To (1) give an overview of rebel nurse leadership by summarising descriptions of positive deviance, tempered radicals and healthcare rebels; (2) examine the competences of nurse rebel leadership; and (3) describe factors that stimulate or hinder the development of rebel nurse leadership.Research shows nurses have lower intention to leave their jobs when they can control their work practices, show leadership and provide the best care. However, organisational rules and regulations do not always fit the provision of good care, which challenges nurses to show leadership and deviate from the rules and regulations to benefit the patient. Three concepts describe this practice: positive deviance, healthcare rebels and tempered radicals.Scoping review using the Joanna Briggs Institute methodology and PRISMA‐ScR checklist.Papers describing positive deviance, healthcare rebels and tempered radicals in nursing were identified by searching Scopus, CINAHL, PubMed and PsycINFO. After data extraction, these three concepts were analysed to study the content of descriptions and definitions, competences and stimulating and hindering factors.Of 2705 identified papers, 25 were included. The concept descriptions yielded three aspects: (1) positive deviance approach, (2) unconventional and non‐confirmative behaviour and (3) relevance of networks and relationships. The competences were the ability to: (1) collaborate in/outside the organisation, (2) gain and share expert (evidence‐based) knowledge, (3) critically reflect on working habits/problems in daily care and dare to challenge the status quo and (4) generate ideas to improve care. The factors that stimulate or hinder the development of rebel nurse leadership are as follows: (1) dialogue and reflection, (2) networking conditions and (3) the managers’ role.Based on our analysis, we summarise the descriptions given of rebel nurse leadership, the mentioned competences and provide an overview of the factors that stimulate or hinder rebel nurse leadership.The descriptions produced in this review of rebel nurse leadership and the stimulating or hindering factors listed should help nurses and managers encourage rebel leadership. Organisational rules and regulations do not always fit the provision of good care, which challenges nurses. When nurses show more leadership in daily practice it will influence and enhance the quality of care and help retain nurses.The understanding of positive deviants, tempered radicals and healthcare rebels, their competences and the factors that stimulate or hinder the development of rebel nurse leadership will help management and nurses to support and develop rebel nurse leadership in daily practice.1The increasing demand for nurses  give an overview of the concepts and descriptions of positive deviants, tempered radicals and healthcare rebels in nursing, (2) examine the competences of rebel nurse leaders, (3) describe factors that stimulate or hinder the development of rebel nurse leadership, resulting in (4) a description of the concept of rebel nurse leadership.33.1A scoping review is a method which provides a preliminary assessment of the potential size and scope of available research literature to identify the nature and extent of research evidence , PubMed and PsycINFO. The keywords used in the search strings included the following: ‘Rebel*’, ‘Tempered Radical*’, ‘Positive Deviance*’ and ‘Health*’  that matched the eligibility criteria.3.2One researcher (EdK) screened the titles and abstracts of the retrieved papers. Then, two other researchers (PL or AW) independently reviewed a randomly selected sample of ten titles and abstracts. The Fleiss Kappa measure of inter‐rated reliability resulted in 1.0. Inclusion criteria were primary research papers written in English, methodology papers, discussion papers and reviews focusing on nurses or nursing practice in all healthcare sectors, including all patient or disease groups. Exclusion criteria were poster presentations, books, policy papers and interviews with researchers about their research.Next, the three researchers independently read and assessed the full papers. Any disagreements on assessment were discussed by the research team up to consensus. Papers were excluded if their focus was on the related deviant behaviour or rebelism of patients and if healthcare professional teams or healthcare professionals were discussed in general. Papers focusing on organisational structures and not on the professionals were also excluded. Of the included papers, the literature references were checked, and additional papers were added.Using a sheet developed by the research team to standardise the data extraction process, one researcher extracted details from the selected papers: author(s), year of publication, country, record type, research aim, study participants, methods, findings related to the aim of the scoping review  and conclusions. Another researcher checked the extractions. Then, working together, all four researchers sorted the extracted data and accompanying narratives into a form that reflects the aims of this scoping review  describe using positive deviance as a method to initiate conscious and systematic  change in an organisation. The positive deviance method is based on the assumption that in each community, individuals or groups can find better solutions and achieve better results than their peers by executing unusual behaviour even though the circumstances and availability of materials and resources are the same for all  knowledge. Their courage and competence in reflection help them to challenge the current status quo, deviating from the rules and regulations to achieve their goal of (solving problems which) improve daily care in both the short and longer term.4.2The included papers were also screened for factors that stimulate or hinder the development of rebel nurse leadership. 22 of the 25 papers describe three important factors  and informal  describe the obstacles to being a positive deviant, healthcare rebel or tempered radical. First, a nurse who acts like a positive deviant risks facing negative perceptions by management, punishment and the ultimate consequence of losing their job or licence  confidential conversations (both planned and spontaneous) and reflective dialogue in a safe work environment to reveal positive deviant behaviour of rebel leadership support the exchange of normative points of view on the current situation and collectively find new solutions for points of improvement; (2) networking in and outside the organisation to spread the deviant actions and ideas that help to encourage others; and (3) management respect and support that stimulates professionals to deviate. Hindering factors are the negative consequences for personal reputation and/or career that urge professionals deviating from the rules and regulations to ‘stay under the radar’.5This scoping review provides an overview of (1) descriptions of positive deviance, healthcare rebels and tempered radicals in nursing; (2) the competences of rebel nurse leaders; and (3) factors that stimulate the development of rebel nurse leadership.Most studies included in the review identify positive deviant healthcare professionals, departments and/or organisations. However, they seldom describe their exact selection criteria. Selection is methodologically challenging, as deviant or rebel behaviour requires a comparison with something regarded as ‘normal’ and is thus highly normative depending on the eye of the beholder. Besides, the methodology applied to ‘organise’ learning from positive deviant behaviour and/or methods might not be all‐encompassing as healthcare professionals prefer or even need to ‘stay under the radar’ to perform deviant behaviour , and no paper shows evidence that these better outcomes can be attributed to the positive deviant(s), healthcare rebel(s) or tempered radical(s) studied. Only the study by Wallenburg et al.  used ethAlthough the concepts of positive deviance, healthcare rebels and tempered radicals are similar, they also have important differences. The positive deviance approach purposefully identifies positive deviants, makes them visible and gives them an exemplary role with the aim of learning from them. Healthcare rebels or tempered radicals, on the other hand, are less visible in organisations as they prefer to ‘stay under the radar’ to avoid criticism  in 2014. The purpose of this education programme is to teach employees ‘to rock the boat and stay in it’  collaboration (networking); (2) communications ; and two are intrapersonal: (3) the ability to critically assess and reflect ; and (4) come up with innovative ideas. Bevan  and MeyeNote that one relevant aspect influencing rebel nurse leaders previously described in literature was not found in the 25 papers. According to Meyerson , p. 5, ‘This scoping review might help researchers bind together the concepts of positive deviance, healthcare rebels and tempered radicals so that studies of nurse rebel leadership will enter the nursing (leadership) literature. Leadership in individual nurses is required when nurses need to balance between being a ‘good’ employee and ‘deviating’ for the benefit of patient care or the organisation. Nurses must streamline processes aimed at better service provision, intertwining the professional and organisational logics as natural aspects of professional action  in‐ and outside their organisation to obtain evidence‐based knowledge. They share information and gain the engagement of others to provide better outcomes for patients and organisations. As a result, these nurse leaders consistently outperform their peers using the same resources.Important competences are the ability to: (1) collaborate and network with diverse professionals and management in‐ and outside the organisation, (2) obtain and share expert (evidence‐based) knowledge, (3) critically reflect on working habits, organisational logistics and problems in daily care and dare to challenge the status quo and (4) generate ideas to improve care. Factors supporting rebel nurse leadership are as follows: (1) formal and informal communication—dialogues and reflection—to reveal positive deviant behaviour, to support the exchange of normative points of view on the current situation and collectively find new solutions to improve quality, (2) networking in‐ and outside the organisation to share deviant activity and ideas that help to encourage others and (3) management's willingness to stimulate professional deviation.7This scoping review describes rebel nurse leaders, their competences, and provides an overview of factors that stimulate or hinder the development of rebel nurse leadership. This understanding will help management and nurses to support and develop rebel nurse leadership. More nurse leadership will influence and enhance the quality of care and help retain nurses.The authors declare that they have no conflicts of interest.EdK, PL and AW designed the study. EdK performed the scoping review. EdK, PL and AW analysed and interpreted the data. EdK and AW prepared the manuscript. PL and LS commented on the manuscript. All authors approved the final version for submission.Supplementary MaterialClick here for additional data file.Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.


