GPs are increasingly confronted with patients with both intellectual disabilities (ID) and mental health disorders (MHD). Currently, the care provided to these patients is found to be insufficient, putting them at risk of developing more severe MHD. Improving the quality of GP care will improve the whole of mental health care for this patient group. Therefore, an overview of the content and quality of care provided to them by the GP may be helpful.To provide an up-to-date literature overview of the care provided by GPs to patients with ID and MHD, identify knowledge gaps, and inform research, practice, and policy about opportunities to improve care.Scoping review.PubMed, PsycINFO, EMBASE, and grey literature were searched for publications concerning primary care and patients with ID and MHD. Selected publications were analysed qualitatively.One hundred publications met the inclusion criteria. Five overarching themes were identified: GP roles, knowledge and experience, caregiver roles, collaboration, and a standardised approach. The results show GPs’ vital, diverse, and demanding roles in caring for patients with both ID and MHD. GPs experience problems in fulfilling their roles, and gaps are identified regarding effective GP training programmes, applicable guidelines and tools, optimal collaborative mental health care, and corresponding payment models.The improvement required in the current quality of GP care to patients with ID and MHD can be achieved by bridging the identified gaps and initiating close collaborations between care professionals, policymakers, and organisational managers. Their care provision constitutes both a demand-driven approach in assessment, treatment, and follow-up of symptoms and disorders, and a more proactive approach aimed at prevention by identifying risk factors and providing health education. Adequate primary care, including both of these approaches, is essential for patients with both ID and MHD to prevent diagnostic delay and ensure appropriate and timely referral and early personalised treatment.16,17 reported practices are mostly on a small scale and lack an orientation towards primary care. This is surprising and disturbing, considering GPs’ important position in the mental healthcare system and the growing demands of this patient group.Although studies are increasingly published on expanding knowledge and skills within mental health care and ID care,A scoping review was conducted to enhance the level of knowledge and provide an up-to-date overview of GP care for patients with both ID and MHD, identify knowledge gaps, and inform research, practice, and policy about opportunities to improve care.18 framework for scoping reviews, revised by Khalil et al,19 and describes methods and results in line with the PRISMA Extension for Scoping Reviews checklist.20This review follows Arksey and O’Malley’sThe guiding research question was: what has been described about the care for adult patients with both ID and MHD provided by GPs? The key concepts are defined in Supplementary Table S1.19 First, PubMed, PsycINFO, and EMBASE were explored (date range from January 1994 to September 2019), using search terms pertaining to ‘primary care’ and ‘intellectual disability’, informed by an information specialist (Supplementary Table S1). Selected publications were searched for keywords missed in the initial search. This yielded an additional search string for ‘ID’ (Supplementary Table S1). Second, relevant publications were retrieved from grey literature, using the recommendations from ‘Grey Matters’.21 Common search terms for ‘primary care’ and ‘intellectual disability’ in English and in Dutch were used (Supplementary Table S1). Third, the reference lists were searched for additional relevant publications.Relevant publications were identified using a three-step literature search.adult focused (≥18 years);originating in Western European and Anglo-Saxon countries, where GPs have a comparable role as gatekeeper for more specialised mental health care;available in full text; andavailable in English or Dutch.Duplicates were removed, and the first author performed a first selection on title and abstract. About 20% were double screened by a second independent researcher. The full texts were then screened by the first author and a second independent researcher. Any judgement differences were discussed to reach consensus within each review pair. When consensus could not be reached, a third reviewer became involved to resolve outstanding conflicts. Publications were included if they concerned adults with an ID, an MHD, and primary care following the prepared definitions. Other criteria were:There was no selection on publication type. Publications on forensic primary care were excluded because they concern a selective group of patients beyond the scope of this review.22 supported by ATLAS.ti software (version 8.4). This process involved repeatedly reading the articles, identifying relevant text fragments, and inductively generating codes related to the research question. All coding was conducted by two researchers independently. Differences in coding were discussed to reach consensus. Codes were then sorted depending on how they were related. From this, major themes were developed and organised. This iterative process was followed critically by the research team, and key findings were discussed relating to the study’s purpose and implications for future research, practice, and policy.A standardised data extraction form was developed to guide data charting for descriptive analysis, including publication year, country of origin, publication type, domain, and the care element(s) described. The selected publications’ content was qualitatively analysed using conventional content analysisn = 39) and primary care (n = 34). The number of yield publications increases steadily over the years. In total, 46 of the publications described a scientific study, none of which were randomised controlled trials. 23–26 Primary care databases show a prevalence of MHDs in adult patients with ID ranging from 21%–34%.4,23,25–27 GPs’ screening of patients with ID or MHD identified 33%–71% of patients as having a possible MHD and needing further medical assessment.28–31 Severe mental illnesses such as schizophrenia, bipolar disorder, and psychosis are more prevalent in patients with ID.3,4,23,32,33 Depression and anxiety are recorded less,33,34 equally,4,34 or more often,23 with an earlier age of onset for depression.35 Smoking, alcohol, and other substance use are less prevalent,23,33 but alcohol misuse is more prevalent in patients with ID.23The publications on register-based cohort studies report that people with ID have a higher risk of MHDs than patients without ID.Thematic analysis revealed five overarching themes: GP roles, knowledge and experience, caregiver roles, collaboration, and a standardised approach. The results are narratively presented accordingly. 31,36–45 Several GP roles in the care for this patient group are described, however, with varying acceptance, experience, and fulfilment among GPs.42,46,47The publications reveal the GP as the key figure in the identification, initiation, and coordination of treatment of patients with ID and MHD.32,43,44,48,49 in the sense of a ‘proactive approach’. This comprises general health promotion and targeted education about healthy living or substance use,32,44,49 but also identification of MHD-provoking risk factors and development of prevention strategies.31,43,48,49The GP roles relate, in the first place, to ‘prevention of MHDs’,diagnostic assessment of MHDs, which is described as challenging for GPs.50 Indications of inaccurate diagnoses48,51 and underdiagnosis in primary care are frequently reported4,31,41,42,48,49,52–56 and may result in inappropriate care and progression of the disorder to a more severe stage that is less responsive to treatment.23,52,57–59 Overdiagnosis occurs as well, however, leading to unnecessary prescriptions of medication.53,57 Diagnostic failure is seen as related to communication problems, with patients with ID described as less able to label their feelings and communicate their needs,44,53,57,60–62 resulting in an atypical presentation of symptoms29,43,44,57,63–65 and a more complicated assessment.42,48,52,54,61,66 It is deemed important for the GP to exclude somatic, environmental, and other causes of symptoms before considering an MHD,43,44,48,51,53,64,65,67–73 which requires a holistic, multidimensional approach.29,44Second, GPs are expected to fulfil an important role in the 40,44,68 For this patient group the same requirements and treatment guidelines apply as for patients with MHD but without ID,44,57,65,71,73 with the necessity to refer patients with more complex disorders to specialised care.44,68 GPs prescribe psychotropic medication to a higher number of patients with ID (17%– 63%) than other patients.4,74,75 In addition, a higher number of patients with ID are reported with psychotropic prescriptions than with recorded MHDs, indicating off-label prescription.4,39,44,49,75–80 Behavioural problems are often described as an indication to start medication,4,39,59,73,74,78,79 specifically in cases of limited access to alternative treatment strategies.4 Prescribed medication is reported as predominantly long-term medication,75 and a large proportion (62%–70%) is prescribed without a psychiatrist’s involvement.50,51,81 Medication prescription can be considered part of a multidisciplinary and holistic care plan;65 however, in primary practice, GPs are less likely than psychiatrists to provide psychosocial interventions.72Third, regarding GPs’ ‘treatment role’, it is indicated that GPs should be able to handle less complex MHDs in people with ID.48,50,65,69,73,82–84 It enables the monitoring of treatment responses and possible adverse side effects, leading to early adjustment of the treatment plan.50,73 However, a lack of effective monitoring of psychotropic medication by GPs is often described.28,42,51,55,74,81,85,86 It is stipulated that this relates to GPs’ lack of specific experience and knowledge,51,81,87 uncertainty about who of the involved professionals is responsible for follow-up,47,83,86,88,89 patient problems in communicating and presenting (side) effects of medication,44,49,65 and dependence on observations by, and cooperation with, caregivers.39,44,49,50,62,69,72Finally, ‘follow up’ by GPs is considered an essential element in the treatment of patients with ID and MHD.24,37,40,42,43,46,50–52,58,66,69,81,87,90–96 caused by a lack of priority in medical training programmes37,40,43,50,52,58,66,93 and a lack of research concerning this patient group.93 This results in limited evidence-based knowledge43,47,50,65,67,93,97 and reliance on experience-based knowledge instead.50 It is indicated that limited knowledge and experience create feelings of insecurity in GPs when addressing patients with ID and MHD,50 lack of caregivers’ confidence in the GP,52 and insufficient care.37,41,44,52,58,66,81,91,92,97 Although GPs are interested in more training and education regarding patients with ID and MHD,24,37,41,42,44,52,58,66,87,90,91 in practice it is seen as a challenge to engage them, caused by the small size of the population and the variety of competing medical issues.58,70 Publications underline the importance of investment in more research and initiatives for effective training, skill development,37,42,50,58,92,96 and evidence-based guidelines for GPs.42,50,98There is general consensus that GPs generally have limited knowledge about, and experience in, managing patients with ID and MHD,23,43,49,57,62,69,72,99 as a first point of reference, to recognise symptoms of MHDs and seek help.23,43,62,73,99 For this task, it is deemed important that caregivers have some knowledge of associated symptoms; however, this knowledge is often lacking.23,42–44,100 Second, patients are frequently dependent on caregivers for joint decision making44 and giving informed consent regarding treatment options such as psychotropic medication.4,49,65,68,72 Third, caregivers have important roles in the execution of the treatment plan regarding medication adherence and identifying and monitoring possible side effects.49,50,73,82 A symptoms checklist is mentioned as a helpful tool for caregivers to provide the GP with the information needed.40,73 Furthermore, it is noted that the referral process can be complex, and support by caregivers can be essential to prevent delay in care.96,100In the publications, it is noted that patients with ID and MHDs are often reliant on formal or informal caregivers for receiving care,29,43,44,53,57,60–65 overcoming communication difficulties,43,57,69,72 and providing additional information.57,63,73 It is indicated that the more severe the ID, the more reliant the GP is on caregivers.63 Therefore, GPs should determine the key people in a patient’s life73 and proactively involve them.49,72 However, GPs should also realise that some caregivers may give information from their personal perspective, use different definitions of medical terms than the GP,44 and themselves have limited knowledge about the patient53,62,72,81,94 or limited communication skills.42,44In addition, the GP is reliant on caregivers understanding symptom presentation,43,44,49,50,56,63,64,72,75 level of communicational skills and cognitive functioning,44,86 and obtaining