SinHumo App); or (2) cognitive–behavioral treatment along with the use of a control App (without active components). The experimental App will be used during the eight treatment sessions and for 12 months after the end of treatment. The primary outcome measures will be 7-days point-prevalence abstinence at 12-months follow-up. We expect the experimental App to obtain higher abstinence rates at the end of treatment and at one-year post-treatment follow-ups and lower relapse rates, compared to the control App.Numerous studies have shown the efficacy of smoking cessation interventions. However, some challenges, such as relapse rates, remain. The availability of information technologies (ICTs) offers promising opportunities to address such challenges. The aim of this paper is to describe the protocol followed to assess the efficacy of a face-to-face cognitive–behavioral intervention for smoking cessation using a smartphone application as a complement, compared with a control group. A single blind, two-arm, randomized controlled trial is proposed (NCT04765813). The participants will be smokers over 18 years old, who smoke at least eight cigarettes per day. Participants will be randomized to one of two conditions, using a 1:1 allocation ratio: (1) cognitive–behavioral smoking cessation treatment along with an App with active therapeutic components ( Smoking remains the leading avoidable cause of disability, mortality, and morbidity worldwide , and it Psychological treatments  for smoking cessation are first-line treatments that have proven efficacy to quit smoking among different populations . A systeNowadays, the availability of information technologies (ICTs)  offers promising opportunities to address such challenges. The use of ICTs in the field of health has grown and developed significantly, demonstrating their utility in several areas, such as diabetes management, health-promoting behaviors , or mental health ,14. For In this context, the use of mHealth  is becoming increasingly promising. mHealth is defined as the use of mobile devices, such as mobile phones or personal digital assistants (PDA), as a means to support or deliver health-related services . SpecifimHealth Apps for smoking cessation are being widely developed, and although they offer promising results, they are still modest . These AThe main aim of the present randomized controlled trial is to examine whether the SinHumo smartphone application (iOS and Android), used as a complement of a face-to-face cognitive–behavioral smoking cessation treatment, improves smoking cessation rates at the end of treatment, and at 3-, 6-, and 12-months follow-up, compared with a control group which receives the same smoking cessation treatment and a control App (without active components). The main hypothesis is that combining a cognitive–behavioral psychological treatment to quit smoking and an App with active therapeutic components will obtain higher abstinence rates at the end of treatment and the 12-month follow-up period and lower relapse rates compared to the control group.The proposed study is a two-arm, single-blind, randomized controlled trial (NCT04765813) to assess the efficacy of a cognitive–behavioral intervention for smoking cessation complemented by an App. The overall study design is summarized in Participants will be recruited through the media, publications on the Smoking Cessation Unit’s social networks (Facebook and Instagram), posters in health-care centers, word of mouth, or referred to the Unit by their primary care physician or other specialized services of the health-care system. Independently of their origin , all potential participants have to personally contact the trial staff by telephone or email. Before participants enroll in the study, written informed consent will be obtained. Then, the different phases of the study  will be carried out.Sample size calculation was performed using the software developed by Wang and Ji . To deteTo be included in the study, participants should meet the following inclusion criteria: (1) 18 years of age or older; (2) smoke at least six cigarettes per day; (3) desire to participate voluntarily in the smoking cessation treatment; (4) correctly fill out all the pre-treatment assessment questionnaires; (5) able to provide written informed consent; (6) currently own a valid email address; and (7) having a smartphone with an Internet connection (Android or iOS) and being willing to use it during treatment.Exclusion criteria include: (1) having a diagnosis of a severe mental disorder (bipolar disorder and/or psychotic disorder); (2) having a substance use disorder , different from a tobacco use disorder; (3) smoke rolling tobacco, snuff, cigars, little cigars, or other tobacco products ; (4) have participated in an effective psychological treatment to quit smoking during the previous 12 months; (5) have received an effective pharmacological treatment to quit smoking in the previous 12 months ; (6) have a physical pathology involving life-threatening risks for the person which would require immediate intervention in an individual format ; and (7) have a visual impairment that impedes the use of the App.This intervention is a multicomponent cognitive–behavioral treatment (“Programa para Dejar de Fumar”) , which hThis intervention is applied in a group format and consists of 8 one-hour sessions once a week. Due to the COVID-19 pandemic, these sessions will be conducted through video calls .Along with the intervention, participants will be provided with an App with active therapeutic components, which will be used during the treatment sessions (Phase 1) and the follow-up period (Phase 2):-During Phase 1 , the App-(a)Abstinent: gains and achievements made since quitting smoking , behavioral and cognitive recommendations for abstinence maintenance, strategies for coping with cravings , motivational strategies , access to the materials in pdf format that were provided during the sessions, and the possibility of self-reporting tobacco use if a lapse or relapse occurs (e occurs . Likewis(b)Relapsed: behavioral and cognitive advice to quit (tips), the possibility of setting a new quit date in a calendar, strategies to cope with cravings , motivational strategies , access to the materials in pdf format that were provided during the sessions, and the possibility of self-reporting tobacco use. They will receive notifications to encourage and support a new quit attempt during this follow-up phase (up phase .(c)Smokers: behavioral and cognitive advice to quit (tips), the possibility of setting a quit date in a calendar, notifications consisting of strategies to be prepared for cessation, strategies to cope with cravings , motivational strategies , access to the materials in pdf format that were provided during the face-to-face sessions, and the possibility of self-reporting tobacco use. Likewise, they will receive notifications to encourage a quit attempt during this follow-up phase .The cognitive–behavioral treatment will be delivered through video calls using Microsoft Teams. The smoking cessation treatment has been manualized to train the therapists and improve the intervention implementation. It includes a detailed session-by-session protocol and follow-up procedures. Study supervisors will assess fidelity by randomly visualizing treatment sessions in both arms.Both conditions will be administered in eight weekly 60-min sessions. At the end of treatment (session 8), there will be a post-treatment assessment and face-to-face follow-ups through video calls at 3, 6, and 12 months. Trained therapists  will conduct the assessment, intervention sessions, and follow-ups. This study was reviewed and approved by the Institutional Ethics Review Board of the University of Santiago de Compostela (USC-15/2020). The study is carried out in accordance with the Declaration of Helsinki. The potential participants will be asked to read and sign an informed consent form before any study procedures. The interested individuals will be initially screened for eligibility, and those who meet the inclusion criteria will be assessed. -Smoking Habit Questionnaire [ionnaire . This qu-Fagerström Test for Cigarette Dependence (FTCD) [e (FTCD) ,32. Thise (FTCD) .-Nicotine Dependence Syndrome Scale (NDSS) [e (NDSS) ,35. This-Structured interview for the assessment of the DSM-5 diagnostic criteria for tobacco use disorder [disorder .-Minnesota Nicotine Withdrawal Scale (MNWS) [e (MNWS) . This 8--Self-Efficacy/Smoking Temptation Scale [on Scale . This 9--Questionnaire of Urgency to Smoke [to Smoke . This qu-Beck Depression Inventory II (BDI-II) [(BDI-II) ,41. This-EuroQoL-5D Quality of Life Questionnaire [ionnaire . This is-Questionnaire about the use of smartphones and Apps. This is an ad hoc questionnaire collecting information about the use of smartphones  and Apps .-End-of-treatment questionnaire. This self-report collects information about quit date, confidence in remaining abstinent, perceived social support, and physical and psychological improvements since the beginning of treatment.-Client Satisfaction Questionnaire [ionnaire . This 8--Satisfaction with App questionnaire, in which data about satisfaction and usability are collected at the end of treatment and at 3-, 6-, and 12-months follow-up.-Follow-up questionnaire, in which abstinence and lapse/relapse data are collected at 3-, 6-, and 12-months follow-up.An online face-to-face structured interview will assess sociodemographic characteristics, tobacco-related information, smoking cessation treatment history, and depression treatment history. In addition, the following instruments will be used (The main smoking cessation outcomes were defined based on the updated recommendations by the Society for Research on Nicotine and Tobacco (SRNT) Treatment Research Network .The primary outcome was the self-reported seven-day point prevalence of complete smoking abstinence (“not even a puff”) at 12-months follow-up. The secondary outcomes were:The self-reported seven-days point prevalence of complete smoking abstinence (“not even a puff”) at the end of treatment (week 8), 3-, and 6-months follow-up;The self-reported 30-days point prevalence smoking abstinence at 3-, 6-, and 12-months follow-up;The self-reported prolonged smoking abstinence with lapses (no more than 5 cigarettes) from the end of treatment and each follow-up point assessment at 3-, 6-, and 12-months;The reduction by 50% or more in the number of cigarettes smoked per day from baseline to the one-year follow-up.We will also explore the adherence, satisfaction, usability of the App, and specific tool usage in relation to smoking cessation outcomes.Data will be collected from the participants in an electronic format using a unique identification code number assigned to each participant for trial documents and electronic databases. All data will be kept in password-protected computer folders at the Smoking Cessation and Addictive Disorders Unit (University of Santiago de Compostela). Only authorized trial staff will have access to trial documents.www.clinicaltrials.gov accessed on 21 February 2021). The participants will be provided with both oral and written information regarding the study before obtaining their informed consent.This study has been designed in accordance with the Declaration of Helsinki. The Bioethics Committee of the University of Santiago de Compostela approved this study (USC-15/2020), which is registered with the international standard randomized controlled trial number, NCT04765813  and a chi-squared test for categorical variables . Logistic regression analyses adjusted for baseline characteristics  will be carried out to examine whether abstinence rates differ significantly between conditions at the end of treatment, and at 3-, 6-, and 12-months follow-up. Mediation analysis will be conducted to analyze the role of different variables  in the relationship between treatment condition and smoking status. Multilevel and survival analysis will also be carried out to examine the relapse process. All data analysis will follow the intention-to-treat principle, which includes in the primary analysis all randomized participants [p value < 0.05 will be considered statistically significant.A descriptive analysis to summarize the characteristics of the total sample will be conducted. Comparisons between the two groups will be performed using an independent sample icipants . A p valThe study results will be reported following the Consolidated Standards of Reporting Randomized Trials of Social and Psychological Interventions (CONSORT-SPI 2018) statements ,47.The present study will assess whether adding an App to a cognitive–behavioural smoking cessation treatment will improve short- and long-term abstinence rates, and reduce relapse rates in a sample of treatment-seeking smokers using a randomized clinical trial. The experimental condition will be provided with an App with therapeutic components  along with the intervention and during a one-year follow-up period. The control group will receive the same smoking cessation treatment along with a control App in which participants are provided with a set of pdf documents that expand on the topics addressed in each session and a smoking self-monitoring tool. Adding an App with active cognitive–behavioral components to support the quitting process to a face-to-face intervention and throughout a year follow-up is innovative and might result in greater abstinence rates and lower relapse rates. We hypothesize that using this App would increase treatment intensity and accessibility to psychological strategies to quit, supporting the participants’ smoking cessation process.Nowadays, the frequent use of smartphones and Apps is part of most people’s daily lives, and this is a resource that is beginning to be used for interventions aimed to promote the health of patients. An App with active components used as a complement to a psychological treatment, such as the one mentioned above, would also gather information about task completion and the tools used , providiInterventions for smoking cessation should pay special attention to relapse prevention, as relapse is a barrier to any treatment that targets addictive behaviors, and one of the main reasons for reduced overall success rates ,49. One Some potential limitations should be acknowledged. As noted earlier, due to the COVID-19 pandemic and resource limitations, abstinence will only be self-reported, and biochemical verification will not be performed. The biochemical verification of abstinence is desirable, as it increases scientific rigor, limiting the impact of misreporting smoking status . HoweverWe expect that adding a smartphone App to a well-established behavioral smoking cessation treatment will improve smoking cessation outcomes at the end of treatment and will reduce relapse rates at follow-ups. These findings will have important clinical implications, potentially transforming the way that people interact with health-care services. Any public health effort that targets smoking cessation is essential to improve people’s health and quality of life, and to reduce public health-care expenditure.


A novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China in 2019 and later ignited a global pandemic. Contrary to expectations, the effect of the pandemic was not as devastating to Africa and its young population compared to the rest of the world. To provide insight into the possible reasons for the presumed immune sufficiency to coronavirus disease 2019 (COVID-19) in Africa, this review critically examines literature published from 2020 onwards on the dynamics of COVID-19 infection and immunity and how other prevalent infectious diseases in Africa might have influenced the outcome of COVID-19. Studies characterising the immune response in patients with COVID-19 show that the correlates of protection in infected individuals are T-cell responses against the SARS-CoV-2 spike protein and neutralising titres of immunoglobin G and immunoglobin A antibodies. In some other studies, substantial pre-existing T-cell reactivity to SARS-CoV-2 was detected in many people from diverse geographical locations without a history of exposure. Certain studies also suggest that innate immune memory, which offers protection against reinfection with the same or another pathogen, might influence the severity of COVID-19. In addition, an initial analysis of epidemiological data showed that COVID‑19 cases were not severe in some countries that implemented universal Bacillus Calmette–Guerin (BCG) vaccination policies, thus supporting the potential of BCG vaccination to boost innate immunity. The high burden of infectious diseases and the extensive vaccination campaigns previously conducted in Africa could have induced specific and non-specific protective immunity to infectious pathogens in Africans. As of 07 September 2021, SARS-CoV-2 had cumulatively infected over 224 686 497 people and caused 4 566 167 deaths in 225 countries, with a case fatality rate of 2.1%.3 The spectrum of COVID-19 manifestation may vary from a self-limiting mild respiratory tract infection to a severe pneumonia that could lead to the failure of multiple organs and death.4 The common symptoms, including fever, cough, and difficulty in breathing, typically emerge within 2–14 days after exposure.5 Certain individuals may, however, exhibit minimal or no symptoms even with a positive reverse transcription polymerase chain reaction test.9 The risk of death is greater among older or immunocompromised patients,10 and the ability of asymptomatic individuals to efficiently transmit the virus11 has made it difficult to control the epidemic.6In December 2019, a group of pneumonia cases of undetermined origin where patients presented with clinical signs that resemble viral pneumonia was first described in the city of Wuhan, Hubei, China.13 Six species of coronavirus species cause human diseases, and four of them, NL63, HKU1, hCoV-229E, and OC43, are predominantly responsible for mild respiratory infections.14 The first SARS-CoV, which emerged in 2002,17 and Middle East respiratory syndrome coronavirus, which became known in 2012,18 are two deadly novel coronaviruses that cause severe pneumonia and have appeared occasionally in different areas. However, in contrast to SARS-CoV-2, the number of confirmed SARS-CoV and Middle East respiratory syndrome coronavirus cases are smaller (8100 and 2500) because of limited transmission from person to person. The probability of the periodic emergence of novel coronaviruses is high as a result of its extensive dissemination among humans and animal species, high genetic variability and recurrent genomic recombination, in addition to other factors such as growing human and animal interactions, regular cross-species infections, and rare spillover events.20 The sequencing of the 2019-nCoV genome showed that it is phylogenetically similar to particular beta-coronaviruses found in bats that belong to the sarbecovirus subgenus in the Coronaviridae family.2Coronaviruses are characteristically single-stranded, positive-sense RNA viruses that disseminate widely in birds, humans, and other mammals, and can cause enteric, respiratory, neurological, and hepatic diseases.3). Besides, a comparison of the incidence of cases and the case fatality ratio among some selected African and Western countries (3) showed that the case fatality ratio and number of cases in Africa were relatively low. This suggests that Africa was mildly impacted by the pandemic despite the weak health infrastructure. This review summarises current literature on the dynamics of infection and immunity to SARS-CoV-2 and other infective diseases in Africa and the unique characteristics of the sub-Saharan African population that might have impacted the course and severity of the pandemic. We also describe the host immune response mechanisms to other microbial infections and the possible reasons for a presumed immune sufficiency to COVID-19 in the African population.Contrary to expectations that the African region would quickly succumb to the devastation of the rampaging COVID-19 pandemic, fewer cases, as shown by the number of cases per million people, are being reported in Africa compared to other parts of the world 3. Besideountries 3 showed The terms ‘epidemiology and immunity to COVID-19’, ‘COVID-19 and associated coronaviruses’, ‘prevalent infectious diseases in Africa’, ‘host immune response mechanisms to viral and other microbial infections’, and ‘immune sufficiency to COVID-19 in the African population’ were used to carry out a systematic search on relevant search engines and websites such as Google, Google Scholar, PubMed, African Journals Online, World Health Organization, Center for Disease Control and Prevention, Nigeria Centre for Disease Control, and Africa Centre for Disease Control and Prevention. We included all relevant studies published in the English language between 2000 and 2021.21 T-cell responses against the viral spike protein have been shown to correlate well with the neutralising titres of immunoglobin G and immunoglobin A antibodies.24 This observation could have important implications for vaccine design and the development of durable immunity. As the primary inflammatory cells, the CD8+ T-cells play a crucial function in clearing the virus. The level of inflammation during SARS-CoV-2 infection is significantly reliant on the association between the CD4+/CD8+ ratio and the total lymphocytes, namely CD4+ T-cells, CD8+ T-cells, and B-cells and natural killer cells.10 In both mild and severe cases, there is a decrease in the absolute numbers of T lymphocytes, CD4+ T-cells, and CD8+ T-cells, but the decrease is more in severe than in mild cases.10 The implication of the lymphopenia observed is that it reduces the ability of the immune system to fight the infection and increases the chances of severe illness. Multivariate data analysis showed that a reduction in B-cells and CD8+ T-cells, and a rise in the CD4+/CD8+ ratio can independently predict a poor treatment outcome.10 In the context of the African population where immune sufficiency is presumed, it is expected that a reduction in the numbers of T lymphocytes would be limited but this needs to be investigated. Interferon-γ expression by CD4+ T-cell induction also tends to reduce in severe cases compared to moderate cases.4 It takes between 10 and 21 days after infection for antibody response to develop in most SARS-CoV-2-infected persons, and it takes between 6 and 15 days after the onset of disease for the immunoglobin M and immunoglobin G antibodies to SARS-CoV-2 to develop.29 In mild cases, antibody development can take up to 4 weeks or longer and may even be undetectable in a small number of cases. The basis of protective immunity from a successive infection is the immune memory derived from either primary infection or immunisation.32 Recently, a predominantly cross-sectional study, which also included a longitudinal component of 188 recovered COVID-19 cases, assessed the involvement of the CD4+ T-cell, CD8+ T-cell, and humoral components of adaptive immunity in the immune memory. The result showed that COVID-19 infection is followed by the generation of considerable immune memory involving all types of adaptive immune components,21 thus suggesting that activation of antibodies or T-cell reactivity are correlates of protection against COVID-19 infection. The question is: how long does the immune protection last?The specific aspects of immunity that define both the protective and pathogenic reactions to SARS-CoV-2 infection are not clear. Though some components of the immune response to SARS-CoV-2 infection appear to be unique, some aspects are similar to the mechanisms of immunity to other human and animal infections. An understanding of the protective components of the immune reaction to SARS-CoV-2 infections is important for effective vaccine development. As is the case with many infectious diseases, an immune reaction to SARS-CoV-2 involves both cell-mediated and antibody-facilitated responses.33 In contrast to SARS-CoV-1 infections where immunoglobin G antibody levels could be sustained for two years in 90% of patients and for three years in 50% of patients,34 immunoglobin M and immunoglobulin G antibody levels in SARS-CoV-2 could only be sustained for over seven weeks35 or until day 49 in at least 80% of the cases.36 A recent study showed that 95% of study subjects retained immune memory lasting approximately six months after infection.21In other coronaviruses, antibody levels decline between 12 and 52 weeks from the inception of symptoms, resulting in homologous reinfections.37 This corresponds to 3.6% of the total number of cases and 4.4% of the total number of deaths reported globally. Within Africa, the total number of COVID-19 cases and deaths have varied between countries and with time37 (3). As of 07 September 2021, South Africa, which is the epicentre of the pandemic in Africa, had recorded the highest incidence of validated COVID-19 infections (2 819 945) in sub-Saharan Africa, followed by Ethiopia (314 984), Kenya (240 172), Zambia (207 114), Nigeria (195 511), and Botswana (162 186).37 Although Nigeria is the most populous African nation, it has the fifth largest case count in sub-Saharan Africa and the largest outbreak in West Africa.37 The number of cases being reported in Africa compared to the other regions of the globe may have been partly influenced by the low level of testing,37 suggesting a high likelihood of many undetected cases. The level of testing in Africa has been hindered by factors that include limited laboratory capacity, availability and accessibility of testing sites, cost of testing, low health literacy, and the stigma associated with testing positive.38 Also, certain characteristics peculiar to Africa in terms of age, health, lifestyle, and previous experiences with other infectious disease outbreaks might have impacted how the pandemic is playing out in Africa.The incidence of SARS-CoV-2 infections in sub-Saharan Africa