Globally, eleven million people sustain burn injuries every year enough to require medical attention. WHO has estimated Disability associated limited years of 84,000 per year just due to deformities and 2100 people die every year due to burn injuries in Nepal. The overall objective of the study is to explore the effectiveness of burn injuries treatment and management approach of hospitals.This qualitative study approached to 40 Health Personnel for Key Informants Interviews and 18 Focus Group Discussions with community people at the ten referral hospitals of eight district from May–June 2016. Qualitative data were analyzed using ATLAS.ti software.Female burn victims are brought late to the hospital compared to male patients and false reporting about incident is usually done by her attendants. More than three-fourth (80%) of the hospitals and about one-third male and female from FGD reported that the community people seek home remedy first rather than medical treatment. Majority of the medical doctors and nursing chiefs reported that first degree cases accounts for 50% of the total burn cases with a success rate of 80%. Medical and Nursing staff reported that deformities like hypertrophic scar, keloids, joint stiffness and compartment syndrome are mostly observed during the treatment. Hypothermia and sepsis were the major causes of death in most of the burn patients.Usually, people who engaged in house and agriculture works, have visited public health posts/hospitals more frequently due to financial constraints and transportation issues where quality of burn care services are unavailable. In Nepal, 55,902 sustain moderate to severe and 2100 people die every year due to burn injuries.4Globally, eleven million people sustain burn injuries every year enough to require medical attention.Current medical facilities which offer treatment/ services related to deformities are rare and usually inaccessible to and unaffordable for the majority of people needing such kind of services. Furthermore, status of burn is unknown that directly have implication over planning and budget allocation for the prevention and management of burns.The overall objective of the study is to explore the effectiveness of burn injuries treatment and management approach of hospitals in perspective of community people and health personnel.The study was a qualitative cross-sectional study, based on primary information. This qualitative study approached to Key Informants interview (KII) and Focus Group Discussion (FGD) with Health Service Providers (HSPs) and community people respectively in the ten referral hospitals and their catchment areas of eight districts across the country from May to June 2016.Ten referral hospitals for KIIs with HSPs were: 1. Koshi Zonal Hospital, Biratnagar, Morang, 2. BP Koirala Institute of Health Sciences, Dharan, Sunsari, 3. Narayani Sub-Regional Hospital, Birgunj, Parsa, 4. Bharatpur Hospital, Chitwan, 5. Tribhuwan University Teaching Hospital (TUTH), Maharajgunj, Kathmandu, 6. Bir Hospital, Kathmandu, 7. Sushma Koirala Memorial Hospital, Sankhu, Kathmandu, 8. Gandaki Sub-Regional Hospital, Pokhara, Kaski, 9. Bheri Zonal Hospital, Nepalgunj, Banke and 10. Seti Zonal Hospital, Dhangadhi, Kailali. Similarly, community people  from the selected 10 hospitals' catchment areas were included for FGDs.5Very limited information exists on burn injuries and post burn deformities, risk factor associated with knowledge, practice and health seeking behavior of people at country level. It naturally demands an alternative sampling approach. Therefore, the research team decided to develop hospital-based sample plan to overcome the pitfalls in the sample plan inherent in the national surveys for burn injuries. Health Service Providers involved in the management of burn injuries were selected for interview using judgmental sampling technique. The design maintains equal sample size for all hospitals irrespective of their catchment population size since population size is not an important determinant of sample size.Summary of tools and techniques used for qualitative data collection: Researchers approached different groups of people for exploring and validated the content of qualitative information as follows:Altogether 40 KIIs (100% response rate) and 18 FGDs (90% response rate) were conducted in the 10 sampled hospitals. FDGs were conducted covering gender, different ethnic groups and occupation at community level. A total of 18 FGDs  were undertaken with a total of 146 participants .For the qualitative method, a content analysis was carried out (transcription and the notes takers' notes were matched). Qualitative data obtained from KIIs and FGDs were analyzed using At. Lasti Software. The findings were presented in narrative forms, comparative charts and quotations. Field work commenced after obtaining ethical approval from Nepal Health Research Council (NHRC).Triangulation approach was used to record and analyze the opinions and perceptions of a range of stakeholders about access, availability and barriers to burn injury treatment, care and services. The following themes were extracted from Key Informants Interview (KIIs) with Medical Superintendents, Doctors, Nursing Chief and staff and Medical Recorder and Focus Group Discussions with Male and female groups.Distribution of burn patients by hospitals: According to the Medical Superintendents (MS), 7 out of ten hospitals have separate burn unit but only 4–5 beds available for burn care management. As reported by the Medical Director of SKMH, in an average, 20–25 cases  are registered each day in the OPD of which 2–3 cases are burn related. All the KII and FGDs highlighted the fact that majority of the burn patient came from either the adjoining districts or across the country .The number of burn patients registered in the hospital is inaccurate and under reported. According to Medical Superintendent of Bharatpur Hospital, “Patients having post-burn deformities mostly get treated in the orthopedic department and since there is no separate section to report burn injury in HMIS, the data instead gets reported under deformities and injury.”Burn Injuries by type of incidents and treatment received: From Narayani Sub-Regional Hospital, Birgunj, majorities of male and female FGD participants expressed that an intentional burn injury occurs less in comparison to unintentional. Reasons for intentional burn injury are usually conflicts within family or community, such as couple or friends, whereas unintentional burn might occur due to various reasons.“Mostly suicidal burn cases of female due to flame/ scald are admitted to the hospital of which 90% cases are referral cases. Cases like fresh burn (acute burn) or patients being primarily treated from other hospitals with Post Burn Contractures (PBC) and scar are handled in this hospital”, said medical staff Knowledge, practice and treatment seeking behavior of burn patients after injuries: More than three-fourth (80%) of the hospitals reported that the community people seek home remedy first rather than medical treatment. About one-third male and female from FGD reported that they primarily rely on home remedy and only visit hospital for further treatment if required. Majority of FGD participants reported using oil (sesame), aloe vera, tomatoes, ghee (butter) paste made from medicinal plants, ice/hailstone, honey, potato, toothpaste, moist mud, and water of Hukka (smoking vessel) in case of minor burns. In case of flame burn, cotton cloths and blankets were used to cover the burnt part as a part of primary treatment at home. Usually home remedies are applied to reduce burning sensation, pain and avoid the formation of blisters.“There is no role of traditional healers amongst the younger generation. Visiting traditional healers was practiced earlier when there was no specific medicine and treatment for burn injuries. However, this practice has been changed in present days”. According to Bharatpur Hospital, Chitwan and Seti Zonal Hospital, Dhangadhi, Kailali.Handling critically burn patients before taking to the Hospital: The doctors, nursing chief and other staff of all ten study hospitals reported that majority of the burn cases are referred to hospital after the first aid treatment (applying silver sulfadiazine cream) at the health posts or druggist/pharmacists. In many instances, burn patients are brought to the hospital late, when wounds have already started to smell. In most of the study sites, community people did not seem to have sufficient knowledge about handling burn injuries (both minor and severe). Very few reported that in case of severe burn, they immediately sent the patients to the hospital in an ambulance/private vehicle or local transportation.“Burn patients from areas that are hard to reach are referred from community level health facilities to the district or Zonal hospitals after fluid management, TT (Inj. Tetanus toxiod) and antibiotics. Heath workers send those patients with full safety measures in an ambulance to prevent infection, while some who come directly are infected as they come with open wounds”, as reported by medical staff from SKMH.Service provision and effectiveness: Most of the Medical Superintendents mentioned that they provide limited burn related services, but cases are managed either by referring the patients to other hospitals or bringing a team of plastic surgeons at their hospitals. They have limited number of trained staff and higher work load which makes them difficult to manage all type of cases. Also limited physiotherapy services and expensive dressing materials are the barriers in providing quality medical care and treatment for burn patient to prevent further complications and death of burn patients. Most of the referrals are made to the hospitals like TUTH, SKMH or other medical institutions where quality of treatment with trained and experienced staff are available and also offer psychological counseling for both the patients and patient's attendees.Medical Superintendents of Bheri Zonal Hospital said, “A team of plastic surgeons from Kirtipur hospital visit our hospital periodically to conduct cleft palate surgery and manage severe cases of post burn contractures upon request, whereas contracture cases are referred to Kirtipur hospital directly.”Success rate : Majority of the medical doctors, nursing chief, and staff  reported that they mostly manage first degree burn cases that account for around 50% of the total burn cases and 25% belong to second degree with a success rate of 80%. They further added that it is relatively difficult to handle second degree and third degree burn cases than first degree. The success rate is determined by various factors such as age, degree of