There are no validated screening measures for depressive or anxiety disorders in childhood Systemic Lupus Erythematosus (cSLE). We investigated cross-sectionally (1) the prevalence of depressive and anxiety disorder in cSLE. (2) the validity of the Centre for Epidemiologic Studies Depression Scale for Children (CES-DC) and the Screen for Childhood Anxiety and Related Disorders (SCARED) measures in identifyingthese disorders.Participants 8-18 years with cSLE/incipient cSLE completed CES-DC, SCARED, and Quality OfMy Life (QOML) measures. Parents completed the SCARED-Parent measure. Diagnosis was by gold-standard psychiatric interview and determined prevalence of psychiatric disorder. Receiver Operating Characteristics Area under the Curve (ROCAUC) evaluated screening measure diagnostic performance.Ofseventy-two parent-child dyads, 56 interviews were completed. Mean screen scores were: CES-DC = 15 , SCARED-C = 22 , SCARED-P = 13 . Depressive disorder screen positivity (CES-DC ≥ 15) was 35% . Anxiety disorder screen positivity (SCARED ≥ 25) was 39% . CES-DC ROCAUC = 0.98 and SCARED-C ROCAUC = 0.7 (cut-points 38 and 32 respectively).Diagnostic thresholds for depressive and anxiety disorderscreening measures are high for both CES-DC and SCARED-C in cSLE. Brief focused interview should follow to determine whether psychiatric evaluation is warranted. Studies investigating the prevalence of depressive and anxiety symptoms in childhood-onset SLE (cSLE) are sparse, particularly with respect to anxiety.Systemic Lupus Erythematosus (SLE) is a chronic, multisystem autoimmune disease which may present with greater disease severity in childhood. The propensity for neuropsychiatric SLE (NPSLE), as well as the common requirement for corticosteroid treatment for disease management, are risk factors for depressive disorder.4 Moreover, children and youth with SLE may be vulnerable to depressive and anxiety disorders for several reasons. The experience of a serious chronic health condition with associated treatment burden may lead to significant psychological distress, fearfulness and hopelessness for the future. Second, depressed mood may present as part of the symptom constellation of NPSLE. Third, corticosteroids administered for disease flares and NPSLE have a known association with adverse psychiatric effects, most commonly depressed mood. Joint pain and arthritis are also common disease manifestations, leading to chronic pain, a risk factor for depression and anxiety and poor quality of life. Finally, cSLE is known to present with more frequent episodes of disease activity and greater risk of hospitalization compared with adult-onset disease.7Depressive and anxiety disorders in cSLE are known to impact negatively on disease self-management and treatment adherence which has been associated with increased healthcare utilization. Several studies investigating depressive and anxiety symptoms in cSLE have equated elevated screening measure scores with a diagnosis of depressive and anxiety disorders, despite the lack of a gold standard diagnostic psychiatric interview to confirm the disorder. Screening questionnaire measures are useful if they can accurately identify psychiatric disorder. However, the validity of screening measures in the detection of depressive and anxiety disorders among children with SLE has not been previously examined. Screening measures should be accurate and minimize the risk of false positive and false negative results. False positive screening results may lead patients to unnecessary consultations and/or prescription of psychotropic medication. In addition, falsely positive screening tests may lead children and families to misunderstand the etiology of their psychological distress, thereby resulting in other changes in behaviour which would otherwise not have occurred – a “nocebo effect”.11 False negatives represent a failure to identify psychiatric disorder, may reduce future healthcare seeking behaviour and may constitute a missed opportunity to address modifiable mental health risk factors.A systematic review of the limited evidence available has shown wide-ranging prevalence rates of depressive and anxiety symptoms in cSLE, in part due to different screening measures, mixed disease samples and methodological limitations. psychiatric disorder. The aims of the present study were to examine the prevalence of depressive and anxiety disorders in cSLE, and to determine the diagnostic performance of commonly used screening measures to detect depressive and anxiety disorders against a validated gold-standard diagnostic psychiatric interview.Findings from studies of psychiatric symptoms in adult-onset SLE or in other chronic pediatric diseases cannot be simply extrapolated to make inferences about screening measure validity in the cSLE population. To our knowledge, there are no studies in cSLE which report on the prevalence of depressive and anxiety symptoms reaching diagnostic threshold for a Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) or SLICC  classification criteria for SLE or had incipient SLE (‘Incipient SLE’ defined by 3 but < 4 ACR classification criteria for SLE). Patients who did not speak English fluently were excluded from the study.Participants were recruited from the paediatric SLE outpatient clinic at The Hospital for Sick Children between July 2017 and November 2019. Patients aged 8 to 18 years, and their families, were approached during routine clinic visits by a member of the research team. Patients were eligible to participate in the study if they met all three criteria: (1) diagnosed with SLE prior to 18 years of age, (2) diagnosed with SLE for at least 6 months to allow for an adjustment period following diagnosis,(3) met American College of Rheumatology (ACR) children and adolescents were deemed capable of ethically and medically consenting for their participation in the research presented in this manuscript. The study was approved by the Research Ethics Board of the Hospital for Sick Children (REB number 1000056640).The study comprised two visits, the first of which involved the collection of socio-demographic data. During the second study visit,participants completed self-report depression and anxiety screening measures;parents (where available) completed a parent-about-child screening measure for anxiety symptoms only. Participants underwent a face-to-face semi-structured diagnostic psychiatric interview by a trained interviewer blinded to the self-report screening scores. Study visits were linked to routine outpatient SLE clinic visits. Participants who met diagnostic criteria for depressive or anxiety disorders following diagnostic interview were offered referral to the Department of Psychiatry for further assessment and/or treatment.Community volunteer hours (a requirement for high school graduation in Ontario) were provided to participants in appreciation for their time in study participation. As there is no age of consent in Canada,17 Convergent validity of the CES-DC with other depression inventories for children and young people has been demonstrated. Items inquire about symptoms occurring over the pastweek. The CES-DC has a four-factor structure: depressed affect (7 items), somatic complaints (7 items), positive affect (4 items), and interpersonal problems (2 items). Responses are based on a four-point Likert Scale from 0-3 . Four of the items (the positive affect domain) are phrased positively e.g. “I was happy” and are thus scored in reverse order.The total score range is 0-60 and higher total scores reflect a greater level of self-reported depressive symptoms. Initial validation of the CES-DCas a screening measure for Major Depressive Disorder has suggested the cut-point score of 15 or greater as suggestive of potentially clinically significant depressive symptoms among children and adolescents in the community.The Center for Epidemiologic Studies Depression Scale for Children (CES-DC) is a freely available, widely-used, 20-item self-report screening questionnaire measure of current depressive symptoms among healthy and unwell children and adolescents aged 8-17 years. The two available measures: The Parent about Child version and the Child (self-report) versionwere offered to the participant and the caregiver for completion. For the self-report, items are phrased as statements which describe feelings the child may have experienced during the past 3 months. Responses are based on a 3-point Likert Scale from 0-2 . The possible score range is from 0-82. Items are further classified into five domains:generalized anxiety (8 items), separation anxiety (8 items), social phobia (7 items), school phobia (4 items) and panic/somatic anxiety (13 items). A total score of 25 or greater indicates a positive screen for the presence of clinically significant anxiety symptoms in community-based samples.The SCARED is a freely available 41-item validated screening questionnaire used for assessment of anxiety symptoms in children and adolescents aged 8-18 years. It contains three items assessing current ratings of QOL, HRQOL and change in QOL since the previous clinic visit. For the first two items, respondents are asked to record ratings for QOL and HRQOL on a 100 mm visual analogue scale ranging from 0 (the worst) to 100 (the best).The third item is the completion of the statement “Since the last time I was here, my life is…”with a response chosen from a 5-point ordinal scale .The QOML is a measure of both Quality of Life (QOL) and Health Related Quality of Life (HRQOL) and was developed in a paediatric rheumatology sample.22 The instrument allows for a diagnostic assessment in accordance with DSM- 5 criteria not only for Major Depressive Disorder (MDD) but for all mood disorders. The brief introductory interview component allows the parent (and child) to provide important information regarding medical and psychiatric history, significant life events and social/educational functioning. This contextual information together with the diagnostic screen interview allows the interviewer to determine the presence of a current/past mood disorder diagnosis and their severity. Interviews were conducted by a child and adolescent psychiatrist (MQ) and clinical psychologist (AD) trained in the use of the instrument in patients with cSLE. The present study focused on current  diagnoses of mood and anxiety disorders. The Depression section of the K-SADS-Present Episode Version (K-SADS-Dep-C) and Anxiety supplements of the K-SADS-PL-5 were used to determine the presence of syndromal level symptoms.The K-SADS-PL-5 has been validated in numerous research and clinical settings and consists of an interview screening section and six disorder-specific supplements.The patient chart was used to provide data regarding date of birth, sex, medical history and associated medical treatments at the time of interview. Dates for cSLE medication treatments and medication doses including corticosteroids and immunosuppressants were recorded. cSLE specific data collected from the Hospital for Sick Children Division of Rheumatology SLE database included: (a) date of SLE diagnosis and SLE manifestations (ACR and SLICC classification criteria) (b) central nervous system involvement (other than mood disorder or anxiety disorder) (c) renal