advice on referral,31,72,78 treatment,30,44,48–50,72,75,86 or prevention.49 GPs’ options include referral for collegial advice,31,48,72,94 handing the patient over to other professionals,44 or joining a multidisciplinary team giving integrative care to the patient.93,98,101 The latter is described as particularly desirable when the patient has a more severe ID or is in a highly complex situation.39,44,99The publications emphasise the importance of GPs collaborating with other professionals in providing care for patients with ID and MHD. The collaborative partners mentioned are diverse and comprise both medical specialists  and services such as community or addiction services. Described areas for collaboration are the assessment of symptoms,28,39,42,44,93,94,96,98,102 as it is believed to increase the identification of MHDs, improve access to mental health care,98,101 and reduce hospitalisation103 and costs.98,101 However, inappropriate referrals are reported,90,94 resulting from unclear referral options and procedures.44,45,96,100,104 Adequate information exchange between GPs and other professionals, in the form of standardised, timely letters, is underlined as important for sharing essential information38,62,94,105–107 and continuity of care.105,106 Yet, audit studies on referral letters and letters from psychiatrists to GPs show that important information is often missing.62,94,100,105,107 Finally, it is stated that, in multidisciplinary collaboration, the alignment of responsibilities in treatment and follow-up should be clear.44,68,108 Particularly in cross-domain collaboration, it may be unclear who is involved, how responsibilities are shared, and how care is financed.47,83,86,88,89,96,104 It is mentioned that adequate division of responsibilities may depend on the main causal factor(s) of the MHD and may necessitate using care plans and convening case conferences.68 Responsibilities should be clearly stated in writing and reviewed regularly.88 Consequently, suggested preconditions for effective collaboration are accessible referral options, clarity about referral procedures, adequate information exchange between the professionals, and consensus on responsibilities.3,24,39,41,88,94,96,107Effective collaboration is seen as beneficial for the outcome of mental health care in primary care98 organisationally,42 and financially.96,98,101 To improve the quality of collaboration, the roles of both GPs and other involved professionals should be defined more clearly,60,72 existing models should be evaluated,42,109 clinical pathways and/or models should be improved,24,42,109 specialist capacity should be enhanced,41 and payment models should be re-examined to stimulate collaborative care.98,101 Policymakers’ involvement in this matter is seen as important.98,101It is noted as a barrier that, from a historical point of view, primary and secondary care services are separate units culturally,43–45,49,50,65,68,83,110 First, standardised screening for MHDs gives GPs the opportunity to consider potential mental health issues at an early stage.44,49 Second, a structured multidimensional approach in the assessment leads to more appropriate and accurate diagnosis, treatment, and referral.44,45,49,65,68 Finally, systematic and standardised medication prescriptions and reviews identify potential medication-related problems at an early stage.43,50,65,83,110In several publications, a standardised approach is seen as a way to improve the quality of care for patients with both ID and MHD.40,43,44,72,73,80 Some publications covered specific guidelines for prescribing and/or monitoring medication for MHDs in patients with ID,39,47,49,54,59,65,67,73,82 and applicable tools for detecting unmet health needs in patients with ID.31,40,49,60,69 It is suggested that GPs are insufficiently familiar with these ID-specific guidelines and tools.51,87Although guidelines and instruments are available to support GPs in applying a standardised approach in the general population, they are often not adapted to patients with ID.To the authors’ knowledge, this is the first scoping review with a focus on patients with both ID and MHD in primary health care. GPs are a key figure in the care for this specific patient group. They have a broad role that can be demanding in the sense that GPs need specific knowledge, experience, and skills for a relatively small patient group. The publications indicate that current GP care is often of an insufficient standard, as reflected in underdiagnosis of MHDs, overmedication, and lack of effective patient follow-up. Gaps are identified regarding effective training programmes for GPs, applicable guidelines and tools, optimal collaborative mental health care, and corresponding payment models. Opportunities for improvement are seen in prioritising and investing in bridging these gaps. This requires the involvement not only of care professionals and scientists, but also of policymakers.19 was used to provide a solid overview of the existing knowledge on GP care for patients with both ID and MHD. Second, only publications from countries where GPs have a gatekeeper role were included. This results in recommendations that can improve not only the quality of GP care, but also the overall mental health care for patients with ID. Finally, to prevent dispersion of the results of an already broad research question, this study focused on adults, thereby giving attention to a vulnerable group that is potentially more overlooked than children.The first strength of this review is that a robust and widely accepted scoping review method21 and checking references lists. Some publications were not accessible for the research team, and publications could have been missed because of the great diversity of possible sources.This review also has limitations. First, a lack of consistency was found in the definition of ID, as many publications did not supply a clear definition of it. This limitation reflects the heterogeneity of the patient group, and results should be interpreted accordingly. Second, the publications retrieved in the grey literature search are presumably not perfectly complete, despite the use of the ‘Grey Matters’ tool58,70 However, this claim regarding the proportion of patients is debatable. In the Netherlands, it is estimated that 6.4% of the population have a mild ID.1 Research in primary care data shows that no more than 0.56% of GPs’ clients are registered as having an ID.23,34 This could be an indication of GPs’ insufficient recognition and underestimation of the size of the ID population. This underestimation is also present in mental health care and is a reason for concern.7 Identification of an ID is essential both for good care provision and for treatment success in MHDs.14 Helpful ID screening tools have been developed for GPs when they are considering an ID, but further implementation in practice is needed.111,112The results of this review indicate that patients with ID constitute a small group within the GP population, accounting for the low priority of this group in education and research.12,113 It is also suggested that GPs should use the same treatment guidelines for mild or less complex MHDs in patients either with or without ID.44,57,65,71,73 However, research to substantiate this is scarce, and research in addiction care shows that alterations in the treatment programmes for substance use disorders are needed for patients with ID.10 Furthermore, previous research projects have led to practical primary care tools, such as the Psychiatric Assessment Schedule for Adults with Developmental Disabilities (PAS-ADD).31,60 However, these tools are not fully implemented in primary care.The results from this study revealed two strategies to improve care for patients with both ID and MHD: adequate medical training and applicable evidence-based guidelines and tools. This is in line with previous reports and publications concerning general health issues in patients with ID.114 This review had an international focus, and the possibilities of multidisciplinary approaches in primary care differ in the various healthcare systems. Within the ambitions and possibilities of the NHS, the UK sees integrated care systems as an important tool for improving health care and for reducing inequalities between different groups of people,115 and has long-term experience with community learning disability teams. These multidisciplinary teams provide health care and advice to people with ID, GPs, carers, families, and to the wider health and social care community.116 Another example of promising collaboration in daily practice is ‘The DD Health Home’ in the US. This care model provides integrative routine care to patients with ID and MHD, including primary care and structural follow-up.98 Despite these best practices, there is at present limited scientific evidence on the effectiveness of these collaborative  healthcare services for persons with ID.117 Preconditions for collaborative care, as listed in 118–120 All these disciplines mention adequate reimbursement as a critical barrier to successful collaboration, and reimbursement needs to be prioritised. Additionally, collaboration is more effective when there is a team vision, shared goals, formal quality processes, and shared ICT information systems.118,120 Research in older person care has revealed that GPs are indispensable in multidisciplinary teams regarding networking activities, integration of care, and showing leadership; the researchers stress that GPs should be made more aware of this, for instance, in GP training programmes.121This review identified various kinds of primary care collaborations in which GPs participate, and shows that effective collaboration can improve care; the latter is widely supported and confirmed by the World Health Organization.13,122,123 The UK National Institute for Health and Care Excellence guideline Mental Health Problems In People With Learning Disabilities: Prevention, Assessment And Management gives special attention to the involvement of people with ID and their caregivers in organising their care. In addition, this guideline covers mental healthcare in a holistic way in different UK settings, and may serve as an example for other countries.124Finally, the results of this review stress the importance of the GP collaborating with caregivers. Remarkably, none of the included publications focused on patients’ needs in their contact with the GP, although research shows that people with ID prefer to be less reliant on caregivers in GP consultation and argue for an improvement of the accessibility of health services.Improvement of care for patients with both ID and MHD needs to be prioritised, justified by the limited quality of care and the substantial size of this patient group. This improvement cannot be achieved by GPs and their collaborative partners alone. It requires adaptations on both the organisational and the political level. However, it remains important to actively engage GPs to ensure that suggested strategies are applicable and feasible in daily practice.Diverse improvement strategies are advisable. First, it is important to invest in effective, frequently recurring post-curriculum training programmes for GPs, focusing on more awareness of this patient group, specific knowledge gaps regarding IDs and MHDs, existing tools and guidelines, and GP roles in multidisciplinary teams. Offering training programmes in an interprofessional setting can support the latter and will additionally promote collaboration between care professionals. Second, ongoing policy changes, such as the move to integrated care systems in the UK, and best practices such as the community learning disability teams in the UK, provide opportunities for further development of optimal collaborative healthcare models for patients with both ID and MHD. Policymakers should re-examine payment models to create incentives for collaborative care, facilitate shared ICT information facilities, and involve potential users in the development of these healthcare models. Third, although the increase in publication over the recent years is a positive sign, more research is still needed on the effectiveness of existing general mental health guidelines and tools to determine whether they are truly applicable to patients with ID or whether specific alterations are needed. Priority should be given to guidelines and tools on MHD assessment, the prescription of psychotropic medication, and patient follow-up. Finally, further research should focus on the needs of caregivers in supporting patients, as well as on the needs of patients with both ID and MHD and how they can enhance their autonomy in GP contacts.This scoping review illustrates GPs’ vital roles in the care of patients with both ID and MHD. Current GP care has generally proved insufficient, and improvement strategies are needed in close collaboration with policymakers and organisational managers. Multidisciplinary approaches in primary care — like those in the UK and US — seem promising, but still lack sufficient scientific evaluation. Investment in education, evidence-based guidelines and tools, and collaborative healthcare models is essential. This, supplemented with enhanced ID identification and attention to the needs of patients and their caregivers, may significantly improve the quality of care for this vulnerable patient group.