was initially low but increased rapidly over time until it became widespread in virtually all countries. As of 07 September 2021, the total number of COVID-19 cases reported in 55 African countries was 7 926 999, with 200 045 deaths and a case fatality ratio of 2.5%.h time37 3. As of 39 Besides, only 3% of the African population is above 65 years, which is the threshold for significant chances of complications and deaths due to COVID-19.40 In Nigeria, the most populous country in Africa, over 44% of the population is below the age of 15 years, the age group with the fewest number of reported cases and mortality.41 However, there are fears that other demographic features peculiar to Africa such as frequent migration across borders, a high number of displaced persons, rapid urbanisation, and large households41 could complicate prevention and mitigation efforts, thereby driving up the case count and the number of deaths. In addition, factors like the worsening burden of existing health conditions such as tuberculosis and HIV/AIDS43 with their attendant effects on the population’s immune status, as well as the high incidence of non-communicable diseases such as hypertension and heart diseases, increase the chances of complications from COVID-19 infections.With a median age of under 20 years, Africa has a relatively young population compared to European Union countries (43 years) and China and the United States (38 years).44 are a serious challenge in Africa due to various underlying factors such as poverty, poor environmental hygiene, overcrowded housing, limited access to affordable healthcare, and lack of basic health education.47 Malaria, HIV/AIDS, tuberculosis, Ebola disease, Lassa fever, guinea worm, elephantiasis, river blindness, lower respiratory tract infection, and diarrheal disease are prevalent or have had outbreaks in Africa.48 There are six infectious diseases in the 2019 WHO report of the top 10 causes of disability-adjusted life years in sub-Saharan Africa.49 These include malaria, AIDS, lower respiratory tract infections, diarrheal infections, meningitis and tuberculosis.49 The spread of these diseases could occur more easily in countries with inadequate infrastructure and fragile health systems.Infectious diseases, responsible for a minimum of 69% of deaths in Africa,50 In 2020, the WHO estimated that 3.2 billion people across 96 countries run the risk of having malaria, with the highest burden being in sub-Saharan Africa. This region accounts for 94% of global cases and 94% of deaths, 67% of which are in children aged under five years.50 The HIV is a retrovirus that progressively destroys and weakens the immune system of an infected person until it becomes vulnerable to opportunistic infections. If untreated, the HIV infection can progress to the most complex stage of the disease referred to as AIDS, resulting in death.52 Over 37.7 million people are living with HIV globally, with 680 000 annual deaths.53 Sub-Saharan Africa is the worst affected, being home to 67% of people living with HIV and 39% of new HIV cases.53 Although most people living with HIV have higher co-morbidities and experience more severe outcomes from COVID-19 than people without HIV, most of them did not have access to COVID-19 vaccines as of mid-2021.53Malaria, caused by plasmodium species, is a vector-borne parasitic disease that infects humans via the bites of infected female Anopheles mosquitoes.Mycobacterium tuberculosis and is an infectious disease that commonly affects the lungs and is transmissible from person to person through coughing, sneezing, or spitting.55 In 2019, there were 10 million cases of tuberculosis (208 000 were in HIV-positive people) and over 1.2 million deaths due to tuberculosis .56 Africa ranked second in the global burden of new tuberculosis cases (25%) in 2019.56 Ebola virus causes an acute, contagious, and deadly disease that is transmitted from person to person through close contact with fluids from the body of symptomatic and asymptomatic living patients or dead victims.58 Periodic, remote outbreaks of Ebola have occurred in many Central African countries.60 The most widespread outbreak of Ebola occurred in Guinea, West Africa, in 2014 from where it spread to neighbouring Sierra Leone and Liberia, killing an estimated 11 000 people by April 2016.63Tuberculosis is caused by the bacterium https://biorender.com/). The innate immune system is the host’s first-line defence against invading pathogens, while adaptive immune responses are triggered by the host’s immune recognition controls.64 With the help of molecular patterns that are pathogen-related, the innate immune system recognises repetitive evolutionarily conserved molecules on pathogens by using germline-encoded pattern recognition receptors such as C-type lectin receptors, Toll-like receptors, nucleotide-binding oligomerisation domain-like receptors, and retinoic acid-inducible gene I-like receptors.65 The immune cells that mediate innate immune defences such as natural killer cells, complement proteins, and phagocytic cells like monocytes, macrophages, and neutrophils do not have effector mechanisms that induce immunological memory.66The human body protects itself from microbial infections through the immune system made up of innate and adaptive arms that are not only linked but consist of an extraordinarily diverse compilation of cells  or bacterial and fungal complex biomolecules , the immune cells undergo metabolic alteration or epigenetic reprogramming.69 These changes, described as ‘trained immunity’, elicit an elevated response when challenged afterwards by the first trigger or different unrelated organisms or molecules through T- or B-cell-independent responses, leading to increased production of inflammatory mediators.72 Unlike the conventional, more precise, epitope-dependent adaptive immune memory that is mediated by lymphocytes, the control of trained immunity is facilitated by a unique mechanism that is not very specific and lasts only for a short while.73 Nevertheless, both fulfil the same major task of eliciting a faster and more robust response that destroys the pathogens and improves the survival of the host. Trained immunity could be beneficially applied to develop improved vaccines75 and limit the adverse effects of inflammatory diseases.76Adaptive immunity comprises cell-mediated and humoral immunity, which have a wider and fine-tuned range of recognition because of exposure to variable antigens. The unique traits of the adaptive immune system are pathogen-specific immunological memory, immune effector functions, tolerance, regulation of host immune homeostasis, and increased production of inflammatory mediators.77 The mild pattern of infection in many patients may be due to an exposure-related cross-immunity to other endemic common cold coronaviruses.78 These viruses cause mild self-limiting respiratory infections and circulate widely in the human population where globally, more than 90% are seropositive for at least three of the common cold coronaviruses.79 There has been evidence that supports the likelihood that circulating memory B-cells and neutralising antibodies developed to one type of coronavirus may cross-react with other members of the coronavirus family.78 Emerging data from studies conducted in unexposed donors from different geographical locations revealed that 20% – 50% had lymphocytes with significant reactivity to pools of SARS-CoV-2 antigen peptides.81 There is also speculation that the SARS-CoV-2-specific T-cells in unexposed individuals originated from the memory T-cells obtained from contact with common cold coronaviruses.83 In a study conducted in Germany, the highest T-cell reactivity occurred against a pool of SARS-CoV-2 spike peptides that are homologous to common cold coronavirus spike proteins.24 The occurrence of SARS-CoV-2 pre-existing primed T-cells and neutralising antibodies acquired through previous exposure to endemic coronaviruses could slow down disease transmission and limit the number of cases and mortality.84 Individuals with a high level of pre-existing CD4+ T-cells with SARS-CoV-2 recognition memory may elicit a faster and more robust immune response upon exposure, thus limiting the severity of the disease. In such individuals, T follicular helper CD4+ T-cells have a memory that could potentially enhance the antibody-neutralising response against SARS-CoV-2. The memory of CD4+ and CD8+ T-cells might also enhance direct antiviral immunity in the lungs and nasopharynx early after exposure, consistent with previous knowledge that CD4+ T-cells in the lungs have antiviral activity against the associated SARS-CoV85 and that memory CD8+ T-cells protect against viral infections.COVID-19 infections are often asymptomatic or mildly symptomatic but may be severe, mostly among vulnerable patients, presenting as acute respiratory distress.86 In separate studies conducted with samples from Gabon , Nigeria, Ghana, Benin (West Africa), Tanzania (East Africa), and Zambia (Southern Africa), the pre-existing immunity was high against the SARS-CoV-2 N and, to a lower extent, S proteins,90 which suggests that high SARS-CoV-2 pre-existing immunity is widespread in Africa. In addition, previous studies conducted in France, England, and the United States have also reported low levels of pre-existing SARS-CoV-2 S protein cross-reactive antibodies in uninfected individuals.93A recent study that used samples collected before the pandemic in Africa, Europe, and South and North America showed the occurrence of pre-existing humoral immunity against the spike (S) and nucleocapsid (N) proteins of SARS‑CoV‑2. Although antibodies specific to the SARS-CoV-2 S and N proteins were not common in all populations, the prevalence of N-specific antibodies was higher in the two African study locations, Gabon and Senegal, than in Europe and South and North America.88 due to the wide distribution of the common human coronaviruses throughout the globe.14 In this regard, samples collected from Africa, Europe, and South Africa were used in a recent serological study to demonstrate the existence of antibodies that cross-react against the N protein of common human coronaviruses, but their presence did not show any correlation with the SARS-CoV-2 N protein cross-reactive antibodies.88 This suggests the possibility that the high cross-reactive immunity reported by the African population is being driven by other main contributors besides the common human coronaviruses. High seropositivity against SARS-CoV-2 N in samples collected before the pandemic could also be an indication of the circulation of other coronaviruses that have not yet been recognised. The limited number of cases and mortality due to SARS-CoV-2 infection in Africa may be attributed to a high cross-reactive immunity background as observed in sera from African populations. Large studies are needed to measure and demonstrate the