involvement (d) presence of antiphospholipid antibodies (e) joint pain/arthritis.Descriptive statistics were used to summarize the sample characteristics . Frequency analysis determined the distribution of screening measure scores for CES-DC (including domains), SCARED-Child and SCARED-Parent measures. Spearman’s correlation co-efficient was used to investigate the relationship between the non-parametrically distributed dichotomous MDD diagnostic status with CES-DC total score, CES-DC domains and QOL. Pearson’s correlation co-efficient investigated the relationship between CES-DC total score and QOL with CES-DC domains. Similarly, the relationship between both SCARED measures and QOL was investigated. Analyses were completed using Addinsoft 2019 XLSTAT statistical analysis and data solution software. was used to evaluate the performance of the CES-DC and both SCARED screeners against diagnostic interview to accurately detect current cases of MDD and any anxiety disorder (by DSM-5 criteria). Cases were defined as participants with diagnostic interview confirmed MDD or anxiety disorder. The ROC curve expresses the true positive rate (sensitivity) as a function of the false positive rate (1-specificity) for a range of screening measure cut-points and evaluates the ability of each screening measure to discriminate cases from non-cases. The area under the ROC curve (AUC) was estimated to quantify this and evaluate the diagnostic performance of each screening measure. An AUC value of 0.5 represents discriminatory ability no better than chance whereas a value of 1 represents perfect discriminatory ability.Receiver operating characteristics (ROC) analysis, Hanley and McNeil method flow diagram of participant enrolment in the study. Of 89 patients who were approached, 72 children and adolescents (81%) consented to take part and completed baseline study questionnaires and demographic forms at the first study visit. Sixteen participants were excluded from the final analysis (see ysis see . The stuThe mean CES-DC score of the sample (n = 56) was 14.9  . The CESThe mean SCARED-Child screening score (n = 56) was 22  . Based oThe mean QOL score for the sample was 70 . Mean HRQOL score was 64  (missing observations n = 5). CES-DC total score had a moderate negative correlation with overall QOL (r = -0.57) and with HRQOL (r = -0.44). SCARED-Child measure correlated weakly with QOL and HRQOL (r = -0.28 and r = -0.36 respectively) . SCARED-Parent measure showed the weakest relationships with QOL (r = -0.08) and HRQOL (r = -0.04) .Current and past psychiatric disorder by diagnostic interview are summarized by DSM-5 diagnosis in The prevalence of any current anxiety disorder was 16.1% (n = 9). Social anxiety disorder was the most prevalent anxiety disorder (7.1%), followed by generalized anxiety disorder (5.3%). Other anxiety disorders are provided in The ability of each screening measure to correctly identify patients with mental disorders from the corresponding diagnostic groups is reported in p < 0.01). The optimal cut-point was a CES-DC score of 35 (point of maximum sensitivity+ specificity). Sensitivity of the CES-DC at this score was 100% and specificity was 96% with positive predictive value of 58% and a negative predictive value of 100%.The SCARED-Child measure ROCAUC was 0.71 (p < 0.05). The optimal cut-point of 30 gave a sensitivity of 56% and a specificity of 85% for this screening measure with PPV of 42% and NPV of 91%. The SCARED-Parent measure ROCAUC was 0.66 however pvalue did not reach statistical significance. The optimal cut-point was 18 providing a sensitivity of 0.57 and specificity of 0.79. PPV and NPV values at this cut-point were 0.34 and 0.91 respectively.The CES-DC achieved an AUC of 0.98 in detecting participants with Major Depressive Disorder . The “cost” outlined in Notwithstanding the elevation of CES-DC measure scores through psychological distress, the relative contribution of somatic symptoms may also be significant. In our sample, high scores in the somatic domain of the CES-DC  may reflect true depressive symptoms,may represent active SLE which is commonly associated with fatigue, or may be a side-effect of medical treatment. When combined, these factors may serve to explain the high number of false positive screening outcomes for MDD when the CES-DC screen-positive threshold is set at the community cut-point of 15. Children with SLE may already have higher baseline somatic items attributable to their disease and the presence of co-morbid depressive illness may serve to inflate somatic symptoms significantly. Based on examination of lower CES-DC cut-points, an argument could be made for a cut-point of 25, also the cut-point for psychiatric populations,32Treating the CES-DC somatic symptom domain with caution is important in medically ill children who may have a propensity for falsely elevated scores and the potential for a false positive diagnosis. However, the disease activity index of the study participants was noted to be low which may mean that CES-DC elicited true somatic depressive symptoms for many participants despite this situation of overlap. The inclusion of somatic symptoms questions in the CES-DC could be viewed as a strength of this measure given that children, and particularly medically ill children, may be more likely to report somatic depressive symptoms. Moreover, when somatic symptoms accompany cognitive and emotional/behavioural symptoms, the course of illness may be more severe and such children may have poorer outcomes. Unfortunately, ROC-analysis of SCARED parent report measures was limited by missing parent-report data, and the lack of statistical significance of the result did not allow for a direct comparison of diagnostic performances of SCARED parent and self-report measures in cSLE. Correlation(r = 0.33) between parent and self-report SCARED measures suggested weak agreement between parent and child informants as seen in other studies of healthy children, in which children have repeatedly been found to be more accurate informants of their anxiety than their parents.The SCARED offers the opportunity for the parent-report measure to complement the self-report measure, however, most studies show low to moderate agreement between parent and child reported anxiety symptoms.The DSM-5 diagnostic criteria for MDD in children and youth specify the pervasive presence of five of nine depressive symptoms, for two weeks or more with a clinically significant impairment in functioning. Symptoms directly arising from the SLE disease process  do not qualify for a comorbid MDD diagnosis. The diagnosis of anxiety disorder by DSM-5 follows a similarly strict set of diagnostic criteria. As such, standardized psychiatric interview captures a distinct subset of children and adolescents with more severe symptoms and impairment, whereas screening measures may capture milder psychological distress or measure other symptoms of disease or associated treatment. Vulnerability to this stress-induced pro-inflammatory state may be a risk factor in cSLE for the progression of subthreshold depressive symptoms to MDD. In screen-positive clinical encounters pediatric rheumatology clinicians should explore with the patient and their caregiver any inconsistencies between self-report questionnaires and the clinical presentation using a biopsychosocial approach. A lower threshold for seeking a psychiatric assessment may be appropriate for children and adolescents with persistent psychological distress and in particular those with significant risk factors for mental disorder. Where self-report measures are elevated, and in the presence of risk factors and/or clinician index of suspicion of mental disorder, ideally, follow-up with a mental health professional  would take place.Despite the low prevalence rate of 5.3% for MDD in our sample, the high CES-DC screen positive rate of 35.7% may represent a high point prevalence of subthreshold depressive symptoms. It highlights the existence of a subgroup of “stressed, but not depressed” children in our cSLE sample who may progress to diagnostic threshold symptom severity. Such prolonged stress in susceptible individuals may result in hypothalamic-pituitary adrenal axis activation and set forth a pro-inflammatory cytokine cascade. and shows mean depressive screening scores just below threshold for screen positivity. The provision of psychiatric diagnosis allows for meaningful longitudinal studies to take place regarding prevalence and correlates of depressive and anxiety disorders in cSLE.The main strength of the present study is the use of semi-structured, diagnostic psychiatric interview as the gold standard against which the diagnostic performance of screening measures is measured. To our knowledge, these are the first robust prevalence data on the co-morbidity of depressive and anxiety disorders with cSLE. The representativeness of the study sample within the Greater Toronto Area with respect to race/ethnicity increases the generalizeability of the study results.This study replicates, with a larger sample size, the findings from a previous study of depressive symptoms in cSLE38 The cross-sectional nature of the study and convenience sample with relatively stable disease may have precluded sample enrichment for specific disease symptoms or specific disease timepoints. Data regarding depressive and anxiety disorders in younger children, and boys in particular, are lacking due to the preponderance of adolescent females in the study. Future studies of larger sample sizes, enriched for psychological distress, are needed to examine the generalizeability of our findings to boys and to younger children with cSLE.Although the current study is the largest of its kind to date, the low prevalence rate of MDD and anxiety disorders resulted in limited data regarding screening measure outcomes on which to assess diagnostic performance. While previous studies examining depression screening outcomes in cSLE have had higher disease activity compared to the present study, these studies have not had depressive disorder diagnoses confirmed by gold standard interview. These preliminary findings underline the importance of examining the validity of psychiatric screening measures in special populations such as children with SLE prior to implementation. Pediatric rheumatology clinics screening for depressive and anxiety disorders are likely to find high rates of distress, among which disorder may be present.This study finds a similar prevalence rate of major depressive disorder and anxiety disorders among children with SLE as in community samples.Click here for additional data file.Supplemental material, sj-pdf-1-lup-10.1177_09612033211018504 for Evaluation of self-report screening measures in the detection of depressive and anxiety disorders among children and adolescents with systemic lupus erythematosus by Michelle Quilter, Linda Hiraki, Andrea M Knight, Julie Couture, Deborah Levy, Earl D Silverman, Ashley N Danguecan, Lawrence Ng, Daniela Dominguez, Katherine T Cost, Kate M Neufeld, Reva Schachter and Daphne J Korczak in LupusClick here for additional data file.Supplemental material, sj-pdf-2-lup-10.1177_09612033211018504 for Evaluation of self-report screening measures in the detection of depressive and anxiety disorders among children and adolescents with systemic lupus erythematosus by Michelle Quilter, Linda Hiraki, Andrea M Knight, Julie Couture, Deborah Levy, Earl D Silverman, Ashley N Danguecan, Lawrence Ng, Daniela Dominguez, Katherine T Cost, Kate M Neufeld, Reva Schachter and Daphne J Korczak in LupusClick here for additional data file.Supplemental material, sj-pdf-3-lup-10.1177_09612033211018504 for Evaluation of self-report screening measures in the detection of depressive and anxiety disorders among children and adolescents with systemic lupus erythematosus by Michelle Quilter, Linda Hiraki, Andrea M Knight, Julie Couture, Deborah Levy, Earl D Silverman, Ashley N Danguecan, Lawrence Ng, Daniela Dominguez, Katherine T Cost, Kate M Neufeld, Reva Schachter and Daphne J Korczak in Lupus