Figure 6 as published. Figure 6 was misplaced and needs to be corrected. The corrected In the original article, there was a mistake in 1, 2. Instead of “In the published article, there was an error in affiliation 1Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China2Department of Urology and Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China”,it should be “1Department of Urology and Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China2Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China”.s for Weide Zhong. As well as having affiliation(s) 1, 3, they should also have, 2.In the published article, there was an error regarding the affiliationThe authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


COVID-19 is the name of an infectious disease called Coronavurus 2019, one of the causes of respiratory failure; The disease was first identified in Wuhan, China, in December 2019, and then spread around the world and also creating the 2019-2020 coronavirus pandemic . Due to Creating emotional problems and mental disorders such as stress, anxiety, and fear is one of the inevitable consequences of this disease that can cause stress, depression, and even suicide. Given that students, as a critical element of the educational system, have a unique role in achieving the educational system, it is essential to pay attention to their mental, emotional and physical health ,7,8. Mos Despite the significant advancement of virtual learning globally, due to courses’ practicality in the higher semesters of nursing students, virtual education can have adverse effects on how they learn. On the other hand, nursing internship students, due to their close interaction with the hospital are affected by various conditions such as: Fear of being a Coronavirus carrier and its transmission to the family, high job fatigue, reduced sleep quality, malnutrition, fear of death, lack of proper communication with the family, frustration, Violent Behavior, etc.Also, in some studies, students’ anxiety and the COVID-19 pandemic were higher than the national norm ,14. So, It is also essential to consider new approaches to teach clinical skills. Due to the clinic’s distance, hospital, and eye to eye contact with patients, nursing internship, students have practical skill gaps. Therefore, encouraging students to use educational multimedia, clinical databases may be effective . Finally


For the formation of a proto-tissue, rather than a protocell, the use of reactant dynamics in a finite spatial region is considered. The framework is established on the basic concepts of replication, diversity, and heredity. Heredity, in the sense of the continuity of information and alike traits, is characterized by the number of equivalent patterns conferring viability against selection processes. In the case of structural parameters and the diffusion coefficient of ribonucleic acid, the formation time ranges between a few years to some decades, depending on the spatial dimension . As long as equivalent patterns exist, the configuration entropy of proto-tissues can be defined and used as a practical tool. Consequently, the maximal diversity and weak fluctuations, for which proto-tissues can develop, occur at the spatial dimension 2.5. The origin of life was a chemical event and life on Earth began some billions of years ago ,2 and, wThe present article considers a pathway for attaining elementary prebiotic processes from a non-equilibrium point of view . Life isReplication: Reactants interact to produce a compound Variation: Spatial patterns  promoting adaptation.The following concepts  are adopStatements (a) and (b) are connected to physical and chemical procedures, where compound  systems .This work is conducted using mathematic and simulation tools; nevertheless, qualitative explanations are offered regularly. Analytic or computational models for environments and prebiotic processes are broadly mentioned and, in this sense, this approach must be considered as a partial contribution to the following complex problem: prebiotic organization and configuration. The substrate where the aggregate of protocells develops is a simple compound, but it is enough to substantiate the notions developed in this work. I emphasize, this work considers only a lineal analysis related to possible final structures (proto-tissues). Explicit solutions and time evolution towards final structures will be performed elsewhere.For simplicity and to maintain basic central ideas, a generic Schnakenberg  reactionmination ). The k As part of the required metabolism, and for simplicity, waste is considered through the loss rate Moreover, the basic spatial solutions of the above equations are assumed as A boundary, a spatial (hyper-) cube, is assumed for mathematical convenience. As usual in reaction–diffusion equations ,28,29,30Here, the wave vector tability ,28,29,30Finally, long-range spatial or temporal (memory) effects ,22,23,24At this stage, for the generation of structures, I assume the realization of the fundamental condition (see Equation (3)) as the following: systems .Equation (5) reveals that the rate of production of compound Finally, semi-analytical solutions of Schnakenberg’s equation, including limit cycles, can be viewed in reference to Noufaey , where EFrom the reaction–diffusion stability, Equations (3) and (4) become an eigenvalue problem ,28,29,30positive . This maFor a finite system of size Equation (5) is necessary, but not sufficient, to satisfy Equation (8).New structures are favored for smaller values of the set n embryo .The generalization of Equation (8) to small spatial dimensions of one or two is direct ), as follows:Equation (8), concerning the generation of new structures from For practical purposes, it is convenient to write the stability parameter Equation (8), for the generation of structures, is straightforwardly reformulated as:Note that Equation (10) formally generates a sphere in the The work thus far has been mostly concerned with the physics and chemistry aspects of the patterns. The next section incorporates the concept of heredity discussed in Temporal continuity, or memory, is, in principle, intrinsically related to reaction–diffusion equations, such as Equations (1) and (2), where the initial conditions formally define the time evolution. However, heredity is not only connected to the continuous history of a system, but is also related to the formation of new structures, diversity, and viability. In this sense, I proceed, as in statistical mechanics, by adopting the notion of equivalent configurations ,13,14,15We are locking, according to pattern diversity, in such a way that some equivalent structures, eventually, are not eliminated (viability) in open systems. This process of selection can include intraspecific competition  for chemAs in statistical mechanics, for the set of integers r-sphere ,13,14,15In the case of a physical interface, such as a smooth rock surface covered by slime ,11, d=2 imension ,39,40,41As long as Moreover, this is useful in making estimations (next section). Concerning the concept of heredity, a large number of equivalent structures Finally, I briefly consider the physical substrate, where a variety of structures can develop. External constraints on a given material can generate cracks under appropriate stress conditions , e.g., cd stress ,48,49. E(a)2/s corresponding to biological molecules, such as ribonucleic acid (RNA) [id (RNA) ,8 at 25 id (RNA) ,11,50.(b)A protocell of size (c)As an estimation, The following parameter values are used in making estimations:At an arbitrary spatial dimension Using the values previously mentioned and Equation (14), the characteristic time: The main graph in surfaces  and relaIf ro-state ,13,14,15In the above expression, the number of configurations is divided by the dimensionless surface to avoid the equivalent of Gibbs’ paradox 12. The Boltzmann’s constant dynamics ,13,14,15dynamics .According to the equipartition principle in thermodynamics ,13,14,15(a)If the spatial dimension is en d~2.5 .(b)In the same way, for a spatial dimension of (c)As a geologic example, in the Atacama Desert of Chile, rock temperatures vary between approximately  0 and 45Accordingly, the following results are obtained from Equation (18) and the inset curve (i.e., In summary, a spatial dimension of iversity .The stability rate obtained . The estWhen variations in the thermodynamic primitive environment are considered, from stability arguments, physical substrates containing proto-tissues with an integer spatial dimension of two or three are associated with thermal fluctuations. In contrast, for fractional dimensions at approximately As stated in the introduction, the question of “what is life?” were not touched upon during this work and are difficult to answer. Nevertheless, these ultimate questions were the motivation for the present work. Interesting efforts, some of which are controversial ,55,56,57Finally, several groups are investigating protocell aggregates ,65,66,67


Correction to: BMC Musculoskelet Disord 22, 212 (2021)https://doi.org/10.1186/s12891-021-04080-4“The Ergon® IASTM technique was created at the Department of Physiotherapy of the University of Patras, where it is taught both in undergraduate and postgraduate level as well as in external educational programs. The authors KM, AP, and KF have participated in developing and disseminating this specific program. In the present study, the authors KM, AP, and KF participated exclusively in designing this study and methods, and they were not involved in the application of therapeutic interventions, measurements, and/or data handling”.Following publication of this article , the aut


