Sickle cell disease (SCD) is a chronic hematologic disease associated with increased morbidity and mortality. Hemoglobinopathies are the most prevalent genetic disease globally, and SCD is estimated to affect 0.7% of Ugandan. The disease may adversely impact on the quality of life of sickle cell patients. This study aimed to evaluate the health related quality of life (HRoL) of adolescents with SCD.This was a mixed-methods study of adolescents with sickle cell disease and their caretakers living in Kampala city, Uganda. All children aged 8–17 years with homozygous sickle cell disease attending the sickle cell clinic at Mulago Hospital during the study period were included in this study. Participants completed the PedsQL™ generic core scales parent-proxy and child self-report questionnaire during a routine clinic visit. HRQoL was the primary outcome measured. Socio-demographics and disease related data were obtained through personal interview with caretakers and reviewing patients’ medical records. Mean scores were used for HRQoL and linear regression for associated factors.p < 0.001). As assessed by caretakers, physical HRQoL scores were negatively associated with pain about-10.02 CI (p = 0.033), whereas it was positively associated with Pneumococcal vaccine with the score of 28.43 CI (p < 0.001) as assessed by adolescents and 31.37CI (p < 0.001) by caretakers. Pneumococcal vaccination impacted positively the psychosocial functioning with a score of 8.67CI  (p = 0.018) as assessed by children and 15.94 CI (p = 0.003) as assessed by the caretakers.Of the 140 adolescents with SCD included in the study, 40% were male. A total of 95 adolescents (68%) were between the age of 8–12 years with a mean age of 14.25 years. The physical function was assessed slightly higher by adolescents with a mean score of57.5 ± 20.3 compare to caretakers with 52.8 ± 22.1(This study highlighted that pain was negatively associated with both physical and psychosocial functioning; whereas getting Pneumococcal vaccine was positively associated with both physical and psychosocial functioning as reported by children and caretakers. Sickle cell disease (SCD) is a group of inherited red blood cell disorders characterized by the presence of abnormal hemoglobin where there is a substitution of hydrophilic glutamic acid by hydrophobic Valine at position 6 of beta-globin chain. The clinical manifestations are diverse and may include vaso-occlusive, hematological and infectious crisis. Sickle cell disease is a serious global health issue with an estimated 400,000 neonates born with the disease each year and about 300,000 of these with sickle cell anemia . The greHealth Related Quality of life (HRQoL) is defined as an extent to which one’s usual or expected physical, emotion and social well-being is affected by a medical condition or its treatment . PreviouA number of disease-related factors have been found to affect quality of life (QoL) in children with SCD such as vulnerable socioeconomic status, age of the patient by physical manifestations of SCD notably in the form of abnormal sexual and physical development, type of pathology, family support, beliefs and values . The cliThis study represents the first investigation of SCD patients’ QoL of adolescent population in Uganda. We hypothesized that SCD in adolescents was associated with low HRQoL and demographic and disease factors might have an impact on HRQoL. In this study we aimed to describe the health-related QoL of adolescents with SCD, and examine explanatory predictors that might be associated with QoL.: All children aged 8–17 years with homozygous sickle cell disease attending the sickle cell clinic at Mulago Hospital during the study period. Exclusion criteria were: a history of a previous chronic disease ; any concomitant serious medical problems (other than those secondary to SCD). A consecutive sampling was done. This process was continued until sample size was reached. Many of our participants were visiting for acute pain and few were in their usual state of health.The present study used a mixed-methods study design with quantitative and qualitative methods that included adolescents with SCD and their caretakers, randomly selected from the Outpatient sickle cell clinic at Mulago National Referral Hospital in Kampala, Uganda from February to April 2018.The study sample consisted of children with SCD aged 8–17 years and their caretakers. Inclusion criteriaAn interviewer administered questionnaire was used to obtain information on the participants and the caregiver’s socio-demographic characteristics  and history of blood transfusion for the last one year. Physical examination findings such as vital signs , presence or absence of complications of the disease, such as infection, dehydration and pain, were recorded. The time period reviewed for pain and fever was information within the 30 days. Fever was defined as axillary temperature equal or more than 38 C (101.3 F). Pain: constant cry restlessness, facial expression and verbal report of pain. Anthropometric measurements were taken. Malaria (positive blood slide), hemoglobin electrophoresis, treatment such as Hydroxyurea, Folic acid and Pneumococcal vaccine were obtained by reviewing patients’ medical records.The acute version of pediatric quality of life questionnaire with 7 days recall was separately administered to parent proxy and children by the research assistant to determine Health Related Quality of Life . The PedQualitative data were collected using focus group discussions (FGDs) with adolescents and caretakers. Two FGDs discussions were conducted with children and 2 FGDs with their caretakers/parents. For each category one FGD was with those who assessed low quality of life and another one with those who assessed high quality of life for children with SCD. Each FGD had 7–10 participants.The quantitative data were entered into Epidata version 3.1 and exported to STATA for analysis. For the qualitative component, audio recorded discussions were transcribed and analyzed manually using content thematic approach which involved grouping data according to study themes and sub-themes with guidance from the qualitative researcher on the team. Direct quotations from study participants were used in the presentation of the study findings.p-values (p) less than 5% were considered as the significantly associated factors. In multiple linear regression analyses, p < 0.05 was considered significant.Descriptive statistics such as means and standard deviation (mean ± SD) were used to describe the quantitative variables. Frequencies (N) and percentages (%) were used to describe categorical variables. At univariate and multivariate analysis stage a multiple linear regression model was fit with HRQoL as the dependent variables and only independent variables with Ethical approval was obtained from Makerere University College of Health Sciences, School of Medicine Research and Ethics Committee and the National Council for Science and Technology. Informed consent for data collection and publication was obtained from parents/caretakers, and informed assent from children.Of the 140 children with SCD included in the study who were all homozygous SS, 40% were male. A total of 95 children (68%) were between the ages of 8–12 years (Table p = 0.12) and physical functioning (p = 0.14) Table As shown in Table g p = 0.1 Table 4.p < 0.001) in both adolescents and caretakers respectively. Having gotten more than 3 blood transfusions impacted positively on the physical functioning as assessed by adolescents and caretakers (p = 0.002) at multivariate analysis .“Pain and coming to the hospital for care stops me from going to school…” (FGD adolescents with low HRQoL).With regard to qualitative results, all adolescents and their caretakers in group discussions mentioned missing school due to frequent pain and hospital visits which translated into poor school performance as key factors negatively affecting the HRQoL for adolescents with SCD. Many adolescents talked about how their academic performance had declined due to SCD as they explained:Most of the adolescents and their caretakers reported stigma to be a major factor affecting HRQoL for adolescents with SCD. Some adolescents felt they had been stigmatized on the basis of how they looked due to SCD and were often excluded from playing with other children as one of them explained: “For me children at school abuse me. They say that I have eyes like for a wild cat because they are yellow. They tell me that they can’t play with me because they don’t want to associate with sicklers. This makes me feel bad and I cry” (FGD with adolescents with low HRQoL).Another adolescent added: “Even me they don’t like me at school. They say that I should take away my sickle cell yet when they want to learn something they come and ask me but for me I tell them the answers but even in class I perform better than them” (FGD caretakers of adolescents with low HRQoL).“For me I can’t participate in sports yet I like football, I do not participate in sports and games because I cannot compete with other children so we lose our skill and yet we always love our hobbies” (FGD adolescents with low HRQoL).