Of participants answering the ACT, 39% scored <20, suggesting poorly controlled asthma. For COPD, 61% of participants answering the CAT scored ≥21, demonstrating a high disease burden. Demographic/clinical characteristics of the cohorts were similar at SLS baseline. EHR data provided a long-term view of participants’ disease, and questionnaires provided information not typically captured. The Ext-SLS cohort is a valuable resource for respiratory research, and ongoing prospective data collection will add further value and ensure the Ext-SLS is an important source of patient-level information on obstructive airways disease.The Extended Salford Lung Study (Ext-SLS) is an extension of the Salford Lung Studies (SLS) in asthma and chronic obstructive pulmonary disease (COPD) through retrospective and prospective collection of patient-level electronic health record (EHR) data. We compared the Ext-SLS cohort with the SLS intention-to-treat populations using descriptive analyses to determine if the strengths (e.g. randomization) of the clinical trial were maintained in the new cohort. Historical and patient-reported outcome data were captured from asthma-/COPD-specific questionnaires . The Ext-SLS included 1147 participants ( Chronic obstructive pulmonary disease (COPD) is the most prevalent chronic respiratory disease globally, followed by asthma, and both are associated with significant illness, disability, and mortality4. Understanding the real-world patient experience of these conditions is crucial to providing appropriate care and treatment5, particularly when taking a “treatable traits” approach to disease management6. However, there are few longitudinal research cohorts available with well-characterized, real-world data. Here, we describe a new research cohort, the Extended Salford Lung Study (Ext-SLS), which combines clinical trial data from asthma and COPD patients with electronic health record (EHR) data and detailed, self-reported, information to assess the impact of respiratory disease on patients’ everyday lives. The aim of the Ext-SLS was to gain a more in-depth and long-term understanding of the patients’ disease journey and improve scientific and clinical understanding of COPD/asthma disease risk, treatment, and progression.Obstructive airway diseases are a leading cause of morbidity and mortality worldwideEthical approval was granted by the North West—Greater Manchester East Research Ethics Committee (REC number: 17/NW/0122). Patients enrolled in the Ext-SLS provided written informed consent for the collection of data via their EHRs both retrospectively to the earliest available record and prospectively for ≤10 years from consent into the study.9. Patients were recruited from general practice clinics in Salford and Greater Manchester, UK, between March 2012 and October 2014 for SLS COPD, and November 2012 and December 2016 for SLS asthma. Patients consented to relevant data being collected from up to 3 years prior to the study and for the 12-month interventional treatment period. Participants were broadly representative of COPD and asthma populations in the United Kingdom (UK)9.The Ext-SLS is an extension study of the SLS. The SLS were first-of-their-kind, Phase IIIb, pragmatic, randomized, controlled clinical trials designed to evaluate the safety and effectiveness of initiating fluticasone furoate/vilanterol  versus continuing usual care (UC)10.Participants were eligible for inclusion in the Ext-SLS if they were randomized to treatment in the original SLS and were able to provide written consent for data collection in the Ext-SLS. Patient recruitment (conducted 2018–2019) was general practitioner (GP) led. Participants consented to share primary care EHR data held by GP sites, as well as secondary care EHR data obtained from the NHS Digital Hospital Episodes Statistics databases covering admitted patient care, outpatient visits and Accident and Emergency attendances11.Primary care EHRs in the Ext-SLS include all non-sensitive and coded information relating to patient demographics, prescriptions, symptoms, diagnoses, referrals to and interactions with secondary care, preventative healthcare, diagnostic testing, and lifestyle information . Primary care EHR data are coded using Read, Systematized Nomenclature of Medicine (SNOMED) and local Egton Medical Information Systems (EMIS) codesRetrospective EHR data were collected to the earliest available record and prospective data are being collected periodically for up to 10 years from the date of consent.Participants completed disease-specific questionnaire booklets that captured information about their disease histories and management at the point of Ext-SLS consent. The questionnaires gathered information not available in EHRs and included validated disease-specific instruments in addition to questions on early life experience, environmental exposures, medication use, physical functioning, and social support Figs. , S2. Val12.To understand whether the Ext-SLS cohort was representative of the wider SLS population, we report descriptive comparisons of the Ext-SLS and SLS intention-to-treat (ITT) cohorts using data captured at entry to the original SLS. Post-hoc analysis was performed using chi-square testing to examine differences in select baseline characteristics. The ITT populations of the SLS included patients who were randomized in the studies and received at least one prescription of study medication (FF/VI or UC). The generalizability of the COPD population to the non-trial COPD population has been assessed previouslyN and % for categorical data; mean and standard deviation (SD) or median and inter-quartile range for continuous data. Secondary care data were not available at the time of analysis. Description of primary care data focused on current lifestyle information , comorbidities, and blood tests  recorded within 24 months prior to the Ext-SLS consent date. For participants with COPD, modified Medical Research Council (mMRC) dyspnea score, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade of airflow limitation (1–4) and lung function (forced expiratory volume in one second [FEV1]) were assessed. Questionnaires were analyzed on a per-question basis using all “known” answers  for each specific question. Additionally, questionnaire data were analyzed using the subset of participants that completed all required questions .A descriptive analysis of the Ext-SLS primary care EHR and questionnaire data was conducted using Further information on research design is available in the n = 798 asthma, n = 349 COPD) completed questionnaires and had primary care data available for analysis. The SLS ITT populations included 4233 asthma patients and 2799 COPD patients. While the intention was to collect full retrospective EHR data, ultimately, only ~10 years of data (including retrospective and some prospective) data were obtained and are available. Participants consented to the Ext-SLS a mean of 3.2 years post-SLS. In the SLS, patients were randomized 1:1 to FF/VI versus UC. In the Ext-SLS, 46% (368) of participants with asthma and 48% (167) of participants with COPD were originally randomized to FF/VI during the SLS. Most Ext-SLS participants were from Salford  or Trafford  and provided consent in 2018 .Overall, 1183/7032 participants (18.9%) from the SLS ITT population consented to the Ext-SLS and 1147 of these (p < 0.0001). Conversely, at entry to the SLS, participants in the Ext-SLS cohort with COPD were, on average, slightly younger at baseline than in the SLS COPD ITT population, with a greater proportion of participants aged <50 years (p = 0.0013). Compared with SLS asthma participants, there were more females in the Ext-SLS (p = 0.0035), and a larger proportion reported never smoking at baseline (p = 0.007). For participants with COPD, there was a greater proportion of “ex-smokers” and a smaller proportion of “current smokers” in the Ext-SLS cohort compared with the SLS cohort; however, these differences were not statistically significant.Baseline demographics collected at the beginning of the SLS were broadly similar between the Ext-SLS and SLS cohorts Table , with so2-agonist (SABA) reliever therapy use  or obese (BMI ≥30 kg/m2). Average BMI measurements in Ext-SLS (at or just prior to the time of consent) reflected measurements recorded at SLS entry  among Ext-SLS asthma participants included atopy (57.0%), pneumonia (53.8%), and diabetes mellitus (14.9%) Table . EvidencAmong Ext-SLS COPD participants, comorbidities included pneumonia 68.5%), atopy (37.0%) and arrhythmia (26.1%). In the 12 months prior to Ext-SLS consent, 21.5% of COPD participants had evidence of current asthma, while 37.2% had no prior asthma diagnosis  and neutrophil counts ; with many having multiple measures  in the 24 months prior to Ex-SLS consent. Compared with asthma participants, a slightly higher proportion of COPD participants had blood eosinophil counts ≥150/μl (69 versus 66%). Neutrophil counts <6000/μl were recorded for 88% of asthma participants and 77% with COPD.1 measurements were taken in the 24 months prior to consent.Among the 349 Ext-SLS COPD participants, 75% had information on GOLD airflow grade; most participants were GOLD Grade 2 (43%). An average of three (range 1–12) FEVPrescriptions of respiratory medicines in the 12 months prior to Ext-SLS consent are detailed in Table All participants completed some of the