyon, France), François Santoli (Réanimation Médico-Chirurgicale, Centre Hospitalier Intercommunal Robert Ballanger, Aulnay-sous-Bois, France), Maleka Schenk (Réanimation Médicale, Strasbourg, France), Francis Schneider (Réanimation Médicale, Strasbourg, France), Shidasp Siami (Réanimation Polyvalente, Centre Hospitalier Sud-Essonne, Etampes, France), Vincent Souday (Réanimation Médicale, Centre hospitalo-universitaire, Angers, France), Tarek Sharshar (Neuroréanimation, GHU-Paris, Site Sainte-Anne, Paris, France), Romain Sonneville (Réanimation Médicale, Hôpital Bichat, Paris, France), Jean-François Timsit (Réanimation Médicale, Hôpital Bichat, Paris, France), Marie Thuong (Réanimation médico chirurgicale, centre Hospitalier René Dubos, Pontoise, France), Nicolas Weiss (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, Paris, France). | PMC9830759 |
Author contributions | HO | RECRUITMENT | TS was involved in conception of the work (PI), funding application, enrolment of participating centres, supervision of the data collection, participation in data analysis verification of the data and interpretation, writing of the manuscript, critical revision of the manuscript. HO and BC helped in conception of the work, funding application, enrolment of participating centres, patients’ recruitment, data collection, interpretation of the results. LG contributed to data management. RP was involved in statistical analysis. VN and AM helped in interpretation of the results, writing of the manuscript, critical revision of the manuscript. Other authors were involved in patients’ recruitment and data collection. All authors read and approved the final manuscript. | PMC9830759 |
Funding | MAY | Programme Hospitalier de Recherche Clinique 2010 of the French Ministry of Social Affairs and Health. VALSE ClinicalTrials.gov number, NCT01791868 registered May 2012. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report, or in the decision to submit the article for publication. | PMC9830759 | |
Availability of data and materials | MYASTHENIA GRAVIS | Data available: Yes. Data types: De-identified participant data. How to access data: De-identified patient data to reproduce results presented in the article when available: With publication Supporting Documents Document types: None. Who can access the data: Researchers whose proposed use of the data has been approved. Types of analyses: Research projects with the same scientific purpose as the original study (treatment of myasthenia gravis), such as meta-analysis, for instance. Mechanisms of data availability: Data will be made available upon approval of a proposal, Data will be made available upon approval of a proposal, authorization from the French Comité de Protection des Personnes (IRB) who authorized the study, and after a signed data access agreement with the trial sponsor. Any additional restrictions: none. | PMC9830759 | |
Declarations | PMC9830759 | |||
Ethics approval and consent to participate | Ethics approval was granted by the French regulatory board ( | PMC9830759 | ||
Consent for publication | Not applicable. | PMC9830759 | ||
Competing interests | RS | RS received grants from the French Ministry of Health, the French Society of Intensive Care Medicine (SRLF), and the European Society of Intensive Care Medicine (ESICM). All other authors declare no competing interests. | PMC9830759 | |
References | PMC9830759 | |||
Background | hearing loss, Hearing loss | HEARING LOSS, AIDS, HEARING LOSS | Hearing loss is a growing health concern worldwide. Hearing aids (HAs) are the treatment of choice for hearing rehabilitation in most cases of mild-to-moderate hearing loss. However, many patients with hearing loss do not use HAs due to their high cost, stigma, and inaccessibility. Since smartphones are widely used, many apps that mimic the amplification function of HAs have been introduced. Smartphone-based HA apps (SHAAs) are affordable and easy to access. However, the audiological benefit of SHAAs has not been determined. | PMC10578122 |
Objective | We compared the audiological performance between an SHAA and a conventional HA in a prospective, multicenter randomized controlled trial. | PMC10578122 | ||
