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Peer review | PMC10589235 | |||
Data availability | De-identified and processed participant data will be shared beginning 3 months and ending 5 years following publication by requesting the corresponding author (Hongbo Wei, E-mail: weihb@mail.sysu.edu.cn) for academic purposes. The corresponding author will reply to the request within 2 months, subject to the approval of the ethics committees of the Third Affiliated Hospital, Sun Yat-Sen University. Source data underlying Figs. | PMC10589235 | ||
Competing interests | The authors declare no competing interests. | PMC10589235 | ||
References | PMC10589235 | |||
ABSTRACT. | MAY | Financial support: The primary early childhood development evaluation was funded by the Authors’ addresses: Jeanette L. Kaiser, Allison Juntunen, Jessica Schueler, Peter C. Rockers, and Nancy A. Scott, Department of Global Health, Boston University School of Public Health, Boston, MA, E-mails: In early 2020, the Zambian Ministry of Health instituted prevention guidelines to limit spread of COVID-19. We assessed community knowledge, motivations, behavioral skills, and perceived community adherence to prevention behaviors (i.e., hand hygiene, mask wearing, social distancing, and limiting gatherings). Within a cluster-randomized controlled trial in four rural districts, in November 2020 and May 2021, we conducted in-depth interviews with health center staff ( | PMC10323997 | |
INTRODUCTION | CORONAVIRUS, DISEASE | Zambia, a lower-middle income country in sub-Saharan Africa, with a population of approximately 18 million people, has been affected by the 2019 coronavirus disease (COVID-19).It is now known that large crowds, particularly indoors with poor ventilation and without face coverings (masks), drive rapid transmission.In March 2020, in addition to other lockdown measures, the Zambian Ministry of Health (MoH) issued guidelines for multiple non-pharmaceutical interventions (NPIs) to slow the transmission of COVID-19, including requiring face masks and social distancing of at least 1 m in public settings and the use of alcohol-based hand sanitizers or handwashing with soap and water.Although the personal and social benefits of following NPI guidelines for containing the spread of COVID-19 have been demonstrated,Applying the IMB Model to behaviors associated with COVID-19 transmission prevention, we assessed the knowledge, motivations, skills, and perceived community-level adherence to MoH guidelines in rural Zambian communities using qualitative data collected in late 2020 and mid-2021. | PMC10323997 | |
MATERIALS AND METHODS | PMC10323997 | |||
Study setting. | infectious disease, CBVs | INFECTIOUS DISEASE, MINOR | This qualitative study was conducted within a large cluster-randomized controlled trial that aimed to assess the impact of two early childhood development interventions in Choma, Kalomo, and Pemba Districts of Southern Province and Nyimba District of Eastern Province.Rural health centers in Zambia are public facilities that provide the surrounding populations (known as populations living in their catchment areas) with a wide range of primary health care services, including preventive and minor curative services. A varied cadre of community-based volunteers (CBVs) have been trained to provide health promotion services in maternal, newborn, and child health; water, sanitation, and hygiene; and/or infectious disease control over time. | PMC10323997 |
Theoretical framework. | finally behaviors | We interpret and present our findings using adapted domains of the IMB Model: information, motivators, behavioral skills, and finally behaviors (Information-motivation-behavioral skills model adapted to COVID-19 transmission prevention behaviors.A number of external and moderating factors likely influence information availability, motivation to perform the behaviors, and behavioral skills. We believe these include the severity of the epidemic locally and nationally; established guidelines and policies; content, methods, and reach of official IEC efforts; and the content, amount, and reach of media coverage, including social media and news sources. Additionally, especially in resource-limited settings, access to the resources needed to perform the behaviors, including masks, water, handwashing basins, soap, and hand sanitizer can be economically or geographically inaccessible. | PMC10323997 | |
Study design. | CBVs | We conducted two cross-sectional qualitative rounds of data collection on community perceptions, knowledge, and behaviors around COVID-19 and the associated government guidelines. In the catchment areas of 10 rural health centers, we conducted in-depth interviews (IDIs) with health center staff and CBVs and focus group discussion (FGDs) with community members. | PMC10323997 | |
Sampling. | One health center staff member was purposively sampled from each rural health center based on availability during data collection ( | PMC10323997 | ||
Data collection methods. | DISEASE | The semi-structured IDI and FGD instruments included questions on what the respondents know about COVID-19 in general, its symptoms, spread, and what activities could make the disease more likely to spread, discussed in the results as “high-risk activities.” The instruments included a question on respondents’ sources of information about COVID-19 in the surrounding communities and multiple questions on knowledge of current COVID-19 prevention guidelines. Lastly, respondents were asked about their perceptions of guideline enforcement of prevention guidelines, examples and reasons for adherence to guidelines, and examples and reasons for non-adherence. Probes were used to elicit more information.The qualitative instruments were translated into the local languages of Chitonga and Chinyanja for use in the Southern and Eastern Provinces, respectively. Project staff trained a team of local data collectors on research ethics, on principles of qualitative data collection, and on the data collection instruments. Round 1 of data collection occurred over 1 month in November 2020. Round 2 followed and lasted 1 month during April/May 2021. Prevention measures were followed to limit the possibility of transmission of COVID-19 during data collection activities, including face mask use, social distancing, and use of alcohol-based hand sanitizers.Demographic data were collected from each respondent using paper forms. Data were extracted at a later time using SurveyCTO® Collect Software (Dobility, Inc, Cambridge, MA) on encrypted tablets. | PMC10323997 | |
Ethics. | CBVs | Ethical approvals for the overarching evaluation and the protocol amendments made to include collection of COVID-19–related perception and behavior data were obtained from the Boston University Medical Campus Institutional Review Board and the University of Zambia Biomedical Research Ethics Committee. The overarching evaluation was approved by the National Health Research Authority; the MoH at the national, provincial, and district levels; and traditional chiefs overseeing the local areas. Written informed consent was obtained from each participant in their language of choice and documented with a signature or thumb print. IDIs and FGDs were audio recorded with consent from each participant. CBVs and community members received a small token of appreciation for their time. Health center staff did not receive any tokens in accordance with MoH guidelines. | PMC10323997 | |
Data analysis. | The audio recordings were concurrently translated into English and transcribed into Microsoft Word by individuals fluent in English and one or both local languages. A mixed inductive-deductive approach was used for coding. An initial codebook was created a priori based on the questions in the instruments. During the coding process, additional sub-codes were added as themes emerged. All coding and analysis was conducted in Nvivo v12 (QSR International, Doncaster, Australia). Three study personnel conducted the coding. At the beginning of each round of analysis, personnel each coded the same interviews to measure inter-rater reliability. We used the Nvivo Coding Comparison query and considered the resulting kappa coefficients. We ensured that the coefficients were over 0.75 each time, per Nvivo’s recommendation, and that coding was as similar as possible among individuals.Although findings from this analysis could not be validated by the participants, they were triangulated with previously published quantitative data from the same communities on attendance at community gatherings and adherence to guidelines.Demographic data were cleaned and analyzed in SAS v9.4 (SAS Institute Inc., Cary, NC). Descriptive characteristics are presented by respondent type. Means and standard deviations were calculated for age highest grade completed. Proportions were calculated for respondent sex, marital status, and clinical position of health center staff. We only collected marital status for FGD respondents. We first present the demographic characteristics of the respondents and then the qualitative results by theme. | PMC10323997 | ||
RESULTS | PMC10323997 | |||
Demographic characteristics of respondents. | CBVs | A total of 334 individuals participated in this qualitative study; 19 health center staff and 34 CBVs participated in IDIs, and 281 community members participated in FGDs (Demographic characteristics by respondent type ( | PMC10323997 | |
Information: knowledge about COVID-19. | PMC10323997 | |||
Prevention guidelines. | Respondents from all groups widely discussed that MoH prevention guidelines include handwashing or the use of hand sanitizer, the need to sit at least 1 m away from others (social distancing), the wearing of face masks, and limiting gathering sizes. | PMC10323997 | ||