questionnaires, with most participants completing all required questions . The distribution of responses for each question was similar when analyzing the responses from all patients who completed the question compared to the subset of patients who completed all required questions Tables S2.n = 738–755, variable number of responders), 31% reported the first occurrence of symptoms at age ≥40 years. The first diagnosis was made ≥40 years of age for 35% of patients, with 40% prescribed medication for the first time aged ≥40 years. Among the participants with asthma who responded to smoking questions (n = 784), 12% identified as current smokers , with 87% scoring <60 out of 100, placing them in the first tertile—indicating low impact  was completed by 787 participants, 61% of whom scored ≥20 suggesting their asthma was well-controlled at the time of consent into the Ext-SLS. Scores suggesting partially controlled (ACT score 16–19) and uncontrolled (ACT score <16) asthma were found in 20 and 19% of participants, respectively. Of the 789 participants who completed the Asthma Control Questionnaire-6 (ACQ-6), 37% scored ≤0.75, indicating controlled asthma, while 31% scored >0.75 and <1.5 suggesting partial control and 32% scored ≥1.5 suggesting uncontrolled asthma. The effect of asthma on sleep, as measured by the COPD and Asthma Sleep Impact Scale (CASIS) total score, was found to be low among the Ext-SLS participants (Commonly reported triggers for asthma symptoms were airway infections and colds (88%), dust (85%), exercise (77%), and cold air (70%) Fig. . AlteratA large proportion of responders 87% of 340) reported early exposure to second-hand tobacco smoke. For 66% of 342 participants, their mother was a smoker Table . Among t40 reportn = 333), was 22.7 (8.7). Overall, 61% of participants scored >20, denoting a high impact of disease; the largest proportion of participants scored 21–30 (40%)—with lower scores denoting less disease burden. Based on the CASIS, most responders (n = 343) reported the little effect of their disease on sleep, with the majority (67%) scoring <60 out of 100   COPD Assessment Test (CAT) score, among participants with COPD who completed this part of the questionnaire , 76% of participants reported visiting friends or family at least once per week; while 36 and 37% described being moderately satisfied and not at all satisfied with their health, respectively. Overall, 36% of participants reported feeling tired nearly every day, 16% on more than half of the days and 34% on several days in the two weeks prior to answering the questionnaire. Pub or social club attendance was reported by 29% of participants, 11% attended a sports club, gym, or golf club, 14% attended other group activities at least once per week but 53% reported that they did not attend any of the activities listed in the questionnaire. Being unable to walk unaided was described by 33% of participants, with COPD being a factor in the need for assistance in 88%.In response to questions on social and physical functioning 14, as more COPD exacerbations were reported in trial patients and/or were more likely to be recorded. However, the largest effect was observed through changes in behavior in patients and general practitioner coding practices.Comparisons of the Ext-SLS cohort with the SLS ITT populations using SLS trial data demonstrated that the Ext-SLS cohort is broadly similar to the wider SLS populations, but with some key differences. Ext-SLS asthma participants were, on average older, with fewer symptoms than the SLS asthma ITT population at the time of SLS entry. Conversely, Ext-SLS participants with COPD were, on average, younger, but similarly had less severe disease (based on airflow obstruction) at the time of SLS entry than the SLS COPD ITT population. Additionally, it is likely that the benefits of randomization have not been carried through to the Ext-SLS, even if the 1:1 ratio of FF/VI to UC participants was broadly maintained. Interestingly, a previous observational cohort study compared the cohort of SLS COPD patients with matched non-trial patients with COPD in England from the Clinical Practice Research Datalink database19. Information on biomarkers, in combination with patient-reported information from the questionnaire, makes the Ext-SLS particularly useful in identifying disease traits  and may help to address questions relating to the impact of a treatable traits20 approach (in contrast to stepwise treatment approaches as are routinely used in asthma management18) in obstructive airways disease.While the Ext-SLS may not fully represent the SLS, it remains a detailed and valuable cohort for respiratory disease study. The comprehensive primary care data available describe participants’ general health over the course of their disease, with measurements of BMI, laboratory parameters and information on comorbidities. The laboratory data provide insight into clinical biomarkers of respiratory disease, such as blood eosinophils and neutrophils, which are both potential biomarkers of disease severityAdditionally, data on the prescription of respiratory medication can indicate common treatment patterns and indirectly provide information on disease control. A noteworthy limitation of the prescribing data is the restriction to prescriptions issued in primary care. Most new and repeat prescriptions for respiratory medications are issued in primary care, except biological therapies for asthma. Additionally, the exact dates of prescriptions were not available at the time of analysis (only month and year), meaning that we could not accurately determine the use of multiple-inhaler triple therapies.The questionnaires (completed in full by a large proportion of participants) complement the EHR data, providing information on disease impact that is not typically available. Among Ext-SLS participants with asthma, the validated ACT, ACQ, and CASIS questionnaires detailed the Ext-SLS asthma population as one where many participants still have uncontrolled asthma, and disturbed sleep, albeit at a low level. The questionnaires also showed a high level of self-management among the participants.21. Data relating to early life and personal history provided valuable insights that could not be gathered from medical records, detailing factors relating to underlying etiologies. The asthma questionnaires indicated that asthma was often adult-onset in this cohort and outlined common triggers of symptoms. For participants with COPD, data from the questionnaires suggested factors that could have contributed to the disease in the household and working environments.Participants with COPD in the Ext-SLS had a mean CAT score >20, suggesting that COPD had a substantial impact on the lives of these participants. However, as with the asthma population, the CASIS results suggested that most participants did not find their sleep suffering as a result of their COPD, though many reported sleep disturbances. The social impact of COPD was demonstrated by the questionnaires, with more than half of participants reporting that they did not attend social activities—aligning with previous research into the social impact of COPD28. Similarly, the nature of real-world data means that data may be error-prone . The time between the original SLS and the Ext-SLS led to patient attrition and there may be bias in the recruitment of patients due to the SLS population ageing and possibly becoming too unwell to participate.The Ext-SLS has some limitations that relate to the nature of the data. Patient-reported outcomes were collected in the disease-specific questionnaires and could be susceptible to inaccuracy or error due to factors such as limitations in recall, recall bias and a subjective assessment of the variables. However, validated instruments were used to collect information about disease impact and managementIn conclusion, the Ext-SLS cohort is a well-characterized and valuable resource in the field of respiratory research and may be particularly useful in addressing questions relating to treatable traits. The cohort is unique due to the inclusion of a randomized clinical trial in its timeline. Ongoing work collecting prospective data from the cohort will further increase the data available over time.Supplementary materialReporting Summary


