Cryptosporidium oocyst shedding, and how shedding may be affected by subtypes and clinical parameters, is limited. Reduced transmission may be a secondary benefit of cryptosporidiosis treatment in high-prevalence areas. We conducted a prospective clinical case series in children of <5 years presenting with diarrhea to a health center and a hospital in Ethiopia over an 18-month period. Stool samples were collected repeatedly from children diagnosed with cryptosporidiosis for up to 60 days. Samples were examined, and Cryptosporidium shedding was quantified, using auramine phenol, immunofluorescent antibody staining, and quantitative PCR (qPCR). In addition, species determination and subtyping were used to attempt to distinguish between new infections and ongoing shedding. Duration and quantity of shedding over time were estimated by time-to-event and quantitative models (sex- and age-adjusted). We also explored how diarrheal severity, acute malnutrition, and Cryptosporidium subtypes correlated with temporal shedding patterns. From 53 confirmed cryptosporidiosis cases, a median of 4 (range 1 to 5) follow-up stool samples were collected and tested for Cryptosporidium. The median duration of oocyst shedding was 31 days  after onset of diarrhea, with similar estimates from the quantitative models . Genotype shift occurred in 5 cases (9%). A 10-fold drop in quantity occurred per week for the first 4 weeks. Prolonged oocyst shedding is common in a pediatric clinical population with cryptosporidiosis. We suggest that future intervention trials should evaluate both clinical efficacy and total parasite shedding duration as trial endpoints.Knowledge on the duration of IMPORTANCE Cryptosporidiosis is an important cause of diarrhea, malnutrition, and deaths in young children in low-income countries. The infection spreads from person to person. After infection, prolonged release of the Cryptosporidium parasite in stool (shedding) may contribute to further spread of the disease. If diagnosis and treatment are made available, diarrhea will be treated and deaths will be reduced. An added benefit may be to reduce transmission to others. However, shedding duration and its characteristics in children is not well known. We therefore investigated the duration of shedding in a group of young children who sought health care for diarrhea in a hospital and health center in Ethiopia. The study followed 53 children with cryptosporidiosis for 2 months. We found that, on average, children released the parasite for 31 days after the diarrhea episode started. Point-of-care treatment of cryptosporidiosis may therefore reduce onward spread of the Cryptosporidium parasite within communities and households. Cryptosporidium hominis. Cryptosporidium parvum is uncommon in livestock in Sub-Saharan Africa, and human C. parvum infections are caused almost exclusively by anthroponotic subtypes in this region  reported a mean shedding duration of 17 days after onset of diarrhea  , a few siarrhea 79. These iarrhea 7. The medTargeted treatment for cryptosporidiosis is currently limited to nitazoxanide, a drug that is not effective in immunocompromised children and regrettably is FDA-approved only for children older than 12 months, although available data indicate no adverse effects in children aged 6 to 11 months –13. Sign–Cryptosporidium shedding, i.e., both overall duration of shedding and quantitative shedding patterns over time, supplemented by subtyping to help distinguish between new infections and ongoing shedding. Cases were identified by near-patient testing using light-emitting diode auramine-phenol fluorescence microscopy (LED-AP), already available in many low-income countries, as the method is used for tuberculosis point-of-care testing . Second, we considered shedding as a quantitative outcome, measured as DNA copies/g of stool in follow-up samples. In addition, cases with a shift in the detected Cryptosporidium DNA was confirmed in 54 of these 56 cases, as two cases had negative Cryptosporidium qPCR in both enrollment and follow-up stool samples (ID34 and ID40). One case that was shedding on enrollment failed to submit any follow-up samples (ID19) and was therefore excluded from the analysis. A median of 4 (range 1 to 5) follow-up stool samples were collected from each of the remaining participants. The lowest positive detection by the qPCR assay was 519 Cryptosporidium copies per gram of stool, corresponding to approximately 130 oocyst equivalents per gram, as there are 4 copies of the cowp gene per oocyst . See Cryptosporidiosis screening was performed by LED-AP microscopy on 878 diarrhea cases; 82 (9%) were positive, and, of these, 56 were eligible and consented to participate in the follow-up study. Shedding of Cryptosporidium genotype occurred in five cases (9%): in three cases, this was reflected by subsequent detections of a different C. hominisgp60 allele family in samples taken 16, 24, and 25 days after onset of diarrhea, respectively , in one case the shift happened after two consecutive negative samples, 34 days after onset of diarrhea (ID 48), and in one case, C. hominisgp60 allele type Ib was detected in a sample obtained at day 37, after three consecutive samples with C. parvum IIc (ID 36). There were no cases where subtype shifted within the same gp60 allele family.Notably, two cases were still shedding oocysts at their last follow-up visits, 63 days after onset of the initial diarrheal episodes. Both were 6- to 11-month-olds, without acute malnutrition, who presented with acute diarrhea; HIV status was unknown for one and the other was HIV negative. A shift in Cryptosporidium declined over time. Cryptosporidium during the follow-up-period.As expected, the proportion of cases shedding Stratification of the time-to-event curves by key subgroups revealed subtle differences by sex and age group, which might confound other comparisons. We therefore fitted a log-logistic parametric time-to-event model  which allowed us to adjust for sex and age. The overall model of the decline in shedding is illustrated by Cryptosporidium, rising to 75% (95% CI 62 to 87) by 6 weeks  had stopped shedding  6 weeks .C. parvum and C. hominis. However, when the shedding curves between the different C. hominisgp60 subtype families were compared, gp60 allele family Id, the second most common gp60 allele family, was associated with a significantly longer duration of shedding than the other C. hominisgp60 allele families.Results from the parametric models, stratified by key predictors, are summarized in Cryptosporidium DNA quantity from 805 copies/g to 158 million copies/g. Quantities declined significantly with days since onset of diarrhea   .Cryptosporidium DNA shedding quantity dropped about 10-fold per week (Table S1). Thereafter, the overall trend line curved gently upwards, likely due to inclusion in the model of two cases who were still shedding after 63 days.The overall trend line was close to a quadratic relationship (effective degrees of freedom [EDF] = 1.9); however, for the first 4 weeks after onset of diarrhea, a striking pattern was seen where C. hominisgp60 allele family Id was associated with a higher quantity of shedding than the other C. hominis allele families during the time window from 11 to 55 days after onset of diarrhea . This yielded an estimate for the duration of Cryptosporidium DNA shedding at 31 days (95% CI from 25 to 37 days).We proceeded to estimate shedding duration by quantity over time by estimating the time point at which Cryptosporidium parasite shedding was investigated by follow-up of individual children presenting to health care with cryptosporidiosis. Shedding duration was approximated using two complementary analytical approaches: first by time-to-event modeling where ongoing shedding was considered a binary outcome, based on microscopic detection of oocysts and/or DNA detection by PCR, and then by quantitative modeling of the drop in DNA quantity over time, using a highly sensitive qPCR assay. Both models yielded remarkably similar estimates for median duration of shedding, at 31 days, with 95% CIs from 26 to 36 days and 25 to 37 days, respectively. The findings demonstrate that prolonged shedding is common in a general pediatric clinical population with cryptosporidiosis. This is a slightly shorter estimate than, but still in keeping with, the 40-day estimate from the MAL-ED study, which was obtained using robust modeling and quantitative PCR for reliable case ascertainment , both of which included confounder adjustment.Third, the observed tendency toward lower shedding in children who were dehydrated on enrollment seems counterintuitive but should at best be interpreted as a trend, as it was not a statistically significant finding in the adjusted models .gp60 subtype as likely ongoing shedding from a single Cryptosporidium acquisition event. This is supported by the overall drop in quantity in repeat detections but is only a plausible assumption; another possibility is that some of the repeat detections represent new acquisitions of the same gp60 genotype, e.g., from a still-present household source. Contact tracing has demonstrated clustering of subtypes in households , we may have missed some low-level mixed subtype infections. Elucidating this further would require the application of techniques to detect gp60 subpopulations that are outside the scope of this analysis, e.g., deep sequencing, vector cloning, single-cell whole-genome amplification  and Serbo Health Center in southwest Ethiopia as a follow-up study of a subset of participants in the CRYPTO-POC diagnostic accuracy study. Details of screening and enrollment have been published previously . In brieCryptosporidium oocysts, stool samples were examined by LED-AP and quantitative immunofluorescent stain antibody test (qIFAT) microscopy, and for Cryptosporidium DNA, stool samples were examined by a well-established quantitative PCR (qPCR) assay targeting the pan-species Cryptosporidium cowp gene. We generated standard curves using 10-fold dilutions of quantitative genomic Cryptosporidium parvum DNA, with final qPCR results expressed as DNA copies/g of wet stool, as described previously (Cryptosporidiosis point-of-care testing was performed by LED-AP microscopy (a semiquantitative test) at both sites, with results communicated back to the study nurse . Positiveviously .Cryptosporidium species qPCR-positive samples, C. parvum and C. hominis species identification was performed in a duplex real-time PCR assay targeting C. parvum- and C. hominis-specific sequences of the lib13 gene, using primer and probe sequences from reference On Cryptosporidium gp60 gene, which codes for a surface glycoprotein that contains a conserved region that allows classification of gp60 allele families and also a hypervariable serine repeat region that allows for classification into gp60 allele family subtypes. The gp60 PCR is a nested PCR, with primary and secondary primer sequences as described in reference gp60 gene sequence data were analyzed directly using the free software CryptoGenotyper  score was calculated based on assessment of general appearance, tears, skin pinch, and respirations; a score of 4 or more was deemed severe dehydration, 2 to 3 as some dehydration, and 0 to 1 as no dehydration .For children aged <6 months, severe acute malnutrition (SAM) was defined as weight-for-height z-score (WHZ) of ≤−3 of the WHO standard curves  and/or pCryptosporidium DNA during the enrollment episode if qPCR was positive in either the enrollment sample or the 1-week follow-up sample. A case was considered no longer shedding Cryptosporidium from the first day, after onset of the diarrheal episode, at which both Cryptosporidium qPCR and oocyst microscopy were negative. Genotype shift was defined as a detection of a new Cryptosporidium genotype  in a later sample. A case was considered having ongoing shedding at the latest time point, in days after onset of diarrhea, with either a positive Cryptosporidium qPCR or positive Cryptosporidium microscopy (LED-AP and/or qIFAT) but excluding those cases where a genotype shift had occurred.A diarrhea case was defined as shedding Time to shedding cessation was the event of interest. The nonparametric maximum likelihood estimate for the time-to-event distribution was approximated by the Turnbull estimator, a generalization of the Kaplan-Meier estimate that accounts for interval-censored data, using the R package interval . We fittCryptosporidium DNA quantity (measured in log10 copies/g of stool) in sequential follow-up samples was plotted against time (in days since onset of diarrhea) for each cryptosporidiosis case. The visual inspection indicated that the temporal drop in quantity followed a nonlinear pattern. We therefore fitted and visualized a trend line  using a generalized additive mixed model (GAMM), using an identity link and thin plate regression splines, with the maximum number of base functions (“knots”) set to 3, using the R package mgcv , sex, disease severity , and Cryptosporidium genotype and by separate plotting of difference smooths with 95% confidence intervals, using the R package itsadug. Overall shedding duration was estimated from DNA quantity, where shedding cessation was defined as the time point at which Cryptosporidium DNA quantity dropped below the reliable detection limit of the qPCR. This was estimated by a separate GAMM where days since onset of diarrhea was the outcome variable and a smoothed trend line for DNA quantity was the main predictor. To all GAMMs were added random effect intercepts for each study participant to account for within-subject clustering and also separate fixed effect linear terms to adjust for confounding by sex and age.age mgcv . The oveJimma University IRB (reference: RPGC/610/2016), the Ethiopian National Research Ethics Review Committee (reference: JU JURPGD/839/2017), and the Regional Committee for Medical and Health Research Ethics of Western Norway (reference: 2016/1096) approved the study.