correlation between pre-existing immunity, prospective infection and disease severity as a way to define the possible function of pre-existing T-cell memory in SARS-CoV-2 infection.Although the reason for the underlying SARS-CoV-2 high seropositivity in African populations has not been established, some have postulated that the immune system could be stimulated to develop cross-reactive antibodies against SARS-CoV-2 as a result of infections with the common human coronaviruses94 Besides trained immunity, the cells of the innate immune system could also reach a status of immune tolerance or hypo-responsiveness, wherein there is a decrease in the production of pro-inflammatory mediators when these cells encounter secondary heterologous stimuli.72 For example, epidemiological data, as well as in vivo and in vitro studies with BCG vaccines conducted among humans and in murine-derived peripheral blood mononuclear cells subjected to immune-stimulatory agents such as lipopolysaccharide, β-glucan, and flagellin, provided evidence of either increased or decreased inflammatory reaction to secondary stimuli that corroborates the concept of trained immunity and immune tolerance.72 In addition, animal studies have shown that immunisation with the BCG vaccine can protect against subsequent infections by Candida albicans and M. tuberculosis.96 Immunisation with the BCG vaccine can also protect against a controlled version of human yellow fever infection97 or malaria98 by augmenting the pro-inflammatory activity of monocytes. It is reasonable to argue that the non-specific nature of this type of cross-protection is not consistent with mediation by adaptive immunity, but it demonstrates that the host defence can develop innate-like immune adaptation mechanisms.In addition to adaptive immunity-mediated cross-immunity, trained immunity and immune tolerance mediated by the innate immune system could also considerably modify the clinical spectrum and mortality of COVID-19 infection. Trained immunity is the memory characteristic in the innate immune system of vertebrates that elicits an increased reaction to secondary infections or sterile activation of inflammation.M. tuberculosis by exposing individuals to a live, attenuated strain of Mycobacterium bovis. Apart from the partial and possibly variable immunity the BCG vaccine offers against tuberculosis, it also protects in an off-target manner against other non‑tuberculosis infectious diseases.99 For example, BCG vaccination-induced trained immunity offers protection against infections with RNA and DNA viruses such as herpes and influenza, reduces yellow fever viraemia, and protects against respiratory tract infections.103 Data from a randomised, double-blind, clinical trial conducted recently showed that there was a reduction in the incidence of respiratory tract infections in BCG-vaccinated patients 65 years and older.104 This protection against a variety of pathogens is achieved through trained immunity.97Several countries have used the BCG vaccine to protect against tuberculosis caused by 105 or up to 50–60 years as shown in a BCG vaccine trial among American Indians and Alaska Natives.106 However, data from these and some other studies have also shown that BCG vaccination-induced protection could also wane over time.107 Apart from its reported prospect to enhance innate immunity, preliminary epidemiological analyses have also shown a reduction in COVID-19 severity in countries that are implementing the policy of widespread BCG vaccination.108 These observations suggest that the BCG vaccine may protect against SARS-CoV-2 infection. Consequently, in 2020, BCG vaccination was proposed as a strategy to prevent infection and combat the COVID‑19 outbreak.108Most countries with a high incidence of tuberculosis have implemented a comprehensive BCG vaccination policy that encourages children to get the BCG vaccine in early childhood. The protection offered by the BCG vaccine may persist for up to 30–40 years after inoculation as described in a study in Norway,111 many of the assessments do not consider likely confounding factors such as testing rate, socio-economic factors, and co-morbidities. One epidemiological study that corrected for confounding variables, particularly the testing rate, did not find evidence that the overall BCG vaccination policy correlated with the spread of SARS-CoV-2 and its associated mortality.112 Available information as of 2020 on the BCG Atlas (www.bcgatlas.org) showed that all African countries except South Sudan have an existing universal BCG vaccination policy. If it is proven that BCG vaccination does indeed offer protection against SARS-CoV-2, the relatively low number of cases and deaths could be attributed to the long-standing universal BCG vaccination policy in African countries rather than under-reporting or diagnostic limitations.Although BCG vaccination is linked to a reduction in the number of COVID-19 cases and mortality,113 Trained immunity and immune tolerance have been demonstrated in studies that focused on circulating mononuclear cells with a short lifespan, as well as progenitor stem cells of the bone marrow, epithelial cells, and resident tissue macrophages with long lifespans.71 This may imply that the host’s innate immune response to different pathogens could last longer.The determinant of whether the innate immune system exhibits either trained immunity or immune tolerance is not known but is thought to be related to the dose and duration of the primary trigger.Trained immunity and immune tolerance may have significant implications for COVID-19 infection. In sub-Saharan Africa, vast portions of the population live under unfavourable conditions such as crowded and unhygienic environments, leading to recurrent infections with bacteria, viruses, and eukaryotic parasites, and thus making it possible to attain immune tolerance against a novel pathogen like SARS-CoV-2. Immune tolerance could prevent the innate immune system from reaching a hyper-inflammatory state or a ‘cytokine storm’, which is generally associated with the ultimate fatality of COVID-19 disease.People living in developed countries with better sanitary conditions are less exposed to multiple pathogens during their lifetime and thus less likely to attain immune tolerance. This may be partially responsible for the clinical spectrum and the heightened vulnerability to novel pathogens like SARS-CoV-2 observed in such populations.114 These variants pose a greater risk to public health because they may be more transmissible or produce more severe disease, escape immune response, cause diagnostic or treatment failure, or reduce the efficacy of vaccines.115 The five main variants of concern are: B.1.1.7 (Alpha), first described in the United Kingdom; B.1.351 (Beta), first reported in South Africa; P.1 (Gamma), originated from Brazil; B.1.617.2 (Delta), first described in India; and B.1.1.529 (Omicron), first detected in South Africa. The Alpha, Beta, and Gamma variants share the N501Y mutation, which likely makes them more transmissible. The E484K and K417N mutations displayed by both the Beta and Gamma variants decrease the binding of neutralising antibodies, thus causing partial immune escape, favouring reinfections, and reducing the in vitro efficacy of some antibody therapies or vaccines.117 The frequent emergence of these variants globally challenges the use of herd immunity as an approach to managing the pandemic and has been responsible for new waves of the pandemic and thousands of deaths globally.114 The Alpha variant was quickly replaced by the highly contagious Delta variant, which was soon outcompeted by the Omicron variant to become the dominant circulating variant.Against the background of increasing population immunity due to vaccination and high rates of natural infection, many new variants of SARS-CoV-2 have emerged and have been designated by the WHO as either variants of concern or variants of interest.118 The Omicron variant has been detected in 77 countries as of December 2021.120 Although several aspects of the behaviour of the Omicron variant and how it will impact the course of the pandemic have not been well defined, current data indicate that immunisation with existing vaccines could reduce the risk of serious illness, hospitalisation, and death.121 However, in vitro studies indicate that the neutralisation efficacy of vaccine sera against Omicron reduces greatly compared to the previously circulating Delta variant.122 If more data confirm that the Omicron variant indeed produces milder forms of the disease, it may suggest a trend that the pandemic is on its way out but the world may have to come to terms with living with the virus. It may require occasional vaccination like in the case of the flu virus to prevent infection. The background of previous exposure to multiple pathogens in the African population may provide a further advantage in conferring protection against the severe form of the disease.The Omicron variant is more highly transmissible than the other variants, being able to infect 3–6 times more people than the Delta variant, including individuals immune to the other variants.122 While the emergence of new diseases may not have a major repercussion on African population dynamics, it may have serious economic and social consequences. When these diseases emerge, we can draw on scientific advances and previous experience, especially with HIV/AIDS and Ebola, to quickly contain them. Africa might be able to withstand some of these emerging diseases owing to enhanced immunity due to prior exposure to numerous pathogens and extensive vaccination programmes within the continent.In Africa, the prospect that new diseases may emerge is high due to the existing burden of infectious diseases and conducive environmental conditions such as high population growth, rapid economic development, increased exploitation of previously untapped natural resources, and increasing interactions between humans and wildlife. A prompt and coordinated global health response would be required to quickly control outbreaks either at the local or regional level as exemplified by the global response to the 2014 Ebola epidemic.This review has shown that pre-existing immunity against SARS-CoV-2 is widespread in Africa and higher than in Western countries. This immunity may be related to previous exposure to endemic coronaviruses or other multiple pathogens and could have been responsible for the reduced disease transmission and the limited number of cases and mortality recorded in African countries. The relatively low number of cases and deaths in Africa could be attributed to the activation of innate immune-mediated trained immunity or immune tolerance due to frequent exposure to multiple pathogens and the impact of long-standing universal BCG vaccination policies in many African countries rather than under-reporting or diagnostic limitations.