“For me I can’t do heavy work because I am weak. Sometimes I faint and my mother doesn’t allow me to carry heavy things. When I do heavy work I start feeling pain and sometimes they end up bringing me to the hospital” (FGD adolescents with low HRQoL).Most adolescents reported that SCD limits them from taking part in community and household activities as well as play which negatively affected their quality of life.SCD has been widely researched on in sub-Saharan Africa, but there is a paucity of studies on the impact of the disease on the school, emotional, physical, and social well-being of the patients despite the high prevalence of SCD in sub-Saharan Africa. In this study, we found that the HRQoL was low in physical functioning, emotional functioning and school functioning as assessed by adolescents, and was also low in physical functioning and school functioning as assessed by the caretakers.The physical and emotional functioning are lower than the study done by Joanita et al. ; this coQualitative results also indicated that SCD affects negatively school functioning. In addition most of the study participants in FGDs reported stigma to be a factor affecting their emotional HRQoL.. Most adolescents reported having a problems with their physical functioning such as in the form of being unable to play and do home activities due to SCD and related complications.Our findings on low HRQoL among children with SCD are consistent with those of previous studies –13. The Panepinto et al. used the PedsQL™ 4.0 and concluded an impaired HRQoL in children with SCD, even after considering the potential effect of family income on HRQoL. In another study, Dale et al. found an overall HRQoL lower in children with SCD and their parent than in healthy children and their parents, a finding that matched our results .Gender influences HRQoL of adolescents with SCD. A previous study using the Child Health Questionnaire found that children /reported statistically significant gender differences in HRQoL with diminished scores on most functioning scales for female subjects . Gender Adolescents with SCD who are taking Hydroxyurea therapy report better physical functioning than those not taking the medication. This is consistent with the study done by Coutney D. et al were they found a better physical functioning in children taking Hydroxyurea .The studStroke influence the HRQoL of adolescents with sickle cell disease. The study done by Chia Yeh Chou also found that, the psychosocial and physical factors impacted stroke-specific HRQoL . The chaAdolescents in pain rated their HRQoL as low in school functioning. Anie found that pain experience accounted for12.3% of hospital and general practice service use, independently of age, sex, number of SCD complications and hemoglobin levels . We founA study done in US by S. K.Ballas et al. found pain as a predictor of quality of life QoL outcomes, in physical and social functioning . AnotherAt multivariate analysis in this study, more than 3 blood transfusions were associated with increase in physical functioning of adolescents with SCD Table . ReducinIt was found in this study that Hydroxyurea influenced positively the physical functioning as reported by caretakers; but it was not statistically significant. Treatment of SCD patients with Hydroxyurea improves their clinical and hematological characteristics. Thornburg et al. in Carolina also found that Children with SCD who were taking Hydroxyurea therapy reported better physical functioning and overall HRQoL than those not taking the medication despite disease severity and older age . Tshilolp < 0.001 as assessed by adolescents and caretakers. The study done by Thornburg et al. in Carolina found no differences between groups of patients on Hydroxyurea and those not on Hydroxyurea in the psychosocial summary score or its individual domains [With regard to psychosocial functioning, we found a negative impact of Hydroxyurea on psychosocial domain with a  domains . The lac domains . In the  domains . In the  domains .Pneumococcal vaccination was associated with increase in physical functioning and psychosocial functioning as assessed by both adolescents and their caretakers Tables  and 6. Pp < 0.001) and the proportion of patients with ≥1 hospitalization per year  in patients who got Pneumococcal vaccine and Hydroxyurea [In a study done by Gayatri et al. concerning initial outcomes of a comprehensive care model for sickle cell disease among a tribal population in rural western India there was a reduction in the proportion of patients with ≥3 pain crises per year (35.4 to 9.8%, roxyurea .In this study, we enrolled patients who were only in the Sickle clinics of the Mulago National Referral Hospital, Kampala, Uganda, which may have resulted in a bias towards enrolling patients who are severely sick. We extracted data on some variables from clinic records some of which had missing values. We did a consecutive sampling. This process was continued until sample size was reached; many of our participants were visiting for acute pain and few were in their usual state of health. That might have impacted HRQoL. We also had lack of qualitative validation of the translated version.This study was done to assess the HRQoL of adolescents with SCD as assessed by adolescents and their caretakers. We found that adolescents with SCD have low HRQoL as assessed by participants. The mean physical, emotional, school and psychosocial functioning were below the cut-off as assessed by adolescents with SCD.We found also that Pneumococcal vaccination and getting more than 3 blood transfusions were positively associated with physical functioning. Taking Hydroxyurea, having stroke and getting more than 3 blood transfusions negatively influenced the psychosocial functioning of adolescents with SCD. Adolescents with SCD experienced regular pain, problems with growth, stigma and missed school which negatively affected their HRQoL. We recommend further studies with long term prospective to identifying causal association of above reported factors.


Spontaneous coronary artery dissection (SCAD) is a common cause of acute coronary syndrome particularly in younger women. Good outcomes with conservative management are generally expected. However, there is uncertainty of how to manage symptomatic or unstable patients. Percutaneous angioplasty may propagate the subintimal hematoma compromising coronary blood flow. Cutting balloon angioplasty can relieve the compressive effects of a propagated subintimal hematoma in SCAD. Spontaneous coronary artery dissection (SCAD) is increasingly being recognized as an important and common cause of acute coronary syndrome. While the etiology and pathophysiology are not fully elucidated, SCAD appears to have a particular preponderance for younger women who are among the lowest risk of atherosclerotic heart disease. Due to the paucity of research data in this patient population, treatment strategies have largely been based on case reports, small cohort studies, and expert opinion.Contemporary recommendations generally support good outcomes with conservative management in patients who are clinically stable Among patients with SCAD who undergo percutaneous coronary interventions (PCIs), short‐ and long‐term outcomes are unclear and propagation of subintimal hematoma has been reported in up to 57% of patients A 51‐year‐old woman with no previous cardiac history and no cardiac risk factors presented to a rural emergency department with severe, nonradiating, substernal chest pain. An electrocardiogram revealed nonspecific ST/T wave changes in the anterolateral leads with a moderately elevated troponin level. The patient was diagnosed and managed as a non‐ST‐segment myocardial infarction (NSTEMI). Initial coronary angiography revealed angiographic evidence of left main (LM) SCAD with a 50% luminal stenosis Fig.  with impThe decision was made to proceed with PCI of the LM‐LAD‐LCx bifurcation. After a brief deliberation, a simultaneous kissing stent (SKS) technique was chosen as the bifurcation strategy. While not optimal, given the acute worsening of the patient's clinical status, the complexity of the coronary disease  and the multistep nature of more evidence‐based bifurcation techniques  which would risk rewiring a false lumen, a SKS approach was felt to best balance the risks and benefits in this case. The SKS technique involved deployment of two 4 × 28 mm Xience Xpedition drug‐eluting stents  into the LM‐LAD and LM‐LCX Fig. B and C. Spontaneous coronary artery dissection can present unique challenges when percutaneous intervention is undertaken. Among these is subintimal hematoma propagation with resultant distal vessel compromise as illustrated in our case. The use of a cutting balloon in the treatment of SCAD has been reported previously We herein describe a novel use of a cutting balloon to treat compressive subintimal hematoma after stenting of LM SCAD. We used a 1:1 balloon‐to‐artery diameter ratio, and inflation was only to nominal pressure. The length of the balloon used was 10 mm to minimize the extent of intimal damage, and only one inflation was required to completely resolve a longer segment of compressive hematoma.While we and others In summary, the use of cutting balloons in patients with SCAD requiring angioplasty can be performed safely with resultant improvement in antegrade blood flow in vessels compromised by subintimal hematoma propagation but needs to be considered with caution.Clinical Case Reports.BM: involved in preparing and writing the manuscript. MV: involved in the angioplasty and revision of the manuscript. Both authors approved the final version of the case report for submission to BM has no disclosures pertinent to the content of this manuscript. MV received speaking fees and proctoring honoria from Boston Scientific and Abbott Vascular.