Burnout, a reaction to chronic emotional stress, affects health and reduces the quality of service. Reportedly, healthcare professionals are especially vulnerable to burnout. This meta-analysis is aimed at examining the factors associated with occupational therapists' burnout. The results of 2,430 occupational therapists, across 17 peer-reviewed English articles, the most recent published in 2020, were analysed. Results revealed significant associations between related variables and burnout. Marital status, work field, and work hours, job challenges, patient age, position, turnover intention, working type, and work addiction showed significant positive correlation effect sizes in relation to burnout, whereas age, education, engagement, job satisfaction, personal identity, professional identity, rewards, and feeling valued showed significant negative correlation effect sizes. The results of this meta-analysis suggest that strategies to reduce occupational therapists' burnout need to consider organizational as well as psychological aspects. As the quality of services provided in hospitals and the demand for patient satisfaction increase, so are the organizational efforts to control emotional expression when providing services. As a result, such efforts can bring about conflict between the emotional labour of the members of the organization and the role they play and may lead to burnout by reinforcing a negative attitude toward the job and organization –3. BurnoHealthcare professionals are reported to be particularly vulnerable to burnout , 7. OccuPsychological exhaustion among occupational therapists is a critical problem that necessitates counteractive measures because it threatens their psychological well-being and is difficult to reverse. Therefore, it is important to develop preventive measures to reduce the incidence of burnout and its promotional factors in order to prevent individuals from becoming psychologically exhausted . StudiesHowever, since it is difficult to present comprehensive results on the factors that affect burnout through a single study, it is necessary to synthesize and analyse the results of previous studies related to burnout among occupational therapists. For this reason, findings from different studies on burnout are often reported together. For instance, Park and Shin  performeSuch studies are suitable for presenting implications according to the variables investigated in the study, such as gender, age, and career; however, they are insufficient for a comprehensive and systematic scientific verification of the variables that affect the burnout of occupational therapists. In addition, individual studies are conducted in different populations, using different tools, sampling methods, and statistical methods, and the characteristics of these individual studies may result in association found in these individual studies may contradict each other. For example, previous studies on the effect of gender on possession showed conflicting results, and for this reason, Purvanova and Muros  conducteMeta-analysis is a research method that is aimed at analysing and integrating several individual studies conducted on the same topic . It usesThe articles to be included in the meta-analysis of factors affecting burnout among occupational therapists were selected through a search of electronic databases ProQuest, PubMed, CINAHL, EBSCOhost, and Science Direct . The keyword combination “occupational therapist” and “burnout” was used. Through this process, a total of 344 articles were identified, which were then reviewed according to the following selection criteria: first, study participants were occupational therapists; second, the dependent variable was burnout; third, article was published in academic journals; fourth, article provided necessary data for calculating the effect size; fifth, article was published in English. The article selection process is presented in The coding variables included author, publication year, burnout, burnout-related variables, participant characteristics , and burnout measurement tools. To check the direction of coding in each article, a coding standard was set, and articles with a different direction from the standard were recoded. The coding was as follows: gender, male “0”, female “1”; position, staff “0”, supervisor “1”; work field, small hospital “0”, large hospital “1”; marital status, unmarried “1”, married “0”; working time, full-time “0”, part-time “1”. Variables with only one effect size, specifically recession effect, control, community, fairness, and problem-solving, were coded as other. The three subdomains of burnout were coded for Maslach Burnout Inventory (MBI), and others were coded as two or more subdomains. A research assistant and the researcher performed coding for five articles , and the reliability between the coders was calculated for each coding variable. Reliability was calculated by dividing the coincidence frequency by the sum of the coincidence and disagreement frequencies and multiplying by 100. The reliability between the coders was 93.75% to 100%. Consensus was reached through discussions between researchers on inconsistent variables. One study, namely, Kim et al. , reporteThe Quality Assessment and Validity Tool for Correlational Studies developed by Estabrooks et al.  was usedZ, exceeding 2.58 (99% confidence level). There were no outliers with residuals above 2.58, and all effect sizes were thus included in further analyses.Since extreme effect size values can cause a decrease in the reliability of the effect size, in this study, outliers were analysed to calculate a reliable effect size, and the effect size showing an outlier was excluded from the analysis. Outliers were evaluated through a review of residuals, and the criterion for judgment was the standardized residual value, N, which is aimed at establishing the stability of meta-analysis results, and examined the funnel plot. At a significance level of 0.05, the fail-safe N, which refers to the number of articles to be added for the effect size to be meaningless, was 228. Rosenthal [p = 0.78), which indicated absent publication bias.To verify the publication bias, Rosenthal  evaluateosenthal  suggestep value derived through this test was used as a reference value for the test of heterogeneity [Q-test yielded a Q value of 1701.075 (p < 0.001), which means that the included studies in this meta-analysis were heterogeneous. Based on these results, a random effect model was employed in this study.To calculate the effect size, an effect size calculation model should be selected. There are two calculation models, a fixed effect model and a random effect model. Depending on which model is selected, the estimation and the precision of the effect size vary. The choice of model depends on whether the articles to be analysed are heterogeneous or homogeneous. In this study, a heterogeneity verification test was used, and the ogeneity . The resZ-transformation was performed [The first step in a meta-analysis that presents the aggregated results of individual research results is the calculation of the effect size for each individual study. In the individual studies related to burnout among occupational therapists, there were cases in which the applied study design involved the comparison of burnout between groups  and cases where a correlation coefficient was derived . To present comparison results between groups and for synthesizing all related research results, the standardized mean difference effect size was first calculated, and then, Fisher's erformed . The efferformed .The characteristics of the 17 included studies are described in Samples' ages generally ranged from 20 to 60 years; however, five studies did not report age, and four studies reported the mean age of their samples (32.0–44.5 years). Samples possessed an extensive range of years of experience, between 0 and 28 years, with four studies reporting only the mean years of experience (7.5–17.4) and three studies reporting no data on experience. Out of the 17 studies, 3 reported only one burnout-related variable, while the rest reported two or more related variables.Z = 0.452, 95%CI = 0.307–0.597), marital status , patient age , position , turnover intention , working type , work addiction , work field , and working hours . Among the positive significant effect sizes, the effect size of marital status, work field, and work hours was small, and that of job challenges, patient age, position, turnover intention, working type, and work addiction was medium. The variables with significant negative effects on burnout were age , education , engagement , job satisfaction , personal identity , professional identity , and feeling valued . All negative significant effect sizes were medium.The overall effects of related variables on burnout are presented in This study is aimed at verifying the effect size of variables related to occupational therapists' burnout through a meta-analysis. To achieve this, quantitative relations between burnout and its associated variables reported in previous studies were analysed.Occupational therapists' burnout has been the subject of several studies, and many factors including challenges to professional identity, the emotionally demanding nature of mental health practice, lack of professional mentoring, and a lack of awareness of the value of the profession have been presented , 39, 40.Overall, marital status (unmarried), work field , work hours, job challenges, patient age, position, turnover intention, working type (part-time), and work addiction were associated with a higher level of occupational therapists' burnout. Conversely, age, experience, education, engagement, job satisfaction, personal identity, professional identity rewards, and values were associated with a lower level of occupational therapists' burnout.Significant associations among personal variables were with marital status, position, age, and education, although there was no large effect size. Maslach and Jackson  reportedAdditionally, significant associations among the organisation-related variables were with patient age, work field, work hours, working type, and reward. The effect size of reward was medium, while the others were small. Reward refers to the compensation that employees receive for the time and effort given to the organisation . The effIn addition, significant associations among the psychological variables were with job challenges, turnover intention, work addition, engagement, job satisfaction, and personal value; the effect sizes of job challenges, job satisfaction, professional identity, and turnover intention were medium. Research on job challenges seems to have yet to reach conclusions. While job challenges can be positively related to ill-health (stress and burnout) as well as well-being (motivation and job satisfaction), as they lead to lower commitment to achieve goals, they also demand satisfaction, which motivates employees to work hard . The resThe strength of this study was first a meta-analysis of the factors associated with burnout among occupational therapists. Among the personal variables related to burnout, those that had a positive association were marital status and position, and those with a negative association were age, education, and experience. All of the organisation-related variables, except for reward, were found to be associated with high level of burnout. Among the psychological variables, higher job challenges, work addition, and turnover intention were found to be associated with high level of burnout, while higher levels of engagement, job satisfaction, personal and professional identity, and feeling valued were found to be associated with low level of burnout. Among the related variables, psychological variables showed a relatively large effect size. As can be seen from the results, among the variables that affect burnout in occupational therapists, the number of personal variables was small and the effect size was also relatively small, whereas the number of related organisational and psychological variables and their effect size were relatively large. These results suggest that a strategy to reduce burnout in occupational therapists is needed. Occupational therapists' burnout can affect not only their quality of life but also the quality and effectiveness of treatment services. It is expected that intervention programs and policies to reduce the burnout of occupational therapists can be designed considering the factors found to be significantly associated with burnout among this population.