burn, BSA, nutritional status and other associated diseases like diabetes and hypertension. In addition to that prompt management, routine dressing and willpower of patients also determines the success rate.As reported by the 7 out of 10 hospitals, the survival rate is 70–75% among total registered burn cases, if burn is more than 40%, success rate reduces to <2%. The hospital could have contributed a higher success rate if they had sufficient resources.Experience during burn injury treatment at the HealthFacilities/hospitals: A very less male and female FGD participants expressed that they do not receive quality treatment at the health facilities due to unavailability of trained Service Providers. Though medicines are available, hospital doesn't want to treat the burn patient and immediately refer to other hospitals. Hence, the community people mostly preferred private clinics than government health facilities. FGD participants from area near Bir Hospital and Bheri Zonal Hospital responded that the doctors are always available in the emergency ward and patients receive prompt admission and treatment.Complications faced during the treatment: Medical and Nursing staff reported that hypothermia and sepsis were the major causes of death in most of the burn patients. Risk of failure of multiple organs and burn syndrome was high with burn patients having more than 40% Total Body Surface Area (TBSA). Delayed burn patients having infected wound requires skin grafting.Types of deformities developed during treatment: Deformities like burn contracture, such as hypertrophic scar, keloids, joint stiffness and compartment syndrome are mostly observed during the treatment as reported by the medical staff of the study hospitals. Doctors from Narayani and Gandaki sub-regional Hospital and BPKIHS further reported non-healing chronic ulcers, deformities of joints, fingers, axilla and fist as deformities developed during burn treatment. The findings showed that contractures or scars, either stable or unstable, are developed mostly in patients with second and third-degree burn.Challenges faced during treatment and management of the burn injuries in the hospitals: Almost all the hospital doctors and nurses said that burn injuries are neglected and there should be burn care unit in all major hospitals of Nepal. Human Resource management was another barrier/issue for treatment of burns such as, irregularity of staff in the health facilities/primary health care centers. Also, lack of beds, ICU, ventilators, isolation ward, bathroom and poor Infection Prevention (IP) management makes it difficult for the medical personnel to manage the burn cases. Most of the patients visiting government hospitals belong to poor socio-economic background hence it is likely for them to develop post burn contractures and deformities as they are unable to afford physiotherapy or other post burn procedures. Hence, the Government must implement separate program in order to support the poor and vulnerable.“For the management of burn injuries, multi sector approach is needed. It's a team work and doctor, nurse, dietician, physiotherapist and psychiatric human resources are also equally important. It is difficult to provide quality care to burn patients with limited human resources”, said Medical Superintendent of Bir Hospital.Gender discrimination and patient non-cooperation: The hospital's staff reported negative or non-cooperative attitudes of the burn patients and their attendants. The nursing In-charge of Narayani SR Hospital informed that female burn victims are brought late to the hospital compared to the male patients. Female patients mostly suffer from physical and mental trauma because of our conservative society. False reporting about the history or incident of the female patient is usually done by her attendants.Lack of training to the service providers on burn care management: Majority of the nurses from the study hospitals reported that they have not received training on counseling and special burn care management. Nurses from TUTH informed that staffs from burn unit receive less training compared to other departments. They further emphasized that training related to burn management must be provided to all staff for better management of burn cases.Suggestion for immediate and effective treatment and management of burn injuries and deformities (contracture): Majority of the doctors, nurses and other staff including medical superintendents highlighted the fact that separate ward for burn patients with sufficient number of beds, physiotherapy ward is required for an effective treatment and management of burn deformities. Also training, capacity building and skill enhancement programs using updated technology for medical personnel will also help to enhance the quality of treatment. They further added that the patients that could not be treated should be referred to the higher center immediately. Moreover, collaboration with development partners would be crucial for training and other support for burn patients.Need a policy and practice in place related to burn injuries care and management: A majority of the hospital authorities as well as service providers reported that there should be a policy and guidelines on burn injury management and post burn contractures and deformities. Government should bring proper law regarding burn injuries  is important and includes separate recording and reporting system in HMIS, skill and knowledge to health workers and formulate proper treatment strategies and guidelines. There should be standard protocol and training package that should be provided among hospital staffs up to FCHVs level. Health education and awareness program need to be developed by the government and implemented up to the community level. Burn related prevention; treatment and management should be included in the school curriculum and mass awareness created among community people on burn injuries.In this study, both Health Service Providers and community people's perception towards burn treatment and outcome were collected from ten major referral hospitals across the country. As reports of burn cases are influenced by various factors, 100 percent responses for all variables were difficult to obtain. The findings of this study are very significant hence it could be used as a future reference for disease prevention programs because there are limited burn care facilities in Nepal like Sushma Koirala Memorial Hospital and Kirtipur Hospital.7 where females were found to be more affected from burn injuries. A female predominance can be explained as females in the younger age group are mostly engaged in cooking and wear loose-fitting clothes such as saree, dupatta, etc., which inadvertently catch fire easily.8In this study, though it was not possible to estimate the population-based estimation of burns, the data indicates a slight female preponderance. This was in accordance with some recent studies10 Main reasons of intentional burn were recorded as a self-inflicted burns/suicidal attempt due to conflicts among couple which was in line with other studies.11According to Health Service Providers and Community people, majority of the injuries was unintentional which was consistent with the other findings.12 and in contrast with few other studies.14Majority of burn patients admitted in the hospitals had Total Burn Surface Area (TBSA) of less than 20%  which was in accordance with Alavi et al. (2012)15Most of patients went to the hospital for treatment at first followed by private clinic/pharmacy and some of them used home remedies. This finding was almost similar to the findings of the study conducted by Shanmugakrishnan et al. (2008).16In this study, more than two third (67.9%) of the patients developed contractures and more than half (54.6%) scars. There were only 1.2% unstable scars in the retrospective record review whereas one in every four patients (41.7%) developed scars after burn injury in the prospective study. Although, findings of the studies conducted in Bangladesh, Colombia, Egypt and Pakistan shows that 17% of children with burns have a temporary disability and 18% have a permanent disability.17The average length of hospital stay in majority of burn injured patients with all degrees of burn was found less than one month. However, study of socio-demographic Profile of Burn Cases Admitted in Shri Chhatrapati Shivaji Maharaj General Hospital, Solapur, India (2011) reported that 36% patients had hospital stay for less than one day.15Death was recorded very high in third degree than among first and second degree burn patients which was in accordance with another study by Shanmugakrishnan, et al (2008) where none of the cases with <30% TBSA burns died while all those with >55% TBSA burns died.12The predominant cause of death was cardiac arrest, abdominal complication, wound infection and pneumonia which was observed very similar in other studies.Majority of the burn patients self-reported that the hospitals provided them quality medical services. To reduce the morbidity and mortality due to burn, few preventive measures are recommended such as immediate transport of patients to the hospital for burn injury treatment and awareness raising campaigns at community level through different channels of communication.The number of patients with burn injuries hospitalized every year is in rising trend and most of them require specialize burn care and surgery. But there are very limited burn care facilities outside of Kathmandu valley. Hence, most of the burn patients visit SKMH followed by BPKIHS for care and treatment services. Due to unavailability of immediate care and timely referral to specialized hospital, morbidity and mortality from burn injuries are still increasing.Intentional burn injuries occur more in female and main reasons of intentional burn are self-inflicted burns/ suicidal attempt. Although, there is good practice at community level for taking hospital immediately (within 6 hours) after burn injuries in majority of cases and getting first aid treatment at the incident places before reaching to the hospital. The length of hospital stays and death of third degree burn patients are more than first and second degree. Cardiac arrest, abdominal complication, wound infection and pneumonia are found major cause of death among burn injured patients.A majority of the hospital authorities as well as service providers reported that Government should bring the law regarding burn injuries . There should be standard protocol, guidelines and training package up to FCHVs level. Burn related prevention, treatment and management should be included in the school curriculum and mass awareness on burn injuries and its management amongst people of the community.