For each group, hierarchical regression was used to investigate whether the total sum of compliance points, Overall Compliance, predicted reductions in depression and in condition‐specific symptoms. Also, in each subgroup, it was tested whether working with specific treatment components, Specific Compliance, predicted reduction of the targeted symptoms. Overall Compliance predicted 15% of the reduction in depression symptoms. For participants with worry, panic, social anxiety, stress, or insomnia, Overall Compliance also predicted symptom reductions in that specific condition. Specific Compliance predicted reduction in the targeted symptoms for participants with social anxiety, stress, and insomnia. Specific Compliance with stress and insomnia components also predicted reductions in depression. Our results strengthen the importance of compliance in internet‐based treatments. Because compliance with stress and insomnia components was particularly important for broad symptom reductions, these conditions should not be ignored when treating patients with co‐morbid symptoms.The objective of this study was to explore the effects of treatment compliance in a guided individually tailored internet‐based treatment (TAIL) in relation to depression and co‐morbid symptoms. Compliance with the homework in the different treatment components in TAIL, each aimed at a specific condition, was rated for 207 participants by independent assessors. Six subgroups ( TAILguided individually tailored internet‐based treatment for depressionMADRS‐SMontgomery–Åsberg Depression Rating Scale – Self‐ratedPSWQPenn State Worry QuestionnairePDSS‐SRPanic Disorder Severity Scale – Self reportLSAS‐SRLiebowitz Social Anxiety Scale – Self‐RatedPSS‐10Perceived Stress Scale – 10 itemISIInsomnia Severity IndexMPIMultidimensional Pain InventoryTreatment compliance was rated in an individually tailored internet treatment.Overall Compliance predicted symptom reductions in all conditions, except pain.Specific Compliance predicted reductions in social anxiety, stress, and insomnia.Compliance with stress and insomnia components predicted reductions in depression.11.1In traditional face‐to‐face psychological treatment, there is a wealth of research on treatment compliance, and there is evidence of a correlation between compliance with homework assignments and symptom reductions , as a predictor of improvement. One well‐established predictor of effect in internet‐based interventions is quantitative adherence to the treatment programme. Quantitative adherence has been defined both as how much of the intervention material the individuals were exposed to  was compared with physical exercise and with treatment as usual in primary care. For a description of the TAIL treatment, please see Table Because TAIL includes a wide range of different components targeting specific conditions and symptoms and is used for a co‐morbid patient group, it constitutes a very good base for exploring the effects that both component‐specific compliance and overall compliance have on treatment outcome.1.5The aim of this study was to explore if compliance with all homework components in the TAIL treatment  and compliance with the condition‐specific homework components (Specific Compliance) predict reductions in condition‐specific symptoms and in symptoms of depression, in patients with depression and co‐occurring conditions who participated in the internet treatment arm of the REGASSA study.2The REGASSA study was approved by the Regional Ethics Review Board in Stockholm, Sweden (2010/1779‐31/4).2.1n = 317) of the participants in the trial were randomized to the internet treatment TAIL, and the 207 of these with post‐treatment self‐report measures were included in the current study. Please see Figure Recruitment to the REGASSA study was done at primary care level in six county councils in Sweden between February 2011 and December 2012. Adults over 18 years who had depressive symptoms, defined as having at least 10 points on the Patient Health Questionnaire  the participant's self‐report that they recognized disorder‐specific symptoms described in a brief text that was distributed during the beginning of the treatment, (b) the participant's rating of the severity of these symptoms, and (c) the participant's score on the symptom scales that they filled out pretreatment . Correlational analyses were used to explore if Overall and Specific Compliance predicted reductions on the symptom scales. Two hierarchical stepwise regression models were used for the whole group, with post‐treatment MADRS‐S as the dependent variable, and for each subgroup, with the condition‐specific symptom scale at post‐treatment as the dependent variable. In the first model, we explored Overall Compliance. Step 1 included the pretreatment symptom measure as a control, and in Step 2, the Overall Compliance measure was added. Step 3 constituted a sensitivity analysis that adjusted for age and sex. In the second model, compliance with specific homework components was explored in four steps. Step 1 was again to control for symptom score at pretreatment, and Step 2 added Specific Compliance as a predictor. Step 3 adjusted for Non‐Specific Compliance including compliance to generic and condition‐unrelated homework components. Step 4 was a sensitivity analysis that adjusted for age and sex. In order to investigate whether the specific homework components, aimed at the specific co‐occurring conditions, had an impact on the primary measure depressive symptoms, we also used the same second model in each subgroup again but with MADRS‐S as the dependent variable.3Descriptive statistics of the whole group and the six subgroups can be found in Table 3.1The Overall Compliance scores predicted reductions in depression and explained 15% of the outcome variance Table . In the 3.2p = 0.025). However, adjusting for Non‐Specific Compliance and demographic variables did not change the results that Specific Compliance was a strong and significant predictor of outcome for social anxiety, stress, and insomnia. When using the same model but with the depression scale as the dependent variable  but also in symptoms of worry (3%), panic (18%), social anxiety (20%), stress (19%), and insomnia (21%), for participants with these co‐occurring conditions. The association of Overall Compliance and the reduction in pain symptoms were not significant. These associations are, except for worry and pain, large in comparison with results from homework compliance studies in face‐to‐face treatment where a meta‐analysis reported an average association of 7% explained variance (Mausbach et al., For participants with social anxiety, stress, and insomnia, compliance with the specific homework components targeting those conditions was also associated with reductions in the corresponding symptoms. On the other hand, Specific Compliance did not predict specific reductions for participants with worry and panic. For participants with pain, neither Overall nor Specific Compliance predicted reductions in pain symptoms. Compliance with specific homework components targeting stress and insomnia also predicted reductions on depression, for participants with these conditions.4.1These exploratory findings are accompanied by some interpretations for each condition below.4.1.1For participants with worry, pretreatment score was the strongest predictor of outcome, but there was also a small effect of Overall Compliance with the treatment material. Because Specific Compliance with the components targeting worry did not seem to have an effect, this result suggests that a transdiagnostic approach, including homework components such as activity scheduling and challenging avoidance behaviours, could be enough for participants with worry.4.1.2For participants with panic disorder symptoms, the results indicated a relatively large dose–response effect of complying to the homework components, but this did not have to be to the panic disorder‐specific components. Earlier research has suggested that good‐quality exposure is a strong predictor of outcome in psychological treatment for panic disorder (Cammin‐Nowak et al., 4.1.3For social anxiety, as for panic, the results suggested a possibly large dose–response relationship of compliance and outcome, but for social anxiety, it was complying to the specific social anxiety homework components that predicted a better outcome. This suggests that individuals with social anxiety may benefit from working with components that are clearly aimed at social anxiety, such as shifting focus outwards and exposure to social situations. However, because the subgroup of participants with social anxiety in this study was small, these results also have to be interpreted with caution.4.1.4Participants with high levels of stress seemed to benefit from Overall Compliance, but the largest predictive effects on outcome were from compliance with specific stress homework components, for example, planned recovery and exposure to not doing things perfectly. Compliance with the stress components was also important for the reduction of depression symptoms for these patients. Stressed participants in primary care may often receive treatment for depression and may thus not benefit from, or recognize themselves in, a treatment lacking content specifically about stress. A high percentage of participants in the study suffered from depression with high amounts of stress, and it seems that they benefited extra from content tailored to help them handle their stress‐related problems.4.1.5Also for participants with insomnia, the results indicated a large dose–response relationship of Overall Compliance and symptom reduction. When separating Specific from Non‐Specific Compliance, both seemed to predict outcome. The finding that Specific Compliance was a significant predictor strengthens earlier research suggesting that specific insomnia treatment components, such as sleep restriction and stimulus control, are important in treatment of insomnia (Kaldo et al., 4.1.6The participants with pain did not improve much on pain symptoms, but they did experience reductions in other symptoms, such as depression. Participants with higher initial levels of pain did not reduce their pain regardless of complying to the pain treatment modules. This suggests that the pain components in the current treatment were without effects on pain and that these participants may instead need a dedicated pain treatment, which have shown small to moderate effects in previous studies (Buhrman, Gordh, & Andersson, 4.2This study has some strengths and limitations. Limitations include that we performed explorative analyses based on correlational data. The absence of an experimental control makes these findings preliminary. The possible existence of confounding variables, influencing both compliance and outcome, cannot be completely controlled for in a correlational design. It is partly managed by controlling for Non‐Specific Compliance when analysing Specific Compliance and by some sensitivity analyses, but this still cannot compensate for the lack of an experimental design. There is however previous research on face‐to‐face psychological treatments suggesting that homework compliance causes reductions in depression rather than the other way around (Burns & Spangler, The number of participants with panic disorder symptoms and social anxiety was small, resulting in low statistical power for these conditions. However, the strong statistical effect of compliance to specific social anxiety components seems to be an indicator of a substantial association in that case.Another limitation, seen in the analysis of compliance with the panic disorder components, is that the components in the introductory modules contained homework assignments, for example, exposure therapy and challenging negative thoughts, that could also have a condition‐specific effect and thus leave less room for further improvement for the following disorder‐specific modules. This sometimes unclear separation of components calls for caution for some interpretations. For example, the result that specific modules for panic disorder did not further improve panic disorder cannot be interpreted as evidence that panic‐specific components are not useful.The strengths of this study include that we created and employed a measure of treatment compliance where both quantity and quality of compliance were systematically rated, as recommended by Kazantzis et al. , and mos4.3These findings support the idea that qualitative and quantitative measures of compliance with internet‐based treatment are of value, especially for individually tailored treatments, when one wishes to assess the maximum efficacy of different treatment components. Future studies could examine compliance with specific treatment components in a randomized setting to investigate the direction of causality. Future studies could also examine how other concepts, such as treatment credibility, or how much time and effort the participants put into the treatment, relate to treatment compliance.5Overall homework compliance was important for outcome in this individually tailored internet‐based treatment for depression in a sample with high levels of co‐occurring conditions. Compliance with specific homework components for social anxiety, stress, and insomnia was important to alleviate the symptoms of these specific conditions. Compliance with homework components for stress and insomnia was important also for reducing depression levels, for participants who presented with these conditions. Because a high degree of participants in the study suffered from stress and insomnia, and these participants benefited extra from complying to the stress‐specific and insomnia‐specific components, the inclusion of tailored content for these conditions should probably be a priority when choosing components to include in interventions for patients with high levels of co‐morbid symptoms.We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.Table S1. Missing data analysis.Click here for additional data file.Guide to compliance scoringClick here for additional data file.