The long-term management of irritable bowel syndrome (IBS) poses many challenges. In short-term studies, eHealth interventions have been demonstrated to be safe and practical for at-home monitoring of the effects of probiotic treatments and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). IBS has been linked to alterations in the microbiota.The aim of this study was to determine whether a web-based low-FODMAP diet (LFD) intervention and probiotic treatment were equally good at reducing IBS symptoms, and whether the response to treatments could be explained by patients’ microbiota.Adult IBS patients were enrolled in an open-label, randomized crossover trial (for nonresponders) with 1 year of follow-up using the web application IBS Constant Care (IBS CC). Patients were recruited from the outpatient clinic at the Department of Gastroenterology, North Zealand University Hospital, Denmark. Patients received either VSL#3 for 4 weeks (2 × 450 billion colony-forming units per day) or were placed on an LFD for 4 weeks. Patients responding to the LFD were reintroduced to foods high in FODMAPs, and probiotic responders received treatments whenever they experienced a flare-up of symptoms. Treatment response and symptom flare-ups were defined as a reduction or increase, respectively, of at least 50 points on the IBS Severity Scoring System (IBS-SSS). Web-based ward rounds were performed daily by the study investigator. Fecal microbiota were analyzed by shotgun metagenomic sequencing (at least 10 million 2 × 100 bp paired-end sequencing reads per sample).P>.99). Responses to either of the two treatments were not able to be predicted using patients’ microbiota.A total of 34 IBS patients without comorbidities and 6 healthy controls were enrolled in the study. Taken from participating subjects, 180 fecal samples were analyzed for their microbiota composition. Out of 21 IBS patients, 12 (57%) responded to the LFD and 8 (38%) completed the reintroduction of FODMAPs. Out of 21 patients, 13 (62%) responded to their first treatment of VSL#3 and 7 (33%) responded to multiple VSL#3 treatments. A median of 3 (IQR 2.25-3.75) probiotic treatments were needed for sustained symptom control. LFD responders were reintroduced to a median of 14.50 (IQR 7.25-21.75) high-FODMAP items. No significant difference in the median reduction of IBS-SSS for LFD versus probiotic responders was observed, where for LFD it was –126.50 (IQR –196.75 to –76.75) and for VSL#3 it was –130.00 (IQR –211.00 to –70.50; The web-based LFD intervention and probiotic treatment were equally efficacious in managing IBS symptoms. The response to treatments could not be explained by the composition of the microbiota. The IBS CC web application was shown to be practical, safe, and useful for clinical decision making in the long-term management of IBS. Although this study was underpowered, findings from this study warrant further research in a larger sample of patients with IBS to confirm these long-term outcomes.ClinicalTrials.gov NCT03586622; https://clinicaltrials.gov/ct2/show/NCT03586622 Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that affects 10% to 20% of the population in westernized countries . StudiesManaging IBS continues to be challenging because of the complexity of its chronicity, heterogeneous patient groups with and without comorbidities, and a lack of both diagnostic tools and well-documented treatment strategies for long-term purposes. Treatment strategies for IBS range from lifestyle and dietary advice to pharmacological solutions that generally target only the primary symptom. Recently, holistic eHealth solutions that monitor symptoms and support patients with digestive diseases have proven valuable in involving and empowering patients, and are used as an adjuvant to current treatment regimens ,8. IdealAn exclusionary diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) has proven effective in reducing gastrointestinal symptoms, in particular abdominal pain, bloating, and diarrhea , with a The composition of gut microbiota differs between subgroups of IBS patients and healthy individuals . This faSo far, no one has been able to fingerprint patients based on their fecal microbial composition and tailor a particular intervention for them individually .The primary aim of this 1-year, web-based study was to determine whether a 4-week probiotic treatment, VSL#3 , and the LFD were equally as effective at reducing IBS symptoms, and whether the response to either of the two treatments could be explained by fecal microbiota. The study’s secondary aims were to evaluate patients’ QoL, the effect of multiple VSL#3 treatments in sustaining symptom control across 1 year, and reintroduction of FODMAPs among LFD responders, as well as to evaluate the web application IBS Constant Care (IBS CC)  for its 2), had been diagnosed with any comorbidities , had previously been on an LFD guided by a dietician, had been on any probiotic or antibiotic treatment within the 3 months prior to inclusion, or had an IBS severity score lower than 175 at inclusion.Adult IBS patients, 18 years or older, fulfilling the Rome III criteria and subdiagnosed with either IBS-diarrhea (IBS-D) or IBS–mixed type (IBS-M) by a gastroenterologist were consecutively included in the study at North Zealand University Hospital . Patients were excluded if they did not have a smartphone, had previously undergone gastrointestinal surgery, had been diagnosed with celiac disease or lactose intolerance, had been subdiagnosed with constipation or unspecified IBS, were pregnant, followed alternative diets, had a history of alcohol or drug abuse, had a BMI below 18.5 or above 35  older than 18 years, with a normal BMI (18.5-25), fecal calprotectin (FC) less than 70 mg/kg, and not taking daily medication or food supplements were recruited internally from our institution.The Ethical Committee of Denmark (H-16023499) and the Danish Data Protection Agency  approved this study. The study was registered at ClinicalTrials.gov , with 1 year of follow-up . HCs homPatients randomized to the LFD group had a consultation at the hospital with a nutritionist, who guided the patients individually through the diet’s principles and how to monitor their symptoms see . After 4Participants (IBS and HCs) were trained at inclusion in downloading the CalproSmart app and performing the FC home test. Participants received FC kits, including pads, frame, and tubes with buffer fluid, and were instructed to perform an FC home test within the first 4 weeks of home monitoring and again after 1 year of follow-up.Participants were provided with easy sampler kits and were instructed to either send fecal samples for microbiota analysis via their general practitioner, or to store fecal samples in their domestic freezer (–20 ◦C). Participants (IBS and HCs) delivered their frozen fecal samples to the study investigator whenever they had an on-site consultation at the hospital. All samples were immediately frozen (–80 ◦C) upon receipt at the hospital. Patients were instructed to store or send fecal samples at study inclusion, at randomization, after 4 weeks of follow-up, and after 1 year of follow-up. Patients responding to probiotic treatment were further instructed to store samples every time they received a new 4-week probiotic treatment, sampled before and just after the treatment . HCs werOne hour of dietary advice was provided on an individual basis by an experienced dietician or nutritionist that took into account the dietary history of each patient. Participants received guidance for the LFD using the Danish Low FODMAP Diet app (Muusmann Publisher), and were further instructed to measure their QoL, weight, adherence to the diet, and any symptoms on the IBS CC web application. In addition, participants also received supplementary materials (prepared by the study authors) on the LFD, with suggestions for LFD-friendly meals and recipes ; these documents were uploaded to each individual patient’s folder on IBS CC. Patients were advised to significantly reduce their intake of foods high in FODMAPs. Patients were advised only to consume foods low in FODMAPs, which were labeled green in the Low FODMAP Diet app; only two yellow-labeled foods, in small quantities, were allowed per day for reluctant participants.Responders in the LFD group were taught to reintroduce foods high in FODMAPs using the food preference approach, all while taking into account their usual, preferred diet , and four strains of Lactobacilli . VSL#3 contains no less than 450 billion colony-forming units (CFU) per sachet. This formulation is sold as an over-the-counter food supplement at pharmacies in Denmark and by a variety of commercial websites.VSL#3, distributed by Ferring Inc in Europe, is a high-concentration multi-strain probiotic mix containing one strain of VSL#3 sachets used in this study were provided by Actial Farmaceutica Srl, Italy, with the following batch numbers: 804033 and 908081. VSL#3 was administered for 26 days (approximately 4 weeks) for subjects allocated to the treatment group. Patients were instructed to take one sachet twice daily and store the sachets in the refrigerator. Patients were advised not to consume VSL#3 together with any hot or carbonated drinks. Side effects, if any, were registered throughout the study period.IBS CC has previously been used in other web-based studies ,25. The Participants made their FC measurements at home using the CE (Conformité Européenne)–marked CalproSmart app. This home test can be performed in 18 minutes and is integrated into the IBS CC application, providing patients with an opportunity to see FC and other measures, such as the IBS-SSS, the Bristol Stool Chart (BSC), bowel movement frequency, weight and BMI, and QoL, all longitudinally and in a traffic light form. Two examples of a 1-year disease course, from a responder in the probiotic group and another in the LFD group, in IBS CC are shown in The Low FODMAP Diet app is available from the App Store or Google Play and was provided free of charge to the patients in this study. The app includes sections about IBS, the LFD, recipes, grocery lists, a diary, and a module illustrating foods in green, yellow, and red. This mobile app is not integrated with IBS CC.IBS severity was measured using the IBS-SSS . This quThe BSC illustrates seven different stool types that represent constipation (types 1 and 2), “normal” stools (types 3-5), and diarrhea (types 6 and 7) . PatientThe