The COVID-19 pandemic led to the UK government enforcing lockdown restrictions to control virus transmission. Such restrictions present opportunities and barriers for physical activity and healthy eating. Emerging research suggests that in the early stages of the pandemic, physical activity levels decreased, consumption of unhealthy foods increased, while levels of mental distress increased. Our aims were to understand patterns of diet, physical activity, and mental health during the first lockdown, how these had changed twelve-months later, and the factors associated with change.N = 636; 78% female) during the first national lockdown (May–June 2020). The survey collected information on demographics, physical activity, diet, mental health, and how participants perceived lifestyle behaviours had changed from before the pandemic. Participants who provided contact details were invited to complete a twelve-month follow-up survey (May–June 2021), 160 adults completed the survey at both time-points. Descriptive statistics, T-tests and McNemar Chi Square statistics were used to assess patterns of diet, physical activity, and mental health at baseline and change in behaviours between baseline and follow-up. Linear regression models were conducted to explore prospective associations between demographic and psycho-social variables at baseline with change in healthy eating habit, anxiety, and wellbeing respectively.An online survey was conducted with UK adults  and confidence in eating healthily (negatively) were associated with change in healthy eating habit. There were no differences between baseline and follow-up for depression or physical activity. Mean anxiety score reduced, and wellbeing increased, from baseline to follow-up. Living with children aged 12–17  was associated with an increase in anxiety, while perceiving mental health to have worsened during the first lockdown (compared to staying the same) was associated with reduced anxiety and an increase in mental wellbeing.While healthy eating habits worsened in the 12 months since the onset of the pandemic, anxiety and mental wellbeing improved. However, anxiety may have increased for parents of secondary school aged children.The online version contains supplementary material available at 10.1186/s12889-022-13888-1. The COVID-19 pandemic has led to unprecedented measures worldwide to control virus transmission. In the UK, on March 23rd 2020, the government announced a nationwide lockdown ordering the public to stay home and leave only for a limited number of reasons, including for exercise (once a day only), to purchase household essentials, for a medical emergency, or to go to work if classed as a key worker . All non-essential businesses were closed and visiting family or friends outside the individual’s household was prohibited. Over time, the initial lockdown was eased in stages with home-nation variations; including being allowed to leave the house to exercise more than once a day, the opening of non-essential shops, and the opening of the hospitality sector. Additional regional and national lockdowns and restrictions were enforced throughout Autumn-Winter 2020–2021, with lockdown restrictions gradually eased across Spring 2021, and almost all restrictions removed in July 2021.Previous research has highlighted the complex associations between diet, physical activity, and mental health and wellbeing –6, and tn = 2524) suggested that self-reported physical activity decreased in all age groups during the first phase of the COVID-19 pandemic  [Several studies have observed a reduction in physical activity levels through the start of the pandemic –16. A laLooking at physical activity alongside other lifestyle factors including diet, an international cross-sectional survey examined lifestyle changes that occurred during COVID-19 lockdowns in 1047 adults primarily from Western Asia, North Africa and Europe . This stn = 42,330), population prevalence of clinically significant levels of mental distress in adults rose from 18.9% in 2018–19 to 27.3% in April 2020, 1 month into UK lockdown [The pandemic and control measures have had an impact on people’s mental wellbeing. In a secondary analysis of the UK Household Longitudinal Study (UKHLS) panel  what were the patterns of lifestyle behaviour in the UK during the initial COVID-19 lockdown measures?, b) how diet, physical activity, and mental health changed between the first UK lockdown measures and twelve-months later?, and c) what factors were associated with change in diet, physical activity and mental health between baseline and twelve-month follow-up?All methods were carried out in accordance with relevant guidelines and regulations. An online survey focusing on physical activity, diet and mental health was hosted using JISC Online Surveys see . The surParticipants were able to choose to complete the survey anonymously or, if they were interested in completing any additional elements of the study , they could provide their contact details at the end of the baseline survey. Participants who provided their contact details were emailed with a link to the diet recall and an invitation to contact the team if they were interested in taking part in an interview. The methods and results from the qualitative interview study are presented elsewhere. The study received ethical approval from the University of Bath Research Ethics Approval Committee for Health (REACH).A follow-up survey was scheduled to take place 12 months after the initial survey. On January 6th 2021, with COVID-19 cases rising, England entered its third national lockdown. The government set out a roadmap to gradually ease restrictions, including groups of six being able to meet outdoors (March 29th 2021), non-essential retail and outdoor hospitality reopening (April 12th 2021), increased social contact indoors and outdoors and indoor hospitality reopening (May 17th 2021), and a planned removal of all social contact restrictions (June 21st 2021), although this was delayed (July 19th 2021). Data were collected for the twelve-month follow-up survey between May 23rd and June 20th 2021, where indoor socialising was permitted but some restrictions were still in place. Participants who provided their contact details when completing the baseline survey were emailed a link to the follow-up survey. Participants were provided with an anonymised ID number that they were instructed to enter when completing the follow-up survey so that their data could be matched with their baseline survey data.The baseline survey was used to collect demographic information and self-reported physical activity, diet, and mental health during the first UK lockdown, as well as how participants perceived these lifestyle behaviours had changed from before the pandemic.http://data.gov.uk/dataset/index-of-multiple-deprivation). Participants were asked to report: their general health on a five-point scale (from excellent to poor); whether they are classed as high risk for COVID-19; and their working situation during the initial COVID-19 lockdown measures .Demographic questions included gender, age category, ethnic group, and number/relationship of other people living in the household. Participants provided their postcode to determine which part of the UK they resided in, and this was also used to assign Indices of Multiple Deprivation (IMD) scores, based upon the English Indices of Deprivation  ; particiParticipants were asked whether their diet had changed during the initial lockdown, and if so, whether it had ‘improved during lockdown’, ‘worsened during lockdown’, or ‘neither improved nor worsened, just different’. The survey included a measure to assess participants’ habit strength for healthy eating using the 4-item Self-Report Behavioural Automaticity Index (SRBAI) , adaptedTo measure prevalence of current depression symptoms, the validated eight-item Patient Health Questionnaire depression scale (PHQ-8) was used . The PHQThe measures included in the follow-up survey closely matched the baseline survey. Participants were asked to rate their general health, and whether anything had changed regarding their household or working situation since the baseline survey. In terms of physical activity, participants were asked to report their physical activity behaviour using the IPAQ-SF , how impDescriptive statistics  were used to examine the distributions of demographic, diet, physical activity, and mental health variables for the baseline survey sample. For the participants who completed the survey at both time-points, paired sample T-tests (continuous variables) and McNemar Chi-Square tests  were conducted to test whether demographic, diet, physical activity, and mental and physical health variables differed between baseline and twelve-month follow-up.p < 0.05), prospective linear regression analyses were not conducted. All analyses were conducted in STATA version 16 .Univariate and multivariate linear regression models were used to calculate prospective associations between predictor variables  at baseline with change in outcome variables  between baseline and twelve-month follow-up. Outcome variables were as follows: change in healthy eating habit (as a proxy for dietary behaviour ), changeAt baseline, 636 eligible participants completed the online questionnaire. Compared to the general UK population , placed high importance on eating healthily during lockdown , and moderate confidence in their ability to do so , but had moderate levels of confidence for doing so  reported moderate-to-severe levels of depression, one fifth (20.5%) reported moderate-to-severe levels of anxiety, while 16.2% reported high levels of mental wellbeing . The twelve-month follow-up sample were generally representative of the baseline sample but tended to be older (20.0% compared to 10% were aged 65+ years), were less likely to live in a deprived area (63.8% compared to 58.2% in less deprived quintiles 1 & 2) and were more likely to be classed as a high risk for COVID-19 (20.9% responded yes).p = < 0.001, d = 0.33), importance of eating healthily , and confidence in eating healthily  showed small reductions between baseline and twelve-month follow-up  nor the proportion of participants reporting moderate-to-severe levels of depression , but there was no difference in the proportion of participants reporting moderate-to-severe levels of anxiety .Neither the continuous PHQ-8 score p = 0.11 nor theIn the univariate models, very good/excellent compared to poor/fair self-rated health at baseline was associated with an increase in healthy eating habit strength at 12-month follow-up . People’s perceived importance  and confidence  of eating healthily during the first COVID-19 lockdown at baseline were both associated with a decrease in their healthy eating habit strength at 12-month follow-up.p = 0.072) and confidence  of eating healthily during the first COVID-19 lockdown at baseline were both associated with a reduction in their healthy eating habits at 12-months follow-up  and very good/excellent  vs poor/fair self-rated health at baseline was associated with an increase in healthy eating habit strength at 12-month follow-up. I.e., the more people rated their health highly during the first lockdown, the stronger their healthy eating habits were after 12-months. People’s perceived importance .In the univariate models, perceiving your mental health had worsened during the first lockdown compared to staying the same was associated with a reduction in symptoms of anxiety at 12-month follow-up . Living with children aged between 12 and 17 vs living alone during the first lockdown was associated with an increase in symptoms of anxiety at 12-months follow-up  . Living with children aged between 12 and 17 vs living alone during the first lockdown was also still associated with an increase in symptoms of anxiety at 12-months follow-up . However, the