High-risk activities. | DISEASE, WEDDINGS | Discussion of high-risk activities revolved around attending gatherings and being in crowded locations (Knowledge of high-risk activities associated with COVID-19 among remote communities by respondent type, including illustrative quotesGatherings and crowds: examples: funerals, football matches, church, weddings, markets, other community meetingsNot following prevention guidelines: not social distancing, not wearing masks, not handwashingGatherings and crowds: examples: funerals, churches, football matchesNot following prevention guidelines: not social distancing, not wearing masks, not handwashingContinuing to shake hands and hugTravel: movement from place to placeGatherings and crowds: includes sitting squeezed and not spacing; examples: church, shops, weddings, funerals, busesNot following prevention guidelines: not social distancing, not wearing masks, not handwashingContinuing to shake hands and hugTravel: movement from place to placeIllustrative quotes
“The high-risk activities [are] where you gather as a crowd and there is no social distancing, there is no proper hygiene like handwashing or face masking. If you do not do those things and if one in that group is infected, then it is possible that most of the people can also get infected.” – Health center staff, male, Nyimba district, round 1“When finding yourself in overcrowded places, you are actually propagating the spread of Covid-19. Generally, I would say at funerals people are not observing social distancing, they are not masked up. And in places where people are watching soccer. Market places, those are high risk areas too.” – Health center staff, male, Choma district, round 2“When we sit in a large group together without social distancing, then the disease can spread very fast. Also not wearing a mask on the mouth, then this disease can spread to you.” – Community-based volunteer, female, Pemba district, round 1“By not adhering to the guidelines which are given by health worker like social distance, meeting in numbers and not wearing of masks. This is what can cause the disease to spread more.” – Community member, male, Kalomo district, round 2 | PMC10323997 | |
Motivation: motivators and demotivators for performing prevention behaviors. | PMC10323997 | |||
Motivators. | 2“We, death, healthSocialClosed | CORONAVIRUS, EVENTS, DISEASE, SHOP | A number of personal and social factors emerged as motivators for good adherence to prevention methods (Motivators for adherence to COVID-19 prevention behaviors among remote communities by qualitative theme and respondent typePersonalFear deadliness of disease: feel at risk in their area, fear of deathSocialLocal gatherings inspected: health center staff routinely observe public places and community meetings to ensure prevention measures are followed; specifically, schools and churchesAdherence enforced at clinic: to receive health servicesPersonalFear deadliness of disease: there is no cure; feel at riskSocialLocal gatherings inspected: health center staff and volunteers ensure guidelines are being followedAdherence enforced in certain settings: in schools, at clinics, at church, in meetingsPersonalFear deadliness of disease: fear contracting the disease; feel at risk; hear about growing case numbers in Zambia from the radio/tvProtect themselves: prevent themselves from contracting the disease; do not want to get sick; maintain their healthSocialClosed doors: began adhering to guidelines when schools, churches, and businesses began closing; realized seriousness of diseaseAdherence enforced in certain settings: in schools, at clinics, at churchIllustrative quotes
“The environmental health technician usually goes to inspect the churches to make sure that people have put the required equipment in place, like hand washing facilities, that people are masking up, that people are also spacing up.” – Health center staff, female, Kalomo district, round 1“[Community members] have come to believe now that COVID-19 is real and they have come to understand it.” – Health center staff, female, Pemba district, round 2“Here at the health facility, when you come without a mask, they would send you to go back and buy a mask. [Only then] they will come and give you the drugs, that is when you’ll be attended to.” – Community-based volunteer, female, Nyimba district, round 1“At the under-five clinic, we see that there is water, in schools we see that there is water and children wash their hands and are wearing masks. Even at church they worship from outside, they do not worship from inside.” – Community-based volunteer, female, Kalomo district, round 2 e. “We follow these guidelines to protect our own lives. When we follow those [guidelines], we cannot get sick. So we protect ourselves from the coronavirus.” – Community member, female, Nyimba district, round 1“They follow because even in schools’ pupils stopped learning the way they used to learn, they just learn for an hour, and they knock off while wearing a mask.” – Community member, female, Choma district, round 2“We have heard about death, thousands and thousands of people have died and in the past days when news is being read, they mention the number of people who have died because we saw that churches were closed, okay most of the things were closed. We just used to say at home and worship from there.” – Community member, female, Choma district, round 2Community members described the closing of schools, churches, and businesses as influencing community adherence to the COVID-19 prevention measures. Additionally, health center staff and CBVs described the inspection and monitoring of local gatherings, particularly early in the pandemic, to ensure adherence to prevention methods in high-risk settings. These inspections are frequently conducted by EHTs and occurred at church services, schools, or other public spaces and events. The EHTs checked the availability of handwashing stations with soap and water, that attendees were wearing masks and social distancing, and that the number of attendees adhered to restrictions.All respondent groups described higher adherence rates in some settings where guideline adherence was “required” or more strictly enforced. Schools, clinics, and churches were repeatedly discussed among all respondent groups. School children were required to wear face masks, and classes were split in size to reduce indoor crowding. At clinics, patients were required to wash their hands, wear masks, and socially distance to receive services. Health center staff described turning away individuals not adhering to these behaviors or sending them to a local shop to procure a face mask when necessary. Church leaders also enforced guideline adherence more than other settings, such as bars and businesses, and ensured handwashing stations were available. | PMC10323997 |
Demotivators. | CBVs | VIRUS, DISEASE, WEDDINGS, WEDDING | All major demotivators to performing prevention behaviors discussed by respondents were at the personal, rather than the social, level (Demotivators for adherence to COVID-19 prevention behaviors among remote communities by qualitative theme and respondent typeDoubt/fatigue about existence of COVID-19: have not seen a case firsthand; have become fatigued of hearing about COVID-19 and prevention measures; do not believe COVID-19 is a threatLack knowledge: do not understand certain aspects including purpose of prevention measures, infectiousness, lethality, the need to perform prevention behaviors in all settingsDoubt/fatigue about existence of COVID-19: have not seen a case firsthand; do not believe COVID-19 is a threat; think the risk is over because COVID-19 has endedLack of knowledge: do not understand why they need to continue adhering to guidelinesDoubt existence of COVID-19/benefit of prevention measures: think COVID-19 is a lie; do not believe it is in Zambia; have never seen it firsthand; feel detached from it because it is a faraway problem; underestimate its severity; doubt due to lack of knowledge, ignorance, or stubbornness; believe COVID-19 is linked to politics and upcoming electionAlcohol: fail to adhere to guidelines when drinkingIllustrative quotes
“I think [community members] don’t understand social distancing because [health center staff] have kept on talking about social distancing but I have observed that whenever there is a wedding, whenever there is a funeral, normally people are actually grouped together without social distancing. So, I think we still have a problem where social distancing is concerned.” – Health center staff, male, Kalomo district, round 1“For those that believe they can’t get COVID-19, it’s because they’ve made up their minds that COVID-19 is not there. [They think] the government and the world have just made it up. It doesn’t exist. They don’t believe that they can have something that doesn’t exist. Then with those that believe that they can get it, we’ve been highlighting on how the disease has been trending. For the others, we show them videos of actual patients. There are some people who only believe when they see something [in person], so when they see those videos, they strongly believe and try to use all the interventions to protect themselves.” – Health center staff, male, Nyimba district, round 2“The biggest barrier for people not to adhere to the guidelines is not believing or not accepting that this pandemic is real.” – Community-based volunteer, female, Nyimba district, round 2“People are just stubborn. Because they have never seen [a case of COVID-19 or] what the disease does.” – Community member, female, Choma district, round 1 e. “It is drunkards who are found in taverns. They are the ones who do not follow the guidelines because they meet anyway, and they sit [together]. If they are normal and not yet drunk, they will be wearing a mask, but when they reach the tavern and start drinking, they put the mask in their pocket.” – Community member, female, Kalomo district, round 2Health center staff and CBVs noted early challenges with adherence when COVID-19 was first detected in Zambia when understanding was low and many individuals lacked knowledge. Lack of knowledge was a stronger theme during round 1 but persisted during round 2. During round 1, health center staff were particularly concerned that many in the community still did not understand some of the most critical aspects of COVID-19, including how the guidelines linked to modes of transmission meant to prevent spread of the virus, how infectious the virus was, and how lethal it could be if widespread transmission occurred.Many community members and a few health center staff and CBVs discussed the role alcohol played in failure to adhere to prevention behaviors. Individuals at drinking establishments were described as sharing glasses, not wearing masks, not social distancing, and not washing hands. They were described as forgetting about prevention behaviors as soon as they began consuming alcohol. A few respondents also described high emotional states, such as excitement or grief (i.e., weddings and funerals), affecting adherence to prevention guidelines. | PMC10323997 |