Is SARS-CoV-2 seropositivity associated with symptoms of myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) in children and adolescents?This cross-sectional study of hospital-based SARS-CoV-2 seroprevalence surveys in Germany compared seropositive and seronegative children and adolescents and identified an excess of possible ME/CFS symptoms with serological evidence of preceding SARS-CoV-2 infection. This association almost disappeared with adjustment for confounders and restriction to children and adolescents unaware of preceding infection.These findings suggest that the risk of ME/CFS after SARS-CoV-2 infection in children and adolescents may be small and that recall bias may contribute to risk estimates. This cross-sectional study assesses the association between SARS-CoV-2 infection and symptoms related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) in children and adolescents in Germany. During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures.To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents.This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years.Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays.Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue.Among 634 participants , 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2–seropositive (40.0%) and 158 of 534 SARS-CoV-2–seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35  to 1.18  and for substantial fatigue from 2.45  to 2.08 . Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS–related symptoms. The adjusted risk ratio was 1.08  for reporting clustered ME/CFS symptoms and 1.43  for fatigue.These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic. In a German study,1 a substantial reduction in quality of life and mental health was already detected in the first months of the pandemic. With only approximately 2% of children and adolescents being infected at this time,4 it is reasonable to conclude that containment measures were at least partially responsible. During parts of the observation period, containment measures such as work-at-home mandates and reduction of social contacts were extended to full lockdown, including closures of shops and schools. The first nationwide lockdown with school closures was maintained from March 22 to April 15, 2020, with stepwise reopening of schools to May 6, 2020. The second nationwide lockdown, including school closures, was maintained from December 16, 2020, to March 3, 2021, when the government decided to gradually ease the lockdown measures depending on a stable incidence of less than 50 new infections per 100 000 inhabitants in a region.During the COVID-19 pandemic, an increase in nonspecific symptoms and mental health problems and a reduction in quality of life among children and adolescents have been reported.5 The etiology and pathomechanisms of ME/CFS are unclear, although infections by different pathogens are frequently reported triggers, and these symptoms are possibly mediated by postinfectious autoimmunity.8Nonspecific somatic symptoms associated with long lockdown have been reported to overlap with key features of myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS), a complex disabling disease with symptoms of at least moderate severity and frequency persistent for at least 3 months, including fatigue, postexertional malaise, pain, sleep, and cognitive dysfunction as well as autonomous, neuroendocrine, and flulike symptoms.10 However, a clear causal link has not been established. In the absence of reliable biomarkers and causative factors for ME/CFS, epidemiological data may indicate associations with specific viral infections. Serological studies, including data on symptoms associated with ME/CFS, seem most appropriate to address this question. Serological data provide information on symptomatic and asymptomatic infections, thus representing the best available data source for a comparative risk assessment of ME/CFS–associated symptoms. Reported symptoms, however, may be prone to recall bias in children and adolescents who are aware of a preceding infection.It has been suggested that SARS-CoV-2 acts as a trigger for ME/CFS, and ME/CFS is considered to be a severe form of the long COVID-19 symptom complex.11 a pediatric screening tool for ME/CFS in epidemiological studies. The DePaul Symptom Questionnaire was developed to achieve maximal screening sensitivity and not to establish a clinical diagnosis. Thus, a substantial proportion of cases reporting clustered ME/CFS symptoms are likely to represent false-positive results.To assess the association between SARS-CoV-2 infection and ME/CFS–related symptoms among children and adolescents, we extended the cross-sectional seroprevalence surveys of SARS-CoV-2 IgG in Germany by items according to the Pediatric DePaul Symptom Questionnaire,We hypothesized that there would be a difference between the proportion of children and adolescents reporting clustered ME/CFS symptoms according to the ME/CFS questionnaire and that for nonspecific individual symptoms possibly related to ME/CFS among seropositive and seronegative children and adolescents. To detect potential recall bias, we additionally considered awareness of a preceding SARS-CoV-2 infection.STROBE) reporting guideline.We performed a substudy of the SARS-CoV-2 KIDS study, which conducted hospital-based, multicenter cross-sectional surveys on the seroprevalence of anti–SARS-CoV-2 IgG antibodies in children in Germany from May 1 to October 31, 2021. Participants were recruited during their inpatient or outpatient stay in a pediatric hospital, regardless of the medical purpose of the stay. The ethics committee of each study center—including the Medical Faculty of Heidelberg University, Medical Faculty of Ludwig-Maximilians-University Munich, Technical University Dresden, North Rhine Medical Association, Albert-Ludwigs-University Freibug, Medical Faculty of the RWTH Aachen, Medizinische Hochschule Hannover, Julius-Maximilians University Wuerzburg, and Technical University Munich—approved the SARS-CoV-2 KIDS study and the amendments that were applied in our substudy. Parents or guardians of the children and adolescents provided written informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology .A study-specific questionnaire provided clinical information. From May to October 2021, in 9 participating study centers, the parent study questionnaire on demographic and clinical information for children and adolescents aged 5 to 17 years was supplemented by screening questions for typical ME/CFS features such as frequent and persistent fatigue or extreme tiredness, pain, sleeping problems, cognitive difficulties, flulike symptoms, or disruptions in school activities. The questions were designed according to the DePaul Symptom Questionnaire.P = .25) . We investigated whether reporting of symptoms of any respiratory disease is associated with the 2 main outcomes of clustered ME/CFS symptoms and severe fatigue by calculating additional multivariable models stratified by SARS-CoV-2 serostatus. We defined children who never reported any respiratory infections as asymptomatic and others as symptomatic. Because the ME/CFS screening questions were implemented within the last months of the SARS-CoV-2 KIDS study only, we performed a post hoc power analysis for tests of 2 independent proportions.P < .05). All statistical tests performed were 2-sided. We used SAS software, version 9.4 (SAS Institute Inc), for all statistical analyses.The significance level was set a priori at 5% (P = .07). Female sex , older age , and preexisting disease  were associated with a higher probability of reporting clustered ME/CFS symptoms , data of 634 participants  were included in the analysis  were seropositive for SARS-CoV-2. Among the 100 seropositive participants, 40 (40.0%) reported clustered ME/CFS symptoms compared with 159 of the 534 seronegative participants (29.6%). After adjustment for sex, age group, and preexisting disease, the risk ratio (RR) for reporting clustered ME/CFS symptoms decreased from 1.35  to 1.18  . FatigueOnly 24 of 634 study participants (3.8%) reported having had past positive test results for SARS-CoV-2. Confinement to children and adolescents with an unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all ME/CFS–related symptoms . In chilP < .001). Stratification of the analysis by SARS-CoV-2 serostatus showed that the adjusted RR for severe fatigue, depending on symptom status in the group of seropositive children, was 3.18  compared with 2.44  in the SARS-CoV-2–seronegative group (The proportion of children and adolescents reporting respiratory symptoms was significantly lower in those who were unaware of their SARS-CoV-2 infection status (16 of 24 [66.7%]) compared with those reporting previous positive SARS-CoV-2 test results  in children with vs children without previous COVID-19.12Comparison of SARS-CoV-2–seropositive and SARS-CoV-2–seronegative children and adolescents identifies an excess of key features of ME/CFS (clustered ME/CFS symptoms) and of substantial fatigue in those with serological evidence of preceding SARS-CoV-2 infections in the crude analysis. The risk estimates of these associations were reduced after adjustment for confounders and restriction to children and adolescents who were unaware of a preceding infection. An RR of less than 1.50 for reporting symptoms for ME/CFS triggered by a SARS-CoV-2 infection in children cannot be excluded based on the sample size of these data. The low RRs observed are in line with a preprinted report of routine health insurance data of a large matched German cohort revealing a statistically nonsignificant relative RR of 1.25  for ME/CFS diagnosis (13 might reflect an association with long lockdown. Our finding of an association between clustered ME/CFS symptoms and older age, female sex, and preexisting disease is consistent with findings of previous studies that have indicated a positive correlation between these parameters and persistent symptoms.13As in the present study, the extent of unspecific symptoms in all children and adolescents during the COVID-19 pandemic reported by others16 have reported a higher percentage of long COVID-19 symptoms in cases vs controls. One of these studies15 provided follow-up data that indicate a short duration of symptoms in most cases. However, these studies may be biased because of unrecognized infections and recall bias and therefore may overestimate the risk among children and adolescents.Previous pediatric