overall model was not significant (Table P = 0.112). Perceiving your mental health had worsened during the first lockdown compared to staying the same was associated with an improvement in mental wellbeing . In the multivariate models perceiving mental health had worsened compared to staying the same was associated with an increase in mental wellbeing score at 12-months  . However, the overall regression model was non-significant  was associated with an increase in anxiety while perceiving mental health to have worsened during the first lockdown (compared to staying the same) was associated with reduced anxiety. Perceiving mental health to have worsened initially (compared to staying the same) was associated with an increase in mental wellbeing.In this study, we found that in the 12 months since the start of the UK COVID-19 lockdown restrictions, the psycho-social variables related to healthy eating  worsened across time. This is a concern, especially considering that a greater proportion of participants perceived their diet had worsened (compared to improved) at the start of the first lockdown restrictions (23.1% versus 19.0%). The associations between the change in the strength of healthy eating habits and participants’ self-rated health at baseline, suggested that this negative impact may be more prevalent for participants in fair or poor physical health at the outset. It is possible that some participants felt more confident in their ability to eat healthily when lockdown restrictions were tighter, when they had more time and opportunity for cooking healthy meals, and there were fewer opportunities to eat out in social settings. Our data also indicated that living with secondary school aged children experienced worsening anxiety relative to people with younger or no children who showed no change.N = 728) examining eating styles and behaviours between April 2020 (during lockdown) and June 2020 (after lockdown). The researchers found that during lockdown, participants reported an increase in healthy food consumption, involvement in cooking, and a decrease in junk food consumption [Early research during the COVID-19 pandemic suggested an increase in consumption of unhealthy food, eating out of control and snacking between meals increased during the initial COVID-19 lockdown measures . Howeversumption . Whereassumption . Time cosumption , therefoAmong our sample, there was variation in the degree to which participants believed their physical activity behaviour to have changed at the onset of COVID-19 lockdown restrictions, with approximately one third of participants perceiving their physical activity to have increased, stayed the same, or decreased respectively. This somewhat contradicts some of the earlier published studies that observed reductions in physical activity through the start of the pandemic –16. WhilN = 13,696) conducted in March–May 2020, found that 44.2% of participants reported no change, 23.7% reported a decrease, and 31.9% reported an increase in their exercise frequency during the COVID-19 pandemic [Similar to our findings, an international cross-sectional survey study (pandemic . The autpandemic . This vaN = 3097) measuring mental health at the start of the pandemic (April 2020), found 31.6% reported moderate-to-severe levels of depression and 26% reported moderate-to-severe levels of anxiety [The impact of COVID-19 lockdown restrictions on mental health has been a major concern , with re anxiety . While l anxiety , 40. Our anxiety . However anxiety .However, our findings do suggest that anxiety deteriorated for people living with 11–17 year older children. Reasons for this warrant further investigation, including whether this reflects parents’ concerns about the continued disruption of education that persisted throughout the 12 months following the first lockdown, their anxiety at having to manage home-education while fulfilling their own work commitments, or other factors such as concern on the long term impact of the ongoing restrictions on their children’s health and wellbeing.N = 105,248) found that the prevalence of being high risk for mental disorders decreased from 25.8% when lockdown restrictions were in place (early-February 2020) to 20.9% when most COVID-19 restrictions were eased (mid-March 2020) [Similar findings have been shown internationally. A large population-based survey study in China (ch 2020) . HoweverStrengths of this study include the longitudinal design, with data collected during the first UK COVID-19 lockdown restrictions and twelve-months later at the same time of year, overcoming the issue of the seasonal variation in physical activity, food intake, and mental health –47. ThisThe study sample was relatively homogenous, primarily female, of White British origin from South-West England, which limits the ability to extrapolate to other ethnic groups in more diverse areas of the UK. Only one quarter of the baseline sample completed the twelve-month follow-up survey. We were not able to analyse diet behaviour. However, healthy eating habit was included as a proxy for diet behaviour because it has previously been found to be strongly correlated with dietary behaviour . While tFurther follow-up and monitoring of diet, physical activity and mental health is needed to understand the long-term impact of the COVID-19 lockdown restrictions both in the UK and worldwide. More longitudinal studies are needed to investigate the factors associated with change in lifestyle behaviours and mental health, to highlight whether there are any specific population sub-groups who have been particularly negatively impacted by the COVID-19 lockdown restrictions. Such data will help to identify relevant interventions and/or government policies that could be developed and implemented to combat any negative impacts of the COVID-19 pandemic and ensure that any positive impacts are capitalised on. Finally, more qualitative studies are needed to provide further insight into some of the key drivers of health behaviours both during and after lockdown.To our knowledge, this is one of the first studies to report twelve-month follow-up data on the longitudinal impact of the UK COVID-19 lockdown measures on lifestyle behaviours and mental health. We provide evidence that healthy eating habits worsened in the 12 months since the pandemic started, while anxiety and mental wellbeing improved. Participants were more confident in their ability to eat healthily when lockdown restrictions were tighter, potentially due to increased opportunities for home cooking and fewer opportunities to eat out. Participants who perceived their mental health had worsened at the start of the lockdown restrictions were more likely to report positive changes in their level of anxiety and mental wellbeing twelve-months later, suggesting there may be a ‘bounce-back’ effect as restrictions were eased. More longitudinal research is needed into how lifestyle behaviours and mental health have changed since the start of the pandemic, and the factors associated with change, so that effective interventions and government policies can be developed and deployed.Additional file 1.


Background and Objectives: An elevated procalcitonin level has classically been linked to bacterial infections. Data on the association between elevated procalcitonin and the outcome of coronavirus disease 2019 (COVID-19) are conflicting. Some linked it to associated bacterial co-infections, while others correlated the elevation with disease severity without coexisting bacterial infections. We aimed to investigate the association between high procalcitonin and the severity of COVID-19. Materials and Methods: Hospitalized patients with confirmed COVID-19 pneumonia were divided into two groups: the normal-procalcitonin group and the high-procalcitonin group (>0.05 ng/mL). Patients with concomitant bacterial infections on admission were excluded. The primary outcomes were the need for intensive care unit (ICU) admission, progression to invasive mechanical ventilation (IMV), and in-hospital 28-day mortality. Results: We included 260 patients in the normal procalcitonin group and 397 patients in the high procalcitonin group. The mean age was 55 years and 49% were females. A higher number of patients in the elevated procalcitonin group required ICU admission  and IMV . In-hospital mortality was significantly higher in the elevated procalcitonin group . After adjusting for other covariates, procalcitonin > 0.05 ng/mL was an independent predictor of progression to IMV , ICU admission , and in-hospital mortality . An elevated procalcitonin level was the strongest predictor of in-hospital mortality. Conclusions: Measurement of procalcitonin can have a prognostic role among COVID-19 patients. The admission procalcitonin level can identify patients at risk of ICU admission, progression to IMV, and in-hospital mortality. The coronavirus disease 2019 (COVID-19), which started as a cluster of pneumonia cases in Wuhan, China, has affected nearly all countries throughout the world . The hosPCT is a glycoprotein precursor of calcitonin that does not have a hormonal action of its own. PCT level is undetectable under normal circumstances but increases with bacterial infections to adjust the host′s immune response and vasoactivity in response to bacterial sepsis . BacteriDespite being a viral infection, COVID-19 may be associated with elevated levels of PCT. The elevated PCT in this setting indicates a more severe illness and a higher risk of mortality, especially among elderly patients . A meta-On the contrary, other studies failed to find an association between PCT and bacterial co-infections in COVID-19 patients and suggested that the high PCT levels are largely related to the disease severity and the associated inflammation rather than bacterial co-infection ,18. CurrIn response to the gaps in the literature, we aimed to investigate the hypothesis that elevated PCT is associated with increasing disease severity, need for invasive mechanical ventilation (IMV), need for ICU admission, and in-hospital mortality.® B.R.A.H.M.S. PCT™, BioMérieux Diagnostics, Inc., Lyon, France). All patients were treated according to the national treatment protocol that included pharmacologic thromboprophylaxis unless contraindicated and corticosteroids for hypoxemic patients . Antibiotics were prescribed according to the treating physician′s discretion. Patient demographics, clinical data, and admission laboratory results were obtained from the hospital records.Our study was a single-center retrospective cohort study. The study included patients who were admitted to the medical ward at Jahra Hospital, Kuwait  with COVID-19 pneumonia between May 2020 and May 2021. Patients were divided into 2 groups according to the admission PCT level: the normal PCT group with a PCT level ≤ 0.05 ng/mL (according to the manufacturer′s reference range) and the high PCT group with a PCT level > 0.05 ng/mL. PCT was measured using an automated Enzyme-Linked Fluorescent Assay  admission to the medical ward with COVID-19 pneumonia ; (2) COVID-19 diagnosis was confirmed with a positive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) on nasopharyngeal swab; (3) PCT concentration was measured on admission.Patients who were transferred to another hospital before the outcome was known, had a bacterial co-infection, or did not have a PCT measurement on admission were excluded from the study. Bacterial co-infection was defined as positive bacterial culture from respiratory samples, blood, or urine, within 48 h from admission. Pregnant females were not included in our study.The severity of COVID-19 respiratory illness on admission was assessed using a 7-category ordinal scale consisting of the following categories: (1) not hospitalized and ambulatory; (2) not hospitalized, but with limitation of activities; (3) hospitalized but did not require