Methods | hearing loss | HEARING LOSS | Patients with mild-to-moderate hearing loss were prospectively enrolled from 2 tertiary hospitals and randomly assigned to either an SHAA (Petralex; IT4YOU Corp LLC) or a conventional HA (Siya 1 miniRITE; Oticon A/S). For the cross-over study design, participants used the alternate device and repeated the same 2-month trial. Audiological measurements were obtained using hearing tests, real-ear measurements, and the hearing-in-noise test (HINT). Subjective satisfaction was evaluated using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and International Outcome Inventory for Hearing Aids (IOI-HA). | PMC10578122 |
Results | ADVERSE EVENTS | Overall, 63 participants were screened and 38 completed the study. In sound-field audiometry testing, the SHAA showed a 20- to 60-dB gain in the low-to-high frequencies of the hearing threshold level. The HA provided adequate gain in the middle-to-high frequencies (55, 65, and 75 dB in real-ear measurements), which is the sound level for most speaking volumes. However, the SHAA could not improve word recognition at 50 dB. The HA showed better audiological performance than the SHAA in both quiet and noisy conditions in the HINT. The IOI-HA scores were significantly improved by both the HA and SHAA versus unaided conditions. Among the SHAA users, 37% (14/38), 42% (16/38), 24% (9/38), and 32% (12/38) showed improvement in APHAB scores for ease of communication, reverberation, background noise, and aversiveness of sounds, respectively. There were no differences in adverse events between the 2 study groups. | PMC10578122 | |
Conclusions | hearing loss | HEARING LOSS | The HA showed better performance than the SHAA in word recognition and the HINT. However, the SHAA was significantly better than unaided hearing in terms of amplification. The SHAA may be a useful hearing assistance device for patients with mild-to-moderate hearing loss when listening to soft sounds in quiet conditions. The SHAA demonstrated poorer performance than the HA in the mid- to high-frequency sounds that are important for word recognition, sound quality, and hearing in noisy conditions. Further development of the signal technology of SHAAs is needed to improve the sound quality of mid- to high-frequency sounds and overcome noisy environments. | PMC10578122 |
Trial Registration | ClinicalTrials.gov NCT05644106; | PMC10578122 | ||
Introduction | hearing amplification, hearing impairment, REMs, hearing loss, Hearing loss | HEARING LOSS, HEARING IMPAIRMENT, AIDS, HEARING LOSS | Hearing loss is a common and growing global health issue. The World Health Organization (WHO) reported that approximately 2.5 billion people will experience hearing loss and 700 million will need hearing rehabilitation by 2050 [Hearing rehabilitation improves audiological performance, daily activity functioning, and quality of life. Hearing aids (HAs) are the most common and important method of hearing rehabilitation [Smartphones can be useful devices for amplification, and many smartphone-based HA apps (SHAAs) have been developed to improve the audibility of sounds for both individuals with and without hearing impairment [Although some SHAAs provide the recommended level of processing delay, conventional HAs have shown better performance than SHAAs in most aspects of amplification. Our previous study on the electroacoustic performance of various SHAAs [This study compared the audiological performance of an SHAA to that of a conventional HA. The study settings included unaided and aided conditions in quiet and noisy situations. The objective benefit of hearing amplification was evaluated in sound-field tests and real-ear measurements (REMs). We used the sound-field test to evaluate the hearing threshold and word recognition scores (WRSs) at 50 dB. REMs were studied using 55-, 65-, and 75-dB stimuli in the 250-8000 Hz range. The subjective benefits were evaluated using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and International Outcome Inventory for Hearing Aids (IOI-HA). | PMC10578122 |
Methods | PMC10578122 | |||