Salt-induced structural transformation of charged hybrid surfactant/polymer micelles formed by potassium oleate and poly(4-vinylpyridine) was investigated by cryo-TEM, SANS with contrast variation, DLS, and 2D NOESY. Cryo-TEM data show, that at small salt concentration beads-on-string aggregates on polymer chains are formed. KCl induces the transformation of those aggregates into rods, which is due to the screening of the electrostatic repulsion between similarly charged beads by added salt. In a certain range of salt concentration, the beads-on-string aggregates coexist with the rodlike ones. In the presence of polymer, the sphere-to-rod transition occurs at higher salt concentration than in pure surfactant system indicating that hydrophobic polymer favors the spherical packing of potassium oleate molecules. The size of micelles was estimated by DLS. The rods that are formed in the hybrid system are much shorter than those in polymer-free surfactant solution suggesting the stabilization of the semi-spherical endcaps of the rods by embedded polymer. 2D NOESY data evidence that in the spherical aggregates the polymer penetrates deep into the core, whereas in tighter packed rodlike aggregates it is located mainly at core/corona interface. According to SANS with contrast variation, inside the rodlike aggregates the polymer adopts more compact coil conformation than in the beads-on-string aggregates. Such adaptive self-assembled polymer-surfactant nanoparticles with water-insoluble polymer are very promising for various applications including drag reduction at transportation of fluids. Amphiphilic molecules of surfactants in aqueous solutions are able to form molecular self-assemblies called micelles ,2,3,4. IThe rodlike micelles of surfactants are widely used as drag reducing additives to diminish the resistance loss in the conveying flow, while petroleum, natural gas and water are transported in the pipeline networks ,19. Non-By now, mainly complexes of ionic surfactants with charged and uncharged water-soluble polymers were studied ,33,34,35As to the complexation of ionic surfactants with oppositely charged polyelectrolytes, it can give a variety of structures including beads-on-string aggregates ,39,40,41An important factor affecting the structure and properties of polymer-surfactant complexes is the concentration of salt in the solution. In the case of the complexation of ionic surfactants with oppositely charged polyelectrolytes salt hinders the complex formation, since it weakens the electrostatic attraction between the components and decreases the gain in translational entropy of counterions released from the polyelectrolyte .In the case of complexes of ionic surfactants with uncharged water-soluble polymers the addition of salt can affect the structure of the complexes and the characteristic concentrations of the complex formation . For exaMuch less is known about the effect of salt on the complexes, containing uncharged water-insoluble polymer. On an example of poly(4-vinylpyridine) (P4VP)/potassium oleate complexes it was shown that in the absence of salt they represent beads-on-string structures , whereasThe present paper is aimed at the investigation of the structural transformations of the complexes of uncharged water-insoluble polymer P4VP with ionic surfactant potassium oleate that were induced by the addition of inorganic salt KCl. Only complexes saturated with polymer were studied. The studies were performed by several complementary techniques: SANS with contrast variation to reveal the structure of the aggregates as a whole and of their components, cryo-TEM to visualize the aggregates, DLS to estimate the size of micelles, 2D NOESY spectroscopy to determine the location of polymer in the complex. The differences in the structure evolution of polymer-surfactant complexes upon addition of salt in comparison with the polymer-free micelles were revealed, which permitted to identify the effect of polymer in this process. The revealed structural transitions offer useful information for designing new polymer/surfactant materials for nanotechnological and drag reduction  applicatAnionic surfactant potassium oleate ; hydrophobic polymer P4VP , inorganic salt potassium chloride  were used as received. Ethanol  was employed for preliminary solubilization of P4VP. Water purified with Millipore Milli-Q system was used as a solvent. For SANS and 2D NOESY experiments, deuterium oxide  was taken instead of water.Aqueous solutions of polymer-free micelles of surfactant were prepared by mixing appropriate amounts of potassium oleate and potassium chloride with purified water. Concentration of potassium oleate was fixed at 0.094 M. The concentrations of KCl were equal to 67, 110 and 160 mM. The pH of the solutions was adjusted to 11 with KOH. Solutions of polymer-free micelles were stirred for 1 day by magnetic stirrer.For preparation of the solutions of polymer-surfactant complexes a stock solution of P4VP in ethanol (5 wt%) was used. Appropriate amount of the stock solution was added to a vial and left at room temperature. After full evaporation of ethanol, a polymer film was formed at the bottom of the vial. To prepare the solutions of polymer-surfactant complexes in the presence of different concentrations of KCl, the corresponding solutions of polymer-free micelles were poured into the vial containing the polymer film. Then the solutions were stirred for 1 day to accelerate the solubilization of P4VP into the micelles.Note that maximum amount of polymer solubilized in the micelles depended on the concentration of salt in the solutions. The maximum content of P4VP in the complexes was determined in the following way. The concentration of P4VP was gradually increased until the appearance of a precipitate. The largest concentration of P4VP in the solution without precipitate was considered as the concentration of polymer in the saturated polymer-surfactant complex. For 67, 110 and 160 mM KCl solutions, this concentration was equal to 0.14, 0.12 and 0.08 mol of monomer units of P4VP/L (monomol/L), respectively. Further experiments were carried out with the complexes saturated with P4VP.Cryo-TEM specimens in the native conditions were prepared with the Vitrobot (FEI)  by apply2. To obtain deconvolved and denoised images Warp software [Cryo-TEM study was conducted using Titan Krios (ThermoFisher Scientific) equipped with Falcon 2 direct electron detector (ThermoFisher Scientific) and Image Corrector  operated at 300 kV. Images were obtained using EPU software (ThermoFisher Scientific) at 37,000× magnification with 1.72 Å pixel size, defocus range 2–4 µm and total dose ~50 e/Åsoftware  was appl−6 Å−2 for D2O, −0.56 × 10−6 Å−2 for H2O, 0.15 × 10−6 Å−2 for potassium oleate and 2 × 10−6 Å−2 for P4VP. The contrast matching technique was applied to get scattering curves separately from potassium oleate molecules and from P4VP chains in the polymer-surfactant complexes. To match the scattering from P4VP the mixture containing 37 vol.% of D2O and 63 vol.% of H2O was used as a solvent. The mixture of 90 vol.% of D2O and 10 vol.% of H2O was used for matching the scattering from molecules of potassium oleate. The temperature was kept at 20 °C.SANS data was obtained at the YuMO instrument  , the cryo-TEM image becomes quite different b. At the0 mM KCl,Q regions. Such behaviour is typical to the solutions of ionic surfactants containing spherical micelles [Q region of the curves [SANS curves of the polymer-free micellar solutions with different concentrations of added KCl are demonstrated in micelles ,57,58,59e curves . Howevere curves ,16,59. TI(Q) in the medium-Q region changes from 0 to −1 that is inherent to the scattering from WLMs [Q values increases with increasing concentration of KCl from 110 to 160 mM. It may be related to the growth of WLMs in length [Q region, the scattering curves perfectly overlap  indicate that in polymer-free micellar solutions of potassium oleate increasing salt concentration induces the transition of spherical to rodlike micelles and then to branched worms. Now let us consider how the hydrophobic polymer P4VP solubilized in the micelles affects the structural transformations of the micelles triggered by added salt.At low salt concentration (67 mM KCl), the structure of polymer-surfactant complexes (beads-on-string) differs essentially from that of the polymer-free surfactant aggregates (spheres and short rods) despite the same potassium oleate content in both systems. This can be explained by the fact that at weak screening of the repulsion between the charged headgroups by salt the incorporation of polymer inside the micelles pushes the surfactant heads farther from each other thereby favoring the spherical geometry of micelles. Since a single bead cannot accommodate the whole macromolecule the beads-on-string structure appears where several beads are formed on the same polymer chain.The value of hydrodynamic radius of the beads obtained by DLS see  coincideAt higher salt concentration (160 mM KCl), in polymer-surfactant system, the beads-on-string structures coexist with hybrid rodlike micelles of different lengths b. To theIn polymer-free solution, the coexistence of spherical and rodlike micelles is also observed, but at much lower salt concentration (67 mM KCl) than in the polymer-surfactant system. So, P4VP shifts the sphere-to-rod transition of potassium oleate micelles towards higher salinity. It could be explained by the stabilization of the spherical micelles by embedded polymer.At very high salt concentration (800 mM KCl) in P4VP/potassium oleate system, only short hybrid rodlike micelles with wide size distribution are observed . Most pr2O/63 vol.