oxygen therapy; (4) hospitalized and required oxygen by nasal prongs or mask; (5) hospitalized and required oxygen therapy by high-flow nasal cannula or noninvasive mechanical ventilation; (6) hospitalized and required IMV; (7) hospitalized and required IMV plus additional organ support, e.g., extracorporeal membrane oxygenation, renal replacement therapy, or vasopressors . The prit-test was used for the comparison of normally distributed quantitative variables. If the quantitative data were not normally distributed, they were expressed as the median and interquartile range (IQR), and the differences between the study groups were compared by the Mann–Whitney test. Logistic regression was done to detect the independent predictors of the various primary outcomes. The association between determinants and outcome was presented as odds ratio (OR) and 95% confidence interval (CI) after controlling for other variables. A p-value < 0.05 was considered statistically significant.Assuming an incidence of the main outcomes of 1% and 6.8% in the two groups, respectively , 174 patAfter assessment against inclusion and exclusion criteria, 657 patients were included in our study: 260 patients in the normal PCT group and 397 patients in the high PCT group, as shown in The mean age of patients was 55 ± 15 years and 51% of them were males. Diabetes and hypertension were the most frequent comorbidities . The median PCT in the normal and the high PCT groups was 0.05 and 0.21 ng/mL, respectively. p < 0.001), and the median length of stay was higher in the elevated PCT group compared to the normal PCT group (p < 0.001).As demonstrated in p < 0.001). The in-hospital mortality was significantly increased in the high PCT group compared to the normal PCT group .p = 0.003), older age , admission PCT > 0.05 ng/mL , and a higher CRP level  as risk factors for ICU admission after control of other variables, as demonstrated in p = 0.013), older age , and admission PCT > 0.05 ng/mL  after adjusting for other covariables, as shown in p < 0.001) and admission PCT > 0.05 ng/mL  exhibited independent increasing risk of in-hospital mortality after adjusting for other covariates. As demonstrated in Different models were designed, and regression analysis was performed to test the effect of the different variables on the primary outcomes . Our model identified male sex  receptors leading to ACE2 dysregulation and renin–angiotensin–aldosterone system (RAAS) activation in several ACE2-expressing tissues, leading to a widespread inflammatory response and tissue injury . The relIn our study, patients with elevated PCT had a significantly higher in-hospital 28-day mortality. In the study by Liu et al., PCT levels ≥0.05 ng/mL correlate with in-hospital mortality and worse survival . Shen etA low burden of bacterial co-infections on admission was detected in our study (21 patients (3%)). A similar percentage of bacterial co-infections in the community-onset COVID-19 infections was detected in other studies  ,35. A meThe hypothesis of the association between elevated PCT and bacterial co-infections in severe COVID-19 was considered in many studies. Pink et al. demonstrated that the peak PCT levels coincide with the diagnosis of secondary bacterial infection, although it was not clear whether these infections were community-acquired or nosocomial. The authors did not establish a direct relation between high PCT levels and severity and stated that patients with secondary bacterial co-infections were expected to have worse clinical outcomes . Many stOur logistic regression model identified high PCT as a predictor of progression to IMV, ICU admission, and in-hospital mortality. In addition, PCT > 0.05 ng/mL was the strongest predictor of in-hospital mortality. Different studies have identified elevated PCT as a risk factor for worse outcomes and mortality. Xu et al. found that elevated baseline PCT is an independent predictor of mortality in hospitalized patients with COVID-19. They suggested using elevated PCT to identify patients with worse prognoses, especially among the elderly and the critically ill patients . AnotherAlthough previous studies found an association between elevated PCT levels and COVID-19 severity, our study has specific features that should be emphasized. First, the timing of PCT measurement was comparable in all patients and all other laboratory parameters were measured simultaneously with PCT on admission. In addition, patients with positive bacterial cultures on admission were excluded. Finally, these findings share our real-life experience on PCT as a biomarker of COVID-19 severity. Nevertheless, our study has limitations. It was an observational retrospective study and included patients from a single hospital. Moreover, serial PCT was not measured; thus, we could not assess the dynamic PCT changes and their effect on the outcomes.In conclusion, our findings demonstrate that early measurement of PCT can have a prognostic role among COVID-19 patients. Admission PCT measurement can identify patients at risk of requiring IMV and death. Our findings add to the growing evidence that elevated PCT level is a risk factor for worse COVID-19 outcomes, and we think that it can be incorporated in a practical strategy to early identify patients at risk of deterioration. Further research is required to determine the role of serial PCT measurement, the effect of drugs, and the mechanisms implicated in the association between elevated PCT and unfavorable outcomes in COVID-19. There is an urgent need to develop new and reliable strategies to diagnose bacterial co-infections among patients with COVID-19 infection.


Bifidobacterium, Sutterella, Butyricimonas and higher abundance of Proteus than those without depression. The relative abundance of microbial short-chain fatty acid production pathways was significantly lower in IBS patients with depression than those without depression in all three subtypes. Female, younger age in IBS-D, and older age in IBS-C were associated with more severe microbiota dysbiosis, and distinct dietary factors had significant effects on the gut microbiota in different IBS subtypes. Our analysis identified the compositional uniqueness of gut microbiota in different IBS subtypes. Distinct associations of the gut microbiota with depression in IBS provide insights into shared pathways in disease pathogenesis. These findings highlight the importance of personalized gut microbiome modulation approaches in different subtypes for optimal therapeutic effects.Irritable bowel syndrome (IBS) is a heterogeneous condition with multifactorial pathogenesis. We studied deeply phenotyped individuals with microbiota sequencing enrolled in the American Gut Project. The IBS subjects were matched by age, gender, body mass index, geography, and dietary patterns with non-IBS controls. A total of 942 subjects with IBS-Diarrhea (IBS-D), IBS-Constipation (IBS-C), unclassified IBS (IBS-U), and 942 non-IBS controls were included. We compared taxonomic and functional composition of gut microbiota based on 16S sequencing data and linked them with clinical characteristics and dietary factors. Subjects with IBS-D or IBS-U but not IBS-C showed significantly reduced bacterial diversity . Distinct bacterial signatures were associated with different IBS subtypes, and the related functional changes were related to IBS pathogenesis, such as the increased hydrogen sulfide production pathway in IBS-D and the increased palmitoleate biosynthesis pathway in IBS-C. IBS subjects with depression showed lower abundance of  Herein, we examined the gut microbiota compositions of 942 comprehensively phenotyped patients with IBS based on sequencing data from the American Gut Project (AGP)13 namely IBS-C vs non-IBS1 (180 pairs), IBS-D vs non-IBS2 (302 pairs), and IBS-U vs non-IBS3 (460 pairs). There was no difference in BMI, sex, age, geographical location, alcohol consumption, and frequency of dietary intake of meat/eggs, dairy, vegetables, whole grain, and salted snacks between the patients with IBS and their paired controls  were paired with 942 non-IBS subjects who were matched by age, BMI, country, diet , and gender, resulting in a total of 1884 subjects  of Bray-Curtis dissimilarities, patients with different subtypes of IBS including IBS-C, IBS-D, and IBS-U showed distinct clustering of their gut microbiota composition  of the bacterial taxa only differed in one of the three IBS subtypes  effect size (LEfSe) analysis for IBS-C, IBS-D, and IBS-U independently with the corresponding paired control group. Six bacterial phyla were identified to be associated with different IBS subtypes . The difference in gut microbiota composition between mixed IBS and non-IBS tested by PERMANOVA  was smaller than that in subtype level  and non-IBS controls were selected and matched from 4974 controls . Principal coordinates analysis (PCoA) based on Bray-Curtis dissimilarities verified the difference in beta-diversity among different IBS subtypes . Again, we observed the significant decrease in alpha-diversity in IBS-D and IBS-U patients and the reduced richness in IBS-D patients . The LEfSe analysis at phylum and genus level also confirmed the distinct gut microbiome signatures in different IBS subtypes .Escherichia/Shigella, which was found to be increased in this subtype, exhibited the strongest positive correlation with hydrogen sulfide production  and the strongest negative correlation with the degradation of lactose and galactose . These results implied that the specific microbiome alteration in each IBS subtypes further lead to distinct functional changes.In stool samples from different subtypes, 6 out of 481 identified microbial metabolic pathways showed significant alteration compared with paired controls , which further illustrated the relationship between bacteria and function.A subset of patients with IBS had a diagnosis of depression . We paired patients with IBS on depression, with others without depression using the above matching algorithm adjusting for age, BMI, country, diet , and sex. There was no difference in alpha diversity (Shannon Index), richness, and the composition structure (PCoA based on Bray-Curtis dissimilarities) between IBS patients with depression and those without depression in all three subtypes p > .05, . We founF pseudo statistic, In this cohort, females account for more than 62% of IBS patients in all three subtypes (Supplementary Table 2). The differences between female and male IBS patients were significant in all subtypes  exhibited larger microbiome alterations than subjects who never had lactose intake (IBS patients versus paired controls divided by lactose intake), while those who drank red wine achieved the opposite effect  and these associations vary with subtypes  where all the selected cases and controls were strictly filtered and paired from AGP of over 27,000 deeply phenotyped participants,Ruminococcus gnavus, which can induces inflammatory cytokine (TNFα) secretion,16 was more abundant in IBS-D, while constipation-related Oscillospira17 were enriched in IBS-C. We also identified several shared microbial signatures across subtypes, such as Sutterella, which provide new targets for developing general anti-IBS interventions. The 101 subtype-specific bacterial signatures also provided a pool of probiotic candidates against specific IBS subtypes, such as Akkermansia, which may alleviate IBS-D.This study identified bacteria related to the clinical phenotype of IBS. For example, 18 while our findings explain that the accumulated hydrogen sulfide is from the increased SO4ASSIM pathway. Some studies have directly confirmed that hydrogen sulfide can induce diarrhea,19 thus it may also be responsible for the altered stool quality in IBS-D patients. In addition, the LACTOSECAT pathway (increased in IBS-C but decreased in IBS-D and IBS-U) is mainly involved in the