This review aimed to identify the behavioral change techniques (BCTs) used in behavioral interventions for tobacco cessation at dental practices in relation to their effect on tobacco use. Six scientific databases were searched for behavior change interventions for tobacco cessation and were coded using the BCT taxonomy of behavioral support for smoking cessation (BCTTsm). Fifteen interventions were identified, and data related to intervention characteristics were abstracted. Sixteen BCTs were identified, mainly related to increased motivation and teaching regulatory skills. Goal setting was the most commonly used BCT. Ten out of fifteen interventions effectively impacted tobacco cessation outcomes (OR = 2 to 5.25). Effective interventions more frequently included goal setting, written materials, readiness to quit and ability assessment, tobacco-use assessment, self-efficacy boost, listing reasons for quitting, action planning and environment restructuring. Other BCTs were not clearly associated with an increased effect. Among the behavioral interventions, certain techniques were associated with successful tobacco quitting. Tobacco cessation interventions in a dental setting appear to benefit from using BCTs that increase motivation and teach regulatory skills. The identified BCTs in this review could provide a source to better inform researchers and dentists about the active ingredients in behavior change interventions for tobacco cessation in a dental setting. The dental setting has a unique position in tobacco cessation interventions. The repeated nature and long duration of dental appointments offer multiple opportunities for oral health professionals to educate and motivate their patients to quit tobacco use . EvidencCommon tobacco cessation interventions in the dental setting might be classified into three categories, which can be provided alone or in combination with each other. These include pharmacological, educational and behavioral interventions . PharmacBCT is a theory-based behavior change method that is used to change one or several psychosocial determinants, such as attitude and self-efficacy . The firMore evidence on the active ingredients of behavior change interventions for tobacco cessation by oral health professionals  is needed. No previous study has reviewed the BCTs used in behavioral interventions for tobacco cessation in dentistry. If we can systematically assess the effects of intervention elements, we can identify what works best, incorporate these elements into future intervention development processes and remove elements that do not add to an intervention impact to lower the user and intermediary burden. Therefore, the aim of this study was to identify the active ingredients (BCTs) used in behavioral interventions for tobacco cessation in dental practices, and explore their impact on intervention effects.This review focused on behavioral interventions for tobacco cessation by oral health professionals. The eligibility criteria for the included studies were as follows: (1) interventions that include effect data, such as randomized or cluster-randomized controlled, quasi-experimental and pretest–posttest evaluations; (2) the intervention group (participants) includes users of any type of tobacco, including smoking and smokeless tobacco; (3) the intervention should be behavioral in nature, but could be combined with educational or pharmacological interventions; (4) the outcome of tobacco cessation at 3, 6 or 12 months after baseline should be reported; and (5) the intervention should be carried out in a dental setting or by oral health professionals.Search methods covered two main sources: (1) the scientific databases PubMed Central via PubMed, Cochrane, PubMed, Web of Science and PsycINFO and (2) recent reviews/meta-analyses focusing on tobacco cessation in a dental setting. The search strategy within the scientific databases included the use of a combination of keywords and phrases appearing in titles, abstracts or keywords, using the following search algorithm: (a) for describing the participants: tobacco, smoking, cigarette smoking, tobacco smoking, tobacco, smokeless, chewing tobacco, oral tobacco and tobacco users; (b) for describing the intervention: behavio(u)r, (brief) counsel(l)ing, cognitive therapy, dental and patient education; (c) for describing the outcome: tobacco use cessation and tobacco abstinence; (d) for the environment: dentists, hygienists and dental. Interventions were screened first by title, then the abstracts were screened, duplicate manuscripts were removed and eventually the full text was screened. The search only included articles published in English, with no timeframe restriction to reflect the explorative nature of the review and to ensure the inclusion of most evidence-based articles up to the study completion date (7 January 2020). A snowball method was used to retrieve relevant articles from the relevant reviews in addition to the database search. The selection process can be seen in Figure 1, a PRISMA flow diagram . A data The included interventions were assigned to specific color codes to ease the visual comparison between them and in relation to the evidence strength and the identified BCTs: dark green represented strong evidence, light green represented moderate evidence, orange represented weak evidence, red represented no evidence and gray was used when the OR calculation was not possible .A deductive approach was used by two coders (MI and JM), whereby they identified the BCTs from a predefined set of codes using BCTTsm ,12. FollBefore extracting the data, an inter-coder reliability calculation was performed to measure the degree to which the code generated by the two coders matched after coding the same text independently and without conferring. Two randomly selected interventions were used to assess the inter-coder reliability and the agreement between MI and JM. To determine the overall inter-coder reliability of coding, the overall inter-coder reliability was calculated by dividing the total number of agreements for all codes by the combined total number of agreements and disagreements for all the codes ,14,15. TFifteen interventions were included in the review after searching, screening and assessing the eligibility of the articles.Of the fifteen studies included, eleven were randomized controlled trials, one was a randomized uncontrolled trial, one applied a quasi-experimental time series design and two used a pretest–posttest design. Four different countries were identified as follows: country (frequency): USA (11), Sweden (2), UK (1) and India (1) (supplementary n = 12) used oral examinations followed by feedback regarding oral tissue change due to tobacco use.n = 10) of these techniques directly focused on the behavior (tobacco use) and aspects relating to motivational and regulatory skills, while the rest of the BCTs promoted auxiliary activities or general interaction with tobacco use. Ten interventions were effective in terms of tobacco use, but there was no clear association between intervention effectiveness and the total number of BCTs applied in the intervention.The aim of this review was to identify the active ingredients used in behavioral interventions for tobacco cessation in general, particularly in relation to their effect on tobacco use. Of the 44 BCTTsm, 16 BCTs were identified in tobacco cessation interventions by oral health professionals. More than half  in tobacco use cessation and in only two of the ineffective ones (2/3). A previous finding from a systematic review and meta-analysis considered goal setting as a fundamental component for the success of behavior change interventions . AdditioSelf-efficacy, or the confidence in one’s ability to quit tobacco use, has received a large amount of attention in many previous studies as a possible predictor of quitting tobacco . SeveralAnother noteworthy method that is performed frequently by oral health professionals, in addition to the BCTs, is examinations for oral cancer. Oral cancer examination shows patients the adverse short-term oral health consequences of tobacco use (visible changes in the color of the teeth and the texture of soft tissue), rather than the long-term health consequences, which is considered more effective in deterring tobacco use ,21,41. OMany interventions were not clear about what the care being received by the comparison group usually entailed. Understanding the active ingredients of both the intervention and usual care groups is important for the effect interpretation , as the To the best of our knowledge, this is the first study that identified the BCTs used in tobacco cessation interventions by oral health professionals using BCTTsm. This review made use of reliable and valid evidence-based methods, such as PRISMA and BCTTsm. Furthermore, it focused on identifying the applied BCTs in a dental care setting and not on an analysis of the effectiveness of these BCTs applied in interventions. This review was limited to interventions published in English, meaning it potentially missed interventions published in other languages. However, the evidence showed that excluding studies published in langagues other than English had little effect on the summary of treatment effect estimates . MoreoveThe BCTTsm can be used to facilitate the detection of interventions’ active components in a dental setting. Among the behavioral tobacco cessation interventions, certain BCTs were associated with effective tobacco abstinence. Tobacco cessation interventions in a dental setting appear to benefit from using BCTs that increase motivation and teach regulatory skills. Additional interventions that thoroughly report its components and the BCTs used would be valuable to confirm the findings from this review.The identified BCTs can provide a source to better inform researchers and oral health professionals about the active ingredients in behavior change interventions for tobacco cessation. Researchers and intervention developers are highly encouraged to provide detailed descriptions of the components in both intervention and comparison groups, possibly in an Open Science Framework to support high-quality reviews on BCT effectiveness in tobacco use cessation. Accurate and complete descriptions of the intervention will be significant for evidence synthesis, as well as for policymakers and clinical practices. Possible research avenues include studies to compare the effectiveness of different BCTs used for tobacco cessation in a dental setting. More tobacco cessation intervention studies are needed in dental settings owing to the uniqueness of this context and its promising result.