Behavioral skills: skills to perform prevention behaviors correctly and at the right times. | PMC10323997 | |||
Hand hygiene. | Cover mouth, infected droplets | CORONAVIRUS, VIRUS, SHOP, DISEASE | Although nearly all respondents cited hand washing as an important aspect of COVID-19 prevention, few discussed proper handwashing technique (Behavioral skills (technique and timing) related to COVID-19 prevention guidelines among remote communities by qualitative theme and respondent typeTechnique: must use water and soap or hand sanitizerTiming: arriving to or leaving gathering; after touching a foreign object or another personTechnique: must use water and soap or hand sanitizerTiming: arriving to or leaving gathering; after touching a foreign object or another personTechnique: must use water and soap or hand sanitizerTiming: arriving to or leaving gathering; after touching a foreign object or another personTechnique: wear over mouth / nose and mouthTiming: wear in crowded locationsTechnique: wear to trap infected droplets and keep them in/outTiming: wear in crowded locationsTechnique: Cover mouth with maskTiming: wear in crowded locationsTechnique: need to sit at least one meter apart from anyone; germs can’t reach another person one meter awayTiming: sit distanced especially when in crowdsTechnique: need to sit at least one meter apart from anyone; saliva can’t reach another person one meter away; don’t sit squeezedTiming: sit distanced especially when in crowdsTechnique: maintain a one-meter distance from othersTiming: important not to sit squeezed during gatheringsTechnique: limit number of attendees; ventilation important; must maintain distancing & adhere to guidelinesTechnique: limit number of attendees; maintain distancing & adhere to guidelinesTechnique: limit number of attendees; must maintain distancing & adhere to guidelinesIllustrative quotes
“You need to have a meter from where your friend is. That is the specification which was given in terms of social distancing.” – Health center staff, male, Nyimba district, round 1“[The guidelines are to] mask up, avoid overcrowded places, proper hand washing, avoid unnecessary movements, and avoid traveling when you’re not feeling too well.” – Health center staff, female, Pemba district, round 2“The face masks are supposed to be worn because the virus uses that route. There should not be exchange of air. If the person has the coronavirus and is talking to the person who does not have, the person who is not wearing a mask can easily contract it.” – Community-based volunteer, female, Kalomo district, round 1“Social distance is also necessary when you have meetings – sitting well-spaced. Also washing hands. We are supposed to be washing hands. They teach the way we are supposed to be washing our hands so that we prevent this disease. Then we were advised that every time we have meetings, we should be wearing masks, so that we can prevent this disease. The health facility has a big role in guiding us, because every time we are in meetings, they talk about all this.” – Community-based volunteer, male, Kalomo district, round 2 e. “Other guidelines from the government are that we are not supposed to gather not more than 50 people in one place. Again, we are not supposed to gather with a lot of people for more than 2 hours.” – Community member, female, Pemba district, round 1“[The guidelines are] washing hands when you enter a shop. When you gather in numbers, you need to wear a face mask so that you don’t catch the disease. And sitting 1 meter apart.” – Community member, female, Kalomo district, round 2“When I reach other people’s homes, they have put a bucket of water at the road, for washing the hands with soap. Even in a shop when I want to enter, water is also there. Then also I am supposed to wear a mask on the face.” – Community member, female, Kalomo district, round 2“The district emphasizes that we should avoid social gatherings. We should sanitize our hands and wash them. Then we should wear masks whenever we are moving, going somewhere, or whenever we want to attend any [gathering]... So those are the regulations that are coming from the district.” – Community member, female, Nyimba district, round 2 | PMC10323997 |
Face masks. | respiratory droplets | Some respondents noted the involvement of both the nose and mouth in spreading COVID-19. For example, community members frequently described the risk of an infected person touching their nose and then shaking hands with someone. However, very few respondents discussed the proper technique of wearing a face mask as covering both the nose and mouth. Respondents generally talked about face masks “covering the mouth” or more vaguely mentioning wearing a face mask as a necessary precaution.All respondent groups discussed wearing face masks as particularly important when in gatherings or crowded areas or when social distancing was not possible. Respondents frequently made the link with the modes of transmission, explaining that face masks keep respiratory droplets (or saliva) in (for an infected individual) or out (for an uninfected individual). | PMC10323997 | |
Social distancing. | CBVs | Respondents widely discussed the need to sit at least 1 m away from others (some implying a person outside one’s household) to limit the spread of COVID-19 because the droplets or “saliva cannot travel more than one meter.” The need for social distancing was especially emphasized when in crowded locations. Emphasis was often on social distancing when sitting. CBVs and community members often described this as the importance of “not sitting squeezed.” | PMC10323997 | |
Avoiding gatherings/high-risk settings. | CBVs | EVENTS, DISEASE | Respondents consistently discussed the need to follow all mask wearing, social distancing and hand hygiene guidelines while in high-risk settings, which were universally linked with gatherings and crowded places. However, there was almost no discussion of communities choosing to avoid high-risk settings, such as not going to church, football matches, or funerals due to COVID-19 aside from when these gatherings were specifically closed by the government in the interest of public safety. Some respondents mentioned the need for gatherings to be short, lasting only 1 or 2 hours.When asked about gathering indoors, the majority of health center staff emphasized the role of proper ventilation to keep air circulating and limit disease spread. Although only a few CBVs and community members noted the detriment of all participants “breathing the same air,” many emphasized that the meeting space must be large enough to maintain distancing provisions. Specific locations, like homes and clinic rooms, were discussed as having little space and poor ventilation, unlike outdoor events. For schools and churches participants discussed them having sufficient space and ventilation but would require restricted group size. | PMC10323997 |
Moderator: information, education, and communication dissemination efforts. | deaths, CBVs | DISEASE | Respondents generally attributed strong community understanding about COVID-19 to widespread sensitization efforts that began soon after the pandemic was declared (Methods and content of COVID-19 information, education, and communication dissemination to remote communities by qualitative theme and respondent typeTeach whenever community gathers: at the health center, health outreach, schools, and churchesEducate other community leaders: involve CBVs, religious, civic, and traditional leaders to disseminate information in their villagesTeach whenever community gathers: at church, schools, and other community meetingsLead by example: along with explaining guidelines, encourage others to follow by showing yourself following guidelinesEducation sessions during community gatherings: at the health center, health posts, churches, schools, community meetings.Radio: announcements and government messagingProvide basic information: education on disease signs, symptoms, and prevention methods; distribute IEC materialsTeach about prevention and self-protection: Explain spread, prevention methods, and high-risk activities; warnings about lack of cure and deadliness of diseaseTaught basic information: existence of COVID-19 and prevention methods; deaths in Zambia and internationally; government messagingIllustrative quotes