degradation of lactose and galactose, and a decrease in this function appears to cause lactose-related dyspepsia, which is an important trigger for IBS symptoms.21 More importantly, our results also revealed that avoiding lactose intake narrows the differences in gut microbiota between IBS patients and controls. All of these provided clues for understanding the effect and mechanism of lactose-free diet on IBS patients. Another novel finding was that the pathway of palmitoleate biosynthesis was increased in IBS-C. While the product of this pathway is palmitic acid, which tends to react with calcium to form insoluble calcium palmitate, and the level of this calcium palmitate is positively correlated with stool hardness.22 Therefore, the enhanced palmitoleate biosynthesis might be the reason for the constipation in IBS-C patients.Subtype-specific microbiota signatures are also reflected in functional alterations. SO4ASSIM pathway that can produce hydrogen sulfide was enhanced in IBS-D and IBS-U. Hydrogen sulfide has antioxidant and immune-regulatory properties, and it can also serve as an oral gas biomarker for IBS-D,23 but the exact pathophysiology underlying this remains unclear.24 Our results showed that IBS patients with depression had a significantly lower abundance of beneficial bacteria such as Bifidobacterium25 and higher levels of pathogenic bacteria including 26Proteus than those without depression. Proteus has been proven to damage neurons in mice,28 so its enrichment in IBS patients with depression may be an important pathogenic factor. In addition, several functional pathways related to SCFAs production were less abundant in IBS patients with depression compared to those without depression. Previous studies have reported reduced concentrations of SCFAs in depressed mice and humans,30 thus lower levels of these pathways may also lead to reduced levels of SCFAs in IBS patients, which may then induce depression. Bacteria depleted in IBS patients with depression like Bifidobacterium are the main strain producing SCFAs, thus supplementing these beneficial bacteria may alleviate the symptoms.Depression is often associated with IBS,31 while our results show that the microbiota compositional difference between female IBS patients and controls is larger than that of males, which suggests that females are more prone to not only IBS but also more severe gut dysbiosis. We also observed an effect of age on the gut microbiota of IBS patients. The magnitude of microbiota compositional difference between IBS patients and non-IBS controls becomes smaller with age in IBS-D but larger in IBS-C, which may explain why young people are prone to IBS-D and older people are prone to IBS-C.2 Diet plays an important role in regulating the gut microbiome.32 Our results show that the effect of dietary factors on gut microbiota varies with IBS subtypes, hence targeted dietary intervention such as eating more fruit or avoiding lactose may help different IBS patients alleviate symptoms.The most important risk factors for IBS are female sex and younger age,This study established the largest deeply phenotyped IBS-control cohort, accurately depicted the gut microbiome signatures at subtype level, and further linked them to depression, age, sex, and diet, which has certain implications for the pathogenesis of IBS. The main findings were also verified by an independent cohort, which further illustrated the robustness of the results. There are also some limitations. This is an observational cross-sectional analysis and some residual and potential confounders maybe not accounted for, and there may be recall bias since diet data is captured using questionnaires. Also, the phenotype data were collected by questionnaire, there may be unknown bias for subtype classification. Moreover, due to the lack of accurate data to meet the criteria of IBS-M, this subtype was not included in our study, and future studies should focus on it to fully understand the association between microbiota and subtypes.In conclusion, our results uncover new insights related to distinct gut microbiome compositional and functional signatures in different subtypes of IBS. These findings highlight the importance of personalized gut microbiome modulation approaches in different subtypes for optimal therapeutic effects.AGP and data availabilityThe AGP was launched by the American Gut Consortium since November 2012.11 Detailed recruitment process for participants is reported on http://americangut.org. A full list of the involved host variables is summarized in Supplementary Table 1. Details about sample collection and processing have been published previously.11 Briefly, samples were collected using BBL culture swabs , returned by mail, and stored at −80°C. All samples were processed using the EMP protocols. The DNA of samples was extracted for 16 rRNA sequencing (V4 region) with an Illumina HiSeq Rapid Run.11 Sequence data are available from the European Bioinformatics Institute (EBI) database under study accession ID: MGYS00000596. Participants’ consents were obtained under the Institutional Review Board human research subject protocols from the University of Colorado, Boulder  or from the University of California, San Diego . No personally identifiable data was included in the public database nor was accessed in the present study.12 the IBS group were further narrowed into 942 subjects by the following exclusion criteria: younger than 18 or older than 80; BMI less than 12.5 or greater than 40; diagnosed with inflammatory bowel disease (IBD) or Type II Diabetes; live outside the United States, the United Kingdom, and Canada; no fecal samples were provided; bowel movement quality was not available; took antibiotics within 6 months. Controls consisted of 5,488 subjects who were selected under the same criterion from a pool of 12,915 subjects who did not have symptoms of IBS.Detailed process about the cohort construction can be found in Supplementary Figure 1. Briefly, 27206 records were downloaded from EBI in Apr 2021, and 3137 of them had IBS symptoms. Self-diagnosed cases of IBS or those diagnosed by an alternative medicine practitioner were excluded, and a total of 2,004 patients diagnosed by a medical professional  were eligible. According to a previous study that evaluated the effects of host factors on gut microbiota,12 including BMI, sex, age, geographical location, alcohol consumption frequency, and dietary intake frequency of meat/eggs, dairy, vegetables, whole grain, and salted snacks. The pairwise Euclidean distances were computed between the IBS and control groups from the above set of matching variables that were normalized to zero-mean and unit variance . Subsequently, an IBS sample and the closest control sample were removed from the selection group and then added to the cohort. The selection process is successive until no IBS samples remain in the selection group. If multiple control samples share the closest distance with IBS sample, the pairwise Euclidean distances among them will be re-calculated based on other host variables (Supplementary Table 1).The pairing algorithm was constructed based on previously identified microbiota-confounding variables,2 based on phenotype data. Specifically, the clinical definition of IBS-D was defined as “I tend to have diarrhea (watery stool)”, and the definition of IBS-C was classified as “I tend to be constipated (have difficulty passing stool)”. Because there were insufficient precise and clear data to meet the criteria for IBS-M that more than 25% of bowel movements with Bristol Stool Score (BSS) 1 or 2 and more than 25% of bowel movements with BSS 6 or 7, thus our analysis did not include the subtype of IBS-M to avoid less robust results. The IBS-U is a distinct category in this study and was classified as subjects who reported to have normal formed stool . Finally, three sub-cohorts were constructed, including IBS-D and their paired controls (non-IBS2), IBS-C, and their paired controls (non-IBS1), as well as IBS-U and their paired controls (non-IBS3). Data released by AGP from Apr-2021 to Dec-2022 were used for constructing a validation cohort using the similar process.Then, the paired case–control cohorts were further divided into sub-cohorts of different IBS subtypes according to the ROME Ⅳ criteriaMetadata with a range of host variables covering clinical characteristics, lifestyle, and diet factors for all participants in AGP were downloaded from the EBI. The majority of host variables in the metadata can be defined as binary with a positive and negative class, which allowed for simple construction of a subset of the samples to be used for binary comparison. Frequency variables were present in the metadata for a set of standard foods and beverage types, in which participants recorded their consumption frequency from a set of five values: daily, regularly (3–5 times per week), occasionally (1–2 times per week), rarely (less than once a week) and never. Binary matched cohorts were constructed from diet frequency variables in which participants who belonged to the ”daily” and ”regularly” consumption groups were matched with the set of participants that belonged to the ”never” group, which was taken as the negative class, and the participants in group ”occasionally” and ”rarely” were excluded to reduce the error rate. Only participants who answered “female” or “male” were reserved for the construction of binary matched cohorts concerning gender. All binary sub-cohorts have a balanced number through the above-mentioned matching algorithm.33 First, samples with fewer than 10,000 reads were removed from the analysis. Reads were denoised by the embedded DADA234 for trimming with a maximum expected error threshold of 1, and reads were truncated at the first base with a Q score of 11 or below. Considering the importance of high-quality sample processing to the results of microbiome profiling,35 previously recognized sequences that were prone to blooming in the process of transporting fecal samples at room temperature were removed by Deblur.36 A table of 16S rRNA amplicon sequence variants (ASVs) was generated, and then annotated using the silva-132-99-515-806-nb-classifier.34 Sequence variants that were present in fewer than 50 samples and in lower total relative abundance than 0.01% were removed from the feature table. The feature tables at different taxa levels (phylum to species) were obtained from QIIME2 online tool (https://view.qiime2.org/). PICRUSt2  was used to generate a function prediction for MetaCyc metabolic pathways.37Raw fastq files were downloaded from the EBI and processed using the QIIME2.http://huttenhower.sph.harvard.edu/galaxy/). Alpha-Diversity (diversity within samples) was assessed using the number of observed species rarefied at the same sequencing depth (10000 sequences per sample in this study). Microbiota compositional characteristics , PCoA, PERMANOVA, and Procrustes analysis were implemented in the vegan R package V.2.5–7. Data were visualized with pheatmap, ggplot2, and dependent R packages. All authors had access to the study data and reviewed and approved the final manuscript.All analyses were carried out in R software V4.0.5. Principal coordinate analysis (PCoA) was used to visualize the clustering of samples based on their bacterial relative abundance, and differences in community composition were tested using paired sample t-test and permutational multivariate analysis of variance (PERMANOVA) with FDR correction. Associations of specific microbial taxa in different levels with participant parameters were identified using the linear discriminant analysis effect size (LEfSe) since we strictly matched the confounding factors of case and control. The multivariate analysis by linear models (MaAsLin2) statistical frameworks was implemented in the Huttenhower Lab Galaxy instance (Click here for additional data file.