% D2O), are demonstrated in Q ranges the scattering curves I(Q) behave similarly to those of polymer-free micelles I was used to obtain the fractal dimensions ca.40 nm . TherefoConsequently, enhanced screening of the repulsion of headgroups by salt ions in P4VP/potassium oleate complexes not only causes the sphere-to-rod transition of surfactant micelles, but also affects their shape on a large scale. This fact can be confirmed by the corresponding zoomed-in cryo-TEM micrographs .To sum up, the addition of KCl to the solutions of P4VP/potassium oleate complexes provides the transformation of beads-on-string structures into the short rodlike hybrid micelles. Since hydrophobic P4VP favors the spherical packing of potassium oleate molecules in the micelles, the transformation in polymer-containing solutions occurs at higher concentration of KCl as compared to the polymer-free surfactant solutions. Furthermore, enhanced screening influences the large-scale shape of the complexes, inducing the transition from highly extended to Gaussian coil conformation.Q region, the scattering intensity varies as I~Q−1. According to the model of persistent polymer chain, the power-law of −1 results from scattering of persistence units [Q region of the curves can be attributed to the scattering from the whole polymer molecule, and the slope k in this region , the hybrid micelles represent beads-on-string structures, where few spherical beads are connected with each other by short polymeric strings. At the same conditions, in polymer-free system, a mixture of spherical and rodlike micelles is formed. It indicates that polymer stabilizes spherical surfactant aggregates (no rods are detected in the hybrid system). At higher salt content (160 mM KCl), an enhanced screening of electrostatic repulsion induces the formation of short rods in the hybrid system and of very long branched WLMs in the polymer-free system. It suggests that semi-spherical end-caps are stabilized by polymer which prevents the growth of micelles in length and their branching. Thus, hydrophobic polymer solubilized within the surfactant micelles shifts the sphere-to-rod transition to higher salt content, makes the rodlike structures shorter and eliminates their branching.By SANS with contrast variation we are the first to demonstrate that at low salt content, the beads-on-string complexes, containing water-insoluble polymer, are aligned like rigid rods at a scale comparable to the size of the whole macromolecule, probably due to the electrostatic repulsion between similarly charged beads. At higher salt concentrations, the screening of electrostatic repulsion lets the complexes adopt a Gaussian coil conformation. Polymer inside the complexes remains always in the coil state, but increasing salt concentration makes the coils more compact. According to 2D NOESY data, this is accompanied by the relocation of polymer inside the micelles. At low salt content, when the micelles are spherical the polymer penetrates deep into the micellar core, whereas at higher salt content, when the micelles are rodlike, the polymer is localized preferentially at core/corona interface. The obtained results give insight to the salt-responsive behavior of new self-assembled polymer-surfactant complexes based on water-insoluble polymer that are promising as stable smart nanoparticles for various applications including drag reduction.


Management guidelines include follow-up until skeletal maturity. Little is known about adherence to this recommendation. This study aimed to investigate loss to long-term spine clinic follow-up (LTFU) among children with spinal TB at a tertiary hospital in the Western Cape Province, South Africa.st December 2020.this retrospective cohort study included all children diagnosed with spinal TB at Tygerberg Hospital between January 2012 and December 2015. Spine clinic follow-up was investigated for five years following diagnosis. Relevant surgical interventions and re-presentation were evaluated until 31thirty-two children, median age 6 years (range 1-14 years), were diagnosed with spinal TB and intended for spine clinic follow-up. Twenty-seven (84%) children were LTFU within five years of diagnosis with 16 (50%) LTFU within 10.5 months. Among children in follow-up, one child had further surgery for progression of deformity two years from diagnosis and one child had further surgery for new-onset neurological deficit eight years from diagnosis.most children with spinal TB did not receive the recommended follow-up until skeletal maturity. Without further data on these children, the clinical significance of this LTFU could not be evaluated. Further studies are needed to investigate sequelae during skeletal maturation in the context of current management for paediatric spinal TB. Mycobacterium tuberculosis to one or more spinal vertebrae and involves gradual destruction of the bony tissue, often accompanied by the development of a cold abscess [Tuberculosis (TB) of the spine accounts for approximately 1-4% of all TB cases and is the most common form of musculoskeletal TB [ abscess . With pr abscess .Spinal TB in children is of particular concern due to an increased risk of severe deformity -8. In thet al. [The outcome of this uneven growth differs between individuals, as demonstrated by Rajasekaran  and Moonet al. . For exaet al. . Progreset al. . Furtheret al. , 12-14. et al. , 14.Risk factors for severe final deformity in children with spinal TB include age ≤ 10 years, vertebral body loss of > 1-1.5, pre-treatment deformity > 30° and cervicothoracic and thoracolumbar junction lesions . Risk ofSouth Africa has one of the highest burdens of TB worldwide and treatment of children with spinal TB is a common occurrence at certain public sector hospitals, including those in the Western Cape Province , 16. StaUpon the completion of TB treatment, it is standard protocol that children healed of spinal TB continue in annual follow-up at the hospital´s spine clinic until skeletal maturity. However, little is known about long-term follow-up for these children within our setting; whether it takes place and what further interventions may occur. Therefore, the main aim of this study was to investigate loss to long-term spine clinic follow-up among children diagnosed with spinal TB at a tertiary hospital in the Western Cape, South Africa. Secondary aims of the study were to investigate re-presentation to the spine clinic following initial LTFU as well as any relevant surgical interventions during the follow-up period.Study design: this retrospective cohort study took place at Tygerberg Hospital, a major tertiary hospital in the City of Cape Town, South Africa. Tygerberg Hospital serves approximately half of the Western Cape Province of South Africa, a catchment area of > 3.4 million individuals. Follow-up at the hospital´s outpatient spine clinic was investigated for five years following spinal TB diagnosis. Furthermore, any relevant surgical interventions during follow-up as well as any re-presentation at the spine clinic after initial loss to follow-up (LTFU) was evaluated up until 31st December 2020.Patients: all patients 0-14 years of age who were diagnosed with spinal TB at the hospital between 1st January 2012 and 31st December 2015 were systematically included in the study. These patients were part of a larger study investigating the burden of spinal TB within the province and further details of case identification and diagnosis have been described elsewhere [Data collection: clinical and demographic data were extracted from medical records, whereas follow-up data was collated from a combination of medical records, the electronic hospital patient administration system and a dataset requested from the Western Cape Department of Health. Follow-up data included the duration of TB treatment, which was determined according to the following hierarchy of sources: medical records, the electronic TB register or pharmacy records.Outcome measure: patients who failed to attend a scheduled spine clinic appointment and had no other spine clinic visits for > 1 year after the missed appointment were considered LTFU. Patients who had consistently attended the spine clinic and for whom the next appointment was scheduled after the end of the five-year study period were considered retained in follow-up. For patients who were LTFU or who completed follow-up within five years, the duration of follow-up was calculated from the date of the diagnostic magnetic resonance imaging (MRI) scan to the date of the last spine clinic appointment attended.Data analysis: categorical data were reported as frequencies and percentages; continuous data were tested for normal distribution and reported as a mean and standard deviation (SD) or median and interquartile range (IQR), as appropriate. Length of orthopaedic follow-up and the outcome LTFU were used to conduct a Kaplan-Meier survival analysis; the effect of selected baseline variables on LTFU was investigated by using a log-rank test to compare survival curves between subgroups of patients. The association between length of follow-up within 12 months of diagnosis and treatment duration was investigated using a Spearman´s correlation and reported with 95% Confidence Intervals (CI). All statistical analyses were performed in Graphpad Prism  with significance accepted at p ≤ 0.05.Funding sources: TM was supported by a postdoctoral fellowship from the Vice Dean of Research Faculty of Medicine and Health Sciences, Stellenbosch University. This party was not involved in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit the article for publication.Ethical considerations: this study was approved by the health research ethics committee of Stellenbosch University, South Africa (reference number N15/07/062). A waiver of informed consent was granted by the ethics committee due to the retrospective nature of the study.Patient characteristics, diagnosis and management: thirty-four children were diagnosed with spinal TB during the study period. Two patients were excluded from the analysis as they were managed by other specialist clinics at the hospital. Details of the remaining 32 children are shown in Loss to follow-up: overall, 27 (84%) children were LTFU from the spine clinic within five years of diagnosis. Of these 27 children, 19 (70%) were ≤ 10 years old at the time of LTFU, 20 (74%) had thoracic or thoracolumbar vertebrae affected, 14 (52%) had > 2 spine-at-risk signs at the time of diagnosis and 16 (59%) had received corrective surgery. The Kaplan-Meier curve representing retention in follow-up showed a rapid decline in the first months following diagnosis with 11 (34%) children LTFU within 4 months and 16 (50%) LTFU within 10.5 months  children, from the electronic TB register in 5 (16%) children and from pharmacy records in 4 (13%) children. Children treated for drug-susceptible and drug-resistant spinal TB completed a median of 10 months (IQR 7-12 months) and 18 months (IQR 14-20 months) of TB treatment, respectively. Among the 27 children treated for drug-susceptible TB, 11 (41%) children completed < 9 months of TB treatment, of whom 6 (22%) completed ≤ 6 months of treatment. Among the five