Malfunctions in ER‐related processes are responsible for the genesis and progression of many diseases, such as heart failure, cancer, neurodegeneration and metabolic disorders. To fulfill many of its vital functions, the ER relies on a sufficient energy supply in the form of adenosine‐5′‐triphosphate (ATP), the main cellular energy source. Despite landmark discoveries and clarification of the functional principles of ER‐resident proteins and key ER‐related processes, the mechanism underlying ER ATP transport remains somewhat enigmatic. Here we summarize ER‐related ATP‐consuming processes and outline our knowledge about the nature and function of the ER energy supply.The endoplasmic reticulum (ER) is a functionally and morphologically complex cellular organelle largely responsible for a variety of crucial functions, including protein folding, maturation and degradation. Furthermore, the ER plays an essential role in lipid biosynthesis, dynamic Ca I.et al., via membrane contact sites further promotes this interconnection. A well‐studied and remarkable example for interorganellar contact sites is provided by the so‐called mitochondria‐associated ER membranes (MAMs), which form a distinct subdomain of the smooth ER dedicated to the interaction with mitochondria. MAMs are thereby engaged in a variety of processes ranging from Ca2+ signalling and lipid metabolism to mitochondrial fission and inflammasome formation Protein synthesis requires energy and the demand for ATP as an energy source is most pronounced at the transcription stage. However, the first ER‐related step of protein synthesis, which is the translation of membrane and secretory proteins by ER‐bound ribosomes, is driven by GTP hydrolysis. Therefore the ER ATP pool is not affected significantly by protein synthesis until the translocation stage.et al., et al., et al., et al., et al., et al., et al., et al., et al., via its so‐called ATPase cycle  protein  assumes control. As another protein with chaperone function, UGGT is capable of sensing the folding state of a protein. When they are not correctly folded, UGGT attaches a glucose residue to the N‐terminal glycan. This enables the protein's reassociation with calnexin or calreticulin and thus, ideally, its correct refolding. The repeated association of calnexin or calreticulin and UGGT is described as the calnexin/calreticulin cycle and contributes crucially to glycoprotein folding  complex, usually in a co‐translational manner  molecules are produced  anchor ‐coated vesicles which are transported to the Golgi et al., The accumulation of un‐ or misfolded proteins as a result of disturbing events like mutant protein expression, nutrient deprivation, viral infection or intoxication commonly causes ER stress, which is sensed by a specialized ER‐associated machinery. Misfolded proteins may be refolded or, if that fails, exported into the cytosol by a mechanism called retrotranslocation, followed by their degradation by the proteasome. This process, referred to as ERAD, together with the UPR, are considered to be the most important mechanisms of protein quality control activated upon ER stress (Bukau (a)Several signalling pathways are responsible for the surveillance of the ER folding machinery. The components of these pathways sense the accumulation of un‐ or misfolded proteins and induce a series of different response mechanisms which increase the ER folding capacity and are collectively described as the UPR  of a basic leucine zipper (b‐Zip) transcription factor  et al., et al., et al., et al., et al., et al., Besides the UPR signalling events, which contribute to the restoration of regular protein folding, the removal of accumulated protein waste itself is accomplished by another set of processes involved in ER protein control, ERAD et al., et al., et al., et al., et al., et al., et al., via activation of the c‐Jun N‐terminal kinases (JNK) pathway   2+ store determines its importance for all processes dependent on Ca2+ signalling, like protein folding by the Ca2+‐dependent chaperones calreticulin and calnexin or the induction of UPR and apoptosis as described above and reviewed by Krebs, Agellon & Michalak  or ryanodine receptor channels. A potential regulatory connection of cellular ATP levels to ER Ca2+ homeostasis is that the InsP3 receptor channel‐opening probability is increased by high cytosolic ATP concentrations The ER can be considered a highly productive compartment as it is crucially involved in the supply of the cell with various molecular components such as proteins, as described above. In addition, lipid synthesis also takes place largely in the (smooth) ER, including the synthesis of phospholipids Vance,  and isopvia the so‐called Kennedy pathway et al. . In the ER they are trimmed by ER aminopeptidases 1 and 2 (ERAP1/2) and then loaded onto MHC‐I molecules by the peptide‐loading complex (PLC)  family  molecules on the cell surface is a vital mechanism of the immune system In the early 1990s, promising results regarding the transport of ATP into the ER formed the foundation for the elucidation of the underlying mechanism. Clairmont, Maio & Hirschberg  demonstret al. in vivo was linked to ADP export, implying the existence of an antiport mechanism. Protein extracts of the proteoliposome membrane were then purified with hydroxyapatite, commonly used for the purification of membrane carrier proteins. The purified fractions were again reconstituted into proteoliposomes to measure ATP transport. The fractions capable of ATP transport were repeatedly subfractionated by chromatography on hydroxyapatite and affinity chromatography with ATP agarose, resulting in a distinct enrichment of the specific ATP transport activity. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS‐PAGE) analysis of the ultimate fraction allowed the identification of a single protein, namely the phosphatidylinositide phosphatase Sac1, which was thus considered to be involved in ATP transport. It was already known that the SAC1 gene was genetically linked with ACT1 P because it cannot be dephosphorylated P gradient from the Golgi to the ER by dephosphorylating PI(4)P in the ER. This gradient may then be used in a counter‐transport mechanism to move sterols against their gradient from the ER to the Golgi  , has been connected to ATP transport and membrane trafficking et al.  forming a monophyletic group with mitochondrial ATP/ADP carriers (AACs)  reporter system and the results showed elevated promotor activities in tissues with highly active ER metabolism, such as pollen, root tips and seeds. Leroch et al. et al., 2+ levels in that a reduction of Ca2+ in the ER causes a significant elevation of ATP levels. Further application of such sensors will certainly reveal other, similar connections.Independent of the mode of ATP transport into the ER, several attempts have been made to characterize this process in a variety of circumstances. Certain observations may help in the design of new strategies for the elucidation of the mechanisms of ER ATP import. For example, ER‐targeted genetically encoded ATP sensors now allow the monitoring of ATP dynamics in live cells (Vishnu (5)et al. , which is denoted SLC25 in the human system. Alternatively, a specific ATP transport protein might not be necessary, since ER‐derived vesicles are permeable to various compounds − into the lumen via high‐performance liquid chromatography (HPLC) or liquid scintillation counting and compared to determine the transport velocity.Studies involving the measurement of ATP transport into reconstituted proteoliposomes have utilized an approach involving radioactively labelled ATP and size‐exclusion chromatography Fig. A Maying. First, via the ϵ‐subunit of the FoF1‐ATP synthase from Bacillus subtilis ‐based indicators for ATP (‘ATeams’) consisting of a cyan and a yellow fluorescent protein linked lis Fig. B via high rates of aerobic glycolysis [the ‘Warburg effect’; reviewed by Liberti & Locasale, via MAM contact sites, while glycolytic ATP might rather enter from the cytosol.ATP is generated during glycolysis and oxidative phosphorylation. The contribution of different metabolic pathways to ATP production may vary in different cell types and under different conditions including ER stress, cell cycle, aging or carcinogenesis. In the case of cancer cells, which have an altered energy metabolism, it is tempting to speculate that there may also be abnormalities in the ER ATP supply. In general, cancer cells produce most of their ATP IV.(1) The adequate supply of the ER with ATP is important for its functions in protein synthesis and turnover, functions that underlie the role of the ER in cell growth. ATP is produced during glycolysis in the cytosol and oxidative phosphorylation in mitochondria; the ER itself is not capable of ATP generation. Thus ATP utilized by the ER must be transported there by a still‐unknown mechanism.(2) Possible ER ATP import routes are summarized in Fig. (3) The dynamics of the ER or Golgi membrane structures during membrane trafficking events might also afford the opportunity for ATP uptake.(4) Membrane contact sites such as mitochondria‐associated ER membranes (MAMs) could serve as a platform for ATP transfer, possibly even directly from mitochondria into the ER.(5) ATP hydrolysis likely follows ATP import rapidly and thus an ATP concentration gradient could provide a driving force for passive diffusion through transient membrane breaks (see point 3 above), or proteinaceous channels. Indeed, ATP concentrations within the ER are considerably lower than in the cytosol and mitochondria. Passive transport could be allowed by the leakiness of the ER, caused by the great number of translocon channels spanning the membrane. However, even if the ER is not leaky for ATP, the translocon might still be associated with ATP import in a translocon‐coupled mechanism which would allow the coordination of ATP supply with the energy‐consuming processes of protein translocation and folding.(6) Irrespective of which of these mechanisms  are actually responsible for ATP import into the ER, this review aims to stimulate discussion that has the potential to yield a wealth of new insights into molecular cell biology. We look forward to future developments in this field.