Mycobacterium tuberculosis (Mtb) infections. Similar risk factors and mechanisms are discussed between the two conditions and in the case of COVID-19. Lastly, we address emerging approaches to address research needs in infection and metabolic disease, and perspectives with regards to deployment or repositioning of metabolically active therapeutics.Patients with type-2 diabetes (T2D) are more likely to develop severe respiratory tract infections. Such susceptibility has gained increasing attention since the global spread of Coronavirus Disease 2019 (COVID-19) in early 2020. The earliest reports marked T2D as an important risk-factor for severe forms of disease and mortality across all adult age groups. Several mechanisms have been proposed for this increased susceptibility, including pre-existing immune dysfunction, a lack of metabolic flexibility due to insulin resistance, inadequate dietary quality or adverse interactions with antidiabetic treatments or common comorbidities. Some mechanisms that predispose patients with T2D to severe COVID-19 may indeed be shared with other previously characterized respiratory tract infections. Accordingly, in this review, we give an overview of response to Influenza A virus and to  Diabetes is a chronic condition characterized by persistently high levels of glucose in blood due to insufficient insulin action or secretion. The international diabetes federation (IDF) estimates that there will be 783 million adults with diabetes in 2045, which is 46% higher compared to the number of cases in 2021 .In such conditions, immune responses are often studied for potential impairments and as mechanistic targets contributing to severity . In norm2D3)] is modulated by vitamin D receptors (VDRs) that are present in the heart, brain, pancreatic islets, immune cells, muscles and adipose tissue. These are all common target organs in the development of diabetes and its complications , but this is only noted at high glucose concentrations which mimic hyperglycemia -ligands during chronic hyperglycemia activates a p38 dependent pathway that epigenetically reprograms naïve T-cells, making them hyper-responsive to subsequent activation by Mtb antigens  Th1 cytokines, poorer lung histology and higher bacterial burdens and dissemination to organs  presents a continuous threat to human health, infecting up to 15% of the population annually , 100. Inneumonia . This inneumonia . Furtherneumonia . Strikinneumonia . TogetheMuch of the current literature regarding the susceptibility of individuals with diabetes to severe IAV infection emerged in response to the 2009 H1N1 pandemic (pH1N1) and has been addressed in a previous review . Specifiper se is a major contributor to disease severity. Studies using an in vivo STZ-induced model of T1D, demonstrated that diabetic mice had increased viral load with a more extensive infection, and lower rates of survival  metabolic dysfunction, ii) increased viral replication, iii) endothelial dysfunction, and iv) dysregulation of the immune response.in vivo that vaccination via a higher dose, or a second low dose, increases antigen levels in diabetic mice to the point that they are able to protect against an otherwise lethal challenge  for patients with diabetes . During hallenge , 121. Tohallenge . Howeverhallenge , 155, wihallenge . Recentlhallenge . On top hallenge . This suThe above examples of respiratory infections in patients with diabetes clearly indicate a strong interaction between metabolism and successful detection and clearance of invading pathogens from the lung. Whether this be at the level of systemic metabolism or cellular immunometabolic defects that alter immune responses, a wealth of knowledge from cases of influenza and of TB can be used to draw comparisons with COVID-19.Global events since March 2020 have made COVID-19 a near singular preoccupation of medical and research professionals due to the unprecedented strain on healthcare services. Early in the outbreak, T2D and associated metabolic syndrome were identified as risk factors for severity and death from COVID-19 . DiabeteThe earliest report dedicated to COVID-19 patients with T2D revealed that glycemic instability/variability increases risk of severe disease . Furthervia the virus’s main entry point, the Angiotensin converting enzyme (ACE)-2 -2 . The RAA (ACE)-2 , 166. Hovia an interaction with monocytes, hyperglycemia may be an important mechanism-based risk-factor for severe COVID-19. Of note, glycemic control tends to deteriorate with infection in patients with T2D  . This suEfficiency of the COVID-19 vaccine response has been evaluated in patients with T2D. Vaccination has been reported to be efficient in patients with good glycemic control compared to patients with uncontrolled T2D. Therefore, the adaptive immune compartment does not seem to be compromised with regards to antibody production in T2D. However, hyperglycemia in uncontrolled diabetes results in weak immunity, indicating that poor glycemic control can indeed impair the antibody producing branch of adaptive immunity. Two independent studies reported similar results , 187.+ T-cell function, however in an already diabetic context, the use of insulin may be a sign of progressed diabetes and thus an overall less healthy metabolic status of the patient. Use of dipeptidyl peptidase-4 inhibitors did not have an effect on disease outcome. So, these studies indicate that use of antidiabetic agents either improve or do not affect outcome in COVID-19 in patients with T2D; unless patients with T2D have progressed to the stage of use of exogenous insulin. With regards to controlling dyslipidemia, the most commonly used class of drugs is Statins and studies have been ambivalent. Some meta-analyses conclude better outcome from retrospective studies . In this study, the COVID-19-dependent proteome and metabolome represented three major pathways: complement system, macrophage function and platelet degranulation . LipoproThe publication by Wu et al  carried Taken together the above studies report generalized metabolic depression in COVID-19. Although metabolic diseases were not discussed, it is reasonable to assume that pre-existing dysmetabolism, sub-optimal liver function, impaired glucose homeostasis, dyslipidemia, or any other disequilibrium associated with metabolic disease will adversely affect the metabolic response to COVID-19. The above studies indicate that higher risk of severity in metabolic disease may be due to a lack of metabolic flexibility, as required to efficiently respond to SARS-CoV-2 infection. Indeed, the 80% of COVID-19 cases that are mild or asymptomatic, may be so because of their adaptable metabolism, capable of ramping up or down their substrate production or utilization to cope with pathogen burden.Several overarching themes can be drawn in the context of these studies. COVID-19 is associated with: 1) Compromised liver function; 2) Dyslipidemia; 3) Depression or a depression-like molecular profile; and 4) Altered cellular metabolism. The liver response in releasing alarm molecules is common in severe infection and sepsis, compromised function may arise from high viral loads, congestion due to outstripped filtering capacity, or pre-existing intrahepatic triglycerides that impair liver function. Dyslipidemia may be due to increased lipolysis from a highly inflammatory background, which would be aggravated in T2D where fatty tissues lose sensitivity to insulin’s anti-lipolytic effects. Importantly, dyslipidemia and increased lipolysis may also arise due to sickness behaviors that modify energy intake and expenditure, notably a loss of appetite and drop in blood glucose levels causing ketogenesis and reliance on lipid metabolism. Finally, effects were reported on cellular pathways of nucleic acid synthesis, lipid synthesis and oxidative metabolism. The loss of substrates for nucleic acid and lipid synthesis, may be explained by virus-host cell dynamics where viral particles usurp nucleotides for their own replication, and make use of cellular lipids to construct their envelopes. SARS-CoV-2 seems particularly efficient in diverting the use of cellular substrates for its own needs, the authors describe this as a ‘hijacking’ of host cell metabolic machinery . A recenTo put findings into context, over recent years immunometabolism research has characterized systemic immunity in metabolic diseases as well as cellular metabolism associated with immune functions. Yet the metabolic demands of viral infection remain relatively understudied. A hallmark publication by Wang et al. in 2017  highlighTo date, few specific therapies have proven to be effective against COVID-19 , 198. GeAA, FA, RT, FS, KH, KS, JB wrote the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Kuwait Foundation for the Advancement of Sciences (KFAS) grant (RA HM-2019-009). FA was supported by the French National Research Agency  ANR-JCJC grant for the MitoFLAME Project ANR-19-CE14-0005. RT was supported by a grant from the European Foundation for the Study of Diabetes (EFSD). FS was supported by Science Foundation Ireland Award 19/FFP/6625. KS is funded by NHMRC investigator grant 2007919.KS is a consultant for Sanofi, Roche and NovoNordisk.