What are the risks of neuropsychiatric disorders in adults surviving COVID-19 hospitalization, and how do these compare with non-COVID severe respiratory infections?In this cohort study of data from more than 8 million adults in England, during the COVID-19 pandemic, risks of new anxiety disorder, dementia, psychotic disorder, and bipolar disorder diagnoses were significantly increased in adults surviving hospitalization for COVID-19 or other severe acute respiratory infections compared with the general population. Risks of neuropsychiatric illnesses or commencement of related medications were similar for COVID-19 and non-COVID severe respiratory infections.The results of this study suggest that disease severity, rather than pathogen, is a relevant factor associated with neuropsychiatric ramifications after severe respiratory infections. Individuals surviving severe COVID-19 may be at increased risk of neuropsychiatric sequelae. Robust assessment of these risks may help improve clinical understanding of the post–COVID syndrome, aid clinical care during the ongoing pandemic, and inform postpandemic planning.To quantify the risks of new-onset neuropsychiatric conditions and new neuropsychiatric medication prescriptions after discharge from a COVID-19–related hospitalization, and to compare these with risks after discharge from hospitalization for other severe acute respiratory infections (SARI) during the COVID-19 pandemic.In this cohort study, adults (≥18 years of age) were identified from QResearch primary care and linked electronic health record databases, including national SARS-CoV-2 testing, hospital episode statistics, intensive care admissions data, and mortality registers in England, from January 24, 2020, to July 7, 2021.COVID-19–related or SARI-related hospital admission (including intensive care admission).New-onset diagnoses of neuropsychiatric conditions  or first prescription for relevant medications  during 12 months of follow-up from hospital discharge. Maximally adjusted hazard ratios (HR) with 95% CIs were estimated using flexible parametric survival models.In this cohort study of data from 8.38 million adults ; 16 679 (0.02%) survived a hospital admission for SARI, and 32 525 (0.03%) survived a hospital admission for COVID-19. Compared with the remaining population, survivors of SARI and COVID-19 hospitalization had higher risks of subsequent neuropsychiatric diagnoses. For example, the HR for anxiety in survivors of SARI was 1.86  and for survivors of COVID-19 infection was 2.36 ; the HR for dementia for survivors of SARI was 2.55  and for survivors of COVID-19 infection was 2.63 . Similar findings were observed for all medications analyzed; for example, the HR for first prescriptions of antidepressants in survivors of SARI was 2.55  and for survivors of COVID-19 infection was 3.24 . There were no significant differences observed when directly comparing the COVID-19 group with the SARI group apart from a lower risk of antipsychotic prescriptions in the former .In this cohort study, the neuropsychiatric sequelae of severe COVID-19 infection were found to be similar to those for other SARI. This finding may inform postdischarge support for people surviving SARI. This cohort study of electronic health care data of more than 8 million individuals in England attempts to quantify the neuropsychiatric sequelae following discharge from COVID-19 hospitalization compared with patients surviving hospitalization due to non–COVID-19 severe acute respiratory infections. Although the postacute COVID-19 syndrome is poorly understood, there are clinically relevant postinfection outcomes associated with several organ systems.3The COVID-19 pandemic has caused over 5 million deaths worldwide and predicated profound social and economic disruption.5 Furthermore, previous SARS virus outbreaks have been associated with notable burdens of neuropsychological sequelae.6 Recent evidence from the US suggests that the risk of such sequelae after COVID-19 of any severity may be significantly higher than that observed after influenza, or acute respiratory infections of any kind, during the time of the COVID-19 pandemic.7 However, such comparisons with influenza have limited follow-up, have not considered medication use, and may be problematic due to differential disease severity and atypical influenza dynamics.8 Other recent studies in England examining posthospitalization sequelae must be considered in terms of limited sample size and follow-up, and their focus on patient-reported, physiological, and biomarker assays without quantifying formal diagnoses and medication use.9 The association between COVID-19 and neuropsychological sequelae, therefore, requires further clarification. In particular, it is important to understand whether the neuropsychiatric components of posthospitalization syndrome for COVID-19 differ from those of other severe respiratory infections treated in the same settings.Prepandemic data suggest that individuals with severe acute respiratory infections (SARI) have increased risks of subsequent neuropsychiatric illness and cognitive impairment compared with the general population.Better understanding of the neuropsychiatric sequelae of severe COVID-19 and non–COVID-19 SARI is relevant to clinical practice, and both pandemic and postpandemic planning. Using electronic health record data for a population-representative cohort of more than 8 million individuals in England, this study aims to quantify the neuropsychiatric sequelae following discharge from COVID-19 hospitalization and to compare findings with patients surviving hospitalization due to non–COVID-19 SARI.10 and is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies. Protocol deviations are described in the eMethods in the This study was conducted in accordance with our protocolWe used QResearch (version 45), a primary care database that has collected routine clinical data for more than 30 million individuals since 1989 registered to more than 1400 general practices in England using the EMIS software system. QResearch has individual-level linkage to Hospital Episode Statistics (HES), the Public Health England Second Generation Surveillance System database regarding SARS-CoV-2 reverse transcriptase–polymerase chain reaction testing, the Intensive Care National Audit and Research Centre Case Mix Program database, and the Office for National Statistics’ national mortality register.This study cohort comprised adults alive and registered with a contributing general practice from January 24, 2020 (date of first COVID-19 case in England), until the data extract date . We extracted a temporally distinct historic cohort to compare incidence rates of post-SARI discharge neuropsychiatric sequelae with the remaining population, intending to statistically compare those in the prepandemic period with those in the contemporary pandemic period. This cohort identified adults aged 18 years and older entering the cohort from January 24, 2015, to January 23, 2020.International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code (U07.1 or U07.2) as the reason for admission to hospital (in the HES data set), or admission to hospital for any reason within 14 days of a positive SARS-CoV-2 reverse transcriptase–polymerase chain reaction test result. SARI-related hospital admissions were defined as those with ICD-10 codes J09 to J22 as a reason for admission in the HES data set, or as the reason for admission to intensive care in the Intensive Care National Audit and Research Centre Case Mix Program data set.Exposures were being discharged alive from (surviving) a COVID-19–related hospital admission and being discharged alive from (surviving) an SARI-related hospital admission. The reference group was the remaining population. COVID-19–related hospital admissions were defined as those with a recorded ICD-10 codes in the HES records to identify individuals formally diagnosed by a health care practitioner with anxiety disorder, depression, dementia, bipolar affective disorder, and psychotic disorder. Although the core QResearch data set is a primary care database, individual level linkage across primary and secondary/specialist care data permitted capture of recorded psychiatric diagnoses in either setting. Primary care records were used to identify prescriptions of relevant medications based on the British National Formulary: antidepressants, hypnotics/anxiolytics, and antipsychotics. These code lists are available on the QResearch website.11Outcomes of interest comprised new-onset diagnoses of selected neuropsychiatric conditions or first prescriptions for selected medications occurring after hospital discharge . For each outcome, we excluded individuals with previously recorded records of the outcome of interest . We used Systematized Nomenclature of Medicine/Read codes in the primary care records, and We compared the risk of new-onset neuropsychiatric diagnoses or first prescriptions in the 12 months following discharge in people surviving a COVID-19–related or SARI-related hospital admission (including intensive care) to the risk in the remaining population. Follow-up time was calculated from the discharge date for those surviving a COVID-19–related or SARI-related hospital admission. Follow-up for the remaining population was from January 24, 2020. Patient follow-up was until the earliest of date of outcome of interest or censoring . Follow-up was truncated to 1 year for analysis. In the historic cohort, SARI admissions, exposures, and outcomes had identical definitions as the main cohort. SARI admission survivors were followed up from date of discharge to date of new-onset diagnosis/first prescription. Follow-up was truncated at 1 year.df for the baseline survival function splines and clustered robust