children with drug-resistant TB, one child appeared to receive only 9 months of treatment compared to ≥ 18 months for the other children. There was a significant association between length of follow-up within 12 months of diagnosis and TB treatment duration among children with drug-susceptible TB  but not when including those with drug-resistant TB .Re-presentation following LTFU: of the 27 children who were LTFU, only two re-presented at the spine clinic in the period up until 31 December 2020. The first child was a male patient diagnosed with spinal TB at 11 years old. He underwent a T6-7 costotransversectomy before being LTFU after approximately 18 months. However, he was seen at the spinal clinic again approximately 3.5 years later, then aged 16 years, following a referral from community health services, who had noted his spinal deformity. It was determined that there had been no progression of deformity during the time LTFU and the patient remained neurologically intact. He was referred for an MRI to further assess the existing deformity but was LTFU a second time before this took place.The second child was a female patient diagnosed with spinal TB involving T4-T10 at 3 years old. She had severe kyphotic deformity with neurological deficit and underwent several weeks in a halo-pelvic frame and subsequent anterior reconstruction. Despite this severe presentation, she was LTFU 13 months after diagnosis. She re-presented to the clinic 6 years later, then aged 10 years, although what prompted this return is unclear. While she still had a severe spinal deformity, there had been no progression during the time of LTFU. Furthermore, her neurological status had improved from Frankel Grade A to Frankel Grade C. The patient was scheduled to attend further spine clinic follow-up beyond the study follow-up period.Surgical intervention during follow-up: two children received surgical intervention during follow-up due to spinal TB sequelae. One child was a 5-year-old boy who presented with three spine-at-risk signs and neurological deficit at diagnosis; he underwent an anterior debridement, strut graft and instrumented fusion of T4-T8. He was initially retained in spine clinic follow-up and after approximately two years, a slight progression of kyphosis was detected. He was readmitted for a T4-T9 posterior onlay fusion and thereafter completed a further 20 months of spine clinic follow-up before being LTFU at 9 years old. At this stage, he was neurologically intact with a stable Cobb angle of 26°.The second child was a 1-year-old girl who presented with severe spinal deformity, three spine-at-risk signs and Frankel Grade B at the time of diagnosis and subsequently underwent a posterior onlay fusion of T8-T11. One year later, there was a progression of her kyphotic deformity and persistent spinal cord compromise. To assist with deformity correction, she underwent halo-pelvic traction followed by anterior fusion. She continued to attend spine clinic follow-up and although a mild loss in deformity correction was noted, it was not deemed severe enough to warrant action at that stage. Approximately eight years after diagnosis, then aged 9 years old, she developed new-onset neurological fallout despite no further progression of deformity. The patient then underwent her third surgery in the form of a vertebral column resection. She remained in spine clinic follow-up at the end of the evaluation period.Annual monitoring until skeletal maturity for children with healed spinal TB is standard procedure in our tertiary hospital spine unit. However, the current study found that it was largely absent in practice - 84% of children diagnosed with spinal TB were LTFU within five years. Two children required further surgical intervention while in follow-up and two different children re-presented to the clinic several years after initial LTFU with no progression of deformity. With so few children remaining in follow-up during the healed phase and no further data on the majority of those LTFU, the clinical significance of LTFU before skeletal maturity could not be determined.The pattern of LTFU showed rapid attrition from the spine clinic within the first months from diagnosis, with half of the children LTFU within 10.5 months and an ongoing decline in follow-up over the remainder of the study period. This pattern suggests that most children were LTFU during or shortly after the active phase of the disease— before annual monitoring in the healed phase had even commenced. Over and above monitoring in the healed phase, this early LTFU is of special concern as deformity may continue to progress until healing of the spine lesion occurs in children managed conservatively . FurtherMore than a third of children with drug-susceptible spinal TB did not complete the conventional ≥ 9 months of treatment and shorter follow-up was associated with shorter treatment duration. There remains uncertainty in the minimum treatment duration required to prevent recurrence in spinal TB  and a shThe study provided very limited data with which to assess the importance of monitoring children with healed spinal TB until skeletal maturity. A high proportion of those LTFU had risk factors that would support the need for long-term monitoring, such as age < 10 years and thoracic or thoraco-lumbar vertebrae affected. It is possible that some of these children may yet develop late-onset sequelae or may be living with sequelae without re-presentation at the hospital. However, without further data on these children, this remains speculation. Further studies are needed to investigate sequelae during skeletal maturation in the context of current management practices for paediatric spinal TB.No progression of deformity in the two children who re-presented to the clinic after several years suggests that, in some cases, annual monitoring may remain a precaution only for long periods. Conversely, two other children did require further surgery and retention in follow-up was valuable for timeously identifying the need for intervention. Both of these children were ≤ 5 years old at diagnosis and surgical correction is particularly challenging in this age group due to the large spinal growth potential and the small, flexible nature of the spinal structures. Although the initial surgeries that each child received were based on the best clinical understanding at the time, they did not accomplish the circumferential fusion that has since become the preferred practice in most cases , 23. In Although the study found a high prevalence of LTFU, the retrospective nature of the study limited the investigation of factors that might explain this phenomenon. Children who underwent initial corrective surgery were found to have significantly slower LTFU. These children likely represent those with more severe disease at diagnosis and, potentially, more sequelae during and after the active phase of the disease. Thus, attending follow-up may have been deemed of greater importance for these children than among those with less severe disease. This pattern is consistent with previous findings in adults whereby less severe clinical presentation was associated with LTFU , 26. NotIt is likely that other factors explaining LTFU are not available in medical records. Children were typically from a low socio-economic setting and financial constraints may have been a significant hindrance to attending appointments. Furthermore, the finding that many children LTFU had no spine clinic appointment booked suggests that administrative factors also play a role. When a patient´s next appointment fell in the next calendar year, caregivers were sometimes asked to call the clinic the following year for an appointment date, rather than being issued with a date before leaving the hospital. This approach carries a high risk of the caregiver forgetting to call or being unable to afford the cost of the call. Addressing this problem constitutes one of the more readily modifiable factors that may contribute to LTFU in our particular setting.Limitations: our study had a number of limitations. Firstly, the retrospective study design meant that the investigation was limited to information routinely available in medical records and was obliged to rely on a hierarchy of evidence when assessing TB treatment duration. Secondly, the study had a relatively small sample size, despite including patients over a period of 4 years in a high TB burden setting. This modest sample is intrinsic to the relatively low absolute numbers of children with spinal TB. Finally, as a single centre experience, the specific LTFU findings have limited generalizability to other settings. Nevertheless, the study has relevance for similar settings in that it raises awareness of the considerations and knowledge gaps related to long-term follow-up for children with spinal TB.Most children with spinal TB did not receive the recommended follow-up until skeletal maturity. Without further data on these children, the clinical significance of this LTFU could not be evaluated. Further studies are needed to investigate sequelae during skeletal maturation in the context of current management for paediatric spinal TB. Such studies may help to identify clinical subgroups that would benefit most from long-term monitoring and could possibly be prioritized for follow-up in a resource-limited setting. Prospective studies, including qualitative research, may also be beneficial to aid understanding of LTFU and how this might be addressed. Finally, de-centralization of follow-up to local hospitals and increased caregiver education regarding the purpose of follow-up may also play a role in optimizing long-term outcomes for children healed of spinal TB.Children with healed spinal tuberculosis are at risk of progressive spinal deformity as they grow to skeletal maturity;Severe spinal deformity is associated with significant morbidity and is complex and risky to correct;Annual monitoring until skeletal maturity in children with healed spinal tuberculosis may facilitate early detection and treatment of sequelae.In a resource-limited setting, many children may be lost to follow up and fail to receive the recommended monitoring until skeletal maturity;Some children may require further surgical intervention during follow-up, even though they received corrective surgery at diagnosis;There may be a delay of several years before the onset of sequelae in children with healed spinal tuberculosis.