Dear editor,Currently, scurvy is an uncommon disease, but it still exists, especially in groups at risk for hypovitaminosis. The authors report the case of a male patient, 63 years, hypertensive, diabetic, with chronic renal failure on hemodialysis for five years. He complained of asymptomatic lesions with progressive increase in the last two months, mainly in the lower limbs. In addition, he reported weakness, episodes of epistaxis, and reported food intake limited to sandwiches and other carbohydrates, denying consumption of fruits and vegetables. On physical examination, he had purpuric areas, plaques and isolated, mostly punctiform with perifollicular location, affecting the lower limbs , upper lScurvy is caused by ascorbic acid (vitamin C) deficiency; vitamin C is found in fresh fruits and vegetables. Ascorbic acid plays an important role in the formation of collagen and extracellular matrix, leukocyte function, iron absorption, folic acid metabolism, and other enzymatic processes. Anomalies in the collagen structure disrupt the integrity of the hair, connective tissue, and blood vessels, leading to the characteristic skin manifestations of scurvy. The initial complaints, after one to three months of deficiency, are usually weakness, malaise, arthralgia, anorexia, and emotional liability. Capillary frailty predisposes to purpura, more frequent in the lower limbs, petechiae, ecchymosis, gingival bleeding, epistaxis, and bone hemorrhage. The diagnosis of scurvy is clinical, confirmed by low serum levels of vitamin C. Symptoms usually occur with plasma concentrations below 0.2 mg/dL. The prognosis for scurvy is excellent. Scurvy is probably underdiagnosed, although its manifestations are relevant to various medical specialties. It is remembered as a disease of ancient times, studied in high school and in history books, and not as a real diagnostic possibility. Attention should be paid to those patients with risk factors for nutritional deficiency, so that the classic findings of scurvy, an easily treatable disease, can be identified early.None declared.Paulo Ricardo Martins Souza: Approval of the final version of the manuscript, drafting and editing of the manuscript, effective participation in research orientation, intellectual participation in propaedeutic and/or therapeutic conduct of studied cases, critical review of the literature, critical review of the manuscript.Letícia Dupont: Approval of the final version of the manuscript, design and planning of the study, drafting and editing of the manuscript, critical review of the literature, critical review of the manuscript.Felipe Eduardo Rodrigues: Drafting and editing of the manuscript, critical review of the literature.None declared.


The resulting societal challenges are manyfold, including changes in consumption patterns, patterns of work and retirement, healthcare issues, and prevalence of chronic diseases and disabilities. Among the latter, mental health is of paramount importance. Indeed, already “healthy” or “normal” aging is accompanied by an age-dependent cognitive decline. Moreover, many older adults experience mental disorders, including but not limited to depression, anxiety, or dementia. Therefore, an in-depth understanding of physiological changes that occur during brain aging is crucial.The rise in life expectancy together with decreasing replacement fertility are causing rapid aging of western societies. In Germany, for example, 47% of the population are expected to have an age of 50 + already in 2035 physiological brain aging including changes in energy provision [This issue of rovision , the agerovision , 14, agirovision , 17 as wrovision , 16, 17 rovision , 15.Physiological aging is associated with a number of challenges to brain homeostasis including the intensification of oxidative stress, compromised bioenergetics, increased levels of pro-inflammatory substances, low-grade immune activation, modified functional properties of main immune cells of the drain, changes in the glymphatic system (responsible for the life-long waste collection), vascular aging, and arterial stiffness, etc. , 14, 17.At the same time, the aging brain possesses remarkable resilience and adaptivity, allowing it to cope with the listed above problems. Indeed, already one of the very first epidemiologic studies, which was published in Cambridge in 1889 and included 900 oldest old , concluded that the brain is preserved much better than many other physiological systems and represents one of the highlights “in the centenarian landscape” . In thisAlthough aging per se is not considered as a disease, it is a major risk factor for cerebrovascular  and neurodegenerative  diseases, which are associated with high morbidity and mortality , 3, 15. Importantly, the brain seems to age in a sex-specific manner, with gender being among the susceptibility predictors for several age-related disorders. AD, for instance, has a higher 1.6–3:1) prevalence in women compared to men, whereas PD has a higher (3.5:1) prevalence in men compared to women :1 preval, 15, resFinally, many articles of this special issue compare aging of brain architecture and function  between humans and commonly used laboratory animals (rats and mice) –15, 17.


In the original article, we neglected to include the funder Ricerca Finalizzata Grant (RF-2010-231-8508) to Elisabetta Ferraro.In the published article, Stefania Gorini was not included as an author and she should have the affiliation Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.Stefania Gorini was not included as an author in the published article. The corrected Author Contributions Statement appears below.RB and EF designed the experiments. RB, AB, LD, MR, SM, and SG performed the experiments and analyzed data. RB, AB, LD, MR, SM, and EF interpreted the data. AT, MC, and AM contributed to the development of the study by the provision of study material and data interpretation. AM, MM, PC, ML, and EF wrote the manuscript and provided the financial support. EF conceived the study. All authors contributed to the manuscript revision, read, and approved the final version of the manuscript for submission.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


In the original article, an author name was incorrectly spelled as Fangrui Mo. The correct spelling is Fanrui Mo.In the original article, there were some errors in the affiliation list. For affiliation 2, instead of “Department of Cardiology, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China”, it should be “Department of Cardiology, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China”.For affiliation 5, instead of “Department of Cardiology, The Forth Affiliated Hospital of Guangxi Medical University, Liuzhou, China”, it should be “Department of Cardiology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China”.Further, Dr. Xiehui Chen should also be listed as a corresponding author.The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The ranges of variability of elements and stable isotope ratios had slightly different results, according to the three geographical origins considered. In particular, Umbria samples presented significantly lower content of metals potentially dangerous for human health. The results of this first exploratory work highlight the possibility of characterizing tobacco from Umbria, and suggest widening the scope of the survey throughout Italy and foreign regions, in order to be used to describe the geographical origin of tobacco in general and verify the origin of the products on the market.Umbrian tobacco of the Virginia Bright variety is one of the most appreciated tobaccos in Europe, and one characterized by an excellent yield. In recent years, the Umbria region and local producers have invested in introducing novel practices (for production and processing) focused on environmental, social, and economic sustainability. Due to this, tobacco from Umbria is a leading commodity in the global tobacco industry, and it claims a high economic value. The aim of this study is then to assess if elemental and isotopic compositions can be used to protect the quality and geographical traceability of this particular tobacco. For the first time the characteristic value ranges of the stable isotope ratios of the bio-elements as a whole (δ Nicotiana genus (Solanaceae family) and the general term for any product prepared from the cured leaves of the tobacco plant. Besides its hedonistic use, tobacco plays an important role in other sectors, and has been increasingly investigated in the last few years [Tobacco is the common name of several plants of the ew years . Its alkew years , refinedew years ,4 and haew years , and tobew years . Last buew years ,9,10,11.Nicotiana tabacum leaves. Even if many studies have been conducted to characterize Nicotiana tabacum from the genetic and molecular points of view  tobacco production ). In Itaw e.g., ,16), to , to Nicod plants ,18,19,20d plants ,22,23. 13C/12C, 15N/14N) and the site-specific deuterium content of nicotine can provide useful information on the geographical origin of tobacco. Similarly, Binette and colleagues [2H/1H and 15N/14N ratios can be useful for identifying foreign counterfeits of Canadian cigarettes. To date, the elemental composition of tobacco has been investigated mainly to assess the presence of toxic elements that can be inhaled or absorbed through cigarette smoke [In order to support the quality assessment, the chemical characterization has to be coupled with analytical techniques that enable the characterization and traceability of the provenance of tobacco, and that can objectively guarantee it. In this area, however, up to now, very few studies focused on the development of analytical methods able to trace the geographical origin of tobacco ,25. Stablleagues  found thte smoke ,22,23. Ote smoke , indeed,te smoke  found diNicotiana tabacum have never been extensively explored for their characterization and the verification of their origin. Therefore, the aim of this study is to fill in this gap and start exploring and determining the characteristic value ranges for elements and the stable isotope ratios of the main cultivated tobacco variety (Virginia Bright). In particular, the investigation focuses on Virginia Bright from Umbria, where it has been cultivated for centuries, and where the cultivation is strictly linked to these territories. Furthermore, in recent years in this area, tobacco producers have changed their way of manufacturing, giving particular attention to environmental, social, and economic sustainability along the entire production chain, from cultivation to processing, in order to obtain products of higher quality. The aim was then to assess if the combination of elemental and isotopic compositions, as already successfully applied in the field of food traceability, can be used to protect the quality and geographical traceability of tobacco from Umbria. In particular, this paper contributes to the creation of the very first isotopic and elemental database, also including toxic elements, for Umbrian Virginia Bright tobacco, comparing the obtained data with data of Virginia Bright samples coming from other geographical regions.To date, the stable isotope ratios of H, C, N, O, and S, and the elemental composition of 18O and basically higher values of Be, Pd, Cd, In, and Bi, whereas the African samples showed basically higher values of Rb, Ba, and La. The Argentinian samples presented a higher value of Li, while Brazil had higher values of Mg and Rb. δ34S was higher for the United States samples, and lower for the Umbria samples. Hungary showed basically higher values of Mn. Such data were checked using the non-parametric Kruskal–Wallis approach (p < 0.05) to detect statistically significant differences according to the geographical origin. It is interesting to note that, as regards the specific characteristics of tobacco with different geographical origin, despite the geographical proximity of Umbria and Veneto, the Umbrian samples presented statistically different values of δ2H, δ13C, δ18O, δ34S, Li, Mo, and Bi  from Veneto. The different δ2H, δ13C, and δ18O values can be explained by the latitude effect. Indeed, mean