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ScienceDirect, Web of Science, and ClinicalTrials.gov from inception to August 2021 for randomized clinical trials (RCTs) of EEG-NF with self-reported ADHD symptom ratings. Comparators included participants on waitlist/treatment as usual (TAU) or receiving other interventions. Of the 279 participants  in five eligible RCTs, 183 received EEG-NF treatment. Forest plot demonstrated no difference in inattention , total score , and hyperactivity/impulsivity  between EEG-NF and comparison groups. Nevertheless, compared with waitlist/TAU, EEG-NF showed better improvement in inattention  but not hyperactivity/impulsivity . Follow-up 6–12 months demonstrated no difference in inattention , total score , and hyperactivity/impulsivity  between the two groups. Dropout rate also showed no difference . Our results support EEG-NF for improving inattention in adolescents/young adults, although its effectiveness against hyperactivity/impulsivity remains inconclusive.Self-reported effectiveness of electroencephalogram-based neurofeedba Although pharmacotherapy remains the mainstay of treatment for severe cases2, its long-term safety and efficacy remain unclear3. Indeed, side-effects associated with pharmacological treatment of ADHD are still an important concern6. To minimize drug-related side-effects and enhance treatment efficacy, a recent review has endorsed a combination of pharmacotherapy and cognitive behavioral therapy (CBT)7, despite a lack of information about its long-term outcome.There are both pharmacological and non-pharmacological treatments for attention-deficit hyperactivity disorder (ADHD), a global illness with a prevalence of up to 5% among children and adolescents9. EEG-NF involves the conversion of extracted signals of brain activities into pre-selected brain parameters in the form of a specific brain potential or frequency band  that are made perceivable to the participant. Such a feedback could allow neuroplasticity to improve cognition and behavior through self-regulation of one’s own brain activity9. EEG-NF is currently used for normalizing aberrant brain activity associated with neurocognitive disorders, enhancing cognitive performance in healthy individuals , and studying the role of neural oscillations in behavior and cognition9. Despite its development as early as in the 1930s8 and the first demonstration of its potential effectiveness against hyperactivity and distractibility in a child with hyperkinetic syndrome10, the benefits of EEG-NF in the treatment of the core symptoms of ADHD remains controversial. While some studies supported its effectiveness against the symptoms of ADHD with minimal-to-no side-effects9, another study on adult patients did not share the same findings11.On the other hand, there has been evidence in favor of the use of electroencephalogram-based neurofeedback (EEG-NF) in the treatment of patients with ADHD15. Nevertheless, previous studies have demonstrated a relative reduction in beta activity with increasing age in patients with ADHD13. Together with the clinical observation of a diminished hyperactivity component in adult patients compared with that in children with ADHD despite persistent impulsivity in the former, a previous study has proposed an association between decreased beta activity and hyperactivity as well as that between increased theta activity and impulsivity13. Hence, the findings may suggest a potential difference in effectiveness of EEG-NF against the core symptoms of ADHD between children and adults. Another issue when considering the difference in effectiveness of EEG-NF against symptoms of ADHD between children and older individuals is the approach to outcome assessment; while children were mostly evaluated by proximal and probably blind observers17, adolescent and adult patients can self-report the efficacy of treatment.Current application of EEG-NF in patients with ADHD mainly focuses on enhancing beta activity or suppressing theta/beta (4–7 Hz/12–21 Hz) ratio (TBR) in central and frontal locations as high theta power, high theta/beta ratios, and/or low beta power are commonly observed in children and adults with ADHDTherefore, focusing on adolescents and adults, the current meta-analysis reviewed the efficacy of surface EEG-NF against the symptoms of ADHD from a patient’s perspective. We also investigated the therapeutic impact of EEG-NF on different core symptoms of ADHD .The current meta-analysis was conducted according to the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and was registered at the PROSPERO international database (Number: CRD42021275952).We searched the databases of PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ScienceDirect, Web of Science, and ClinicalTrials.gov from inception to August 2021. The keywords used in different databases are listed in Supplemental Table 1. No publication date or language restriction was applied. To expand our search results, the reference lists of specific review/original articles were also searched for cross-referencing.Studies meeting the following PICOS criteria were considered eligible for inclusion: (1) Population: patients who had a diagnosis of ADHD compatible with that documented in the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Statistical Classification of Diseases and Related Health Problems (ICD); (2) Intervention: surface electroencephalography neurofeedback (EEG-NF); (3) Comparison interventions: waitlist, treatment as usual (TAU) or any interventions other than surface EEG-NF such as pharmacological treatment or cognitive training; (4) Outcome: self-reported rating scales for symptoms of ADHD; and (5) Study design: randomized controlled trials (RCTs). The exclusion criteria included: (1) animal studies, (2) unavailable information about target outcomes, and (3) non-RCTs.After removal of duplicates, two authors examined the eligibility of the articles according to the titles and abstracts. In the situation of discrepancy, the corresponding author was involved. On full-text review, an independent author selected trials for inclusion and documented reasons for exclusion of the ineligible studies. The above three authors also extracted the data of primary and secondary outcomes as well as clinical variables of interest, such as duration of follow-up, mean age, gender distribution, and number of NF sessions. When data were unavailable in the included trials, the authors of the selected studies were contacted for missing information up to two times over a month for data acquisition.Primary outcomes were improvements in self-reported rating scales, including sub-scales such as inattention and hyperactivity/impulsivity for symptoms of ADHD, and secondary outcomes were dropout rates.18. The risk of bias was classified as “low”, “unclear”, or “high” for the following key domains: (a) sequence generation; (b) allocation concealment; (c) blinding of participants and personnel; (d) blinding of outcome assessment; (e) incomplete outcome data; (f) selective outcome reporting; and, (g) other sources of bias. Disagreements were solved by discussion.For each trial, two authors independently assessed the risk of bias using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions, including the overall risk of bias of all the included trials and the risk of bias of individual studies2 statistic was utilized for heterogeneity assessment 19. To evaluate stability of the results, sensitivity analysis was conducted by removing one study each time. We examined the funnel plots when we identified 10 or more studies reporting on a particular outcome to investigate the potential of reporting and publication bias. The significance level was set at 0.05 for all analyses.Cochrane Review Manager  was applied for data synthesis. For dichotomous outcomes, risk ratios (RRs) with 95% confidence intervals (CIs) were calculated by using a random effects model. The Mantel–Haenszel (M–H) method was used to pool dichotomous data and to compute pooled RRs with 95% CIs. As the included trials may use different scales to measure the same outcomes, standardized mean differences (SMD) with 95% CIs were calculated to estimate the effect size. The I23.The PRISMA flowchart summarizing the process of study selection in this systematic review is shown in Fig. 21 allowed the use of psychostimulants in different proportions of participants (13.3–60%) in their study groups  biofeedback23, medications21, and sham control11. Of all the eligible studies, four conducted a follow-up investigation23. The post-treatment follow up duration ranged from 6 to 12 months. Focusing on the risk of bias , 2.9% (1/35), and 31.4% (11/35) of the included studies had an overall low, unclear, and high risk of bias, respectively. None of the studies received financial support from pharmaceutical companies.The characteristics of studies