FODMAP Adherence Report Scale (FARS) and the Medical Adherence Report Scale (MARS) measured adherence to the diet and probiotic treatment, respectively. The FARS and the MARS are self-assessment questionnaires consisting of five questions that have been used previously in IBD web intervention trials ,27, one QoL was measured using the IBS-QoL questionnaire   were evaluated during the course of 1 year for multiple responders. Participants evaluated their satisfaction with IBS CC, including FC home testing, before their randomization on a VAS from 1 to 10, where 10 was the greatest possible satisfaction. Patient satisfaction with the study and IBS CC at 1 year, including FC home testing, was assessed using an e-questionnaire in IBS CC that was prepared by the authors, consisting of nine “yes or no” questions and two other questions: one regarding the time used for home monitoring and the other asking for suggestions on improving IBS CC for future clinical use. Clinical metadata were exported from the IBS CC database for statistical analyses.Fecal samples were analyzed by CeGaT GmbH in Tübingen, Germany. The method used by CeGaT GmbH is based on culture-independent, whole-genome, shotgun metagenomic, next-generation sequencing. Genomic DNA was extracted from the participants’ fecal samples using CeGaT GmbH’s proprietary protocol, including enzymatic cleavage of genomic DNA. Approximately 100 ng of DNA was used per sample for library preparation, which was performed with the Nextera DNA Flex Library Prep Kit (Illumina). Sequencing was performed on the NovaSeq 6000 Sequencing System (Illumina), which resulted in at least 10 million 2 × 100 bp paired-end sequencing reads (2 Gb) per sample. Demultiplexing of the sequencing reads was performed with bcl2fastq Conversion Software  . AdapterP value lower than .05 was considered significant. We used a uniform manifold approximation and projection (UMAP) [P values. Clinical outcomes were assessed in a post hoc analysis by linear mixed-effect models [Counts, means, medians, and IQRs were computed from the PROMs. Wilcoxon rank-sum tests, Wilcoxon signed-rank tests with continuity correction, or Dunn all-pair tests were performed to compare medians. Analysis of sequence counts or reads and visualization of results were performed in R . A list of R packages used in this study can be found in n (UMAP)  techniqun (UMAP) , with fat models . PatientIn total, 34 IBS patients were included in the study . A totalThe median time spent dieting by LFD responders  was 36 days (IQR 28.00-41.25), and the median time spent for reintroduction of high-FODMAP foods  was 296 days (IQR 227.00-305.75). For “true” responders . The corresponding changes in QoL among LFD and probiotic responders was not significant compared to nonresponders, nor were the median increases in QoL significant between the two responder groups, which were 7 (IQR 2.75-14.20) for LFD responders and 3 (IQR 0-16.00) for probiotic responders (P>.99). During reintroduction to high-FODMAP foods, patients deviated significantly from the principles of the LFD (P=.004), resulting in a small but significant median increase in symptom severity relative to the time period where they were on the LFD  participants completed the process of reintroducing high-FODMAP foods  and succNo adverse events were registered for either intervention. The evaluation at 1-year follow-up showed overall satisfaction with the study, the support received during the study, and with IBS CC itself (further details can be found in P=.79). They had high IBS-QoL scores at inclusion and 1-year follow-up . The primary purpose for the inclusion of HCs was to generate microbiome profiles that could serve as a reference.HCs did not receive any intervention during the study period and were in IBS-SSS remission at inclusion and at 1-year follow-up. No significant change was detected . There was also a significantly higher median of intraindividual Bray-Curtis dissimilarity in IBS-D compared to IBS-M patients (P=.03). UMAP plots based on IBS subtypes and responder types are shown in P=.07). No significant changes in α diversity for probiotic responders and nonresponders were found. Nonresponders to both probiotics and LFD showed a significantly higher median of intraindividual Bray-Curtis dissimilarity relative to probiotic responders  microbial species per sample. Median α diversity (measured by inverse Simpson index) was significantly greater for HCs (n=6) than for IBS patients (n=31), with median values of 51.60 (IQR 23.5) and 42.10 (IQR 16.1), respectively P=.03; . Across s P=.01; .No significant differential species abundances were found when comparing nonresponders to LFD and probiotic responders. Significant changes in relative species abundances induced by interventions  relative to baseline are shown in In this study, we have shown that the new and expanded IBS CC web application for long-term management of IBS is practical, safe, and useful in clinical decision making. This was demonstrated by two year-long treatment interventions: the LFD (with subsequent reintroduction of high-FODMAP foods for LFD responders) and a probiotic treatment (repeated for 4 weeks every time a symptom flare-up occurred in probiotic responders). These therapeutics were found to be equally good at managing IBS symptoms in the short term and the long term. We also investigated participants’ fecal microbiota, in order to try to predict response to the interventions, in the hope of being able to individualize future treatments for IBS; however, we were unable to make these predictions. Due to the small sample size of the study, larger ones are needed to confirm our results and would, ideally, include other medical options for managing IBS, especially for nonresponders to the LFD and probiotic treatments.Although the prevalence of IBS is high in westernized countries  such as S thermophilus, L paracasei, L acidophilus, and B animalis) that are representative of strains contained in the VSL#3 mixture. Furthermore, all four species were completely absent from baseline samples, which means that the consumption of VSL#3 is the most plausible explanation for their presence. Future long-term studies need to investigate whether it is safe for patients to stop probiotic treatment after 4 weeks and to only resume when symptom flare-ups occur. Abrupt suspension of probiotics have been hypothesized to increase host pathogen susceptibility by inducing gut dysbiosis [The response rates, adherence, effect sizes of median reductions in symptoms, and increases in QoL for probiotic and LFD responders were similar ; however, probiotic responders experienced a significant increase in median symptom severity and a decrease in QoL in the times between the 4-week probiotic treatments, as compared to the effect obtained during active probiotic treatment. However, the linear mixed-effect model estimated that probiotic “true” responders sustained significant symptom control in between their 4-week treatments relative to their first measure . This is also partly explained by the study design, which instructed probiotic responders to contact the study investigator for a new 4-week probiotic treatment upon experiencing a symptom flare-up . Sustaining IBS symptom control in between active probiotic treatments has, to our knowledge, not been investigated before among “true” responders. The concept of sustaining symptom control among “true” responders—with a median of three 4-week treatments across the year-long study—and the timing of new probiotic treatments using eHealth, require further investigation in larger, clinical web-based trials. The high dose (2 × 450 billion CFU per day) and short duration combination used in this study seems reasonable, based on a meta-analysis that concluded that (1) probiotics are effective and safe for IBS patients (moderate evidence) and (2) single probiotics at a higher daily dose and for a shorter duration (less than 8 weeks) seem to be more efficacious (needs further evidence) [ysbiosis .Clostridium cluster XIVa (reduced), A muciniphila (reduced), and R torques (increased) relative to a normal Australian diet [Bifidobacterium (reduced), an unclassified genus in the Ruminococcaceae family (reduced), and Bacteroides (increased) [Bifidobacterium [Faecalibacterium prausnitzii, a commensal bacterium of the Ruminococcaceae family that produces short-chain fatty acids (SCFAs) from dietary fiber [Faecalibacterium prausnitzii H that was significantly increased; G, E, J, K, and I were decreased, while C and F were increased, but none significantly so  . The samacterium , or thatacterium . Our resry fiber , was sigantly so . The maiAlthough significant median increases in symptoms were observed during reintroduction of high-FODMAP foods, in this study, and relative to the changes caused by the LFD, a post hoc analysis  suggests that sustained long-term symptom control and improvement of QoL could be obtained relative to patients’ baseline. Sustained symptom control during reintroduction has recently been documented by other researchers in Italy, who concluded that the benefit of an LFD persisted during reintroduction (after 3 months) and at 6 months follow-up . Based oOther researchers have suggested that web-based and app-based LFD and probiotic treatments may provide therapeutic benefits  and shouHowever, it is our recommendation that future electronic-based IBS management include valid and quick point-of-care measures that can (1) predict response to treatments and (2) be correlated to symptom severity scores, both of which can support the patients and the personnel doing the daily web-based ward rounds in tailoring treatments and guiding their supervision. We were unable to predict response to treatments  based on the microbiota alone. Others have also failed in this attempt in IBS using a different method  than the one we used . It coulThe strength of this study is its use of an updated and expanded eHealth web application to monitor and treat IBS patients according to their treatment response across 1 year of follow-up. To our knowledge, this is the first eHealth trial to monitor the effect, prospectively and longitudinally, of multiple probiotic treatments and the LFD with subsequent reintroduction of foods high in FODMAPs, and to compare responses to patients’ microbiota.in situ genome sequences likely differ compared to our reference due to, for example, horizontal gene transfer.The main limitations of the study are its sample size and that it is based on a single study center. Another limitation is the use of the Rome III criteria rather than the Rome IV criteria for IBS . FurtherIn conclusion, we have shown the IBS CC web application to be practical, safe, and useful for clinical decision making in the long-term management of IBS. A probiotic treatment, VSL#3, and the LFD were equally efficacious in short- and long-term treatment strategies for managing IBS. We failed to predict response to treatments based on patients’ fecal microbiota, which might someday help individualize treatments. To confirm our results, larger studies are needed and would ideally combine LFD and probiotic treatments or other medical options for managing IBS, especially for nonresponders to the LFD and probiotic treatments.