SEs to account for patient clustering within individual practices.Crude and age-standardized incidence rates for each end point were calculated in contemporary and historic cohorts for initial comparisons. Flexible parametric survival models were used to estimate hazard ratios (HRs) with 95% CIs for each of the outcomes, using 4 12 Missing data were observed for ethnicity, smoking status, alcohol status, body mass index (BMI) and Townsend Deprivation Index quintile. Under the missing at random assumption, multiple imputation with chained equations was used to replace missing values.13 The imputation model included all covariates and outcomes. Five imputations were generated, with model coefficients and SEs pooled across imputations in accordance with Rubin’s rules.14All final analysis models were adjusted for demographic and clinical factors identified from clinical/epidemiological understanding as summarized in the directed acyclic graphs in the protocol and shown in For a direct comparison of exposures, we repeated these analyses restricting the data set to those that survived either a COVID-19–related or SARI-related hospital admission. Herein, HRs with 95% CIs were calculated to estimate the hazards of neuropsychiatric sequelae in survivors of COVID-19 hospitalization, with survivors of SARI hospitalization as the reference group.With 1-year follow-up for modeling in the context of 1.5-year study period, the time frames in which different exposure groups contributed follow-up varies due to follow-up starting postdischarge for the exposed groups, but at the index date set at January 24, 2020, for the general population. There is also potential for baseline diagnostic rate variation during the pandemic, especially considering several lockdowns in England. Therefore, we repeated the modeling steps, but those in the reference population group were randomly assigned a cohort start date in between the first discharge date and the latest discharge date identified in the exposed groups. We also adjusted for the calendar month of this updated study start date . We repeated our analyses excluding those that did not have COVID-19 as the primary reason for their hospital admission or admission to the intensive care unit  from the COVID-19 exposure group.ICD-10 code group I21) during the same period . Those with both acute myocardial infarction admissions and SARI-related or COVID-19–related hospitalizations during the study period were excluded; maximally adjusted HRs were estimated as described above; the acute myocardial infarction group was the reference group.We also compared the risks of our end points of interest after SARI/COVID-19 with individuals surviving an admission with acute myocardial infarction .There were 8 380 190 people included in the final contemporary study cohort and 12 162 155 included in the prepandemic cohort (SARI or remaining population). In the former, 7 058 199 reached 1 year follow-up (84.22%).This cohort study comprised data from 8.38 million adults . Of the contemporary cohort, 519 134 had at least 1 positive SARS-CoV-2 reverse transcriptase-polymerase chain reaction test result recorded, and there were 50 798 hospital admissions with COVID-19. At the time of data extract, 16 679 (0.02%) had survived (reached discharge after) a hospital admission with SARI, and 32 525 (0.04%) had survived (reached discharge after) a hospital admission with COVID-19. Due to the low event counts for some endpoints, we did not undertake a subanalysis of survivors of intensive care unit admissions.In the primary study cohort, patients surviving SARI or COVID-19–related admissions had higher risks of all new-onset neuropsychiatric diagnoses within 12 months compared with the remaining population, and the adjusted HRs for both exposures were generally similar . CompareWhen the analysis was restricted to survivors of SARI hospitalization as the reference group and survivors of COVID-19 hospitalization as the comparator, no significant differences were observed in the postdischarge rates of new-onset anxiety disorder , dementia , depression , or bipolar affective disorder . Further, the 2 groups did not differ in terms of their postdischarge risks of antidepressant medication prescription  or hypnotic/anxiolytic medication prescription . Those surviving COVID-19–related hospitalization did have a 20% lower risk of receiving their first-ever antipsychotic medication prescription compared with those surviving an SARI-related admission . eTable 2 in the The results after accounting for calendar time were similar to the primary analyses for both diagnoses and prescriptions  had COVID-19 recorded as the primary reason for admission. The remaining 33.65% were admitted within 14 days of a positive SARS-CoV-2 test result, but COVID-19 was not specifically coded as the primary reason for admission. Excluding the latter, we observed HRs consistent those found in the primary analysis , risks associated with COVID-19 and SARI admissions varied . There wIn this study using a population-level cohort comprising linked electronic primary and secondary health care data sets for more than 8 million adults, we estimated that the neuropsychiatric ramifications of severe COVID-19 infection were similar to those of other SARIs. Individuals surviving severe COVID-19 infection and other SARIs were at significantly increased risk of receiving a neuropsychiatric illness diagnosis and of being prescribed antidepressant, hypnotic/anxiolytic, or antipsychotic medications in the first year after discharge compared with the wider population. Apart from a reduced risk of being prescribed antipsychotic medication, the differences between risks post–COVID-19 hospitalization and post-SARI hospitalization were not significant. Although the relative risks of these outcomes in survivors of COVID-19 and SARI hospitalizations are significantly higher than for the remaining population, the absolute risks for some formally diagnosed neuropsychiatric sequelae are low  exceed those for any respiratory tract infection (including influenza) at 6 months of follow-up. However, comparison with influenza may be problematic because of its atypically low incidence during the COVID-19 pandemic and its markedly different risk profile.21 Comparisons with recorded diagnosis of any acute respiratory infection may also be complicated owing to different severity profiles. In contrast, we compared outcomes following severe infection with COVID-19  with severe infection with a broader set of SARIs. We saw similar rates of neuropsychiatric outcomes, both substantially higher than in the general population. Our results suggest that increased rates of the neuropsychiatric outcomes may be associated with the severity of respiratory disease rather than the underlying organism. Notably, the Taquet et al study20 also appeared to have higher incidence of neuropsychiatric diagnoses than we encountered in our English cohort, which may reflect different diagnostic practices and/or disruption thereto in the US and England.Using the TriNetX data set, the Taquet and colleagues20 analyzing data from during the COVID-19 pandemic, we also explored background risk factors in the general population during and prior to the pandemic. Our source data sets minimize selection and recall bias because they use health record data from a large representative population. Our comparison with SARI enabled more informative benchmarking than some other studies using a less severe infection.20Strengths of our study include using a large cohort that is broadly representative of the English general population, and the use of multiple validated electronic health care data sets linked at the individual level for accurate ascertainment of exposures (including lifestyle factors), outcomes, and relevant confounders. In contrast to previous studiesThis study also has limitations, including the fact that several of the neuropsychiatric conditions examined typically first manifest in younger age . The use of routinely collected health care data means that not all outcomes and exposures are formally adjudicated, as the database is dependent on coding by individual practitioners. There may also be information or recording bias due to disruption in patient attendance at general practices during the study period, reduced service availability, or changes in help-seeking behaviors such as avoidance of hospital-based or outpatient care by some individuals. In contrast, increased attention to post–COVID-19 syndrome may risk surveillance bias, increasing diagnosis rates in the COVID-19 group. Optimal comparison group selection therefore, may be complex in the setting of multifaceted indirect effects of the pandemic in terms of health care services. Prepandemic rates of new-onset posthospitalization neuropsychiatric diagnoses appeared to differ from that seen in the contemporary cohort, precluding temporal comparisons, and patients admitted to hospital with non–COVID-19 SARI during the COVID-19 pandemic may be different from those admitted prepandemic. However, we believe that our contemporaneous design is the most robust with regard to indirect effects of the pandemic and offered a meaningful comparison. It could be informative to compare neuropsychiatric complications and potential mediators in individuals surviving admissions for other conditions beyond acute myocardial infarction in future studies.In this cohort study, SARI were found to be associated with significant postacute neuropsychiatric morbidity, for which COVID-19 is not distinctly different. These results may help refine our understanding of the postsevere COVID-19 phenotype and may inform postdischarge support for patients requiring hospital-based and intensive care for SARI regardless of causative pathogen.