Study Design | sensorineural, hearing amplification, tinnitus, Hearing impairment, hearing loss | SENSORINEURAL HEARING LOSS, ADVERSE EVENTS, TINNITUS, HEARING IMPAIRMENT, HEARING LOSS | A prospective randomized controlled trial was conducted at 2 tertiary hospitals in South Korea (the Department of Otolaryngology, Seoul National University Hospital and the Department of Otolaryngology, The Catholic University of Korea, Seoul St. Mary’s Hospital) from August 2020 to November 2022. The inclusion criteria were (1) acquired symmetrical, sensorineural, and mild-to-moderate hearing loss; (2) current use of a smartphone; and (3) no previous experience with hearing amplification. Mild and moderate hearing loss ranged from the 26- to 40-db hearing level and from the 41- to 55-dB hearing level, respectively (according to the American Speech-Language-Hearing Association) [To identify sensorineural hearing loss, otoscopy, pure-tone audiometry (PTA) by air and bone conduction, and tympanometry were performed. All participants visited 4 times and all tests were conducted in a sound-treated room. At the first visit, demographic assessment, otoscopy, tympanogram, tinnitogram, PTA, and speech audiometry were conducted. At the second visit, the participants who passed the screening test were enrolled; otoscopy, sound-field unaided and aided PTA, and WRS testing were performed; and our questionnaire was completed. At this time, the participants were randomly given their first hearing amplification to use for 2 months. At the 2-month visit, the same tests were conducted except for unaided PTA and WRS testing. The hearing amplification method was then switched to be used for another 2 months. At the final visit, participants completed the same tests as in the previous visit. Hearing impairment (>20-dB change in 1 frequency, >10-dB change in 2 consecutive frequencies, or >5-dB change in 3 consecutive frequencies) and tinnitus (>1 mo for at least 8 h/d) were considered adverse events in this study. | PMC10578122 |
Ethical Considerations | This study was registered in the clinical trials registry in South Korea (Clinical Research Information Service; KCT0005458) [ | PMC10578122 | ||
Hearing Amplification Systems (HA and SHAA) | A pilot study that conducted behavioral evaluations of 3 SHAAs provided the evidence used to select an SHAA for this study [For the conventional HA, we used the Siya 1 miniRITE (Oticon A/S), coupled with two 85-dB receivers and single closed ear tips. The Siya 1 miniRITE is an essential-level HA, first introduced in 2018 with 48 channels and 10 adjustable bands. The Siya 1 miniRITE has basic modern digital HA technology including advanced feedback management, noise reduction, and multiband directionality. During the study, special functions of the Siya 1 miniRITE were activated, including instantaneous noise management, binaural bandwidth processing, and a feedback shield. However, noise reduction was not activated. All participants used each method, alternating at 2 months. Before the study, all measurement materials were calibrated. | PMC10578122 | ||
Sound-Field Audiometry and WRS Tests | WRS, hearing amplification | Sound-field audiometry (SFA) and WRS tests were performed using a calibrated Interacoustics AC40 (Interacoustics A/S). To determine the difference between the SHAA and the conventional HA, SFA was obtained at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz for both hearing amplification systems. Warble tone was used to avoid standing waves. The WRS was evaluated using the Korean Standard Monosyllabic Word List for Adults [ | PMC10578122 | |
REM Test | REMs | This test measures actual HA gain by comparing the difference between the HA target value and the sound pressure measured using a microphone probe tip in the ear canal. We used Affinity 2.0 software (version 2.6.0; Serif Ltd) to conduct the REMs. To validate the HA performance, the REMs were performed using speech stimuli divided into a soft level (55-dB sound pressure level [SPL]), a medium level (65-dB SPL), and a loud level (75-dB SPL) based on the National Acoustic Laboratory–NL2 prescription. For the SHAA, the gain control and parameters were modified manually to match the targets. | PMC10578122 | |
Hearing-in-Noise Test | The hearing-in-noise test (HINT) was developed to measure binaural speech recognition ability under quiet and noisy situations [ | PMC10578122 | ||
Questionnaires | For the measurement of subjective satisfaction, the APHAB and IOI-HA were used. The APHAB consists of 4 items: ease of communication, reverberation, background noise, and aversiveness of sounds. Each item has 6 questions, and higher scores indicate greater disability. This survey can be used to evaluate the performance of an HA in unaided and aided conditions. The IOI-HA is a self-estimation tool designed to check the efficiency of HA fitting [ | PMC10578122 | ||