MMP1, RAB6C, ACCSL, RGS21 and MOCOS) appeared as hub genes, being closely related to the occurrence and development of DLBCL. Finally, both differentially expressed genes and key driver genes were subjected to CREEDS analysis, and 10 potential agents were predicted to have the potential for application in advanced-stage DLBCL patients. In conclusion, we propose a novel pipeline to utilize perturbed gene-expression signatures during DLBCL progression for identifying agents, and we successfully utilized this approach to generate a list of promising compounds.Over 50% of diffuse large B-cell lymphoma (DLBCL) patients are diagnosed at an advanced stage. Although there are a few therapeutic strategies for DLBCL, most of them are more effective in limited-stage cancer patients. The prognosis of patients with advanced-stage DLBCL is usually poor with frequent recurrence and metastasis. In this study, we aimed to identify gene expression and network differences between limited- and advanced-stage DLBCL patients, with the goal of identifying potential agents that could be used to relieve the severity of DLBCL. Specifically, RNA sequencing data of DLBCL patients at different clinical stages were collected from the cancer genome atlas (TCGA). Differentially expressed genes were identified using DESeq2, and then, weighted gene correlation network analysis (WGCNA) and differential module analysis were performed to find variations between different stages. In addition, important genes were extracted by key driver analysis, and potential agents for DLBCL were identified according to gene-expression perturbations and the Crowd Extracted Expression of Differential Signatures (CREEDS) drug signature database. As a result, 20 up-regulated and 73 down-regulated genes were identified and 79 gene co-expression modules were found using WGCNA, among which, the thistle1 module was highly related to the clinical stage of DLBCL. KEGG pathway and GO enrichment analyses of genes in the thistle1 module indicated that DLBCL progression was mainly related to the NOD-like receptor signaling pathway, neutrophil activation, secretory granule membrane, and carboxylic acid binding. A total of 47 key drivers were identified through key driver analysis with 11 up-regulated key driver genes and 36 down-regulated key diver genes in advanced-stage DLBCL patients. Five genes ( MYC and BCL2/BCL6 rearrangements failed to predict poorer prognosis in limited stage DLBCL (Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed non-Hodgkin lymphoma (NHL), representing approximately 25% of new NHL cases each year in the United States . In pracage DLBCL. Ajay, M0 years) . Compari0 years) . Also, t0 years) . All of However, there is limited knowledge regarding the genomic and transcriptomic differences between limited- and advanced-stage DLBCL. Two previous large analyses exploring the genetic landscape of DLBCL were not intended to compare the limited and advanced stages of the disease . MoreoveAlthough frontline chemoimmunotherapies have been shown to cure up to 60% of patients with advanced-stage disease, with a clear plateau in progression-free survival (PFS) and rare relapses beyond 5 years , there sIn this study, we propose a new strategy for identifying new agents that have the potential to specifically target advanced-stage DLBCL. In general, we retrieved advanced-stage DLBCL-specific expressed genes by comparing the transcriptome of advanced-stage disease with that of limited-stage DLBCL. These differentially expressed genes (DEGs) were then subjected to weighted gene correlation network analysis (WGCNA) to discover the co-expression modules that may contribute to the progression of this disease. Finally, potential personal agents were obtained from the Crowd Extracted Expression of Differential Signatures (CREEDS) based on the down-regulation and up-regulation of genes . We aimed to specifically reveal the transcriptomic scenario occurring in advanced-stage DLBCL and to elucidate the genes that were most likely contributing to disease progression. Based on this knowledge, we then identified some potential agents for the treatment of advanced-stage DLBCL in future clinical practice.RNA sequencing data from patients with DLBCL cancer were collected from the cancer genome atlas (TCGA). Based on the imaging results, including computed tomography (CT) scans, magnetic resonance imaging (MRI) or positron emission tomography (PET) scanning, patients were divided into four stages (I–IV) according to the Ann Arbor system .2 |fold change| ≧ 1 and a p value ≦ 0.05.An expression matrix of 42 patients and their group information (stage I/II or III/IV) were used as the input for DEG discovery. DEGs between samples at stage I/II and stage III/IV were obtained using DESeq2  using loAfter identifying DEGs, we performed survival analysis on these genes for all of the patients. Next, Kaplan-Meier  survivalThe WGCNA package in R  was usedKEGG pathway  analysisp value_whole ≦ 0.05 was used to filter out key drivers. The hub genes were of great significance in terms of the occurrence and development of DLBCL.For key driver analysis, we used up- or down-regulated genes separately as inputs to identify key drivers. Key driver analysis  (KDA) waCREEDS includes single gene perturbation signatures, as well as disease and drug perturbation signatures, and it can be used to identify the relationship between gene, disease and drug . CREEDS For the purpose of specifically developing new agents that could be utilized in combination with R- CHOP backbones to treat advanced stage DLBCL patients, we proposed a new method of drug repurposing based on gene expression and network perturbation . In ordeThe clinical characteristics of DLBCL cancer patients collected from TCGA are presented in 2 |fold change| ≧ 1 and a p value ≦ 0.05, 20 genes were up-regulated and 73 genes were down-regulated in advanced DLBCL. The top 10 genes that were differently expressed between advanced and limited stage DLBCL are shown in After collecting data from TCGA, DEGs were obtained using DESeq2, by comparing the transcriptome of advanced stage DLBCL with limited stage DLBCL. Of the 93 DEGs that were identified with a logDAB1 was negatively correlated with overall survival, while other DEGs were not correlated with overall survival.We aimed to evaluate whether this set of differentially expressed genes could define a group of patients with poorer prognosis. We dichotomized 42 DLBCL cases into either the high expression group or the low expression group as per the mean expression level of each DEG. In addition, the Kaplan-Meier survival estimation method was used to evaluate all DEGs to study the relationship between gene expression and overall survival. Through this Kaplan-Meier survival estimation analysis, we found that WGCNA, based on a scale-free network to analyze genes according to their expression patterns, was used to cluster highly related genes into one module. As can be seen from Staphylococcus aureus infection and viral protein interaction with cytokine and cytokine receptor  (MOCOS)   include  (MOCOS)  can lead)  rate in unselected patients. The prognosis of patients with DLBCL with refractory tumors or relapse remains dismal. As a result, designing more sophisticated personal treatment modalities has the potential to improve the outcomes in high-risk DLBCL patients. Although a wealth of studies has focused on targeted therapies based on the molecular classification of DLBCL, the clinical stage of DLBCL remains an important factor for choosing an appropriate treatment regime. DLBCL patients with advanced- and limited-stage disease have different responses to standard chemoimmunotherapies, due to the different genomic profiles of advanced-stage disease relative to limited-stage disease . In thisied DEGs . Howeveried DEGs . During P1. MMP1  can alteBased on gene expression and network perturbations, 10 potential agents for the treatment of DLBCL were obtained. For instance, NC1153 can inhibit JAK3 specifically and induce the apoptosis of certain leukemia/lymphoma cell lines. Using Affymetrix microarray profiling following NC1153 treatment, Nagy et al. reported that JAK3-dependent survival modulating pathways  were altered in Kit225 cells . EPZ-643In summary, we proposed a novel pipeline to utilize perturbed gene-expression signatures during DLBCL progression for identifying agents, and we successfully utilized this approach to generate a list of promising compounds. Whether this can be used clinically needs further research. We will continue to follow the latest developments of these agents in the treatment of DLBCL and explore its pharmaco-mechanisms under the aid of stage-of-art technologies in the future.