P = 0.0006) and disease-free survival  in the allo-HSCT group, with increased relapse rate in the chemotherapy group . Sensitivity analysis including prospective studies alone and excluding studies that reported the comparison only on intermediate-risk patients confirmed the benefit of allo-HSCT on OS. Further research should focus on individualizing allo-HSCT indications based on molecular stratification and MRD monitoring.Identification of pediatric patients with acute myeloid leukemia (AML) candidates to receive allogeneic hematopoietic stem cell transplantation  in first complete remission (CR1) is still a matter of debate. Currently, transplantation is reserved to patients considered at high risk of relapse based on cytogenetics, molecular biology, and minimal residual disease (MRD) assessment. However, no randomized clinical trial exists in the literature comparing transplantation with other types of consolidation therapy. Here, we provide an up-to-date meta-analysis of studies comparing allo-HSCT in CR1 with chemotherapy alone as a post-remission treatment in high-risk pediatric AML. The literature search strategy identified 10 cohorts from 9 studies performing as-treated analysis. The quantitative synthesis showed improved overall survival (OS) (relative risk, 1.15; 95% confidence interval [CI], 1.06–1.24; The online version contains supplementary material available at 10.1007/s00277-022-04965-x. Acute myeloid leukemia (AML) is the second most common leukemia in children, accounting for approximately 20% of pediatric leukemias , 2. TreaThis achievement is mainly due to the cooperative efforts of multiple international study groups that have led to a significant improvement in patient stratifications with a subsequent optimal refinement of the risk-adapted therapy, and thanks to the refinements in supportive care , 5. NowaAllogeneic hematopoietic stem cell transplantation  has been widely used as post-remission therapy . In adulIn the 1990s, many protocols applied a Mendelian/genetic randomization, reserving allo-HSCT in CR1 to those children who had an available matched sibling donor (MSD). A meta-analysis of these studies published in 2002 found that patients allocated to allo-HSCT on the basis of having an MSD available had a reduced relapse risk (RR) and an improved disease-free survival (DFS) and OS . HoweverBased partly on these results and mainly on a better risk-based stratification of subgroups, contemporary protocols have removed the availability of MSD as an indication for allo-HSCT in CR1 for all patients , 6, 12. Nowadays, the improvement in the understanding of the genetic basis of AML has led to an enhanced implementation of molecular biology and cytogenetics into risk stratification , 4, 16. There is general agreement that allo-HSCT must not be recommended in CR1 for children with Down syndrome, acute promyelocytic leukemia, and core-binding factor leukemia, namely AML with t, inv16), and t [, and t guidelines .Electronic databases, namely PubMed and Trip, were searched the 11/09/2021 in order to identify relevant studies. The string used to perform the search is provided in the Supplementary Material.The search was restricted to English language studies involving AML pediatric patients addressing the use of allo-HSCT in CR1. We included both prospective and retrospective studies that were performed an as-treated analysis.Two reviewers (E.M. and R.M.) independently identified potentially eligible studies by screening titles and abstracts. The same authors assessed the full texts of potentially relevant studies for inclusion and consulted the references of previously published primary and secondary papers to manually search for additional relevant papers. Any disagreement regarding eligibility and inclusion in the systematic review was resolved through discussion and consensus between the 2 readers. If consensus was not reached, the opinion of a third author (D.G.) who acted as a “blind” final arbiter was requested. Investigators and corresponding authors were contacted to obtain additional information about studies with incomplete data.We used the same methodology for data extraction, performed independently by the same 2 reviewers (E.M. and R.M.) with the help of the third author (D.G.) if disagreement occurred. Data were summed and analyzed using Microsoft Office Excel 2013 . Subsequently, we performed a meta-analysis of data regarding the comparison between allo-HSCT and other types of consolidation therapy in CR1 for high-risk patients. The different outcomes that were reported consistently enough in the studies to be considered eligible for the meta-analysis and were, therefore, included in the quantitative synthesis are OS, RR, and DFS. If multiple articles reported results from the same cohort, the most recent data were analyzed. Studies including young adults and not reporting separately their outcome were not excluded from the analysis.https://revman.cochrane.org).We analyzed statistical heterogeneity to determine the feasibility of summing the results of the different included studies. We assessed heterogeneity by graphic funnel plots and by calculating the I2 statistic. An I2 statistic > 50% was considered significantly heterogeneous. When the number of studies was < 5 or studies were substantially heterogeneous, we used a random-effects model in accordance with the Cochrane Handbook for Systematic Reviews of Interventions , 23. We We used the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement to assess the study quality of the experimental and observational original studies included in this meta-analysis. We opted not to use the Cochrane Tool for Quality Assessment because no inserted randomized study performed the randomization on the use of allo-HSCT. The STROBE statement is a 22-item tool designed to evaluate the quality of observational studies . Items aThe literature search strategy identified 2141 references .Potentially relevant papers were identified by full titles and abstracts. Full-text articles assessed for eligibility were 85 Fig. . Among tIncluded papers reported prospective and retrospective studies assigning pediatric patients with AML in CR1 to undergo allo-HSCT vs non-allo-HSCT treatment, using as-treated analysis to compare outcomes .Five articles reported the results of prospective trials –30, whilThe quality of the included clinical studies was assessed as described in “P = 0.0006). Heterogeneity among studies was absent (0%)  Fig. .Fig. 2FoP = 0.005) with 0% heterogeneity  and absent heterogeneity . Heterogeneity among the cohorts was 23% . Heterogeneity among studies was low (1%)  Fig. .Pediatric AML is a heterogeneous disease characterized by the presence of numerous, recurrent cytogenetic and molecular abnormalities with significantly different impact on prognosis . DespiteIn the present meta-analysis, we addressed the use of allo-HSCT as a post-remission therapy for children with newly diagnosed high-risk AML compared to chemotherapy alone. The analyzed studies included 1448 patients from 1998 to 2017 with higher-risk AML allocated to receive or not allo-HSCT from any donor. We observed improved OS and DFS with reduced RR in the allo-HSCT group. The beneficial effect of allo-HSCT on OS was observed even after removing from the quantitative synthesis the retrospective cohorts or the two studies that included only intermediate-risk patients. Few studies reported DFS and RR, and therefore sensitivity analysis was not possible regarding these outcomes. A consensus statement proposed that in adult patients allo-HSCT should be favored if the projected DFS is expected to improve by at least 10% based on individual’s risk assessment . ConsideThese results are different from the one of a previous systematic review, which observed lower relapse risk but no improvement in OS for patients given allo-HSCT . This maThe present results support the use of allo-HSCT in CR1 in pediatric patients considered at higher relapse risk based on cytogenetics, molecular biology, and MRD monitoring, supporting the notion that transplantation can abolish the detrimental impact imparted by specific molecular lesions and poor response to therapy . HoweverWe performed the quantitative synthesis including data only from as-treated analysis. This permitted the comparison of patients according to the treatment they actually received. However, this approach presents some methodological intrinsic pitfalls. Patients allocated to receive allo-HSCT but who experienced early relapse or early treatment-related death in CR are included in the chemotherapy group with this type of analysis. Therefore, more compromised patients often do not undergo allo-HSCT, leading to a selection bias. In the included studies, the primary endpoint of the trial was not always the comparison between allo-HSCT and chemotherapy in higher-risk patients. Accordingly, the number of patients that should have been allocated to allo-HSCT, but instead received chemotherapy in this distinct subgroup, is not clearly described in all studies. In the trials where it was feasible to be extrapolated, it ranges between 5% and 28%, with most studies settling around 12–13% , 34. TheCorrecting as-treated analysis for time to transplantation could reduce this methodological limitation, enabling the researchers to adjust for the events occurring before transplantation . In the Another limitation to be taken into account consists in the fact that chemotherapy protocols and consolidation strategies in the chemotherapy groups were different among included studies, as well as risk stratification and conditioning regimen deployed  patients could make this subgroup at higher risk [KMT2A rearrangements have a different impact on prognosis dependent not only upon the presence of additional cytogenetic abnormalities [KMT2A lesions [KMT2A rearrangements are detectable only by FISH or molecular methods and not by conventional cytogenetics, highlighting the need to perform an accurate diagnostic panel at AML diagnosis [FLT3 mutations. In general, FLT3-ITD AML should be considered for allo-HSCT in CR1, but in the subgroup of patients with low allelic ratio and concomitant NPM1 mutation who achieve MRD negativity after induction therapy transplant indication remains controversial [The various risk classification strategies can also be considered quite similar, though not identical. However, no universal agreement on the definition of high-risk patients exists among different cooperative groups . In parther risk , 42 and her risk . On the malities , but alsmalities . Therefo lesions . Howeveriagnosis . Recurreoversial .NPM1 mutations and biallelic CEBPα aberrations are rarely found in pediatric AML patients compared to adults, but they still seem to be associated with improved outcomes [FLT3-ITD and NPM1 mutations in the absence of DNMT3A mutations appear to bear a favorable prognosis, while the co-occurrence of FLT3-ITD and WT1 mutations or NUP98-NSD1 is associated with worse outcomes [Some molecular lesions instead confer favorable prognosis. Isolated outcomes , 49, andoutcomes . Furtheroutcomes .FLT3-ITD, NPM1 mutation, RUNX1-2,RUNXT1, CBFB-MYH11; PML-RARA) [MRD monitoring of treatment response has also been shown to be a powerful and independent predictor of relapse in childhood AML  and has ML-RARA) . Flow cyML-RARA) . The incML-RARA) .In conclusion, we observed that allo-HSCT offers significant OS and DFS benefits for higher-risk pediatric AML in CR1. Our findings support the indication for allo-HSCT in subgroups of newly diagnosed AML considered at greater risk of relapse, providing evidence to guide future protocol design. Enrollment in therapeutic trials must be encouraged to further corroborate the results of the present meta-analysis. In particular, randomized clinical trials comparing transplantation with other types of post-remission therapy are warranted. Moreover, it remains the need to further individualize allo-HSCT indications based on refined genetic, genomic, and MRD monitoring informed stratification.Supplementary file1 (DOCX 114 KB)Below is the link to the electronic supplementary material.