“We [health center staff] are using the community-based volunteers too…We equip them and then we send them out to go and teach on our behalf. We [health center staff] have also gone in all the schools to teach the school staff, to teach the pupils on the preventive measures and what COVID-19 is all about. We also involved the pastors, the church leaders, and the civil and the civic leaders that is the counsellors and the headmen and the alike. We had to bring them together teach them on COVID-19 so that they could also help us disseminate the information in the communities. ” – Health center staff, male, Kalomo district, round 1“Wherever there are gatherings the message about COVID-19, I do not leave it out when talking. When we gather… even in churches, I am one of those sensitizing about COVID-19. Wearing masks, washing hands, social distancing, not holding hands, not greeting. So we spread this message well.” – Community-based volunteer, female, Pemba district, round 1“Information about COVID-19 is spread whenever you gather or if there is a meeting. Wherever we gather, they announce that this disease kills.” – Community member, female, Kalomo district, round 1“We first heard in the radios that there is COVID-19. Then from the radio, then again the health personnel came and also told us. Then, when the health personnel finished telling us, they started moving in the churches, and in schools, saying if the children should not be using masks, then the schools will be closed. So, that’s when we started seeing that COVID-19 is really there. That’s how we heard the message.” – Community member, male, Pemba district, round 2“I heard that in Lusaka and in Monze that people have died of Covid-19. I heard on the radio they were announcing.” – Community member, female, Pemba district, round 2Many community members also discussed hearing about COVID-19 through announcements on the radio. They reported learning about the existence of COVID-19, hearing news reports about deaths from COVID-19 in Zambia and internationally, and hearing government messaging about prevention. | PMC10323997 |
DISCUSSION | A scoping review of knowledge, attitudes, and practice (KAP) studies found that high knowledge of COVID-19 was not always associated with positive attitudes or adherence to prevention behaviors | PMC10323997 | ||
Information and behavioral skills. | Generally, all respondent groups showed good knowledge of COVID-19, consistent with KAP studies in sub-Saharan Africa. | PMC10323997 | ||
Personal experiences and sources of information. | deaths, CBVs | DISEASE | Personal experience with COVID-19 was a particularly important motivator for performing prevention behaviors, with an individuals’ fear versus doubt of the disease raised as a critical deciding factor in adherence. Misinformation spreading doubt about the severity of COVID-19 or need for prevention behavior adherence has been reported in many African communities.Respondents in this study discussed non-adherence as particularly widespread when case numbers were still low in Zambia, with adherence to prevention behaviors increasing as case numbers grew and media coverage of daily cases and high-profile deaths expanded. Due to the rural, impoverished nature of these areas, these communities have limited access to internet and television, lacking access to widespread national information campaigns on these platforms.Even with these challenges and limitations, the Government of Zambia was able to reach and educate many remote-living individuals by implementing television, radio, and social media campaigns and ensuring that health center staff, CBVs, and community leaders provided widespread sensitization. This is common practice for sharing health education in LMICs and could be more broadly applicable for reaching geographically remote or otherwise vulnerable and hard-to-reach populations globally. | PMC10323997 |
Resources. | hand hygiene behaviors | ASH | Although knowledge was generally widespread within these rural communities, lack of resources remained a persistent barrier, a common theme in many areas of life particularly in rural areas of LMICs. Although community members knew the importance of hand hygiene, they were not always able to perform the behavior correctly. Soap, universally recognized as a critical piece for performing hand hygiene behaviors, was noted by some respondents as a challenge, with ash being used as a substitute. Although ash has been recommended by the WHO as a substitute for soap in emergencies, | PMC10323997 |
Institutional versus non-institutional settings. | CBVs | EVENTS, WEDDINGS | Although respondents were largely positive when discussing community-level adherence to COVID-19 prevention methods, they repeatedly described instances of widespread non-adherence within these rural communities. Social motivators appeared to play a major role in general community adherence, particularly in high-risk settings. Institutional settings, including clinics, church services, and meetings with traditional leadership, were described as experiencing higher levels of perceived adherence among the community at large. Institutional settings generally had stronger adherence enforcement measures in place and had clear leaders who supported guideline adherence. Additionally, respondents explained that visits to institutional settings frequently began with COVID-19 sensitization sessions, which systematically reinforces messages community members may have heard through other channels.Informal, non-institutional community settings, such as at weddings, funerals, and football (soccer) matches, often lacked similar social expectations and leaders to model or enforce adherence. These settings were described as problematic and often had lower levels of general adherence for hand washing, mask wearing, social distancing, and restricted group sizes. Although health center staff and CBVs discussed repercussions for individuals not following prevention guidelines at the clinics (refusal of services), churches (revoking permits for gatherings), or meetings with traditional leaders (disbanding and rescheduling), such repercussions were not discussed for these other informal community events. These findings are consistent with concurrent quantitative data from these same communities, which found that rural Zambian participants reported attending large gatherings throughout the pandemic; higher levels of prevention behavior adherence were perceived at clinics and churches, whereas funerals experienced larger crowds with much lower levels of reported mask wearing among participants.In addition to low social pressure for adherence, the high (positive or negative) emotions of the crowds at informal community events may override personal-level motivators for adherence and perceived risk. A few respondents discussed non-adherence in this way, stating that joy at weddings and football matches and grief at funerals made attendees “forget” about COVID-19 and the need to practice prevention behaviors in these settings. Similarly, long-engrained cultural expectations around physical touch while greeting (i.e., shaking hands, hugging), particularly in emotional or ceremonial settings, could potentially override perceived risk. A systematic review of COVID-19 risk communication and community engagement in 13 African countries acknowledged widespread resistance to attendance guidelines at funerals and resistance to stop shaking hands or hugging in many communities.During a resurgence of COVID-19 or during a potential future pandemic, efforts to increase community-level adherence to prevention guidelines should target these informal, non-institutional, low-adherence community events that continued to occur outside of regulations. Although respondents repeatedly stated that more information dissemination was needed to convince doubters and outstanding non-adherers at these informal, non-institutional community events, this is unlikely to have drastically changed behaviors because lack of information did not seem to be a major influencer of non-adherence here or in other KAP studies.On the other hand, increasing social pressure through greater enforcement measures and provision of needed supplies (i.e., handwashing stations) could have more widely affected general adherence in these informal settings and affected potential transmission occurring during these community gatherings. Engaging with local leaders in religious, civic, and traditional leadership positions has been shown as critical for many health-related interventions | PMC10323997 |
Strengths and limitations. | Although this was a purely qualitative study, it included a rigorous design with a large sample size of respondents at different levels who confirmed each other’s responses at two different points in time. Furthermore, the qualitative results were interpreted against the IMB model, a well-known socio-behavior model from the HIV literature that has only been posited once before for use with COVID-19, making this analysis a unique contribution of the literature.Second, responses from participants may have been subject to social desirability bias. Adherence to guidelines may have been emphasized, whereas unfavorable views and non-adherence may have been downplayed. We attempted to limit the likelihood of social desirability bias in the data by asking questions “about the community” instead of about the respondents themselves. Because the data sources are IDIs and FGDs, we are only able to report on what people perceive. Additionally, respondents were not asked to demonstrate proper prevention behavior techniques. Observational data would be needed to confirm accurate performance of these behaviors, determine actual adherence rates in various settings, and confirm reported perceptions.Additionally, approximately one-third of the participating community women received additional health education around COVID-19 twice monthly through the ECD intervention. However, we did not find any noteworthy differences between the overarching study arms. Nonetheless, caution should be taken when generalizing these data outside of the immediate communities from which they were collected.Lastly, the qualitative instruments did not include questions on COVID-19 vaccine perceptions or uptake due to the timing of data collection. During our first round of data collection (November 2020), COVID-19 vaccines were still in testing internationally and had not yet been distributed. During the second round of data collection (April/May 2021), the first shipments of vaccines were only just reaching Zambia and were concentrated in urban areas. At the time of instrument development, ethics approval, and data collection, there was no vaccine distribution within our study areas. Futher information on COVID-19 vaccine perceptions and uptake among these rural community members and stakeholders is important. | PMC10323997 | ||