Vaccination is one of the cornerstones in the efforts towards ending the coronavirus disease 2019 (COVID-19) pandemic. However, several adverse effects of COVID-19 vaccination have been identified. Pityriasis rosea (PR)-like eruption is a rare cutaneous complication of immunization. To the best of our knowledge, there have been no reports of PR-like eruptions following inoculation with Oxford/AstraZeneca ChAdOx1 nCoV-19 (AZD1222) vaccine. Here, we described a case of PR-like eruption that developed 14 days after Oxford/AstraZeneca vaccination in a 52-year-old Thai woman with glioblastoma. Treatment with topical 0.1% triamcinolone acetonide twice per day showed partial response after seven days. Despite this rare complication, our report highlights that the presence of PR-like eruption is not a contraindication for subsequent vaccinations. Pityriasis rosea (PR)-like eruption is a cutaneous complication associated with several medications and vaccinations. Due to the rising incidence of coronavirus disease 2019 (COVID-19) worldwide, mass vaccination has been the cornerstone in preventing viral spread and decreasing morbidity and mortality. However, adverse effects to COVID-19 vaccines, particularly cutaneous reactions, have been reported. Here, we describe a case of PR-like eruption following ChAdOx1 nCoV-19 (AZD1222) vaccination in a Thai patient with glioblastoma.A 52-year-old Thai woman with a one-year history of recurrent glioblastoma was admitted to our hospital for a planned targeted therapy. Following the national COVID-19 vaccination guidelines, she received a shot of ChAdOx1 nCoV-19 (AZD1222) vaccine before the therapy. However, after 14 days, she developed multiple discrete blanching erythematous oval patches and plaques on the lower abdomen, back, and bilateral upper thighs . PhysicaLaboratory investigation results  for human herpesvirus (HHV)-6 and HHV-7, and reverse transcription-PCR for COVID-19) were unremarkable. Dermoscopy showed dotted and linear vessels forming a network on a yellowish background, with some whitish peripheral scales . HistopaPR is a common self-limited papulosquamous eruption typically presenting with a large solitary pink-colored patch or plaque , followed by secondary eruptions of smaller erythematous patches or plaques with associated peripheral collarette scaling distributed along the cleavage lines of the trunk, forming a Christmas tree pattern . HoweverAlthough the exact pathogenesis of PR remains unknown, the endogenous systemic reactivation of HHV  in the skin has been implicated as a precipitating factor. Among the common cutaneous manifestations of COVID-19 , PR and PR-like eruptions have rarely been described , 4. MoreDrug-induced PR-like eruption accounts for 2% of all cutaneous adverse drug reactions . Common n = 1) or second dose (n = 2) of BNT162b2 mRNA-based vaccines  vaccination. Fortunately, PR-like eruption is responsive to topical corticosteroids without any systemic adverse effects. Despite this rare complication, our report highlights that the presence of PR-like eruption is not a contraindication for subsequent vaccinations. With COVID-19 vaccines being authorized for emergency use, monitoring for potential adverse effects  is necessary.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.KL drafted the original manuscript. KL and KP collated resources. PS conceptualized the case report and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes.In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial , we assessed the indirect impact of the 10-valent pneumococcal Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009―2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010―2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years , and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010.From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years.This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms. The indirect effects of a vaccination programme are the protective or detrimental effects that are mediated by the intervention-induced changes in transmission . Herd imStreptococcus pneumoniae has about 100 circulating serotypes ) * 100%. To estimate IRRs and consider the possible overdispersion in the cluster-specific incidences, a negative binomial model was used. The cases were grouped by cluster, and the cluster-specific person-years were used as an offset in the model. The factors used in the stratified randomisation  were included as explanatory variables. Results are presented as point estimates and 95% confidence intervals (CIs). Relative rate reduction was considered statistically significant if the 95% CI did not include 0%. Bold font indicates statistical significance in tables. No correction for multiple testing was applied.Wide variations in the incidence rates of several outcomes in the trial clusters were observed. Therefore, we obtained historical aggregate data for the Finnish population in years 2004―2008 to perform explorative post-hoc analyses. We used the incidence of selected outcomes  by cluster from these years as an additional explanatory variable to adjust for the background variation between clusters. The statistical program R version 3.4.4  was usedIn the 72 clusters considered for the indirect impact analysis, 41188 children were enrolled in the FinIP trial and 4210 in the TAUVRC trial from February 2009 to October 2010 with a total of 45398 children.The annual number of episodes in 2010―2015 in the unvaccinated population across age groups ranged from 572 to 628 for laboratory-confirmed IPD, from 10100 to 14961 for non-laboratory-confirmed IPD or unspecified sepsis, from 35103 to 42223 for HDP, from 7966 to 9455 for TTPs (children ≤7 years of age), and from 216971 to 255554 for outpatient antimicrobial purchases (children ≤7 years of age). The annual follow-up time ranged from 187065 to 223950 person-years in children <5 years of age, and from 3981437 to 4032499 person-years in age-group ≥5 years. The numbers of episodes in age groups <5, 5―7 and ≥5 years as well as the corresponding person-years are presented in  Tables.The trial vaccination coverage increased steadily in time up to 38% in the trial eligible cohort  and the trial enrolment needed to be stopped when the universal immunisations in PCV-NVP started in September 2010. Therefore, the trial vaccination coverage may not have been high enough to induce detectable differences in indirect effects against most of the disease outcomes between the treatment arms. However, our trial setting can be considered representative for the whole population due to the large regional coverage of the clusters and the use of nation-wide health registers.A small proportion of older adults were concomitantly administered individual pneumococcal vaccinations , 25. HowOur results should be considered exploratory. We performed statistical testing including several outcomes, multiple calendar years, and several age groups, but did not correct for multiple testing. Only a few findings were considered statistically significant according to the descriptive criterium. However, they all point towards positive indirect impact against vaccine-type disease and none towards negative impact. This suggests true herd effects rather than chance findings that would be expected to be even in either direction, i.e. either positive or negative. On the other hand, replacement by some non-vaccine serotypes was observed. Our results are compatible with those of the two satellite carriage studies conducted in the context of the FinIP trial . In thosAccording to WHO Expert Committee on Biological Standardization, randomisation of groups or clusters, rather than individuals, is preferable when the indirect effects of vaccination are of interest . The FinIn conclusion, although no consistent evidence of the indirect impact was seen in this clinical trial setting, several observational studies have shown that PCVs induce herd effects in unvaccinated populations. The development of the indirect effects takes a few years, and high vaccination coverage with catch-up vaccinations speeds up the development. Not all of these prerequisites were fulfilled in this trial because the average vaccination coverage reached only 38% in the PHiD-CV10 clusters. Moreover, PCV-NVP started right after the trial enrolment with high vaccination coverage among infants. It caused strong indirect effects, levelled out the possible differences between the treatment arms, and eliminated the potential to observe indirect impact in the trial setting. Nevertheless, our study contributes to the evidence for the overall impact of PHiD-CV10 against several pneumococcal disease syndromes.S1 Checklist(PDF)Click here for additional data file.S1 FigTreatment arms are indicated with different colours and the lines represent the boundaries of Finnish municipalities, the number of which ranged from 1 to 12 per cluster. Six biggest cities included several clusters. In the trial, there were altogether 78 clusters which all are presented in the Figure. For the indirect effect analysis, 72 clusters were included.(TIFF)Click here for additional data file.S2 FigAge groups of the study were children less than 5 years and population 5 years or older . Children under 3 months of age, a subgroup who were too young to be vaccinated during the PCV-NVP, were evaluated separately.(TIFF)Click here for additional data file.S3 FigSolid line: all children; dashed line: infants 6 weeks to 6 months of age; dotted line: catch-up children 7 to 18 months of age.(TIFF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 TableResults obtained from explorative post-hoc analyses using data from year 2004―2008 to adjust the impact analyses for the background variation detected in the study clusters.(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 TableResults obtained from explorative post-hoc analyses using data from year 2004―2008 to adjust the impact analyses for the background variation detected in the study clusters.(DOCX)Click here for additional data file.