are shown in Table cipants 1.3–60% inp = 0.46; I2 = 25%; five trials, n = 277), total score , and hyperactivity/impulsivity  between EEG-NF and comparison groups   and hyperactivity/impulsivity  between patients receiving EEG-NF and those serving as waitlist/TAU controls , total score , and hyperactivity/impulsivity  between EEG-NF and comparison groups  available for the analysis of dropout rate showed no significant difference between EEG-NF and comparison groups   of EEG-NF up to 24% to 50% being reported in patients with ADHD when comparing the rating by most proximal  evaluators with that by probably blind observers17. Therefore, it is important to understand the patients’ subjective feelings about the effectiveness of surface EEG-NF, especially for adolescents and adults who have a better self-awareness of ADHD symptoms than that in children, because their views may be different from those of their parents or teachers29. Moreover, motivation to participate in a treatment program is also an important factor influencing the therapeutic outcome, especially for adolescents30. From our research, it is surprising that we were only able to identify five RCTs which included self-reported rating scales in their outcome measurements23, even though there were more than 20 RCTs investigating the efficacy of surface EEG-NF in patients with ADHD17. It seems that therapeutic effects of surface EEG-NF from patients’ own perspective were largely ignored in the previous RCT studies, perhaps partly due to a poor awareness of the patients’ own attentional status among young children31. Due to the relative paucity of previous RCTs focusing on self-reported efficacy of surface EEG-NF, our results were only preliminary. Our findings showed a significantly better improvement in inattention among adolescents and young adults with ADHD receiving surface EEG-NF  than that in those in the waitlist/TAU group. However, surface EEG-NF was not significantly more effective for improving symptoms of ADHD when compared with a mixed group of comparators .To our best knowledge, this is the first meta-analysis to focus on the efficacy of surface EEG-NF against the symptoms of ADHD based on subjective reports from patients’ perspective. Although there were many previous meta-analyses investigating the therapeutic effects of surface EEG-NF on ADHD symptomsp = 0.009) but not from the evaluation by blind evaluators 17. Our study result, which failed to show significantly better therapeutic effects of surface EEG-NF than other active interventions, is consistent with the observation from probably blind evaluators in that meta-analysis17. Moreover, apart from the impact of evaluators on treatment outcomes of surface EEG-NF17, age could also be an important confounder. Because children may be less aware of their attentional problems, they may benefit more from EEG-NF than adults based on the theories of operant conditioning32 and brain plasticity33. Therefore, the inclusion of much older age groups (mean age: 23.48 years) in our meta-analysis than those in previous meta-analyses focusing on children17, may also contribute to the relatively weak efficacy of NF in our study. Indeed, previous studies on exclusively adult patients demonstrated that, although surface EEG-NF was effective for alleviating symptoms of ADHD, it offered no additional therapeutic benefit than that in sham controls or those undergoing meta-cognitive training or EMG biofeedback 23. Therefore, further studies are warranted to investigate the effects of age and patients’ subjective perception on the efficacy of surface EEG-NF in adolescents and adults.Previous meta-analyses failed to demonstrate a consistent finding regarding the efficacy of surface EEG-NF between most proximal  and probably blind  evaluators. A meta-analysis which included both active and non-active treatments in the comparison group showed a superior effectiveness of surface EEG-NF against the symptoms of ADHD only from the observations of most proximal evaluators . Nevertheless, because our subgroup analysis only included two RCTs that enrolled participants with age ranging from 12 to 24 years17, the finding may not be extrapolated to older adults whose brain plasticity and learning process may be different from those in the younger age group33. A possible difference in mechanism underlying the improvement in inattention between children and adults was highlighted by the finding of one of our five included studies that focused on older age groups (18–60 years)11. That study demonstrated that clinical improvements in adults were unrelated to the theta-to-beta ratio in EEG11, which is believed to be a treatment target for children with ADHD9. Further studies are needed to validate our findings and elucidate the impact of age in this setting.Despite the failure of our preliminary findings to show a better effectiveness of EEG-NF than that of other active interventions, our subgroup analysis found a significantly better improvement in inattention in patients receiving surface EEG-NF compared with that in the TAU or waitlist group with a moderate effect size (SMD: -0.48). This result suggests the effectiveness of surface EEG-NF when used as a single or add-on therapy against attentional problems in adolescents or young adults with ADHD who only receive routine care. Consistently, a previous meta-analysis comparing surface EEG-NF with non-active controls showed that surface EEG-NF was effective for improving inattention in patients with ADHD  could not exclude possible improvement in hyperactivity/impulsivity associated with the use of surface EEG-NF in adolescents and adults. In addition, the TB protocol, which was the most common treatment approach in our included studies , was originally designed to enhance arousal rather than suppress impulsivity9. Therefore, its therapeutic effect may be better reflected by an improvement in arousal-related manifestations  than that in hyperactivity/impulsivity. This was supported by the finding of smaller effect sizes associated with EEG-NF treatment against hyperactivity/impulsivity compared to those related to improving inattention in previous meta-analyses17.In contrast to the findings of previous meta-analyses that showed consistent positive therapeutic effects of EEG-NF against hyperactivity/impulsivity in children35. On the other hand, when focusing on comparison with comparators with non-active treatments, that meta-analysis showed more durable treatment effects associated with surface EEG-NF. However, the availability of only one study with follow-up information on patients receiving non-active interventions in the current meta-analysis precluded our conduction of relevant analysis. Finally, the lack of difference in dropout rate between surface EEG-NF and comparison groups with other interventions suggests their comparable tolerability.With regards to long-term treatment effects, our study did not find superiority of surface EEG-NF to comparison groups which included both active and non-active treatments. Our result was similar to that from a previous meta-analysisn = 279) and need to be supported by more large-scale clinical trials. Second, despite being the first meta-analysis to investigate the therapeutic impact of surface EEG-NF from a patient’s perspective among adolescents and young adults, our findings may not reflect the improvement in neurocognitive ability or observations from teachers or parents. Third, because most of the included studies did not use double-blinding design, the possibility of subjective placebo effects could not be excluded. Fourth, the confounding effects of medications cannot be excluded because four out of our five included trials did not control medication use in the study arm. Therefore, further studies are needed to elucidate the impacts of medications on the therapeutic effects of surface EEG-NF. Finally, although subgroup analyses focusing on different interventions in the comparison groups would minimize bias in the current study, it was only performed to compare surface EEG-NF with TAU/waitlist because of insufficient number of studies for the conduction of other subgroup analyses. Further studies are warranted to evaluate the differences in therapeutic efficacy between surface EEG-NF and other interventions.The present meta-analysis had its limitations. First, our results are preliminary because of the inclusion of only five RCTs with a limited number of participants (Focusing on self-reported efficacy of surface EEG-NF, the results of the current meta-analysis support the use of surface EEG-NF for improving inattention in adolescents and young adults, either as single or add-on therapy, despite the small numbers of included trials. Nevertheless, current evidence supporting the therapeutic effect of surface EEG-NF against hyperactivity/impulsivity remains inconclusive. Further large-scale randomized controlled trials focusing on adolescents or adults are warranted to support our findings.Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.