studies defining infected cases and controls by results of SARS-CoV-2 reverse transcriptase–polymerase chain reaction testing19 have compared nonspecific symptoms in seronegative and seropositive children and adolescents. These investigators found slight differences in proportions of nonspecific symptoms between seropositive and seronegative patients, but none of these differences were statistically significant. In all pediatric studies comparing children with and without serological evidence of SARS-CoV-2 infection,20 the difference in prevalence in unspecific symptom burden between cases and controls was less than 4% and was statistically not significant.Only a few pediatric studiesA novel aspect of our analysis consists of using a validated screening tool for certain symptoms potentially indicating ME/CFS. By collecting information about the frequency of symptoms, it was possible to distinguish between occasional symptoms and those experienced more than half the time. Our findings revealed slightly increased unadjusted RRs for reporting clustered ME/CFS symptoms, substantial fatigue, and several additional symptoms in seropositive children and adolescents. However, adjustment for confounders and inclusion of knowledge about a preceding SARS-CoV-2 infection yielded decreased effect estimators.This study has some limitations. The importance of serology as a marker of prior SARS-CoV-2 infection has been discussed among experts, and false-negative results are a factor in all studies based on serology. Because seroconversion does not provide information about the time of infection, the time span between infection and study participation cannot be determined. Therefore, the cross-sectional design does not consider the possible correlation between time of infection and occurrence of ME/CFS symptoms. Nevertheless, an advantage of this study design is that asymptomatic infections were also included in the analysis.21 After restricting our analysis to patients who were unaware of their prior SARS-CoV-2 infection, the effect estimates for almost all outcomes were reduced markedly.A further limitation pertains to external validity. The hospital-based study design may limit the representativeness of our sample in that children who did not require specialist outpatient or hospital care during the study period were not able to participate. Nevertheless, this study design allowed the inclusion of children and adolescents of all ages. Additionally, our findings may be limited by recall bias, which is a common feature among case-control studies.22 our data suggest similar effect estimates of preceding symptomatic respiratory disease regarding the risk of clustered ME/CFS symptoms and severe fatigue irrespective of a confirmed SARS-CoV-2 infection. Indeed, many infectious diseases are known to cause persistent symptoms and infection-associated sequelae.24 The increased risk of fatigue among children reporting respiratory illness in the past may be attributable to SARS-CoV-2 infection as well as other infectious diseases. A recent study from Sweden reported an association between longer hospitalization and more severe persistent long COVID-19 symptoms among a small sample of children.25 However, rates of hospitalization for COVID-19–related therapy and severe courses with the need for intensive care treatment in children and adolescents are less than 1 in 1000,26 which may not be relevant with respect to our data.An alternative explanation for the reduction of effect estimates in children who lacked knowledge of a prior SARS-CoV-2 infection could be that recalled positive test results are associated with a high risk of symptomatic COVID-19. Unfortunately, the effects of COVID-19 severity cannot be evaluated using this data set owing to the lack of information about the pathogen responsible for the reported symptoms. The proportion of children reporting respiratory symptoms was significantly lower among participants who were unaware of their previous SARS-CoV-2 infection. However, the association of symptoms with the risk of clustered ME/CFS symptoms and severe fatigue was independent of serostatus. Thus, the reduction in the effect estimates of seropositivity as it pertains to the risk of clustered ME/CFS symptoms and severe fatigue could be attributed to recall bias. Although studies in adults have suggested that COVID-19 severity could be an independent risk factor for developing long COVID-19,The findings of this cross-sectional study suggest that a symptom cluster that possibly indicates ME/CFS, as well as fatigue that is of at least moderate severity and is present approximately half of the time, are frequent features among children and adolescents with and without documented SARS-CoV-2 seroconversion. However, a small additional risk of ME/CFS symptoms associated with a preceding SARS-CoV-2 infection cannot be excluded owing to lack of power. Recall bias may account for overestimating the risk of long COVID-19 symptoms in any studies in which children were aware of their infection status. Without reliable biomarkers, it will remain difficult to differentiate long COVID-19, long lockdown, and many other diagnoses manifesting with unspecific symptoms among children and adolescents during the course of the COVID-19 pandemic.


This cross-sectional study examines the number and characteristics of hospitals that performed well or poorly across 3 Medicare value-based programs in fiscal year 2020. Prior work has shown that each program disproportionately penalizes hospitals caring for patients from low-income and racial and ethnic minority groups, raising concern that aggregate penalties may impede their ability to provide and improve care.4 At the same time, understanding the types of hospitals that perform well across all programs could inform strategies to improve care delivery.Over the past decade, the Centers for Medicare & Medicaid Services (CMS) has introduced 3 major hospital value-based payment programs that aim to improve quality: the Hospital Value-Based Purchasing Program (HVBP), the Hospital Readmissions Reduction Program (HRRP), and the Hospital-Acquired Condition Reduction Program (HACRP). Hospitals penalized by all 3 programs may experience a reduction in Medicare revenue of up to 6%—a major loss, given that many US hospitals operate on narrow margins.P < .05 was considered statistically significant. All analyses were performed using R, version 3.5.2 . The Beth Israel Deaconess Medical Center institutional review board deemed this study exempt because it used only publicly available data without patient identifiers. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.In this cross-sectional study, we examined the number and characteristics of hospitals that performed well or poorly across all 3 value-based programs in fiscal year (FY) 2020 . Using Medicare’s Hospital Compare files, we identified the FY 2020 scores of hospitals participating in the HVBP, HRRP, and HACRP. Hospital characteristics were obtained from the American Hospital Association Annual Survey and CMS Impact File, and county characteristics from the American Community Survey File. In each program, we categorized hospitals into performance quartiles and identified hospitals that ranked in the top (high-performing) and bottom (low-performing) quartiles across all 3 programs, and classified all other hospitals as average-performing. Cochran-Armitage test (binary variables) and linear regression (continuous variables) were used to assess for monotonic patterns across hospital groups, and Cochran-Mantel-Haenszel tests for mean differences . Two-sided P < .001), more likely to be for-profit , and similarly likely to be safety-net hospitals  (P < .001) or non-US-born  adults and were concentrated in states in the South Atlantic (27.0%) and East South Central (17.6%) regions  were identified as high-performing sites, while 74 (2.7%) had low performance across all 3 programs; the proportion receiving penalties in each hospital group is shown in the P = .95) . Low-per regions . Across 6Less than 5% of US hospitals demonstrate high performance across all 3 of Medicare’s hospital value-based payment programs. This could reflect efforts by CMS to capture separate domains of quality and would imply that very few US hospitals provide high-quality care globally. Alternatively, it may result from idiosyncrasies of program design and measures that hamper reliable assessment of hospital quality and that may warrant attention and reform.Hospitals that performed poorly across programs were more likely to be located in areas with a higher proportion of socially vulnerable populations, including immigrants and racial and ethnic minority groups. Nearly half of low-performing hospitals were located in the Southeastern US, where many communities experience disproportionately poor health outcomes. Financial penalties levied by hospital value-based programs, particularly when compounded, may exacerbate disparities in care for these populations.A limitation of this study is that we only focused on FY 2020, which reflects hospital performance over a 3-year period (2015 to 2018).Very few hospitals demonstrate high performance across all 3 value-based programs , and hospitals penalized by all 3 programs (low performers) were more likely to be located in communities with a high proportion of Black individuals and in the Southeastern US.