Background: Radiomics involving quantitative analysis of imaging has shown promises in oncology to serve as non-invasive biomarkers. We investigated whether pre-treatment T2-weighted magnetic resonance imaging (MRI) can be used to predict response to neoadjuvant chemotherapy (NAC) in breast cancer.Materials and Methods: MRI scans were obtained for 102 patients with locally advanced breast cancer (LABC). All patients were treated with standard regimens of NAC as decided by the treating oncologist, followed by surgery and adjuvant treatment according to standard institutional practice. The primary tumor was segmented, and 11 texture features were extracted using the grey-level co-occurrence matrices analysis of the T2W-images from tumor cores and margins. Response assessment was done using clinical-pathological responses with patients classified into binary groups: responders and non-responders. Machine learning classifiers were used to develop a radiomics model, and a leave-one-out cross-validation technique was used to assess the performance.p < 0.05) different between the two response groups. The best classification accuracy was obtained using a k-nearest neighbor (kNN) model with sensitivity, specificity, accuracy, and area under curve of 63, 93, 87, and 0.78, respectively.Results: 7 features were significantly (Conclusions: Pre-treatment T2-weighted MRI texture features can predict NAC response with reasonable accuracy. Locally advanced breast cancer (LABC) is defined as breast cancer with tumors greater than 5 cm, primary disease involving the chest wall, skin, or advanced regional lymph node metastasis, without distant metastases . Neoadju“Pre” and “post”-treatment MRI scans are often undertaken as the standard of care for patients with LABC for disease staging, assessment of response post-NAC, and surgical decision making. T1 and T2-weighted contrast-enhanced sequences are used to assess tumor extent and characterize malignancy based on morphological characteristics . T2-weigA common and useful method of describing texture involves computing features from the grey-level co-occurrence matrices (GLCMs) of images . GLCMs rThe study examined T2 non-contrast images in predicting the treatment response to NAC. Specifically, we investigated a number of parameters, including quantization level, region of interest (ROI) selection method (tumor core and margin), GLCM pixel distances, classifier type, and tuning parameters to examine whether treatment response can be predicted before starting NAC.n = 83) of patients were classified as responders, and 19% (n = 19) of patients were classified as non-responders.The study included 102 patients with LABC treated with NAC. Clinical and pathological details of the analyzed patient cohort are summarized in p-values, the different texture features were as follows: maximum (MAX), correlation (COR), angular second moment (ASM), energy (ENE), entropy (ENT), standard deviation (STD), variance (VAR), mean (MEA), contrast (CON), homogeneity (HOM), and dissimilarity (DIS).p ≤ 0.05), and the final four not showing significant differences between the two groups (p > 0.05). For the tumor margin, none of the features were independently significant. The first seven texture features showing a significant difference between non-responders (NR) and responders (R) . When varying pixel distance between 1 and 15, there was no significant change in classification performance , whereas the results for 32 vs. 128 grey levels had different trends . For the ROI selection method, a margin of 15 pixels was consistently the least sensitive with quantization of 32 grey levels but consistently the most sensitive with quantization of 128 grey levels.  Additionally, 128 grey levels resulted in higher accuracies than 32 grey levels for all classifiers except SVM-Lin. Across all models trained using 128 grey levels, those trained using the margins had better accuracy than those from the core. A quantization of 128 grey levels with the margin of 10 pixels had the individual classifier with the highest overall accuracy . Models were tested using the core and margin features together. This did not improve performance, as the features selected in the optimal model were solely from the margin. This was a significantly better performance than from tumor core features (accuracy 87% versus 71%). Radiomics is an emerging discipline in medicine and oncology involved with the advanced processing of imaging data . Radiomip = 0.042, predicting pathologic complete response [Similar work carried out using T2-weighted MRI texture has either analyzed different endpoints , not exaresponse .In this study, the ROI selection method was varied to examine the effects of the tumor core alone and tumor margins of different sizes. Quantitative ultrasound research on NAC breast cancer response has demonstrated that the tumor boundary contents can be significant in predicting patient response . IndepenOur working model is that as tumors become more aggressive and less likely to respond to chemotherapy, their structure becomes more disorganized. This is in alignment with the fact that as grade increases, tumors become less like normal breast tissue and more aggressive. Whereas pathologists limit characterization to 3 tumor grades, recent genetic tests have been better able to categorize tumor subsets based on genetic “disorganization”. Here we postulate that this characterization is based rather on structural disorganization with indirect links to the genetic alterations responsible for changes in cellular structure and higher-order organization that changes with the development of malignant neoplasia.One limitation of the current study was the use of different chemotherapy regimens. While a model that is invariant of treatment type is useful, a variety of models trained only for a specific treatment type might in the future yield a greater classification accuracy. Additional texture features could be extracted from tumors using alternative methods of representation such as grey run-length matrices (GRLMs), grey-level size zone matrices (GLSZMs), and first-order features, which will be included in future follow up studies. We intend to expand the current study cohort to include a higher number of patients to perform more robust validation strategies, including consideration of external validation from a different institution. In comparison to other studies, we had used a different endpoint towards detection of chemotherapy response. Rather than using pathological complete response as an endpoint, we had used responder and non-responder classification outputs. We believe in clinical practice; it will be more prudent to continue NAC in patients demonstrating some or partial response rather than considering a stricter criterion of complete response.This study was approved by the research ethics board of Sunnybrook Health Sciences Centre, Toronto. Patients with LABC who received NAC were included in this retrospective study. Waiver of consent was approved by the ethics committee, given the retrospective nature of the study.After NAC, surgery was performed, followed by radiation therapy, according to institutional guidelines. Before treatment initiation, a core needle biopsy was acquired from each patient for histopathological confirmation and assessment of molecular characteristics. MRI images were obtained before starting NAC.The response was classified using a modified RECIST score, using a combination of post-NAC imaging and histopathological specimen, which served as the gold standard . PatientAll patients were scanned with a 1.5 T Signa HDxt  with 8 breast-specific receiving coils. The sequences analyzed were from sagittal T2-weighted scans pre-contrast . All MRI data were obtained from the same scanner dedicated to breast imaging at a single institution.The ROI was selected freehand using the lasso tool from GIMP (GIMP 2.10) guided by a radiologist specializing in breast radiology. The ROIs were selected on a per-slice basis, spanning the tumor volume on the sagittal T2 pre-treatment MRI. Also, for tumor margin, a set of additional ROIs was created, which expanded on the original ROI by 5, 10, and 15 pixels in all directions within the breast tissue.Grey-level co-occurrence matrices (GLCMs) represent pixel contrast probabilities determined from an image and were used to calculate Haralick’s texture features , 28. AllQuantization or grey-level binning was performed after the ROI had been selected, so any data from outside of the tumor mass did not influence the process. Quantization was varied for the purpose of this work, with values of 16, 32, 64, 128, and 256 grey levels, since in the literature, there was no consensus on the optimal value for MRI analysis , 31.A set of 11 features including contrast (CON), dissimilarity (DIS), homogeneity (HOM), angular second moment (ASM), energy (ENE), maximum (MAX), entropy (ENT), mean (MEA), variance (VAR), standard deviation (STD), and correlation (COR) were determined for the T2-weighted ROIs. These features were described and compiled by Hall-Beyer . FeatureFor each of the machine learning methods below, the data were tested using 1–4 features for each parameter combination. Limiting the maximum number of features to 4 was done to avoid the curse of dimensionality . Machinek values for kNN). The algorithm assessed the sensitivity, specificity, accuracy, F-score, and AUC as evaluation metrics. In this study, we defined true positives as non-responders. The results were tested with leave-one-out cross-validation. This method regenerated the model using all the available data but withholding data from a single patient, running such that all patients are left out in one instance and generating an average of the classifier performance evaluation metrics.Algorithms investigated maximized the accuracy in the first execution and the F-score in the next. Algorithms returned the features used in the generation of the classifier in addition to the values of all tuning parameters  analysis . This wa1 to 210 and γ = 2−15 to 25.Additionally, support vector machines (SVMs) were used, with two kernel functions: linear (Lin) and radial basis function (RBF). SVMs use the kernel function to find a hyperplane to differentiate the data. The SVMs were executed on a balanced dataset. Within SVM analysis, two classifier parameters were tuned so that the model better fit the data when using the RBF as the kernel. These include the C and the γ parameters . The optimal C and γ were selected by grid search in the ranges of C = 2k is variable). k was varied from 1–5 neighbors with an increment of 1.The final algorithm investigated was k-nearest neighbors (kNN), a technique that classifies the data depending on the classes of the k nearest neighbors , necessary data monitoring, and appropriate conduct of the research. The ethics committee approved the waiver of consent given the retrospective nature of the study.In conclusion, classifiers trained with pre-treatment MRI texture were shown to have an accuracy of 87% in predicting NAC treatment response. Here a classifier based on tumor margin performed better than one based on tumor core alone. Radiomic analysis of MR images using simple machine learning classifiers could predict response and guide clinicians in prescribing effective treatments.