Statistical Analysis | A sample size of 26 would achieve 90% power to detect noninferiority with a 1-sided significance level of .025, and a cross-over design would have a margin of noninferiority of −10%, a true mean difference of 0, and an SD of the paired differences of 15, based on the test results from a previous study for understanding speech in noise [ | PMC10578122 | ||
Results | PMC10578122 | |||
SFA and WRS Results | WRS | The SHAA showed a slightly lower gain at all frequencies than the conventional HA, with statistical significance at 1000 Hz (Sound-field (warble-tone) audiometry thresholds in the HA and SHAA groups. Error bars indicate the SD. db HL: decibel of hearing level; HA: hearing aid; SHAA: smartphone-based hearing aid app. *Improvements in WRS, comparing unaided and aided conditions at 50-dB hearing level stimuli. Error bars indicate the SD. SHAA: smartphone-based hearing aid app; WRS: word recognition score. | PMC10578122 | |
REM Results | In real-ear aided responses at 55 dB, the HA showed a larger gain at 1000, 2000, 3000, 4000, and 6000 Hz than the SHAA. The SHAA showed a larger gain at low frequencies (250 and 500 Hz) than the HA. Statistical significance was found at 500 Hz (Real-ear aided responses (REARs) of the hearing aid and SHAA groups measured at the 55-, 65-, and 75-dB sound pressure levels (SPLs): average REAR in the right ear at the (A) 55-, (B) 65-, and (C) 75-dB SPLs and average REAR in the left ear at the (D) 55-, (E), 65-, and (F) 75-dB SPLs. Error bars indicate the SD. SHAA: smartphone-based hearing aid app. * | PMC10578122 | ||
HINT Results | The mean SNRs (HINT performance) in the unaided, HA, and SHAA groups were 51.3 (SD 5.6), 47 (SD 3.4), and 56 (SD 6.4) dB, respectively, in a quiet situation (Hearing-in-noise test (HINT) in quiet, front noise, left noise, and right noise conditions for the unaided, hearing aid, and SHAA groups. Error bars indicate the SD. RTS: reception threshold for speech; SHAA: smartphone-based hearing aid app; SNR: signal-to-noise ratio. | PMC10578122 | ||
Questionnaire Results | The mean score of the IOI-HA was 7 (SD 0), 23.4 (SD 4.0), and 16.3 (SD 4.9) in the unaided, HA, and SHAA groups, respectively (International Outcome Inventory for Hearing Aids (IOI-HA) items for the unaided, hearing aid, and SHAA groups. Error bars represent the SD. SHAA: smartphone-based hearing aid app. *In the ease of communication subscale item of the APHAB, the mean scores were 45.6 (SD 20.0), 51.2 (SD 20.9), and 33.2 (SD 18.0) in the unaided, SHAA, and HA groups, respectively (Mean score of the Abbreviated Profile of Hearing Aid Benefit (APHAB) items for the unaided, hearing aid, and smartphone-based hearing aid app (SHAA) groups. Error bars indicate the SD. AV: aversiveness of sounds; BN: background noise; EC: ease of communication; RV: reverberation. *A comparison of individuals in the SHAA group between unaided and aided conditions found that 37% (14/38), 42% (16/38), 24% (9/38), and 32% (12/38) of users showed improvements in the ease of communication, reverberation, background noise, and aversiveness of sound APHAB subscales, respectively. In the same subscales of the APHAB, the mean postintervention scores were 43.1 (SD 24.0), 50.2 (SD 10.8), 45.8 (SD 8.0), and 35.4 (SD 16.1), respectively (Mean scores of the Abbreviated Profile of Hearing Aid Benefit (APHAB) items for the unaided and aided conditions in the SHAA group, with improvements in ease of communication, reverberation, background noise, and aversiveness of sound. | PMC10578122 | ||
Discussion | PMC10578122 | |||
Principal Findings | REMs, WRS | This study used a noninferiority study design to compare the audiological performance between an SHAA and a conventional HA. The SHAA did not show noninferiority to the HA in the WRS test, which was the primary measurement used in the original study. However, the SHAA showed feasibility in some users, especially in unaided conditions and for the amplification of soft sounds. In this study, 63 participants were screened and 38 finished the study. The objective audiological performance was evaluated using the warble-tone hearing test, the WRS test, REMs, and the HINT, and subjective satisfaction was evaluated using the APHAB and IOI-HA questionnaires. The aided hearing thresholds for the SHAA were 20-60 dB, from low to high frequencies. Although the SHAA group showed a lower gain at the 1000- to 8000-Hz levels