N = 1,360; 27.5% women) were assigned randomly to DM (N = 682) or usual care (UC) (N = 678). Study intervention did not significantly affect the rate of hospital admissions or mortality. This study evaluates sex-related differences in baseline characteristics, clinical manifestations, adherence to treatment and outcomes among the study cohort.This is a sub-analysis of a randomized controlled trial on heart failure (HF) disease management (DM) in which patients with HF  and lower frequency of ischemic heart disease (IHD) (p ≤ 0.001). Females had shorter 6-min walking distance and worse quality of life and depression scores at baseline (p < 0.001). The proportion of patients receiving HF recommended medical treatment was similar among females and males. During a median follow-up of 2.7 years (range: 0–5), there were no significant differences between females and males with respect to the time elapsed until the study primary endpoint and its components in univariate analysis . Multivariable analysis showed that females were significantly less likely than males to experience the primary outcome  or to die from any cause . The sex-related mortality differences were especially significant among patients with non-preserved EF, with IHD or with recent HF hospitalization. Females also had lower rates of all-cause hospital admissions  and were more likely to adhere to HF medical therapy compared to males.Compared to males, females recruited in the study were on average 3 years older [median age 72  vs. 75 , Females with HF fare better than men. Sex related differences were not explained by baseline and morbidity-related characteristics or adherence to medical treatment. Heart failure (HF) incidence is increasing in both males and females and becoming a major and growing problem globally. There are significant sex related differences in HF etiology, pathophysiologic mechanisms, clinical expression and age at disease onset, as females are more likely to be diagnosed with HF at an older age compared to males –5. One oAge, sex and comorbidities are important considerations in HF outcomes and may be closely related to cardiovascular as well as non-cardiovascular events, leading to hospitalizations and mortality. There are conflicting data regarding sex-related differences in mortality among HF patients. While some studies reported a better survival for females compared to males –8, otherOur study aims were to examine sex-related differences in baseline characteristics, clinical manifestations, adherence to treatment and outcomes in a large cohort of HF patients who participated in a prospective randomized controlled trial on HF disease management (DM).This is a sub-analysis of a multicenter, open-labeled, prospective, randomized controlled trial on the effect of a DM program in community-dwelling patients with HF. The study design and methods were described elsewhere . In brieBaseline assessment included a physician-filled questionnaire on patient’s clinical characteristics, 6-min walk-test, NYHA classification, health-related quality of life (HRQoL) assessed with the 36-item short-form questionnaire (SF-36)  and deprHospital discharge summaries, available for 5,748 (99.7%) of 5,766 hospital admissions, were classified by two independent investigators after masking the patients’ identifying information. Each hospital admission was classified as either HF exacerbation related or as other cause for all non-HF related hospitalization. The primary composite outcome was the time elapsed until first HHF or all-cause mortality.Overall, the study intervention (nurse-led DM intervention vs. UC) had a neutral effect with respect to the primary composite outcome, its individual components, the total number of hospital admissions and in-hospital days for HF and for any other cause .post hoc analysis of the original HF DM trial design to evaluate sex related differences in baseline characteristics, medical treatment, hospitalization, morbidity and mortality among the study cohort.The current study is a t-test for comparisons of continuous variables with normal distribution, and the Mann-Whitney test for continuous variables with other distribution.Unadjusted comparisons of the baseline characteristics by sex were made using the chi square test for discrete variables. We used the unpaired Unadjusted comparisons by sex with respect to the primary composite endpoint  and its two individual components were made using the log-rank statistic.The Cox proportional hazards model was used to compare males and females with respect to the primary composite endpoint and its components, adjusted for baseline characteristics , and adherence to drug therapy for HF during follow-up, as time-dependent covariates. The time elapsed from recruitment until death from any cause and its 95% confidence interval (CI) was estimated for males and females, separately, standardized to the most common patients’ baseline profile, using an inverse transformation of the predicted survival curve at 75%. Predefined interactions between sex and baseline variables, including study group, LVEF, diabetes, underlying cause of HF (ischemic/non-ischemic), source of referral , and NYHA functional class were also tested. The proportional hazards assumption for sex group was tested in all these models.To compare hospital admission data recorded every 6 months for males and females, non-linear mixed models were used with a random intercept for each subject, allowing for correlation between repeated measurements of the same subject. Due to the over-dispersion commonly seen in hospital admission data, a negative binomial model was used. Using the NLMIXED procedure (SAS version 9.4), this method was implemented for the following secondary outcomes: number of hospital admissions and days of hospitalization, for HF and all other causes. These models were adjusted for baseline characteristics, adherence to drug therapy during follow-up and time since randomization in intervals of 6 months, and effectively dealt with the varying length of follow-up among individuals due to censoring. The coefficient of the sex group variable represented the log rate ratio for 6 months.We used information from the baseline patient-questionnaire completed by the cardiologist and data from Maccabi Health Services databases to create a chronic morbidity score. This score included baseline renal failure and history of cancer, chronic obstructive pulmonary disease, acute myocardial infarction, stroke or transient ischemic attack and peripheral vascular disease. This score was designed to weight in the different comorbidities and evaluate their effect on prognosis.Using the Maccabi Health Services database on drug purchases, adherence to medical therapy was defined as the number of days in a 6-month period covered by ACEi/ARB and BB therapy according to the defined daily dose, classified into 5 categories (1st category representing no treatment and 2nd–5th categories representing defined daily dose quartiles for patients taking the medication). The treatment odds ratio (OR) of attaining a higher level of coverage by drug therapy was estimated using an ordered logistic regression model within the non-linear mixed-model framework (NLMIXED Procedure in SAS). The assumption of proportional odds for each cut-point of the adherence variables was tested.All analyses were carried out according to the intention-to-treat principle, at a critical two-sided significance level of 0.05.p = 0.001], and presented with worse functional capacity, lower HRQoL scores and more depression symptoms . symptoms . Femalessymptoms .At recruitment, there were no sex-related differences with respect to treatment with guidelines directed HF medications , but females were less likely than males to be treated with statins and anti-aggregants .p = 0.5; p > 0.05 for all, During a median follow-up of 2.7 years (range: 0–5), 557 (56.5%) males and 218 (58.3%) females had a primary composite endpoint event , and 334 (33.9%) males and 116 (31.0%) females died from any cause. The median (interquartile range) time elapsed until a primary endpoint event was 1.9 years  among males, and 1.9 years  among females p = 0.5; . There wp = 0.29, Although there were no significant sex-based differences with respect to the time elapsed until death in univariate analysis  died from any cause was 2.75 years  among males and 3.80 years  among female patients .p = 0.36, There was no significant difference between females and males with respect to the time elapsed until first HHF during follow-up, both in univariate analysis , after recent HHF, or with HF due to IHD were less likely to die from any cause during follow-up, than males with the same attributes .p = 0.0007), adjusted for age, study group, study period, year of recruitment, source of referral, baseline NYHA functional class and 6-min, walking distance, BMI and chronic morbidity score.Female patients were more likely to adhere to medical therapy with ACEi or ARB and BB during follow up period compared to males .In this study, we investigated sex-related differences in demographic and clinical characteristics, treatment and long-term outcomes among a large cohort of HF patients recruited for a HF DM prospective randomized trial. Our findings confirmed sex-related differences in patients’ clinical profile and HF pathophysiology among a study population with a median age above 70 years old. The crude risk of morbidity and mortality represented by the study composite endpoint of HHF and all-cause mortality was similar between female and male patients. However, after adjustments for differences in baseline characteristics observed between the groups, females had a better prognosis than males, with a lower risk to experience a primary endpoint event during follow-up. This finding was attributed mainly to reduced risk of all-cause mortality among HF female patients. The sex-related mortality differences were especially significant among patients with non-preserved EF, with IHD or with recent HHF. We also found significant sex-related differences in the number of all-cause hospitalizations and in-hospital days, as female HF patients had lower overall admission rates and fewer in-hospital days compared to male patients. Our study demonstrates better adherence to HF medications during follow-up among females compared to males.Our findings support data published in previous studies showing that there are significant differences in clinical phenotype of HF between females and males. The incidence of IHD and HF with reduced ejection fraction (HFrEF) is lower, and the prevalence of HFpEF is twice as high among females compared to males –5. NeverAlthough many studies evaluated sex-related differences in mortality among HF patients, data are still conflicting. While several studies reported no difference in mortality –11 otherAnother potential explanation for the sex related differences in outcomes is the higher incidence of IHD among male HF patients. In a meta-analysis from the Meta-Analysis Global Group in Chronic HF (MAGGIC) study group females with non-ischemic HF etiology had better prognosis than males with non-ischemic HF etiology, while among patients with HF due to IHD, the advantage of being a female was somewhat smaller . In contAcute admission for HF exacerbation may represent deterioration in HF status and a worse prognosis , 10. ScrAge and comorbidities may also be associated with poor outcome in HF patients. Previous HF studies have consistently demonstrated significant older age and higher incidence of multiple comorbidities in females compared to males , 20–22. Although HF is a heterogeneous syndrome, varying by etiology and left ventricular function, HRQoL is impaired in many HF patients compared to patients without HF . HoweverOne of the main strengths of our study is that all participants were insured by the same health plan provider, hence, all clinical and outcome data were available including documentation of medicines purchase.Several limitations of this study should be acknowledged; First, our study population was enrolled in a clinical trial, so it is deemed selective due to inclusion and exclusion criteria. This may affect the external validity of the study since people with severe comorbidity were excluded. Second, the median age of our study cohort is above 70 years old, hence generalization of the results should be applied with caution to a younger patient population with HF. Third, the study was carried out in an environment with universal access to high-quality health care which may limit the generalizability of our findings in other health-care systems with barriers to universal access. Nevertheless, the extensive information on independent variables associated with HF outcomes that were controlled for in the multivariable models, the long-term follow-up and complete information of study endpoints provide significant contribution to our understanding of sex-related differences in HF outcomes.Females with HF have lower all-cause hospital admission and mortality rates. These sex-based differences were not explained by HF characteristics, comorbidity or adherence to HF recommended medical treatment. Our study provides novel information regarding better survival even among females with HFrEF and IHD compared to males. Despite better outcomes, females with HF reported more depression and lower HRQoL. The observed sex related differences in HF patients highlight the need for further research in this field and better representation of females in HF studies.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Sheba Medical Center Ethic Committee. The patients/participants provided their written informed consent to participate in this study.All authors has contributed significantly to the submitted work and seen and approved the final version of the manuscript.