Insertable cardiac monitors (ICMs) have undergone advancements in size and functionality over the past decade, resulting in the introduction of small, easily insertable devices capable of long-term remote monitoring. We define first-generation ICMs as implantable cardiac monitoring devices that require an incision and surgical creation of a subcutaneous pocket and second-generation ICMs as devices implanted using a custom-made tool for subcutaneous insertion, respectively. The aim of this study was to understand the differences between first- and second-generation pediatric ICM implants, implant indications, and time to diagnosis. We performed a retrospective, single-center chart review of patients who underwent ICM implantation from 2009–2019, spanning a 5-year course of first-generation ICM implantations and 5-year course of second-generation ICM implantations. Demographic data, past medical history, implant indication, and time to diagnosis were obtained. A total of 208 patients were identified over the 10-year time period, including 38 (18%) who underwent implantation with a first-generation device and 170 (82%) who underwent implantation with a second-generation device. Implant indications for first-generation ICMs included syncope (71%), palpitations (16%), inherited arrhythmia syndrome (IAS) management (5%), and premature ventricular contractions/ventricular tachycardia (VT) (8%); implant indications for second-generation ICMs included syncope (48%), palpitations (19%), IAS management (40%), premature ventricular contractions/VT (11%), atrial fibrillation (2%), tachycardia (3%), and heart block (0.5%). The average time to diagnosis was 38 weeks for patients with first-generation devices and 55 weeks for those with second-generation devices. With innovations in ICM technologies, there are expanding indications for ICM implantation in pediatric patients for long-term monitoring, specifically regarding the management of IAS patients. However, readily available external monitors and wearables may not be ideally suited for pediatric patients who are unable to articulate symptoms, have infrequent symptoms, or require longer-term cardiac monitoring.5Advances in cardiac monitoring for patients with paroxysmal symptoms have evolved from fully external devices to wearable devices, including on-body patch devices and watches. A careful assessment of the patient’s symptoms, including the character, frequency, and duration, can help determine the optimal device for establishing the symptom–rhythm correlation.7 Technical advances in devices have resulted in smaller, easily implantable or insertable devices with longer battery lives that can provide remote wireless monitoring over a multiyear timespan.8 ICMs have proven to be useful in pediatric patients12 and in patients with inherited arrhythmia syndromes (IASs), allowing for the documentation of rhythm during symptom events, arrhythmia surveillance, return to sports/reassurance, and documentation of subclinical arrhythmias.13 Current common uses for ICM implantation in pediatric patients include diagnosis of arrhythmias in patients with syncope or palpitations, assessment of premature ventricular complex (PVC) or ventricular tachycardia (VT) burden, and surveillance in patients with IASs.15Insertable cardiac monitors (ICMs) are widely used in adult and pediatric patients who require chronic arrhythmia burden assessment or symptom–rhythm correlation with infrequent symptoms.The aim of this single-center study was to describe the frequency and clinical indications for implantation of first-generation versus second-generation ICMs within a pediatric population. The diagnostic yield of the ICMs was measured by assessing the time to diagnosis and time to intervention. There was an increase in the total number of devices implanted per year and in the number of second-generation ICMs implanted per year compared to first-generation devices over the duration.After obtaining approval from the Washington University School of Medicine Institutional Review Board, a retrospective, single-center chart review was performed spanning the years 2009–2019. At our institution, the transition from first- to second-generation ICMs occurred in 2014. First-generation ICMs were defined as implantable cardiac monitoring devices that require an incision and surgical creation of a subcutaneous pocket. Second-generation ICMs were defined as insertable devices that have a smaller form factor defined as hardware design features that guide and define the size, shape, and other physical specifications of electronic components. Newer second-generation ICMs use a custom-made tool for subcutaneous insertion.During the chart review, the following information was collected from the medical records: patient demographics (including name and age), date of ICM implantation, make and model of the device, clinical indication for ICM placement, patient diagnosis, current status of ICM (including if the patient has been lost to follow-up or the ICM is still in place), time to diagnosis, occurrence of patient intervention based on ICM data as well as time to intervention, and any complications. The time to diagnosis was defined as the time from the date of implantation to the date of transmission received that yielded a diagnosis. Interventions included pacemaker implantation, implantable cardioverter-defibrillator (ICD) placement, electrophysiology study (EPS) with or without catheter ablation, or replacement of ICM due to battery depletion. The time to intervention was defined as the time from the date of ICM implantation to the date of diagnostic/therapeutic procedure.Patients with IAS as their primary diagnosis, regardless of symptoms, included those diagnosed with long QT syndrome (LQTS), catecholaminergic polymorphic VT, Brugada syndrome, and hypertrophic cardiomyopathy. All IAS patients were phenotype-positive, regardless of the genotype status .P < .05 was used for statistical significance.Descriptive data are presented as mean ± standard deviation values or percentages as appropriate. Two-proportion Z tests were performed to assess the proportion differences between populations. . There was no significant difference in sex, age, weight, or height of the patients implanted with first-generation versus second-generation ICMs. There was an increase in the total number of devices implanted per year, as well as in the number of second-generation ICMs implanted per year compared to first-generation devices, over the duration of the study .A total of 208 patients were identified during the study period; of these, 38 patients had first-generation ICMs and 170 patients had second-generation ICMs . There was a significant decrease in the use of second-generation ICMs for syncope/near-syncope  and a significant increase in the use of second-generation ICMs in patients with IASs .For first-generation ICM implants, the most common indication for implantation was syncope/near-syncope  followed by palpitations , PVCs/VT , and IASs . In contrast, second-generation ICMs were most commonly implanted for syncope/near syncope , followed by IASs ; palpitations ; PVCs/VT ; tachycardia, which was defined as symptomatic tachycardia with the inability to diagnose arrhythmia from an external cardiac monitor ; atrial fibrillation ; and heart block  P = not significant). The majority of first-generation ICMs were explanted . Eight patients (21%) proceeded to have a second intervention, including a pacemaker implant , an ICD implant , an EPS with catheter ablation , and a new ICM implant   and 4. The average time to intervention with first-generation ICM was 76 weeks  . In patients with second-generation ICMs, 64 (38%) had the original ICM in place; 41 (24%) had had an ICM explanted; and 38 (22%) had an additional intervention, including a pacemaker implant , an ICD implant , an EPS + ablation , and a new ICM implant . The average time to intervention was 74 weeks   and 4.Thirty-seven (18%) patients were lost to follow-up  . Importantly, erosions were only seen early on in the second-generation ICM implant experience  and occurred early in the implant experience with these devices (≤6 months). During this time, devices were not sutured into position, and closure was done with topical skin adhesive. This resulted in a change in our clinical practice with the implanting electrophysiologist placing 1–2 subcutaneous sutures to better approximate the incision; following that practice change, no further device erosions were seen in 150 implants.Complications were seen in both groups, occurring in 5% of first-generation versus 4% of second-generation ICM patients  were genotype-positive, but 8 (22%) patients were either genotype-negative or -untested/-unknown. Indications for initial implant included long-term arrhythmia surveillance  and liberalization of guideline-recommended activity restrictions . When ICMs reached end of life, 6 patients underwent ICM replacement (8%). Two patients had an upgrade of their ICMs to other cardiac devices, 1 to a pacemaker  and 1 to an automatic ICD .There was a significant increase in the prevalence of IAS diagnosis among patients implanted with second-generation ICMs compared to those implanted with first-generation ICMs, with IAS patients making up 24% of second-generation ICM recipients versus only 5% of first-generation ICM recipients 17 specifically with an increased use of second-generation ICMs in patients with IAS. Broad clinical adaptation within our institution was multifactorial, including a miniaturized form factor and ease of insertion.In this study, we quantified the significant increase in the utilization of second-generation ICMs compared to first-generation ICMs in a pediatric population. Additionally, we demonstrated that the clinical practice and utility for implantation may be broader than current guidelines would indicate,9 these data show that second-generation ICMs had an increased usage, with a 5-fold increase in use for IAS patients (5% first-generation vs. 24% second-generation). The main reasons for implanting ICMs in IAS patients were for return to sports clearance (based on the physician’s preference) and arrhythmia surveillance. It is also important to note that a smaller proportion of second-generation ICMs were implanted for syncope or near-syncope (71% first-generation vs. 48% second-generation).The increased utilization of second-generation ICMs in patients with IAS is an important shift in our practice. While first-generation ICMs were predominantly used for pediatric patients with syncope and palpitations,. Second-generation ICMs had a 6-fold reduction in device volume and a 5-fold reduction in device weight. Additionally, second-generation ICMs were half the length and 6.5-fold less broad than the first-generation ICMs. Despite this miniaturization in form factor, these data did not show a significant shift toward use in younger/smaller patients.One factor that likely influenced the increased utilization of second-generation ICMs was the miniaturization in form factor, which was particularly important in our pediatric population 18 Anesthetic use may also contribute to increased insertion rates of second-generation ICMs, with Bezzerides et al. reporting that the most frequent type of anesthesia for ICM implants in pediatric patients was conscious sedation (50% of patients), followed by general anesthesia (41%) and local anesthesia (16%).10Another influencing factor was faster insertion due to the smaller form factor described above, coupled with the custom implant tools, both of which likely contributed to greater utilization. Previous studies have shown that the second-generation ICM implant technique has led to shorter procedure and recovery times as well as increased use within pediatric cardiology.20 The longer duration in the second-generation group may reflect the increased use in IAS patients who required long-term arrhythmia monitoring. In these cases, or in cases with infrequent symptoms, external monitors or wearables may not be the best option. External monitors also pose an issue for young children and toddlers due to skin reactions to the adhesive or intolerance to prolonged monitor wearing. For patients whose symptoms occur during physical activity, there may be difficulty with adherence of patches or perceived interference with performance, causing non-compliance of device use. While external monitors and wearables remain an excellent modality for a short period of time, ICMs may be a more reasonable option for longer-term monitoring.21The average time to diagnosis for both first- and second-generation devices solidifies the need for ICMs in the pediatric population. The average time to diagnosis was 38 weeks for patients with first-generation devices and 55 weeks for those with second-generation devices, demonstrating that some patients require long-term monitoring solutions.18 Following this change, there were no further erosions documented.Lastly, there was no difference noted in complication rates between first-generation and second-generation implants (5% vs. 4%), which would affect practice. After 2 patients with second-generation ICM implants experienced device erosions, the closure technique was modified to include 1–2 subcutaneous sutures to tightly approximate the incision.This is a single-center study and therefore reflects the selection bias of the pediatric electrophysiologists at this center. Given the small sample size of first-generation devices compared to the larger sample size of second-generation devices, it is difficult to make statistically significant conclusions between the groups. In addition, a substantial percentage of patients were lost to follow-up, a consequence of the retrospective study design.In our population of pediatric patients, the use of ICMs has evolved dramatically, with both a rapid increase in annual implant volume and increasingly common use in patients with IASs. While we did not assess the attitudes of implanting clinicians, we speculate that the overall increased utilization of ICMs can be at least partly attributed to the smaller form factor and ease of implant. In our practice, second-generation ICMs have become a useful diagnostic and long-term monitoring tool in pediatrics.