The global burden of diabetes mellitus and its complications are currently increasing. Diabetic cardiomyopathy (DCM) is the main cause of diabetes mellitus associated morbidity and mortality; therefore, a comprehensive understanding of DCM development is required for more effective treatment. A disorder of epigenetic posttranscriptional modification of histones in chromatin has been reported to be associated with the pathology of DCM. Recent studies have implicated that histone deacetylases could regulate cardiovascular and metabolic diseases in cellular processes including cardiac fibrosis, hypertrophy, oxidative stress and inflammation. Therefore in this review, we summarized the roles of histone deacetylases in the pathogenesis of DCM, aiming to provide insights into exploring potential preventative and therapeutic strategies of DCM. Diabetes mellitus is a metabolic disease characterized by hyperglycemia. With the improvement of living standard, the incidence of diabetes mellitus continues to rise across the world . DiabeteA concerted definition of epigenetic trait, “stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence”, was reached at a Cold Spring Harbor meeting –20. TherEpigenetic mechanisms such as histone modification, DNA methylation and microRNA changes may play an important role in the development of DCM –34. PrevReversible modifications of histones indicate covalent posttranslational modification of histone proteins, including methylation, acetylation, phosphorylation, ubiquitination and sumoylation . HistoneTo date, there have been 18 HDACs reported that can be divided into four categories based on their sequence identity and catalytic activity . DescripClass I HDACs contain HDAC1, HDAC2, HDAC3 and HDAC8.Class II HDACs are subdivided into Class IIa  and Class IIb (HDAC 6 and 10) ( and 10) , 82.Class III HDACs are called sirtuins sharing sequence homology with the yeast Sirt 2 protein, which contains seven sirtuin members, namely, SIRT1-SIRT7  proteins accumulation including collagen I and collagen II. Fibrosis increases the passive stiffness of the myocardium and impairs relaxation and diastolic dysfunction . Elevatevia SIRT1-induced inhibition of ROS generation. Moreover, the TGF-β1/Smad3 signaling pathway played a key role in mediating ROS generation to pathologic fibrosis  and histone acetylation at the promoters of inflammatory genes was increased under diabetic conditions, which indicated that HDACs were associated with inflammation  for clinical use, particularly for cancer treatment  are chemical compounds that block Znreatment . Moreovereatment .Currently, five HDACIs that are structurally divided into hydroxamic acid derivates , short chain fatty  acids , cyclic peptides, benzamides and sirtuin inhibitors have been approved and are being used globally –142. WhiThe current evidence indicates that HDACs are involved in several biological pathways relevant to the pathogenesis of DCM as presented in in vitro and in vivo revealed that HDACs plays a critical role in the pathogenesis of DCM, suggesting that HDACs could be molecular intervention targets for the prevention and treatment of DCM. However, more endeavors are needed to further understand the roles of HDACs in the pathogenesis of DCM and the mechanism that regulate them. A comprehensive understanding of the mechanism of HDACs may provide a novel option for the prevention and treatment of DCM.Increasing evidence from XK, XJ and GL prepared the initial draft of the manuscript. ZL, ZY, ML, BC and CJ edited the manuscript for intellectual content. Figures and Tables were created by XK and GL. All authors contributed to the article and approved the submitted version.This work was supported by the Science and Technology Program of Guangzhou , the Science Foundation of Guangdong Second Provincial General Hospital , and Doctoral workstation foundation of Guangdong Second Provincial general Hospital .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In settings with limited resources that lack standards to ensure the quality of childbirth and newborn care, the use of antenatal corticosteroids is potentially harmful. Safe, effective use of antenatal corticosteroids requires providing standardized evidence-based practices and supportive supervision, training staff, and a facility-level actionable health information system. Most of the 37 public health facilities in northern India that we assessed were not readied for providing quality care for threatened preterm birth and ensuring the safe use of antenatal corticosteroids (ACS).Deficiencies were identified in areas of evidence-based practices, competent workforce, actionable health information system, physical resources, and communication.The existing ACS guidelines were not up-to-date with current evidence and were not disseminated or implemented uniformly across facilities.Attention to accurate gestational age estimation and the quality of childbirth and preterm care were inadequate in all the facilities.Increasing uptake of ACS for threatened preterm birth without providing adequate-quality maternal and newborn care and meeting essential preconditions outlined by World Health Organization recommendations will not improve preterm outcomes.Facility-level actions are needed for the safe and effective use of ACS in support of the delivery of quality care. In 2014, the Government of India (GOI) released operational guidelines on the use of antenatal corticosteroids (ACS) in preterm labor. However, without ensuring the quality of childbirth and newborn care at facilities, the use of ACS in low- and middle-income countries is potentially harmful. This study assessed the readiness to provide ACS at primary and secondary care public health facilities in northern India.A cross-sectional study was conducted in 37 public health facilities in 2 districts of Haryana, India. Facility processes and program implementation for ACS delivery were assessed using pretested study tools developed from the World Health Organization (WHO) quality of care standards and WHO guidelines for threatened preterm birth.Key gaps in public health facilities’ process of care to provide ACS for threatened preterm birth were identified, particularly concerning evidence-based practices, competent workforce, and actionable health information system. Emphasis on accurate gestational age estimation, quality of childbirth care, and quality of preterm care were inadequate. Shortage of trained staff was widespread, and a disconnect was found between knowledge and attitudes regarding ACS use. ACS administration was provided only at district or subdistrict hospitals, and these facilities did not uniformly record ACS-specific indicators. All levels lacked a comprehensive protocol and job aids for identifying and managing threatened preterm birth.ACS operational guidelines were not widely disseminated or uniformly implemented. Facilities require strengthened supervision and standardization of threatened preterm birth care. Facilities need greater readiness to meet required conditions for ACS use. Increasing uptake of a single intervention without supporting it with adequate quality of maternal and newborn care will jeopardize improvement in preterm birth outcomes. We recommend updating and expanding the existing GOI ACS operational guidelines to include specific actions for the safe and effective use of ACS in line with recent scientific evidence. ACS use has been widely studied in high-income countries where most facilities are equipped with adequate childbirth and preterm care and have the ability to estimate accurate gestational age. In a recent review of trials done mostly in high-resource settings, ACS use was associated with a reduction in respiratory distress syndrome (34%), intraventricular hemorrhage (45%), necrotizing enterocolitis (50%), and newborn mortality (31%).Use of Antenatal Corticosteroids in Preterm Labour (Under Specific Conditions by ANM): Operational Guidelines.–,–In June 2014, the Government of India (GOI) published the The World Health Organization (WHO) provided recommendations on threatened preterm birth in 2015, specifying essential preconditions for ensuring safe use of ACS.ACS benefits can only be achieved with appropriate selection of patients and the provision of minimum standards of maternal and newborn care.,Health systems are also challenged by the resources required to adequately support the provision of ACS for threatened preterm birth. Two different multicountry analyses in 2015 and 2018 identified major bottlenecks in leadership and governance, health service delivery, health financing, health information system (HIS), essential medicine and technologies, community ownership, and partnership that hinder the uptake of ACS.This study was conducted in India to assess the current utilization and clinical practice of ACS use in threatened preterm birth at the health facility level. We assessed the training, knowledge, and attitudes of all levels of providers of obstetric care. The findings are intended to inform policy makers regarding facility readiness, recommend essential actions to support implementation, and catalyze the revision of the GOI operational guidelines to ensure safe and effective use of ACS.To undertake this study, the role of key stakeholders including policy makers, professionals, and state representatives was critical. The Ministry of Health and Family Welfare, Child Health Division, GOI, established a project advisory group to approve the study framework and approach and review findings and current evidence to expand the scope of national operational guidelines for safe and effective use of ACS in threatened preterm birth. Representation included the Ministry of Health and Family Welfare, Global Alliance to Prevent Prematurity and Stillbirth, Haryana State Department of Health officials, Indian Council of Medical Research, National Neonatology Forum-India, Norway–India Partnership Initiative, Society for Women and Child Health, United Nations Children’s Fund (UNICEF), United States Agency for International Development, and leading Indian medical faculty.A cross-sectional mixed-methods study was conducted in government health facilities in Hisar and Ambala districts of Haryana, India. The study assessed the facilities’ process of care and readiness for using ACS in threatened preterm birth. Health care providers (HCPs) were interviewed using a semistructured questionnaire to assess their knowledge and attitudes regarding ACS administration and evidence-based practices for ACS administration. Women were interviewed using a semistructured questionnaire to identify mothers’ perspectives on accessing care during preterm labor and their level of communication with HCPs.The selection of study districts was based on a purposeful selection process in consultation with the project advisory group to include 1 National Health