Serum cotinine has become the most widely used biomarker of secondhand smoke exposure (SHS) over time in all ages. The aim of this study was to review the serum cotinine cut-points used to classify children under 5 years as exposed to SHS.A systematic review performed in the Pubmed (MEDLINE) and EMBASE databases up to April 2021 was conducted using as key words "serum cotinine", “tobacco smoke pollution” (MeSH), "secondhand smoke", "environmental tobacco smoke" and “tobacco smoke exposure”. Papers which assessed SHS exposure among children younger than 5 years old were included. The PRISMA 2020 guidelines were followed. Analysis was pre-registered in PROSPERO (registration number: CRD42021251263).247 articles were identified and 51 fulfilled inclusion criteria. The selected studies were published between 1985–2020. Most of them included adolescents and adults. Only three assessed postnatal exposure exclusively among children under 5 years. None of the selected studies proposed age-specific cut-points for children < 5 years old. Cut-point values to assess SHS exposure ranged from 0.015 to 100 ng/ml. The most commonly used cut-point was 0.05 ng/ml, derived from the assay limit of detection used by the National Health and Nutrition Examination Survey (NHANES).No studies have calculated serum cotinine age-specific cut-points to ascertained SHS exposure among children under 5 years old. Children’s age-specific cut-points are warranted for health research and public health purposes aimed at accurately estimating the prevalence of SHS exposure and attributable burden of disease to such exposure, and at reinforcing 100% smoke-free policies worldwide, both in homes, private vehicles and public places. The assessment of the involuntary smoking or exposure to secondhand smoke (SHS) in children during pregnancy and early childhood is essential for public health and research purposes. Estimating the children at-risk from environmental tobacco can have important public health implications in terms of determining the population attributable burden of disease and evaluating the impact of the information, cessation interventions and prohibition laws on this target group. SHS is defined as tobacco smoke produced by an active smoker from exhaled mainstream smoke together with sidestream smoke. Sidestream smoke is a combination of smoke from the smoldering tobacco product between and during puffs and smoke components which diffuse through cigarette paper ,2.Pediatric population is especially vulnerable to the effects of SHS due to their narrower bronchi, faster respiratory rate and immature immune system . PrejudiCotinine, the major metabolite of nicotine, is considered the best biomarker for assessing recent SHS exposure due to its high specificity and sensitivity, as well as its relatively prolonged half-life which ranges from 16 to 20 hours in children . CotininSerum cotinine allows for differentiating active smokers from passive and non-smokers. Nonetheless, the determination of SHS exposure is rather challenging as currently there is no standardized consensus regarding the optimal cut-point to be used to classify SHS exposure among young children. Some prior studies, based on NHANES data for older children and adolescents, proposed the serum cotinine cut-point of 0.05 ng/ml which derives from the assay limit of detection (LOD) ,11. ThisThe aim of this study is to review serum cotinine cut-points used so far to assess SHS exposure in children under 5 years and assess the changes on the cut-point values over time and across different countries.We performed a systematic review in PubMed (MEDLINE) and EMBASE databases following the PRISMA 2020 guidelines . Search To be selected for this review, articles had to assess pre-natal SHS exposure in newborns and/or post-natal SHS exposure in children younger than 5 years by using serum cotinine assays in addition to or in lieu of parental self-report. We included investigations with mother-child pairs and those grouping children under 5 with older ones, adolescents and adults. Among the latter, when data was stratified by age groups, we selected that including children younger than 5 years. On the other hand, we excluded studies with serum cotinine obtained just from mothers; without cut-point values to distinguish between exposed and unexposed children, and those measuring cotinine from other biological fluids as urine, saliva, hair, meconium or maternal milk. In the case of longitudinal studies, we only considered the information corresponding to the period of time in which SHS exposure was ascertained accompanied with serum cotinine in a sample including children under 5 years.After excluding duplicate articles from the search, the title and abstract of the records were screened individually by two independent reviewers to ascertain that they met eligibility criteria. Full text of the eligible papers was obtained for potentially relevant articles. Bibliography from the selected papers was revised to manually complete the initial search. Thereafter, data from those meeting eligibility criteria were extracted and discrepancies in its interpretation were solved by consensus. A modified Newcastle-Ottawa scale was used to assess appropriateness of the representativeness of the sample, participation rate, ascertainment of the exposure, and the adequacy of the method used for the selection of the cut-points. Score disagreements were resolved by consensus and a final agreed-upon rating was assigned to each study.The data extracted for analysis were: study characteristics  and country); population characteristics ; information regarding the analytical technique used to quantify serum cotinine (radioimmunoassay (RIA), enzyme-linked immunosorbent essay (ELISA), gas chromatography (GC), gas-chromatography mass spectrometry (GC/MS), gas-liquid chromatographic procedure with nitrogen-phosphorus-specific detector (GLC/NPD) and isotope dilution liquid chromatography tandem mass spectrometry (LC-MS)); serum cotinine cut-point values to classify SHS exposure in children and method for the selection of the cut-points.A total of 247 articles were obtained and 51 of them fulfilled the inclusion criteria. The PRISMA flow diagram of the included studies is displayed in The 51 papers included were published between 1985 and 2020. They included one case-control study , 13 cohoStudies were mainly conducted in the USA (34 papers) and Europe (15 studies) .Thirty-three out of 51 papers measured postnatal exposure to SHS with serum cotinine; 17 prenatal exposure with newborns’cord serum cotinine and one both pre- and post-natal exposure . 38 studConsidering those studies assessing prenatal exposure, sample sizes ranged from 8 to 1,323 newborns. Among the 33 studies assessing postnatal exposure, 27 papers grouped children under 5 years with older/adolescents (aged 12–19) and 3 papers, also with adults (aged ≥ 20). The remaining 3, measured postnatal SHS exposure exclusively in children under 5 years with sample sizes ranging from 132 to 504 children ,56,59 T.Isotope dilution liquid chromatography tandem mass spectrometry (LC-MS) was used in 35 of the selected papers followed by RIA in 7, GC/GC-MS/ GLC/NPD in 7 and ELISA in 2 . A totalOne study calculated age-specific cut-point with receiver operating characteristic (ROC) curves : 0.9 ng/As summarized in Several studies have concluded that cotinine metabolism is influenced by sex, race and age after having observed higher cotinine concentrations among children, females and non-Hispanic Blacks ,44,64. WIn our systematic review, we have observed that serum cotinine cut-point values to characterize children’s exposure to SHS have varied remarkably since 1985 and across the countries, being the highest value mentioned in a Chilean study conducted in 1990s, more than 6,600 times that of the lowest used in US studies, 100 versus 0.015 ng/ml. European studies used values between 0.2–35 ng/ml. We only found three studies assessing postnatal exposure exclusively among children under 5 years, between 1–3 years, with disparate cut-points ranging from 2.5 ng/ml to 100 ng/ml.We have observed that some of the studies that classified pre- or postnatal SHS exposure selected the threshold used to distinguish between smoker and non smoker (ranging from 3 to 20 ng/ml) and thus, being liable to have underestimate exposure on this target group. The only paper included in our review, which measured both pre- and postnatal exposure to SHS with serum cotinine, used the same cut-point for newborns and children aged 1 and 2 years .The most widely used cut-point for the classification of prenatal SHS exposure, via newborns’ cord serum cotinine, was 1 ng/ml; One study obtained a cut-point of 1.78 ng/ml from the ROC curves to discriminate newborns from nonexposed and exposed nonsmokers with a sensitiviy and specificity of 60% ; this vaIn general terms, a decrease in the serum cotinine cut-point values has been observed over time and this could be partly explained by the better LOD threshold of the analytical techniques. Beginning in 2001–2002, the LC/MS assay LOD used