Diabetic neuropathy (DN) is a common complication of diabetes and can be either painful or non‐painful. It is challenging to diagnose this complication, as no biomarker or clear consensus on the clinical definition of either painful or non‐painful DN exists. Hence, a hierarchical classification has been developed categorizing the probability of the diagnosis into: possible, probable or definite, based on the clinical presentation of symptoms and signs. Pain is a warning signal of tissue damage, and non‐painful DN therefore represents a clinical and diagnostic challenge because it often goes unnoticed until irreversible nerve damage has occurred. Simple clinical tests seem to be the best for evaluation of DN in the general care for diabetes. Screening programs at regular intervals might be the most optimal strategy for early detection and interventions to possibly prevent further neuronal damage and to lower the economic burden of this complication. Diabetes and its complications represent major and increasing challenges to healthcare systems worldwide. According to the International Diabetes Federation, 425 million people worldwide aged ≥20 years had diabetes in 2017, and this number is expected to increase to 629 million by 2045Diabetic neuropathy (DN) represents a common, disabling and, until recently, largely neglected problem affecting approximately 50% of patients with diabetes at some pointThe present review addresses the clinical characteristics of painful and non‐painful DN, and the possibilities for diagnosing these conditions. As the majority of patients with type 2 diabetes are treated in general practice, we focused on proposals for simple assessments of DN outside specialized hospital clinics.The phenotype of DN is heterogeneous. The most common form of DN is a chronic symmetrical length‐dependent sensorimotor polyneuropathy, termed diabetic polyneuropathy (DPN), which accounts for 75–90% of all DN cases. Other types of DN include autonomic neuropathy, diabetic radiculoplexopathy , mononeuropathies and treatment‐induced neuropathies Figure ;Table 14The development of DPN is insidious, usually starting in the toes and under the feet, and gradually ascending up the leg. When the symptoms have reached knee level, they usually start to occur in the fingertips, progressing further up in the hands and arms, reflecting the “dying‐back” progression of neuronal damage. Patients eventually present with a characteristic “stocking–glove” like distribution of neuronal dysfunction Figure 4, 21, 22In DPN, the characteristics of symptoms and signs are broadly divided into so‐called “negative” and “positive” symptomsNegative symptoms are often described as numbness or a feeling of reduced sensation when walking: “It is like walking on cotton or foam”. Symptoms start slowly, and the unnoticeable loss of sensory function often remains unrecognized until irreversible nerve damage has occurredPositive symptoms range from non‐painful to painful symptomsSigns of DPN include a reduced sensation to different sensory modalities involving small fibers (temperature and pinprick) and large fibers Pain represents a particular problem in PDPN, because it is associated with reduced quality of life and might compromise rehabilitationThere has been an emerging interest in the potential differences in risk factors of PDPN and DPN, and the underlying pathogenesis of these conditions. Risk factors of both PDPN and DPN have recently been elegantly reviewed by Spallone and GrecoThe British Pain In Neuropathy Study (PiNS) aimed to identify sensory phenotypes of patients with PDPN and DPNet al.Raputova et al.The PiNS study evaluated clinical characteristics of sensory dysfunction, and the relationship between signs and symptoms in PDPN and DPN using QST and structural neurological examinations. Patients with PDPN had more pronounced neuronal abnormalities compared with patients with DPN, and mainly sensory loss involving both small and large nerve fibers. A small fraction (15%) of patients with PDPN had brush‐evoked allodynia, not seen in patients with DPN. The sensory phenotype of socalled “irritable nociceptor”  was rareet al.The strength of all three studies is the robust definition of PDPN and DPN, reflecting the highest level of certainty of the diagnosis including symptoms, signs and a confirmatory testIn summary, many studies have compared PDPN and DPN in order to identify risk factors for the development of pain, to show the mechanisms underlying pain with the ultimate goal of identifying interventions for PDPN. Only a few and not fully consistent risk factors have been identified for PDPN. The most consistent objective finding is that PDPN presents with more profound sensory loss than DPN.Longitudinal studies of patients with diabetes could be useful to determine the temporal course of nerve fiber damage and related clinical characteristics of patients with PDPN and DPN.DPN requires symptoms of decreased sensation  or signs . Probable DPN requires symptoms and signs, including two or more of the following: neuropathic symptoms, decreased distal sensation or decreased or absent ankle reflexes. Definite DPN requires abnormal nerve conduction studies or an abnormal validated measure of small fiber damage in combination with a symptom or a sign. Importantly, these criteria permit for the changing course of nerve fiber damage in DPN, but at the same time they also illustrate the clinical challenge that there is no specific measure to diagnose DPN in any individual at all times throughout the course of DPN.Diabetic neuropathies are complex diseases, and no robust definition or gold standard exist that fully encompass the complexity and changing course of nerve fiber damage in DPN. The hierarchical classification of DPN by the Toronto criteria into possible, probable or definite addresses this issueThe examination for DPN starts at the “bedside” with simple assessments of signs of neuropathy Figure . In addiA number of scoring systems have been developed for the screening of DPN. The most widely used in previous clinical studies are as follow Table .The Toronto Clinical Neuropathy Scoring SystemThe Diabetic Neuropathy Symptom ScoreThe Michigan Neuropathy Screening InstrumentThe Utah Early Neuropathy Scale (UENS)et al.et al.Because of the progressive nature of DPN, it is important to determine the severity of neuropathy, and follow up the course of the condition in patients. The Neuropathy Disability Score used in the North‐West Diabetes Foot Care StudyPain Detect is based on a self‐administered questionnaire with nine different questions related to pain typeLeeds Assessment of Neuropathic Symptoms and Signs (LANS) combines five questions with two examination itemsDouleur Neuropathique en 4 question (DN4), includes seven questions and three examination itemsFor PDPN, similar screening tools as the ones described for DPN have been developed. The Neuropathic Pain Questionnaire consists of 12 questions, and the German developed The sensitivity of these screening tools is 80–85%, and the specificity a little higher. It has been pointed out that the screening tools fail to identify approximately 10–20% of patients with clinical neuropathic pain in generalA number of other diagnostic tests are available for DPN, PDPN and neuropathic pain in general™ or a sharp wooden pin is used. Failure to identify the prick sensation is abnormal. Lesioning of the skin should be avoided. For temperature sensation assessment, different devices, such as glass tubes filled with cold and warm water, thermorollers or a simple thermal tip device termed “Thermotip”, have been developed. Failure to sense a cool and warm sensation on the dorsum of the first toe or dorsum of the foot is considered abnormal. In case of distal abnormalities, the examination should identify the proximal level for involvement of sensory abnormalities.From the perspective of primary care and secondary care outside neurological specialized units, a simple questionnaire for DPN is important. Three symptoms are considered highly suggestive of DPN: numbness, tingling and painAdditional examination for allodynia is carried out by stroking with a brush or cotton wool to determine the presence of pain by non‐noxious dynamic stimulus. If pain is evoked, this indicates allodynia.In the statement by The American Diabetes AssociationDiabetic neuropathy in type 2 diabetes presents in a painful and a non‐painful form. The non‐painful variant is the most dangerous because of its insidious nature, and gradual loss of sensation in the feet and lower limbs. Neuropathy might therefore go unnoticed by the patient until irreversible nerve damage has occurred, carrying an associated high risk for foot ulcers, foot deformities and limb amputation. Early detection of DN is therefore crucial, and simple screening assessments at regular intervals are suggested to be the best strategy in the general care for diabetes to possibly avoid further neuronal damage.T.S. Jensen has received consultancy fees from Pfizer, Biogen and Mundipharma. The other authors declare no conflict of interest.