Mission’s high-priority district (HPD) and 1 non-HPD. HPDs were identified based on process/outcome indicators for maternal health, child health, and family planning.Health facilities for assessment were selected in consultation with the local district health authorities based on the provision of delivery services and distance from district hospitals. All health facilities within the study districts had been classified according to the level of care. The primary health care centers (PHCs) and subcenters (SCs) were classified as primary care facilities, and community health centers (CHCs), subdistrict hospitals (SDHs), and district hospitals (DHs) were classified as secondary care facilities. A total of 37 health facilities, including 25 primary care (8 PHCs and 17 SCs) and 12 secondary care facilities , were included in the study.For the facility assessment component of the study, 17 SCs were excluded from 37 health facilities in the study districts because they were not providing delivery services.For assessment of knowledge and attitudes regarding the safe use of ACS, a total of 88 HCPs involved in ACS administration, including medical doctors, staff nurses, and ANMs, were selected through convenience and purposive sampling.To assess the care-seeking behavior of preterm delivered mothers who received ACS, 19 women up to 4 weeks postpartum and aged 15 years or older who delivered a preterm newborn were identified from clinical record registers.HCPs involved in ACS administration were invited by trained field investigators to participate in the study through scheduled interviews. Eligible women were approached at the time of discharge. In addition, at the primary facilities, interviewers contacted health extension workers twice weekly to identify women who met the study criteria and had delivered at home. The health extension workers then informed these women either by telephone or in person about the interviewer’s visit. Consenting women were interviewed either immediately at a designated area of the health facility that was quiet and private, or at a more convenient time at the woman’s home. To avoid possible coercion, no financial incentives were provided. Inclusion criteria for facilities and participants are presented in WHO Standards for Improving Quality of Maternal and Newborn Care in Health Facilities.For a comprehensive assessment of ACS use, a framework for this study was developed from the WHO Recommendations on Interventions to Improve Preterm Birth Outcomes,Quantitative data were collected by using (1) a facility assessment tool; (2) a semistructured questionnaire for HCPs; (3) a clinical verification checklist and a case history extraction form; (4) a semistructured questionnaire for mothers; and (5) HIS indicator report summary. Data collection instruments were developed through a multistep process. Based on the study framework and the BOXEvidence-based care: Practices assessed by focusing this domain to threatened preterm birth care in line with the WHO Recommendations on Interventions to Improve Preterm Birth Outcomes.Use of Antenatal Corticosteroids in Preterm Labour Under Specified Condition by ANM: Operational Guidelines.Availability of guidelines for ACS use: Availability in print/digital format of the national ACS guideline: Gestational age assessment: Different methods used by health care providers for estimation of gestational age such as use of fundal height, last menstrual period, and use of ultrasound. The most accurate estimate is from ultrasound scan before 24 weeks of gestation.Identification of imminent preterm birth: Birth anticipated within 7 days .Adequate obstetric care: The basic emergency obstetric care services were assessed based on availability of drugs , manual removal of retained placenta, removal of retained products of conception, assisted vaginal delivery, and resuscitation with bag and mask of nonbreathing neonate. The comprehensive emergency obstetric care services were assessed based on obstetric surgery with anesthesia and blood transfusion availability.Adequate newborn care: Newborn care was assessed based on availability of newborn care corner, newborn stabilization unit, and special newborn care unit at the prescribed public health facilities and practices for thermal care; safe oxygen delivery; feeding support and infection management.Infection prevention and management in mother and newborns: This was assessed based on prescribed infection prevention interventions and clinical practices during antenatal, intranatal, and postnatal periods.Competent and motivated workforce: Availability of trained health care providers and their knowledge and attitude about providing adequate preterm care.–Availability and training requirements: Availability of trained health care providers  as per Indian Public Health Standards.Indications of ACS: ACS is indicated in preterm birth for gestational age 24 to 34 weeks expected within 7 days with one of the following: preterm labor, PPROM, severe pre-eclampsia/eclampsia, and antepartum hemorrhage.Preconditions: ACS use is recommended only when the following conditions can be met: threatened preterm birth between 24 and 34 weeks of gestation with accurate assessment of gestational age, preterm birth is considered imminent within 7 days, no clinical evidence of maternal infection, availability of adequate childbirth care (including the capacity to recognize and safely manage preterm labor and birth), and adequate preterm newborn care .Clinical parameters: Gestational age, fetal heart sounds, imminent preterm birth, cervical dilatation, PPROM, evidence of vaginal bleeding, and evidence of maternal infection.Signs of true labor: Regular uterine contractions, descent of presenting fetal part, and evidence of cervical shortening/dilatation.Minimum and maximum gestational age for ACS use: Minimum age is 24 weeks of gestation and maximum age is 34 weeks of gestation.Conditions that put woman at risk of preterm birth: Preterm labor, PPROM, severe pre-eclampsia/eclampsia, and antepartum hemorrhage.Route and dose of ACS administration: Administered intramuscularly and dose of dexamethasone is 4 doses of 6 mg at 12-hour intervals.Authority for ACS use by providers and existing supervision and monitoring practices.Actionable information system: Availability of standard forms, review of completeness and accuracy of case sheets and registers of mothers who had received ACS and use of this data to improve care of mother and newborn. Documentation of ACS specific indicators as mentioned in Government of India 2014 ACS operational guidelines.Physical resources: Availability of adequate physical environment, medicines, and equipment required for threatened preterm care.Effective communication: Communication or counseling by health care providers and availability of IEC material on threatened preterm birth.Respect and preservation of dignity: Communication or counseling by health care providers and availability of IEC material on threatened preterm birth.Functioning referral system: Presence of an existing referral mechanisms for timely identification and safe referral with documentation of relevant information.Abbreviations: ACS, antenatal corticosteroids; ANM, auxiliary nurse midwife; CPAP, continuous positive airway pressure; IEC, information, education, and communication; PPROM, preterm premature rupture of membranes.The data were entered digitally using XLSForms and hosted on a server using KoBoToolbox.This project was reviewed and approved by the institutional review boards of the PGIMER, Chandigarh India (No. IEC-08/2016-491), and Project Concern International (No. 21). Letters of support were secured from all district offices and facilities where data were collected. We obtained written consent from potentially eligible and interested participants in their preferred language. We also informed them that their participation would be voluntary and there would be no professional or personal consequences or benefits of participation. Mothers were given the option to read or hear their consent form according to their literacy level. No financial incentives were provided.A total of 25 PHCs and 12 secondary health care facilities were included in the study. A total of 88 HCPs and 19 mothers were interviewed . AdditioWHO Recommendations on Interventions to Improve Preterm Birth Outcomes.Basic emergency obstetric care services were reported to be available across all the facilities but a few SDHs, CHCs, and PHCs lacked services including manual removal of retained placenta, removal of retained products of conception, and assisted vaginal delivery. Comprehensive emergency obstetric care services were available at DHs and SDHs in both districts. However, none of the facilities had a comprehensive protocol for identification and management of conditions that put a woman at risk of threatened preterm birth such as severe preeclampsia and eclampsia, premature preterm rupture of membrane, antepartum hemorrhage, and spontaneous preterm labor. Most of the facilities were using partograph for monitoring of labor.Newborn care corner, newborn stabilization unit, and special newborn care unit were present as prescribed by GOI guidelines.The second subdomain assessed the knowledge and motivation of the workforce to provide adequate preterm care. All facilities reported a shortage of health care staff especially of physician specialists at CHCs, SDHs, and DHs and medical officers at DHs, SDHs, and PHCs. Only 23 out of 46 nurses (50.0%) and 8 out of 17 ANMs (47.1%) were trained in facility-based integrated management of neonatal and childhood illness. Among HCPs, ACS-related training was attended by 1 out of 6 specialists (16.6%), 3 out of 19 medical officers (15.7%), 3 out 46 staff nurses (6.5%), and 1 out of 17 ANMs (5.8%). The details of ACS-related knowledge about the clinical requirement for ACS use are presented in The HCPs’ attitudes regarding the effectiveness of ACS and its safety and their confidence in ACS use were measured using Likert scales. A disconnect was observed between knowledge and attitude among all the HCPs; although HCPs reported they were confident about using ACS, their knowledge of essential clinical requirements was poor. This disconnect was observed more among ANM and staff nurses . In bothA disconnect was observed between knowledge and attitude; although HCPs reported confidence about using ACS, their knowledge of essential clinical requirements was poor.A total of 76 of 88 HCPs (86.4%) reported that decisions for ACS administration were made mainly by doctors; 29 of 88 HCPs (32.9%) reported that the decision was made by staff nurses; and 7 of 88 HCPs (7.9%) reported that the decision was made by ANMs.None of the facilities had a routine audit or supportive supervision strategy in place to ensure safe and effective use of ACS.Dexamethasone, oxytocin, magnesium sulfate, and