to determine serum cotinine concentrations in the samples collected in NHANES was lowered in some studies from 0.05 to 0.015 ng/ml as a result of the introduction of a more sensitive mass spectrometer . These tThe lowering of the thresholds also results from the acknowledgement that no safe levels of SHS exposure can be established. Some prior investigators have emphasized that even very low levels of SHS exposure (serum cotinine concentrations < 0.1 ng/mL) can cause adverse effects on cognitive outcomes among children  and thisThis review has some limitations. First, we only used PubMed and EMBASE databases but we do not expect to have missed any relevant papers because we have expanded the search by including articles from the bibliography of those papers selected. Second, when limiting the search to English, Spanish, French and German, papers published in other languages might have been excluded. To the best of our knowledge, 1 paper published in Polish was excluded. Third, period of study was not especified in 4 cross-sectional studies ,28,32,52As the main strength, this is the first review on the serum cotinine cut-points used across different countries to assess SHS exposure in children. Prior investigations have identified the cotinine cut-point values used over time to discriminate between smokers and nonsmokers. The 2006 Surgeon General´s report mentioned the need to review the cut-points used when assessing tobacco consumption and SHS exposure among pregnant women considering the higher metabolic clearance rates and therefore, the shorter half-life of cotinine during pregnancy . For thoIt is necessary to raise public awareness of the need to adopt 100% smoke-free policies worldwide aimed at avoiding the long-term adverse effects resulting from early exposures to tobacco smoke. SHS exposure has been associated with cognitive impairment and chronic diseases (such as respiratory and cardiovascular diseases) which begin early in childhood and cause premature disability, death and high healthcare costs. Thus, adequate classification of SHS exposure is warranted to accurately estimate the prevalence of SHS exposure and the attributable burden of disease to such exposure. Biomarker assessment of SHS provides an advantage over questionnaire assessment with respect to their accuracy; however, valid non-biased cotinine cut-points are needed. Considering that young children are especially vulnerable to the health consequences derived from SHS exposure, and the developmental changes in child behaviour, anatomy and physiology during the first years of life, further well-designed studies would be recommended to propose age-specific serum cotinine cut-points or multiple cut-point values which maximises both sensitivity and specificity to minimise misclassification either as exposed or unexposed based on cotinine concentrations.No studies have calculated serum cotinine age-specific cut-points to ascertained SHS exposure among children under 5 years old. The adverse health consequences derived from any level of SHS exposure, especially from the sidestream smoke, and the developmental changes in child behaviour, anatomy and physiology during the first years of life, support the need for age-specific cut-points for health research and public health purposes aimed at accurately estimating SHS exposure and attributable burden of disease to such exposure, and at reinforcing 100% smoke-free policies worldwide, both in homes, private vehicles and public places.S1 Checklist(DOC)Click here for additional data file.


To study the long-term treatment outcome of vestibular paroxysmia (VP).Retrospective study.Tertiary referral hospital.We analyzed records of 29 consecutive patients who were diagnosed with VP and who were treated with VP-specific anticonvulsants for at least 3 months. Patients were followed for a minimum of 6 months. We recorded and assessed starting and target dosage of medications, time to achieve adequate therapeutic response, adverse effects, and the rates of short-term and long-term remission without medication.All 29 patients were started on oxcarbazepine as first-line treatment, and 93.1% and 100% of patients reported good-to-excellent therapeutic response within 2 and 4 weeks, respectively. Three patients switched to other anticonvulsants at 3 months. At long-term follow-up (8–56 months), most (84.6%) oxcarbazepine-treated patients maintained good therapeutic response at doses between 300 and 600 mg/day. Eleven (37.9%) patients experienced complete remission without medication for more than 1 month, of which six (20.7%) had long-term remission off medication for more than 12 months. Nineteen (65.5%) patients had neurovascular compression (NVC) of vestibulocochlear nerve on MRI, but its presence or absence did not predict treatment response or remission.Low-dose oxcarbazepine monotherapy for VP is effective over the long term and is generally well-tolerated. About 20% of patients with VP in our study had long-term remission off medication. Vestibular paroxysmia (VP) is a debilitating clinical condition characterized by brief episodes of spontaneous or positional vertigo. Similar to trigeminal neuralgia (TN), VP is felt to be caused by neurovascular compression (NVC) of the vestibular nerve near the root entry zone . VasculaThe consensus paper on VP published by the Classification Committee for International Classification of Vestibular Disorders (ICVD) in 2016 has been widely adopted as a gold standard of diagnosis  (2). TheDespite significant therapeutic response to carbamazepine/oxcarbazepine, detailed outcome after treatment, especially long-term treatment, remains unknown. Clinicians intuitively suppose that most patients need life-long medical control unless undergoing microvascular decompression surgery, which is thought to be the only means of true “cure.” In our clinical experience, however, after a period of medical control we have seen some patients discontinue medication and remain symptom-free. If it holds true that some patients of VP have short-term or long-term remission, discontinuation of carbamazepine/oxcarbazepine may be a valuable option for patients who have been symptom-free for a period . In addition, if medical management effectively controls symptoms over the long term, surgical intervention may not be the exclusive choice for cure. It has been demonstrated that various periods of complete remission is a characteristic of TN , 5. It iTo answer these questions, we reviewed consecutive patients diagnosed with VP and followed them longitudinally at our center, with particular emphasis on their presenting clinical features, therapeutic response, and most importantly, long-term outcomes.The data from this study come from a well-curated institutional registry on all patients with dizziness (The Dizziness Registry System) based out of the Dizziness and Balance Disorder Center at Taipei Medical University, Shuang Ho Hospital in Taipei, Taiwan. All patients who have received medical services at the center since its founding in 2017 were included and their diagnoses were recorded according to International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9-CM) or International Classification of Diseases, 10th Edition (ICD-10). A well-trained case manager constantly updates data entries of registered patients by chart review and telephone interview. There are ongoing monthly team conferences to inspect and analyze the data. The study protocol was approved by our institution's Joint Institutional Review Board (N202108060). The board granted a waiver for written informed consent because of the retrospective nature of the study.We retrospectively reviewed clinical information for all patients in our registry diagnosed with VP between 2017 and 2020. In order to investigate the long-term outcome and remission after medical treatment, we included the patients who fulfilled all of the following: (i) met ICVD criteria for “definite VP,” (ii) had received VP-specific anticonvulsants at least 3 months, (iii) had been continuously followed up for at least 6 months, and (iv) were not taking other anti-vertigo medications. In keeping with previous reports, carbamazepine, oxcarbazepine, gabapentin, pregabalin, lacosamide, and lamotrigine were all accepted as VP-specific anticonvulsants for the purposes of study enrollment . Figure All included patients were followed until July 31, 2021. At the conclusion of the study, records were reviewed and patients were classified into one of two groups: (i) those who remained on VP-specific anticonvulsants, or (ii) those who had discontinued said medications. Through chart review and telephone interview, we collected detailed information about initial symptoms, neurologic and neuro-otologic signs, medications, dosage, therapeutic response, and neuroimaging results. For the patients who had discontinued VP-specific medications, detailed information about the symptom-free duration, time of recurrence, and current use of non-specific vestibular suppressant medications were obtained. Patient records that had not been updated in the last 3 months