CONCLUSION | WEDDINGS | Assessing the factors associated with COVID-19 prevention behaviors adherence in a rural Zambian population has revealed generally strong understanding of COVID-19 symptoms, spread, and high-risk activities with some knowledge and skills gaps that suggest the need for additional targeted messaging. The findings suggest that performance of prevention behaviors is driven by personal and social factors, that the different factors can motivate or demotivate adherence, and that behaviors are also affected by epidemic severity and its associated media coverage. Additionally, our findings highlight specific high-risk settings where perceived community-wide adherence is lowest: informal, non-institutional settings without clear community leaders, including funerals, weddings, and football games. Based on the responses about motivators and demotivators to adherence, specific interventions can be designed to target those settings where the potential for rapid spread of COVID-19 is greatest. | PMC10323997 | |
ACKNOWLEDGMENTS | We appreciate the efforts of the data collection teams and Dalitso Swazi who oversaw data collection. We acknowledge the Ministry of Health at the national, provincial, and district levels; the National Health Research Authority; and the local chiefs and headmen for providing their approval and support of the overarching evaluation. We are grateful for the time and perspectives of the health center staff, community-based volunteers, and community members who participated in this study and helped us continue working and learning even during these challenging times. The American Society of Tropical Medicine and Hygiene has waived the Open Access fee for this COVID-19 article. | PMC10323997 | ||
REFERENCES | PMC10323997 | |||
Subject terms | NSCLC | NON-SMALL CELL LUNG CANCER, NSCLC | EMERGING-CTONG 1103 showed improved progression-free survival (PFS) with neoadjuvant erlotinib vs. chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer (NSCLC) (NCT01407822). Herein, we report the final results. Recruited patients were randomly allocated 1:1 to the erlotinib group (150 mg/day orally; neoadjuvant phase for 42 days and adjuvant phase to 12 months) or to the GC group (gemcitabine 1250 mg/m | PMC9950485 |
Introduction | lung cancer, cancer death, stage IIIA-N2 NSCLC, tumours | LUNG CANCER, STAGE IV NSCLC, TUMOURS, STAGE II NSCLC | Despite therapeutic advances, lung cancer keeps a leading cause of cancer death worldwideSurgery, radiotherapy, and chemotherapy are the primary modalities of stage III NSCLC treatment. However, molecular characterisation of tumours is essential to detect specific mutations, which is even more relevant in advanced lung cancer stages. For patients with stage IV NSCLC and epidermal growth factor receptor (The EMERGING-CTONG 1103 (ClinicalTrials.gov identifier: NCT01407822) was a multicentre (17 centres in China), open-label, phase II, randomised controlled trial of erlotinib versus gemcitabine combination with cisplatin (GC) as perioperative therapy in patients with stage IIIA-N2 NSCLC and EGFR sensibility mutations. | PMC9950485 |
Results | PMC9950485 | |||
Safety | anaemia, diarrhoea, decreased white blood cell count, neutropoenia, nausea, neutropenia, vomiting, rash, cough, dyspnoea, anorexia, shortness of breath | ADVERSE EVENTS, ANOREXIA, NEUTROPENIA, ANAEMIA | The population for safety comprised 37 patients who received erlotinib and 34 who received GC except for one patient who refused to receive chemotherapy after randomisation. The adverse events (AEs) of any grade occurred in 70.3% (26/37) of patients with erlotinib and 58.8% (20/34) with GC during postoperative therapy. In brief, the most common AEs were rash (43.2%), diarrhoea (24.3%) and cough (24.3%) in patients treated with erlotinib; and those in the GC group were neutropenia (38.2%), decreased white blood cell count (32.4%), anorexia (26.5%) and vomiting (26.5%). The grade 3 or 4 AEs occurred in 5 (13.5%) patients of the erlotinib group and in 10 (29.4%) patients of the GC group. The most common grade 3 or 4 AEs were rash (5.4%), diarrhoea (2.7%), shortness of breath (2.7%), elevated total bilirubin (2.7%), elevated aminotransferases (2.7%), and decreased white blood cell count (2.7%) in the erlotinib group. In the GC group, those were neutropoenia (29.4%), decreased white blood cell count (11.8%), vomiting (2.9%), nausea (2.9%), anaemia (2.9%) and dyspnoea (2.9%). | PMC9950485 |
Discussion | NSCLC, EGFR-mutant, toxicity, heterogeneous disease | DISEASE PROGRESSION, DISEASE, NSCLC | IIIA-N2 NSCLC with potentially resectable disease (IIIA3 with N2 confirmed by EBUS/Mediastinoscopy or PET/CT) represents a highly heterogeneous disease in treatment modalities and prognosis. The EMERGING-CTONG 1103 study is the first randomised phase II trial to evaluate the feasibility and safety of neoadjuvant and adjuvant targeted therapy with erlotinib compared with standard chemotherapy. The results of PFS have previously been published in the The CHEST study showed that preoperative Cisplatin and Gemcitabine followed by radical surgery had significantly prolonged PFS and OS compared with surgery alone in patients with clinical stage IIB/IIIA NSCLC.The CTONG 1104 study was the first to introduce targeted therapy into the post-operative setting and showed remarkable improvements in disease-free survival (DFS) compared with conventional chemotherapy.In addition, these updated results continued to demonstrate superior median PFS with erlotinib compared with chemotherapy, with approximately 10 months of PFS benefit. However, this PFS benefit did not translate into a significant difference in OS between the erlotinib and GC groups. This finding may result from the complex multifactorial therapeutic approaches and the introduction of other highly potent EGFR-TKIs during later lines of treatment. Related to this is the fact that more patients in the GC group received EGFR-TKIs than those in the erlotinib group (69.7% vs. 46.9%) when disease progression occurred; such therapeutic crossover during subsequent treatment may have confounded the OS results. Unsurprisingly, patients without subsequent treatment had the worst prognosis in both groups.We also explored whether patients who received upfront EGFR-TKIs may retain sensitivity to subsequent EGFR-TKIs and achieve a survival benefit. Among patients receiving subsequent EGFR-TKIs after disease progression, ORRs were 53.3% (erlotinib) and 47.8% (GC), and respective disease control rates were 93.3% (erlotinib) and 73.9% (GC). However, only 25% of patients in the erlotinib group responded to subsequent osimertinib treatment, while the ORR was 45.5% for patients who did not receive subsequent osimertinib. Due to the small number of patients receiving osimertinib (Recent advances in EGFR-TKI therapy development have resulted in highly potent EGFR-TKIs with increased intracranial penetration that might be additional therapeutic options for this patient population after disease progression. The ADAURA study,One of the main limitations of this study was that not all enroled patients had pathologically confirmed N2 disease, which may have led to an underestimation of the disease stage, thereby influencing the robustness of the survival analysis. Another limitation is that we did not obtain biopsy samples of all the recurrent lesions and could not further investigate if upfront targeted therapy may biologically impact subsequent treatment. Then, RCT studies with a larger sample size are needed to further explore the benefit of neoadjuvant EGFR-TKI on stage IIIA-N2 EGFR-mutant patients with NSCLC in the future.In conclusion, the updated analysis of CTONG1103 indicated that erlotinib continued to improve PFS and OS numerically compared with platinum-based chemotherapy. Moreover, there was no evidence of cumulative toxicity in erlotinib during the long-term follow-up. The present results support the use of erlotinib in both the neoadjuvant and adjuvant settings for resectable stage IIIA-N2 | PMC9950485 |
Materials and methods | PMC9950485 | |||
Ethics statements | This study was approved by the Ethics Committee of Guangdong Provincial People’s Hospital (No. [2011] 28, Full names of the Ethics committees are: Jinrui Ou, Jianxing Cui, Nianqiao Zhang, Jianwei Mo, Deying Qian, Jimei Chen, Feizhou Jiang, Zuoyue Liu, Peihua Zheng, You Huang). All patients provided written informed consent prior to participating in the study. | PMC9950485 | ||
Study design | stage IIIA-N2 NSCLC | The EMERGING-CTONG 1103 study was a multicentre (17 centres in China), national, open-label, phase II, randomised controlled trial for comparing erlotinib with GC as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 NSCLC and exon 19 or 21 | PMC9950485 | |
Patients | As previously described, | PMC9950485 | ||
Randomisation and masking | adenocarcinoma | ADENOCARCINOMA | All patients were randomly assigned in a 1:1 ratio to receive either of the two interventions by computer. Treatments were randomly assigned based on single-station N2 or multiple-station N2, adenocarcinoma or non-adenocarcinoma, never smoked or former smoked or currently smoked, male or female. Neither the study investigators nor the patients were masked. | PMC9950485 |
Treatment | One group received neoadjuvant therapy with erlotinib 150 mg/day orally for 42 days and adjuvant therapy with erlotinib 150 mg/day orally for up to 12 months. The Chemo group received neoadjuvant therapy with gemcitabine 1250 mg/m | PMC9950485 | ||