parenteral antibiotics were available in most of the facilities, except dexamethasone in 1 CHC and 1 PHC in the past 6 months. However, antihypertensives, oxygen, and antipyretics were not available at some of the facilities. Ultrasound machines were available only at DHs and 50% of the SDHs. The necessary equipment for thermal regulation, oxygen delivery, and feeding were either unavailable or nonfunctional at the time of facility assessment. The remaining equipment, such as blood pressure machine, stethoscope, and baby weight scale, were available in all health facilities. All facilities had a continuous water supply and power backup.The clinical record documentation of 19 mothers who had received ACS in health facilities was assessed. Of these mothers, 79% were given ACS between 24 and 34 weeks, and 21.1% were given ACS after 34 weeks. In all the cases, ACS-specific indicators as per the 2014 guideline were not recorded or monitored. Moreover, indicators on the quality of ACS use, such as administration beyond 34 weeks and use of ultrasound for gestational age estimation, were lacking in the existing guidelines. Moreover, these facilities lacked monitoring of ACS-specific facility readiness in terms of existing infrastructure, human resources, clinical practices, and documentation of relevant information.We interviewed 19 mothers who had a preterm delivery in the previous 1 month and those who had received ACS in an SDH or DH regarding their experiences with the care provided. More than two-thirds (68.4%) of the mothers were informed about recognizing true labor, and 4 out of 19 mothers (21.2%) were informed about the risk of preterm labor. The newborn’s condition was explained to 58% of the mothers, and 16% were informed regarding ACS before administration. Although danger signs of pregnancy were printed on the antenatal maternal child protection card, ACS-specific information in the vernacular language was not available.Out of 19 women, 11 were referred for care. Eleven women were referred by an HCP and 8 others reached secondary care facilities on their own. The reasons for referral were pain, bleeding, leakage, and weakness. Referrals were made mainly to DHs that the patient could reach within 30 to 60 minutes using the state ambulance services. Eleven mothers were provided an ambulance for referral. Referral slips were given to 9 women. A separate referral card was made for newborns in all DHs, 1 out of 2 SDHs (50%), 6 out of 8 CHCs (75%), and 3 out 8 PHCs (37.5%). The documentation of information about ACS use on referral slips/cards was poor.This study is the first systematic analysis of facility process of care in the context of the 2014 GOI guidelines to provide ACS for threatened preterm birth in public health facilities. Our findings suggest that most of the facilities were not equipped for providing quality care for threatened preterm birth and ensuring safe use of ACS. The facilities that were deficient in the quality of care domains of evidence-based practices, competent workforce, actionable information, physical resources, and communication and respect failed to fulfill the preconditions outlined in the 2015 WHO recommendations.Our findings suggest that most of the facilities were not equipped for providing quality care for threatened preterm birth and ensuring safe use of ACS.,,In comparisons across levels of facilities, DHs were better equipped with infrastructure and trained human resources. The reported use of different methods  by HCPs for estimating gestational age indicates the need to emphasize the importance of standardizing the accurate estimation of gestational age by ultrasonography within 24 weeks of pregnancy. Although most of the facilities were using a partograph for monitoring labor, the completion of the form was not assessed. The basic emergency obstetric care packages in SDHs, CHCs, and PHCs need to be strengthened in the guidelines. A comprehensive protocol for the identification and management of threatened preterm birth should be developed, tested, and implemented in the health facilities.–Similarly, ACS clinical knowledge was better among doctors at the secondary care level and poorest among ANMs. But there is a shortage of doctors, especially physicians and specialists at CHCs, SDHs, and DHs and medical officers at DHs, SDHs, and PHCs. Therefore, a cadre-specific training curriculum updated with the latest evidence on identification and management of threatened preterm birth should be in place to train HCPs based on their assigned level of facility. Additionally, to address the shortage of health care staff, regular recruitment should be in place to ensure continuous service delivery. Periodic audits and supportive supervision should also be in place to sustain the quality of care. Decision for ACS administration should only be made either by a medical officer or a staff trained in the management of threatened preterm birth. Health systems can be further strengthened to provide timely ACS at secondary-level facilities through strict monitoring of the supply of ACS and by adequate inventory management. The necessary equipment for thermal regulation, oxygen delivery, and feeding should be made available or made functional.Timely referral with details of the diagnosis, investigations, treatment given , and reason for referral of the mother as well as the newborn can facilitate appropriate and prompt decision making and improve maternal and newborn outcomes.,,,,This assessment of facility readiness to provide ACS for threatened preterm birth was aligned with the WHO quality of care framework, in contrast to previously published assessments.In 2020, WHO published a multicountry double-blind randomized trial in Bangladesh, India, Kenya, Nigeria, and Pakistan to assess the safety and efficacy of dexamethasone in women in hospitals in low-resource countries who were at risk for early preterm birth.For the safe and effective use of ACS in threatened preterm birth, facility readiness to meet the preconditions outlined by the 2015 WHO guidelines is an essential prerequisite.Suggested actions for ensuring safe and effective use of ACS include (1) expanding the scope of existing guideline from preterm labor to threatened preterm birth; (2) developing facility readiness criteria; (3) regular training and audit of HCPs; (4) expanding existing indicators on ACS coverage to indicators on the quality of ACS use; (5) developing efficient logistic management; (6) strengthening of existing referral system; (7) improving counseling practices of HCPs; and (8) developing information, education, and communication material on preterm birth care in the local language and engaging mothers/family in childbirth care/process .For this assessment of the readiness of facilities to provide ACS, we followed the WHO quality of care frameworkWe did not include the tertiary care level because the national guidelines are generally implemented by individual states up to the district level. The 2014 GOI guideline did not stratify the strategies for ACS use at respective primary, secondary, and tertiary care levels and did not include the facility readiness for safe and effective use of ACS.Tertiary care centers that are referral centers do not follow specific guidelines, and treatment is physician specific based on the condition of the patients. Most of these centers are either medical colleges or advanced institutes that have trained staff, and they are well equipped in providing very advanced maternal and newborn services.Another limitation of this study is the generalizability of the finding to other states in India. Moreover, private health facilities were not included in the study. However, this study can be replicated in other states and the findings can be used for the expansion of existing guidelines. The data presented on evidence-based practices were self-reported by HCPs and could not be verified by observation.Health facilities at primary and secondary levels lack facility readiness to provide quality of care for threatened preterm birth and safe use of ACS for threatened preterm birth. This study suggests a need to strengthen the existing health system by improving advocacy for ACS programs and quality of health care delivery, training of HCPs, and developing an actionable information system. Merely increasing uptake of any single intervention


Recently, the possibility of tumour classification based on genetic data has been investigated. However, genetic datasets are difficult to handle because of their massive size and complexity of manipulation. In the present study, we examined the diagnostic performance of machine learning applications using imaging-based classifications of oral squamous cell carcinoma (OSCC) gene sets.RNA sequencing data from SCC tissues from various sites, including oral, non-oral head and neck, oesophageal, and cervical regions, were downloaded from The Cancer Genome Atlas (TCGA). The feature genes were extracted through a convolutional neural network (CNN) and machine learning, and the performance of each analysis was compared.The ability of the machine learning analysis to classify OSCC tumours was excellent. However, the tool exhibited poorer performance in discriminating histopathologically dissimilar cancers derived from the same type of tissue than in differentiating cancers of the same histopathologic type with different tissue origins, revealing that the differential gene expression pattern is a more important factor than the histopathologic features for differentiating cancer types.KCNA10, FOSL2, and PRDM16, and extracted leader genes from pairwise comparisons were FGF20, DLC1, and ZNF705D.The CNN-based diagnostic model and the visualisation methods using RNA sequencing data were useful for correctly categorising OSCC. The analysis showed differentially expressed genes in multiwise comparisons of various types of SCCs, such as The online version contains supplementary material available at 10.1186/s12903-021-01642-9. Traditionally, the choice of treatment modality for cancer primarily depends on the histopathologic diagnosis, and a definite diagnosis plays a major role in choosing a treatment strategy and determining the prognosis of the disease , 2. ThusUnderstanding the genetic heterogeneity of cancers can provide clues for increasing diagnostic accuracy and developing efficient biomarkers as well as improving treatment efficacy –11. A maOSCC, the most common cancer of the oral cavity, derives from the oral mucosa (which is lined by stratified squamous epithelium) and shares morphologic findings and histochemical features with SCC of other sites or tissues. All SCCs are diagnosed as the same type of disease due to similar histologic findings, but the gene expression of each SCC has not been compared. Therefore, it is not well understood whether the genetic features of SCCs of various tissues or organs