Background: Peer-led approaches improve satisfaction with participation, wheelchair skills and wheelchair use self-efficacy in adults, but the evidence is limited in children. This pilot study aimed to explore the influence of community-based, peer-led, group wheelchair training program  on satisfaction with participation (primary outcome), wheelchair skills, and wheelchair use self-efficacy in children and adolescents with cerebral palsy and spina bifida. Methods: A single group pre-post design was used. Invitations were shared online and diffused by clinicians and advocacy and provider groups to recruit a convenience sample of eight pediatric wheelchair users. Participants completed the Seating To Go program in groups that were facilitated by adult wheelchair users. Satisfaction with participation (Wheelchair Outcome Measure-Young People), wheelchair skills (Wheelchair Skills Test), wheelchair use self-efficacy , and perceived wheelchair skills capacity  were evaluated before and after the Seating To Go program. Descriptive statistics and nonparametric longitudinal data analysis were conducted to explore changes in all outcomes from baseline to post-intervention. Results: Pediatric wheelchair users (ranging in age from 5 to 15 years) and their parents reported statistically significant improvements in satisfaction with participation. The improvements in wheelchair skills and wheelchair confidence were also statistically significant, but not the parents’ perception of their children’s wheelchair skills. Conclusions: A community-based peer-led approach to wheelchair skills training seems promising for improving wheelchair outcomes in pediatric wheelchair users. Further controlled studies with larger samples are warranted. Approximately 2 of 1000 children are born with cerebral palsy ,4. TheseFindings from a cross-sectional study revealed that the majority of pediatric wheelchair users (PWCUs) with cerebral palsy did not acquire basic manual wheelchair skills ,14. MoreEvidence from two meta-analyses confirmed the effectiveness of wheelchair skills training for improving wheelchair skills in various adult populations  ,19. The Training is recognized as one of eight essential steps of wheelchair service provision . HoweverPeer-led training, wherein experienced wheelchair users are trained to teach others wheelchair skills through sharing of experiential knowledge, represents one possible solution to expand the delivery of wheelchair skills training into the community ,32. AlthIn 2013, Seating To Go, a private community-based wheelchair assessment and training service in New-Zealand, implemented an evidence-based peer-led wheelchair skills training program for PWCUs. However, the influence of the program on PWCUs’ mobility and participation has not yet been documented. Given the limited knowledge about peer-led approaches to wheelchair skills training in pediatrics, the primary objective of this pilot study was to explore the influence of the Seating To Go program on satisfaction with participation among PWCUs with cerebral palsy and spina bifida. The secondary objectives were to explore the influence of the program on wheelchair skills capacity, parent perceived wheelchair skills capacity, and wheelchair use self-efficacy. The hypotheses were that there would be a statistically significant improvement in satisfaction with participation after the Seating To Go program and increases in all secondary outcomes.A pilot-study using a single group pre-post design was conducted in Hamilton and Auckland, New Zealand. Ethics approval was obtained through the Ethics, Quality Assurance and Safety  of the Ministry of Health New Zealand (#19/NTB/41). All parents provided informed consent and PWCUs provided assent to participate in the study.Eight PWCUs were recruited using a convenience sampling method. Invitations to attend the Seating To Go free training sessions were shared online , distributed by clinicians from Seating To Go, and were diffused by advocacy and provider groups . PMWUs who registered for the Seating To Go program and who fit the inclusion criteria were invited to participate in the study. Children and teenagers ranging from 4 to 15 years of age, with cerebral palsy or spina bifida, who had their own manual and power wheelchair, could roll forward without assistance for at least 10 m and were able to follow two-steps instructions  were included. PMWUs were excluded if they had a medical condition or were anticipated to receive a medical procedure during the time of the study that contraindicated training  or were attending or planned to attend other wheelchair skills training.The Seating To Go program consisted of two, two-hour sessions of wheelchair skills training facilitated by three adult peer-trainers who had between one and eight years of experience with wheelchair skills training. Peer-trainers taught PWCUs how to perform indoor and community wheelchair skills required for everyday life activities  using the motor learning principles and wheelchair skills techniques of the Wheelchair Skills Program (WSP) version 5.0 as a guide . A wheelEach skills training sessions occurred as follows: (1) a short introduction; (2) a five-minute review of spotter techniques; (3) a 10-min warm-up activity ; (4) 60During the 60-min skills practice, the peer-trainers explained the skill and provided a demonstration of the appropriate way to perform it. Multi steps skills, that consist of a sequence of sub-skills, were broken down into small components to facilitate the learning  . MoreoveParents completed a sociodemographic and wheelchair use questionnaire on the phone with the Seating To Go wheelchair skills coordinator at baseline . The questionnaire included the following information: age, sex, ethnicity, diagnosis, type of wheelchair and driving method, number of hours per day in a wheelchair, contexts in which the wheelchair is used, number of years using a wheelchair and the current wheelchair, previous wheelchair skills training, accidents in the past year and use of other mobility devices.Outcome measures were collected at baseline  and post-intervention  for comparison. All outcomes were collected with young people in person in Seating To Go premises in Auckland or Hamilton by wheelchair and seating therapists, except the subjective wheelchair skills capacity that was measured on the phone with parents by the wheelchair skills coordinator. All testers were employees of Seating To Go or Auckland District Health Board who attended a three-hour workshop on the administration and scoring of the assessments led by study investigators or study  or study coordinator (DW).Satisfaction with participation. The Wheelchair Outcome Measure for Young People (WhOM-YP) was used to evaluate PWCUs’s and parents’ satisfaction with participation in meaningful activities that require the use of a wheelchair [eelchair . The WhOeelchair . Perceiveelchair . Child-reelchair .Objective Wheelchair Skills Capacity. Children’s wheelchair skills capacity was measured using a modified Wheelchair Skills Test—Version 5.0 (WST) for manual or power wheelchair use [hair use ,42,43. Thair use . Two modhair use .Subjective Wheelchair Skills Capacity. The Wheelchair Skills Test-Questionnaire (WST-Q), a self-report tool, was used to assess parent-perceived manual (33 skills) or power (25 skills) wheelchair skills capacity [capacity ,45. Scorcapacity .Wheelchair use Self-efficacy. The pediatric versions of the Wheelchair Use Confidence Scales for manual (WheelCon-M) and power (Wheelcon-P) wheelchair users were used to evaluate PWCUs’ belief in their ability to use their wheelchair in a variety of challenging situations [tuations ,47. The tuations ,47. Resptuations ,47. The n = 5 to 10) [p < 0.05.Descriptive statistics , frequency, percentage) were calculated to describe the sample and to summarize all outcomes. A nonparametric longitudinal data (nparLD) analysis was used to explore differences between baseline and post-intervention for the primary outcome (WhOM) and all secondary outcomes . Given the same overall construct was being measured by each tool, the calculated total scores for WST, WST-Q and WheelCon were merged for manual and power wheelchair outcomes. The nparLD test is robust regarding outliers and for non-parametric distributions of ordinal or non-ordinal data that may change overtime, thus has been recommended for small and variable samples size  , The npa5 to 10) . Intentin = 7), with diagnoses of spina bifida (n = 4) or cerebral palsy (n = 4) and used a manual (n = 4) or power (n = 4) wheelchair. Previous experience using the current wheelchair ranged from 1 month to 6 years. Both mothers (n = 7) and fathers (n = 1) completed the WST-Q. There were no adverse events during testing or training. Further sociodemographic information is presented in Eight PWCUs (and a parent) completed the study between June and December 2019. Children ranged in age from 5 to 15 years (median (IQR) = 10 (2.5) years), were mostly male  and reported statistically significant improvement in confidence . However, parents’ perception of their children’s wheelchair skills capacity did not improve significantly . Children demonstrated statistically significant differences from baseline to post-intervention in wheelchair skills capacity , whereas the parents’ goals were more focused on the child’s function  and participation in domestic tasks . This is not surprising given that PWCUs with cerebral palsy and spina bifida have less opportunities to participate in activities outside of the home with similar-aged peers and parents commonly experience a high burden from caring for their child with special needs ,55,56. FThe change in wheelchair skills capacity from baseline to post-intervention  was larger than parent-perceived improvements. This may be explained by several factors. For example, children and adolescents may be able to perform the skills in training and evaluation contexts, which are more reassuring given the presence of peers and spotters. However, they may not use their newly acquired skills in everyday life situations, which tend to be more challenging and less predictable. Another possible explanation may be that the post-intervention evaluations of the wheelchair skills test questionnaire were completed by the parents within one to 21 days after training, thus the parents may have not yet had the opportunity to observe any improvement in the child’s skills. Moreover, parents of children and adolescents with physical disabilities express challenges gauging the appropriate amount of assistance for ensuring success and safety while encouraging independence . This maPWCUs in this study had a higher relative improvement in wheelchair skills capacity after receiving the Seating To Go program (32%) compared to a group of PWCUs who received group-based wheelchair skills training in an institutional setting (14%) . This diStudies have suggested the potential power of peer and group approaches, respectively for providing mentorship and support for people with disability, including wheelchair users ,58,59,60Although the small sample size of mostly males limits generalizability, subgroup analyses , and exploration of confounding factors , additional knowledge about community-based pediatric wheelchair skills training contributes to the dearth of evidence. Manual and power wheelchairs outcomes were merged for analyses. Although the physical and cognitive demands of power and manual wheelchair skills may vary, all tools have been validated for measuring the same constructs  ,46,47,62The Seating To Go program had a positive influence on satisfaction with participation, wheelchair skills capacity and wheelchair use confidence in a sample of eight pediatric manual and power wheelchair users. This study contributes to expand knowledge on the use of peer-led approaches for ensuring a continuum of wheelchair skills services from rehabilitation institutions to the community. The next steps may involve conducting a randomized control trial with PWCUs to evaluate the effectiveness of the Seating To Go program for improving satisfaction with participation and other mobility outcomes.