latitude in Umbria is 43°, whereas Veneto is at a higher latitude of around 45.5°. According to Dansgaard [2H and δ18O values as latitude increases. A similar effect, albeit smaller compared to that of δ2H and δ18O, occurs also in δ13C, and is related to the water stress and light irradiance conditions. Indeed, in warmer climate regions, plants tend to close their stomata under conditions of water stress and high light irradiance, which results in an enrichment in δ13C values by a few ‰ [The isotopic and elemental data variability of tobacco from Umbria, Veneto, and other geographical origins are reported in the ansgaard , the lat a few ‰ .34S, Li, Mo, and Bi, the content differences by geographical origin can be related to the different geological origin of the areas considered, as well as to the pedological characteristics of the soil and the proximity to the sea [As regards δ the sea ,34.p < 0.05) between the Umbrian samples and those from Poland and Africa. The results of previous works suggest the usefulness of these parameters in food authentication [It is noteworthy that the concentration of rare earth elements (RREs) in the Umbria samples is generally lower than that of the products from other locations, probably reflecting the different distributions of RREs in the growth soils. The concentrations of RREs are in agreement with the values already reported in other studies on vegetal matrices ,36, conftication .p < 0.05) in Umbria compared to Poland, Veneto compared to Spain, Greece compared to Africa, and Bulgaria compared to Hungary. Furthermore, the Umbria samples were statistically different (p < 0.05) on the basis of the content in Tl (from those of Africa), Th and U (from those of Spain and Poland), and Pb and Te (from those of Bulgaria and Poland).The content of Be, Na, Mg, Cr, Ni, Ga is statistically different between Umbria and Spain, Africa, Hungary, Greece, and Poland. Ge, As, Rb, and Ag resulted as statistically different . Further details about the distribution of the data within each group are shown in the According to d values) was found for δ2H, δ18O, Li, Na, and δ13C (in decreasing order) and for Mo and Bi in the opposite direction. It is interesting to note that the main differences between the Umbria and Veneto samples pertain to the isotopes and the content of elements like Na and Li, which are alkali metals already used for the geographical traceability of food products [34S, Be, Ce, Tm, Mg, and Te, in an inverse relationship. It is noteworthy that many of the elements having a higher impact on the differences between the Umbria and “other” samples belong to the rare earths. In particular, in the comparison between Umbrian and Veneto samples, the highest positive effect  in all the elements, except for As, Mo, Pd, Ag, Sn, Pb, Bi, U, Cr, In, Cd, K , Li, Na, Cu, Zn, Sr, Sb, and Rb  when compared to Veneto tobacco. Metals and elements are acquired by the growing tobacco plant from soil, fertilizers, and industrial pollution. In addition, metals and elements also derive from tobacco curing treatments and processing  Technical Report, 2012). Therefore, the amounts of metals and elements in tobacco products vary widely, depending on the geographical location in which the tobacco leaf is grown, as well as on the treatments administered during the processing . In particular, it should be noted that the content in elements that are potentially dangerous for human health  is significantly lower in Umbrian tobacco. Furthermore, Umbrian data for Al, As, Ba, Be, Cd, Co, Cr, Fe, Mn, and Pb were lower overall, whereas Cu and Ni contents were quite similar to data reported by the World Health Organization for cigarette tobacco , therefore indicating a high-quality product in this respect. The same situation was recorded for the Veneto samples, whereas in the case of the “other” group, the content in these elements varies much more, as expected due to the different origins. This point is particularly important, as the World Health Organization recommends regulatory authorities to test cured tobacco in particular for its content in As, Cd, Pb, and Ni, in order to limit human exposure to these particularly toxic elements.More generally, Umbrian tobacco is distinguishable from tobacco with other geographical origins (both the Veneto and “other” groups) by the value of the isotopic ratios of δthe area . Indeed,Due to the encouraging results of the univariate analysis, a multivariate, unsupervised statistical approach was applied by combining the 59 variables together, in order to highlight the factors that contribute to the differentiation between the Umbrian tobacco and tobacco from Veneto and other geographical origins. Principal component analysis (PCA) was performed on data, and the relative score plot is shown in The plot shows that the three classes of samples are partially separated in a projection, which accounts for almost 50% of the variance , with 38% variance explained for the first PC and 10% for the second PC). The isotopic and elemental composition of the Umbrian (blue triangles) and Veneto samples (green squares) are generally different from those of most samples of “other” origins (red dots). In particular, the majority of the samples of “other” origin fall into the region of the PCA, with positive values of PC1. The distribution of the “other” origin samples is much more spread than that of the Umbria and Veneto samples, confirming a more varied isotopic and elemental composition, due to the different geographical provenances. In order to identify the most influential variables that are driving the separation in the multivariate space, the random forest (RF) approach was applied. The outcomes of this analysis were validated with the “random region” scheme described in the Material and Methods section. The overall efficiency of the classifier is shown in The variables with the most predictive power are reported in 34S, La, Y, Co, Na, Pb, Er, As, Bi, and δ2H, showed a consistent role in the models aimed at distinguishing the three groups, suggesting their usefulness as markers of geographical origin. Many of the most important variables in the model are REEs, and their potential use as food tracers has already been determined [In particular, Rb and Tl in primis, followed by Mo, Mn, δtermined ,37,40. ISixty-three samples of Virginia Bright tobacco leaves were analyzed. Of these, 20 samples were from Umbria, 10 from Veneto, and 33 from other geographical origins . Each saBefore the elemental analysis, an aliquot of about 0.5 g was acid-digested after the addition of 4 mL of ultrapure, 67–69% nitric acid , by means of a microwave single-reactor chamber  equipped with 15 mL quartz vessels, following a multi-step temperature program as described in Bertoldi et al. . Mineral13C, δ15N, and δ34S in one run, and 0.2 mg in silver capsules for δ18O and δ2H analysis. The analyses were carried out using an Isotope Ratio Mass Spectrometer  equipped with an elemental analyzer  for the 13C/12C, 15N/14N, and 34S/32S ratio determinations. The 2H/1H and 18O/16O ratios were measured using an IRMS  coupled with a pyrolyser . The isotope ratios were expressed in δ‰ versus VPDB (Vienna Pee Dee Belemnite) for δ13C, VSMOW (Vienna Standard Mean Ocean Water) for δ18O and δ2H, air for δ15N, and VCDT (Vienna Canyon Diablo Troilite) for δ34S, according to the following formula:sampleR is the isotope ratio measured for the sample, and referenceR is the isotope ratio of the international standard; superscript i denotes the mass number of the heavier (higher atomic mass) isotope. The delta values were multiplied by 1000 and expressed in units per mil (‰). Sample analysis was carried out in duplicate. The isotopic values of δ13C, δ15N, and δ34S were calculated against in-house working standards  42 and two flours for δ34S), which were themselves calibrated against international reference materials: L-glutamic acid USGS 40 , fuel oil NBS-22 , Vienna, Austria), and sugar IAEA-CH-6 (IAEA) for 13C/12C; L-glutamic acid USGS 40 and potassium nitrate IAEA-NO3 (IAEA) for 15N/14N; and barium sulphates IAEA-SO-5 and NBS 127 (IAEA) for 34S/32S. The isotopic values of δ2H and δ18O were calculated against USGS 54  and USGS 56  standards.Around 4 mg of sample was weighted in tin capsules for the analysis of δ13C/12C and 15N/14N, 0.3‰ for 18O/16O of bulk, 0.4‰ for 34S/32S, and 1‰ for 2H/1H.The precision of measurement, expressed as one standard deviation when measuring the same sample 10 times, was 0.1‰ for 2). To minimize polyatomic interference, a collision cell was used for Na, Mg, V, Cr, Fe, Ni, Cu, Zn, As, and Eu analysis, while the reaction cell was used for Ca, Ga, and Se analysis.The analysis of 56 elements  was carried out with an inductively coupled plasma–mass spectrometer (ICP-MS), the Agilent 7500ce  equipped with quartz torch, micromist nebulizer, Ni cones, and an octopole reaction system . Al-, Ca-, Cs-, K-, Fe-, P-, and Rb-certified standard solutions were purchased from CPI International . ICP-MS calibration standard 4 solution and Sc-, Rh-, and Tb-certified standard solutions were provided by Aristar BDH . Multi-element calibration standard 1 and 3 solutions, Hg standard 2A solution, and tuning solution  were from Agilent Technologies . A solution of Sc, Rh, and Tb was used as added online internal standard to correct eventual instrumental signal drift during time.++/Ce+ %) were minimized, following the manufacturer’s specification and using an Li, Y, Ce, and Tl solution.Before analysis, the sensitivity, resolution, and P/A  factor were optimized, whereas the oxide ratio (CeO/Ce %) and double-charged ratio  for each element was calculated as three times the standard deviation of the signal obtained for 10 blanks analyzed in a sequence. All data were higher than the calculated DL, except for Ir, Pt, and Au, which were always below 1.5 µg/kg, and therefore are not further reported or discussed. Repeatability was determined by preparing and analyzing five samples in duplicate, and by calculating the average coefficient of variation with results below 10% for all quantified elements. Accuracy was obtained by analyzing a certified reference material in each batch, and by calculating the average recovery for each element. Recoveries ranged between 79% and 112%, and were considered satisfactory for the scope of this research.d effect size [Samples’ values were analyzed with R , relying on the following packages for data handling, visualization, and analysis: tidyverse , FactoMiect size . Two mulect size . PCA wasect size  and clasThe variable importance in the model was assessed by comparing the ranks of the variable importance in the 500 training/test splits.2H, δ13C, δ15N, δ18O, and δ34S, Ag, Al, As, B, Ba, Be, Bi, Ca, Cd, Ce, Co, Cr, Cs, Cu, Dy, Er, Eu, Fe, Ga, Gd, Ge, Hg, Ho, Ir, K, La, Li, Mg, Mn, Mo, Na, Nd, Ni, P, Pb, Pd, Pr, Rb, Re, Sb, Se, Sm, Sn, Sr, Th, Tl, Tm, U, V, Y, Yb, and Zn) of Virginia Bright tobacco samples collected in Umbria, Veneto, and in other geographical areas were investigated. It was confirmed that the main factor influencing the isotopic and elemental signatures of tobacco is its geographical origin. In particular, Umbrian tobacco is characterized by an isotopic and elemental profile that makes it different from tobacco of different origins. Umbrian tobacco showed significantly higher values of δ2H, δ13C, and δ18O, and lower values of δ34S, Ag, Al, As, Be, Bi, Ce, Co, Cr, Cs, Dy, Er, Eu, Fe, Ga, Gd, Ge, Ho, In, La, Mg, Mn, Nd, Pb, Pr, Rb, Sm, Sn, Th, Tl, Tm, U, V, Y, and Yb. It is worth noting that Umbrian tobacco has a significantly lower content in elements that are potentially dangerous for human health, like As, Pb, Sn, Be, Cr, and Tl. The proposed machine learning approach has shown strong potential for the geographical classification of tobacco from Umbria on the basis of its isotopic and elemental fingerprint.In this study, the isotopic and elemental profiles (δThe study, if enhanced with a greater number of samples that are representative of the production, will make it possible to develop an analytical model of traceability of tobacco, which can be used to verify the geographical origin of this product on the market.