Outcomes | death, tumour, N0, Cancer | DISEASE PROGRESSION, ADVERSE EVENT, TUMOUR, CANCER | Details of dynamic assessment were described previously.Secondary endpoints included: (1) lymph node downgrade rate defined as the proportion of patients with pathological confirmed lymph nodes downstaging from N2 to N1 or N0 in the intention to treat (ITT) population. (2) complete resection rate defined as the proportion of patients who received complete resection (R0 section) in the intention to treat (ITT) population. (3) pCR rate is determined as % residual viable tumour cells in the primary tumour and sampled lymph nodes. (4) OS was defined as the time from random assignment to the date of death from any cause, or data on patients were censored at the last confirmation of their survival. OS at 3 and 5 years is defined as the percentage of people still alive 3 or 5 years after the day of randomisation. (5) PFS defined as the time from surgery to the first confirmed disease progression or death from any cause, or data on patients were censored at the last tumour assessment. (6) safety (assessed by the US National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). | PMC9950485 |
Statistical analysis | tumour | TUMOUR | Details of sample size calculations were described previously.An Independent Review Committee (IRC) provided a review of the patient’s images, including CT, MRI, PET/CT and bone scan. Differences in the OS, PFS and the cumulative proportion of patients surviving at 3 and 5 years were compared using the Kaplan–Meier method. The response rate between the subsequent treatments was assessed using the Chi-square test. The effect of neoadjuvant treatment on OS in predefined subgroups (age, gender, N2 status and Based on the investigator’s evaluation of the tumour response from patients’ medical records, Post hoc analyses for subsequent treatments were conducted for patients who experienced relapse or progression after surgery. All analyses were performed using SPSS 25.0 (IBM, Armonk, NY, USA) and R statistical packages (3.4.3). All tests were two-sided and | PMC9950485 |
Supplementary information |
Supplementary materials CleanThese authors contributed equally: Wen-Zhao Zhong, Hong-Hong Yan | PMC9950485 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41392-022-01286-3. | PMC9950485 | ||
Acknowledgements | The authors thank all patients and their families. The authors would like to acknowledge the editorial support provided by Keyra Martinez Dunn, MD, of Edanz ( | PMC9950485 | ||
Author contributions | Y.-L.W., W.-Z.Z., and H.-H.Y. contributed to trial design and data analysis. Y.-L.W., W.-Z.Z., H.-H.Y., X.-N.Y., R.-Q.L., J.-J.Y., X.-C.Z., S.-Y.L., and Q.Zhou wrote the report. All authors contributed to data collection and reviewed the final report. All authors have read and approved the article. | PMC9950485 | ||
Data availability | Overall clinicopathological data were summarised in corresponding tables. All other relevant individual data are available from the corresponding author of this study (Y.-L.W., syylwu@live.cn) upon reasonable request. | PMC9950485 | ||
Competing interests | Y.-L.W. reports receiving speaker bureau fees from AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., Roche AG, Boehringer Ingelheim, Eli Lilly & Co., Merck Sharp & Dohme, and Sanofi and research grants from AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., and Roche AG. W.-Z.Z. reports receiving speaker fees from AstraZeneca and Roche. All other authors declare no competing interests. | PMC9950485 | ||
References | PMC9950485 | |||
Background | migraine, headache | MIGRAINE, PATHOGENESIS, PITUITARY | Pituitary adenylate cyclase-activating polypeptide (PACAP), structurally related to vasoactive intestinal peptide (VIP), is one of the important mediators in the pathogenesis of migraine and is known to dilate cranial arteries and induce headache and migraine. Our objective was to determine whether Lu AG09222—an investigational humanized monoclonal antibody directed against PACAP ligand—would inhibit the PACAP-signaling cascade by abolishing its vasodilatory and headache-inducing abilities. | PMC10210362 |
Methods | HEADACHE DISORDERS | In a randomized, double-blind, parallel-group, single-dose, placebo-controlled study of Lu AG09222, healthy volunteers aged 18–45 years without history of headache disorders were randomly allocated to three treatment sequences (1:2:2) on two experimental infusion visits with 9 ± 3 days’ interval: placebo + saline + saline ( | PMC10210362 | |
Results | SE | In participants who received Lu AG09222 + PACAP38 infusion, there was a significantly lower STA diameter (mean (SE) [95% CI] AUC ‒35.4 (4.32) [‒44.6, ‒26.3] mm × min; | PMC10210362 | |
Conclusions | migraine, headache | MIGRAINE, VASODILATION, DISEASES | This proof-of-mechanism study demonstrated that Lu AG09222 inhibited PACAP38-induced cephalic vasodilation and increases in heart rate, and reduced concomitant headache. Lu AG09222 may be a potential therapy against migraine and other PACAP-mediated diseases. | PMC10210362 |
Trial registration | ClinicalTrials.gov: NCT04976309. Registration date: July 19, 2021. | PMC10210362 | ||
Graphical Abstract | PMC10210362 | |||
Supplementary Information | The online version contains supplementary material available at 10.1186/s10194-023-01599-w. | PMC10210362 | ||
Keywords | PMC10210362 | |||
Background | neurological disease, headache, migraine, Migraine, disability | MIGRAINE, MIGRAINE, NEUROLOGICAL DISEASE | Migraine is a common neurological disease affecting 1 billion people worldwide and the leading cause of disability in individuals younger than 50 years of age [Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are part of the same glucagon/secretin superfamily of structurally related vasoactive peptides and share significant similarities [An investigational humanized monoclonal antibody directed against PACAP, Lu AG09222, is currently being developed for migraine prevention [This proof-of-mechanism randomized controlled trial investigated the effect of Lu AG09222 on vascular responses and headache after PACAP38 and VIP infusion in healthy volunteers. We hypothesized that pre-treatment with Lu AG09222 binds and neutralizes exogenously administered PACAP38 and prevents PACAP38-induced vasodilatory responses and headache, thereby confirming target engagement in this human model [ | PMC10210362 |
Materials and methods | PMC10210362 | |||
Study design and participants | headache | This was a phase 1, interventional, randomized, double-blind, parallel-group, placebo-controlled, single-dose study investigating the effect of Lu AG09222 in a headache model with healthy volunteers. This study was designed in accordance with the Declaration of Helsinki and conducted in compliance with Good Clinical Practice and applicable regulatory requirements; all participants provided informed consent prior to participation. There were four notable protocol deviations, none of which affected the integrity of the study or subject safety; see Additional file Healthy adults aged 18–45 years (inclusive) with a body mass index ≥ 18.0 and ≤ 30.0 kg/m | PMC10210362 | |
Randomization, masking, and interventions | Potential participants were assessed for eligibility and screened (Additional file Study design. | PMC10210362 | ||
Data collection and outcome measures | headache, flushing | Vascular parameters (superficial temporal artery [STA] diameter and radial artery [RA] diameter measured by high-resolution ultrasonography; facial flushing measured by speckle contrast imager), heart rate and headache were documented before Lu AG09222 or placebo infusion and PACAP38 or saline infusion at visit 1 and before VIP or saline infusion at visit 2. After PACAP38, VIP and saline infusions, vascular parameters, heart rate and headache were documented every 10 min from 0 to 2 h. After the observation period, participants were provided with a headache diary and discharged from the clinic. The diary was filled out every hour from 3 to 8 h (or until sleep) after the start of infusion with PACAP38, VIP, or saline, then at 24 h and daily thereafter until 1 week after the VIP or second saline infusion (if applicable). Participants recorded the presence of a headache and evaluated headache intensity, characteristics and localization, facial flushing, other associated symptoms and use of acute medication.The primary outcome measure was the area under the curve (AUC) of the change in STA diameter from 0 to 120 min after start of PACAP38 infusion (AUC | PMC10210362 | |
Statistical analysis | A sample size of 10 participants per treatment sequence provided more than 90% power to detect a difference in the AUC of change from the start of infusion of PACAP38 in STA diameter (AUCAll randomized participants who received either placebo or Lu AG09222 were included in the safety analysis; all participants who received an infusion of PACAP38 or saline and had a valid pre-infusion STA diameter measurement and a valid AUCThe primary endpoint was analyzed using an analysis of covariance (i.e., change from start of infusion in AUC | PMC10210362 | ||
Data availability | In accordance with EFPIA’s and PhRMA’s ‘Principles for Responsible Clinical Trial Data Sharing’ guidelines, Lundbeck is committed to responsible sharing of clinical trial data in a manner that is consistent with safeguarding the privacy of patients, respecting the integrity of national regulatory systems and protecting the intellectual property of the sponsor. The protection of intellectual property ensures continued research and innovation in the pharmaceutical industry. Deidentified data are available to those whose request has been reviewed and approved through an application submitted to | PMC10210362 | ||