Uncertainty regarding the risk of coronavirus disease 2019 (COVID-19), its complications and the safety of immunosuppressive therapies may drive anxiety among adults and parents of children and young people (CYP) with rheumatic diseases. This study explored trajectories of COVID-related anxiety in adults and parents of CYP with rheumatic diseases.Adults and parents of CYP participating in the international COVID-19 European Patient Registry were included in the current study if they had enrolled in the 4 weeks following 24 March 2020. COVID-related anxiety scores (0–10) were collected weekly for up to 28 weeks.Group-based trajectory models explored COVID-related anxiety clusters in adult and parent populations, with optimal models chosen based on model fit, parsimony and clinical plausibility. Demographic, clinical and COVID-19 mitigation behaviours were compared between identified clusters using univariable statistics.In 498 parents of CYP and 2640 adults, four common trajectory groups of COVID-related anxiety were identified in each cohort: persistent extreme anxiety (32% and 17%), persistent high anxiety (43% and 41%), improving high anxiety (25% and 32%) and improving moderate anxiety (11% and 10%), respectively. Few characteristics distinguished the clusters in the parent cohort. Higher and more persistent anxiety clusters in the adult cohort were associated with higher levels of respiratory comorbidities, use of immunosuppressive therapies, older age and greater self-isolation.COVID-19-related anxiety in the rheumatic disease community was high and persistent during the COVID-19 pandemic, with four common patterns identified. In the adult cohort, higher COVID-related anxiety was related to perceived risk factors for COVID-19 morbidity and mortality. Key messagesCoronavirus disease 2019 (COVID-19)-related anxiety is persistently high in adults and parents of CYP with rheumatic diseases.Higher and more persistent anxiety in adults with rheumatic diseases is related to perceived COVID-19 risk factors.Immunosuppressant safety during the COVID-19 pandemic should be shared with the rheumatic disease community.The coronavirus disease 2019 (COVID-19) pandemic has prompted dramatic changes to everyday lifestyles. Social distancing, self-isolation and limited time spent engaging in social, recreational and physical activities have become the new normal , with maChildren, young people and adults with rheumatological conditions may be at increased risk of contracting or experiencing greater complications from COVID-19 due to a combination of autoimmune conditions and commonly prescribed immunosuppressive therapies , 9. TherUnsupervised machine learning methods, such as latent class trajectory modelling, can identify different patterns in outcomes, such as anxiety, that may differ between groups, or clusters, of people . It is cThis study explored the burden of COVID-related anxiety and whether there are clusters of people with different patterns of anxiety among adults and parents of children and young people with rheumatic diseases recruited globally since March 2020.http://www.hra-decisiontools.org.uk/ethics/). However, written informed consent was provided by adults and parents/guardians of CYP with rheumatic diseases. For the current study, participants with a rheumatic disease were selected if they enrolled in the registry during the 4 weeks following 24 March 2020, to allow for at least 6 months of follow-up.The COVID-19 European Patient Registry is an international, parent-led, online, self-referred prospective cohort. It was initiated in March 2020 to understand the impact of the COVID-19 pandemic on people with rheumatic diseases. As such, it recruits people of all ages from around the globe, specifically targeting those with rheumatic diseases, but it is also open to those with no rheumatic disease. Since this was a parent-/patient-led study comprising online, self-referred and completed questionnaires, healthcare ethical approval was not required, as confirmed by the National Health Service Research Ethics Committees online tools , rheumatic disease  and factors related to COVID-19, including mitigation methods . Following enrolment, weekly surveys ascertained any changes in medication, rheumatic disease control, contact with healthcare professionals and COVID factors.As part of the initial and follow-up questionnaires, participants were asked to rate their anxiety related to COVID-19 on a scale from 0 to 10, ranging from ‘not at all worried’ (0) to ‘extremely worried’ (10), based on the following question: ‘On a scale of 0 to 10, how worried are you about coronavirus affecting [you/your child]?’.Group-based trajectory models were used to cluster participants based on shared patterns of COVID-19-related anxiety over the 6 months following enrolment. Models were built separately for CYP and adult cohorts. The models were constructed using censored normal distributions and were tested using 1–10 trajectory groups within linear, quadratic and cubic polynomial trajectory shapes [Models with a cluster representing <1% of the cohort were excluded, as were those with average posterior probabilities for group membership <70% or relative entropy <0.5. From the remaining shortlist, an optimal model was selected for each CYP and adult cohort using a combination of statistical fit (Bayesian information criteria), parsimony and clinical plausibility . ClusterCharacteristics collected at enrolment  were compared between identified clusters descriptively and through univariable statistics. Differences in categorical variables were explored via chi-squared or Fisher’s exact tests and continuous variables via Kruskal–Wallis metrics.No imputations of missing data were undertaken for the outcome since group-based trajectory modelling is robust to bias from missing-at-random data, as a maximum likelihood–based technique. Data were analysed using Stata 14 . Data visualization was completed in R version 3.6.1  using RStudio version 1.2.5001.n = 498) and adult (n = 2640) cohorts, the majority were female  and the most common region of residence was the UK . In the CYP cohort, the most common rheumatic disease diagnoses were polyarticular JIA (37%) and oligoarticular JIA (29%), with RA most common in the adult cohort (63%). Most participants were taking at least one immunosuppressive therapy  and respiratory comorbidities were uncommon . At recruitment, 88% in the CYP cohort and 79% in the adult cohort were self-isolating (Rheumatology Advances in Practice online).Within the CYP (Rheumatology Advances in Practice online).Four trajectory clusters of COVID-19-related anxiety were identified in the CYP and adult cohorts with similar patterns: persistent extremely high anxiety (32% and 17%), persistent high anxiety (43% and 41%), high anxiety that marginally improved (25% and 32%) and moderate anxiety that improved (11% and 10%), respectively (Rheumatology Advances in Practice online).Few features within the CYP cohort differed between the anxiety clusters. Only country of residence was significantly associated with anxiety, with greater representation of the UK, Ireland, Italy and Slovenia in the highest anxiety groups and greater representation of France, Spain and the USA in the lower anxiety groups , higher levels of respiratory comorbidities  and higher levels of initial self-isolation  and were marginally older .The current study identified four common patterns of COVID-19-related anxiety that are consistent across adults and parents of CYP with rheumatic diseases recruited globally. Anxiety levels were high and persistent among most of the cohort, with only two of four clusters experiencing any substantial improvement in anxiety in the 6 months following March 2020. Although there were few features in parents of children with rheumatic disease that distinguished the clusters, characteristics that may be associated with a higher risk of COVID-19 morbidity and mortality were associated with assignment to higher and more persistent anxiety clusters among adults with rheumatic diseases.The four anxiety trajectories identified in both the CYP and adult cohorts in the current study represent an exceptionally high burden of anxiety in the rheumatic disease community. Approximately one-third of parents of CYP with rheumatic disease experienced extremely high anxiety (median 10/10) that persisted over the 6 months. Over 40% of both cohorts experienced high anxiety that also persisted over the 6 months with little improvement. The similarity between the CYP and adult cohorts may reflect high anxiety in the general population that has translated to these potentially vulnerable people, with estimates of anxiety symptoms in the general population of several countries ranging from 6.3 to 50.9% during the COVID-19 pandemic . HoweverFew factors were associated with anxiety clusters in parents of CYP with rheumatic diseases. The only significant factor was country of residence, which may be associated with different COVID-19 policies, guidelines and infection and morbidity/mortality rates, in addition to overall cultural differences that may influence anxiety. Factors related to the burden of COVID-19 infection were not related to anxiety, suggesting persistent high levels of anxiety regardless of risk. Therefore there is a clear unmet need for anxiety management programs or interventions for parents of CYP with rheumatic diseases, whose anxiety is high despite their children being at low risk of infection or complications from COVID-19 .In the adult cohort, factors that may be associated with COVID-19 morbidity and mortality, such as respiratory comorbidities , older aThis study benefitted from a large international cohort obtained by recruiting people across age ranges using surveys in several languages. As an online survey, the study could continue to safely recruit and gather a large volume of pandemic-specific data even during a global outbreak. In addition, responses to most questions were compulsory, which limited the amount of missing data. Finally, novel machine learning methods were implemented to identify several unique clusters of anxiety. By identifying distinct COVID-19-related anxiety patterns, the current study has identified key risk factors for high and persistent anxiety. These factors may be used to target interventions to people in specific disease clusters and/or prevent COVID-19-related anxiety across the rheumatic disease population.vs online schooling and caregiver responsibilities or infection of family members or other contacts of study participants. While the study could not adjust for underlying anxiety disorders in participants, the picture of high to extreme high COVID-19-related anxiety highlights an area for mental health intervention, regardless of pre-existing diagnoses.The limitations of this study include the location of the study population, most of whom were based in the UK, which limited generalizability to countries where fewer participants were recruited. In addition, the outcome of anxiety was tested using a COVID-19-specific question. While this question has not been formally validated, it was considered the optimal method to ascertain levels of anxiety quickly, and specifically relating to COVID-19 risk, at the start of the pandemic. This study may have benefitted from investigating anxiety levels in CYP themselves, with the current data allowing for the evaluation of parental anxiety in this population. Similarly, it was unclear whether anxiety patterns observed were related to factors not captured by the study, such as governmental policies, key worker status, in-person Four common patterns of COVID-19-related anxiety were identified in adults and in parents of CYP with rheumatic diseases. For the majority of the cohort, anxiety was high and persistent in the 6 months following March 2020, during the COVID-19 pandemic. Few factors were associated with anxiety burden in parents. Factors potentially related to COVID-19 morbidity and mortality were associated with higher and more persistent anxiety in adults with rheumatic diseases. Interventions for anxiety should target the entire population of people with rheumatic disease and specifically promote information regarding the safety of immunosuppressive therapies during the COVID-19 pandemic.rkad007_Supplementary_DataClick here for additional data file.