Microfluidic systems have advanced beyond natural and life science applications and lab‐on‐a‐chip uses. A growing trend of employing microfluidic technologies for environmental detection has emerged thanks to the precision, time‐effectiveness, and cost‐effectiveness of advanced microfluidic systems. This paper reviews state‐of‐the‐art microfluidic technologies for environmental applications, such as on‐site environmental monitoring and detection. Microdevices are extensively used in collecting environmental samples as a means to facilitate detection and quantification of targeted components with minimal quantities of samples. Likewise, microfluidic‐inspired approaches for separation and treatment of contaminated water and air, such as the removal of heavy metals and waterborne pathogens from wastewater and carbon capture are also investigated. While industrialization has been a key driver in economic growth, the trade‐off for environmental conservation has brought about adverse effects as toxic wastes and pollutions are discharged into the ecosystems. Following that, various detection, monitoring, and cleanup technologies, ranging from simple separation techniques to advanced remediation technologies, have emerged. While some of the pollutants can be easily captured and retained following established work on macro‐ or industrial scale, the limit of detections and the costs of current available technologies are still major hitches.The past decade sees the rapid development of microfluidic technologies in various fields for ubiquitous applications. Miniaturized systems are favorable, especially for analytical purposes, as they require only trace quantities of samples and reagents, effectively cutting down on the time and effort in sampling and sample preparation, with minimal wastes produced. The concept of “miniaturized total analysis system” (μTAS) was coined by Manz et al. whereby some analytical procedures and techniques are integrated to allow all sample handlings at close proximity to where measurements are carried out.Many have produced comprehensive reviews on the advances of microfluidic technologies and applications in environmental monitoring and detection. Marle and Greenway first reported on various microfluidic devices for environmental monitoring and demonstrated the different methodologies of detection, while Li and Lin and Saxena et al. further discussed the trends of integrating and miniaturizing the detection systems onto the chips, or coupling of microdevices to larger apparatus, with various multianalyte methods for sample processing and analysis having been reviewed by Jokerst et al.To the best of our knowledge, no comprehensive review has been performed on microfluidic inspired innovations for environmental remediation, such as the use of microfluidic‐synthesized functional materials in pollutant separation and removal. Droplet‐based microfluidics is a subcategory microfluidics that centers on the generation and manipulation of discrete droplets with microdevices. It has recently emerged as a promising platform for designing and production of functional materials that can be used for environmental remediation.2Microdevices possessing fluidic channels and miniaturized analytical equipment are emerging as portable devices ideal for on‐site sampling. The development of handheld electrochemical sensors and biosensors for pollutant sampling has partly resolved challenges faced by laboratory‐based analyses, such as lengthy preparation time and quality change in samples prior to analysis, while LOC sensors assimilated various conventional procedures into a single system.2.1Prior to any chemical or analytical processes, bulk water or air samples have to be preconcentrated before separation due to the low concentrations of pollutants in samples typically in the range of parts per million (ppm) or parts per billion (ppb). Preconcentration of environmental samples in microdevices can be achieved through the integration of an automated pretreatment module onto the device, which eliminates any arduous and labor‐intensive operations and prevents sample handling loss or contamination.−9m of nonpolar analyte BODIPY 493/503, a fluorescent dye was retained on the bed and then eluted with the CEC.On‐chip preconcentration technologies are generally classified as static and dynamic mechanism–based techniques.2, conventional liquid–liquid laminar extraction in microdevices is ineffective, due to slow interfacial exchange rate within short path lengths.At low Reynolds number <10Escherichia coli, Salmonella, and Pseudomonas) and viruses (Enterobacteria phage MS2 and Echovirus) in reclaimed and bottled water samples.Saccharomyces cerevisiae cells.−1 with a concentration factor of 27.7 ± 3.4 within 20 min.Capillary electrophoresis (CE) is widely used in the separation and transport of various types of analytes, and has also been used in concentrating pathogens and microorganisms.Figure2S and sulfur dioxide, SO2.2, H2S, and CH3SH. The honeycomb‐structured microchannel was used as a micro‐gas desorber to strip and concentrate gases generated from the source reagent solutions before transferring the gases into another microchannel scrubber with fluorant‐containing scrubbing agent for fluorescence detection.Gas preconcentration and analysis, on the other hand, are even more challenging as there are possibilities of gas leakage and adsorption onto other substrates during transport. Toda et al. developed a microchannel scrubber made of poly(dimethylsiloxane) (PDMS) with a PDMS gas permeable membrane of 7 µm thickness for concentrating hydrogen sulfide in the inflow gas.Microparticles and microorganisms can also be sorted through the simple use of geometries such as spiral channels.The techniques for concentrating analytes of large‐volume samples are rather well‐developed, yet in doing so for ultrasmall volume samples, challenges lie in enhancing the selectivity and sensitivity of microdevices especially within confined spaces in tiny reservoirs and microchannels with limited heat and mass convection.2.2−9m to 10 × 10−6m, with a limit of detection of 14 × 10−9m.N‐(9‐acridynyl)maleimide (NAM) and 2,3‐diaminonaphthalene (DAN).2 in the atmosphere flowed through a porous glass plate embedded in the chip into triethanolamine (TEA) solution flowing within the channel, producing NO2− ions which could be detected under the excitation of ultraviolet light‐emitting‐diode (UV‐LED).2− ions below 1 fmol, corresponding to atmospheric nitrogen dioxide in the range of 10–80 ppbV.Optical detection involves the monitoring and detection of light properties such as absorbance, fluorescence, and luminescence patterns emitted from the samples upon excitation. Nitrite levels in drinking water and water bodies are constantly monitored as excess will cause adverse effect to both human and marine life.(μPADs) were used to determine Cr(III) level in tap water and other water bodies.In gas–liquid systems, challenge may arise from the formation of gas bubbles when both the phases are mixed directly. Gao et al. replaced standard use of porous glass or permeable membrane interface with a thin layer of luminol solution held between two convex structures by surface tension alone.The use of Raman‐microscopic systems has received increasing attention in recent years. As a nondestructive approach for analysis of gaseous, aqueous, and solid samples, Raman spectroscopy can facilitate superior analysis at microfluidic scales as it can enable high spatial resolutions.2.3−1, while common electrodes can hardly give any higher sensitivity.When subjected to an electrical field, electroactive species or electrolytes with ionic species can be efficiently separated and detected. A micellar electrokinetic chromatography with electrochemical detection (MEKC‐EC) was proposed for the separation and detection of trace phenolic compounds in water samples amperometrically.2+, Cl−, Pb2+ ions and the pH of solutions had been carried out by holding an ISE and a reference electrode vertically and pressing lightly onto a paper soaked in liquid sample.−, K+, Na+, and Ca2+), and the reference electrode of Ag/AgCl was stencil‐printed onto the wax‐printed chromatography paper, as shown in FigureIon‐selective electrodes (ISEs) are vastly used in potentiometric detection to continuously measure ion activity in untreated samples.−6m (600 ppb or 900 fg) of potassium ion in a 2 × 10−3m Tris‐HCl buffer (pH 8.7) with a linear range of 2 orders of magnitude without any stacking. A contactless conductivity detector was integrated into a PDMS microchip which completely insulated the electrodes from the measuring solution.