Discussion | migraine, flushing and heart rate increase, migraine-related disability, headache | MIGRAINE, VASODILATION | Mechanism-specific migraine preventive therapy can reduce frequency and severity of migraine attacks and improve migraine-related disability [Endogenous PACAP plays a role in the regulation of cephalic haemodynamics and is present in perivascular parasympathetic and trigeminal afferent fibers [The PAC1 receptor has previously been suggested as a potential target for treating migraine, inhibiting a key part of the PACAP signalling pathway, since PACAP38 has high affinity on this receptor [Lu AG09222—which in this study prevents PACAP38-induced vasodilatory responses and headache, thereby confirming target engagement—is not dependent on receptors but instead binds and neutralizes the PACAP ligand; therefore, by inhibiting PACAP from binding to its target receptors (PAC1, VPAC1 and VPAC2), the PACAP signalling cascade may be prevented from initiating any physiological responses [VIP infusion induced a short-lived vasodilation of STA, facial flushing and heart rate increase, compared to saline, in the placebo group. This is consistent with previous findings of VIP-induced cephalic vasodilation in healthy volunteers [ | PMC10210362 |
Strengths and limitations | DILATION | This study has a relatively small sample size. However, the study was adequately powered based on the study design and considering previous findings of substantial STA dilation in provocation studies with PACAP38 [ | PMC10210362 | |
Conclusion | migraine, headache | MIGRAINE, VASODILATION | Lu AG09222 significantly inhibited PACAP38-induced cephalic vasodilation and reduced concomitant headache in healthy volunteers. These results demonstrate that Lu AG09222 binds to and effectively inhibits PACAP38-mediated physiological responses and indicate Lu AG09222 as a future treatment for migraine and other conditions that would benefit from inhibition of the PACAP signalling cascade. | PMC10210362 |
Acknowledgements | The authors thank Julia L. Jones, Ph.D., and Nicole Coolbaugh, CMPP, of The Medicine Group, LLC (New Hope, PA, USA) for providing medical writing support, which was funded by H. Lundbeck A/S (Copenhagen, Denmark) and in accordance with Good Publication Practice guidelines. | PMC10210362 | ||
Authors’ contributions | Study concept and design: Messoud Ashina, Nadja Bredo Rasmussen, Charlotte Granhall, Casper Emil Christensen, Faisal Mohammad Amin. Acquisition of data: Messoud Ashina, Nadja Bredo Rasmussen, Charlotte Granhall, Faisal Mohammad Amin, Christina Deligianni, William Kristian Karlsson, Haidar Al-Khazali. Analysis and interpretation of data: Messoud Ashina, Nadja Bredo Rasmussen, Charlotte Granhall, Casper Emil Christensen, Faisal Mohammad Amin, Christina Deligianni, William Kristian Karlsson, Tom Van de Casteele. Drafting of the manuscript: Messoud Ashina, Nadja Bredo Rasmussen, Charlotte Granhall, Casper Emil Christensen, Faisal Mohammad Amin, Tom Van de Casteele. Revising for intellectual content: Messoud Ashina, Nadja Bredo Rasmussen, Charlotte Granhall, Casper Emil Christensen, Faisal Mohammad Amin, Tom Van de Casteele. Final approval of the completed manuscript: Nadja Bredo Rasmussen, Christina Deligianni, Casper Emil Christensen, William Kristian Karlsson, Haidar Al-Khazali, Tom Van de Casteele, Charlotte Granhall, Faisal Mohammad Amin, Messoud Ashina. | PMC10210362 | ||
Funding | This study was sponsored and funded by H. Lundbeck A/S. The publication was supported by H. Lundbeck A/S, Copenhagen, Denmark. M.A. was supported by the Lundbeck Foundation Professor Grant (R310‑2018–3711). | PMC10210362 | ||
Availability of data and materials | The dataset supporting the conclusions of this article is are available to those whose request has been reviewed and approved through an application submitted to | PMC10210362 | ||
Declarations | PMC10210362 | |||
Ethics approval and consent to participate | This study was designed in accordance with the Declaration of Helsinki and conducted in compliance with Good Clinical Practice and applicable regulatory requirements; all participants provided informed consent prior to participation. | PMC10210362 | ||
Consent for publication | Not applicable. | PMC10210362 | ||
Competing interests | Rasmussen, Headache, Nordisk, Pain | BRAIN, NEUROMUSCULAR DISEASES | Dr. Karlsson has nothing to disclose. Dr. Rasmussen is a member of the editorial group G (neuromuscular diseases) of the neurological National Treatment Guidelines, Danish Neurological Society. Dr. Deligianni was supported by an IHS research fellowship grant and serves as a board member for the European Headache Federation. Dr. Christensen has received consulting fees and lecture honoraria from Teva; serves as a board member for the Danish Headache Society; and is a member of the steering committee for the Danish National Knowledge Center for Headache. Dr. Al-Khazali serves as a board member for the Danish Headache Society. Drs. Van de Casteele and Granhall are employees of Lundbeck. Dr. Amin has received personal fees from Eli Lilly, Lundbeck, Novartis, Pfizer and Teva; has received institutional payments from Novartis and Teva; has served on advisory boards for Pfizer, Eli Lilly, Lundbeck, Novartis and Teva; and serves as associate editor for Acta Neurologica Scandinavica, for Headache Medicine and for Frontiers in Pain Research, as junior associate editor for Cephalalgia and member of the editorial board of The Journal of Headache and Pain; is the President of Danish Headache Society and is a member of the European Headache Federation’s Board of Directors. Dr. Ashina is a principal investigator on clinical trials for AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis and Teva; has received personal fees from AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer and Teva; has received institutional research grants from Lundbeck Foundation, Novartis and Novo Nordisk Foundation; and serves as an Associate Editor of Cephalalgia, The Journal of Headache and Pain and Brain. | PMC10210362 |
References | PMC10210362 | |||
INTRODUCTION | Postoperative shivering, postoperative pain, nausea, shivering, hypoxia, postoperative nausea and vomiting, pain, sleepiness, postoperative shivering, nausea, vomiting | POSTOPERATIVE SHIVERING, POSTOPERATIVE COMPLICATIONS, HYPOXIA, COMPLICATIONS, COMPLICATION, WOUND INFECTIONS, INTRAOCULAR PRESSURE | Postoperative shivering is a common complication that can lead to increased postoperative complications. This study aimed to compare the effectiveness of intravenous ibuprofen and meperidine in preventing shivering following laparoscopic cholecystectomy. A total of 120 patients, aged 20-70 and classified as ASA I–II, were enrolled in this triple-blind clinical trial. The participants were randomly assigned to one of three groups: ibuprofen (800mg IV), meperidine (30 mg), or placebo (normal saline 2 ml), administered 30 minutes before the end of surgery. The occurrence of postoperative shivering was assessed and recorded at regular intervals (0, 5, 10, 15, 30, and 60 minutes after surgery). Additionally, postoperative pain levels were measured using a visual analog scale (VAS), sedation levels were evaluated using the Ramsay Sedation Scale (RSS), and the incidence of postoperative nausea and vomiting was documented. The prevalence and severity of postoperative shivering were not statistically significant between groups. The VAS was significantly lower in the meperidine group than the ibuprofen group throughout the study (p <0.001). The VAS was significantly lower in the ibuprofen group than the placebo group at 0 and 15 minutes after surgery. Although the incidence of nausea was slightly higher in the meperidine group, the difference was not statistically significant (p=0.75). Sedation scores were consistently lower in the ibuprofen group and higher in the meperidine group compared to the other groups (p<0.0001) The meperidine group had a significantly higher sedation score indicative of deep sleepiness (score of 4) than the other groups. Intravenous ibuprofen demonstrated comparable efficacy to meperidine in controlling shivering. Additionally, the incidence of nausea, vomiting, and sleepiness was lower in the intravenous ibuprofen group, suggesting it is a potential alternative to meperidine.Postoperative shivering is a frequent and unpleasant complication experienced during the recovery phase from anesthesia, with reported incidences ranging from 5% to 60% in various studies [Post-operative shivering can have significant physiological effects, including increased cardiac output, oxygen consumption, CO2 production, blood pressure, circulating catecholamines, intracranial and intraocular pressures, wound suture opening, wound infections, hospitalization time, ventilation of the lung, ocular pressure and surgical site elongation. These consequences result in increased patient pain, compromised monitoring accuracy (especially with pulse oximeters), and in rare cases, hypoxia and delayed awakening [Pharmacological methods for treating shivering include using drugs such as meperidine, alfentanil, clonidine, physostigmine, ketanserin, and magnesium sulfate [Ibuprofen, a non-steroidal anti-inflammatory drug with analgesic and antipyretic effects, is inexpensive, widely available, and associated with fewer complications [ | PMC10600668 |
MATERIAL AND METHODS | PMC10600668 | |||
Study design and participants | This triple-blind clinical trial study was registered at the Iranian Clinical Trial Registry (IRCT20171217037921N1) and approved by the Ethics Committee of Ardabil University of Medical Sciences (Ethics Code ARUMS. REC. 1396. 164). The study was conducted at Emam Khomeini Hospital in Ardabil, Iran, between 2017-2018, including 120 adult patients. | PMC10600668 | ||
Sample size calculation and participant selection | The sample size was estimated based on similar studies [ | PMC10600668 | ||