were regarded as invalid and were excluded from this analysis.Since VP is a paroxysmal disorder, we defined therapeutic response as reduction in frequency of attacks. Change in attack frequency after treatment was dichotomized as follows: poor response (0–20% reduction), modest response (20–50% reduction), good response (50–80% reduction), and excellent response (80–100% reduction). In addition to vestibular attacks, episodes of concomitant paroxysmal cranial nerve disorders, including typewriter tinnitus, hemifacial spasm (HFS), TN, glossopharyngeal neuralgia, and inferior oblique myokymia, were also counted as attacks . “StableWe recorded and analyzed the starting dosage of medications, therapeutic period of achieving good or excellent response for vestibular symptoms, stable dosage, durations of treatment, adverse effects, therapeutic responses for concomitant NVC disorders, and durations of remissions. The rates of short-term and long-term remissions without medication were calculated. We reported descriptive statistics and the cumulative remission rate after VP medical treatment. One-way ANOVA was used to compare the stable dosage of oxcarbazepine between the patients with and without NVC. Univariate logistic regression was used to determine if the duration of VP, age, the NVC in MRI, the concomitant paroxysmal cranial nerve disorders, the stable drug dosage or the duration of treatment can predict remission. Odds ratios and 95% confidence intervals (CI) were calculated. The statistical analysis was performed using SPSS v23 .After excluding three invalid entries, 29 patients met study inclusion. Twenty-two (75.9%) patients were on active treatment at the end of follow-up. Seven (24.1%) patients were not on active treatment at the end of follow-up. The cohort comprised 19 males and 10 females, aged 44–79 and the follow-up periods ranged from 8 to 56 months . Specifically, 27 (93.1%) patients reported good-to-excellent therapeutic response within 2 weeks. At 3-month follow-up, 26 patients (89.7%) maintained good-to-excellent responses on oxcarbazepine while the other three patients (10.3%) switched to other anticonvulsants despite the initial good response of oxcarbazepine. Two of them switched to pregabalin due to intolerable side effects of oxcarbazepine (weakness and hyponatremia). One switched to gabapentin because the therapeutic effect of oxcarbazepine diminished.p = 0.90, One-way ANOVA).At long-term follow-up, the same 26 patients continued on oxcarbazepine monotherapy and had satisfactory control. Among them, 15 patients remained at a stable dosage of 300 mg/day, one at 450 mg/day, six at 600 mg/day, two at 900 mg/day, and two at 1,200 mg/day. Most  of the patients had optimal response at doses between 300 and 600 mg/day. Two patients who had concomitant HFS required higher dosages  to relieve their dizziness (see n = 2) were both “excellent” while the responses for HFS (n = 2) were both “poor.” An optimal therapeutic dose range for these poorly-responsive tinnitus and HFS symptoms was not clear because clinicians targeted at the most bothersome vestibular symptoms of these patients and did not necessarily up-titrate the dosages to treat other concomitant paroxysmal cranial nerve disorders.Of the patients with concomitant typewriter tinnitus, 12 patients were treated with oxcarbazepine  and one Overall, 11 of 29 patients (37.9%) experienced various periods of complete remission without medication, including 6 (20.7%) with long-term remission and 4 (13.8%) who experienced short-term remission but subsequent relapse . AnotherThere are two important findings of this study in long-term outcome (>6 months) after medical treatment for VP. First, we found that complete remission off anticonvulsants occurs in about 40% of VP patients, and about 20% of these patients remain symptom-free for more than 1 year after discontinuing their medication. To our knowledge, this phenomenon has not been well-documented in the literature. Second, most patients (93.1%) report good-to-excellent therapeutic effect within 2 weeks of oxcarbazepine treatment, and most (84.6%) remain well-controlled at a low dosage of oxcarbazepine  in long-term follow-up.The underlying pathophysiology of VP is assumed to be microvascular compression of the eighth cranial nerve. We were somewhat surprised to see such a high rate of remission (37.9%) because one might not expect medical treatment (sodium channel blockade) to physically relieve NVC or restore myelination. However, a similar finding has been shown in another study with 73 definite VP patients, of which 56% became attack-free after discontinuing carbamazepine or oxcarbazepine . In clinIn our study, response to VP-specific medication was almost stable and long-lasting. This suggests only very selected patients should be considered for microvascular decompression surgery. Moreover, given the number of our patients with long periods of remission of medication, this study hints at the possibility that a drug taper can be attempted after patients have achieved an initial satisfactory response. Though some patients will still require continuation at the lowest effective dose, a large enough proportion of patients achieved remission in our study that tapering should be considered. More work is needed to confirm these observational findings.Although the ICVD criteria include a positive response of sodium channel blockers to support the diagnosis of definite VP, studies about the long-term efficacy of oxcarbazepine are still limited , 13. HufIn our study, most patients (93.1%) reported good-to-excellent improvement within the first 2 weeks of medical therapy. This finding also has diagnostic value. If a patient fails to show improvement on oxcarbazepine in 2 weeks, VP may not be the correct diagnosis. We also found that most patients (84.6%) obtained satisfactory results at a stable dosage of oxcarbazepine 300–600 mg/day while only four patients  needed a dosage higher than 600 mg/day. As a result, one should expect to see significant improvement in most patients at a dosage of oxcarbazepine 600 mg/day. Patients who fail to show any improvement at this dosage should be considered to have other etiologies of dizziness. Our proposed dosing plan is listed in Besides, our study illustrated the treatment results of anticonvulsants on concomitant typewriter tinnitus. In a literature review of combined VP and typewriter tinnitus, only 5 of 21 (23.8%) cases were able to achieve complete remission of tinnitus by drug therapy alone . In our Interestingly, our study revealed that only 65.5% of VP patients had the evidence of NVC in MRI, which was lower than the previous reports , 19, 20.Some limitations of this study should be addressed here. Firstly, this was a retrospective study. Two factors may have unduly influenced our remission rate: (i) duration of follow-up differed among patients, and (ii) and some patients were more hesitant than others to discontinue medications for fear of relapse—even though they remained symptom-free on medication. In addition, to meet diagnostic criteria for VP, all patients in this study had to already show positive therapeutic response to carbamazepine or oxcarbazepine . Therefore, we did not include the patients who potentially had NVC-induced vertigo but were resistant to these two medications. Additionally, metrics on dizziness frequency were self-reported and thus subject to recall bias. We also did not use formal scales for assessing the severity of dizziness, such as the Dizziness Handicap Inventory. Lastly, none of our patients received carbamazepine so we did not compare the efficacy of carbamazepine and oxcarbazepine.Vestibular paroxysmia is a debilitating but treatable condition. In this study, medical treatment for VP remains remarkably effective even when patients are followed longitudinally. Moreover, a significant number of patients see complete remission off medication, supporting the notion that medication taper can be considered in select cases. Given the long-term stable response to medication, surgical microvascular decompression should be reserved only for truly refractory cases. In the future, a randomized controlled trial is needed for further confirming the long-term efficacy and outcome of drug treatment for VP.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Taipei Medical University Joint Institutional Review Board (N202108060). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.C-CC designed the study, collected, analyzed, and interpreted the data, drafted the manuscript, and approved the final manuscript. T-YL and H-HL collected the data and designed the tables, and approved the final manuscript. Y-HK performed statistics and analyzed the results. AB revised the manuscript and approved the final manuscript. T-PC designed the study, interpreted the data, revised the manuscript, and approved the final manuscript. All authors contributed to the article and approved the submitted version.This research was supported by Taipei Medical University (TMU106-AE1-B07).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.