In the published article, there was an error in the affiliations.Instead of“Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia, UPM, Seri Kembangan, Malaysia” it should be “Department of Medical Microbiology, Universiti Putra Malaysia, Seri Kembangan, Malaysia.”And“Department of Biotechnology, Bharath Institute of Higher Education and Research, Chennai, India” should be “Centre for Materials Engineering and Regenerative Medicine, Bharath Institute of Higher Education and Research, Chennai, India.”In the published article, there was an error regarding the affiliations for Avin Ee-Hwan Koh. They have two affiliations, which are “Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia.” And “Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Seri Kembangan, Malaysia.”The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Polygala paniculata  characteristics for evolutionary studies of legume–rhizobia symbiosis, written by Yuji Tokumoto, Kayo Hashimoto, Takashi Soyano, Seishiro Aoki, Wataru Iwasaki, Mai Fukuhara, Tomomi Nakagawa, Kazuhiko Saeki, Jun Yokoyama, Hironori Fujita and Masayoshi Kawaguchi, was originally published Online First without Open Access. After publication in volume 133, issue 1, page 109–122 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2021 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The article Assessment of The original article has been updated.


COVID-19 (coronavirus disease 2019) vaccines have become available; now, everyone has the opportunity to get vaccinated. We used Google Trends (GT) data to assess the global public interest in COVID-19 vaccines during the pandemic. For the analysis, a period of 17 months was chosen . Interest in user queries was tracked by keywords . The geographic analysis of queries was also carried out. The interest of users in the vaccine is significantly increasing. It is focused on the side effects of vaccines, and users pay attention to vaccines’ developers from different countries. The correlation between the scientific publications devoted to vaccine development and such requests of users on the internet is absent. This study shows that internet search patterns can be used to gauge public attitudes towards coronavirus vaccination. Safety concerns consistently high follow an interest in vaccine side effects. This data can be used to track and predict attitudes towards vaccination of populations from COVID-19 in different countries before global vaccination becomes available to help mitigate the adverse effects of the pandemic. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a new human virus that causes COVID-19 (coronavirus disease 2019). The human population does not have the necessary immunity to protect themselves against the transmission of the virus and disease Google Trends (GT) is one of the essential tools for cataloguing internet queries, and this indexed information is available The use of GT in various diseases outbreak is nothing new and has previously been used in infectious diseases such as influenza and Zika virus Corona Vaccine, Corona Vaccine Development, COVID-19 Vaccine Development, China Corona Vaccine, Corona Chinese Vaccine, US Corona Vaccine, UK Corona Vaccine, Korea Corona Vaccine, Russian Vaccine, Sputnik v, Moderna Vaccine, Pfizer Corona Vaccine, AstraZeneca Vaccine, 2019 Novel Coronavirus Disease, 2019 Novel Coronavirus Infection, 2019 Novel Coronavirus, 2019nCoV Disease, 2019nCoV Infection, 2019nCoV, 2019nCoV-co, Coronavirus Disease 2019 Virus, Coronavirus Disease 2019, Coronavirus Disease-19, Covid 19, COVID19 Virus, COVID-19 Virus, COVID19, COVID-19, COVID-2019, SARS2, SARS-CoV-2, Vaccina, Vaccine, Vaccines, Vaccination, Wuhan Corona Virus, Wuhan Seafood Market Pneumonia Virus, Severe Acute Respiratory Syndrome Coronavirus 2, Coronavirus.To assess the status of inquiries related to the coronavirus vaccine, we used “Worldwide” as the search range, “01/19/2020-07/04/2021” as the time range, ”All categories“ as the category, and ”Web Search“ as the search type. The English terms were selected after searching Naver (the Korean search engine) where we evaluated their popularity. The final selection included the following 39 keywords or possible combinations: We tracked overall interest in keywords on the Internet and then compared interest in terms by country over a selected period. The data is downloaded from the Internet in “.csv” format. The countries with the highest volume of queries always have the highest rankings. The number of queries received is scaled from 0 to 100, depending on the topic's relationship to all searches across all topics. GT uses a relative popularity metric, meaning that the maximum number of queries for the selected period will always be 100. Google's normalized trend data is a useful metric for assessing the popularity of topics as measured by the number of published medical studies. The number of publications was assessed using the PubMed service with the same keywords selected earlier.COVID-19 Vaccine and COVID-19 Vaccine Development . However, for terms like the Coronavirus Vaccine, the Development of a Coronavirus Vaccine, the dynamics are opposite .From August 1st till December 31st, 2020, the relative search volume for 21 of the 31 search terms significantly increased compared to the period from February 1st till July 31st, 2020. However, nine search terms showed a significant increase in the same period . From Jaelopment A, 1B. Hoopposite A, 1B.TabUS Corona Vaccine, UK Corona Vaccine, Indian Corona Vaccine) periodically observed surges of interest. For example, an increased interest in Russian Corona Vaccine was manifested in the summer of 2020, and interest in UK Corona Vaccine grew in the winter of 2020–2021 (Korean Corona Vaccine were not significant (not shown in the figure).Considering the type of Covid-19 vaccines, the period from Jan 2020 to Jun 2021 showed a stable interest in all vaccines  of the Russian Corona Vaccine requests come from Russia. After excluding countries that are interested in a vaccine of only one origin, we got Fig. 3.Total (100%) of the The annual trend analysis revealed an upward trend for most of the branded vaccines reviewed .Fig. 4ThSputnik v , Sinovac Vaccine . For AstraZeneca Vaccine there was a power-law trend growth , for Pfizer Vaccine there was exponential growth . For Moderna Vaccine there was exponential growth too .To calculate the trends, a shorter time was used: from May 24, 2020, to Jul 04, 2021 . A polynomial growth is noted for Sputnik v and AstraZeneca by countries  was observed in countries such as Argentina, Venezuela, Bolivia, Cuba, Uzbekistan, Kazakhstan, Paraguay, Russia (listed in descending order of the number of requests from 98 to 91%).In countries such as Turkmenistan and Belarus, the users were interested only in the AstraZeneca Vaccine.Countries like Fiji, Barbados, Malta, Jamaica, St Kitts & Nevis, Solomon Islands, Anguilla, Antigua & Barbuda, Vanuatu, British Virgin Islands, Isle of Man, St Lucia, Papua New Guinea, San Marino, Timor-Leste, Grenada, Malawi, Bahamas, Belize, Guernsey, Dominica, Suriname, Bermuda, Jersey, Brunei, Somalia, Bhutan, Rwanda, Seychelles, Eswatini, Sint Maarten, Faroe Islands, Gambia, South Sudan, Lesotho, Gibraltar, Sierra Leone, Andorra, Aruba, Liberia, Cayman Islands, Sudan, Togo, Afghanistan, Madagascar, Senegal, Mali, Guam, Haiti, Macao, Mozambique, Mauritania, Congo – Kinshasa, Tajikistan, Cote d'Ivoire, Benin, Yemen were only interested in the More than 90% of search queries were for this vaccine in countries such as Trinidad & Tobago, United Kingdom, Ethiopia, Zambia, Ireland, Canada, Namibia, Australia, Saudi Arabia, Malaysia, Cambodia, Nigeria, Botswana, Kuwait, St Helena, St Vincent & the Grenadines, Denmark, Egypt, Iraq, Oman, Uganda, United States, China, Kosovo, Vietnam, Maldives, Singapore, Estonia, Mauritius, Kenya, Jordan, Cyprus, South Africa, New Zealand, Taiwan (listed in descending order of the number of requests from 99 to 90%).COVID-19 vaccine, Coronavirus vaccine according to PubMed monthly data for 2020 , Covid 19 (+39.51%), COVID19 (+38.71%), COVID19 Virus (+20.49%). In addition, the number of requests for the term COVID19 Virus Vaccine increased significantly (+28.47%). The dynamics of weekly recommendations showed a significant increase in interest in the terms COVID-19 Vaccine and COVID-19 Vaccine Development. On the contrary, the number of requests decreased significantly for the Coronavirus Vaccine for the Development of a Coronavirus Vaccine, the number of requests decreased significantly. This is due to the growing awareness of the population about the disease and related terminology.From Jan 19, 2020, to Jan 19, 2021, relative searches for 31 keywords showed a significant upward trend in the number of global searches for terms such as Coronavirus Vaccine from China, USA, UK, Russia, Korea from February 2020 to March 2020, when WHO announced the coronavirus pandemic on March 11. A surge of interest in the Russian vaccine was noted in July-August. In early August, the registration of the world's first coronavirus vaccine was announced in Russia. The growing interest in the vaccine from the UK is since the authorities announced the start of vaccination against coronavirus in early December.There has been a significant increase in the number of requests globally for the terms Sputnik v vaccine. This vaccine prevails in the requests from the countries: Argentina (98%), Venezuela (97%), Bolivia (96%), Cuba (95%), Uzbekistan (94%), Kazakhstan and Paraguay (93%), and Russia (91%).We analyzed vaccine requests where users indicate the country of origin of vaccine development. The example of China shows that the more popular query is the one that includes the name of the country followed by the terms. The geographical distribution of requests for national vaccines was reviewed. It turned out that only the Chinese vaccine is interested in such countries as Kuwait, Singapore, Malaysia, Portugal, Egypt, Brazil, Mexico, France, and Zimbabwe. Only South Korea is interested in the Korean vaccine. 