−6m. Different detection techniques have been coupled for the simultaneous detection of different species and for improved performances.Conductivity detection (CD) can be contact or contactless. In the contact mode, the electrodes in galvanic contact with the working solution is exceptionally effectual for the analysis of small ions.2.4TableMass spectrometry (MS) performs separation and detection based on their mass‐to‐charge ratio, and is most regularly coupled with biological assays for laboratory analysis needing high sensitivity and low limit of detection. In the past, due to the bulk of MS, as well as the advanced sample preparations needed, this technique was not highly sought after especially for quick and on‐site analyses. To date, several coupling methods of microdevices to off‐chip mass spectrometers have already been developed, and the miniaturization of mass spectrometers to fieldable sizes has also been reported. Snyder et al. summarized the advances in miniaturization of mass spectrometers of which individual components such as sample ionization, ion transportation, analyzers, and even the miniaturization of power and data systems to suit the needs of on‐site field analyses.3The environment is on the line due to excessive discharge of harmful by‐products from industrial activities in the face of growing economies. As the demand for clean resources grows with urbanization and industrialization, it becomes exceedingly challenging to effectively handle the voluminous waste emitted either into water bodies or into the atmosphere. As conventional cleanup technologies are becoming inadequate in meeting effluent limits regulatory, more efficient and cost‐effective alternatives are highly sought after. The selection of each treatment technique, either in treating water or air discharge, is subjected to various factors, such as the concentration and types of waste, required level of cleanup, and choice of postprocessing technologies.3.1Figure2) which is seen as the ideal material for photocatalysis.meta‐, para‐, and ortho‐xylenes (BTEX) in water to the corresponding permissible level established by the US Environmental Protection Agency.Photocatalytic water treatment has been a difficult yet trending research topic for the past two decades, drawing in interests across multiple science disciplines.3.2FigureDroplet‐based microfluidics has recently received great attention in fabricating emulsions of uniform sizes.3O4 have also been incorporated into microparticles for functionalization purposes.Emulsions are used as templates for the production of functional microparticles, such as Janus microparticles, core–shell microemulsions, and hybrid microparticles which have been developed with the advances of microtechnologies.There have been numerous reports on the extensive development of functional polymeric microparticles with advanced functions from controllable microfluidic emulsions for drug delivery and controlled release, and other applications such as cell encapsulation and synthetic biology.3.2.1Adsorption has always been an important and established technique in waste treatment, regardless of handling liquid or gas phase. With growing interest in sorbent studies, more low‐cost sorbents and alternative materials that possess enhanced adsorption capacities, such as polymeric matrices have been developed.3O4 nanoparticles, chitosan–cellulose hydrogel beads, silica/chitosan composite, magnetic Cu(II) ion–imprinted composite.Biosorbents are especially favorable, such as activated carbon and chitosan. Chitosan is a promising biosorbent due to its abundance and performance, and has been known as being an effective sorbent for removing heavy metals from coal mining wastewater, and has been used as the packing sorbent materials in column adsorber for the removal of oil from the wastewater stream produced in oil industry.n‐octane with the former as the cross‐linking reagent. The microemulsions showed good sphericity and monodispersity with a sponge‐like structure. The hybrid chitosan microspheres with spongy pores reached adsorption equilibrium faster at faster adsorption kinetics than the nonhybrid ones and had greater adsorption capacity at 53.0 mg g−1 than the latter at 43.0 mg g−1 adsorbent.Chitosan microspheres have been conventionally prepared via emulsion polymerization or emulsification–diffusion method.−1 of Cu(II) ions. Zhu et al. also tested the microsphere adsorption capacity for Na(I), Al(III) in different combinations at various concentrations, however the microspheres appeared to show greater affinity for Cu(II).Zhu et al. also reported the synthesis of chitosan microspheres with a PMMA microfluidic chip with cross‐junction and orifices.3O4 nanoparticles and later calcinated to induce porous structure; while the Fe3O4 nanoparticles gave the beads the magnetic properties for ease of recovery and motion control. The MCNTBs had uniform diameters of ≈200 ± 10 µm, and possessed superhydrophobic and oleophilic properties which are vital in adsorbing oil and organic pollutants. Graphene was later incorporated into the MCNTBs and magnetic porous graphene/multiwalled carbon nanotube beads (MPGCBs) were obtained by the same group via the same fabrication method.Carbon nanotubes (CNTs) have been widely used in water treatment, of which some of the uses include adsorptive media for various organic and inorganic pollutants,3.2.22 without compromising energy security. Conventional techniques for large‐scale carbon reduction include chemical and physical absorption, adsorption with solid sorbents, selective separation with membrane systems, and also cryogenic separation.Carbon capture and storage (CCS) has widely been regarded as an indispensable pathway in containing atmospheric CO2 in biogas purification, even in the presence of moisture. Other reported works on producing MOPs for CO2 capture include decorating nanocavities in mesoporous polymer particles with tunable amine for CO2 molecule recognition properties.Kaliva et al. first reported on the facile use of microporous polystyrene particle for biogas purification.2 solvent (MECS), which are microscopic double emulsions of a thin layer of shell encapsulating a liquid solvent core.2 into the liquid core containing carbonate solutions. Carbonate solutions are being investigated as alternatives for CO2 absorbent, as they are abundant, environmentally benign, and resistant to degradation and have low volatility. The investigators successfully generated monodispersed MECS of 185 and 600 µm with wall thickness ranging from 10 to 50 µm in a microfluidic double capillary device. The MECSs were subjected to multiple absorption–desorption cycles under realistic thermal cycling conditions; with repeated loading and unloading of CO2 at varying temperatures ranging from 40 to 100 °C, yet the MECS retained their absorption capacity/performance within 90% of the initial equilibrium capacity without signs of rupturing. The regeneration of the MECS sorbents yielded purified CO2 that can be easily recovered. Cyclen  was also added into the capsule cores to enhance the capture kinetics of the MECS. A colorimetric approach used to confirm the absorption of CO2 into the capsule core by addition of thymol blue, a pH indicator, is shown in FigureMicroencapsulated sorbents as a new form of capture materials are considered to have the desirable characteristic features of both a solid and liquid sorbents. Aines et al. fabricated microencapsulated CO2 and carbonate solution is easier to handle. Following the group's work on developing MECS, a more comprehensive study has been carried out to identify more polymeric materials with good permeability to CO2.2‐binding organic liquids (CO2 BOLs) had also been examined. The advantages of ionic liquid over monoethanolamine (MEA) are the negligible vapor pressure which minimizes loss of ionic liquid and lower energy consumption for regeneration; the disadvantage however is the high viscosity which is mitigated by encapsulation.2222benzimidazole/water in thiol–ene, and NDIL0231/water in SiTRIS had been successfully generated, which opens up more opportunities and research potentials for the encapsulation of ILs and CO2 BOLs. A list of functional microparticles and microspheres synthesized via different approaches for environmental treatment is included in TableEncapsulation allows the containment of solvents that are highly viscous, corrosive, or difficult to handle. In the case of encapsulated carbonate solutions, solid precipitation that forms following the reaction between CO42O2, into water and oxygen forming microbubbles that propelled the movement of microbots, thereby improving the removal efficiency as microbots swim in the pollutant‐containing fluid. Layers of platinum and nickel were added to the microbots such that the motion of microbots could be controlled when magnetic force was applied externally. The microbots successfully removed 80% of Pb from the contaminated water having initial concentration of 1 ppm of Pb. Recovery of the microbots was possible by removing Pb in acidic solution. The regenerated microbots did not show sign of deterioration in their performances, while H2O2 could be added to the microbots for self‐propelling purpose. Scaling up seems possible for microbots, and this application is suitable for dye removal as well.There have been many other innovations inspired by microfluidics for environmental application, such as graphene‐based microbots for the removal or recovery of toxic heavy metal from waste water streams.Indoor air quality monitoring is also now possible with a portable microdevice that carries out sampling and separation of fine particulate matter (PM).5The demand for more efficient technologies to recover the ecosystems has seemingly brought about growing interest in research and development of microfluidic technologies for environmental applications. While conventional use of microfluidics has been on detection and analysis, droplet‐based microfluidics has recently diverted attention to the development of functional microparticles for environmental remediation. At present, however, the greatest challenge for the application of microfluidic systems in effective treatment of water and air pollutants remains to be both technical and economic barriers to industrialize microsystems or microtechnologies such that they can be employed or retrofitted into currently available technologies at industrial scale. The majority of the microsystems as they stand now are generally limited to “one‐design‐one‐application” basis, whereby due to highly functionalized design for each system, more customization work needs to be carried out to expand the functionality for other applications. Irrefutably, microfluidic technology is still at its infant stage and is an emerging area of technological development with great potential, especially in the area of environmental care.Massive research work is still pouring into venturing varying microfluidic designs and applications. Efforts to address the challenges for on‐chip detection, such as poor sensitivity and selectivity, have led to slow but firm progress, thanks to the recent and ongoing research and development activities in these areas, as partly highlighted by the successful development of the coupling methodologies of the microdevices to analytical facilities that have effectively facilitated the automation of the integrated analytical systems.The authors declare no conflict of interest.