than the HA group, it showed gains similar to those of the HA group at low frequencies. The REMs results at 75 dB, as well as the common speaking levels of 55 and 65 dB, indicated that the HA group showed greater gains in the middle-to-high frequencies than the SHAA group. One-third (14/38, 37%) of the SHAA group showed slight improvements in WRS. However, most SHAA users (24/38, 63%) showed no difference in their WRS compared to the unaided group. The HA group showed significantly better audiological performance than the unaided and SHAA groups in all HINT situations. The HA group showed the highest scores in the IOI-HA, but the SHAA users also showed significantly greater improvement than the unaided group. A comparison of individuals in the SHAA group between unaided and aided conditions found that 37% (14/38), 42% (16/38), 24% (9/38), and 32% (12/38) of users showed improvements in the ease of communication, reverberation, background, and aversiveness of sound subscales of the APHAB, respectively. | PMC10578122 | |
Strengths and Limitations | To the best of our knowledge, this is the first prospective, multicenter randomized controlled trial comparing an SHAA and a conventional HA. Hearing performance was evaluated for comprehensive objective functional gain and for subjective satisfaction.In this study, we enrolled Android users who used their own smartphones. Although the performance varies depending on which app is used on different smartphone models, de Sousa et al [ | PMC10578122 | ||
Conclusion | hearing loss | HEARING LOSS | In our study, the SHAA demonstrated a significant benefit when compared to an unaided situation. Our results indicate that the SHAA could be a useful assistive device for patients with mild-to-moderate hearing loss in quiet conditions. In addition, people with poor access to hearing amplification devices can more easily download an SHAA at a more reasonable price than a conventional HA. Although, the SHAA performed poorly when compared with the HA at a conversational sound level and in noisy conditions, the future signal technology of SHAAs should improve and perform better in noisy environments.This research was supported by a grant from the Korea Health Technology Research and Development Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant HC19C0128).None declared. | PMC10578122 |
Abbreviations | Abbreviated Profile of Hearing Aid Benefithearing aidhearing-in-noise testInternational Outcome Inventory for Hearing Aidspersonal sound amplification productpure-tone audiometryreal-ear measurementsound-field audiometrysmartphone-based hearing aid appsignal-to-noise ratiosound pressure levelWorld Health Organizationword recognition score | PMC10578122 | ||
References | CONSORT-eHEALTH checklist (V 1.6.1). | PMC10578122 | ||
1. Introduction | deaths, death, premature illness | PROLIFERATION, DISEASE, DISEASES | Young children are particularly vulnerable to harms from tobacco smoke exposure (TSE). This study aimed to compare TSE: (1) between children who live in smoking families and those who do not; and (2) among children who live in smoking households with varying smoking locations. The data came from two studies that were conducted concurrently in Israel (2016–2018). Study 1: a randomized controlled trial of smoking families (Tobacco use continues to be the leading preventable cause of premature illness and death in the world. Tobacco kills up to half of those who use it, resulting in over 7 million global deaths each year. An additional 1.2 million people die from diseases caused by exposure to secondhand smoke (SHS) [Scientific evidence showing the causal relationship between tobacco smoke exposure (TSE), which includes both second- and third-hand exposure, and death and disease, has led to a proliferation of smoke-free laws in public places throughout the world, particularly in bars, restaurants, hospitality venues, and workplaces [Restricting smoking to outside of the home has long been thought to help reduce and even eliminate a child’s exposure to tobacco smoke. However, studies have shown that even when parents restrict smoking to areas outside the home, exposure may occur, increasing the risk of disease for children. A study in California by Matt et al. found that young child TSE, based upon cotinine levels, was 5–7 times higher in households of smokers who smoked outdoors than in households of nonsmokers [Smoking rates are high in Israel (1 in 5 adults smoke), and over 60% of children are exposed to TSE [We aimed to (1) assess TSE exposure in study samples of children living in non-smoking and smoking families in Israel and (2) assess whether TSE differed by smoking location (inside, on the balcony/porch, or in the yard, garden, or other place outside of the home). We hypothesized that an unrestricted smoking policy, where smoking is allowed in any room or part of the home, would be associated with the highest levels of TSE; however, based on previous literature, we also anticipated detectable levels of TSE among children whose parents restricted smoking to balconies or yards. | PMC9965201 |
2. Materials and Methods | PMC9965201 | |||
2.1. Study Design, Samples and Procedures | The data came from two studies that were conducted in Israel at the same time between 2016 and 2018. The first study (Study 1) was a randomized controlled trial (RCT), “Project Zero Exposure,” which included 159 families with at least one parent who smoked cigarettes living in the household. The RCT assessed an intervention program to help parents protect their children from tobacco smoke. Details about Project Zero Exposure can be found elsewhere [ | PMC9965201 | ||
2.2. Eligibility Criteria | Inclusion criteria included: (1) at least one smoking parent living in the household who smoked at least 10 cigarettes per week (Study 1) or no parents who smoked in the household (Study 2); (2) having a child aged up to 8 years; (3) the parent(s) were willing to provide a hair sample for research purposes; and (4) children had a sufficient hair sample for the laboratory analysis. | PMC9965201 | ||
2.3. Ethics and Registration | National Institute of Health (NIH) Clinical Trials Registry: NCT02867241. Ethical approval was obtained from the Helsinki Committee of Asaf Harofe Hospital (0143-16 ASF), the Israel Ministry of Health (920090057), and the Tel Aviv University Ethics Committee. All parents provided written consent for their children to participate. | PMC9965201 | ||
2.4. Measures | PMC9965201 | |||
2.4.1. Primary Outcome | The primary outcome for this analysis was child exposure to tobacco smoke, measured by hair nicotine. Child hair nicotine was chosen because it reflects long-term exposure (approximately 1 cm of hair growth/month) [We analyzed TSE in two ways. First, we assessed TSE as a binary variable indicating “exposed” (yes, above the limit of detection) versus “unexposed” (no, below the limit of detection). This approach is useful because there is no safe level of exposure to tobacco smoke, so any exposure is important, and also because it provides information on the proportion exposed, which is easily understandable. Second, we assessed TSE as a continuous variable based on the levels of hair nicotine and used the natural log transformation because of the known non-normal distribution of hair nicotine. Hair nicotine was analyzed in ten separate batches over the course of the research. | PMC9965201 | ||
2.4.2. Independent Measures | Study 1 vs. Study 2: The independent variable for the first analyses was whether the children were from smoking or non-smoking families. Study 1: The independent variable for the second assessment was the location of smoking. We asked parents to show us where they usually smoked, with the question “Where does smoking usually take place?” and recorded and categorized the responses into four categories: (1) garden/yard/other place outside of the home; (2) balcony (without differentiating between degree of enclosure of the porch or whether the balcony had a roof); (3) designated smoking areas inside the home (DSA) (e.g., enclosed service/laundry balcony/clearly indoor balcony, designated room, or smoking at the window); or (4) anywhere inside the house. Because only 3 families reported smoking in the entire house, we combined categories 3 and 4 into a single category, “in the home,” for the purpose of statistical analysis. We asked about the daily number of cigarettes smoked by the parents and created a variable that indicated the combined number of cigarettes smoked daily. We asked about which parent smokes (mother only, father only, both), and categorized the variable into two categories: (1) Both parents smoke; or (2) only one parent smokes.Sociodemographic questions: sociodemographic data were used in adjusted models. Data collected were: child age in months; parental nationality (both parents Israel-born/other); maternal education (categorized into non-academic and academic; at least some university-level education); paternal education (categorized into non-academic and academic); monthly household income (categorized into above average, average, and below average); neighborhood SES (scale of 1–20, with 20 the highest) [ | PMC9965201 | ||