Interventions and anesthesia protocol | Participants were randomly assigned to one of the three groups: ibuprofen 800mg IV (Ibuprofen800, 800mg/8ml, Caspian, Rasht, Iran), meperidine 30 mg (Pethidine 100, 100mg/2ml, Caspian, Rasht, Iran) or normal saline as a placebo (8 ml). The allocation concealment was ensured using a random number generator, and the assignment results were placed into consecutively numbered sealed envelopes by a third person who was not involved in the trial. Neither the patients, the researcher responsible for data collection, nor the analyzer were aware of the assigned intervention, ensuring a triple-blind study design.The three injections (ibuprofen, meperidine, and placebo) were prepared in identical syringes with a total volume of 2 ml. The investigator responsible for controlling and recording the clinical signs remained blinded to the specific drugs administered. The injections were administered 30 minutes prior to the conclusion of surgery.Anesthesia was induced using fentanyl at 1 µg/kg, propofol at 2 mg/kg, and atracurium at 0.5 mg/kg, following a standardized protocol for all patients. Tracheal intubation was performed, and anesthesia was maintained by infusing propofol at 100 µg/kg/min. Muscular relaxation was maintained during the operation to facilitate intubation and optimize surgical conditions. Atracurium was administered as required, and patients were mechanically ventilated throughout the surgical procedure. All patients were monitored in the recovery room. | PMC10600668 | ||
Outcome measures and data collection | postoperative shivering | The primary outcome measure was the occurrence and severity of postoperative shivering, assessed using the grading scale developed by Crossley Patients level of shiveringScores of sedation in patients according to the Ramsay Sedation Scale | PMC10600668 | |
Statistical analysis | All data analysis was performed using SPSS software version 20. Descriptive statistics were presented as frequencies, percentages, and mean±standard deviation (SD). Categorical data were analyzed using the Chi-square test or Fisher exact test, while continuous variables were analyzed using analysis of variance (ANOVA), repeated measure analysis, and t-test. Within-group comparisons were made using Tukey's post-hoc analysis. Statistical significance was set at p<0.05. | PMC10600668 | ||
RESULTS | postoperative pain, nausea, vomiting, pain, shivering | A total of 120 eligible patients were enrolled in the study, and no patients were excluded. All enrolled patients completed the trial and were included in the analysis. The flow of patients throughout the study is presented in a Consolidated Standards of Reporting Trials (CONSORT) flow diagram (CONSORT flow diagram of patients in the studyAccording to demographic data for the 3 study groups, no differences were determined between groups in terms of sex, age, weight, surgery duration, and ASA physical status (p>0.05) (Demographic characteristics of study participants (n=120)The incidence of shivering after surgery was 28.2% in the ibuprofen group, 23.7% in the meperidine group, and 35.9% in the placebo group, which was not statistically significant (p=0.72).After entering the recovery room, no significant differences in shivering intensity were found between the groups (p=0.22). Similarly, the grade of shivering at all evaluation time points (5, 10, 15, 30, and 60 minutes after entering the recovery room) did not show any significant differences among the three groups (p=0.87) (Mean shivering score after surgery in the recovery roomVAS pain scores were assessed upon entering the recovery room. The results revealed a statistically significant difference between the groups, with the meperidine group exhibiting lower pain scores (ranging from 1.88±0.93 to 3.38±2.12) compared to the ibuprofen group (ranging from 2.68±0.83 to 4.68±2.1) and placebo group (ranging from 2.98±1.6 to 5.1±2.1). In all three groups, postoperative pain intensity increased up to 15 minutes after entering the recovery room, followed by a subsequent decrease (Mean pain score after surgery in the recovery roomAt all time points, the Ramsay sedation score was consistently highest in the meperidine group and lowest in the ibuprofen group. The difference in sedation scores between the groups was not statistically significant except at the 60-minute time point (p=0.066) after recovery (Sedation score in groups at postoperative time pointsThe incidence rate of nausea was 7.5% in the ibuprofen group, 20% in the meperidine group, and 0.0% in the placebo group. This difference was significant only at the 15-minute mark after entering the recovery room (p=0.025). Four patients in the ibuprofen group (10%), 6 patients in the placebo group (15%), and 5 patients in the meperidine group (12.5%) experienced vomiting. However, there was no significant difference in the incidence of vomiting among these groups (p=0.75). | PMC10600668 | |
DISCUSSION | nausea, postoperative pain, Postoperative pain, hypoxia, nausea and vomiting, vomiting, respiratory dysfunction, pain, Shivering, lactic acidosis, shivering, nausea, vomiting | HYPOXIA, COMPLICATION, LACTIC ACIDOSIS | Reducing the side effects of opiates, such as respiratory dysfunction, nausea and vomiting, and sedation, is very important in patients after surgery. Shivering, a common and harmful complication of general anesthesia, can lead to hypoxia, pain, and lactic acidosis and interfere with monitoring ECG, blood pressure, and oxygen saturation [Our study findings show a comparable incidence of shivering when using intravenous ibuprofen or meperidine. We searched for similar studies but found no investigations specifically examining intravenous ibuprofen as an anti-shivering drug. Therefore, we compared the results of studies investigating intravenous drugs with a similar mechanism of action as ibuprofen, such as cyclooxygenase inhibition.Consistent with our study, Khezri The exact anti-shivering effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is still unknown. Prostaglandin E2, one of the main mediators of the hypothalamus, causes shivering after anesthesia via a central thermoregulatory pathway. This mediator is stimulated by COX-2 in the brain [Despite the low intensity of pain in laparoscopic surgery compared to open surgery, treating pain after laparoscopic surgery is a clinical and research dilemma and a challenge. Postoperative pain can lead to prolonged hospital stays and delayed recovery after laparoscopic cholecystectomy [In contrast to the results of our study, previous studies have demonstrated statistically significant differences [In our study, the ibuprofen group showed comparable or better control of nausea and vomiting than other groups, while the meperidine group had a higher incidence of nausea (20%) and vomiting (12.5%). This finding is consistent with published data in other studies. For example, the study by Southworth According to our findings, patients in the intravenous ibuprofen group experienced significantly less sedation compared to those who received meperidine and placebo. This difference was statistically significant at all time points of the study, except at the 60-minute mark.A meta-analysis of 12 randomized controlled trials involving 994 patients who received parecoxib for postoperative pain management compared to those who received placebo or standard treatment analgesia, found lower incidence rates of nausea, vomiting, and early (1-hour) postoperative sedation scores in the parecoxib group [Some limitations of our study include its short duration, which may limit the generalization of the results. Further studies with longer follow-ups are recommended to confirm our findings. Additionally, a single dose of 800 mg of ibuprofen, regardless of patient weight, and its administration only 30 minutes before the end of surgery (according to our study design) may be considered a potential criticism. Another limitation is the lack of assessment of anesthesia duration, hospital stay, and cost-effectiveness. Moreover, the results may not be generalizable to other types of surgeries. Further studies are needed to explore the optimal dosing regimen of intravenous ibuprofen to prevent postoperative shivering and its potential therapeutic effect on postoperative shivering. | PMC10600668 |
CONCLUSION | nausea, vomiting | In conclusion, according to the results of the present study, 800 mg intravenous ibuprofen appears to be an effective and low-risk intervention for the prevention of postoperative shivering after general anesthesia of laparoscopic cholecystectomy (by reducing the side effects associated with opioids such as sedation, nausea, and vomiting). However, 30 mg of intravenous meperidine was found to be a more effective analgesic compared to intravenous ibuprofen. Nonetheless, for patients who encounter challenges with meperidine administration, intravenous ibuprofen can serve as a suitable alternative for controlling postoperative shivering. | PMC10600668 | |
ACKNOWLEDGMENTS | PMC10600668 | |||
Conflict of interest | The authors declare no conflict of interest. | PMC10600668 | ||
Ethical approval | This study was approved by the ethics committee of Ardabil University of Medical Sciences (Ethics Code ARUMS.REC.1396.164). | PMC10600668 | ||
Consent to participate | Informed consent was obtained from all study participants. | PMC10600668 | ||
Personal thanks | The authors are very thankful to the Research Deputy of Ardabil University of Medical Sciences due to their financial support regarding this study | PMC10600668 | ||
Authorship | KhI, ME, and GA contributed to the study concept and design. ME, GA, and SR were involved in the acquisition of data. AK, KhI, and SR performed the analysis and interpretation of data. KhI, GA, and AK participated in the drafting of the manuscript. KhI, ME, AK, and GA critically revised the manuscript for important intellectual content. KhI and AK conducted the statistical analysis. ME and GA provided administrative, technical, and material support. GA, ME, and KhI supervised the study. | PMC10600668 |
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