Conclusions: Encouraging results were observed in terms of medication adherence. Caution is needed in chronic disease patients living in urban places as well as those presenting psychological distress and worse self-reported mental health to reduce unhealthy behaviours.Background: We aimed to investigate the impact of the first COVID-19 lockdown on medication adherence, physician access, lifestyle behaviours, and mental health in patients with chronic conditions. Methods: A cross-sectional phone survey was conducted in 1274 housebound adults recruited from 8 regional chronic disease cohorts (CLEO CD study: NCT04390126). Results: Medication adherence was 97%; 305 (41%) patients declared that at least one scheduled visit with a physician was missed during the first lockdown. The main changes in lifestyle behaviours were deterioration in sleep time , increase in screen time (46%), and decrease in physical activity (46%). Nineteen percent experienced psychological distress (Kessler-6 score ≥ 5). An urban living place (OR, 1.76 vs. rural; 95% CI, 1.32–2.33;  On 11 March 2020, the World Health Organization characterized the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak as a pandemic .The French Restez Chez Vous decree  . Oral consent was obtained for each patient before enrolment.The COVID-19-related Lockdown Effects on Chronic Diseases (CLEO-CD) study is a cross-sectional phone survey that was conducted among homebound patients with chronic conditions. Phone calls were made between 14 April 2020 and 2 June 2020 . The CLEO-CD study was registered on The CLEO-CD population includes patients with chronic diseases aged 18 years and over, living at home, and recruited from 8 regional  cohorts: Observatoire des Infarctus de Côte d’Or (RICO) for chronic coronary syndromes; Registre des Hemopathies Malignes de Côte d’Or (RHEMCO) for haematological malignancies; Haemophilia Comprehensive Care Centre for haemophilia; Reference Constitutive Centre for Rare Pulmonary Diseases for idiopathic pulmonary fibrosis and pulmonary arterial hypertension; age-related macular degeneration cohort; giant cell arteritis cohort; heart failure cohort; and multiple sclerosis cohort ,7,8,9.For rare diseases , each cohort was enrolled in full. For other diseases, a sample was randomly drawn from each cohort or registry. A total of 1394 patients were contacted by phone for the study.Exclusion criteria were not responding to one of three phone calls at different times of the day and different days of the week, inability to respond to a questionnaire (language barrier or cognitive impairment), refusal to participate, and death. In case of patients included in two or more cohorts, only data from the first phone call were kept for analysis. Patients were interviewed cohort by cohort, starting from patients with chronic coronary syndromes and finishing with haemophilia patients.Twelve trained interviewers collected data using standardised questionnaires by phone. The telephone interview lasted approximately 30 min. Patients responded to a general questionnaire and a specific questionnaire according to their cohort/chronic disease. Prior to the study, questionnaires were tested by a sample of 8 physicians (one per cohort) for content and 8 non-physicians  for clarity. Minor changes were made before starting interviews.In the general CLEO-CD questionnaire, patients were asked about socio-demographic data, including marital status, education level, living conditions , and place of residence  during lockdown. The questionnaire also assessed the impact of the COVID-19-related lockdown on overall physical and mental health, including psychological distress as well as lifestyle behaviours, including alcohol intake, smoking/vaping, eating and body weight, physical activity, screen time, and sleep quality and quantity. Psychological distress was assessed based on the Kessler Psychological Distress Scale K6 score . The K6 Specific CLEO-CD questionnaires focused on disease-related symptoms/complications, management, and medication adherence. Patients were considered as non-adherent if they spaced out, discontinued, or changed the dosage of at least one of their current medicines without first consulting a healthcare professional .p < 0.20 in univariate analyses were introduced into a multiple logistic regression analysis. Highly correlated variables were not used together in the logistic regression models in order to avoid collinearity. During the backward elimination process, variables were excluded if the corresponding p-value for the Wald test was higher than 0.05. All statistical analyses were performed using SAS statistical software .Medication adherence, physician access, lifestyle behaviours, and mental health were described for each cohort and for the overall study population as frequencies and percentages for categorical data and means and standard deviations for continuous data. Logistic regression models were used to identify factors associated with at least one unhealthy patient behaviour, including medication non-adherence, increase in alcohol intake/new drinker, increase in cigarette consumption/new smoker, increase in vaping/new user, decrease in physical activity, deterioration in sleep time or quality, increase in screen time, and increase in body weight. Variables that reached a significance of n = 86, 6%), death , inability to respond , refusal to participate , or hospitalization . Two (<1%) patients from the haematological malignancy cohort were not interviewed because they had already been interviewed in the heart failure or multiple sclerosis cohort.A total of 1274 patients participated in the study. Of the 1394 eligible patients, 120 (9%) participants were excluded either for not responding to the three phone calls  patients had been tested for SARS-CoV-2 by polymerase chain reaction, and only one was found to be positive. Other baseline characteristics are reported in In the full cohort, 33 (3%) patients declared that they discontinued and/or modified the dosage of at least one of their current medicines themselves without any medical advice. The proportion of medication non-adherence varied from 0% (giant cell arteritis and heart failure cohorts) to 11% (multiple sclerosis cohort). The main reason given to explain the lack of adherence was fear . Media influence was reported by only two patients to explain non-adherence. Among the 738 (58%) patients that reported having one or more scheduled visits with their general practitioner or another physician during the period, 305 (41%) declared that they did not attend at least one visit. The frequency of missed scheduled visits was the highest in the chronic respiratory diseases cohort (39%), while the proportion of performed scheduled visits  was the highest in the haematological malignancy group (57%) .Lifestyle and mental health changes compared to the pre COVID-19 period are detailed in n = 217, 48%) and a decrease in physical activity . Among the 328 patients with two unhealthy behaviours, the most frequent behaviours were  increase in screen time and decrease in physical activity .Eight hundred and forty-nine (69%) patients reported at least one unhealthy behaviour. One, two, three, and at least four unhealthy behaviours were reported in 453 (37%), 328 (27%), 64 (5%), and 4 (0.5%) patients, respectively. Among the 453 patients with one unhealthy behaviour, the most frequent were an increase in screen time (p = 10−4), worse self-reported mental health , and a K6 score ≥ 5   .In a large, community-dwelling population of 1274 participants with one or several chronic diseases, we found that during the first lockdown, medication adherence remained high (97%). In contrast, we reported a deterioration in lifestyle behaviours, in particular sleep time, screen time, and physical activity.Our study has major strengths. The CLEO-CD population was composed of patients with chronic diseases aged 18 years and over, living at home, and recruited from eight regional  cohorts. The rate of participation (91%) compares favourably with most health-related surveys, highlighting the high level of patient implication for this subject. Most studies or reviews that reported COVID-19-related consequences included patients with chronic diseases of the same type, mostly auto-immune/inflammatory , neuroloWe found encouraging results for adherence to medication in our population . Not surprisingly, the lowest levels of adherence were observed in multiple sclerosis patients treated with immunosuppressive agents because of fear of developing a life-threatening form of COVID-19 and in age-related macular degeneration patients who refused to go to hospital for intravitreal injections because of fear of contamination. ACE inhibitors were also discontinued in patients with chronic coronary syndromes or heart failure based on initial speculations that the use of ACE inhibitors, leading to increased expression of ACE2, which could potentially facilitate infection with COVID-19. Our observation highlights the ability of the patients and/or their family members to effectively self-manage and their discernment regarding alarming information circulating in the media during the first lockdown. Only 2 of 1274 patients declared that the media influenced non-adherence, and none blamed their loss of adherence on limited healthcare access. This positive result may be explained by the rapid onset of regional management protocols in accordance with the French or international recommendations, such as those established by the World Federation of Haemophilia for optimal management and follow-up of haemophilia patients . For insIn terms of lifestyle behaviours, our results were globally in line with the literature in healthy patients. Surveys conducted between March and June 2020, in which participants reported their perceived changes in lifestyle factors since the start of the pandemic, underscored a general worsening of sleep quality ,20, mildUnlike most of the reviewed web-based surveys, the CLEO-CD study relied on telephone interviews and used information on participants’ health behaviours and health status collected in-home before the pandemic, thus reducing the risk of information bias . As the COVID-19 epidemic evolves, and new social distancing measures are implemented, and in case of future pandemics, it is critical to identify population subgroups that have an increased risk of deteriorated health. This is particularly important for older patients because they live more frequently alone and are most vulnerable to the development and progression of diseases, including COVID-19, in the absence of medical follow-up. To our knowledge, our study is the first to identify urban living place, psychological distress, and worse self-reported mental health as independent factors associated with at least one unhealthy behaviour in individuals with chronic diseases.Our study has four main limitations. First, it was restricted to a single French region, so our results cannot be generalized. Second, our patients had mainly rare, chronic diseases. They were not representative to all chronic patients. The third limitation is the absence of patient follow-up. Lastly, due to the design of our study, we did not compare our lifestyle-related findings with those reported in healthy individuals in other studies.To conclude, we found a very high rate of medication adherence (97%) during the first COVID-19-related lockdown in a French region that was an early epicentre of the pandemic in Europe. This encouraging result may partly be explained by the adequation of previously established protocols. In contrast, we reported a deterioration in lifestyle behaviours, in particular sleep time, screen time, and physical activity. Among patients with chronic conditions, those living in an urban environment as well as those presenting psychological distress or mental health issues need to be carefully monitored to reduce unhealthy behaviours. The adequacy of previously established protocols may explain.