2.5. Statistical Analyses | Descriptive statistics were used to describe the study samples. | PMC9965201 | ||
2.5.1. Analyses, Smoking Families vs. Nonsmoking Families (Study 1 vs. Study 2) | We compared child TSE (above the LOD: yes vs. no) between non-smoking and smoking families using a chi-squared test. We used a linear model to compare child exposure between non-smoking and smoking families as measured by log-hair nicotine (LHN) while controlling for laboratory batch. Because of the small number of participants in the non-smoking family cohort, we did not perform multivariable analyses. | PMC9965201 | ||
2.5.2. TSE by Location of Home Smoking and Other Explanatory Variables (Study 1) | CPD | REGRESSION | We first assessed TSE by location of home smoking using the LOD (dichotomous outcome: exposed vs. not exposed) using a chi-squared test. We also tested the bivariate relationship between above-LOD exposure and each of the following variables: number of parental smokers (both or one), child sex, parental nationality, maternal education, paternal education, and income, using chi-squared tests, and child age, parental combined cigarettes per day (CPD), and neighborhood SES, using t-tests. Next, we conducted an adjusted logistic regression analysis to examine whether TSE differed by location of smoking and to identify any correlates that were associated with TSE while controlling for batch. Finally, we ran parallel analyses to those above using the continuous outcome (log hair nicotine) using a multivariable linear model while controlling for batch. We also performed a sensitivity analysis using Tobit regression. | PMC9965201 |
3. Results | PMC9965201 | |||
3.2. Characteristics of Smoking and Non-Smoking Families | Among non-smoking families, 3 of the 20 families reported that smoking sometimes took place on porches, but none of them reported smoking occurring in any other setting. | PMC9965201 | ||
3.3. Laboratory Batch Results | For the ten batches analyzed, LOD (ng/mg) ranged from 0.014–0.18 (mean LOD: 0.034, median LOD: 0.038). One batch had an LOD of 0.18 and another of 0.09. All other batches had LODs between 0.01 and 0.05. A histogram of hair mass can be found in | PMC9965201 | ||
3.4. Child TSE in Smoking vs. Nonsmoking Families | REGRESSION | Of the 141 children from smoking families with sufficient hair, 68.8% (In the linear regression of LHN, which included a term for laboratory batch, the group variable was borderline significant ( | PMC9965201 | |
3.6. The Association between Child TSE and Other Variables in Smoking Families | The only variable to reach statistical significance in the bivariable comparisons of the proportion of children exposed (Model 1) was paternal education ( | PMC9965201 | ||
4. Discussion | The purpose of this study was to compare tobacco smoke exposure [TSE] among children who live in smoking families versus those who do not, as well as among children who live in smoking households with varying smoking locations. We found that about a third of children of non-smoking parents were measurably exposed to tobacco smoke, and roughly double that proportion were exposed in smoking families. Among smoking families, a majority of children in all locations were exposed to detectable TSE, even when parents limited smoking to a porch, a designated room in the house, a window, or the yard. The location of smoking in and around the home was not significantly associated with child exposure, implying that there is no smoking location which reliably protects children from TSE in many Israeli homes.The finding that about a third of children in non-smoking families were exposed raises questions about how this exposure occurred. Most of the families (85%) in this small sample reported that smoking was not allowed anywhere in or around the home, including indoors, on porches, in yards, or in gardens. Exposure may have taken place via numerous potential routes, such as tobacco smoke incursion from neighboring apartments [The greater proportion of children exposed to tobacco smoke in smoking families relative to non-smoking families indicates that parental smoking has a key role in child exposure, regardless of where it occurs, and that parental cessation should be encouraged. The exposure is likely caused by a combination of factors, including second- and third-hand exposure. Parents may smoke in close proximity to their children [see Most families in our study (99/141 = 70.2%) allowed smoking on the porch. We found that 61.8% of children from smoking families where home smoking was restricted to the balcony had measurable TSE. Similarly, Bahceciler et al. in Turkey found that 67.6% of children whose parents restricted smoking to outdoor porches were exposed [Indeed, many porches in Israel are entirely or partially within the perimeter of the apartment itself (see Smoke drift plays an important role in contamination. Sureda et al. conducted a systematic review of SHS in open and semi-open settings and concluded that high SHS levels were present in smoke-free indoor settings that were adjacent to open or semi-open smoking areas [Living conditions in Israel may have affected the exposure of children from both smoking and nonsmoking families. Israel has a very high population density, and most people (74%) live in multi-unit apartment buildings [Because tobacco smoke incursion from outside the home affects many Israelis, even parental cessation will not completely protect children. An Israeli cross-sectional study showed that 44% of Israelis have experienced tobacco smoke incursion into their own homes, with those of low socio-economic status being disproportionally affected [This study has some limitations. First, the study of smoking families, though it included objective TSE assessment through biomarkers in 141 children, had limited power to detect small differences in exposure. The study of nonsmoking families was small and did not allow multivariable analyses. Second, it is possible that social desirability bias affected the parents’ reporting regarding smoking in the home, resulting in misclassification of the location of smoking even though the interviewers were present in the home at the time of the interview. Third, we did not have information on the smoking habits of visitors (frequent or not) to the home or on whether the children regularly spent time outside of the home with people who smoked or in places where smoking was common, including in cars. We did not have information on the possible confounders of tobacco smoke incursion from nearby apartments, crowding in the home, or small dwelling size. Neither sample was based on a random sample of the population. Finally, it is likely that the effect of smoking in the vicinity of the home on child TSE differs in different areas due to different architectural customs and local climates. | PMC9965201 | ||
Public Health Implications | In order to protect children from tobacco smoke exposure, consistent with current scientific evidence on smoke drift outdoors and indoors, smoking should not take place anyplace within at least 9 m [Parents will need substantial support to be able to make changes to better protect their children. We recommend intensive campaigns to normalize the distancing of smoking from homes and children. This information should be included in tobacco package inserts, which have been regulated but not yet implemented [The governmentally approved “Plan for the Decrease of Smoking and Smoking-attributable Harms in Israel” [ | PMC9965201 | ||
5. Conclusions | Most children in participating smoking families were exposed to tobacco smoke regardless of whether the parents restricted smoking to a balcony, to designated indoor places such as “in the window,” or to the yard. To protect children from tobacco smoke in the Israeli setting, indoor home porches and outdoor porches that are small and adjacent to indoor living areas, or enclosed or partially enclosed, should be considered part of the home environment and subject to full smoking bans. Full protection of children from the damaging effects of tobacco smoke exposure is likely dependent on reducing smoking prevalence among parents in particular and society as a whole and on complete denormalization of smoking around others, especially vulnerable populations such as children. | PMC9965201 |
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