are similar. Knowledge of the genetic features distinguishing OSCC from SCCs of other tissues might provide clues for differential diagnosis and the development of treatment paradigms. In the present study, we examined the diagnostic performance of machine learning applications using CNN image classification for OSCC samples. In addition, we investigated the differences in genetic features between OSCC and other types of SCC, which may provide a basic rationale for potential diagnostic models and the development of targeted therapy.http://cancergenome.nih.gov/). The platforms used, experiment types, and numbers of samples analysed for mRNA expression for each cancer are shown in Additional file RNA sequencing data from samples of OSCC, non-oral head and neck SCC (HNSCC), oesophageal SCC, oesophageal adenocarcinoma, and cervical SCC were downloaded from the TCGA database , and noise data were filtered out by using a variance threshold of 1. Then, the data were embedded into 1-D images.The differentiation step used the CNN model to process the 1-D images output from the preprocessing step. The training and testing were performed using a 10-fold cross validation method.The class activation map method was used to visualise what the CNN had learned and heatmap images representing the contribution of each gene were produced from the image input.Since each pixel corresponds to one gene, feature extraction methods take the most important pixels with the most intensity within the image and categorise the corresponding represented genes into a list of dominant genes.A CNN model , 22, whiBecause we needed to extract features learned through CNN analysis, we employed the class activation map (CAM) method to visualise the learned features from the CNN output. The CAM method helps understand what regions of an input image influence the CNN’s output prediction. The technique relies on the generation of a heatmap for visualisation, which highlights pixels of the image that trigger the model to associate the image with a particular class. In this experiment, since each pixel represented a corresponding gene, the CAM method could visualise which gene was dominant for each type of cancer.To evaluate the performance of the tool in OSCC diagnosis, its performance capabilities, such as test recall, test precision, and test accuracy, were compared using the dataset containing OSCC, non-oral HNSCC, cervical SCC, and oesophageal SCC samples in a multiwise fashion. After repeated training using the dataset, the tool showed ~ 82% test precision and test accuracy in diagnosing SCCs of various origins Fig. . The finTo clearly determine diagnostic accuracy in differentiating OSCC from SCC of other tissues or organs, a confusion matrix was generated, as shown in Fig. To further clarify the importance of the origin of cancer cells, the set of differentially expressed genes between oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma was compared to that between OSCC and ESCC. Although both OSCC and ESCC share very similar histopathologic features, the machine learning tool differentiated them easily, with only ~ 2% error when discriminating ESCC from OSCC, whereas 38% of ESCCs were misdiagnosed as oesophageal adenocarcinoma Fig. A, B, impTo identify valuable genes for diagnosing OSCC, the dominant genes that could discriminate OSCC from other SCCs were extracted through the class activation map feature extraction method in a multiwise manner. In addition, data on the characteristic genes of OSCC were extracted by individually comparing OSCC with other types of SCC in a pairwise manner: comparison 1) between OSCC and non-oral HNSCC, (2) OSCC and cervical SCC, and (3) OSCC and ESCC. Then, the shared genes from each comparison were selected  that were not found in our results [PRDM16 and DLC1 have been studied in various types of cancers, and the significance of these genes in OSCC has not been examined [KCNA10 and ZNF705D in the pathogenesis of cancer, including OSCC, have not been investigated, implying the novel insights gained from this study and new avenues for the diagnosis of and new treatment strategies for OSCC.In addition, a previous study using the TCGA and Gene Expression Omnibus (GEO) databases reported 6 primitive biomarkers of OSCC ( results . This diexamined –26. FurtIn summary, we implemented a computation approach to develop novel biomarkers for OSCC based upon site-specific genetic variations that occur during the process of cancer progression. Further validation of these biomarkers in both experimental and clinical settings will strengthen the power of this computation approach in improving the accuracy of diagnosis and the assessment of treatment outcome and prognosis, in addition to its aid in development of optimized therapeutic strategies.Additional file 1. Numbers and types of tumor samples used in this study.


This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world’s largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, “Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research,” devoted to key topics within the field of alcohol research. This article is based on Dr. Tapert’s presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift. The past 50 years of research supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) have resulted in an accumulation of invaluable data to address the multifaceted problems surrounding underage drinking. Youth use of alcohol remains a pervasive social and public health concern in the United States and a leading cause of disability and mortality during adolescence.7High-risk alcohol consumption patterns and associated problems alone increase risk for adverse outcomes—such as motor vehicle accidents, high-risk sexual behaviors, other illicit substance use, and mental health challenges—for adolescents who drink. These risks are further compounded by the fact that adolescence is a period of crucial brain development and maturation.11This article begins with an overview of typical adolescent brain development, followed by a summary of four key themes in the current understanding of alcohol and the adolescent brain: (1) predictors of underage drinking; (2) consequences of alcohol on adolescent brain structure and function; (3) moderating and confounding factors, including age of onset, sex disparities, family history, co-use of other substances, and mental health comorbidities; and (4) reversibility of and recovery from alcohol misuse. The article concludes with a discussion of where the data lead us to reach the next milestones in NIAAA-supported research.The brain of an adolescent, much like teenage behavior, undergoes significant developmental changes. This neurodevelopment continues after adolescence, typically until around age 25.16Executive functioning typically matures during this developmental stage,28One of the studies investigating adolescent alcohol use and its effects is coordinated by the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), which is conducting a multisite longitudinal study supported by funding from NIAAA and other National Institutes of Health partner institutes. Launched in 2012, this five-site consortium recruited a community cohort of 831 diverse adolescents ages 12 to 21 from five U.S. regions . Half the sample was enriched for key characteristics conveying risk for heavy drinking among adolescents . Most of the sample (85%) reported very limited alcohol use at project entry; the remaining 15% exceeded typical age thresholds for alcohol at project entry in this cohort-sequential design.Resting-state fMRI findings from NCANDA and other studies have shown that intrinsic functional networks subserving cognitive control and limbic circuitry develop across adolescence and may be influenced by adolescent heavy drinking.32Being able to identify youth at higher risk for alcohol misuse could lead to early intervention and ultimately help reduce the significant personal and public health burden of AUD; however, relatively few studies have explored individual-level precursors of adolescent alcohol use. Prospective longitudinal studies of substance-naïve youth are uniquely positioned to identify factors predating the onset of alcohol use. Squeglia et al. identified several markers of alcohol initiation by age 18 in 137 adolescents.NCANDA seeks to expand on these findings using a greater number of measurements in a large sample to lead to more accurate individual-level forecasting. The consortium is employing machine learning models, which can avoid multiple-comparison correction and reduce measures to a single, individual-level prediction.36n = 75) .Unlike white matter, gray matter volume peaks in the primary school-age years, around age 10.These findings were confirmed in a recent analysis spanning five time points in the NCANDA study and using linear mixed-effects models.40Functional MRI studies further suggested that adolescents with histories of heavy drinking showed aberrant patterns of activation in response to cognitively challenging tasks,Throughout adolescence, white matter volume increases and matures, resulting in myelination that increases speed of neuronal transmission and modulates the timing and synchrony of neuronal firing patterns that convey meaning in the brain.13To examine the potential for a neurotoxic effect of alcohol use on adolescent development of white matter, Zhao et al. conducted a whole-brain analysis of fractional anisotropy of NCANDA participants ages 12 to 21 at baseline.46Along with altered development and maturation of gray and white matter, studies have reported neurocognitive consequences of underage drinking, such as impairments in attention,51Another set of studies demonstrated that youths who drank heavily exhibited greater brain activation while viewing alcohol advertisementsStudies examining longer-term impacts of adolescent alcohol misuse have yielded mixed results. Some studies reported a maturing-out without significant consequences in adulthood, while others found ongoing effects on mental health, physical health, and social functioning, as well as higher levels of alcohol use and AUD.57N = 215) to assess the association between age of adolescent drinking onset and neurocognitive performance found that earlier age of drinking onset predicted poorer performance on tasks requiring psychomotor speed and visual attention. Similarly, an earlier age of onset of regular (weekly) drinking predicted poorer performances on tests of cognitive inhibition and working memory.The first study of adolescents  Study, which is currently underway; NCANDA; the IMAGEN study in Europe; the Pediatric Imaging, Neurocognition, and Genetics (PING) study; and the Lifespan Human Connectome Project (HCP) study. NCANDA has already been able to confirm impressions from prior smaller studies that adolescent heavy drinking appears linked to accelerated gray matter decline,