Cholangiocarcinoma (CCA) still has a poor prognosis and remains a major therapeutic challenge. When curative resection is not possible, palliative systemic chemotherapy with gemcitabine and platinum derivate as first line followed by a 5-FU doublet combination as second line is the standard therapy. Recently, targeted therapy and immunotherapy have rapidly emerged as personalized therapeutic approaches requiring previous tumor sequencing and molecular profiling. BRCA mutations are well-characterized targets for poly (ADP-ribose) polymerase inhibitors (PARPi). However, BRCA gene mutations in CCA are rare and few data of PARPi in the treatment of CCA are available. Immunotherapy with programmed death receptor-1 (PD-1) has been shown to be effective in combination with chemotherapy or in PD-L1-positive CCA. However, data from immunotherapy combined with targeted therapy, including PARPi, are lacking. In this report, we present the case of a male patient with PD-L1-positive and BRCA2-mutated metastatic intrahepatic cholangiocarcinoma, who was treated with a combined therapy with PARP (PARPi), olaparib, and a PD-1 antibody, pembrolizumab, as second-line therapy after gemcitabine/platinum derivate failure. Combined therapy was able to induce a long-lasting complete remission for over 15 months. The combined therapy was feasible and well tolerated. Only mild anemia and immune-related thyroiditis were observed, which were easily manageable and did not result in discontinuation of olaparib and pembrolizumab.The presented case showed substantial clinical activity of a combination with olaparib/pembrolizumab in advanced BRCA2-mutated CCA. Thus, identifying targetable molecular signatures and combinations of targeted therapies with immunotherapy reveals a promising strategy to effectively treat patients with cholangiocarcinoma and should be considered after failure of standard chemotherapy. Cholangiocarcinoma (CCA) is a comparably rare, albeit highly aggressive tumor entity. It is reported to represent 3% of malignant gastrointestinal diseases , 2. Its Cholangiocarcinoma is usually distinguished by anatomical localization and categorized as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). This classification is clinically highly relevant as pathogenesis, clinical presentation prognosis, and molecular profile differ distinctly between these subgroups –8.Even with oncological resection and following adjuvant therapy, the rate of recurrence might be up to 50%–70% within the first 2 years , 10 and In metastatic or irresectable cases, palliative chemotherapy, mostly with gemcitabine in combination with platinum derivate, is the first-choice treatment based on the findings of the pivotal randomized phase III trial ABC-02. Further local therapies, such as radiation therapy , 13, endHere, we report on a case of a patient with PD-L1-positive and BRCA2-mutated metastatic intrahepatic cholangiocarcinoma who was treated with the PARP inhibitor olaparib and the PD-1 inhibitor pembrolizumab as second-line therapy after gemcitabine and platinum derivate and who achieved sustainable and complete remission.In August 2017, a 53-year-old Caucasian man was referred to the university hospital of Bonn, Germany, with elevated liver transaminases and cholestasis parameters after cholecystectomy in March 2017, which was performed due to cholecystolithiasis. The patient had a known medical history of arterial hypertension as well as Hashimoto’s thyroiditis that did not require hormone substitution at that time.via biliodigestive anastomosis was performed in August 2017. The examination of the resectate confirmed high-grade intrahepatic CCA with postoperative pT2, pN0, L1, V1, Pn1, and R1 stages. Ca 125 increased to 111 U/ml after surgery. Due to the R1 situation and the postoperative positive CA125, an additive therapy with gemcitabine/cisplatin was initiated in October 2017. Due to a grade 3 (CTCAE) polyneuropathy, cisplatin had to be discontinued in February 2018, after seven cycles. Since radiology imaging presented a complete remission at this time and initial resection revealed marginal involvement, a second-look exploration with follow-up resection of the former resection site was performed in March 2018 following the decision of our interdisciplinary tumor conference. A histological review of the suspected remaining carcinoma revealed no microscopic malignancy. Therefore, a close follow-up was initiated hereafter beginning in March 2018.CT as well as MRI scan revealed a 35 mm × 45 mm mass forming lesion in liver segment V/VIII without signs of thoracoabdominal metastasis  to identify possible molecular targetable alterations. One of the findings revealed an alteration in the BRCA2 gene (E1493fs*10). Further alterations were detected in the NF2 gene, APC gene, TP53 gene, CDKN2A gene, and MLL 2. The microsatellite status was stable. Tumor mutational burden was comparably low (4 mutations/Mb). There was no evidence of FGFR2 mutation or fusion, NTRK fusion, IDH1, IDH2, BRAF, or NRAS mutations.Previously, during the past follow-up in June of 2019, cancer tissue was analyzed using next-generation sequencing (FoundationOne®) of BRCA1 and -2 genes was performed upon revelation of BRCA2 mutation in tumor tissue, which showed a matching BRCA2 mutation in the germline.Family history of the patient was positive in first-degree relatives for pancreatic carcinoma (father) and mammary carcinoma (sister). Therefore, germline analysis  and postoperative stenosis of the portal vein. Eventually, after one cycle, chemotherapy had to be discontinued when platelet count decreased further under treatment.In February 2020, an additional immunohistochemical examination of the recurrence lesion was conducted. In contrast to the initial biopsy of the primary lesion in 2017, immunohistochemistry revealed a positive PD-L1 status with positivity for PD-L1 in immune cells (CPS 30) and tumor cells (TPS 20) . With this 50% dose adaptation, the therapy with olaparib was continuously tolerated by the patient.Pembrolizumab was initially tolerated without side effects. In January 2021, TSH was noticeably suppressed (<0.01 µU/ml) for the first time, with elevated fT4 (2.9 ng/dl) and fT3 (5.84 pg/ml) as well as significantly increased antibodies against thyroglobulin (752 IU/ml) and TPO (356 IU/ml). Since the overall constellation of findings, including patient history with known Hashimoto’s thyroiditis, pointed toward an immune-related thyroiditis, we initiated thyreostatic therapy with carbimazol at 30 mg per day and referred the patient for endocrinological consultation. In line with typical findings of an acute autoimmune thyroiditis, sonographic thyroid examination showed an increased total volume of 45 ml and strong vascularization with only faint and diffuse tracer distribution of Tc-99-m pertechnetate in scintigraphy at the same time  plays a growing role in a variety of tumor entities, partially even independent of PD-L1 status. Regarding CCA, the TOPAZ-1 phase III trial has recently shown a benefit for durvalumab (PD-L1 inhibition) combined with standard gemcitabine/cisplatin compared to chemotherapy alone . Further for ICI –45. PD-Lo models , 45, 46.o models . A phaseo models . Final ro models .To our knowledge, the combination of ICI with a PARP inhibitor in cholangiocarcinoma has been described in only one further case . HoweverIn contrast to the case described above, our patient presented with CCA with a BRCA-2 mutation, a PD-L1 CPS expression of 30%, and the fact that the patient had a previous exposition to platinum derivate.Platinum-based chemotherapy has been shown to be effective in patients with BRCA-mutated tumors, mostly due to germline mutations. Recently, a sequential therapy with platinum derivate and the poly (ADP-ribose) polymerase inhibitor, olaparib as monotherapy, has shown clinical benefit in BRCA-mutated metastatic pancreatic cancer in the phase III trial (POLO), allowing approval of olaparib for these patients . FurtherAlthough our patient also presented with HER2neu overexpression, which might respond to targeted therapy with pertuzumab and trastuzumab , we deciAlready 12 weeks after therapy onset, the patient experienced a rapid response to the combined therapy resulting in an excellent tumor response with complete remission sustained for over 15 months. At the time of this report in April 2022, the patient was still in complete remission and presented an ECOG of 0. Immune-related thyroiditis and anemia were manageable adverse events and have not resulted in discontinuation of olaparib and pembrolizumab to this day. These results are supported by the results of numerous phase II trials on combination therapy of PARP inhibitors and ICI in breast and ovarian cancer , 56 but Preclinical data support the rationale of a superior effect of olaparib and pembrolizumab in our patient due to an induction with platinum derivate. Furthermore, the combination of checkpoint inhibition with PARP inhibition may induce a synergistic antitumoral effect. PARP inhibition is known to cause an accumulation of DNA damage, which in turn can increase the mutation load of tumors. This effect could increase the expression of immune checkpoint receptors, such as PD-L1, on tumor cells increasing the predisposition to respond to checkpoint inhibition .In summary, the presented case showed substantial clinical activity of a combination therapy with olaparib and pembrolizumab in advanced BRCA2-mutated and PD-L1-positive cholangiocarcinoma as second-line therapy after platinum derivate chemotherapy. The therapy was well tolerated, but close screening for immune-related adverse events is necessary, especially in susceptible patient groups. Thus, identifying targetable molecular signatures and combinations of targeted therapies with immunotherapy revealed a promising strategy to effectively treat patients with cholangiocarcinoma and should be considered after failure of standard chemotherapy.The original contributions presented in the study are included in the article/Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.TZ: acquisition of data, drafting of the manuscript. RM: critical revision of the manuscript for important intellectual content. ChM: critical revision of the manuscript for important intellectual content. FS: critical revision of the manuscript for important intellectual content. CaM: figure curation, critical revision of the manuscript for important intellectual content. MT: figure curation, critical revision of the manuscript for important intellectual content. BSK: figure curation, critical revision of the manuscript for important intellectual content. ME: critical revision of the manuscript for important intellectual content. TG: critical revision of the manuscript for important intellectual content. HM: critical revision of the manuscript for important intellectual content. JK: critical revision of the manuscript for important intellectual content. CS: critical revision of the manuscript for important intellectual content. MG-C: acquisition of data, drafting of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by a BONFOR grant from the University of Bonn and grant number 109255 from the German Cancer Aid Association (Deutsche Krebshilfe) awarded to MG-C.M-GC has contributed to advisory boards for Roche, Eisai, MSD, BMS, AZ and Lilly.