87% of requests for a UK vaccine came from the United Kingdom. Overall, 52% of recommendations for a vaccine from the United States came from the United States, that is, Americans are more interested in vaccines from other countries. Belarus and Turkmenistan are exclusively interested in the AstraZeneca Vaccine. This vaccine dominates among user requests from Trinidad & Tobago, United Kingdom, Ethiopia, Zambia (99%), Ireland, Canada, Namibia, Australia, Saudi Arabia (98%), Malaysia, Cambodia, Nigeria (97%), Botswana, Kuwait, St Helena (96%), St Vincent & the Grenadines, Denmark, Egypt, Iraq (95%), Oman, Uganda, United States, China (94%), Kosovo, Vietnam (93%), Maldives, Singapore, Estonia (92%), Mauritius, Kenia, Jordan (91%), and Cyprus, South Africa, New Zealand, Taiwan (90%).Users of countries of Barbados, Malta, Jamaica, St Kitts & Nevis, Anguilla, Antigua & Barbuda, British Virgin Islands, Isle of Man, St Lucia, San Marino, Timor-Leste, Grenada, Bahamas, Belize, Guernsey, Dominica, Suriname, Bermuda, Jersey, Brunei, Somalia, Bhutan, Rwanda, Seychelles, Eswatini, Sint Maarten, Faroe Islands, Gambia, South Sudan, Gibraltar, Sierra Leone, Andorra, Aruba, Liberia, Cayman Islands, Sudan, Togo, Afghanistan, Madagascar, Senegal, Mali, Guam, Haiti, Macao, Mozambique, Mauritania, Tajikistan, Yemen, some countries of Oceania and Africa are exclusively interested in the For Sputnik v and Sinovac vaccines, a polynomial increase in the number of requests was noted. For Pfizer and Moderna vaccines, an exponential increase in the number of requests was noted. For the AstraZeneca vaccine, there was a power-law trend growth.COVID-19 Vaccine Good.Comparison of publication activity with the number of requests showed no correlation between scientific research and user requests. The analysis showed that users from United Arab Emirates, Singapore, Ireland, South Africa, Israel, Pakistan, Saudi Arabia, and Malaysia were exclusively interested in the vaccine's side effects. User interest in vaccine side effects prevailed in countries such as the United Kingdom (74%), the United States (69%), Australia (64%), Philippines (57%), and Canada (56%). Users from India were the most supportive of the vaccine, with 55% searching for the term WHO has launched an international campaign entitled “Managing the COVID-19 infodemic: Promoting healthy behaviors and mitigating the harm from misinformation and disinformation” to draw the attention of governments to counter the spread of misinformation. One of the main current concerns is the spreading of unconfirmed data about vaccines and vaccination, which could seriously undermine the international strategy to combat SARS-CoV-2. Therefore, the need for new effective and efficient infodemiological methods is more urgent than ever. The relationship between Internet inquiries, media reports, and evidence of morbidity is multifactorial and requires further study. Nevertheless, the main trends in Internet search queries during a pandemic can serve as an additional component of epidemiological surveillance.Rovetta Our research used GT, which shows the search behavior of people using the Google search engine. Future research should consider exploring the same topic on a different search engine including social networks to reach a more diverse user audience.While analyzing the number of requests, we deal not with the absolute, but with the relative number of requests. In addition, this tool does not consider repeated searches from the same user in a short period, distorting the results' objectivity. The limitation of the study is the lack of GT data about China because of the general unavailability of Google in China.Interest in vaccines produced by different countries and companies varied in time and space. For example, the bursts of interest were timed to the announcement of the vaccine registration in Russia (August 2020), and to the announcement of the start of vaccination in the UK (December 2020). There was a geographical differentiation of interest in vaccines produced by a specific country or pharmaceutical company. All applied vaccines are of particular interest to users. We were investigating the use of search engines to gauge user interest in COVID 19 vaccines. Our results demonstrated the potential for using GT as a complementary tool to help understand Internet searches that can determine the demand for vaccines from different countries or companies and the geographic distribution of these demands.This study shows that Internet search patterns can be used to gauge public attitudes towards coronavirus vaccination. Interest in vaccine side effects is consistently high, followed by safety concerns. The flow of inquiries about side effects especially increased in December, when the vaccination company began in Russia, Germany, France, Spain, Austria, Bulgaria, Czech Republic, Italy, Turkey, and other countries. This data can be used to track and predict attitudes towards vaccination of populations from COVID-19 in different countries before widespread vaccination becomes available to help mitigate the adverse effects of the pandemic.The search queries can reflect the interests of users in the field of unreliable information. For example, the testing period for coronavirus vaccines is not yet very long; therefore, due to a lack of knowledge, fakes arise . In addition, the information provided to the public can be politically charged. Statistical processing of information shows more reliable results with an increase in the amount of processed data.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Trials in health care are prospective human research studies designed to test the effectiveness and safety of health care interventions, such as medications, surgeries, medical devices and other treatment or prevention interventions. Statistics is an important and powerful tool in trials. Inappropriately designed trials and/or inappropriate statistical analysis produce unreliable results and a lack of transparency when reported, with limited clinical use.This systematic literature review aimed to identify, describe and synthesise factors contributing to or influencing the statistical planning, design, conduct, analysis and reporting of trials.Information sources were retrieved from the following electronic citation databases: PubMed, Web of Science, PsycINFO, and CINAHL and the grey literature repository: OpenGrey. 90 articles and guidelines were included in this review. A narrative, thematic synthesis identified the key factors influencing the statistical planning, design, conduct, analysis and reporting of trials in health care.We identified three analytical themes within which factors are grouped. These are: “what makes a statistician?“, “the need for dynamic statistical involvement and collaboration throughout a trial – it's not just about the numbers”, “and the “accountability of statisticians in ensuring the safety of trial participants and the integrity of trial data”. While important insights emerged about the qualifications, training, roles, and responsibilities of statisticians and their collaboration with other team members in a trial, further empirical research is warranted to elicit the perceptions of trial team members at the centre of statistics in trials. Such interventions include drugs, cells , surgical procedures, medical devices, behavioural treatments, radiological procedures, and interventions for preventative care . Findings from trials have the potential to change clinical practice, and the care patients receive. For this reason and to minimise harm to patients, trials must be planned, data collected, and analysed for efficacy and safety, to the highest standard. This is best practice for adherence to sound ethical principles.a branch of mathematics dealing with the collection, analysis, interpretation, and presentation of masses of numerical data”  and the School of Nursing, Midwifery and Health Systems, University College Dublin, Ireland. The funding source had no involvement in the study design, collection, analysis, and interpretation of data in the report's writing or in the decision to submit the article for publication.Marina Zaki: Conceptualisation, Methodology, Formal analysis, Investigation, Data Curation, Writing- Original draft preparation, Writing- Review and Editing, Visualisation, Project Administration. Lydia O'Sullivan: Methodology, Formal analysis, Investigation, Data Curation, Writing- Original draft preparation, Writing- Review and Editing, Visualisation. Declan Devane: Conceptualisation, Methodology, Writing- Original draft preparation, Writing- Review and Editing, Supervision, Funding Acquisition. Ricardo Segurado: Writing- Review and Editing, Supervision. Eilish McAuliffe: Conceptualisation, Methodology, Investigation, Writing- Original draft preparation, Writing- Review and Editing, Visualisation, Supervision, Project Administration, Funding Acquisition.☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:


Sandra Frisenda was not included as an author in the published article. The corrected Author Contributions Statement appears below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.TR, HN, PS, RV, MA, and LB: conceived and designed the research. SF, TR, HN, KR, BK, and LB: performed the experiments. KR and BK: contributed the reagents. TR, SF, PS, RV, MA, and LB: collected and provided the clinical data. TR, HN, BK, PS, MA, and LB: interpreted the data. TR, HN, MA, and LB: performed the statistical analysis. TR, HN, PS, and LB: wrote the initial draft. All authors critically revised and approved the manuscript and are accountable for the accuracy and integrity of the work.