This paper describes the derivation of these parameter estimates for England that can be adapted to create ROI models for use by other countries.Estimating ‘return on investment’ (ROI) from smoking cessation interventions requires reach and effectiveness parameters for interventions for use in economic models such as the EQUIPT ROI tool (Estimates were derived for interventions in terms of their reach and effectiveness in: (1) promoting quit attempts and (2) improving the success of quit attempts (abstinence for at least 12 months). The sources were systematic reviews of efficacy supplemented by individual effectiveness evaluations and national surveys.Quit attempt rates were estimated to be increased by the following percentages (with reach in parentheses): 20% by tax increases raising the cost of smoking 5% above the cost of living index (100%); 10% by enforced comprehensive indoor public smoking bans (100%); 3% by mass media campaigns achieving 400 gross rating points (100%); 40% by brief opportunistic physician advice (21%); and 110% by use of a licensed nicotine product to reduce cigarette consumption (12%). Quit success rates were estimated to be increased by the following ratios: 60% by single‐form nicotine replacement therapy (NRT) (5%); 114% by NRT patch plus a faster‐acting NRT (2%);124% by prescribed varenicline (5%); 60% by bupropion (1%); 100% by nortriptyline (0%), 10) 298% by cytisine (0%); 40% by individual face‐to‐face behavioural support (2%); 37% by telephone support (0.5%); 88% by group behavioural support (1%); 63% by text messaging (0.5%); and 19% by printed self‐help materials (1%). There was insufficient evidence to obtain reliable, country‐specific estimates for interventions such as websites, smartphone applications and e‐cigarettes.Tax increases, indoor smoking bans, brief opportunistic physician advice and use of nicotine replacement therapy (NRT) for smoking reduction can all increase population quit attempt rates. Quit success rates can be increased by provision of NRT, varenicline, bupropion, nortriptyline, cytisine and behavioural support delivered through a variety of modalities. Parameter estimates for the effectiveness and reach of these interventions can contribute to return on investment estimates in support of national or regional policy decisions. Cost‐effectiveness (CE) estimation is usually expressed in terms of cost per ‘quality‐adjusted’ life‐year gained, ‘disability‐adjusted’ life‐year gained or sometimes simply life‐year gained Both CB, and therefore ROI, estimates depend upon assumptions about the effects of the interventions in promoting smoking cessation in a real‐world setting. Effectiveness of behaviour change interventions is often context‐sensitive and depends upon specific features of those interventions ROI estimates also depend upon the reach of interventions. A highly effective intervention that reaches a small only proportion of the target population may have a lower overall ‘impact’ (reach × effectiveness) than an intervention with a small effect but to which a large proportion of the population is exposed Effectiveness and reach of smoking cessation interventions have been estimated in several reviews, and the findings incorporated into CB or ROI estimation exercises The proportion of a population that stops smoking in a given time‐period is the proportion who try to quit multiplied by the proportion of those who maintain abstinence Through the Smoking Toolkit Study (STS) This paper reports the process used to arrive at up‐to‐date effectiveness (in terms of quit attempts and quit success) and reach estimates for smoking cessation interventions, using England as a case example. It presents the estimates relating to a wide range of interventions together with rationales and caveats. The parameters derived from this process have been incorporated into a spreadsheet and combined with cost and health outcome data to generate ROI estimates in EQUIPT. Any of the parameters are potentially modifiable, so that individual countries can reflect their own local data and circumstances.We first identified interventions that were judged suitable for inclusion and specified versions of these for which effect‐size estimates could be derived. We then assessed the reach of those interventions in England, and finally carried out effectiveness estimation.We first identified broad types of smoking cessation interventions for which it was judged to be possible to arrive at effectiveness estimates. Effectiveness estimates can only be derived from: (1) randomized controlled trials (RCTs), (2) quasi‐experimental studies, (3) comparative observational studies or, in the case of population‐level interventions, (4) time–series analyses. We excluded interventions in which evidence was judged insufficient for confident effect‐size estimation at the time of writing .The lead author had recently undertaken a major review of clinical interventions that combined evidence, primarily from Cochrane Reviews acknowledged to be of high quality, with additional RCT evidence and evidence from real‐world evaluations being checked to confirm the estimates from the reviews For population‐level interventions, we began by searching for those that had been reviewed by Cochrane, and then undertook a review of reviews to assess whether there were any additional interventions that could be included. This involved searching Pubmed and Web of Science using the terms ‘Tobacco control’ + ‘intervention’ + ‘review’. We identified reviews from which we could derive effect‐size estimates for quit attempts or quit success.We excluded reviews that focused on: (1) specific subgroups such as women, smokers with psychiatric disorders e.g.  or smokeHaving identified broad types of smoking cessation interventions, we then sought to characterize a particular variant of that intervention for use in the effectiveness and reach estimation. Thus, any of the interventions could take a wide variety forms in terms of the way they are delivered and their intensity. For example, increasing tax on tobacco products can be undertaken in many ways and by varying amounts. Given that the effect depends critically upon this translating into an increase in the financial cost of smoking, it is essential to capture this feature of the tax increase in the description of the intervention. Similarly, mass media campaigns can take different forms and to very different levels of intensity. We needed to arrive at a specific case that could be used for modelling purposes.The process for arriving at specific variants of the intervention types involved analysing the key ingredients of the intervention and the typical level of intensity, and specifying this at a level of descriptive detail that could guide the development of new instances of that intervention type. For each intervention type, the rationale for specifying a given variant and the caveats attached to the choices made are reported in this paper.http://www.smokinginengland.info). We used figures for 2016 published on the website.Reach of the interventions was estimated using data from the Smoking Toolkit Study In the case of population‐level measures it was assumed to be 100%. This did not mean that we assumed that all smokers would be exposed to the intervention, but rather that the effect‐size estimate already captured the extent to which reach may have been less than 100%. For example, tax increases leading to a given increase on the cost of smoking may not have done so for all smokers because of cost‐minimizing strategies, such as switching to hand‐rolled tobacco, reducing the number of cigarettes consumed or purchasing from illicit sources. However, the effect size from studies will have already taken into account those strategies as they were enacted at the time.P) + (P × OR)], where P is the probability of the outcome of interest in the non‐exposed/control group, obtained from the source that provided the OR.For the purpose of ROI modelling, effectiveness estimation needed to be expressed using a single metric that could be applied to varying contexts. Given that the outcomes (making an attempt to stop and success of that attempt) were binary, many of the reviews expressed effects in terms of odds ratios. Quit attempts have been defined variously in the research literature, but refer generally to a serious attempt to stop smoking permanently. In some studies, the definition also requires at least 24 hours of abstinence. Quit success is also subject to multiple definitions. Given that ROI modelling assumes that abstinence is permanent, the outcome measure needs to be predictive of lasting abstinence. Longitudinal studies of smoking cessation have shown that 12 months of continuous abstinence provides a reasonably accurate estimation of permanent cessation, with approximately 70% of those who are abstinent for 12 months managing to maintain this for many years In the case of the clinical interventions, we were able to draw upon the methods and findings from the review undertaken previously by the lead author In the case of the population‐level interventions, we started with estimates from the most recent reviews and compared these with findings from earlier ones to assess the stability of the estimates. In some cases, the reviews did not differentiate between effects on quit attempts and quit success. In those cases we sought out studies that did make this differentiation. If there were none, we made an assumption that all the effect was on one or the other. This assumption may not have been correct (e.g. there may have been an effect on both attempt and success rates), but this would not have an impact on the overall cessation rates produced by combining attempt and success rate in the ROI model as it was derived from those overall cessation rates.Table Table Table Table While the clinical interventions to support cessation have relatively low reach, the effect‐size estimates are more robust and they appear to be subject to somewhat less variation than the population‐level interventions.A wide range of smoking cessation interventions were identified for which it was judged possible to derive effect‐size estimates in relation to quit attempts or success of quit attempts. In terms of interventions to increase the rate of quit attempts these were: tax increases and associated measures to increase the financial cost of smoking, introduction of comprehensive public indoor smoking bans, mass media campaigns, brief opportunistic advice from health professionals and use of licensed nicotine products for smoking reduction. In terms of interventions to increase the success rate of quit attempts the interventions identified were: NRT (single form), NRT , varenicline (standard duration), varenicline (extended duration), bupropion, nortiptyline, cytisine, behavioural support , behavioural support (group face‐to‐face), behavioural support (proactive telephone), behavioural support (text messaging) and behavioural support . While the effect‐size estimates are subject to a number of caveats, there can be a high degree of confidence that each of these interventions, if delivered as specified in a way that is appropriate to the context, will make a significant contribution to increasing population smoking cessation rates.Most of the interventions identified in this review are similar to ones shown previously to be important in reducing smoking prevalence. However, there were some additions, including differentiating single‐ and dual‐form NRT and standard‐ and extended‐duration varenicline. We also included interventions that are not used widely in western countries, but have been shown to be effective, such as nortriptyline and cytisine. An additional novel feature of this review is the estimation of reach and effectiveness of interventions specifically on quit attempts and quit success. This was necessary for the EQUIPT model, but more generally provides useful information for tobacco control strategy development in different countries that wish to focus attention on these different parts of the quitting process.Combining the quit attempt and quit success effectiveness estimates can be used to generate an estimate of effect of interventions on cessation, and these estimates can be combined with reach estimates to arrive at figures for intervention impact. The Supporting information file contains an Excel spreadsheet with these calculations for England. In modelling the impact of combinations of interventions (e.g. mass media campaigns plus provision of single‐form NRT), some additional assumptions need to be made. The most important of these is that the intervention effects are independent of each other, and so the ratios representing effect sizes combine multiplicatively. Another is that the effect and reach are independent of each other. For example, if a mass media campaign leads more smokers to try to quit, increasing the reach of interventions aimed at increasing quit success rates, this does not influence the effects of those interventions.http://roi.equipt.eu) and its country applications using the data presented here are described elsewhere An example ROI model . He is an unpaid adviser to the UK's National Centre for Smoking Cessation and Training.