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Eligible participants were divided into three groups according to the quartiles of HOMA-IR: Group 1 (HOMA-IR <1.46), Group 2 (1.46 to <2.71) and Group 3 (HOMA-IR ≥2.71). Baseline data, clinical characteristics during the assisted reproductive technology (ART) procedure, pregnancy, and neonatal outcomes were compared among the three groups. Subgroup analysis based on presence or absence of the polycystic ovary syndrome (PCOS) status was also performed to analyze the effects of HOMA-IR among non-PCOS populations.The late miscarriage rate and percentage of macrosomia increased with the HOMA-IR group . Increased HOMA-IR (HOMA-IR≥2.71) was positively associated with late miscarriage . In the subgroup analysis, there were 3,165 participants in the non-PCOS group and 450 were assigned to the PCOS group. Late miscarriage rate increased with the HOMA-IR group among non-PCOS populations . Late miscarriage rate of PCOS women were comparable among the three HOMA-IR groups . Among non-PCOS women, increased HOMA-IR (HOMA-IR≥2.71) was positively associated with late miscarriage .Late miscarriage rate and prevalence of macrosomia increased with the HOMA-IR index. Preconception HOMA-IR is an independent risk factor for late miscarriage in normolipidemic women undergoing IVF/ICSI-ET. Controlling insulin resistance before ART might prevent the occurrence of late miscarriage and macrosomia. Preconception HOMA-IR is an independent risk factor for late miscarriage in normolipidemic women undergoing IVF/ICSI-ET.Insulin resistance (IR) refers to an impairment in insulin-mediated control of glucose homeostasis, which is characterized by hyperinsulinemia and defective response of target cells or a whole organism to the insulin exposure , 2. Any via modulating cellular glucose uptake that met the growing energy demands of decidual cells  populations for the high prevalence of IR among them . IR indual cells . Decreasal cells  In lightAs the gospel for infertile couples, assisted reproductive technology (ART) enables these couples to obtain pregnancy. However, various obstacles hinder the achievement of this goal and unsatisfactory pregnancy outcomes have been reported among women presenting with IR. In recent meta-analysis, IR and high body mass index (BMI) were two risk factors for spontaneous abortion in infertile PCOS patients who underwent ART . Even afin vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycle  cycle . TherefoT) cycle .This study was a retrospective analysis and approved by the ethical committee of Xiangya Hospital of Central South University (CSU) (No. 2021008). All patients underwent the first IVF/ICSI-ET cycle in the Reproductive Medicine Center of Xiangya Hospital, CSU between January 2014 and October 2021. This study was conducted according to the tenets of the Declaration of Helsinki. Because of its retrospective nature the informed consent of individual patients was waived.The inclusion criteria were as follows: women aged between 20 and 40 years, normal blood lipids profile according to the Chinese adult dyslipidemia management guideline , serum tThe exclusion criteria were as follows: women with diagnosed diabetes mellitus or had a history of hypoglycemic and hypolipidemic medications within three months before the ART treatment;severe hydrosalpinx and did not receive tubal ligation or salpingectomy; severe adenomyosis; endometrial abnormalities such as endometrial polyps, endometrial hyperplasia, submucosal fibroids, intrauterine adhesions or chronic endometritis without management; genital tuberculosis; other severe systemic comorbidities, such as hypertension, prethrombotic conditions, autoimmune connective tissue diseases and malignant tumor. Moreover, semen or oocytes from donated cycles were also excluded.Eligible participants were divided into three groups according to the quartiles of HOMA-IR . Serum blood lipid levels were measured as previously described . BrieflyReproductive hormone measurements were obtained at baseline coinciding with days 2-5 of the menstrual cycle or on the day of human chorionic gonadotrophin (HCG) triggering. FSH, LH, estradiol (E2), testosterone (T) and progesterone (P4) were quantified by ECLI in the laboratory at our center.The controlled ovarian hyperstimulation (COH) protocols were individualized according to the age and ovarian reserve of infertile women as previously described . For theExogenous highly purified FSH (Lishenbao) and/or human menopausal gonadtrophin (HMG) (Lebaode) was injected to induce follicular development. Mainly based on age, BMI, and ovarian reserve, the initial dose of Gn ranged from 112.5-300.0IU/day and adjusted every 3-4 days according to ovarian response. When two or more follicles had reached a mean diameter of 18mm and the average E2 per mature follicle was 200-300pg/ml, 6000-10,000IU HCG was injected to promote the final maturation of the follicles. Oocytes were retrieved 36h after HCG administration, and this was followed by conventional IVF or ICSI.At least one good quality cleavage-stage embryos were transferred on 3 days after follicle aspiration. Cleavage-stage embryos were evaluated according to ASEBIR embryo assessment criteria . All patSerum β-HCG concentration was measured 12 days after ET. Transvaginal B-ultrasound was performed on 28 and 35 days after ET to confirm an intrauterine pregnancy. After that, we would call the couple regularly to inquire about and record pregnancy and neonatal outcomes.Clinical pregnancy was defined as observation of the gestational sac(s) in the uterine cavity by vaginal ultrasound on 4-5 weeks after ET. Clinical pregnancy rate was calculated by the ratio of clinical pregnancy cycle to the total ET cycle. Pregnancy that only detects β-hCG positivity in serum without seeing the gestational sac was termed as biochemical pregnancy. The implantation rate was defined as the number of gestational sacs divided by the number of transferred embryos. Early miscarriage was referred to intrauterine pregnancy loss before 12 weeks of pregnancy, while late miscarriage was referred to pregnancy loss prior to 28 weeks of gestational age. Preterm birth and term birth were defined as live birth before or after 37 gestational weeks. Low birth weight and macrosomia were defined as birth weight less than 2500g or more than 4000g, respectively .Statistical analysis was carried out using SPSS (version 25). For continuous variables, if data satisfied a normal distribution, it was expressed as mean ± standard deviation, otherwise it was represented by the median and interquartile range (IQR). Categorical variables were presented as frequency and percentage. The between-group differences among variables were analyzed by one-way analysis of variance (ANOVA) or Kruskal-Wallis test, Pearson’s chi-squared test, or Fisher’s exact test for continuous and categorical variables, respectively. The Bonferroni method was used to correct P values for pairwise comparisons. The multivariable logistic regression model was adjusted for age, BMI, main aetiology of infertility, TG, LDL-C, HDL-C, antral follicle count (AFC), and endometrial type to demonstrate the association between HOMA-IR and late miscarriage rate. The associations were presented as an adjusted OR with a 95% confidence interval (CI). The P value was two-sided and value < 0.05 indicated statistical significance.A total of 3,615 patients were enrolled in this study. The distribution of HOMA-IR was shown in The demographic and clinical characteristics of the 3,615 participants are presented in With respect to clinical characteristics during the IVF/ICSI-ET procedure, duration of stimulation, total Gn dose, and the percentage of Type C endometrium on day of HCG triggering increased with the HOMA-IR group . Serum E2 and LH levels on HCG administration day decreased with the HOMA-IR group . The highest number of oocytes retrieved was observed in the Group 2, and the number of Group 1 was higher than that of Group 3 (P=0.008). Ovarian stimulation protocol, P4 level and endometrial thickness on day of HCG triggering, fertilization method, number of MII oocyte, MII oocyte rate, number of good-quality embryos, good-quality embryos rate, number of transferred embryos, number of good-quality embryos transferred, and good-quality embryos transferred rate exhibited no significant difference among the three groups .Pregnancy and neonatal outcomes are illustrated in Therefore, we further evaluated the association between HOMA-IR and late miscarriage . However, pregnancy outcomes were comparable among the three groups (P>0.05).Consequently, we evaluated the association between HOMA-IR and late miscarriage among non-PCOS populations by adopting univariate logistic regression and multivariable logistic regression models  than those in Group 2 (HOMA-IR 1.46 to < 2.71) and Group 1 (HOMA-IR<1.46). After controlling of potential confounders, a higher level of HOMA-IR was a risk factor for late miscarriage. The subgroup analysis indicated that this conclusion was applicable to the non-PCOS women. We failed to distinguish significant difference between HOMA-IR and late miscarriage rate in women diagnosed with PCOS and this might be ascribed to the limited population number in our study. These controversial results may be attributed to multifaceted factors such as the heterogeneity in terms of study design, study populations, sample size, diagnostic criteria of IR, ovarian stimulation protocols, inclusion, and exclusion criteria.Associations between IR and recurrent miscarriage or pregnancy loss in women who conceived naturally has been reported in previous studies –35. The To our current knowledge, there is no report regarding the relationship between preconception IR and late miscarriage among non-dyslipidemic populations. Consistent with a previous study , 32, ourIn conclusion, late miscarriage rate and prevalence of macrosomia increased with the HOMA-IR index. Preconception HOMA-IR is an independent risk factor for late miscarriage in normolipidemic women undergoing IVF/ICSI-ET. Control of insulin resistance before ART might prevent the occurrence of late miscarriage and macrosomia.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethical Committee of Xiangya Hospital of Central South University (CSU) (2021008). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.TY and YY were responsible for data collection, article review and draft of the manuscript. QZ, DL, and NL contributed to the data verification. YML and ZY performed the statistical analysis. ZY and FT were responsible for the manuscript revision and designs of tables and figure. JZ and YPL are corresponding authors and they critically revised the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by the National Key Research and Development Program of China (2021YFC2700404) and the Key Project of Research and Development Plan in Hunan Province (2021SK2028).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.