Neoadjuvant therapy, which aims to achieve a pathological complete response (pCR) for better overall survival (OS) has several advantages for patients with early breast cancer (eBC) and subtypes of HER2-positive (HER2+) and triple-negative breast cancer (TNBC). However, there has been no large-scale real-world investigation on the clinical outcomes associated with trastuzumab-based and platinum-based neoadjuvant treatments for patients with HER2+ and TNBC, respectively.Taiwan Cancer Registry and National Health Insurance Research Database were utilized in this study. Patients diagnosed with clinically lymph-node-positive (LN+) HER2+ or TNBC were identified for analysis. Logistic regression and Cox proportional hazard models were employed to estimate the adjusted odds ratios (aOR) of achieving pCR and adjusted hazard ratios (aHR) of overall survival associated with treatment agents, respectively.A total of 1,178 HER2+ eBC and 354 early TNBC patients were identified, respectively. Neoadjuvant trastuzumab significantly increased the pCR rates by 3.87-fold among HER2+ patients. Trastuzumab-associated survival benefit was found in HER2+ patients who achieved pCR (aHR [95% CI]: 0.30 [0.11-0.84]) but not in those without pCR (1.13 [0.77-1.67]). Among the TNBC patients, platinum was associated with a 1.6-fold increased pCR rate; however, it did not improve OS regardless of pCR status.Trastuzumab improved pCR and OS for patients with HER2+ subtype. Using platinum agents for TNBC patients increased pCR rates but was not linked to better survival. Optimal neoadjuvant anti-HER2 therapy for patients with HER2+ eBC and the introduction of novel therapy for patients with TNBC should be considered. Neoadjuvant therapy offers some advantages for patients with early breast cancer (eBC), including down-sizing of tumors, an opportunity for less extensive surgical resection, and outcome assessment and risk stratification based on results of pathological status . AttainiFor patients with HER2+ eBC, anti-HER2 monoclonal antibodies with chemotherapy are the standard of care in neoadjuvant settings. Trastuzumab, the first anti-HER2 monoclonal antibody, significantly enhances the pCR rates for the HER2+ population –7 and isFor TNBC, the benefit of adding platinum agents, which have cytotoxic DNA-damaging effects, to neoadjuvant therapy to enhance pCR rates has been observed in trial –13 and rAgainst this background, the present study assessed the real-world survival outcomes associated with specific neoadjuvant treatments among high-risk eBC patient populations  using large-scale real-world databases to allow long-term observation of survival outcomes as well as rigorous analytic strategies to ensure the validity and practicability of study findings for daily treatment and health policy decision-making.The Taiwan Cancer Registry (TCR) and the National Health Insurance Research Database (NHIRD), two nationally representative data sources in Taiwan, were utilized in this study. The TCR is a nationwide cancer registry database that covers 97% of Taiwanese patients with confirmed cancers and provides essential information for newly diagnosed cancer cases such as the clinical and pathological tumor, node, and metastasis staging at cancer diagnosis . The NHIde novo eBC during 2011-2016 and without any malignancy history before BC diagnosis to avoid potential confounding from prior cancers. Patients without available information for measuring the date of BC diagnosis and its subtypes  and determining the eligibility of receiving neoadjuvant therapy  were excluded to minimize potential misclassification bias. Second, among patients who were eligible for neoadjuvant therapy, those having the clinical staging of lymph-node-positive (LN+) were further identified under consideration of available neoadjuvant drugs. To reduce the heterogeneity of the study subjects, patients who had not received BC surgery within 1 year of BC diagnosis were excluded. Third, patients who received neoadjuvant therapy and whose pCR status was available were identified. The initiation date of neoadjuvant therapy was defined as the index date. Lastly, we only included patients with the HER2+ or TNBC subtype in the study cohort for analyzing treatment-associated outcomes .First, we included patients aged ≥ 18 years with The study subjects were followed from the first date of neoadjuvant therapy  until death, loss of follow-up, or the end of data availability of the NHIRD , whichever came first. The cohort selection is detailed in Information on neoadjuvant therapy and exposure to the given treatment agents were obtained from the NHIRD and defined using the Anatomical Therapeutic Chemical Classification System . The treatment-associated outcomes, pCR (defined as ypT0/is ypN0) and survival status of study subjects, were confirmed by the TCR and the Cause of Death File in the NHIRD, respectively. Patients’ baseline comorbidities in the year prior to or at the index date were measured based on the disease diagnosis records in the NHIRD using the International Classification of Diseases, Ninth Revision, Clinical Modification and the International Classification of Diseases, Tenth Revision, Clinical Modification, and are presented according to the Charlson Comorbidity Index (CCI) .t-test and the chi-squared test for continuous and categorical variables, respectively. The pCR rate was calculated as the number of patients with pCR divided by the number of total study subjects. The OS values of patients with and without pCR are plotted separately using Kaplan-Meier (KM) curves. The association between pCR achievement and patients’ OS was analyzed using Cox proportional hazard models, which modeled the time-to-death of individual subjects as a function of treatment exposure  with adjustment for patients’ baseline characteristics. The relative hazards of the all-cause death of patients with pCR versus those of patients without pCR are presented as adjusted hazard ratios (aHRs) with the associated 95% confidence intervals (CIs).The adoption rate of neoadjuvant therapy was calculated as the number of patients who had undergone neoadjuvant therapy divided by the number of patients who were eligible for neoadjuvant therapy. The Cochran-Armitage test was used to evaluate the time trend of adoption rates in the period 2011-2016. The descriptive statistics of patients’ baseline characteristics were measured and are presented as mean values with standard deviations for continuous variables and frequencies with proportions for categorical variables. In addition, the differences in patients’ baseline characteristics between study comparison groups  were evaluated using Student’s p-values were two-tailed; values of less than 0.05 were considered statistically significant. The above statistical analyses were conducted using SAS 9.4 software .Further, the clinical effectiveness of achieving pCR associated with individual treatment agents, namely trastuzumab for HER2+ patients and platinum agents for TNBC patients, was assessed using logistic regression models and is presented as adjusted odds ratios (aORs) with the associated 95% CIs. Survival analyses  were also applied to evaluate the trastuzumab- and platinum-associated survival outcomes for HER2+ and TNBC patients, respectively. All p-values for time trend <0.0001). Overall, for the period 2011-2016, a total of 1,178 HER2+ and 354 TNBC patients who received neoadjuvant therapy and had a known pCR status were identified as study patients for the analysis of treatment-associated outcomes. Among selected study subjects, docetaxel, cyclophosphamide and epirubicin were the most commonly prescribed chemotherapy agents for both HER2+ and TNBC patients . Second, the present study was conducted in a clinical setting with treatments mainly covered by the NHI program. Third, only patients with clinically LN+ status were included in this study, which led to a higher risk of mortality compared with that in previous studies. We only collected data from LN+ patients because trastuzumab is not a reimbursed neoadjuvant item for patients with negative-lymph-node status in Taiwan and taxanes could not be used for the TNBC population without lymph node metastasis before September 2012. Although this cohort enrolled patients with higher risk of recurrence and no assistance from novel agents, we still demonstrated that achieving pCR by neoadjuvant treatment was associated with better survival outcomes compared to those of patients who did not achieve pCR 4. NeverIn neoadjuvant settings, the benefit of trastuzumab for enhancing pCR rates among HER2+ eBC patients has been reported worldwide , 6. HoweBy using a large Asian patient cohort that allowed comprehensive and detailed stratification analyses, we corroborated a significantly higher pCR rate following trastuzumab therapy (aOR [95% CI]: 4.87 [3.34-7.10]) and further showed the apparent survival benefit of trastuzumab treatment among patients with pCR achievement (aHR [95% CI]: 0.30 [0.11-0.84]). Accordingly, we infer that achieving pCR using anti-HER2 target therapy  is promising for favorable survival outcomes of HER2+ patients.Regarding patients who did not achieve pCR following trastuzumab-based neoadjuvant chemotherapy, trastuzumab may offer little survival benefit compared with chemotherapy alone. A possible solution is to incorporate other anti-HER2 targeted agents such as pertuzumab to increase the pCR rate –10. AnotBRCA1/2 mutations improved TNBC patients’ prognosis. Therefore, neoadjuvant treatment remains an important strategy for achieving pCR, which is a key treatment goal for these patients . Some neoadjuvant drugs such as nanoparticle albumin-bound paclitaxel, bevacizumab, and pertuzumab, which have been reported in the literature, are not reimbursed by Taiwan’s NHI program and thus the use of these drugs could not be ascertained in this study. However, there is no indication for the use of nanoparticle albumin-bound paclitaxel or bevacizumab for eBC in Taiwan, and the indication of pertuzumab for eBC was filed in August 2015. Therefore, the utilization of these neoadjuvant drugs may have less impact on our study findings. Second, because the recording of recurrent or metastatic status is not mandatory in the TCR, it is difficult to differentiate the primary malignancy, secondary malignancy, or even recurrent events. As a result, the event-free survival of patients was difficult to justify in our data and thus not analyzed in this study. Third, the relationship between survival and adjuvant therapy after surgery was not assessed. Considering treatment patterns after surgery, the escalation of treatment intensity may be more frequently observed in the non-pCR population in contrast to the de-escalation of treatment in the pCR population. Therefore, because the difference in survival outcomes between the pCR and non-pCR populations is statistically apparent, providing detailed information of adjuvant treatments offers a trivial benefit. Fourth, details of patients’ treatment plan for neoadjuvant therapy  were not available in our administrative claims database. Therefore, additional information on the completion or tolerance of neoadjuvant treatment regimen among study populations were unable to be demonstrated or analyzed. Lastly, the generalizability of our study findings might be limited to Asian settings with national health insurance programs. However, the treatments that are reimbursed in the health insurance setting in our study reflect standard care in the most health care systems in developing countries. Therefore, our findings may be of value for real-life decisions in routine care settings.Achieving pCR was confirmed to be an important goal for better survival outcomes in HER2+ eBC and TNBC populations. Trastuzumab therapy provided HER2+ eBC patients a better chance of achieving pCR and overall survival. However, the use of platinum agents in TNBC settings only increased pCR rates; it did not further contribute to better survival outcomes. Therefore, optimal use of anti-HER2 target therapy in HER2+ eBC populations and the urgent need for novel therapy for TNBC should be considered in clinical treatment and health care policy decisions.The datasets presented in this article are not readily available due to the data privacy and protection policy of the Health and Welfare Data Science Center. Requests to access the datasets should be directed to the corresponding author/s.This study was approved by the Institutional Review Board of National Cheng Kung University (A-EX-106-029). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Conception and design: W-PC, S-RY, C-TY, C-YS, H-WS, S-YL, H-TO. Analysis and interpretation of the data: W-PC, C-TY, H-TO. Drafting of the article: W-PC, C-TY, H-TO. Critical revision of the article for important intellectual content: W-PC, C-TY, H-TO. Provision of study materials or patients: H-TO. Statistical expertise: C-TY, H-TO. Administrative, technical, or logistic support: C-YS, H-WS, S-YL, H-TO. All authors contributed to the article and approved the submitted version.